INTERNATIONAL CONFERENCE ON HARMONISATION OF TECHNICAL
REQUIREMENTS FOR REGISTRATION OF PHARMACEUTICALS FOR HUMAN USE
DRAFT CONSENSUS GUIDELINE
GUIDELINE FOR ELEMENTAL IMPURITIES
Q3D
Current Step 2b version
dated 26 July 2013
At Step 2 of the ICH Process, a consensus draft text or Guideline, agreed by the
appropriate ICH Expert Working Group, is transmitted by the ICH Steering
Committee to the regulatory authorities of the three ICH regions (the European
Union, Japan and the USA) for internal and external consultation, according to
national or regional procedures.
Q3D
Document History
Current Step 2a version
Code History Date
Q3D Approval by the Steering Committee under Step 2a. 6 June
2013
Current Step 2b version
Code History Date
Q3D Approval by the Steering Committee under Step 2b
and release for public consultation.
6 June
2013
Q3D
Post sign-off corrigendum in:
• Table 4.1 W and Al were removed from the list of
included elemental impurities in Class 2B and 3
respectively.
• Table A.2.1 the Class for Ni was changed to read 3
instead of 2.
14 June
2013
Q3D
Post sign-off minor editorial corrections including:
removal of references to Appendix 5 (pgs i & 13);
deletion of redundant text (pg 4); change of Option 2
to Option 2a (pg 10); insertion of omitted text under
Safety Limiting Toxicity (pg 35); removal of
duplicated redundant text (pg 41); replacing
references to “metals” in text and “metal” in Table
A.4.7 title with “elementals” and “elements” (pg 73);
and deletion of header Table A.4.10 (pg 75).
26 July
2013
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GUIDELINE FOR ELEMENTAL IMPURITIES
Draft ICH Consensus Guideline
Released for Consultation on 26 July 2013, at Step 2b of the ICH Process
TABLE OF CONTENTS
1. INTRODUCTION .................................................................................................................... 1
2. SCOPE ................................................................................................................................... 1
3. SAFETY ASSESSMENT OF POTENTIAL ELEMENTAL IMPURITIES ..................................... 2
3.1 Principles of the Safety Assessment of Elemental Impurities for Oral,
Parenteral and Inhalation Routes of Administration .................................................. 2
3.2 Other Routes of Administration ....................................................................................... 3
3.3 Justification for Element Impurity Levels Higher than the PDE ............................ 3
3.4 Parenteral Products ............................................................................................................. 4
4. ELEMENT CLASSIFICATION ................................................................................................ 4
5. ASSESSMENT AND CONTROL OF ELEMENTAL IMPURITIES .............................................. 5
5.1 General Principles ............................................................................................................... 5
5.2 Potential Sources of Elemental Impurities .................................................................... 6
5.3 Assessment – Identification of Potential Elemental Impurities ............................... 7
5.4 Assessment – Analysis and Evaluation .......................................................................... 9
5.5 Converting Between PDEs and Concentration Limits ................................................ 9
5.6 Assessment Summary ....................................................................................................... 11
5.7 Control of Elemental Impurities ..................................................................................... 12
5.8 Periodic Verification Testing ........................................................................................... 13
5.9 Special Considerations for Biotechnologically-Derived Products ........................... 13
6. SPECIATION ........................................................................................................................ 14
7. ANALYTICAL PROCEDURES .............................................................................................. 14
8. LIFE-CYCLE MANAGEMENT OF THE CONTROL STRATEGY FOR ELEMENTAL
IMPURITIES ........................................................................................................................ 14
9. RECOMMENDATIONS FOR SUBMISSION OF ELEMENTAL IMPURITIES CONTROL
STRATEGY ........................................................................................................................... 14
REFERENCES .............................................................................................................................. 15
GLOSSARY ................................................................................................................................... 16
Appendix 1: Method for Establishing Exposure Limits ................................................. 20
Appendix 2: Established PDEs for Elemental Impurities .............................................. 23
Appendix 3: Individual Safety Assessments ..................................................................... 25
Appendix 4: Illustrative Example – Calculation Options for Converting PDEs to
Concentrations ......................................................................................................................... 69
i
GUIDELINE FOR ELEMENTAL IMPURITIES
Q3D
1. INTRODUCTION
Elemental impurities in drug products may arise from several sources; they may be
added intentionally in synthesis, or may be present as contaminants (e.g., through
interactions with processing equipment or by being present in components of the drug
product) and are consequently detectable in the drug product. Since elemental impurities
do not provide any therapeutic benefit to the patient, element impurity levels should be
controlled within acceptable limits in the drug product. There are three components of
this guideline: the evaluation of the toxicity data for potential elemental impurities, the
establishment of a Permitted Daily Exposure (PDE) for each element of toxicological
concern, and development of controls designed to limit the inclusion of elemental
impurities in drug products to levels at or below the PDE. It is not expected that an
applicant tightens the limits based on process capability provided that the elemental
impurities in drug products are held at or below the PDE. The PDEs established in this
guideline are considered to be protective of public health for all patient populations,
including pediatric patients. In some cases, lower levels of elemental impurities may be
needed when levels below toxicity thresholds have been shown to have an impact on
other quality attributes of the drug product (e.g., element catalyzed degradation of drug
substances). In addition, in the case of high PDEs, other limits may have to be
considered from a pharmaceutical quality perspective; other guidelines should be
consulted.
Developing a strategy to limit elemental impurities in the drug product is consistent
with risk management processes identified in ICH Q9. The process is described in this
guideline as a four step process to assess and control elemental impurities in the drug
product: identify, analyse, evaluate, and control.
The PDE of the elements may change if new safety data become available. The guideline
may be updated to include other elemental impurities or other routes of administration
as new data become available. Any interested party can make a request and submit the
relevant safety data to be considered.
2. SCOPE
The PDEs in this guideline have been established based on acceptable safety limits of
potentially toxic elemental impurities. The guideline applies to new finished drug
products (as defined in ICH Q6A and Q6B) and new drug products employing existing
drug substances. The drug products containing: proteins and polypeptides (produced
from recombinant or non-recombinant cell-culture expression systems), their derivatives,
and products of which they are components (e.g., conjugates) are in the scope of this
guideline. In addition, drug products containing synthetically produced polypeptides,
polynucleotides, and oligosaccharides are within scope of this guideline.
This guideline does not apply to herbal products, radiopharmaceuticals, vaccines, cell
metabolites, DNA products, allergenic extracts, cells, whole blood, cellular blood
components, crude products of animal or plant origin, dialysate solutions not intended
for systemic circulation or drug products containing elements that are intentionally
included for therapeutic benefit.
This guideline does not apply to drug products used during clinical research stages of
development. In the later stages of development, the principles contained in this
1
Guideline for Elemental Impurities
guideline can be useful in evaluating elemental impurities that may be present in new
drug product prepared by the proposed commercial process.
The application of this guideline to existing marketed drug products will be addressed by
regional regulatory processes.
3. SAFETY ASSESSMENT OF POTENTIAL ELEMENTAL IMPURITIES
3.1 Principles of the Safety Assessment of Elemental Impurities for Oral,
Parenteral and Inhalation Routes of Administration
The method used for establishing the PDE for each element impurity is discussed in
detail in Appendix 1. Elements evaluated in this guideline were assessed by reviewing
the publicly available data contained in scientific journals, government research reports
and studies, international regulatory standards (applicable to drug products) and
guidance, and regulatory authority research and assessment reports. This process
follows the principles employed in ICH Q3C: Residual Solvents. The available
information was reviewed to establish the oral, parenteral and inhalation PDEs provided
in the guideline.
A summary safety assessment identifying the critical study for setting a PDE for each
element is included in Appendix 3. There are insufficient data to set PDEs by any route
of administration for osmium, rhodium, ruthenium and iridium. The PDEs for these
elements were established on the basis of their similarity to platinum. The PDEs for
each element included in the guideline are summarized in Appendix 2, Table A.2.1.
The factors considered in the safety assessment for establishing the PDE were:
• The oxidation state of the element likely to be present in the drug product;
• Human exposure and safety data when it provided applicable information;
• The most relevant animal study;
• Route of administration;
• Selection of the relevant endpoints or designations (e.g., International Agency for
Research on Cancer [IARC] classification, animal carcinogenicity, reproductive
toxicology, target organ toxicity, etc);
• The longest duration animal study was generally used to establish the PDE. In
some instances, a shorter duration animal study was considered the most
relevant study. The rationale for using the shorter duration study is provided in
the individual PDE assessment;
• In the absence of data and/or where data were available but were not considered
sufficient for a safety assessment for the parenteral and or inhalation route of
administration, default factors (see below) were used to derive the PDE from the
oral PDE;
• In inhalation drug products, soluble salts are more relevant than particulates to
assess elemental impurity toxicity. Therefore, inhalation studies using soluble
salts (when available) were preferred over studies using particulates for
inhalation assessment and derivation of inhalation PDEs.
In some cases, standards for daily intake for some of the elemental impurities discussed
in this guideline exist for food, water, air, and occupational exposure. These standards
have developed over time with different regional processes and may use different
modifying factors or other estimates (e.g., body weight for an individual). In some cases,
these standards are not only safety based, rather, based on practical considerations or
analytical capability. Where appropriate, these standards were considered in the
assessment and establishment of the PDEs using the approach as outlined in Appendix 1.
2
Guideline for Elemental Impurities
3
For PDEs established for inhalation (oral or parenteral routes as applicable), doses were
normalized to a 24 hour, 7 day exposure. If data were available for local toxicity to the
lung, those data were considered in establishing the inhalation PDE.
Where data were available but were not considered sufficient for a safety assessment for
the parenteral route of administration, modifying factors were employed as follows:
Oral bioavailability <1% divide by a modifying factor of 100
Oral bioavailability < 50% divide by a modifying factor of 10
Oral bioavailability between 50% and 90% divide by a modifying factor of 2
Oral bioavailability > 90% divide by a modifying factor of 1
Where inhalation and/or parenteral data were available but were not considered
sufficient for a safety assessment or Threshold Limit Value (TLV)/Time Weighted
Average (TWA) values were not available for the inhalation route of administration, a
calculated PDE was used based on the oral PDE divided by a modifying factor of 100
(Ball et al. 2007). In cases where the TLV/TWA or a nonclinical inhalation study was
used, the dose levels were normalized to a 24 hour, 7 day week.
PDEs for elements of low risk to human health as impurities in drug products were not
established. The elements in this category include: Fe, B, Al, W, Zn, K, Ca, Na, Mn, and
Mg.
For elements not included in this guideline for which there is limited or insufficient data,
the concepts used in this guideline can be used to determine appropriate PDEs.
3.2 Other Routes of Administration
PDEs were only established for oral, parenteral and inhalation routes of administration.
Sufficient data to permit the establishment of a PDE for other routes of administration
were generally unavailable. However, the concepts applied and described in this
guideline can be used to determine appropriate PDEs for other routes of administration.
Application of the parenteral PDE can provide the basis of a route-specific safety
assessment.
3.3 Justification for Element Impurity Levels Higher than the PDE
Levels of elemental impurities higher than the PDE may be acceptable in certain cases.
These cases could include, but are not limited to the following situations:
• less than daily dosing
• short term exposures (i.e., 30 days or less)
• specific indications (e.g., life-threatening, unmet medical needs, rare diseases)
Justification for increased levels in these situations should be made on a case by case
basis justifying the proposed level using a risk based approach. ICH Q3C and this
guideline use modifying factors for interspecies (Factor F1) and individual (Factor F2)
variability. These modifying factors serve as starting points in extrapolating available
data to obtain a PDE. The sub-factor approach (WHO, 2009), may be used to justify a
higher PDE, where data are available, using knowledge of the mode of action and
pharmacokinetic considerations. A justification may also include but is not limited to a
consideration of the duration of the study used to set the PDE relative to the intended
clinical use (Factor F3), the nature and severity of the toxicity observed, and whether the
toxicity was reversible (Factor F4).
An example of the sub-factor approach can be found elsewhere in a risk assessment for
boron (US Environmental Protection Agency [EPA], 2004).
Guideline for Elemental Impurities
3.4 Parenteral Products
The parenteral PDEs are applied irrespective of dose volume.
4. ELEMENT CLASSIFICATION
The elemental impurities included in this guideline have been placed into categories that
are intended to facilitate decisions during the risk assessment.
• Class 1 elemental impurities, As, Cd, Hg, and Pb, are significantly toxic across all
routes of administration. Typically they have limited or no use in the
manufacture of pharmaceuticals but can be present as impurities in commonly
used materials (e.g., mined excipients) and can not be readily removed from the
material. Because of their unique nature, these four elemental impurities require
consideration during the risk assessment across all potential sources of elemental
impurities.
• Class 2 elemental impurities are toxic to a greater or lesser extent based on route
of administration. In addition, some of the elements present in this category are
infrequently observed as impurities in materials used to produce drug products
and as such, unless intentionally added have a low probability of inclusion in the
drug product and do not present a significant risk. Class 2 elemental impurities
are further categorized to establish when they should be considered in the risk
assessment and when their contribution can be judged to be negligible.
o Class 2A: The following elemental impurities require assessment across all
potential sources and routes of administration: V, Mo, Se, and Co due to
their higher relative natural abundance (US Geological Survey, 2005).
o Class 2B: The following elemental impurities require assessment across
potential elemental impurity sources only if they are intentionally added
to the processes used to generate the material under evaluation: Au, Tl,
Pd, Pt, Ir, Os, Rh, Ag and Ru.
• Class 3 elemental impurities are impurities with relatively low toxicity (high
PDEs) by the oral route administration but require consideration in the risk
assessment for other routes of administration (e.g., inhalation and parenteral
routes). For oral routes of administration, unless these elements are intentionally
added as part of the process generating the material, they do not need to be
considered during the risk assessment. For parenteral and inhalation products,
the potential for inclusion of these elemental impurities should be evaluated
during the risk assessment. The elemental impurities in this class include: Sb,
Ba, Li, Cr, Cu, Sn, and Ni.
• Class 4 elemental impurities are elemental impurities that have been evaluated
but for which a PDE has not been established due to their low inherent toxicity
and/or regional regulations. If these elemental impurities are present or included
in the drug product they are addressed following the practices defined by other
guidelines and regional regulation. The elements in this class include: Al, B, Fe,
Zn, K, Ca, Na, Mn, Mg, and W.
The classification system is summarized in Table 4.1.
4
Guideline for Elemental Impurities
5
Table 4.1: Elemental Impurity Classification
Included Elemental
Impurities
Include in Risk
Assessment?
Class 1
As, Pb, Cd, Hg Yes
Class 2A V, Mo, Se, and Co Yes
Class 2B Ag, Au, Tl, Pd, Pt, Ir,
Os, Rh, and Ru
Yes only if intentionally
added
Class 3 Sb, Ba, Li, Cr, Cu, Sn,
Ni
Dependent upon route
of administration – see
Class 3 description
Class 4 B, Fe, Zn, K, Ca, Na,
Mn, Mg, W, Al
No
5. ASSESSMENT AND CONTROL OF ELEMENTAL IMPURITIES
In developing the control strategy for elemental impurities in drug products, the
principles of quality risk management, described in ICH Q9, should be considered. The
risk assessment should be based on scientific knowledge and principles. It should link
patient safety considerations with an understanding of the product and its
manufacturing process (ICH Q8 and Q11). In the case of elemental impurities, the
product risk assessment would therefore be focused on assessing the levels of elemental
impurities in a drug product in relation to the PDEs presented in this guidance.
Information for this assessment includes but is not limited to: data generated by the
applicant, information supplied by drug substance, reagent and/or excipient
manufacturers or data available in published literature.
The applicant should document the assessment and control approaches in an appropriate
manner. The level of effort and formality of the assessment should be proportional to the
level of risk. It is neither always appropriate nor always necessary to use a formal risk
management process (using recognized tools and/or formal procedures, e.g., standard
operating procedures.) The use of informal risk management processes (using empirical
tools and/or internal procedures) can also be considered acceptable. Tools to assist in the
risk assessment are described in ICH Q9 and will not be presented in this guideline.
5.1 General Principles
For the purposes of this guideline, the assessment process can be described in four steps:
identify, analyse, evaluate and control. In many cases, the steps are considered
simultaneously. For example, the analyse and evaluate steps may be iterative steps that
initiate adjustments to control elements. The outcome of the assessment may be the
result of iterations to develop a final approach to ensure the potential elemental
impurities do not exceed the PDE.
Identify: Identify known and potential sources of elemental impurities that may
find their way into the drug product.
Analyze: Determine the probability of observance of a particular elemental impurity
in the drug product.
Guideline for Elemental Impurities
Evaluate: Compare the observed or predicted levels of elemental impurities with the
established PDE.
Control: Document and implement a control strategy to limit elemental impurities
in the drug product.
5.2 Potential Sources of Elemental Impurities
In considering the production of a drug product, there are several broad categories of
potential sources of elemental impurities.
• Residual elemental impurities resulting from elements intentionally added to
reactions or processes leading up to the preparation of the drug substance,
reagents, starting materials or excipients (e.g., metal catalysts).
• Elemental impurities known or suspected of being present in the drug substance,
reagents, water, starting materials or excipients used in the preparation of the
drug product.
• Elemental impurities known or suspected of being introduced into the drug
substance and/or drug product from manufacturing equipment.
• Elemental impurities that are known or suspected of being leached into the drug
substance and drug product from container closure systems.
The following diagram shows an example of typical materials or components used in the
production of a drug product. Each of these materials or components may contribute
elemental impurities to the drug product, through any individual or any combination of
the potential sources listed above. During the assessment, the potential contributions
from each of these materials or components should be considered to determine the
overall contribution of elemental impurities to the drug product.
Elemental
impurities
in drug
Product
Container
Closure
System
Drug
Substance
Excipients
Manufacturing
equipment *
Water **
* The risk of inclusion of elemental impurities can be reduced through process
understanding, equipment selection, equipment qualification and Good Manufacturing
Practice (GMP) processes.
** The risk of inclusion of elemental impurities from water can be reduced by complying
with compendial (e.g., European Pharmacopoeia, Japanese Pharmacopoeia, US
6
Guideline for Elemental Impurities
7
Pharmacopeial Convention) water quality requirements, if purified water or water for
injection is used in the process(es).
5.3 Assessment – Identification of Potential Elemental Impurities
Class 1 elemental impurities: Due to their inherent toxicity, the risk assessment
should include an assessment of the Class 1 elemental impurities. All potential sources
of elemental impurities should be evaluated for the potential to transfer the Class 1
elemental impurities to the drug product.
Potential elemental impurities derived from intentionally added catalysts or
reagents: For this category, the identity of the potential impurities is known and
techniques for controlling the elemental impurities are easily characterized and defined.
The predominant elemental impurities that comprise this group are the Class 2 and 3
elemental impurities. Table 5.1 shows the suggested consideration in the risk
assessment for each of the elemental impurities covered in this guideline. As identified,
if any (Class 1, 2, or 3) elemental impurity is added, it should be considered in the risk
assessment.
Potential elemental impurities with a relatively high abundance and/or are
impurities in excipients or reagents: Elemental impurities known or suspected of
being present in the drug substance, reagents, starting materials or excipients used in
the preparation of the drug product should be considered. These elemental impurities
are often associated with mined materials and excipients. The presence of these
impurities can be variable, especially with respect to mined excipients, which can
complicate the risk assessment. The variation should be considered when establishing
the probability for inclusion in the drug product. The elemental impurities that are of
most significant to this potential source include the Class 1 and Class 2A elemental
impurities (see Table 4.1). For parenteral and inhalation routes of administration, the
risk assessment should evaluate the probability for inclusion of the Class 1 and most 3
elemental impurities as shown in Table 5.1.
Potential elemental impurities derived from manufacturing equipment: The
contribution of elemental impurities may be limited and the subset of elemental
impurities that should be considered in the risk assessment is relatively small and is
dependent on the equipment involved. Application of process knowledge, selection of
equipment, equipment qualification and GMP controls ensure a low contribution from
manufacturing equipment. The specific elemental impurities of concern should be
assessed based on knowledge of the composition of the components of the manufacturing
equipment. The assessment of this source of elemental impurities is one that can be
utilized potentially for many drug products using similar process trains and processes.
Elemental impurities leached from container closure systems: Identifying the
potential elemental impurities extracted from container closure systems should be based
on a scientific understanding of likely interactions between a particular drug product
type and its packaging. When a review of the materials of construction demonstrates
that the container closure system does not contain elemental impurities, no additional
assessment needs to be performed. It is recognized that the probability of elemental
leaching into solid dosage forms is minimal and does not require further consideration in
the assessment. For liquid and semi-solid dosage forms there is a higher probability that
elemental impurities could leach from the container closure system into the drug product
during the shelf-life of the product. Studies to understand potential extractables and
leachables from the final/actual container closure system (after washing sterilization,
irradiation) should be performed.
Guideline for Elemental Impurities
Factors that should be considered (for liquid and semi-solid dosage forms) include but are
not limited to:
• Hydrophilicity/hydrophobicity
• Ionic content
• pH
• Temperature (cold chain vs room temperature and processing conditions)
• Contact surface area
• Container/component composition
• Terminal sterilization
• Packaging process
• Component sterilization
• Migration potential
• Duration of storage
• Inclusion of metal chelating agents in the formulation (e.g., Ethylenediamine
Tetraacetic Acid [EDTA]).
Table 5.1: Recommendation for Consideration During Risk Assessment
Element Class If intentionally
added (across
all routes of
administration)
If not intentionally added
Oral Parenteral Inhalation
As 1 yes yes yes yes
Cd 1 yes yes yes yes
Hg 1 yes yes yes yes
Pb 1 yes yes yes yes
Co 2A yes yes yes yes
Mo 2A yes yes yes yes
Se 2A yes yes yes yes
V 2A yes yes yes yes
Ag 2B yes no no no
Au 2B yes no no no
Ir 2B yes no no no
Os 2B yes no no no
Pd 2B yes no no no
Pt 2B yes no no no
Rh 2B yes no no no
Ru 2B yes no no no
Tl 2B yes no no no
Ba 3 yes no no yes
Cr 3 yes no no yes
Cu 3 yes no yes yes
Li 3 yes no yes yes
Ni 3 yes no yes yes
Sb 3 yes no yes yes
Sn 3 yes no yes yes
8
Guideline for Elemental Impurities
9
5.4 Assessment – Analysis and Evaluation
As the potential elemental impurity identification process is concluded, there are several
possible outcomes: the process and product review does not identify any potential
elemental impurities or the process identifies a list of one or more potential elements.
When present, the elemental impurities may have a single source or multiple sources. In
addition, a number of elemental impurities will be excluded from consideration based on
the assessment of their probability of occurrence and their potential to exceed the PDE.
In order to accurately complete the assessment, data regarding potential elemental
impurity levels may be needed. The data for this assessment can come from a number of
sources that include, but are not limited to:
• Prior knowledge
• Published literature
• Data generated from similar processes
• Supplier information or data
• Analysis of the components of the drug product
• Analysis of the drug product
The applicant’s risk assessment can be facilitated with information about the potential
elemental impurities provided by suppliers of drug substances, excipients, starting
materials, reagents, container closure systems, and manufacturing equipment.
Since the PDE is established on the drug product, it is necessary to compare the
predicted or known levels of the elemental impurities identified with the established
PDE in order to define the appropriate steps to take in developing an approach to control
potential elemental impurities in the drug product. This may be done in several different
ways and the applicant should consider which option is most appropriate for their use
given the elemental impurities identified in combination with the source of the elemental
impurity.
5.5 Converting Between PDEs and Concentration Limits
The PDEs, reported in micrograms per day (µg/day) provided in this document give the
maximum permitted quantity of each element that may be contained in the maximum
daily intake of a drug product. Because the PDE reflects only total exposure from the
drug product, it is useful to convert the PDE, into concentrations as a tool in evaluating
elemental impurities in drug products or their components. The following options
describe some acceptable approaches to establishing concentrations of elemental
impurities in drug products or components that would assure that the drug product
meets the PDEs. The applicant may select any of these options as long as the resulting
permitted concentrations assure that the drug product meets the PDEs for elemental
impurities. In the choice of a specific option the applicant must have knowledge of, or
make assumptions about, the daily intake of the drug product. In all cases, the PDE
should be met. The permitted concentration limits may be used:
• As a tool in the risk assessment to compare the observed or predicted levels to the
PDE;
• In discussions with suppliers to help establish upstream controls that would
assure that the product meets the PDE;
• To establish concentration targets when developing in-process controls on
elemental impurities;
• To convey information regarding the controls on elemental impurities in
regulatory submissions.
Guideline for Elemental Impurities
As discussed in Section 5.2, there are multiple sources for elemental impurities in drug
products. When applying any of the options described below, elemental impurities from
container closure systems and manufacturing equipment should be taken into account
prior to calculating the maximum permitted concentration in the remaining components
(excipients and drug substance). If it is determined during the risk assessment that the
container closure systems and manufacturing equipment do not contribute to the
elemental impurity level in the drug product, they do not need to be considered. Where
contributions from container closure systems and manufacturing equipment exist, these
contributions may be accounted for by subtracting the estimated daily intake from these
sources from the PDE prior to calculation of the allowed concentration in the excipients
and drug substance.
Option 1: Common permitted concentration limits of elements across drug
product components for drug products with daily intakes of not more than 10
grams:
This option is not intended to imply that all elements are present at the same
concentration, but rather provides a simplified approach to the calculations.
The option assumes the daily intake (amount) of the drug product is 10 grams or less,
and that elemental impurities identified in the risk assessment (the target elements) are
present in all components of the drug product. Using equation (1) below, and a daily
intake of 10 grams of drug product, this option calculates a common permissible target
elemental concentration for each component in the drug. This approach, for each target
element, allows determination of a fixed common maximum concentration in micrograms
per gram in each component. The calculated values are provided in Appendix 2 Table
A.2.2.
)/(
)/()/(
daygproductdrugofamountdaily
daygPDEggionConcentrat μμ = (1)
If all the components in a drug product meet the Option 1 concentrations for all target
elements identified in the risk assessment, then all these components may be used in
any proportion in the drug product. An example of this calculation is shown in Appendix
4 Table A.4.1. If the permitted concentrations in Appendix 2 Table A.2.2 are not applied,
Options 2a, 2b, or 3 must be followed.
Option 2a: Common permitted concentration limits across drug product
components for a drug product with a specified daily intake:
This option is similar to Option 1, except that the drug daily intake is not assumed to be
10 grams. The common permitted concentration of each element is determined using
Equation 1 and the actual maximum daily intake.
This approach, for each target element, allows determination of a fixed common
maximum concentration in micrograms per gram in each component based on the actual
daily intake provided. An example of this calculation is provided in Appendix 4 Table
A.4.2.
If all components in a drug product meet the Option 2a concentrations for all target
elements identified in the risk assessment, then all these components may be used in
any proportion in the drug product.
Option 2b: Permitted concentration limits of elements across drug product
component materials for a product with a specified daily intake:
10
Guideline for Elemental Impurities
11
This option requires additional information that the applicant may assemble regarding
the potential for specific elemental impurities to be present in specific drug product
components. The applicant may set permitted concentrations based on the distribution
of elements in the components (e.g., higher concentrations in components with the
presence of an element in question). For each element identified as potentially present
in the components of the drug product, the total mass of the elemental impurity in the
final drug product can be calculated as the sum of the product of the component material
masses at the maximum permitted concentrations established by the applicant. The
total mass of the elemental impurity in the drug product cannot exceed the PDEs given
in Appendix 2 Table A.2.1., as shown in equation 2. If the risk assessment has identified
that a specific element is not a potential impurity in a specific component, there is no
need to establish a quantitative result for that element in that component. This approach
allows that the maximum permitted concentration of an element in certain components
of the drug product may be higher than the Option 1 or Option 2a limit, but this should
then be compensated by lower allowable concentrations in the other components of the
drug product. Equation 2 may be used to set component-specific limits for each element
in each component of a drug product.
( ) ∑
=
⋅≥
N
1k
kk MCdaygPDE μ (2)
k = an index for each of N components in the drug product
Ck = concentration of the elemental impurity in component k (µg/g)
Mk = mass of component k in the maximum daily intake of the drug product (g)
An example of this calculation is provided in Appendix 4 Tables A.4.3 – A.4.5.
Option 3: Finished Product Analysis:
The concentration of each element may be measured in the final drug product. Equation
1 may be used with the maximum total daily dose of the drug product to calculate a
maximum permitted concentration of the elemental impurity. An example of this option
is provided in Appendix 4 Table A.4.6.
5.6 Assessment Summary
The process described above is intended to enable the applicant to focus on those
elements that require additional control elements. The process permits the applicant to
utilize information and knowledge gained across products to establish the particular
elemental impurities of concern in the specific drug product.
A number of factors can influence the level of the potential impurity in the drug product
and should also be considered in the assessment. These include but are not limited to:
• Efficiency of removal of elemental impurities during further processing;
• Natural abundance of elements (especially important for the categories of
elements which are not intentionally added);
• Prior knowledge of elemental impurity concentration factors from specific
sources.
For elements that are added or are known to be potentially present in excipients or raw
materials, the analysis should consider the percentage of the excipient or raw material in
the drug product. Assessment of probable concentrations based on this percent of the
total composition of the drug product is an additional tool to determine if the
contribution is relevant. The analysis may include an assessment of the levels or
concentrations that are identified either in each component (including contributions from
the container closure system) or in the drug product.
Guideline for Elemental Impurities
The initial design of the facility and qualification of utilities and equipment, as part of
process qualification, would be expected to identify potential elemental impurities and
anticipated potential contributions to the drug product. In general, the contribution of
elemental impurities from manufacturing equipment and utilities is likely to be
negligible and would normally be addressed by implementing appropriate GMP
procedures. However, if the assessment demonstrated that the contribution was
significant, the anticipated levels of the identified elements should be reviewed as part of
the risk evaluation process.
Finally the applicant should consider the significance of the observed level relative to the
PDE of the element. As a measure of the significance of the observed elemental impurity
level, a control threshold is defined as a level that is 30% of the established PDE in the
drug product. This threshold is used to determine if additional controls may be required.
If the total elemental impurity level from all sources in the drug product is consistently
less than 30% of the PDE, applying appropriate assessment of the data and
demonstrating an adequate control strategy, then additional controls are not required.
If the assessment fails to demonstrate that an elemental impurity level is below the
control threshold, controls should be established to ensure that the elemental impurity
level does not exceed the PDE in the drug product.
In order to apply the control threshold, sources of variability should be understood.
Important factors include:
• Variability of the analytical method
• Variability of the elemental impurity level in the specific sources
• Variability of the elemental impurity level in the drug product
There are many acceptable approaches to document the assessment and may include:
tables, written summaries of considerations and conclusions of the assessment. The
summary should identify the elemental impurities, their sources, and the controls and
acceptance criteria as needed.
5.7 Control of Elemental Impurities
Control of elemental impurities includes decision making steps designed to reduce or
accept the presence of elemental impurities and their respective concentrations that
were identified and evaluated through the assessment process. When the assessment
determines that the levels of elemental impurities are below the control threshold, no
further control is required but periodic verification testing may be used to confirm that
the expected levels are consistent and predictive of future (see Section 5.8). The applicant
should provide a justification for the application of periodic verification testing.
When the control threshold is exceeded, the controls established should ensure that the
PDE is not exceeded. There are a number of control elements or approaches that an
applicant can pursue to control the elemental impurities in drug products. These include
but are not limited to:
• Identification of the steps in the manufacturing process that result in the
reduction of elemental impurities through specific or non-specific purification
steps;
• Implementation of in-process or upstream controls, designed to limit the
concentration of the elemental impurity in the drug product;
• Establishment of material (e.g., synthetic intermediates and raw materials) or
excipient specifications to limit the level of elemental impurity contributions
from those sources;
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13
• Establishment of specification limits for the drug substance;
• Establishment of specification limits for the drug product;
• Reliance on the compliance with compendial standards for materials used in
drug product processes;
• Selection of appropriate container closure systems.
Where testing and acceptance criteria are established, periodic verification testing may
be appropriate in some cases (see Section 5.8).
An illustration of the risk assessment process described above can be found in Appendix
4.
5.8 Periodic Verification Testing
In situations where a test is recommended to be included in the specification to provide
suitable control of elemental impurities, but where routine measurement for release of
every batch may not be necessary, it may be possible to apply periodic verification testing
(periodic or skip lot testing as described in ICH Q6A). It should be noted that allowance
of periodic verification testing is considered to be helpful to provide periodic confirmation
that the controls contained within a process perform consistently over the lifecycle of the
product. Periodic testing is a means to ensure that the risk assessment assumptions are
valid and ensure that unintended or unknown process or material attributes have not
changed over time. Application of periodic verification testing should be applied to
processes or materials that are under a state of control (i.e., consistently meets
specifications and conforms to an appropriately established facility, equipment,
processing, and operational control regimen). If upon testing, the elemental impurity
level exceeds the PDE, the applicant should investigate the cause of the failure, reassess
the controls that are in place and determine if additional controls may be required.
Failures observed in periodic verification testing should be reported to the appropriate
regulatory authorities following the established procedures.
5.9 Special Considerations for Biotechnologically-Derived Products
For biotechnology-derived products, the risks associated with elemental impurities being
present at levels of safety concerns at the drug substance stage are considered low. This
is largely due to the following factors: a) elements are not typically used as catalysts or
reagents in the manufacturing of biotech products; b) elements are added at trace levels
in media feeds during cell culture processes, without accumulation and with significant
dilution/removal during further processing; c) typical purification schemes used in
biotech manufacturing such as chromatography steps and dialysis or Ultrafiltration-
Diafiltration (UF/DF) have the capacity to clear elements introduced in cell
culture/fermentation steps or from contact with manufacturing equipment to negligible
levels. As such, a specific control strategy that relates to the control of elements up to the
biotech drug substance is not generally needed. In cases where the biotechnology derived
drug substance contains synthetic elements (such as antibody-drug conjugates),
appropriate controls on the small molecule element for elemental impurities should be
performed.
However, potential elemental impurity sources included in drug product manufacturing
(e.g., excipients) and other environmental sources should be considered for
biotechnologically derived drug products. The contribution of these sources to the
finished product should be assessed as typically they are introduced in the drug product
manufacture at a step in the process where subsequent elemental impurity removal is
not generally performed. Risk factors that should be considered in this assessment
should include the type of excipients used, the processing conditions and their
Guideline for Elemental Impurities
susceptibility to contamination by environmental factors (e.g., controlled areas for sterile
manufacturing and use of purified water), as well as the overall dosing frequency.
6. SPECIATION
Speciation is defined as the separation of elemental impurities based on oxidation state,
organic combination or complexation state. The PDE has been established using the
toxicity information on the species expected to be in the drug product.
The applicant is not expected to provide speciation information; however, such
information could be used to justify higher levels for the more relevant or less toxic
species.
7. ANALYTICAL PROCEDURES
The determination of elemental impurities should be conducted using appropriate
procedures suitable for their intended purposes. Unless otherwise justified, the test
should be specific for each elemental impurity identified for control during the risk
assessment. Pharmacopoeial procedures or suitable validated alternative procedures for
determining levels of elemental impurities should be used.
8. LIFE-CYCLE MANAGEMENT OF THE CONTROL STRATEGY FOR ELEMENTAL
IMPURITIES
The quality system elements and management responsibilities described in ICH Q10 are
intended to encourage the use of science-based and risk-based approaches at each
lifecycle stage, thereby promoting continual improvement across the entire product
lifecycle. Product and process knowledge should be managed from development through
the commercial life of the product up to and including product discontinuation.
The effectiveness of the control strategy should be periodically evaluated throughout the
product lifecycle. Knowledge gained from development combined with commercial
manufacturing experience and data can be used to further improve process
understanding and process performance which can be used to make improvements to the
control strategy. It is recognized that the elemental impurity data available for some
components is somewhat limited at this time which may direct the applicant to a specific
series of control elements. Additional data, if developed, may lead to modifications of the
control strategy.
If changes to the drug product process(es) have the potential to change the elemental
impurity content of the drug product, the established control elements for elemental
impurities should be re-evaluated. Such changes could include but are not limited to:
changes in synthetic route, excipient supplier, raw materials, processes, equipment, or
facilities. All changes are subject to internal change management process (ICH Q10) and
if needed appropriate regional regulatory requirements.
9. RECOMMENDATIONS FOR SUBMISSION OF ELEMENTAL IMPURITIES CONTROL
STRATEGY
The information on the control strategy that is provided in a regulatory submission
should include the outcome of the risk assessment and a description of the controls
established to limit elemental impurities. A good location for the description of the
control strategy is Section 3.2.P.5.6. This summary should include appropriate references
to the locations of controls on elemental impurities defined in the control strategy (e.g.,
3.2.S and 3.2.P). A summary of the approach used to develop the control strategy may be
included in the Quality Overall Summary.
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15
REFERENCES
Ball D, Blanchard J, Jacobson-Kram D, McClellan R, McGovern T, Norwood DL et al.
Development of safety qualification thresholds and their use in orally inhaled and nasal
drug product evaluation. Toxicol Sci 2007;97(2):226-36.
Haxel GB, Hedrick JB, Orris GJ. Rare earth elements-critical resources for high
technology. US Geological Survey 2005;Fact Sheet 087-02.
IPCS. Principles and methods for the risk assessment of chemicals in food, chapter 5:
dose-response assessment and derivation of health based guidance values.
Environmental Health Criteria 240. International Programme on Chemical Safety.
World Health Organization, Geneva. 2004; Table 5.5.
US EPA. 0410 Boron and Compounds. Integrated Risk Management System (IRIS).
2004.
Guideline for Elemental Impurities
GLOSSARY
ATSDR:
Agency for Toxic Substances and Disease Registry.
CEC:
Commission of the European Community.
CFR:
Code of Federal Regulations (USA).
Change Management:
A systematic approach to proposing, evaluating, approving, implementing and reviewing
changes. (ICH Q10)
Container Closure System:
The sum of packaging components that together contain and protect the dosage form.
This includes primary packaging components and secondary packaging components, if
the latter are intended to provide additional protection to the drug product. A packaging
system is equivalent to a container closure system. (ICH Q1A)
Control Strategy:
A planned set of controls, derived from current product and process understanding,
which assures process performance and product quality. The controls can include
parameters and attributes related to drug substance and drug product materials and
components, facility and equipment operating conditions, in-process controls, finished
product specifications, and the associated methods and frequency of monitoring and
control. (ICH Q10)
Control Threshold:
A limit that is applied during the assessment of elemental impurities to determine if
additional control elements may be required to ensure that the PDE is not exceeded in
the drug product. The limit is defined as 30% of the PDE of the specific elemental
impurity under consideration.
Daily Dose:
The total mass of drug product that is consumed by a patient on a daily basis.
EFSA:
European Food Safety Agency.
EHC:
Environmental Health Criteria. (WHO)
EU SCOEL:
European Scientific Committee on Occupational Exposure Limits.
IARC:
International Agency for Research on Cancer.
Inhalation Unit Risk:
The upper-bound excess lifetime cancer risk estimated to result from continuous
exposure to an agent at a concentration of 1 µg/L in water, or 1 µg/m3 in air. The
interpretation of inhalation unit risk would be as follows: if unit risk = 2 x 10-6 per µg/L,
2 excess cancer cases (upper bound estimate) are expected to develop per 1,000,000
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Guideline for Elemental Impurities
17
people if exposed daily for a lifetime to 1 µg of the chemical in 1 liter of drinking water.
(US EPA)
IPCS:
International Programme for Chemical Safety.
IUPAC:
International Union of Pure and Applied Chemistry.
IRIS:
Integrated Risk Identification System, United States Environmental Protection Agency.
Lowest-Observed-Adverse-Effect Level (LOAEL):
Lowest concentration or amount of a substance (dose), found by experiment or
observation, which causes an adverse effect on morphology, functional capacity, growth,
development, or life span of a target organism distinguishable from normal (control)
organisms of the same species and strain under defined conditions of exposure. (IUPAC)
Limit of Detection (LOD):
The limit of detection of an individual analytical procedure is the lowest amount of
analyte in a sample which can be detected but not necessarily quantitated as an exact
value. (ICH Q2)
Lowest-Observed-Effect Level (LOEL):
The lowest dose of substance in a study or group of studies that produces biologically
significant increases in frequency or severity of any effects in the exposed humans or
animals.
Modifying Factor:
A factor determined by professional judgment of a toxicologist and applied to bioassay
data to relate that data to human safety. (Q3C) (See related term Safety Factor)
MRL:
Minimal Risk Level.
No-Observed-Adverse-Effect Level (NOAEL):
Greatest concentration or amount of a substance, found by experiment or observation,
which causes no detectable adverse alteration of morphology, functional capacity, growth,
development, or life span of the target organism under defined conditions of exposure.
No-Observed-Effect Level (NOEL):
The highest dose of substance at which there are no biologically significant increases in
frequency or severity of any effects in the exposed humans or animals.
NTP:
National Toxicology Program.
OELV:
Occupational Exposure Limit Value.
OSHA:
Occupational Safety and Health Administration (USA).
PEL:
Permitted Exposure Limit.
http://sis.nlm.nih.gov/enviro/iupacglossary/glossaryc.html#concentration
http://sis.nlm.nih.gov/enviro/iupacglossary/glossaryd.html#dosesubstance
http://sis.nlm.nih.gov/enviro/iupacglossary/glossarya.html#adverseeffect
http://sis.nlm.nih.gov/enviro/iupacglossary/glossaryt.html#target
http://sis.nlm.nih.gov/enviro/iupacglossary/glossarye.html#exposure
http://sis.nlm.nih.gov/enviro/iupacglossary/glossaryc.html#concentration
http://sis.nlm.nih.gov/enviro/iupacglossary/glossarye.html#exposure
Guideline for Elemental Impurities
Permitted Daily Exposure:
The maximum acceptable intake of elemental impurity in pharmaceutical products per
day.
Product Lifecycle:
All phases in the life of the product from the initial development through marketing
until the product’s discontinuation. (ICH Q9)
Quality:
The degree to which a set of inherent properties of a product, system, or process fulfills
requirements (see ICH Q6A definition specifically for quality of drug substance and drug
products). (ICH Q9)
Quality Risk Management:
A systematic process for the assessment, control, communication, and review of risks to
the quality of the drug product across the product lifecycle. (ICH Q9)
Quality System:
The sum of all aspects of a system that implements quality policy and ensures that
quality objectives are met. (ICH Q10)
Raw Material:
A general term used to denote starting materials, reagents, and solvents intended for use
in the production of intermediates or Active Pharmaceutical Ingredients (APIs). (ICH
Q7)
Risk:
The combination of the probability of occurrence of harm and the severity of that harm.
(ISO/IEC Guide 51, ICH Q9)
Risk Acceptance:
The decision to accept risk. (ISO Guide 73)
Risk Analysis:
The estimation of the risk associated with the identified hazards. (ICH Q9)
Risk Assessment:
A systematic process of organizing information to support a risk decision to be made
within a risk management process. It consists of the identification of hazards and the
analysis and evaluation of risks associated with exposure to those hazards. (ICH Q9)
Risk Control:
Actions implementing risk management decisions. (ISO Guide 73)
Risk Identification:
The systematic use of information to identify potential sources of harm (hazards)
referring to the risk question or problem description. (ICH Q9)
Risk Management:
The systematic application of quality management policies, procedures, and practices to
the tasks of assessing, controlling, communicating, and reviewing risk. (ICH Q9)
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19
Safety:
Practical certainty that adverse effects will not result from exposure to an agent under
defined circumstances. (EHC 240)
Safety Assessment:
An approach that focuses on the scientific understanding and measurement of chemical
hazards as well as chemical exposures, and ultimately the risks associated with them.
Often (and in this guideline) used synonymously with risk assessment. Related term:
Risk assessment. (EHC 340)
Safety Factor:
A composite (reductive) factor applied by the risk assessment experts to the No-
Observed-Adverse-Effect Level (NOAEL) or other reference point, such as the
benchmark dose or benchmark dose lower confidence limit, to derive a reference dose
that is considered safe or without appreciable risk, such as an acceptable daily intake or
tolerable daily intake (the NOAEL or other reference point is divided by the safety factor
to calculate the reference dose). The value of the safety factor depends on the nature of
the toxic effect, the size and type of population to be protected, and the quality of the
toxicological information available. Related terms: Assessment factor, Uncertainty factor.
(EHC 240)
Severity:
A measure of the possible consequences of a hazard. (ICH Q9)
Starting Material:
A material used in the synthesis of a new drug substance that is incorporated as an
element into the structure of an intermediate and/or of the new drug substance. Starting
materials are normally commercially available and of defined chemical and physical
properties and structure. (ICH Q3A)
Threshold Limit Value (TLV):
The concentration in air to which it is believed that most workers can be exposed daily
without an adverse effect (i.e., effectively, the threshold between safe and dangerous
concentrations). The values were established (and are revised annually) by the ACGIH
and are time-weighted concentrations (TWA) for a 7- or 8-hour workday and 40-hour
workweek, and thus are related to chronic effects. (IUPAC）
Time Weighted Average (TWA):
As defined by ACGIH, time-weighted average concentration for a conventional 8-hour
workday and a 40-hour workweek. (IUPAC)
URF:
Unit Risk Factor.
US DoL:
United States Department of Labor.
US EPA:
United States Environmental Protection Agency.
WHO:
World Health Organization.
http://goldbook.iupac.org/AT06809.html
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Guideline for Elemental Impurities
Appendix 1: Method for Establishing Exposure Limits
The Gaylor-Kodell method of risk assessment (Gaylor DW, Kodell RL. Linear
Interpolation algorithm for low dose assessment of toxic substance. J Environ Pathol
Toxicol 1980;4:305) is appropriate for carcinogenic elemental impurities. Only in cases
where reliable carcinogenicity data are available should extrapolation by the use of
mathematical models be applied to setting exposure limits. Exposure limits for
carcinogenic elemental impurities could be determined with the use of a large safety
factor (i.e., 10,000 to 100,000) with respect to the No-Observed-Effect Level (NOEL).
Acceptable exposure levels for elemental impurities in this guideline were established by
calculation of PDE values according to the procedures for setting exposure limits in
pharmaceuticals (Pharmacopeial Forum, Nov-Dec 1989), and the method adopted by
IPCS for Assessing Human Health Risk of Chemicals (Environmental Health Criteria
[EHC] 170, WHO, 1994). These methods are similar to those used by the US EPA (IRIS)
and the US FDA (Red Book) and others. The method is outlined here to give a better
understanding of the origin of the PDE values. It is not necessary to perform these
calculations in order to use the PDE values tabulated in Appendix 2 of this document.
PDE is derived from the NOEL, or the Lowest-Observed-Effect Level (LOEL) in the most
relevant animal study as follows:
PDE = NOEL x Mass Adjustment/[F1 x F2 x F3 x F4 x F5] (1)
The PDE is derived preferably from a NOEL. If no NOEL is obtained, the LOEL may be
used. Modifying factors proposed here, for relating the data to humans, are the same
kind of "uncertainty factors" used in Environmental Health Criteria (EHC 170, World
Health Organization [WHO], Geneva, 1994), and "modifying factors" or "safety factors" in
Pharmacopeial Forum. The assumption of 100% systemic exposure is used in all
calculations regardless of route of administration.
The modifying factors are as follows:
F1 = A factor to account for extrapolation between species
F1 = 5 for extrapolation from rats to humans
F1 = 12 for extrapolation from mice to humans
F1 = 2 for extrapolation from dogs to humans
F1 = 2.5 for extrapolation from rabbits to humans
F1 = 3 for extrapolation from monkeys to humans
F1 = 10 for extrapolation from other animals to humans
F1 takes into account the comparative surface area: body mass ratios for the species
concerned and for man. Surface area (S) is calculated as:
S = kM0.67 (2)
in which M = body mass, and the constant k has been taken to be 10. The body masses
used in the equation are those shown below in Table A.1.1
F2 = A factor of 10 to account for variability between individuals
A factor of 10 is generally given for all elemental impurities, and 10 is used consistently
in this guideline
F3 = A variable factor to account for toxicity studies of short-term exposure
F3 = 1 for studies that last at least one half lifetime (1 year for rodents or rabbits; 7
years for cats, dogs and monkeys)
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21
F3 = 1 for reproductive studies in which the whole period of organogenesis is covered
F3 = 2 for a 6-month study in rodents, or a 3.5-year study in non-rodents
F3 = 5 for a 3-month study in rodents, or a 2-year study in non-rodents
F3 = 10 for studies of a shorter duration
In all cases, the higher factor has been used for study durations between the time points,
e.g., a factor of 2 for a 9-month rodent study.
F4 = A factor that may be applied in cases of severe toxicity, e.g., non-genotoxic
carcinogenicity, neurotoxicity or teratogenicity. In studies of reproductive toxicity, the
following factors are used:
F4 = 1 for fetal toxicity associated with maternal toxicity
F4 = 5 for fetal toxicity without maternal toxicity
F4 = 5 for a teratogenic effect with maternal toxicity
F4 = 10 for a teratogenic effect without maternal toxicity
F5 = A variable factor that may be applied if the no-effect level was not established
When only an LOEL is available, a factor of up to 10 could be used depending on the
severity of the toxicity.
The mass adjustment assumes an arbitrary adult human body mass for either sex of 50
kg. This relatively low mass provides an additional safety factor against the standard
masses of 60 kg or 70 kg that are often used in this type of calculation. It is recognized
that some adult patients weigh less than 50 kg; these patients are considered to be
accommodated by the built-in safety factors used to determine a PDE.
As an example of the application of this equation, consider a toxicity study of cobalt in
human volunteers is summarized in Agency for Toxic Substances and Disease Registry
(ATSDR, 2004, op/. cit., Davis JE and Fields JP. Proc Soc Exp Biol Med 1958;99:493-5).
The Lowest-Observed-Adverse-Effect Level (LOAEL) for polycythemia is 1 mg/kg/day.
The PDE for cobalt in this study is calculated as follows:
PDE = 1 mg/kg/day x 50 kg/[1 x 10 x 10 x 1 x 10] = 0.05 mg/day = 50 µg/day
In this example,
F1 = 1 study in humans
F2 = 10 to account for differences between individual humans
F3 = 10 because the duration of the study was only 3 weeks
F4 = 1 because no severe toxicity was encountered
F5 = 10 because a LOAEL was used
Guideline for Elemental Impurities
Table A.1.1: Values Used in the Calculations in this Document
Rat body weight 425 g Mouse respiratory volume 43 L/day
Pregnant rat body weight 330 g Rabbit respiratory volume 1440 L/day
Mouse body weight 28 g Guinea pig respiratory volume 430 L/day
Pregnant mouse body
weight
30 g Human respiratory volume 28,800 L/day
Guinea pig body weight 500 g Dog respiratory volume 9,000 L/day
Rhesus monkey body weight 2.5 kg Monkey respiratory volume 1,150 L/day
Rabbit body weight
(pregnant or not)
4 kg Mouse water consumption 5 mL/day
Beagle dog body weight 11.5 kg Rat water consumption 30 mL/day
Rat respiratory volume 290 L/day Rat food consumption 30 g/day
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23
Appendix 2: Established PDEs for Elemental Impurities
Table A.2.1: Permitted Daily Exposures for Elemental Impurities1
Element Class2 Oral PDE
µg/day
Parenteral
PDE, µg/day
Inhalation
PDE, µg/day
As 1 15 15 1.9
Cd 1 5.0 6.0 3.4
Hg 1 40 4.0 1.2
Pb 1 5.0 5.0 5.0
Co 2A 50 5.0 2.9
Mo 2A 180 180 7.6
Se 2A 170 85 140
V 2A 120 12 1.2
Ag 2B 170 35 6.9
Au 2B 130 130 1.3
Ir3 2B 1000 10 1.4
Os3 2B 1000 10 1.4
Pd 2B 100 10 1.0
Pt 2B 1000 10 1.4
Rh3 2B 1000 10 1.4
Ru3 2B 1000 10 1.4
Tl 2B 8.0 8.0 69
Ba 3 13000 1300 340
Cr 3 11000 1100 2.9
Cu 3 1300 130 13
Li 3 780 390 25
Ni 3 600 60 6.0
Sb 3 1200 600 22
Sn 3 6400 640 64
1 PDEs reported in this table are rounded to 2 significant figures (µg/day).
2 Classification as defined in Section 4.
3 Insufficient data to establish an appropriate PDE; the PDE was established based on
platinum PDE.
Table A.2.2: Permitted Concentrations of Elemental Impurities for Option 1
The values presented in this table represent permitted concentrations in micrograms per
gram for elemental impurities in drug products, drug substances and excipients. These
concentration limits are intended to be used when Option 1 is selected to assess the
elemental impurity content in drug products with daily doses of not more than 10 grams
per day. The numbers in this table are based on Table A.2.1.
Element Class Oral Concentration
µg/g
Parenteral
Concentration
µg/g
Inhalation
Concentration
µg/g
As 1 1.5 1.5 0.29
Cd 1 0.50 0.60 0.34
Hg 1 4.0 0.40 0.12
Pb 1 0.50 0.50 0.50
Co 2A 5.0 0.50 0.29
Guideline for Elemental Impurities
Mo 2A 18 18 0.76
Se 2A 17 8.5 14
V 2A 12 1.2 0.12
Ag 2B 17 3.5 0.69
Au 2B 13 13 0.13
Ir** 2B 100 1.0 0.14
Os** 2B 100 1.0 0.14
Pd 2B 10 1.0 0.10
Pt 2B 100 1.0 0.14
Rh** 2B 100 1.0 0.14
Ru** 2B 100 1.0 0.14
Tl 2B 0.80 0.80 6.9
Ba 3 1300 130 34
Cr 3 1100 110 0.29
Cu 3 130 13 1.3
Li 3 78 39 2.5
Ni 3 60 6.0 0.60
Sb 3 120 60 2.2
Sn 3 640 64 6.4
** Insufficient data to establish an appropriate PDE; the PDE was established based on
platinum PDE
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Appendix 3: Individual Safety Assessments
ANTIMONY
Summary of PDE for Antimony
Antimony (Sb)
Oral Parenteral Inhalation
PDE (µg/day) 1200 600 22
Introduction
Antimony (Sb) is a silvery white naturally occurring metalloid element that is used in
various manufacturing processes. Small amounts of Sb are found in the earth's crust. It
exists in valence states of 3 and 5. Metallic Sb and a few trivalent Sb compounds are the
most significant regarding exposure potential and toxicity. Some antimonials, such as Sb
potassium tartrate, have been used medicinally as parasiticides. Antimony trioxide is
being used as a catalyst (e.g., in the manufacturing of PolyEthylene Terephthalate [PET]
used for container closure system components). Antimony is nutritionally not essential
and no metabolic function is known (ATSDR, 1992).
Safety Limiting Toxicity
Because of the limited in vitro genotoxicity data and the lack of in vivo tests, the
genotoxicity of Sb cannot be determined (ATSDR, 1992). In humans and animals, the
gastrointestinal tract (irritation, diarrhea, vomiting) appears to be the primary target
organ after oral exposure. In subchronic studies in rats lower mean body weights and
adverse liver findings were the most sensitive endpoints. Inhalation of high levels of Sb
over a long period can cause adverse respiratory effects in both humans and animals.
PDE – Oral Exposure
Limited oral data on Sb exposure is available in mice and rats (Schroeder et al. 1968;
Schroeder et al. 1970; Poon et al. 1998). The WHO evaluated Sb in drinking water (WHO,
2003). Lynch et al. concluded that a NOAEL from a 90 day drinking water rat study
using antimony potassium tartrate was 6 mg/kg/day based on lower mean body weight
and reduced food consumption (Lynch, 1999). This finding is consistent with the earlier
reports from Schroeder et al. Thus, the Permitted Daily Exposure (PDE) for oral
exposure was determined on the basis of the lowest NOAEL, i.e., 50 mg/L (equivalent to
6.0 mg Sb/kg/day).
Taking into account the modifying factors (F1-F5 as discussed in Appendix 1), the oral
PDE is calculated as below:
PDE = 6000 µg/kg/day x 50 kg / 5 x 10 x 5 x 1 x 1 = 1200 µg/day.
PDE – Parenteral Exposure
Adverse liver findings were the most sensitive endpoint in rats after repeated
intraperitoneal administration. Thus, the PDE for intraperitoneal exposure was
determined on the basis of the lowest NOAEL, i.e., 3.0 mg Sb/kg/day. This value was
obtained from a 90-day study in rats (based on adverse liver findings at 6 mg/kg in male
rats exposed to Sb potassium tartrate via intraperitoneal injection) (NTP, 1992).
Taking into account the modifying factors (F1-F5 as discussed in Appendix 1), the
human intraperitoneal PDE is calculated as below:
Guideline for Elemental Impurities
PDE = 3000 µg/kg/day x 50 kg / 5 x 10 x 5 x 1 x 1 = 600 µg/day.
PDE – Inhalation Exposure
Sub chronic and chronic inhalation rat studies have been conducted. The lung effects
observed across these studies were consistent. Using the data from a 13 week inhalation
rat study using antimony trioxide dust, (Newton et al. 1994), a NOAEL of 1.08 mg/m3
was used to determine the inhalation PDE (~83% Sb). At higher dose levels an increase
in mean absolute and relative lung weights were observed, a finding not seen in the one
year oncogenicity study.
Taking into account the modifying factors (F1-F5 as discussed in Appendix 1), the
inhalation PDE is calculated as:
For continuous dosing = 0.9 mg/m3 x 6 h x 5 d = 0.16 mg/m3 = 0.00016 mg/L
24 h x 7 d 1000 L/m3
Daily dose = 0.00016 mg/L x 290 L/d = 0.11 mg/kg/d
.425 kg bw
PDE = 0.11 mg/kg/d x 50 kg / 5 x 10 x 5 x 1 x 1 = 22 µg/d.
REFERENCES
ATSDR. Toxicological profile for antimony and compounds. Agency for Toxic Substances
and Disease Registry, Public Health Service, U.S. Department of Health and Human
Services, Atlanta, GA. 1992.
Lynch BS, Capen CC, Nestmann ER, Veenstra G, Deyo JA. Review of subchronic/chronic
toxicity of antimony potassium tartrate. Reg Toxicol Pharmacol 1999;30(1):9-17.
Newton PE, Bolte HF, Daly IW, Pillsbury BD, Terrill JB, Drew RT, et al. Subchronic
and chronic inhalation toxicity of antimony trioxide in the rat. Fundam Appl Toxicol
1994;22:561-76.
NTP. Technical report on toxicity studies of antimony potassium tartrate in F344/N rats
and B6C3F1 mice (drinking water and intraperitoneal injection studies). National
Toxicology Program, Public Health Service, U.S. Department of Health and Human
Services, Research Triangle Park, NC. 1992; NTP Toxicity Report Series No. 11.
Poon R, Chu I, Lecavalier P, Valli VE, Foster W, Gupta S, et al. Effects of antimony on
rats following 90-day exposure via drinking water. Food Chem Toxicol 1998;36:20–35.
Schroeder HA, Mitchner M, Nasor AP, Balassa JJ, Kanisawa M. Zirconium, niobium,
antimony and fluorine in mice: effects on growth, survival and tissue levels. J Nutr
1968;95:95-101.
Schroeder HA, Mitchner M, Nasor AP. Zirconium, niobium, antimony, vanadium and
lead in rats: life term studies. J. Nutr 1970;100(1):59-68.
WHO. Antimony in drinking-water. Background document for development of WHO
guidelines for drinking-water quality. World Health Organization, Geneva. 2003.
26
Guideline for Elemental Impurities
27
ARSENIC
Summary of PDE for Arsenic
Arsenic (As)
Oral Parenteral Inhalation
PDE (µg/day) 15 15 1.9
Introduction
Arsenic (As) is ubiquitous in the environment and present in food, soil, drinking water
and in air. Inorganic As occurs in trivalent (e.g., arsenic trioxide, sodium arsenite) or
pentavalent forms (e.g., sodium arsenate, arsenic pentoxide, arsenic acid). Arsenic has no
known useful biological function in human or mammalian organisms. This assessment
focuses on inorganic As, since this is most relevant for drug products.
Safety Limiting Toxicity
Inorganic arsenic has shown to be genotoxic, but not mutagenic and has been
acknowledged as a human carcinogen (Group 1; IARC, 2012).
Due to its ubiquitous nature and toxicity profile, there have been many risk assessments
conducted of arsenic and arsenic compounds, which utilize non-threshold, linear dose
response approaches (Meharg and Raab, 2010).
The effects of arsenic in humans for the most part have not been reproduced in animals,
so the risk assessments have to rely heavily upon epidemiology data in populations with
high exposure concentrations (Schuhmacher-Wolz et al. 2009). In humans, both cancer
and non-cancer effects have been linked to arsenic exposure. Oral exposure has been
linked to cancers of the skin, liver, lung, kidney and bladder. Following inhalation
exposure there is evidence for an increased risk of lung cancer (ATSDR, 2007; IARC,
2012; EU EFSA, 2009; WHO, 2011; US EPA, 2010).
The skin (dyspigmentation, palmoplantar keratosis) and gastrointestinal tract (e.g.,
nausea) appear to be the most sensitive targets for non-cancer adverse effects after oral
ingestion while vascular disease, reproductive effects and neurological effects are also
reported as non-cancer endpoints (IARC, 2012; Schuhmacher-Wolz et al. 2009; US EPA,
2007). Oral exposure studies suggest that skin lesions may appear at levels above 0.02
mg As/kg/day; no effects were generally seen at levels from 0.0004 to 0.01 mg As/kg/day
(ATSDR, 2007). There are insufficient epidemiological data to set a LOEL or NOEL for
other endpoints. The regions of hyperkeratosis may evolve into skin cancers (ATSDR,
2007) and can possibly be considered predictive of skin and internal cancers and the non-
cancer long-term adverse health effects (Chen et al. 2005; Hsu et al. 2013; Ahsan and
Steinmaus, 2013).
Studies of large populations (~40,000) exposed to arsenic concentrations in well water at
1000 µg/L and higher in southwestern Chinese Taipei have been the basis of risk
assessments of skin cancer, and more recently of bladder and lung cancer (US EPA,
2010). Recent meta-analyses of cancer risk have indicated no additional bladder cancer
risk at low dose exposure (<100–200 µg/L) (Chu and Crawford-Brown, 2006, 2007; Mink
et al. 2008). This is consistent with the work of Schuhmacher-Wolz et al. (2009).
The inhalation unit risk for cancer is 0.0043 per µg/m3 has been established by the US
EPA based on data from two US smelters
(US EPA, 2007). The Texas Commission on
Environmental Quality provided an update to the US EPA Unit Risk Factor (URF),
incorporating additional years of follow-up to the US EPA data and additional data on
Guideline for Elemental Impurities
workers from the United Kingdom and Sweden, and calculated a URF of 0.0015 per
µg/m3. This URF translates to an air concentration of 0.067 µg/m3 at a risk of 1 in
100,000 excess lung cancer mortality (Erraguntla et al. 2012).
PDE – Oral Exposure
The oral PDE is based on the chronic effects of As to skin and sets the limit at 15 µg/day
based on ATSDR Minimal Risk Level (MRL) and US EPA limit of 0.0003 mg/kg/day
(ATSDR, 2007; US EPA 2007; EU EFSA, 2009). The PDE calculated based on the
ATSDR MRL is consistent with drinking water standards (WHO, 2011).
0.0003 mg/kg/day x 50 kg human = 0.015 mg/day = 15 µg/day.
No modifying factors were applied because they are incorporated into the derivation of
the MRL.
PDE – Parenteral Exposure
The oral bioavailability of As is ~95%. The most direct evidence is from a study that
evaluated the 6-day elimination of arsenic in healthy humans who were given water
from a high-arsenic sampling site (arsenic species not specified) and that reported
approximately 95% absorption (Zheng et al. 2002). Therefore the PDE is identical to the
oral PDE.
PDE = 15 µg/day.
PDE – Inhalation Exposure
Increased risk of lung cancer and other respiratory disorders have been reported
following inhalation exposure to workers in the occupational setting. The rationale for
using a cancer endpoint for inhalation to set the PDE is the relative lack of information
on linear-dose extrapolation, as compared to the oral route. No modifying factors are
needed as the URF were determined for the protection of the general public. Based on
the assessment conducted by Erraguntla et al. (2012), based on the risk of 1:100.000, the
inhalation PDE is:
0.067 µg/m3 ÷ 1000 L/m3 x 28800 L/d = 1.9 µg/d.
No modifying factors were applied because the PDE is based on the multiplicate relative
risk model described by Erraguntla et al. (2012).
REFERENCES
Ahsan H, Steinmaus C. Invited commentary: use of arsenical skin lesions to predict risk
of internal cancer-implications for prevention and future research. Am J Epidemiol
2013;177:213-16.
ATSDR. Toxicological profile for arsenic. Agency for Toxic Substances and Disease
Registry, Public Health Service, U.S. Department of Health and Human Services,
Atlanta, GA. 2007.
Chen CJ, Hsu LI, Wang CH, Shih WL, Hsu YH, Tseng MP, et al. Biomarkers of exposure,
effect, and susceptibility of arsenic-induced health hazards in Taiwan. Toxicol Appl
Pharmacol 2005; 206:198-206.
Chu HA, Crawford-Brown DJ. Inorganic arsenic in drinking water and bladder cancer: a
metaanalysis for dose-response assessment. Int J Environ Res Public Health 2006;3:316-
22.
28
Guideline for Elemental Impurities
29
Chu HA, Crawford-Brown DJ. Inorganic arsenic in drinking water and bladder cancer: a
metaanalysis for dose-response assessment. Int J Environ Res Public Health 2007;4:340-
41.
Erraguntla NK, Sielken RL Jr, Valdez-Flores C, Grant RL. An updated inhalation unit
risk factor for arsenic and inorganic arsenic compounds based on a combined analysis of
epidemiology studies. Regul Toxicol Pharmacol 2012;64: 329-41.
EU EFSA. Scientific opinion on arsenic in food. European Food Safety Authority. EFSA
Journal 2009;7(10):1351.
Hsu LI, Chen GS, Lee CH, Yang TY, Chen YH, Wang YH, et al. Use of arsenic-induced
palmoplantar hyperkeratosis and skin cancers to predict risk of subsequent internal
malignancy. Am J Epidemiol 2013;173:202-12.
IARC. Arsenic, metals, fibres, and dusts: a review of human carcinogens. Monographs on
the Evaluation of Carcinogenic Risks to Humans. International Agency for Research on
Cancer, World Health Organization, Lyon. 2012;100C.
Meharg AA, Raab A. Getting to the bottom of arsenic standards and guidelines. Environ
Sci Technol 2010;44:4395-99.
Mink PJ, Alexander DD, Barraj LM, Kelsh MA, Tsuji JS. Low-level arsenic exposure in
drinking water and bladder cancer: a review and meta-analysis. Regul Toxicol
Pharmacol 2008;58:299-310.
Schuhmacher-Wolz U, Dieter HH, Klein D, Schneider K. Oral exposure to inorganic
arsenic: and evaluation of its carcinogenic and non-carcinogenic effects. Crit Rev Toxicol
2009;39:271-98.
US EPA. Arsenic, inorganic. Integrated Risk Information System (IRIS). 1998.
US EPA. Inorganic arsenic. TEACH Chemical Summary. 2007.
US EPA. Toxicological review of inorganic arsenic (CAS No. 7440-38-2). In support of
summary information on the Integrated Risk Information System (IRIS). 2010.
WHO. Arsenic in drinking-water. Background document of development of WHO
Guidelines for Drinking-water quality. World Health Organization. 2011.
Zheng Y, Wu J, Ng JC, Wang G, Lian W. The absorption and excretion of fluoride and
arsenic in humans. Toxicol Lett 2002;133:77-82.
Guideline for Elemental Impurities
BARIUM
Summary of PDE for Barium
Barium (Ba)
Oral Parenteral Inhalation
PDE (µg/day) 13000 1300 340
Introduction
Barium (Ba) is a dense, silver-white, soft alkaline earth metal that oxidizes readily in
moist air and reacts with water. The Ba2+ ion and the water soluble compounds of Ba
(chloride, nitrate, hydroxide) are toxic. The insoluble compounds of barium, such as
barium sulfate, do not generate free Ba2+ ions in the gastrointestinal tract and therefore
are generally nontoxic to humans. Ba is nutritionally not essential and no metabolic
function is known. Barium sulfate is used as a support for catalyst (e.g., Pd).
Safety Limiting Toxicity
In animals and humans, the kidney appears to be the most sensitive target of toxicity
resulting from repeated ingestion of soluble Ba salts. Chronic rodent studies support the
evidence for an association between Ba exposure and renal toxicity. In humans, repeated
exposure to Ba oxide via inhalation may cause bronchitis, including cough, phlegm,
and/or shortness of breath.
PDE – Oral Exposure
Mice and rat Ba drinking water studies have been conducted (NTP, 1994). Based on the
review of these data, the mouse was determined to be the more sensitive species. The 2-
year drinking water study in mice with barium chloride dihydrate was selected as the
principal study and compound-related nephropathy was identified as the critical effect
for deriving a PDE for Ba and its soluble salts. The lesions were characterized by tubule
dilatation, renal tubule atrophy, tubule cell regeneration, hyaline cast formation,
multifocal interstitial fibrosis, and the presence of crystals, primarily in the lumen of the
renal tubules. These changes were characterized as morphologically distinct from the
spontaneous degenerative renal lesions commonly observed in aging mice.
The oral PDE was determined on the basis of the NOAEL of 500 mg/L (equivalent to 30
mg Ba/kg/day), using the modifying factors (F1-F5 as discussed in Appendix 1).
PDE = 30 mg/kg/day x 50 kg / 12 x 10 x 1 x 1 x 1 = 12.5 mg/day ~13.000 µg/day.
PDE – Parenteral Exposure
No relevant data on parenteral exposure to barium compounds were found. The
bioavailability of Ba is estimated to be 20 – 60% in adults and infants, respectively
(ATSDR, 2007). Thus, a modifying factor of 10 of the oral PDE was used.
PDE = 13.000 µg/day/ 10 = 1300 µg/day.
PDE – Inhalation Exposure
No relevant data on inhalation exposure to barium compounds were found. US DoL
(2013) has a reported TWA of 0.5 mg/m3 based on soluble Ba salts.
Taking into account the modifying factors (F1-F5 as discussed in Appendix 1), the
inhalation PDE is calculated as:
30
Guideline for Elemental Impurities
31
For continuous dosing = 500 µg/ m3 x 8 hr/day x 5 days/week
24 hr/day x 7 days/week X 1000 L/m3
= 0.119 µg/L
Daily dose = 0.119 µg/L x 28800 L = 68.6 µg/kg
50 kg
PDE = 68.6 µg/kg x 50 kg = 343 µg/day ~340 µg/day.
1 x 10 x 1 x 1 x 1
REFERENCES
ATSDR. Toxicological profile for barium and barium compounds. Agency for Toxic
Substances and Disease Registry, Public Health Service, U.S. Department of Health and
Human Services, Atlanta, GA. 2007.
NTP. Technical report on the toxicology and carcinogenesis studies of barium chloride
dihydrate (CAS No. 10326-27-9) in F344/N rats and B6C3F1 mice (drinking water
studies). National Toxicology Program, Public Health Service, U.S. Department of
Health and Human Services, Research Triangle Park, NC. 1994;NTP TR 432.
US DoL (OHSA). 29 CRF 1910.1000 Table Z-1. Limits for air contaminants. U.S.
Department of Labor. 2013.
Guideline for Elemental Impurities
CADMIUM
Summary of PDE for Cadmium
Cadmium (Cd)
Oral Parenteral Inhalation
PDE (µg/day) 5.0 6.0 3.4
Introduction
Cadmium (Cd) is a transition metal whose most abundant naturally-occurring isotope is
non-radioactive. It is found in nature in mineral forms and is obtained for commercial
uses principally from cadmium ore (ATSDR, 2012). Cadmium exists as a salt form in the
+2 oxidation state only. Some cadmium salts are water soluble such as cadmium chloride,
cadmium sulfate and cadmium nitrate; other insoluble salts can become more soluble by
interaction with acids, light or oxygen. Cadmium, cadmium oxide, cadmium salts on
borosilicate carrier are used as catalysts in organic synthesis. Silver cadmium alloy is
used in the selective hydrogenation of carbonyl compounds.
Safety Limiting Toxicity
Cadmium has shown to be genotoxic, but not mutagenic and has been acknowledged as a
human carcinogen (Group 1; IARC, 2012). Cadmium and cadmium compounds cause
cancer of the lung. Also, positive associations have been observed between exposure to
cadmium and cadmium compounds and cancer of the kidney and of the prostate.
A sensitive endpoint for oral exposure to cadmium and cadmium salts is renal toxicity
(Buchet et al. 1990). Skeletal and renal effects are observed at similar exposure levels
and are a sensitive marker of cadmium exposure (ATSDR, 2012).
Evidence from numerous epidemiologic studies assessing inhalation exposures to
cadmium via both occupational and environmental routes has demonstrated an
increased risk of developing cancer (primarily lung) that correlates with inhalation
exposure to cadmium (IARC, 2012; NTP, 2004).
PDE – Oral Exposure
A sensitive endpoint for oral exposure to cadmium and cadmium salts is renal toxicity
(Buchet et al. 1990). Skeletal and renal effects are observed at similar exposure levels
and are a sensitive marker of cadmium exposure (ATSDR, 2012). A number of oral
exposure studies of cadmium in rats and mice showed no evidence of carcinogenicity.
Therefore the renal toxicity endpoint was used to establish the oral PDE for cadmium,
following the recommendations of ATSDR, a level of 0.1 µg/kg for chronic exposure is
used to set the oral PDE. This is in line with the WHO drinking water limit of 0.003
mg/L/day (WHO 2011).
Taking into account the modifying factors (F1-F5 as discussed in Appendix 1), the oral
PDE is calculated as:
PDE = 0.1 µg/kg/day x 50 kg = 5.0 µg/day.
32
Guideline for Elemental Impurities
33
PDE – Parenteral Exposure
12 week study in rats given daily subcutaneous injections of 0.6 mg/kg Cd, 5 days per
week showed renal damage at week 7 and later (Prozialeck, 2009). The LOAEL of this
study is 0.6 mg/kg.
Taking into account the modifying factors (F1-F5 as discussed in Appendix 1), the
parenteral PDE is calculated as:
PDE = 0.6 mg/kg/day x 50 kg / 5 x 10 x 5 x 10 x 2 = 6.0 µg/day.
F4 was chosen as 10 because cadmium is carcinogenic by the inhalation route. F5 was
set at 2, since no NOAEL was identified in this study.
PDE – Inhalation Exposure
The use of 5 µg/m3 as the PEL (US DoL, 2013) was considered acceptable as cadmium is
non-mutagenic. This PDE is similar to the quantitative estimate of carcinogenic risk
from inhalation exposure to cadmium (1:10.000 risk, US EPA, 1992; EU SCOEL, 2010).
Taking into account the modifying factors (F1-F5 as discussed in Appendix 1), the
inhalation PDE is calculated as:
For continuous dosing = 5 µg/m3 ÷1000 L/m3 = 0.005 µg/L
0.005 µg/L x 8 hours x 5 days ÷ 24 hours x 7 days = 0.0012 µg/L
Daily Dose = 0.0012 µg/L x 28800 L/day ÷ 50 kg = 0.69 µg/kg
PDE = 0.69 µg/kg x 50 kg / 1 x 10 x 1 x 1 x 1 = 3.4 µg/day.
A modifying factor F2 of 10 was applied to cover the full population with the data coming
from the worker population.
REFERENCES
ATSDR. Toxicological profile of cadmium. Agency for Toxic Substances and Disease
Registry, Public Health Service, U.S. Department of Health and Human Services,
Atlanta, GA. 2012.
Buchet JP, Lauwerys R, Roels H, Bernard A, Bruaux P, Claeys F, et al. Renal effects of
cadmium body burden of the general population. Lancet 1990;336:699-702.
EU SCOEL. Recommendation from the scientific committee on occupational exposure
limits for cadmium and its inorganic compounds. European Union Scientific Committee
on Occupational Exposure Limits. 2010;SCOEL/SUM/136.
IARC. Arsenic, metals, fibres, and dusts: a review of human carcinogens. Monographs on
the Evaluation of Carcinogenic Risks to Humans. International Agency for Research on
Cancer, World Health Organization, Lyon. 2012;100C.
NTP. Technical report on toxicity studies of cadmium oxide (CAS No. 1306-19-0)
administered by inhalation to F344/N Rats and B6C3F1 mice. National Toxicology
Program, Public Health Service, U.S. Department of Health and Human Services. 2004.
Prozialeck WC, Edwards JR, Vaidya VS, Bonventre JV. Preclinical evaluation of novel
urinary biomarkers of cadmium nephrotoxicity. Toxicol Appl Pharmacol 2009;238:301-
305.
US EPA. Cadmium. Integrated Risk Information System (IRIS). 1992.
US DoL (OHSA). 29 CRF 1910.1000 Table Z-1. Limits for air contaminants. U.S.
Department of Labor. 2013.
Guideline for Elemental Impurities
WHO. Cadmium in drinking water. Background document for development of WHO
Guidelines for drinking-water quality. World Health Organization.
2011;WHO/SDE/WSH/03.04/80/Rev/1.
34
Guideline for Elemental Impurities
35
CHROMIUM
Summary of PDE for Chromium
Chromium (Cr III)
Oral Parenteral Inhalation
PDE (µg/day) 11000 1100 2.9
Introduction
Chromium (Cr) is found in a variety of oxidation states, the most important being Cr 0
(in stainless steel) Cr II, III and VI. Cr II is readily oxidized and is used as a reducing
agent in chemical synthesis. Cr VI is a powerful oxidant, chromate, CrO42-, and
dichromate, Cr2O72-, being the best known oxyanions. Cr III, the most abundant
environmental form, is an essential element that plays a role in glucose metabolism.
Chromium deficiency causes changes in the metabolism of glucose and lipids and may be
associated with maturity-onset diabetes, cardiovascular diseases, and nervous system
disorders (Anderson, 1993, 1995). Sources of chromium in pharmaceuticals may include
colorants, leaching from equipment or container closure systems, and catalysts. With
the exception of use as a catalyst, intake of chromium from pharmaceuticals will be in
the form of metallic chromium (Cr 0) or Cr III rather than the more toxic Cr VI; therefore,
for drug products, this safety assessment is based on the known toxicity of Cr III and Cr
VI is excluded from this assessment. Chromium present as a colorant (e.g., chromium
oxide green, chromium hydroxide green; see 21 CFR 72) is intentionally added and thus
beyond the scope of this guidance.
Safety Limiting Toxicity
The data was reviewed to identify the safety limiting toxicities based on routes of
administration.
PDE – Oral Exposure
No specific target organ toxicities have been identified for the oral intake of
chromium. Generally oral intake of 5 mg/kg/day Cr III (US EPA, 1998) is not expected to
be associated with adverse health.
The 2 year NTP studies (2010) on the carcinogenicity of Cr (III) picolinate administered
in feed to rats and mice provided the most relevant safety information for Cr as present
in drug products. The NOAEL was 90 mg/kg Cr (III) picolinate (11.9 weight %; 10.7
mg/kg/day CrIII) in rats based on increase in the incidence of preputial gland adenoma
in male rats at 460 mg/kg. This finding was not dose-dependent and was considered an
equivocal finding by the study authors. This finding was not observed male mice or in
the female counterpart in either species (clitoral gland). In the absence of a treatment-
related carcinogenic finding, F4 was set at 1.
Taking into account the modifying factors (F1-F5 as discussed in Appendix 1), the oral
PDE is calculated as:
PDE = 10.7 mg/kg/day x 50 kg/ 5 x 10 x 1 x 1 x 1 = 10.7 mg/day ~11000 µg/day.
PDE – Parenteral Exposure
Recommendation for the nutritional intravenous administration of Chromium (III) vary
per age group between 0.05 µg/kg/day in preterm infants and 15 µg/kg in adults
(Moukazel, 2009). There is insufficient information to assess if exceeding these
Guideline for Elemental Impurities
recommended daily doses may lead to adverse responses e.g., for the kidney especially in
newborns and preterm infants.
The safety review for Cr was unable to identify any significant assessments upon which
to calculate a PDE for parenteral routes of exposure. On the basis of an oral
bioavailability of about 10% for chromium and inorganic chromium compounds (ATSDR,
2012), the recommended PDE for chromium for a parenteral exposure is:
PDE = 11000 µg/day/10 = 1100 µg/day.
PDE – Inhalation Exposure
The study by Deralenko (1999) used inhalation of Cr (III) sulfate particles during 13
weeks (6h/day and 5 days per week) causing predominantly chronic inflammation of the
airways (mononuclear infiltrate, particular material) and locally thickening of alveolar
walls. The effect was observed at all doses. The LOAEL is 17 mg/m3 (3 mg CrIII/m3). A
lack of systemic toxicity was noted in a 13 week inhalation study in rats administered
soluble or insoluble Cr (III). Based on these data the on these data, the inhalation MRL
of 0. 1µg/m3 was used to set the PDE (ATSDR, 2012).
PDE =0.0001 mg/ m3 /1000 m3/L x 28800 L/day = 2.9 µg/day.
REFERENCES
Anderson RA. Recent advances in the clinical and biochemical effects of chromium
deficiency. Prog Clin Biol Res 1993;380:221-34.
Anderson RA. Chromium and parenteral nutrition. Nutr 1995;11(1 suppl.):83-6.
ATSDR. Toxicological profile of chromium. Agency for Toxic Substances and Disease
Registry, Public Health Service, U.S. Department of Health and Human Services,
Atlanta, GA. 2012.
Derelanko MJ, Rinehart WE, Hilaski RJ, Thompson RB, Löser E. Thirteen week
subchronic rat inhalation toxicity study with a recovery phase of trivalent chromium
compounds, chromic oxide, and basic chromium sulfate. Toxicol Sci 1999;52:278-88.
Glaser U, Hochrainer D, Klöppel H, Oldiges H. Carcinogenicity of sodium dichromate
and chromium (VI/III) oxide aerosols inhaled by male Wistar rats. Toxicology. 1986;42(2-
3):219-32.
Moukarzel A. Chromium in parenteral nutrition: too little or too much. Gastroenterology
2009;137:S18-S28.
NTP. Technical report on the toxicology and carcinogenesis studies of chromium
picolinate monohydrate in F344/N rats and B6C3F1 mice. National Toxicology Program,
Public Health Service, U.S. Department of Health and Human Services. 2010;NTP TR
556.
US DoL (OHSA). 29 CRF 1910.1000 Table Z-1. Limits for air contaminants. U.S.
Department of Labor. 2013.
US EPA. Chromium (III), insoluble salts. Integrated Risk Information System (IRIS).
1998.
36
Guideline for Elemental Impurities
37
COBALT
Summary of PDE for Cobalt
Cobalt (Co)
Oral Parenteral Inhalation
PDE (µg/day) 50 5.0 2.9
Introduction
Cobalt (Co) is a naturally-occurring element, often combined with other elements such as
oxygen, sulfur, and arsenic. Co is essential in the human body because it is an integral
component of Vitamin B-12 and functions as a co-enzyme for several enzymes critical in
the synthesis of hemoglobin and the prevention of pernicious anemia. The Recommended
Dietary Allowance of vitamin B12 is 2.4 µg/day, which corresponds to 0.1 µg of Co. No
essential biological function of inorganic Co in the human body has been identified.
Cobalt compounds (e.g., cobalt octoate) are being used as catalysts in selective
hydrogenation.
Safety Limiting Toxicity
The IARC (2006) concluded that Co sulphate and other soluble Co (II) salts are possible
human carcinogens (Group 2B). The data indicate the location of tumors is limited to the
lung in rats and humans.
Polycythemia is considered to be the most sensitive finding after repeated oral exposure
to humans. Inhalation exposure of humans to Co has been associated with a severe and
progressive respiratory disease known as hard-metal pneumoconiosis, as well as asthma
and contact dermatitis.
PDE – Oral Exposure
The oral PDE is based on the available human data. Polycythemia was the most
sensitive finding in humans after repeated oral exposure to 150 mg of cobalt chloride
(~1 mg Co /kg/day). The oral PDE was determined on the basis of the LOAEL of 1
mg/kg/day in male human volunteers after oral exposure over a period of 22 days (WHO,
2006).
Taking into account the modifying factors (F1-F5 as discussed in Appendix 1), the oral
PDE is calculated as below:
PDE = 1 mg/kg/day x 50 kg / 1 x 10 x 10 x 1 x 10 = 0.05 mg/day = 50 µg/day.
PDE – Parenteral Exposure
No relevant data on parenteral exposure to cobalt compounds were found. On the basis of
the oral bioavailability ranging largely from 18-97% for cobalt and inorganic cobalt
compounds (ATSDR, 2004). Using a safety factor of 10 to account for low bioavailability,
the PDE for cobalt for parenteral exposure is:
PDE = 50 µg/day / 10 = 5.0 µg/day.
PDE – Inhalation Exposure
Co sulphate and other soluble Co (II) salts are possible human carcinogens (Group 2B)
which can induce lung tumors.
Guideline for Elemental Impurities
Pneumoconiosis, asthma and contact dermatitis were the principal non-carcinogenic
effects in humans after chronic inhalation. For the calculation of the inhalation PDE, the
chronic inhalation MRL of 0.1 microgram / m3 was used (ATSDR, 2010).
0.0001 mg/ m3 /1000 m3/L x 28800 L/day = 2.9 µg/day.
REFERENCES
ATSDR. Toxicological profile for cobalt. Agency for Toxic Substances and Disease
Registry, Public Health Service, U.S. Department of Health and Human Services,
Atlanta, GA. 2010.
IARC. Cobalt in hard metals and cobalt sulfate, gallium arsenide, indium phosphide and
vanadium pentoxide. International Agency for Research on Cancer, World Health
Organization, Lyon. 2003;86, updated in 2006.
WHO. Cobalt and inorganic cobalt compounds. Concise International Chemical
Assessment Document. Inter-Organization Programme for the Sound Management of
Chemicals (IOMC). World Health Organization. 2006;69.
38
Guideline for Elemental Impurities
39
COPPER
Summary of PDE for Copper
Copper (Cu)
Oral Parenteral Inhalation
PDE (µg/day) 1300 130 13
Introduction
Copper (Cu) is a Group 11 element of the first transition series and has two main
oxidation states, Cu I and Cu II. It is an essential trace element in both animals and
humans. Copper plays a vital role in a number of critical enzyme systems and is closely
linked with normal hematopoiesis and cellular metabolism. Copper compounds (e.g.,
copper chromite) are being used as catalysts in hydrogenolysis and decarboxylation
reactions
Safety Limiting Toxicity
A general review of relevant safety data for animals and humans indicates that copper
can produce adverse effects to the gastrointestinal tract, liver, and kidney upon ingestion
of toxic doses (Araya et al. 2003).
PDE – Oral Exposure
Studies on cupric sulfate and copper 8-quinolinolate have been conducted in mice and
rats and dogs (EHC, 1998). Rats were determined to be the more sensitive species to
effects on liver and kidney. In a 13 week study in rats the NOAEL was 17 mg/kg/day for
copper sulfate, equivalent to 6.7 mg Cu/kg/day (Hebert, 1993).
Taking into account the modifying factors (F1-F5 as discussed in Appendix 1), the oral
PDE is calculated as:
PDE = 6.7 mg/kg/day x 50 kg / 5 x 10 x 5 x 1 x 1 = 1.34 mg/day = 1340 µg/day ~1300
µg/day.
PDE – Parenteral Exposure
The safety review for copper was unable to identify any significant assessments upon
which to calculate a PDE for parenteral routes of exposure. The human gastrointestinal
system can absorb 30-40% of ingested copper from the typical diets consumed in
industrialised countries (Wapnir, 1998). On the basis of limited oral bioavailability of
30%-40% for copper and inorganic copper salts, the recommended PDE for copper for
parenteral exposure is:
PDE = 1340 µg/day / 10 = 134 µg/day ~130 µg/day.
PDE – Inhalation Exposure
The available data on the toxicity of inhaled copper were considered inadequate for
derivation of acute-, intermediate-, or chronic-duration inhalation MRLs (ATSDR, 2004).
The inhalation PDE was calculated by dividing the oral PDE by 100 (as described in
Section 3.1).
1340/100 = 13.4 µg/day ~13 µg/day.
Guideline for Elemental Impurities
REFERENCES
Araya M, Olivares M, Pizarro F, González M, Speisky H, Uauy R. Gastrointestinal
symptoms and blood indicators of copper load in apparently healthy adults undergoing
controlled copper exposure. Am J Clin Nutr 2003;77(3):646-50.
ATSDR. Profile for copper. Agency for Toxic Substances and Disease Registry, Public
Health Service, U.S. Department of Health and Human Services, Atlanta, GA. 2004
Hébert CD, Elwell MR, Travlos GS, Fitz CJ, Bucher JR. Subchronic toxicity of cupric
sulfate administered in drinking water and feed to rats and mice. Fundam Appl Toxicol
1993;21:461-75.
IPCS. Copper. Environmental Health Criteria 200. International Programme on
Chemical Safety. World Health Organization, Geneva. 1998.
Wapnir RA. Copper absorption and bioavailability. Am J Clin Nutr
1998;67(suppl):1054S-60S.
WHO. Copper – toxicological evaluation of certain food additives. WHO Food Additive
Series 17 1982. World Health Organization.
40
Guideline for Elemental Impurities
41
GOLD
Summary of PDE for Gold
Gold (Au)
Oral Parenteral Inhalation
PDE (µg/day) 130 130 1.3
Introduction
Gold (Au) exists in metallic form and in oxidation states of +1 to +5, the monovalent and
trivalent forms being the most common. Elemental gold is poorly absorbed and
consequently is not considered biologically active. Gold is being used on a carrier or in
complexes like gold chloride and L–Au+ (where L is a phosphane, phosphite, or an arsine;
Telles, 1998), as catalysts in organic synthesis. The only source for gold in drug products
comes from the use as catalyst. Gold (I) salts are used therapeutically.
Safety Limiting Toxicity
Most knowledge of gold toxicity is based on therapeutic uses of gold. Currently available
therapies are gold salts of monovalent gold (I) with a sulfur ligand (Au-S), but metallic
gold has also been studied. No toxicity was seen in 10 patients administered colloidal
metallic gold (monoatomic gold) at 30 mg/day for one week followed by 60 mg/day the
second week or the reverse schedule. The patients were continued on trial for an
additional 2 years at 30 mg/day. There was no evidence of hematologic, renal or hepatic
cytotoxicity but some improvement in clinical symptoms of rheumatoid arthritis and in
cytokine parameters were noted (Abraham and Himmel, 1997).
Long term animal data are available with Au compounds. However, these studies have
been performed with monovalent gold Au I and are not considered sufficiently relevant to
assess the potential toxicity of Au in pharmaceutical products.
Au (III) is thought to be the more toxic form and is used in catalysis, e.g., as gold
trichloride. There is only limited data on gold (III) complexes. In one study, the gold (III)
compound [Au(en)Cl2]Cl (dichloro(ethylenediamine-aurate(III) ion) caused minimal
histological changes in the kidney and liver of rats, and no renal tubular necrosis, at a
dose of 32.2 mg/kg in mice administered the compound intraperitoneally for 14 days
(Ahmed et al. 2012).
PDE – Oral Exposure
The toxicologically significant endpoint for gold exposures is renal toxicity.
Taking into account the modifying factors (F1-F5 as discussed in Appendix 1), the oral
PDE is calculated as:
PDE = 32.2 mg/kg x 50 kg / 12 x 10 x 10 x 1 x 10 = 134 µg/day ~130 µg/day.
F5 was put at 10 because the NOAEL was not established and the toxicological
assessment was not complete.
PDE – Parenteral Exposure
In humans, 50 mg intramuscular (IM) injections of gold sodium thiomalate resulted in
>95% bioavailability (Blocka, 1986). In rabbits, ~70 % of the gold sodium thiomalate was
absorbed after an IM injection of 2/mg/kg (Melethil, 1987).
Based on high bioavailability, the parenteral PDE is equivalent to the oral PDE.
Guideline for Elemental Impurities
PDE = 130 µg/day.
PDE – Inhalation Exposure
In the absence of relevant inhalation and parenteral data, a modifying factor of 100 was
applied to the oral PDE as described in Section 3.1.
PDE = 134 /100 = 1.34 µg/day ~1.3 µg/day.
REFERENCES
Abraham GE, Himmel PB. Management of rheumatoid arthritis: rationale for the use of
colloidal metallic gold. J Nutr Environ Med 1997;7:295-305.
Ahmed A, Al Tamimi DM, Isab AA, Alkhawajah AMM, Shawarby MA. Histological
changes in kidney and liver of rats due to gold (III) compound [Au(en)Cl2]Cl. PLoS ONE
2012;7(12):1-11.
Blocka KL, Paulus HE, Furst DE. Clinical pharmacokinetics of oral and injectable gold
compounds. Clin Pharmacokinet 1986;11:133-43.
Melethil S, Schoepp D. Pharmacokinetics of gold sodium thiomalate in rabbits. Pharm
Res 1987;4(4):332-6.
Telles JH, Brode S, Chabanas M. Cationic gold (I) complexes: highly efficient catalysts
for the addition of alcohols to alkynes. Angew Chem Int Ed 1998;37:1415-18.
42
Guideline for Elemental Impurities
43
LEAD
Summary of PDE for Lead
Lead (Pb)
Oral Parenteral Inhalation
PDE (µg/day) 5.0 5.0 5.0
Introduction
Lead (Pb) is the most common heavy element. It occurs in organic and inorganic forms.
The generally bivalent Pb compounds include water-soluble salts such as Pb acetate as
well as insoluble salts such as Pb oxides. Organic Pb compounds include the gasoline
additives tetramethyl- and tetraethyl-lead. Organic Pb compounds undergo fairly rapid
degradation in the atmosphere and form persistent inorganic Pb compounds in water
and soil. Pb has no known useful biological function in human or mammalian organisms
(ATSDR, 2007).
Safety Limiting Toxicity
In humans and animals, exposure to Pb may cause neurological, reproductive,
developmental, immune, cardiovascular and renal health effects. In general, sensitivity
to Pb toxicity is greater when there is exposure in utero and in children compared to
adults. A target blood level of 1-2 µg/dL was set, and using modelling programs (US EPA,
2009) that assumed 100% bioavailability and no other exposure, a PDE was obtained.
For this reason, the PDEs are the same regardless of the route of administration.
PDE – Oral Exposure
Adverse neurobehavioral effects are considered to be the most sensitive and most
relevant endpoint in humans after oral exposure. Data from epidemiological studies
show that blood Pb levels <5 µg/dL may be associated with neurobehavioral deficits in
children (NTP, 2011).
According to the US EPA model (Integrated Exposure Uptake Biokinetic (IEUBK) Model,
1994) (100% absorption, no other sources of lead), oral intake of 5 µg/day translates into
a blood level of 1-2 µg/dL for children age 0-7 years (0-82 months).
PDE = 5.0 µg/day.
PDE – Parenteral Exposure
The oral effects of Pb are based on blood levels. Therefore, the parenteral PDE is equal
to the oral PDE of 5.0 µg/day.
PDE – Inhalation Exposure
The oral effects of Pb are based on blood levels. Therefore, the inhalation PDE is equal
to the oral PDE of 5.0 µg/day.
REFERENCES
ATSDR. Toxicological profile for lead. Agency for Toxic Substances and Disease Registry,
Public Health Service, U.S. Department of Health and Human Services, Atlanta, GA.
2007.
NTP. Monograph on health effects of low-level lead. National Toxicology Program, U.S.
Department of Health and Human Services. 2011.
Guideline for Elemental Impurities
US EPA. Integrated Exposure Uptake Biokinetic (IEUBK) Model for Lead. 1994,
updated 2009.
44
Guideline for Elemental Impurities
45
LITHIUM
Summary of PDE for Lithium
Lithium (Li)
Oral Parenteral Inhalation
PDE (µg/day) 780 390 25
Introduction
Lithium (Li) is a common metal that is present in plant and animal tissues. Lithium is
used as a therapeutic agent to treat bipolar disease. Lithium is being used alone or in
combination with other metals as catalyst. Lithium compounds (e.g., lithium aluminum
hydride) are being used as reagents in organic synthesis.
Lithium exists commonly as a salt in the +1 form oxidation state only.
Safety Limiting Toxicity
The data was reviewed to identify the safety limiting toxicities based on routes of
administration.
PDE – Oral Exposure
There is a minimal amount of data on the effects of lithium carbonate on the immune
system. A 14 day mouse study was conducted to assess the effects of lithium carbonate
on the immune system (NTP, 1986). Doses were modified to 100, 300 and 400 mg/kg in
repeat and later studies because of a lack of effect at 50 and 200 mg/kg. Findings
included dose-dependent effects on decreased in liver and thymus weight, and changes in
leukocytes and red blood cells and associated parameters.
Using 200 mg/kg/day (18.7 mg Li/kg/day) as the NOAEL and modifying factors (F1-F5 as
discussed in Appendix 1), the PDE is:
PDE = 18.7 mg/kg/day x 50 kg/ 12 x 10 x 10 x 1 x 1 = 0.78 mg/day = 780 µg/day.
PDE – Parenteral Exposure
There are no adequate data to develop a parenteral PDE. However, based on oral
bioavailability of 85% (Grandjean, 2009) and using a modifying factor of 2, the parenteral
PDE is calculated as:
PDE = 0.77 mg/day / 2 = 0.39 mg/day =390 µg/day.
PDE – Inhalation Exposure
Rabbits were exposed to lithium chloride at 0.6 and1.9 mg/m3 for 4-8 weeks, 5 days/week
for 6 hours/d (Johansson et al. 1988). Lungs were studied by light and electron
microscopy with focus on inflammatory changes. No significant effects were reported, so
the highest dose was used to set the PDE.
Taking into account the modifying factors (F1-F5 as discussed in Appendix 1), the oral
PDE is calculated as:
For continuous dosing: PDE = 1.9 mg/m3 /1000 L/m3 = .0019 mg/L
0.0019 mg/L x 6 h/day x 5 days / 24h/day x 7days = 0.000339 mg/L
Daily dose: 0.339 µg/L x 1440 L/day/4 kg = 122.04 µg/kg/day
PDE = 122.04 µg/kg/day x 50kg /2.5x10x10x1x1 = 25 µg/day.
Guideline for Elemental Impurities
REFERENCES
Grandjean EM, Aubry JM. Lithium: updated human knowledge using an evidence-based
approach. Part II: Clinical pharmacology and therapeutic monitoring. CNS Drugs
2009;23(4):331-49.
Johansson A, Camner P, Curstedt T, Jarstrand C, Robertson B, Urban T. Rabbit lung
after inhalation of lithium chloride. J Appl Toxicol 1988;8:373-5.
NTP. Immunotoxicity of lithium carbonate in female B6C3F1 mice (CAS No. 554-13-2).
National Toxicology Program, U.S. Department of Health and Human Services.
1986;NTP Report Number IMM85001.
46
Guideline for Elemental Impurities
47
MERCURY
Summary of PDE for Mercury
Mercury (Hg)
Oral Parenteral Inhalation
PDE (µg/day) 40 4.0 1.2
Introduction
Mercury (Hg) is an element widely existing in the global environment. Hg exists in three
forms: elemental mercury, inorganic mercury and organic mercury. The most likely form
of residual mercury in drug products is the inorganic form. Therefore, this safety
assessment is based on the relevant toxicological data of elemental or inorganic Hg. This
safety assessment and derived PDEs do not apply to organic mercury.
Safety Limiting Toxicity
There is no data to indicate that inorganic mercury is carcinogenic in human. There is
limited evidence in experimental animals for the carcinogenicity of mercuric chloride.
IARC concluded that inorganic mercury compounds are not classifiable as to their
carcinogenicity to humans (Group 3; IARC, 1997).
Inorganic mercury compounds show significantly lower oral bioavailability compared to
organic mercury and induce different toxicological effects including neurological,
corrosive, hematopoietic, renal effects and cutaneous disease (acrodynia). The safety
limiting toxicity for inorganic mercury and salts is renal toxicity.
PDE – Oral Exposure
There were well organized NTP studies of HgCl2 up to 2 years. The 6 month gavage
study in rats was selected because it had more detailed clinical pathology assessment
and wider range of doses than the 2 year study. Based on adverse renal effects from the
6-months rat study (NTP, 1993), the LOAEL was 0.23 mg/kg/day for mercury (0.16
mg/kg day for mercury when corrected for 7 days of exposure/week).
Using the modifying factors (F1-F5 as discussed in Appendix 1) the oral PDE is
calculated as:
PDE = 0.16 mg/kg /day x 50 kg / 5 x 10 x 2 x 1 x 2 = 0.04 mg/day = 40 µg/day.
F5 was set to 2, because no NOAEL was identified in the study and the effect at the
LOAEL was a slight increase in incidence of an effect also present in the control animals.
PDE – Parenteral Exposure
Animal studies indicate that the oral bioavailability of inorganic mercury is in the 10-
30% range (ATSDR, 1999). Therefore, the oral PDE is divided by a factor of 10 (as
described in Section 3.1).
PDE = 40/10 = 4.0 µg/day.
PDE – Inhalation Exposure
Neurobehavioral effects are considered to be the most sensitive endpoint following
inhalation exposure in humans as shown in occupational studies at the range of air TWA
levels between 14 and 20 µg/m3 (US EPA, 1995; EU SCOEL, 2007).
Guideline for Elemental Impurities
The presence of neurobehavioral effects at low-level mercury exposures (14 µg/m3) in
dentists (Ngim et al. 1992) indicates that the TWA needs to be considered as a LOAEL.
Taking into account the modifying factors (F1-F5 as discussed in Appendix 1), the
inhalation PDE is calculated based on the long-term inhalation exposure to elemental
mercury vapor:
For continuous dosing = 14 µg/m3 x 8 hr/day x 6 days/week
24 hr/day x 7 days/week x 1000 L/m3
= 0.004 µg/L
Daily dose = 0.004 µg/L x 28800 L = 2.30 µg/kg
50 kg
PDE = 2.30 µg/kg x 50 kg = 1.2 µg/day.
1 x 10 x 1 x 1 x 10
REFERENCES
ATSDR. Toxicological profile for mercury. Agency for Toxic Substances and Disease
Registry, Public Health Service, U.S. Department of Health and Human Services,
Atlanta, GA. 1999.
EU SCOEL. Recommendation from the scientific committee on occupational exposure
limits for elemental mercury and inorganic divalent mercury compounds. European
Union Scientific Committee on Occupational Exposure Limits. 2007;SCOEL/SUM/84.
IARC. Beryllium, cadmium, mercury, and exposures in the glass manufacturing industry.
Monographs on the Evaluation of Carcinogenic Risks to Humans. International Agency
for Research on Cancer, World Health Organization, Lyon. 1993;58, updated in 1997.
Ngim CH, Foo SC, Boey KW, and Jeyaratnam J. Chronic neurobehavioural effects of
elemental mercury in dentists. Br J Ind Med 1992;49(11):782-90.
NTP. Technical report on the toxicology and carcinogenesis studies of mercuric chloride
(CAS No. 7487-94-7) in F344 rats and B6C3F1 mice (gavage studies). National
Toxicology Program, Public Health Service, U.S. Department of Health and Human
Services, Research Triangle Park, NC. 1993;NTP TR 408.
US EPA. Mercuric chloride (HgCl2). Integrated Risk Information System (IRIS). 1995.
WHO. Elemental mercury and inorganic mercury compounds: human health aspects.
Concise International Chemical Assessment Document 50. International Programme on
Chemical Safety (IPCS). World Health Organization. 2003.
48
Guideline for Elemental Impurities
49
MOLYBDENUM
Summary of PDE for Molybdenum
Molybdenum (Mo)
Oral Parenteral Inhalation
PDE (µg/day) 180 180 7.6
Introduction
The main oxidation states for Mo are IV and VI, the most common forms of which are
oxyanions. The predominant form of Mo occurring in soils and natural waters is the
molybdate ion, MoO42- which forms soluble compounds with a variety of cations including
K+, NH4 + and Ca2+. Mo exists in soil in various forms at concentration of 0.1-10 mg/kg.
MoO2 and MoS2 are insoluble in water. It is widely present in vegetables, dairy products
and meats. Mo combinations (e.g., Bi-Mo, Fe-Mo, molybdenum oxide and Mo-complexes)
are being used as catalysts in organic synthesis.
Mo deficiency is characterized by night blindness, nausea, disorientation, coma,
tachycardia, tachypnea and associated with various biochemical abnormalities including
high plasma methionine. In addition an almost undetectable serum uric acid
concentration has been reported in a patient receiving total parenteral nutrition
(Abumrad et al. 1981).
Safety Limiting Toxicity
Molybdenum as the trioxide was not mutagenic (NTP, 1997). Carcinogenicity has not
been evaluated by IARC or US EPA.
Alteration of estrus cycle is the most sensitive effect observed in the various rat studies.
Absorption and retention of Mo is markedly influenced by interactions with dietary Cu
and sulfate and the typical symptoms from excessive Mo intake were similar to those of
copper deficiency including weight loss, growth retardation, anorexia, anemia, diarrhea,
achromotrichia, testicular degeneration, poor conception, deficient lactation, dyspnea,
incoordination and irritation of mucous membranes (Engel et al. 1956).
PDE – Oral Exposure
Fungwe et al. (1990) examined the effects on fertility and reproductive performance of
sodium molybdenate in female rats given drinking water containing 0, 5, 10, 50 or 100
mg Mo/L. After 6 weeks the effect of Mo on the estrous cycle (3 cycles) and vaginal
cytology was determined, and some animals then mated to untreated males. Pregnant
dams continued to be dosed to day 21 of gestation with Mo and fetal effects determined.
Effects on the estrous cycle, gestational weight gain, and the fetus were observed at 10
mg/L and higher; thus, a dose level of 5 mg/L can be considered a NOAEL. Vyskocil and
Viau (1999) calculated this NOAEL to be 0.9 mg Mo/kg/day.
Using modifying factors (F1-F5 as discussed in Appendix 1) the oral PDE is:
PDE = 0.9 mg/kg/day x 50 kg / 5 x 10 x 1 x 5 x 1 = 0.180 mg/day = 180 µg/day.
F4 was selected to be 5 based on the presence of fetal effects.
Guideline for Elemental Impurities
PDE – Parenteral Exposure
In Vyskocil and Viau (1999), it was reported that oral bioavailability in humans ranged
from 28-77%. Turnland et al. (2005) report that molybdenum absorption was about 90%
in healthy men. Therefore, the parenteral PDE is the same as the oral PDE.
PDE= 180 µg/day.
PDE – Inhalation Exposure
Chronic inflammation in the alveoli was seen in rat and mouse. In addition, a slight
trend for bronchiolar alveolar adenoma and carcinoma was observed in male rats
exposed to molybdenum trioxide in a 2-year inhalation study (NTP, 1997). Lung
neoplasms were not seen in female rats. In mice, bronchiolar alveolar adenoma and
carcinoma were observed at the lowest dose of 10 mg/m3 (6.7 mg/m3 of Mo).
The inhalation PDE was calculated based on the low dose in the mouse carcinogenicity
study, where findings of alveolar and bronchiolar carcinoma were observed, using the
modifying factors (F1-F5 as discussed in Appendix 1).
6.7 mg/m3 ÷1000 m3/L = 0.0067 mg/L
For continuous dosing = 0.0067 mg/L x 6 hr x 5 d = 0.0012 mg/L
24 hr x 7 d
Daily dose = 0.0012 mg/L x 43 L/d = 1.83mg/kg
0.028 kg
PDE = 1.83 mg/kg x 50 kg = 7.6 µg/day.
12 x 10 x 1 x 10 x 10
REFERENCES
Abumrad NN, Schneider AJ, Steel D, Rogers LS. Amino acid intolerance during
prolonged total parenteral nutrition reversed by molybdate therapy. Am J Clin Nutr
1981;34(11):2551-9.
Engel RW, Miller RF, Price NO. Added dietary inorganic sulfate and its effect upon rats
fed molybdenum. J Nutr 1956;60(4):539-47.
Fundwe TV, Buddingh F, Demick DS, Lox CD, Yang MT, Yang SP. The role of dietary
molybdenum on estrous activity, fertility, reproduction and molybdenum and copper
enzyme activities of female rats. Nutr Res 1990;10:515-24.
NTP. Toxicology and carcinogenesis studies of molybdenum trioxide (CAS No. 1313-27-5)
in F344 rats and B6C3F1 mice (inhalation studies). National Toxicology Program, Public
Health Service, U.S. Department of Health and Human Services. 1997.
Turnland JR, Keyes WR, Peiffer GL. Molybdenum absorption, excretion, and retention
studied with stable isotopes in young men at five intakes of dietary molybdenum. Am J
of Clin Nutr 1995;62:790-6.
Vyskocil A, Viau C. Assessment of molybdenum toxicity in humans. J Appl Toxicol.
1999;19:185-92.
50
Guideline for Elemental Impurities
51
NICKEL
Summary of PDE for Nickel
Nickel (Ni)
Oral Parenteral Inhalation
PDE (µg/day) 600 60 6.0
Introduction
Nickel (Ni) is a Group 10 element of the first transition series. Although Ni may have
valences of 0, I, II and III, its main oxidation state is +2. Ni is a naturally occurring
metal existing in various mineral forms. In general, the more soluble Ni compounds,
including Ni chloride, Ni sulfate, and Ni nitrate, tend to be more toxic than less soluble
forms, such as Ni oxide and Ni subsulfide. Ni is nutritionally not essential for humans,
but Ni deficiency may cause adverse effects in animals. Nickel as Ni-Al alloys is being
used as catalyst in hydrogenation reactions.
Safety Limiting Toxicity
Nickel is genotoxic, but not mutagenic (IARC 2012). There is no indication of
carcinogenicity of Ni salts after oral administration. Depending on the type of salt there
was an increase in tumors in some rodent inhalation studies (ATSDR, 2005; EU EFSA,
2005). Combining all forms of Ni, IARC (2012) classified Ni as a human carcinogen
(Group 1).
In humans and animals, ingestion of large amounts of Ni may cause stomach pain,
depression of body weight and adverse effects on blood and kidneys. Humans generally
become sensitised to Ni after prolonged contact with the skin. Chronic inhalation may
produce adverse changes in lung and nasal cavity in both humans and animals.
PDE – Oral Exposure
Human sensitisation to Ni was used to establish the oral PDE, because it is the most
sensitive endpoint. Human data show that an oral challenge dose of 0.012 mg Ni/kg can
induce dermatitis in nickel-sensitized individuals. Exposure to these nickel
concentrations did not result in dermatitis in non-sensitized individuals (Nielsen 1999).
Similar data were presented for 0.02 mg/kg by ATSDR (2005).
PDE = 0.012 mg/kg/day x 50 kg = 0.60 mg/day = 600 µg/day.
PDE – Parenteral Exposure
A human study using a stable nickel isotope estimated that 29–40% of the ingested label
was absorbed (based on fecal excretion data) (Patriarca et al. 1997). On the basis of
limited oral bioavailability of Ni and water-soluble Ni compound. Therefore, the oral
PDE is divided by a factor of 10 (as described in Section 3.1).
PDE = 600 µg/day / 10 = 60 µg/day.
PDE – Inhalation Exposure
For calculation of the inhalation PDE, a relevant form of Ni was selected from the
available data. In 2 year studies with nickel oxide (the form commonly used in stainless
steel coatings), no tumors were observed in hamsters (Wehner et al. 1984) or mice (NTP,
1996), but there was some evidence of carcinogenicity in rats (NTP, 2006) and no
evidence of carcinogenicity with inhalation of metallic nickel (Oller, 2008).
Guideline for Elemental Impurities
Taking into account the modifying factors (F1-F5 as discussed in Appendix 1), the
inhalation PDE is calculated based on the NOAEL in the rat study of 0.5 mg Ni/m3 /day.
For continuous dosing 0.5 mg/m3 / 1000L/m3 = 0.0005 mg/L
0.0005 mg/L x 6 hr x 5 d /24 hr x 7 d = 0.000089 mg/L
Daily dose 0.000089 mg/L x 290 L/d / 0.425 kg = 0.060 mg/kg
PDE = 0.060 mg/kg x 50 kg / 5 x 10 x 1 x 10 x 1 = 6.0 µg/day.
REFERENCES
ATSDR. Toxicological profile for nickel. Agency for Toxic Substances and Disease
Registry, Public Health Service, U.S. Department of Health and Human Services,
Atlanta, GA. 2005.
Dunnick JK, Elwell MR, Benson JM, Hobbs CH, Hahn FF, Haly PJ, et al. Lung toxicity
after 13-week inhalation exposure to nickel oxide, nickel subsulfide, or nickel sulfate
hexahydrate in F344/N rats and B6C3F1 mice. Fundam Appl Toxicol 1989;12(3):584-94.
Dunnick JK, Elwell MR, Radovsky AE, Benson JM, Hahn FF, Nikula KJ, et al.
Comparative carcinogenic effects of nickel subsulfide, nickel oxide, or nickel sulfate
hexahydrate chronic exposures in the lung. Cancer Res 1995;55(22):5251-6.
EU EFSA. Opinion of the scientific panel on dietetic products, nutrition and allergies on
a request from the Commission related to the tolerable upper intake level of nickel.
European Food Safety Authority. EFSA Journal 2005;146:1-21.
Goodman JE, Prueitt RL, Thakali S, Oller AR. The nickel ion bioavailability of the
carcinogenic potential of nickel-containing substances in the lung. Crit Rev Toxicol
2011;41:142-74.
Haney JY, McCant DD, Sielken RL, Valdez-Flores C, Grant RL. Development of a unit
risk factor for nickel and inorganic nickel compounds based on an updated
carcinogenicity toxicity assessment. Reg Toxicol Pharmacol 2012;62: 191-201.
Heim KE, Bates HK, Rush RE, Oller AR. Oral carcinogenicity study with nickel sulphate
hexahydrate in Fischer 344 rats. Toxicol Sci 2007;224:126-37.
IARC. Arsenic, metals, fibres, and dusts: a review of human carcinogens. Monographs on
the Evaluation of Carcinogenic Risks to Humans. International Agency for Research on
Cancer, World Health Organization, Lyon. 2012;100C.
Nielsen GD, Søderberg U, Jørgensen PJ, Templeton DM, Rasmussen SN, Andersen KE,
et al. Absorption and retention of nickel from drinking water in relation to food intake
and nickel sensitivity. Toxicol Appl Pharmacol 1999;154:67-75.
NTP. Report on carcinogens. National Toxicology Program, Public Health Service, U.S.
Department of Health and Human Services, Bethesda, MD. 2002.
NTP. Toxicology and carcinogenesis studies of nickel oxide. National Toxicology
Program, U.S. Department of Health and Human Services. 2006;Technical Report Series
No. 451.
Oller AR, Kirkpatrick DT, Radovsky A, Bates HK. Inhalation carcinogenicity study with
nickel metal powder in Wistar rats. Toxicol Appl Pharmacol 2008;233:262-75.
Ottolenghi AD, Haseman JK, Payne WW, Falk HL, MacFarland HN, et al. Inhalation
studies of nickel sulfide in pulmonary carcinogenesis of rats. J Natl Cancer Inst
1974;54:1165-72.
52
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http://jnci.oxfordjournals.org/search?author1=J.+K.+Haseman&sortspec=date&submit=Submit
http://jnci.oxfordjournals.org/search?author1=W.+W.+Payne&sortspec=date&submit=Submit
http://jnci.oxfordjournals.org/search?author1=H.+L.+Falk&sortspec=date&submit=Submit
http://jnci.oxfordjournals.org/search?author1=H.+N.+MacFarland&sortspec=date&submit=Submit
Guideline for Elemental Impurities
53
Patriarca M, Lyon TD, Fell GS. Nickel metabolism in humans investigated with an oral
stable isotope. Am J Clin Nutr 1997;66:616-21.
Wehner AP, Dagle GE, Busch RH. Pathogenicity of inhaled nickel compounds in
hamsters. IARC Sci Publ 1984;(53):143-51.
Guideline for Elemental Impurities
PALLADIUM
Summary of PDE for Palladium
Palladium (Pd)
Oral Parenteral Inhalation
PDE (µg/day) 100 10 1.0
Introduction
Palladium (Pd) is a steel-white, ductile metallic element resembling and occurring with
the other platinum group metals and nickel. It exists in three states: Pd0 (metallic), Pd2+
and Pd4+. It can form organometallic compounds, only few of which have found industrial
uses. Palladium (on various supports) is being used as catalyst in hydrogenation
reactions. Palladium metal is stable in air and resistant to attack by most reagents
except aqua regia and nitric acid.
Several mutagenicity tests of different palladium compounds with bacterial or
mammalian cells (Ames test with Salmonella typhimurium; SOS chromotest with
Escherichia coli; micronucleus test with human lymphocytes) in vitro gave negative
results.
Safety Limiting Toxicity
The data was reviewed to identify the safety limiting toxicities based on routes of
administration.
PDE – Oral Exposure
A number of long-term animal studies have been conducted exploring the toxicity and
carcinogenicity of palladium salts. However, none to date have been executed in
accordance with current guidelines for toxicological studies. The available data suggest
potential NOAELs for palladium in the range of 0.8 – 1.5 mg/kg. A lifetime study with
mice given palladium(II) chloride in drinking-water at a dose of about 1.2 mg Pd/kg/day
found a significantly higher incidence of amyloidosis in several inner organs of males and
females and suppressed growth in males, but not in females (Schroeder and Mitchner,
1971; IPCS, 2002). This study also contained a signal that suggested a possible
carcinogenic endpoint; however, the design of the study (single dose level, pooling of the
tumor rates from male and female animals, and a significant increase in the age of the
treated vs control animals) limited the utility of the data to assess the carcinogenic
potential.
Taking into account the modifying factors (F1-F5 as discussed in Appendix 1), the oral
PDE is calculated based on the LOEL of 1.2 mg/kg/day.
PDE = 1.2 mg/kg/day x 50 kg / 12 x 10 x 1 x 5x 1 = 0.1 mg/day = 100 µg/day.
PDE – Parenteral Exposure
The safety review for Pd was unable to identify any significant assessments upon which
to calculate a PDE for parenteral routes of exposure. Palladium(II) chloride (PdCl2) was
poorly absorbed from the digestive tract (<0.5% of the initial oral dose in adult rats or
about 5% in suckling rats after 3-4 days). Absorption/retention in adult rats was higher
following intratracheal or intravenous exposure, resulting in total body burdens of 5% or
20%, respectively, of the dose administered, 40 days after dosing (IPCS, 2002). On the
basis of an oral bioavailability the PDE for palladium for parenteral exposure is:
54
Guideline for Elemental Impurities
55
PDE = 100 µg/day / 10 = 10 µg/day.
PDE – Inhalation Exposure
There are no adequate inhalation data on Pd. Therefore, the inhalation PDE for
palladium was derived from the oral PDE by division by a factor of 100 (as described in
Section 3.1).
PDE = 100 µg/day / 100 = 1.0 µg/day.
REFERENCES
IPCS. Palladium. Environmental Health Criteria 226. International Programme on
Chemical Safety. World Health Organization, Geneva. 2002.
Schroeder HA, Mitchener M. Scandium, chromium (VI), gallium, yttrium, rhodium,
palladium, indium in mice: Effects on growth and life span. J Nutr 1971;101:1431-8.
Guideline for Elemental Impurities
PLATINUM
Summary of PDE for Platinum
Platinum (Pt)
Oral Parenteral Inhalation
PDE (µg/day) 1000 10 1.4
Introduction
Platinum (Pt) is a Group VIII element of the third transition series. It is the most
important of the six heaviest of the group VIII elements, collectively called the “platinum
group metals” or “platinoids”, including palladium, osmium, rhodium, ruthenium and
iridium. Platinum and Pd are more chemically reactive than the other platinoids.
Metallic Pt has been shown to catalyze many oxidation-reduction and decomposition
reactions and the major industrial use of Pt is as a catalyst. Pt complexes exhibiting a
range of oxidation states are known, although the principal valences are Pt II and IV. Pt
II forms a tetra-coordinate aqua ion [Pt (H2O)4]2+. The most common Pt IV catalysts are
chloroplatinate salts such as tetra and hexachloroplatinate ions.
Safety Limiting Toxicity
The data was reviewed to identify the safety limiting toxicities based on routes of
administration.
Chlorinated salts of platinum are responsible for platinum related hypersensitivity and
are a major occupational health concern (US EPA, 2009). The hypersensitivity appears to
be the most sensitive endpoint of chloroplatinate exposure, at least by the inhalation
route. Signs include urticaria, contact dermatitis of the skin, and respiratory disorders
ranging from sneezing, shortness of breath, and cyanosis to severe asthma (IPCS, 1991).
Exposure reduction was effective in resolving symptoms (Merget et al. 2001). Neutral
complexes and complexes without halogenated ligands do not appear allergenic (US EPA,
2009; EU SCOEL, 2011). The risk of hypersensitivity appears to be related to sensitizing
dose and dose and length of exposure (IPCS, 1991; US EPA, 2009; Arts et al. 2006) and
cigarette smoking (US EPA, 2009; Merget et al. 2000; Caverley, 1995).
PDE – Oral Exposure
No experimental data are available on the carcinogenicity of platinum and platinum
compounds, and toxicology data are limited (US EPA, 2009). In one study in male rats
administered PtCl2 (relatively insoluble) and PtCl4 (soluble) for 4 weeks, the toxicity of
the two platinum salts was investigated. No significant effects on body weight gain or
food consumption for either compound, and no effects were observed on hematological
parameters for PtCl2. Some hematological parameters were influenced by PtCl4; a
reduction of about 13% in hematocrit and erythrocyte parameters was reported at the
dose of 50 mg Pt/kg in the diet. Platinum concentration increased in tissues in animals
dosed with either compound, particularly the kidney. For this reason plasma creatinine
was examined, and found to be increased in animals dosed with PtCl4 when added in the
diet at 50 mg Pt/kg diet for 4 weeks, but not PtCl2. This dose corresponded to 21 mg
Pt/animal (Reichlmayr-Lais et al. 1992). This study was used in the determination of the
PDE as one endpoint in the study was renal toxicity (plasma creatinine), a target organ
of platinum and a site of accumulation. Renal toxicity is an also an adverse effect of
treatment with chemotherapeutic agents such as cisplatin.
Taking into account the modifying factors (F1-F5 as discussed in Appendix 1), the oral
PDE is calculated based on the NOAEL of 10 mg/kg/day.
56
Guideline for Elemental Impurities
57
PDE = 10 mg/kg/day x 50 kg / 5 x 10 x 10 x 1 x 1 = 1 mg/day = 1000 µg/day.
PDE – Parenteral Exposure
The safety review for platinum identified limited assessments of platinum salt toxicity
for parenteral routes of administration. The oral absorption of platinum salts is very low
(<1%) (US EPA, 2009). Therefore, the oral PDE is divided by a factor of 100 (as described
in section 3.1).
PDE = 1000 µg/day / 100 = 10 µg/day.
PDE – Inhalation Exposure
Due to the use of the chloroplatinates in catalytic converters, numerous animal (Biagini
et al. 1983) and human (Pepys et al. 1972; Pickering 1972; Merget et al. 2000; Cristaudo
et al. 2007) studies have been conducted. The US EPA (1977; 2009) and the EU SCOEL
(2011) have also examined the safety of chloroplatinates based on sensitization. The EU
SCOEL concluded that the database does not allow for setting an occupational limit for
soluble platinum salts. The US DoL (2013) has established an occupational limit for
soluble Pt salts at 2 µg/m3; however, whether this exposure level is completely protective
of workers has been questioned (Merget and Rosner, 2001).
Taking into account the modifying factors (F1-F5 as discussed in Appendix 1), the
inhalation PDE is calculated as:
2 µg/m3 ÷1000 m3/L = 0.002 µg/L
For continuous dosing = 0.002 µg/L x 8 hr x 5 d = 0.00048 µg/L
24 hr x 7 d
Daily dose = 0.00048 µg/L x 28800L/d = 0.27 µg/kg/d
50 kg
PDE = 0.27 µg/kg/d x 50 kg = 1.37 µg/day ~1.4 µg/day.
1 x 10 x 1 x 1 x 1
REFERENCES
Arts JHE, Mommers C, de Heer C. Dose-response relationships and threshold levels in
skin and respiratory allergy. Crit Rev Toxicol 2006; 36:219-51.
Biagini RE, Moorman WJ, Smith RJ, Lewis TR, Bernstein IL. Pulmonary
hyperreactivity in cynomolgus monkeys (Macaca fasicularis) from nose-only inhalation
exposure to disodium hexachloroplatinate, Na2PtCl6. Toxicol Appl Pharmacol
1983;69:377-84.
Caverley AE, Rees D, Dowdeswell RJ, Linnett PJ, Kielkowski D. Platinum salt
sensitivity in refinery workers: incidence and effects of smoking and exposure. Int J
Occup Environ Med 1995;52:661-66.
Cristaudo A, Picardo M, Petrucci F, Forte G, Violante N, Senofonte O, Alimonti A.
Clinical and allergological biomonitoring of occupational hypersensitivity to platinum
group elements. Anal Lett 2007;40:3343-59.
EU SCOEL. Recommendation from the scientific committee on occupational exposure
limits for platinum and platinum compounds. European Union Scientific Committee on
Occupational Exposure Limits. 2011;SCOEL/SUM/150.
IPCS. Platinum. Environmental Health Criteria 125. International Programme on
Chemical Safety. World Health Organization, Geneva. 1991.
Guideline for Elemental Impurities
Merget R; Kulzer R; Dierkes-Globisch A, Breitstadt R, Gebler A, Kniffka A, Artelt S,
Koenig HP, Alt F, Vormberg R, Baur X, Schultze-Werninghaus G. Exposure-effect
relationship of platinum salt allergy in a catalyst production plant: conclusions from a 5-
year prospective cohort study. J Allergy Clin Immunol 2000;105:364-370.
Merget R, Caspari C, Kulzer SA, Dierkes-Globisch R, Kniffka A, Degens P, et al.
Effectiveness of a medical surveillance program for the prevention of occupational
asthma caused by platinum salts: a nested case control study. J Allergy Clin Immunol
2001;107:707-12.
Merget R, Rosner G. Evaluation of the health risk of platinum group metals emitted
from automative catalytic converters. Sci Total Environ 2001;270:165-73.
Pepys J, Pickering CAC, Hughes EG. Asthma due to inhaled chemical agents--complex
salts of platinum. Clin Exp Allergy 1972;2:391-96.
Pickering CAC. Inhalation tests with chemical allergens: complex salts of platinum. Proc
R Soc Med 1972;65:2-4.
Reichlmayr-Lais AM, Kirchgessner M, Bader R. Dose-response relationships of
alimentary PtCl2 and PtCl4 in growing rats. J Trace Elem Electrolytes Health Dis
1992;6(3):183-7.
US DoL (OHSA). 29 CRF 1910.1000 Table Z-1. Limits for air contaminants. U.S.
Department of Labor. 2013.
US EPA. Platinum-group metals. Environmental Health Effects Research Series
1977;EPA-600/1-77-040.
US EPA. Toxicological review of halogenated platinum salts and platinum compounds.
Integrated Risk Information System (IRIS). 2009.
US EPA. Toxicological review of halogenated platinum salts and platinum compounds.
In support of summary information on the Integrated Risk Information System (IRIS).
2009.
58
Guideline for Elemental Impurities
59
SELENIUM
Summary of PDE for Selenium
Selenium (Se)
Oral Parenteral Inhalation
PDE (µg/day) 170 85 140
Introduction
Selenium is present in the earth's crust, often in association with sulfur-containing
minerals. It can assume four oxidation states (-2, 0, +4, +6) and occurs in many forms,
including elemental selenium, selenites and selenates. Selenium is an essential trace
element for many species, including humans. Selenium is incorporated into proteins via
a specific selenocysteine tRNA. Selenium is being used as a catalyst in the manufacture
of rubber. Ru-Se catalysts are used in oxygen reduction. Aryl- and alkyl-Selenium
reagents have various applications in organic synthesis.
Safety Limiting Toxicity
Selenium was listed as a Group 3 compound by IARC (1987), not classifiable for
carcinogenesis. The only selenium compound that has been shown to be carcinogenic in
animals is selenium sulfide (NTP, 1980). According to the US EPA, selenium sulfide is
in Group B2 (probable human carcinogen) (US EPA, 2002). Other selenium compounds
are classified as D; not classifiable as to carcinogenicity in humans.
The most significant toxicity observed in these assessments was hepatotoxicity.
PDE – Oral Exposure
In a rat carcinogenicity study of selenium sulfide, the NOAEL for hepatocellular carcinoma
was 3 mg/kg/day (1.7 mg Se/kg/day) (NTP, 1980). There is insufficient data to assess
carcinogenicity of other forms of selenium, and the human relevance of the rodent liver
tumors has been questioned (IARC, 1999). Some human data are available but only in a
limited number of subjects (ATSDR, 2003). The PDE is in line with the MRL of 5
µg/kg/day for Se (ATSDR 2003).
Taking into account the modifying factors (F1-F5 as discussed in Appendix 1), the oral
PDE is calculated as below.
PDE = 1.7 mg/kg/day x 50 kg / 5 x 10 x 1 x 10 x 1 = 170 µg/day.
PDE – Parenteral Exposure
The safety review for selenium was unable to identify any significant assessments upon
which to calculate a PDE for parenteral routes of exposure. Studies in humans and
experimental animals indicate that, when ingested, several selenium compounds
including selenite, selenate, and selenomethionine are readily absorbed, often to greater
than 80% of the administered dose (ATSDR, 2003). On the basis of oral bioavailability of
~80%, the PDE for selenium for parenteral exposure is (as described in section 3.1).
PDE = 170 µg/day / 2 = 85 µg/day.
Guideline for Elemental Impurities
PDE – Inhalation Exposure
The safety review for selenium was unable to identify any significant animal models or
clinical studies of inhalation toxicity. However, occupational limits have established
time weighted averages for selenium exposures of 0.2 mg/m3 (US DoL, 2013).
Taking into account the modifying factors (F1-F5 as discussed in Appendix 1), the
inhalation PDE is calculated as below.
0.2 mg/m3 /1000 L/m3= 0.0002 mg/L
For continuous dosing = 0.0002 mg/L x 8 h x 5 d/24 x 7 = 0.0000476 mg/L
Daily dose = 0.0000476 mg/L x 28800 L/50 kg = 0.027 mg/kg
PDE = 0.027 mg/kg x 50 kg = 0.135 mg/day = 140 µg/day.
1 x 10 x 1 x 1 x 1
REFERENCES
ATSDR. Toxicological profile for selenium. Agency for Toxic Substances and Disease
Registry, Public Health Service, U.S. Department of Health and Human Services,
Atlanta, GA. 2003.
IARC. Overall evaluations of carcinogenicity: An update of IARC monographs volumes 1
to 42. Monographs on the Evaluation of the Carcinogenic Risks to Humans. International
Agency for Research on Cancer, World Health Organization, Lyon.1987;Suppl 7.
IARC. Some aziridines, N-, S- and O-mustards and selenium. Summary of data reported
and evaluation. Monographs on the Evaluation of Carcinogenic Risks to Humans.
International Agency for Research on Cancer, World Health Organization, Lyon. 1999.
NTP. Bioassay of selenium sulfide (gavage) for possible carcinogenicity. National
Toxicology Program, US Department of Health and Human Services. 1980;Technical
Report Series No 194.
US DoL (OHSA). 29 CRF 1910.1000 Table Z-1. Limits for air contaminants. U.S.
Department of Labor. 2013.
US EPA. Selenium and compounds (CAS No. 7782-49-2). Integrated Risk Information
System (IRIS). 2002.
60
Guideline for Elemental Impurities
61
SILVER
Summary of PDE for Silver
Silver (Ag)
Oral Parenteral Inhalation
PDE (µg/day) 170 35 6.9
Introduction
Silver (Ag) is present in silver compounds primarily in the oxidation state +1 and less
frequently in the oxidation state +2. Ag occurs naturally mainly in the form of very
insoluble and immobile oxides, sulfides and some salts. The most important silver
compounds in drinking-water are silver nitrate and silver chloride. Most foods contain
traces of silver in the 10–100 µg/kg range. Ag is nutritionally not essential and no
metabolic function is known. Silver is being used as a catalyst in the oxidation of
ethylene to ethyleneoxide. Silver-Cadmium alloy is used in selective hydrogenation of
unsaturated carbonyl compounds. Silver oxide is used as a mild oxidizing agent in
organic synthesis.
Safety Limiting Toxicity
Silver is not mutagenic. Animal toxicity studies and human occupational studies have
not provided sufficient evidence of carcinogenicity. Based on these data Ag is not
expected to be carcinogenic in humans (ATSDR, 1990).
Argyria appears to be the most sensitive clinical effect in response to human Ag intake.
Silver acetate lozenges are used in smoking cessation (Hymowitz and Eckholdt, 1996).
Argyria, a permanent bluish-gray discoloration of the skin, results from the deposition of
Ag in the dermis combined with an Ag-induced production of melanin. Inhalation of high
levels of silver can result in lung and throat irritation and stomach pains (ATSDR, 1990).
PDE – Oral Exposure
Silver nitrate was added at 0.015% to the drinking water of female mice (0.9 g/mouse;
32.14 mg/kg silver nitrate; 64% silver) for 125 days to examine neurobehavioral activity
of the animals based on potential neurotoxicity of silver (Rungby and Danscher, 1984).
Treated animals were hypoactive relative to controls; other clinical signs were not noted.
In a separate study, silver was shown to be present in the brain after mice were injected
with 1 mg/kg ip silver lactate (Rungby and Danscher, 1983). The oral PDE is in line with
the reference dose of 5 µg/kg/day (US EPA, 2003).
Taking into account the modifying factors (F1-F5 as discussed in Appendix 1), the oral
PDE is calculated as below.
20 mg/kg x 50 kg / 12 x 10 x 5 x1 x 10 = 167 µg/d ~170 µg/day.
A factor 10 was chosen for F5 as a NOAEL was not seen in this study and few
toxicological endpoints were examined.
PDE – Parenteral Exposure
US EPA (2003) identified a LOAEL of 0.014 mg/kg Ag/d using long-term (2 to 9 years)
human iv data based on argyria following colloidal and organic silver medication.
Taking into account the modifying factors (F1-F5 as discussed in Appendix 1), the
parenteral PDE is calculated as below.
Guideline for Elemental Impurities
0.014 mg/kg/d x 50 kg = 700 ug/d/1 x 10 x 1 x 1 x 2 = 35 µg/day.
A factor of 2 was chosen for F5 as the finding of argyria was not considered a serious
toxicity and a factor of 10 is used for F2, for a combined modifying factor of 20.
PDE – Inhalation Exposure
Lung and throat irritation and stomach pains were the principal effects in humans after
inhalation of high Ag levels.
Using the TLV of 0.01 mg/m3 for silver metal and soluble compounds (US DoL, 2013),
taking into account the modifying factors (F1-F5 as discussed in Appendix 1), the
inhalation PDE is calculated as:
0.01 mg/m3 /1000 L/m3= 0.00001 mg/L
For continuous dosing = 0.00001 mg/L x 8 h x 5 d/24 x 7 = 0.00000238 mg/L
Daily dose = 0.00000238 mg/L x 28800 L/day = 0.00137 mg/kg/day
50 kg
PDE = 0.00137 mg/kg x 50 kg = 0.0069 mg/day = 6.9 µg/day.
1 x 10 x 1 x 1 x 1
The factor F2 was set to 10 to extrapolate to the general population.
REFERENCES
ATSDR. Toxicological Profile for Silver. Agency for Toxic Substances and Disease
Registry, Public Health Service, U.S. Department of Health and Human Services,
Atlanta, GA. 1990.
Hymowitz N, Eckholt H. Effects of a 2.5-mg silver acetate lozenge on initial and long-
term smoking cessation. Prev Med 1996;25:537-46.
Rungby J, Danscher G. Hypoactivity in silver exposed mice. Acta Pharmacol Toxicol
1984;55:398-401.
Rungby J, Danscher G. Localization of exogenous silver in brain and spinal cord of silver
exposed rats. Acta Neuropathol 1983;(60)1-2:92-98.
US DoL (OHSA). 29 CRF 1910.1000 Table Z-1. Limits for air contaminants. U.S.
Department of Labor. 2013.
US EPA. Silver (CASRN 7440-22-4). Integrated Risk Information System (IRIS). 2003.
62
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63
THALLIUM
Summary of PDE for Thallium
Thallium (Tl)
Oral Parenteral Inhalation
PDE (µg/day) 8.0 8.0 69
Introduction
Pure thallium (Tl) is a bluish-white metal. It exists primarily in two valence states:
monovalent (thallous) and trivalent (thallic). Monovalent thallium is similar to
potassium (K+) in ionic radius and electrical charge, which contribute to its toxic nature.
Many of the thallium salts are soluble in water with the exception of the insoluble
thallium (III) oxide. Tl sulfate has been used in medicine, primarily as a depilatory agent,
but also to treat infections, such as venereal diseases, ringworm of the scalp, typhus,
tuberculosis, and malaria. Thallium(III) salts are being used in organic synthesis. Tl is
nutritionally not essential and no metabolic function is known (ATSDR, 1992).
Safety Limiting Toxicity
In humans and animals, the skin, especially the hair follicles, appears to be the most
sensitive target of toxicity from repeated oral exposure to Tl (US EPA, 2009).
PDE – Oral Exposure
The primary target organ for oral exposure to Tl in humans and animals appears to be
the skin, especially the hair follicles, as shown in a 90-day toxicity rat study with Tl
sulfate. The NOAEL was defined at 0.04 mg Tl/kg on the basis of an increased incidence
of alopecia at the higher doses (Stoltz et al. 1986; US EPA, 2009). Thus, the oral PDE
was determined on the basis of the NOAEL of 0.04 mg Tl/kg in rat.
Taking into account the modifying factors (F1-F5 as discussed in Appendix 1), the oral
PDE is calculated as below.
PDE = 0.04 mg/kg/day x 50 kg / 5 x 10 x 5 x 1 x 1 = 0.008 mg/day = 8.0 µg/day.
PDE – Parenteral Exposure
No relevant data on parenteral exposure to thallium compounds were found. The
bioavailability of soluble thallium salts is high (> 80%) (US EPA, 2009). Therefore, the
parenteral PDE is the same as the oral PDE.
PDE = 8.0 µg/day.
PDE – Inhalation Exposure
No relevant data on inhalation exposure to thallium compounds were found. Using the
TLV of 0.1 mg/m3 for thallium, soluble compounds (US DoL, 2013; CEC, 2000).
Taking into account the modifying factors (F1-F5 as discussed in Appendix 1), the
inhalation PDE is calculated as:
0.1 mg/m3 /1000 L/m3= 0.0001 mg/L
For continuous dosing = 0.0001 mg/L x 8 h x 5 d/24 x 7 = 0.0000238 mg/L
Daily dose = 0.0000238 mg/L x 28800 L/day = 0.0137 mg/kg/day
Guideline for Elemental Impurities
50 kg
PDE = 0.0137 mg/kg x 50 kg = 0.069 mg/day = 69 µg/day.
1 x 10 x 1 x 1 x 1
REFERENCES
ATSDR. Toxicological profile for thallium. Agency for Toxic Substances and Disease
Registry, Public Health Service, U.S. Department of Health and Human Services,
Atlanta, GA. 1992.
CEC. Commission of the European Communities. Commission Directive 2000/39/EC of 8
June 2000 establishing a first list of indicative occupational exposure limit values in
implementation of Council Directive 98/24/EC on the protection of the health and safety
of workers from the risks related to chemical agents at work. Official Journal of the
European Communities 2000;L142 (16/06/2000):47-50.
Stoltz ML, Stedham MA, Brown LK, et al. Subchronic (90-day) toxicity of thallium (I)
sulfate (CAS No. 7446-18-6) in Sprague-Dawley rats. Final Report. Project no. 8702-
L(18). 1980. Prepared for U.S. Environmental Protection Agency by Midwest Research
Institute; cited in: OEHHA. Public health goal for thallium in drinking water. Office of
Environmental Health Hazard Assessment, Berkeley and Sacramento, CA. 1999
US DoL (OHSA). 29 CRF 1910.1000 Table Z-1. Limits for air contaminants. U.S.
Department of Labor. 2013.
US EPA. Toxicological review of thallium and compounds (CAS No. 7440-28-0). Integrated
Risk Information System (IRIS). 2009.
64
Guideline for Elemental Impurities
65
TIN
Summary of PDE for Tin
Tin (Sn)
Oral Parenteral Inhalation
PDE (µg/day) 6400 640 64
Introduction
Tin (Sn) is a silvery-white metal that exists in valence states of 2 and 4. The most
important inorganic compounds of tin are its oxides, chlorides, fluorides and halogenated
sodium stannates and stannites. Tin is present in some multi-vitamin and mineral food
supplements (levels up to 10 µg Sn/tablet). Tin is possibly nutritionally essential for
some animals, it has not been shown to be essential for humans. Tin(II) chloride is being
used as a reducing agent, and as a stabilizer of polyvinylchloride (PVC). This safety
assessment focuses on inorganic tin considering that the more frequent occurrence of
inorganic tin is more relevant with respect to metal impurities in drug products than
organic tin compounds.
Safety Limiting Toxicity
There is no indication of in vivo genotoxicity or carcinogenicity for tin and tin salts. In
several studies in rats, a decrease in hemoglobin as an early sign for anemia, was the
most sensitive endpoint.
PDE – Oral Exposure
Anemia was the most sensitive endpoint in rats after repeated oral administration. Thus,
the PDE for oral exposure was determined on the basis of the lowest NOAEL, i.e., 150
ppm (equivalent to 32 mg Sn/kg/day). This value was obtained from a 90-day study in
rats based on signs of anemia starting at 500 ppm in rats exposed to stannous chloride
via diet (De Groot et al. 1973).
Taking into account the modifying factors (F1-F5 as discussed in Appendix 1), the oral
PDE is calculated as below.
PDE = 32 mg/kg/day x 50 kg / 5 x 10 x 5 x 1 x 1 = 6.4 mg/day = 6400 µg/day.
PDE – Parenteral Exposure
The safety review for tin was unable to identify any significant assessments upon which
to calculate a PDE for parenteral routes of exposure. On the basis of an oral
bioavailability of about 5% for tin and inorganic tin compounds (ATSDR, 2005), and
using the default factor of 10, the PDE for tin for a parenteral exposure is (as described
in Section 3.1).
PDE = 6400 µg/day / 10 = 640 µg/day.
PDE – Inhalation Exposure
The safety review for tin was unable to identify any significant assessments on inorganic
tin upon which to calculate a PDE for inhalation routes of exposure. Although a TLV is
available for tin (2 mg/m3; US DoL, 2013), there is insufficient data to set a MRL (ATSDR
2005; EU SCOEL 2003).
Therefore, the PDE for tin is calculated by using a factor of 100 to convert the oral PDE
to the inhalation PDE (as described in Section 3.1).
Guideline for Elemental Impurities
PDE = 6400 µg/day / 100 = 64 µg/day.
REFERENCES
ATSDR. Toxicological profile for tin and tin compounds. Agency for Toxic Substances and
Disease Registry, Public Health Service, U.S. Department of Health and Human
Services, Atlanta, GA. 2005.
De Groot AP, Feron V, Til H. Short-term toxicity studies on some salts and oxides of tin
in rats. Food Cos and Toxicol 1972;11:19-30.
EU SCOEL. Recommendation from the scientific committee on occupational exposure
limits for tin and inorganic tin compounds. European Union Scientific Committee on
Occupational Exposure Limits. 2003;SCOEL/SUM/97.
US DoL (OHSA). 29 CRF 1910.1000 Table Z-1. Limits for air contaminants. U.S.
Department of Labor. 2013.
66
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67
VANADIUM
Summary of PDE for Vanadium
Vanadium (V)
Oral Parenteral Inhalation
PDE (µg/day) 120 12 1.2
Introduction
Vanadium (V) is present as a trace element in the earth’s crust and can exist in a variety
of oxidation states (-1, 0, +2, +3, +4 and +5). V is also present in trace quantities in most
biological organisms with the principal ions being vanadate, VO3- and vanadyl, VO2+.
Absorption of vanadium from the gastrointestinal tract is poor. Estimates of total
dietary intake of vanadium in humans range from 10 to 60 µg/day. Intake from drinking
water depends on the water source and estimates are up to 140 µg/day. Human
populations have variable serum concentrations of vanadium, with 2 µg/L being the high
end of the normal range. Despite its ubiquitous presence in the body, an essential
biological role for vanadium in humans has not been established. Vanadium has been
reported to have potentially beneficial effects in treatment of osteoporosis, osteopenia,
cancer, and diabetes. Oral vanadyl sulfate in amounts up to 20 mg/day is included in
some dietary supplements intended to promote muscle growth. Vanadium oxide is used
as a catalyst in the manufacturing of sulfuric acid.
Safety Limiting Toxicity
Vanadium is genotoxic, but not mutagenic (ATSDR, 2009). Vanadium pentoxide is
classified as a possible human carcinogen (Group 2B; IARC, 2012).
PDE – Oral Exposure
Following oral administration to animals and humans the gastrointestinal tract,
cardiovascular, and hematological system are the primary targets of toxicity. The most
appropriate study to assess vanadium toxicity through oral administration was
conducted in humans exposed to vanadium for 12 weeks. In these studies, no significant
alterations in hematological parameters, liver function (as measured by serum enzymes),
cholesterol and triglyceride levels, kidney function (as measured by blood urea nitrogen),
body weight, or blood pressure were observed in subjects administered via capsule 0.12
or 0.19 mg vanadium as ammonium vanadyl tartrate or vanadyl sulfate for 6–12 weeks
(ATSDR, 2012). The oral NOAEL of 0.12 mg vanadium/kg/day for hematological and
blood pressure effects was used to calculate the oral PDE.
Taking into account the modifying factors (F1-F5 as discussed in Appendix 1), the oral
PDE is calculated as below.
PDE = 0.12 mg/kg/day x 50 kg / 1 x 10 x 5 x 1 x 1 = 0.12 mg/day = 120 µg/day.
PDE – Parenteral Exposure
The safety review for vanadium was unable to identify any significant assessments upon
which to calculate a PDE for parenteral routes of exposure. On the basis of an
approximate oral bioavailability of <1–10% for vanadium and inorganic vanadium
compounds (ATSDR, 2012), the oral PDE was divided by 10 (as described in Section 3.1).
PDE = 120 µg/day / 10 = 12 µg/day.
Guideline for Elemental Impurities
PDE – Inhalation Exposure
A two year chronic inhalation exposure study in rats was considered for use for the
inhalation PDE for vanadium. In this study, carcinogenic effects were observed to the
lowest dose tested, 0.5 mg/m3 vanadium pentoxide (Ress et al. 2003). Vanadium
pentoxide is a caustic agent and is not considered to be present in drug products.
Therefore, the inhalation PDE for vanadium was derived from the oral PDE by division
by a factor of 100 (as described in Section 3.1).
PDE = 120/100 = 1.2 µg/day.
REFERENCES
ATSDR. Toxicological profile for vanadium. Agency for Toxic Substances and Disease
Registry, Public Health Service, U.S. Department of Health and Human Services,
Atlanta, GA. 2012.
IARC. Arsenic, metals, fibres, and dusts: a review of human carcinogens. Monographs on
the Evaluation of Carcinogenic Risks to Humans. International Agency for Research on
Cancer, World Health Organization, Lyon. 2012;100C.
Ress NB, Chou BJ, Renne RA, Dill JA, Miller RA, Roycroft JH, et al. Carcinogenicity of
inhaled vanadium pentoxide in F344/N rats and B6C3F1 mice. Toxicol Sci
2003;74(2):287-96.
68
Guideline for Elemental Impurities
69
Appendix 4: Illustrative Example – Calculation Options for Converting PDEs
to Concentrations
Examples for Converting PDEs into Permitted Elemental Impurity
Concentrations
Option 1: Permitted common concentration limits of elemental impurities across drug
product component materials for products with daily intakes of not more than 10 grams.
For this example, consider a solid oral drug product with a maximum daily intake of 2.5
grams, containing 9 components (1 drug substance and 8 excipients, see Table A.4.1).
Because this drug product does not exceed a maximum daily intake of 10 grams, the
concentrations in Table A.2.2 may be used. As Option 1 has a common permitted
concentration, each of the 9 components can be used at any level in the formulation. The
drug substance synthesis uses Pd and Ni catalysts, and the applicant is also concerned
about Pb, As, Cd, Hg, and V on the basis of the risk assessment. The maximum daily
intake of each elemental impurity in the drug product is given in Table A.4.2 assuming
that each elemental impurity is present at the concentration given in Table A.2.2. The
maximum potential daily intake of an elemental impurity is determined using the actual
drug product daily intake and the concentration limit for the elemental impurity in Table
A.2.2 (concentration multiplied by the actual daily intake of the drug product of 2.5
grams). The maximum daily intake given for each elemental impurity is not a
summation of values found in the individual columns.
This calculation demonstrates that no elemental impurities exceed their PDEs. Thus if
these concentrations in each component are not exceeded, the drug product is assured to
meet the PDEs for each identified elemental impurity.
Table A.4.1: Maximum Daily Intake of Components of the Drug Product
Component Daily Intake, g
Drug Substance 0.200
MCC 1.100
Lactose 0.450
Ca Phosphate 0.350
Crospovidone 0.265
Mg Stearate 0.035
HPMC 0.060
Titanium Dioxide 0.025
Iron Oxide 0.015
Drug Product 2.500
Guideline for Elemental Impurities
Table A.4.2: Permitted Concentrations from Table A.2.2 (assuming uniform
concentrations and 10 grams daily intake)
Maximum Permitted Concentration (µg/g)
Component
Pb As Cd Hg Pd V Ni
Drug
Substance 0.5 1.5 0.5 4 10 12 60
MCC 0.5 1.5 0.5 4 10 12 60
Lactose 0.5 1.5 0.5 4 10 12 60
Ca Phosphate 0.5 1.5 0.5 4 10 12 60
Crospovidone 0.5 1.5 0.5 4 10 12 60
Mg Stearate 0.5 1.5 0.5 4 10 12 60
HPMC 0.5 1.5 0.5 4 10 12 60
Titanium
Dioxide 0.5 1.5 0.5 4 10 12 60
Iron Oxide 0.5 1.5 0.5 4 10 12 60
Maximum
Daily intake,
µg
1.25 3.75 1.25 10 25 30 150
PDE, µg/day 5.0 15 5.0 40 100 120 600
Option 2a: Permitted common concentration limits across drug product component
materials for a product with a specified daily intake:
For this example, consider the same solid oral drug product with a maximum daily
intake of 2.5 grams, containing 9 components (1 drug substance and 8 excipients, see
Table A.4.1) used in Option 1. As Option 2a has a common permitted concentration,
each of the 9 components can be used at any level in the formulation. The drug
substance synthesis uses Pd and Ni catalysts, and the applicant is also concerned about
Pb, As, Cd, Hg, and V on the basis of the risk assessment. The concentration of each
elemental impurity identified in the risk assessment can be calculated using the PDEs in
Table A.2.1 and equation 1.
The maximum potential daily intake of an elemental impurity is determined using the
actual drug product daily intake and the concentration limit for the elemental impurity
in Table A.4.3 (concentration multiplied by the actual daily intake of the drug product of
2.5 grams). The maximum daily intake given for each elemental impurity is not a
summation of values found in the individual columns.
This calculation also demonstrates that no elemental impurities exceed their PDEs. Thus
if these concentrations in each component are not exceeded, the drug product is assured
to meet the PDEs for each identified elemental impurity.
The factor of 4 increase in Option 2a for permitted concentration seen when comparing
Option 1 and Option 2a concentration limits is due to the use of 10 grams and 2.5 grams
respectively as daily intake of the drug product.
70
Guideline for Elemental Impurities
71
Table A.4.3: Calculation of Maximum Permitted Concentrations Assuming
Uniform Concentrations in a Product with a Specified Daily Intake:
Maximum Permitted Concentration (µg/g)
Component
Pb As Cd Hg Pd V Ni
Drug
Substance
2 6 2 16 40 48 240
MCC 2 6 2 16 40 48 240
Lactose 2 6 2 16 40 48 240
Ca Phosphate 2 6 2 16 40 48 240
Crospovidone 2 6 2 16 40 48 240
Mg Stearate 2 6 2 16 40 48 240
HPMC 2 6 2 16 40 48 240
Titanium
Dioxide
2 6 2 16 40 48 240
Iron Oxide 2 6 2 16 40 48 240
Maximum
Daily intake,
µg
5.0 15 5.0 40 100 120 600
PDE, µg/day 5.0 15 5.0 40 100 120 600
Option 2b: Permitted concentration limits of elemental impurities across drug product
component materials for a product with a specified daily intake:
For this example, consider the same solid oral drug product with a maximum daily
intake of 2.5 grams, containing 9 components (1 drug substance and 8 excipients, see
Table A.4.1) used in Option 1 and 2a. The drug substance synthesis uses Pd and Ni
catalysts, and the applicant is also concerned about Pb, As, Cd, Hg, and V on the basis of
the risk assessment. To use Option 2b, the applicant must use the composition of the
drug product and have additional knowledge regarding the content of each elemental
impurity in the components. The applicant has generated the following data on
elemental impurities in the components of the drug product:
Table A.4.4: Measured Concentrations of Elemental Impurities (µg/g) in the
Components
Measured Concentration (µg/g)
Component
Pb As Cd Hg Pd V Ni
Drug
Substance ND 0.5 ND ND 20 ND 50
MCC 0.1 0.1 0.1 0.1 * ND ND
Lactose 0.1 0.1 0.1 0.1 * ND ND
Ca Phosphate 1 1 1 1 * 10 5
Crospovidone 0.1 0.1 0.1 0.1 * ND ND
Mg Stearate 0.5 0.5 0.5 0.5 * ND 0.5
HPMC 0.1 0.1 0.1 0.1 * ND ND
Titanium
Dioxide 20 1 1 1 * 1 ND
Iron Oxide 10 10 10 10 * 2000 50
ND = Below the detection limit
* = The risk assessment identified that Pd was not a potential elemental impurity; a quantitative
result was not obtained.
Guideline for Elemental Impurities
The applicant also knows the maximum daily intake of the drug product is 2.5 grams
and determines the maximum daily intake for each component as shown in Table A.4.5.
Based on the observed levels (see Table A.4.4), the applicant evaluated the potential
maximum permitted concentrations of each elemental impurity in the components. The
concentrations selected (see Table A.4.5) were set at levels that would ensure the PDE is
met if the maximum permitted concentration was reached for each component. The
maximum daily intake in Table A.4.5 is the summation of the values obtained by
multiplying the actual weight of the component by the maximum permitted
concentration for each elemental impurity across all components.
Table A.4.5: Maximum Permitted Concentrations of Elemental Impurities in the
Components
Maximum Permitted Concentration (µg/g)
Component
Pb As Cd Hg Pd V Ni
Drug Substance ** 5 ** ** 500 ** 2000
MCC 0.5 5 1 10 * ** **
Lactose 0.5 5 1 10 * ** **
Ca Phosphate 5 5 5 40 * 125 475
Crospovidone 0.5 5 1 10 * ** **
Mg Stearate 5 10 5 100 * ** 50
HPMC 2.5 5 1 10 * ** **
Titanium Dioxide 40 20 10 25 * 50 **
Iron Oxide 20 100 50 200 * 5000 2000
Maximum Daily
intake, µg 4.3 14.5 4.8 39.9 100 120 598
PDE, µg/day 5.0 15 5.0 40 100 120 600
* The risk assessment identified that Pd was not a potential elemental impurity; a quantitative
result was not obtained.
** Quantitative results demonstrated less than the limit of detection.
Option 3: Finished Product Analysis
For this example, consider the same solid oral drug product with a maximum daily
intake of 2.5 grams, containing 9 components (1 drug substance and 8 excipients) used in
Option 1, 2a and 2b. The drug substance synthesis uses Pd and Ni catalysts, and the
applicant is also concerned about Pb, As, Cd, Hg, and V on the basis of the risk
assessment. The maximum concentration of each elemental impurity in the drug
product may be calculated using the daily intake of drug product and the PDE of the
elemental impurity using equation 1. The total mass of each elemental impurity should
be not more than the PDE.
)/(5.2
)/()/(
dayg
daygPDEggionConcentrat μμ =
Table A.4.6: Calculation of Concentrations for the Finished Product
Maximum Permitted Concentration (µg/g)
Daily Intake (g) Pb As Cd Hg Pd V Ni
Drug Product 2.5 2 6 2 16 40 40 800
Maximum
Daily Intake
(µg)
5 15 5 40 100 120 600
72
Guideline for Elemental Impurities
73
Illustrative Example – Elemental Impurities Assessment
The following example is intended as illustration of an elemental impurities risk
assessment. This example is intended for illustrative purposes and not as the only way
to document the assessment. There are many different ways to approach the risk
assessment process and its documentation.
This example relies on the oral drug product described in Appendix 4. Consider a solid
oral drug product with a maximum daily intake of 2.5 grams, containing 9 components (1
drug substance and 8 excipients). The drug substance synthesis uses Pd and Ni catalysts.
The applicant conducts the risk assessment starting with the identification of potential
elemental impurities following the process described in Section 5. Since the applicant
had limited historical data for the excipients used in the drug product, the applicant
determined that the Class 1 elementals (As, Cd, Hg, Pb) would be taken through the
evaluation phase. The table below shows a summary of the findings of the identification
stage of the assessment.
Table A.4.7: Identification of Potential Elemental Impurities
Potential Elemental Impurities
Component Intentionally
added
Potential
elemental
impurities
with a
relatively high
abundance
and/or are
impurities in
excipients or
reagents
Potential
elemental
impurities
from
manufacturing
equipment
Potential
elemental
impurities
from container
closure
systems
Drug
Substance
Pd, Ni As Ni None
MCC None As, Cd, Hg, Pb None
Lactose None As, Cd, Hg, Pb None
Ca Phosphate None As, Cd, Hg, Pb V, Ni None
Crospovidone None As, Cd, Hg, Pb None
Mg stearate None As, Cd, Hg, Pb Ni None
HPMC None As, Cd, Hg, Pb None
Titanium
Dioxide
None As, Cd, Hg, Pb V None
Iron Oxide None As, Cd, Hg, Pb V, Ni None
The identification phase of the assessment identified seven potential elemental
impurities requiring additional evaluation. Three of the identified elemental impurities
were found in multiple components. The applicant continued the risk assessment
collecting information from the vendor and available development data. The summary of
the results can be found in Table A.4.3. The application of the individual component data
to the evaluation in the assessment process is shown below in Table A.4.8.
Guideline for Elemental Impurities
Table A.4.8: Elemental Impurity Assessment – Evaluation of Daily Contribution to the Total Mass of Elemental Impurities in the Drug Product
Measured Concentration (µg/g)
Total Daily Mass of Elemental
Impurity, µg
Component
Daily
intake, g Pb As Cd Hg Pd V Ni Pb As Cd Hg Pd V Ni
Drug Substance 0.2 ND 0.5 ND ND 20 ND 50 0 0.1 0 0 4 0 10
MCC 1.1 0.1 0.1 0.1 0.1 * ND ND 0.11 0.11 0.11 0.11 0 0 0
Lactose 0.45 0.1 0.1 0.1 0.1 * ND ND 0.045 0.045 0.045 0.045 0 0 0
Ca Phosphate 0.35 1 1 1 1 * 10 5 0.35 0.35 0.35 0.35 0 3.5 1.75
Crospovidone 0.265 0.1 0.1 0.1 0.1 * ND ND 0.0265 0.0265 0.0265 0.0265 0 0 0
Mg stearate 0.035 0.5 0.5 0.5 0.5 * ND 0.5 0.0175 0.0175 0.0175 0.0175 0 0 0.0175
HPMC 0.06 0.1 0.1 0.1 0.1 * ND ND 0.006 0.006 0.006 0.006 0 0 0
Titanium
Dioxide 0.025 20 1 1 1 * 1 ND 0.5 0.025 0.025 0.025 0 0.025 0
Iron Oxide 0.015 10 10 10 10 * 400 50 0.15 0.15 0.15 0.15 0 6 0.75
total daily
mass, µg/day 1.2 0.8 0.7 0.7 4.0 9.5 12.5
Table A.4.9: Assessment Example – Data Entry Descriptions
Column 1: Review the components of drug product for any elements intentionally added in the production (the primary source is the
drug substance). For those used, record the elements for further consideration in the assessment.
Column 2: Identify any potential elements or impurities that are associated with excipients or reagents used in the preparation of the
drug product. Record the source(s) for further consideration in the assessment.
Column 3: Identify any elemental impurities known or expected to be leached from the manufacturing equipment. Record the specific
elemental impurities for further consideration in the assessment.
Column 4: Identify any elemental impurities known or expected to be leached from the container closure system. Record the specific
elemental impurities for further consideration in the assessment.
Column 5: Calculate the total contribution of the potential elemental impurity by summing the contributions across the components
of the drug product.
74
Guideline for Elemental Impurities
75
Column 6: Assess the variability of the elemental impurity level(s) in the components
Column 7: Enter the control threshold of each potential elemental impurity identified. If the variability is known and it is within
acceptable limits, the control threshold (30% of the PDE) for each elemental impurity can be applied.
Column 8: Describe action taken – none if the value in column 6 is less than or equal to the control threshold (column 7). Define
control element if material variability is high or control threshold is exceeded.
1 2 3 4 5 6 7 8
Element Intentionally
added
(if used in the
process)
Elemental impurities
with a relatively high
abundance and/or are
impurities in
excipients or reagents
Manufacturing
equipment
Leached
from
container
closure
systems
Total
elemental
impurity
contribution
µg/day
Acceptable
variability of
elemental
impurity
contribution
Control
threshold
Action
As No Observed contaminant
in all excipients and
drug substance
No No 0.8 yes 4.5 no further
controls required
Cd No Observed contaminant
in all excipients
No No 0.7 yes 1.5 no further
controls required
Hg No Observed contaminant
in all excipients
No No 0.7 yes 12 no further
controls required
Pb No Observed contaminant
in all excipients
No No 1.2 yes 1.5 no further
controls required
Pd API catalyst No No No 4.0 yes 30 no further
controls required
Ni API catalyst Observed in 3
excipients
No No 12.5 yes 180 no further
controls required
V No Observed in 3
excipients
No No 9.5 yes 36 no further
controls required
1. Introduction
2. Scope
3. Safety Assessment of Potential Elemental Impurities
3.1 Principles of the Safety Assessment of Elemental Impurities for Oral, Parenteral and Inhalation Routes of Administration
3.3 Justification for Element Impurity Levels Higher than the PDE
3.4 Parenteral Products
4. Element Classification
5. Assessment and Control of Elemental Impurities
5.1 General Principles
5.2 Potential Sources of Elemental Impurities
5.3 Assessment – Identification of Potential Elemental Impurities
5.4 Assessment – Analysis and Evaluation
5.5 Converting Between PDEs and Concentration Limits
5.6 Assessment Summary
5.7 Control of Elemental Impurities
5.8 Periodic Verification Testing
5.9 Special Considerations for Biotechnologically-Derived Products
6. Speciation
7. Analytical Procedures
8. Life-Cycle Management of the Control Strategy for Elemental Impurities
9. Recommendations for Submission of Elemental Impurities Control Strategy
References
Glossary
Appendix 1: Method for Establishing Exposure Limits
Appendix 2: Established PDEs for Elemental Impurities
Appendix 3: Individual Safety Assessments
Appendix 4: Illustrative Example – Calculation Options for Converting PDEs to Concentrations
04.08.2014
Datei
PD
Version 8.1 1
ICH DRAFT: STEP 2
Topic Reference: Q8 (R1)
Subject: Pharmaceutical Development Revision 1
Draft No. 8.1 Dated: 1 November 2007
Rapporteur: Dr. John Berridge (To Step 2)
Address: Pfizer Ltd
Sandwich
Kent
CT13 9NJ
United Kingdom
e-mail: john.berridge@pfizer.com
Version 8.1 2
TABLE OF CONTENTS
1. Introduction......................................................................................................... 1
2. Elements of Pharmaceutical Development ........................................................ 2
2.1 Target Product Profile................................................................................... 2
2.2 Critical Quality Attributes ........................................................................... 2
2.3 Linking Material Attributes and Process Parameters to CQAs – Risk
Assessment ........................................................................................................... 3
2.4 Design Space .................................................................................................. 3
2.4.1 Selection of variables. ............................................................................... 3
2.4.2 Defining and describing a design space in a submission ............................ 4
2.4.3 Unit operation design space(s) .................................................................. 4
2.4.4 Relationship of design space to scale and equipment................................. 4
2.4.5 Design space versus proven acceptable ranges .......................................... 5
2.4.6 Design space and edge of failure ............................................................... 5
2.5 Control Strategy ............................................................................................ 5
2.6 Product Lifecycle Management and Continual Improvement..................... 6
3. Submission of Pharmaceutical Development and Related Information in
Common Technical Document (CTD) Format................................................... 6
3.1 Quality Risk Management and Product and Process Development ............... 6
3.2 Design Space ............................................................................................... 7
3.3 Control Strategy........................................................................................... 7
3.4 Drug Substance Related Information............................................................ 7
4. GLOSSARY........................................................................................................ 8
Appendix 1. Differing Approaches to Pharmaceutical Development................ 9
Appendix 2. Illustrative Examples.....................................................................10
Version 8.1 1
1. Introduction 1
2
This guidance is an annex to ICH Q8 Pharmaceutical Development and provides 3
further clarification of key concepts outlined in the core guideline. In addition, this 4
annex describes the principles of quality by design (QbD). The annex is not intended 5
to establish new standards; however, it shows how concepts and tools (e.g., design 6
space) outlined in the parent Q8 document could be put into practice by the applicant 7
for all dosage forms. Where a company chooses to apply quality by design and quality 8
risk management (ICH Q9, Quality Risk Management), linked to an appropriate 9
pharmaceutical quality system, then opportunities arise to enhance science- and risk-10
based regulatory approaches (see ICH Q10, Pharmaceutical Quality Systems). 11
12
1.1. Approaches to Pharmaceutical Development 13
14
In all cases, the product should be designed to meet patients’ needs and the intended 15
product performance. Strategies for product development vary from company to 16
company and from product to product. The approach to, and extent of, development 17
can also vary and should be outlined in the submission. An applicant might choose 18
either an empirical approach or a more systematic approach to product development. 19
An illustration of the potential contrasts of these approaches is shown in Appendix 1. A 20
more systematic approach to development (also defined as quality by design) can 21
include, for example, incorporation of prior knowledge, results of studies using design 22
of experiments, use of quality risk management, and use of knowledge management 23
(see ICH Q10) throughout the lifecycle of the product. Such a systematic approach can 24
enhance the process to achieve quality and help the regulators to better understand a 25
company’s strategy. Product and process understanding can be updated with the 26
knowledge gained over the product lifecycle. 27
28
A greater understanding of the product and its manufacturing process can create a 29
basis for more flexible regulatory approaches. The degree of regulatory flexibility is 30
predicated on the level of relevant scientific knowledge provided in the registration 31
application. It is the knowledge gained and submitted to the authorities, and not the 32
volume of data collected, that forms the basis for science- and risk-based submissions 33
and regulatory evaluations. Nevertheless, appropriate data demonstrating that this 34
knowledge is based on sound scientific principles should be presented with each 35
application. 36
37
Pharmaceutical development should include, at a minimum, the following elements: 38
39
• Defining the target product profile as it relates to quality, safety and efficacy, 40
considering e.g., the route of administration, dosage form, bioavailability, 41
dosage, and stability 42
43
• Identifying critical quality attributes (CQAs) of the drug product, so that those 44
product characteristics having an impact on product quality can be studied and 45
controlled 46
47
• Determining the quality attributes of the drug substance, excipients etc., and 48
selecting the type and amount of excipients to deliver drug product of the 49
desired quality 50
51
• Selecting an appropriate manufacturing process 52
Version 8.1 2
53
• Identifying a control strategy 54
55
An enhanced, quality by design approach to product development would additionally 56
include the following elements: 57
58
• A systematic evaluation, understanding and refining of the formulation and 59
manufacturing process, including: 60
61
o Identifying, through e.g., prior knowledge, experimentation, and risk 62
assessment, the material attributes and process parameters that can have 63
an effect on product CQAs 64
o Determining the functional relationships that link material attributes 65
and process parameters to product CQAs 66
67
• Using the enhanced process understanding in combination with quality risk 68
management to establish an appropriate control strategy which can, for 69
example, include a proposal for design space(s) and/or real-time release 70
71
As a result, this more systematic approach could facilitate continual improvement and 72
innovation throughout the product lifecycle (See ICH Q10 Pharmaceutical Quality 73
System). 74
75
2. Elements of Pharmaceutical Development 76
77
The section that follows elaborates, by means of description and example, possible 78
approaches to gaining a more systematic, enhanced understanding of the product and 79
process under development. The examples given are purely illustrative and are not 80
intended to create new regulatory requirements. 81
82
2.1 Target Product Profile 83
84
A target product profile is a prospective and dynamic summary of the quality 85
characteristics of a drug product that ideally will be achieved to ensure that the desired 86
quality, and hence the safety and efficacy, of a drug product is realised. The target 87
product profile forms the basis of design for the development of the product. 88
89
Considerations for the target product profile should include: 90
91
• Dosage form and route of administration 92
• Dosage form strength(s) 93
• Therapeutic moiety release or delivery and pharmacokinetic characteristics 94
(e.g., dissolution; aerodynamic performance) appropriate to the drug product 95
dosage form being developed 96
• Drug product quality criteria (e.g., sterility, purity) appropriate for the intended 97
marketed product. 98
99
2.2 Critical Quality Attributes 100
101
A critical quality attribute (CQA) is a physical, chemical, biological, or 102
microbiological property or characteristic that should be within an appropriate limit, 103
Version 8.1 3
range, or distribution to ensure the desired product quality. CQAs are generally 104
associated with the drug substance, excipients, intermediates, and drug product. 105
106
Drug product CQAs include the properties that impart the desired quality, safety, and 107
efficacy. CQAs of solid oral dosage forms are typically those aspects affecting 108
product purity, potency, stability, and drug release. CQAs for other delivery systems 109
can additionally include more product specific aspects, such as aerodynamic properties 110
for inhaled products, sterility for parenterals, and adhesive force for transdermal 111
patches. For drug substances or intermediates, the CQAs can additionally include 112
those properties (e.g., particle size distribution, bulk density) that affect downstream 113
processability. 114
115
Drug product CQAs are used to guide the product and process development. Potential 116
drug product CQAs can be identified from the target product profile and/or prior 117
knowledge. The list of potential CQAs can be modified when the formulation and 118
manufacturing process are selected and as product knowledge and process 119
understanding increase. Quality risk management can be used to prioritize the list of 120
potential CQAs for subsequent evaluation. Relevant CQAs can be identified by an 121
iterative process of quality risk management and experimentation that assesses the 122
extent to which their variation can have an impact on the quality of the drug product. 123
124
2.3 Linking Material Attributes and Process Parameters to CQAs – Risk 125
Assessment 126
127
Risk assessment is a valuable science-based process used in quality risk management 128
(see ICH Q9) that can aid in identifying which material attributes and process 129
parameters have an effect on product CQAs. While the risk assessment is typically 130
performed early in the pharmaceutical development, it can be helpful to repeat the risk 131
assessment as information and greater knowledge become available. 132
133
Risk assessment tools can be used to identify and rank parameters (e.g., operational, 134
equipment, input material) with potential to have an impact on product quality based 135
on prior knowledge and initial experimental data. For an illustrative example, see 136
Appendix 2. The initial list of potential parameters can be quite extensive, but is likely 137
to be narrowed as process understanding is increased. The list can be refined further 138
through experimentation to determine the significance of individual variables and 139
potential interactions. Once the significant parameters are identified, they can be 140
further studied (e.g., through a combination of design of experiments, mathematical 141
models, or studies that lead to mechanistic understanding) to achieve a higher level of 142
process understanding. 143
144
2.4 Design Space 145
146
The linkage between the process inputs (input variables and process parameters) and 147
the critical quality attributes can be described in the design space. 148
149
2.4.1 Selection of variables. 150
151
The risk assessment and process development experiments described in Section 2.3 152
can not only lead to an understanding of the linkage and effect of process inputs on 153
product CQAs, but also help identify the variables and their ranges within which 154
consistent quality can be achieved. These input variables can thus be selected for 155
Version 8.1 4
inclusion in the design space. 156
157
An explanation should be provided in the application to describe what variables were 158
considered, how they affect the process and product quality, and which parameters 159
were included or excluded in the design space. An input variable or process parameter 160
need not be included in the design space if it has no effect on delivering CQAs when 161
the input variable or parameter is varied over the full potential range of operation. The 162
control of these variables would be under good manufacturing practices (GMP). 163
However, the knowledge gained from studies should be described in the submission. 164
165
2.4.2 Defining and describing a design space in a submission 166
167
A design space can be defined in terms of ranges of input variables or parameters, or 168
through more complex mathematical relationships. It is possible to define a design 169
space as a time dependent function (e.g., temperature and pressure cycle of a 170
lyophilisation cycle), or as a combination of variables such as principal components of 171
a multivariate model. Scaling factors can also be included if the design space is 172
intended to span multiple operational scales. Analysis of historical data can provide 173
the basis for establishing a design space. Regardless of how a design space is 174
developed, it is expected that operation within the design space will result in a product 175
meeting the defined quality attributes. 176
177
Examples of different potential approaches to presentation of a design space are 178
presented in Appendix 2. 179
180
2.4.3 Unit operation design space(s) 181
182
The applicant can choose to establish independent design spaces for one or more unit 183
operations, or to establish a single design space that spans multiple operations. While a 184
separate design space for each unit operation is often simpler to develop, a design 185
space that spans the entire process can provide more operational flexibility. For 186
example, in the case of a drug product that undergoes degradation in solution before 187
lyophilisation, the design space to control the extent of degradation (e.g., 188
concentration, time, temperature) could be expressed for each unit operation, or as a 189
sum over all unit operations. 190
191
2.4.4 Relationship of design space to scale and equipment 192
193
When defining a design space, the applicant should keep in mind the type of 194
operational flexibility desired. A design space can be developed at small scale or pilot 195
scale. The applicant should justify the relevance of a design space developed at small 196
or pilot scale to the proposed production scale manufacturing process and discuss the 197
potential risks in the scale-up operation. 198
199
If the applicant wishes the design space to be applicable to multiple operational scales, 200
the design space should be described in terms of relevant scale-independent 201
parameters. For example, if a product was determined to be shear sensitive in a mixing 202
operation, the design space could include shear rate, rather than agitation rate. 203
Dimensionless numbers and/or models for scaling also can be included as part of the 204
design space description. 205
206
The creation of a design space can be helpful for technology transfer or site changes. 207
Version 8.1 5
The subsequent regulatory processes will be region-specific. 208
209
2.4.5 Design space versus proven acceptable ranges 210
211
A combination of proven acceptable ranges does not constitute a design space. 212
However, proven acceptable ranges based on univariate experimentation can provide 213
some knowledge about the process. 214
215
2.4.6 Design space and edge of failure 216
217
It can be helpful to know where edges of failure could be, or to determine potential 218
failure modes. However, it is not an essential part of establishing a design space. 219
220
2.5 Control Strategy 221
222
A control strategy is designed to consistently ensure product quality. 223
224
The elements of the control strategy discussed in Section P.2 of the dossier should 225
describe and justify how in-process controls and the controls of input materials (drug 226
substance and excipients), container closure system, intermediates and end products 227
contribute to the final product quality. These controls should be based on product, 228
formulation and process understanding and should include, at a minimum, control of 229
the critical parameters and attributes. 230
231
A comprehensive pharmaceutical development approach will generate process and 232
formulation understanding that identifies sources of variability. Critical sources of 233
variability that can lead to product failures should be identified, appropriately 234
understood, and managed or controlled. Understanding sources of variability and their 235
impact on downstream processes or processing, intermediate products and finished 236
product quality can provide flexibility for shifting of controls upstream and minimise 237
the need for end product testing. This process understanding, in combination with 238
quality risk management (see ICH Q9), will support the control of process parameters 239
so that the variability of raw materials can be compensated for in an adaptable process 240
to deliver consistent product quality. 241
242
This process understanding enables an alternative manufacturing paradigm where the 243
variability of input materials might not need to be tightly constrained. Instead it can be 244
possible to design an adaptive process step (a step that is responsive to the input 245
materials) to ensure consistent product quality. 246
247
Enhanced understanding of product performance can justify the use of surrogate tests 248
or support real-time release in lieu of end-product testing. For example, disintegration 249
could serve as a surrogate for dissolution for fast-disintegrating solid forms with 250
highly soluble drug substances. Unit dose uniformity performed in-process (e.g., 251
using weight variation coupled with near infrared (NIR) assay) can enable real-time 252
release and provide an increased level of quality assurance compared to the traditional 253
end-product testing using compendial content uniformity standards. 254
255
Elements of a control strategy can include, but are not limited to, the following: 256
257
Version 8.1 6
• Control of input material attributes (e.g., drug substance, excipients, primary 258
packaging materials) based on an understanding of their impact on 259
processability or product quality 260
• Product specification(s) 261
• Controls for unit operations that have an impact on downstream processing or 262
end-product quality (e.g., the impact of drying on degradation, particle size 263
distribution of the granulate on dissolution) 264
• In-process or real-time release in lieu of end-product testing 265
• A monitoring program (e.g., full product testing at regular intervals) for 266
verifying multivariate prediction models. 267
268
A control strategy can include redundant or alternative elements, if justified. For 269
example, one element of the control strategy could rely on end-product testing, 270
whereas an additional or alternative element could depend on real-time release using 271
process analytical technology (PAT). The use of these alternative elements should be 272
described in the submission. 273
274
Adoption of the principles in this guideline can support the justification of alternative 275
approaches to the setting of specification attributes and acceptance criteria as 276
described in Q6A and Q6B. 277
278
2.6 Product Lifecycle Management and Continual Improvement 279
280
Throughout the product lifecycle, companies have opportunities to evaluate innovative 281
approaches to improve product quality (see ICH Q10). 282
283
For example, once approved, a design space provides the applicant flexibility to 284
optimize and adjust a process as managed under their quality system. A design space 285
is not necessarily static in nature and should be periodically reassessed to ensure that 286
the process is working as anticipated to deliver product quality attributes. For certain 287
design spaces using mathematical models (e.g., chemometrics models of NIR) 288
periodic maintenance could be essential to ensure the models’ performance (e.g., 289
checking calibration), or to update the model based upon additional data. Expansion, 290
reduction or redefinition of the design space could be desired upon gaining additional 291
process information. 292
293
3. Submission of Pharmaceutical Development and Related Information in 294
Common Technical Document (CTD) Format 295
296
Pharmaceutical development information is submitted in Section P.2 of the CTD. 297
Other information resulting from pharmaceutical development studies could be 298
accommodated by the CTD format in a number of different ways and some specific 299
suggestions are provided below. Certain aspects (e.g., product lifecycle management, 300
continual improvement) of this guidance are handled under the applicant’s 301
pharmaceutical quality system (see ICH Q10) and need not be submitted in the 302
registration application. 303
304
3.1 Quality Risk Management and Product and Process Development 305
306
Quality risk management can be used at many different stages during product and 307
process development and manufacturing implementation. The assessments used to 308
guide and justify development decisions can be included in the relevant sections of 309
Version 8.1 7
P.2. For example, risk analyses and functional relationships linking material attributes 310
to product CQAs can be included in P.2.1, P.2.2, and P.2.3. Risk analyses linking the 311
design of the manufacturing process to product quality can be included in P.2.3. 312
313
3.2 Design Space 314
315
As an element of the proposed manufacturing process, the design space(s) can be 316
described in the section of the application that includes the description of the 317
manufacturing process and process controls (P.3.3). If appropriate, additional 318
information can be provided in the section of the application that addresses the 319
controls of critical steps and intermediates (P.3.4). The relationship of the design 320
space(s) to the overall control strategy can be explained in the section of the 321
application that includes the justification of the drug product specification (P.5.6). The 322
product and manufacturing process development sections of the application (P.2.1, 323
P.2.2, and P.2.3) are appropriate places to summarise and describe product and process 324
development studies that provide the basis for the design space(s). 325
326
3.3 Control Strategy 327
328
The section of the application that includes the justification of the drug product 329
specification (P.5.6) is a good place to summarise the control strategy. The summary 330
should be clear about the various roles played by different components of the control 331
strategy. However, detailed information about input material controls, and process 332
controls should still be provided in the appropriate CTD format sections (e.g., drug 333
substance section (S), control of excipients (P.4), description of manufacturing process 334
and process controls (P.3.3), controls of critical steps and intermediates (P.3.4)). 335
336
3.4 Drug Substance Related Information 337
338
If drug substance CQAs have the potential to affect the CQAs or manufacturing 339
process of the drug product, some discussion of drug substance CQAs can be 340
appropriate in the pharmaceutical development section of the application (e.g., P.2.1). 341
342
Version 8.1 8
4. GLOSSARY 343
344
Control Strategy: A planned set of controls, derived from current product and process 345
understanding, that assures process performance and product quality. The controls can 346
include parameters and attributes related to drug substance and drug product materials 347
and components, facility and equipment operating conditions, in-process controls, 348
finished product specifications, and the associated methods and frequency of 349
monitoring and control. (ICH Q10) 350
351
Critical Quality Attribute (CQA): A physical, chemical, biological or microbiological 352
property or characteristic that should be within an appropriate limit, range, or 353
distribution to ensure the desired product quality. 354
355
Critical Process Parameter: A process parameter whose variability has an impact on a 356
critical quality attribute and therefore should be monitored or controlled to ensure the 357
process produces the desired quality. 358
359
Edge of Failure: The boundary to a variable or parameter, beyond which the relevant 360
quality attributes or specification cannot be met. 361
362
Proven Acceptable Range: A characterised range of a process parameter for which 363
operation within this range, while keeping other parameters constant, will result in 364
producing a material meeting relevant quality criteria. 365
366
Quality by Design: A systematic approach to development that begins with predefined 367
objectives and emphasizes product and process understanding and process control, 368
based on sound science and quality risk management. 369
370
Real-time release: The ability to evaluate and ensure the acceptable quality of in-371
process and/or final product based on process data, which typically include a valid 372
combination of assessed material attributes and process controls. 373
374
Version 8.1 9
Appendix 1. Differing Approaches to Pharmaceutical Development 375
376
Note: This table is intended only to illustrate some potential contrasts between what 377
might be considered a minimal approach and an enhanced approach regarding 378
different aspects of pharmaceutical development and lifecycle management. It is not 379
intended to specifically define the approach. Current practices in the pharmaceutical 380
industry vary and typically lie between these approaches. 381
Aspect Minimal Approach Enhanced, quality by design Approach
Overall
Pharmaceutical
Development
• Mainly empirical
• Developmental research often
conducted one variable at a time
• Systematic, relating mechanistic
understanding of input material attributes
and process parameters to drug product
CQAs
• Multivariate experiments to understand
product and process
• Establishment of design space
• PAT tools utilised
Manufacturing
Process
• Fixed
• Validation primarily based on initial
full-scale batches
• Focus on optimisation and
reproducibility
• Adjustable within design space
• Lifecycle approach to validation and,
ideally, continuous process verification
• Focus on control strategy and robustness
• Use of statistical process control methods
Process
Controls
• In-process tests primarily for go/no go
decisions
• Off-line analysis
• PAT tools utilised with appropriate feed
forward and feedback controls
• Process operations tracked and trended to
support continual improvement efforts
post-approval
Product
Specifications
• Primary means of control
• Based on batch data available at time of
registration
• Part of the overall quality control strategy
• Based on desired product performance
with relevant supportive data
Control
Strategy
• Drug product quality controlled
primarily by intermediate and end
product testing.
• Drug product quality ensured by risk-
based control strategy for well understood
product and process
• Quality controls shifted upstream, with
the possibility of real-time release or
reduced end-product testing
Lifecycle
Management
• Reactive (i.e., problem solving and
corrective action)
• Preventive action
• Continual improvement facilitated
382
Version 8.1 10
Appendix 2. Illustrative Examples 383
384
Example of use of a risk assessment tool. 385
386
For example, a cross-functional team of experts could work together to develop an 387
Ishikawa (fishbone) diagram that identifies all potential variables which can have an 388
impact on the desired quality attribute. The team could then rank the variables based 389
on probability, severity, and detectability using failure mode effect analysis (FMEA) 390
or similar tools based on prior knowledge and initial experimental data. Design of 391
experiments or other experimental approaches could then be used to evaluate the 392
impact of the higher ranked variables, to gain greater understanding of the process, 393
and to develop a proper control strategy. 394
395
Ishikawa Diagram 396
397
398
399
400
401
402
403
404
405
406
407
408
409
410
411
412
413
414
415
416
417
Water
Content
Drying
Granulation
Raw
Materials
Compressing
Plant
Factors
Temp/RH
Precompressing
Main Compressing
Feeder Speed
Press Speed
Punch Penetration
Depth
Temp
RH
Air Flow
Shock Cycle
Drug
Substance
P.S.
Process Conditions
LOD
Diluents
P.S.
LOD
Other
Lubricant
Disintegrant
Binder
Water
Binder
Temp
Spray Rate
Spray Pattern
P.S.
Scrape Down
Chopper Speed
Mixer Speed
Endpoint
Power
Time
Age
Tooling
Operator
Training
Analytical
Method
Sampling
Feed
Frame
Tablet
Drying
Granulation
Raw
Materials
Compressing
Plant
Factors
Temp/RH
Precompressing
Main Compressing
Feeder Speed
Press Speed
Punch Penetration
Depth
Temp
RH
Air Flow
Shock Cycle
Drug
Substance
P.S.
Process Conditions
LOD
Diluents
P.S.
LOD
Other
Lubricant
Disintegrant
Binder
Water
Binder
Temp
Spray Rate
Spray Pattern
P.S.
Scrape Down
Chopper Speed
Mixer Speed
Endpoint
Power
Time
Age
Tooling
Operator
Training
Analytical
Method
Sampling
Feed
Frame
Version 8.1 11
Example of depiction of interactions 418
419
The figure below depicts the effect of interactions, or lack thereof, between three 420
process parameters on the level of degradation product Y. The figure shows a series 421
of two-dimensional plots showing the effect of interactions among three process 422
parameters (initial moisture content, temperature, mean particle size) of the drying 423
operation of a granulate (drug product intermediate) on degradation product Y. The 424
relative slopes of the lines or curves within a plot indicate if interaction is present. In 425
this example, initial moisture content and temperature are interacting; but initial 426
moisture content and mean particle size are not, nor are temperature and mean particle 427
size. 428
0
0.5
1.0
1.5
%
Y
Initial
moisture
content
100°C
15 20 25 30
15%
30%
Temperature
700 µm
60 80 100
Mean
particle size
1 2 3 4 5 6 7
0
0
100 µm
60°C
700 µm
100 µm
15%
30%
100°C
60°C
(MPS = 400 µm)
(MPS = 400 µm)
(Temp = 80°C)
(Temp = 80°C) (IMC = 22.5%)
(IMC = 22.5%)
IMC (%) Temp (°C) MPS (x100 µm)
0.5
1.0
1.5
%
Y
0.5
1.0
1.5
%
Y
429
430
Version 8.1 12
Illustrative examples of presentation of design space 431
432
Figure 1: Design space described with the aid of response surface plot (Figure 1a) or 433
contour plot (Figure 1b) and defined by non-linear (Figure 1c) or linear combination 434
(Figure 1d) of process parameter ranges. In this example, the effects of the two 435
parameters are additive, but the two parameters do not interact. 436
437
438
439
Figure 1a: Response surface plot of
dissolution as a function of two
parameters of a granulation operation.
Dissolution above 80% is desired.
Figure 1b: Contour plot of dissolution
from example 1a.
440
441
442
Figure 1c: Design space for granulation
parameters, defined by a non-linear
combination of their ranges, that delivers
satisfactory dissolution (i.e., >80%). In
this example, the design space can be
optionally expressed by equations that
describe the boundaries, i.e.,
• Parameter 1 has a range of 41 to 56
• Parameter 2 has a lower limit of 0
and an upper limit that is a function of
Parameter 1
Figure 1d: Design space for granulation
parameters, defined by a linear
combination of their ranges, that delivers
satisfactory dissolution (i.e., >80%).
This design space is a subset of the non-
linear design space from Example 1c,
and can be optionally expressed as the
following:
• Parameter 1 has a range of 44 to 53
• Parameter 2 has a range of 0 to 1.1
443
Where multiple parameters are involved, the design space can be presented for two 444
parameters, in a manner similar to the examples shown above, at different values (e.g., 445
high, middle, low) within the range of the third parameter, the fourth parameter, and 446
so on. A stacked plot of these design spaces can be considered, if appropriate. 447
Version 8.1 13
Figure 2: Design space determined from the common region of successful operating 448
ranges for multiple CQAs. The relations of two CQAs, i.e., friability and dissolution, 449
to two process parameters of a granulation operation are shown in Figures 2a and 2b. 450
Figure 2c shows the overlap of these regions and the maximum ranges of the potential 451
design space. 452
453
454
455
Figure 2a: Contour plot of friability as a
function of Parameters 1 and 2.
Figure 2b: Contour plot of dissolution as
a function of Parameters 1 and 2.
456
457
458
459
Figure 2c: Potential process design
space, comprised of the overlap region
of design ranges for friability and or
dissolution.
460
Version 8.1 14
Figure 3: The design space for a drying operation that is dependent upon the path 461
of temperature and/or pressure over time. The end point for moisture content is 1-462
2%. Operating above the upper limit of the design space can cause excessive 463
impurity formation, while operating below the lower limit of the design space can 464
result in excessive particle attrition. 465
466
467
468
469
470
0%
5%
10%
15%
20%
25%
30%
35%
0 2 4 6 8 10 12
time (hr)
M
oi
st
ur
e
C
on
te
nt
Design space
lower limit
Design space
upper limit
Target drying curve
Excessive
impurity
formation
Excessive
particle
attrition
Endpoint
criterion
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Datei
PD
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E-mail info@ema.europa.eu Website www.ema.europa.eu An agency of the European Union
© European Medicines Agency, 2010. Reproduction is authorised provided the source is acknowledged.
December 2010
EMA/CHMP/ICH/265145/2009
Committee for medicinal products for human use (CHMP)
ICH guideline Q8, Q9 and Q10 - questions and answers
volume 4
Step 5
Transmission to CHMP for information December 2010
Release for information December 2010
ICH guideline Q8, Q9 and Q10 - questions and answers volume 4
EMA/CHMP/ICH/265145/2009 Page 2/17
ICH guideline Q8, Q9 and Q10 - questions and answers
volume 4
Table of contents
1. Introduction ............................................................................................ 3
1.1. For general clarification....................................................................................... 4
2. Quality by design topics .......................................................................... 5
2.1. Design space ..................................................................................................... 5
2.2. Real time release testing..................................................................................... 7
2.3. Control strategy............................................................................................... 10
3. Pharmaceutical quality system.............................................................. 11
4. ICH new quality guidelines’ impact on GMP inspection practices........... 13
5. Knowledge management ....................................................................... 14
6. Software solutions................................................................................. 16
1. Introduction
This Questions and Answers document (Q&A) refers to the current working procedure of the ICH Q-
IWG on implementing the guidelines of Q8, Q9 and Q10 which have been approved by the ICH
Steering Committee.
The benefits of harmonizing technical requirements across the ICH regions can only be reached if the
various Q-ICH guidelines are implemented and interpreted in a consistent way across the three
regions. Implementation Working Group is tasked to develop Q&As to facilitate implementation of
existing guidelines.
References
ICH
Q8(R2)
Pharmaceutical Development
Part I: ‘Pharmaceutical Development’
Part II: ‘Annex to Pharmaceutical Development’
http://www.ich.org/LOB/media/MEDIA4986.pdf
approved Aug. 2009
approved Nov. 10 2005
approved Nov. 13 2008
ICH Q9 Quality Risk Management
http://www.ich.org/LOB/media/MEDIA1957.pdf
approved Nov. 09 2005
ICH Q10 Pharmaceutical Quality Systems
http://www.ich.org/LOB/media/MEDIA3917.pdf
approved Jun. 04 2008
ICH guideline Q8, Q9 and Q10 - questions and answers volume 4
EMA/CHMP/ICH/265145/2009 Page 3/17
http://www.ich.org/LOB/media/MEDIA4986.pdf
http://www.ich.org/LOB/media/MEDIA1957.pdf
http://www.ich.org/LOB/media/MEDIA3917.pdf
Q8, Q9 and Q10 - questions and answers volume 4
EMA/CHMP/ICH/265145/2009 Page 4/17
Q8, Q9 and Q10 - questions and answers volume 4
1.1. For general clarification 1
Date of
Approval
Question Answer
1 June
2009
Is the minimal approach accepted by regulators? Yes. The minimal approach as defined in Q8(R2) (sometime also called
‘baseline’ or ‘traditional’ approach) is the expectation which is to be
achieved for a fully acceptable submission. However the ‘enhanced’
approach as described in ICH Q8(R2) is encouraged (Ref. Q8(R2) Appendix
1).
2 Oct.
2009
What is an appropriate approach for process validation
using ICH Q8, Q9 and Q10?
The objective of process validation are unchanged when using ICH Q8, Q9
and Q10. The main objective of process validation remains that a process
design yields a product meeting its pre-defined quality criteria. ICH Q8, Q9
and Q10 provide a structured way to define product critical quality
attributes, design space, the manufacturing process and the control
strategy. This information can be used to identify the type and focus of
studies to be performed prior to and on initial commercial production
batches. As an alternative to the traditional process validation, continuous
process verification [see definition in ICH Q8R(2) glossary] can be utilised
in process validation protocols for the initial commercial production and for
manufacturing process changes for the continual improvement throughout
the remainder of the product lifecycle.
3 Oct.
2009
How can information from risk management and
continuous process verification provide for a robust
continual improvement approach under ICH Q8, Q9 and
Q10?
Like the product itself, process validation also has a lifecycle (process
design, process qualification and ongoing process verification). A risk
assessment conducted prior to initial commercial validation batches can
highlight the areas where particular focus and data is needed to
demonstrate the desired high level of assurance of commercial process
robustness. Continual monitoring (e.g. via Continuous Process Verification)
Q8, Q9 and Q10 - questions and answers volume 4
EMA/CHMP/ICH/265145/2009 Page 5/17
Date of
Approval
Question Answer
can further demonstrate the actual level of assurance of process
consistency and provide the basis for continual improvement of the
product. Quality Risk Management methodologies of ICH Q9 can be
applied throughout the product lifecycle to maintain a state of process
control.
2. Quality by design topics 2
Date of
Approval
Question Answer
1 April
2009
Is it always necessary to have a Design Space (DS) or
Real Time Release (RTR) testing to implement QbD?
Under Quality by Design, establishing a design space or using real time
release testing is not necessarily expected [ICH Q8(R2), Step 4].
2.1. Design space 3
Date of
Approval
Question Answer
1 April
2009
Is it necessary to study multivariate interactions of all
parameters to develop a design space?
No, the applicant will need to justify the choice of material attributes and
parameters for multivariate experimentation based on risk assessment and
desired operational flexibility.
2 April
2009
Can a design space be applicable to scale-up? Yes, when appropriately justified [additional details see Q8(R2) Section
2.4.4]. An example of a scale-independent design space is provided in the
EFPIA Mock P2 document [EFPIA Mock P2 submission on “Examplain”:
Chris Potter, Rafael Beerbohm, Alastair Coupe, Fritz Erni, Gerd Fischer,
Staffan Folestad, Gordon Muirhead, Stephan Roenninger, Alistair Swanson,
A guide to EFPIA's "Mock P.2" Document, Pharm. Tech. (Europe), 18,
December 2006, 39-44].
This example may not reflect the full regulatory requirements for a scale-
Date of
Approval
Question Answer
up.
3 April
2009
Can a design space be applicable to a site change? Yes, it is possible to justify a site change using a site independent design
space based on a demonstrated understanding of the robustness of the
process and an in depth consideration of site specific factors, e.g.,
equipment, personnel, utilities, manufacturing environment, and
equipment. There are region specific regulatory requirements associated
with site changes that need to be followed.
4 April
2009
Can a design space be developed for single and/or multiple
unit operations?
Yes, it is possible to develop a design space for single unit operations or
across a series of unit operations [see Q8(R2) Section 2.4.3].
5 April
2009
Is it possible to develop a design space for existing
products?
Yes, it is possible. Manufacturing data and process knowledge can be used
to support a design space for existing products. Relevant information
should be utilised from e.g., commercial scale manufacturing, process
improvement, CAPA and development data.
For manufacturing operations run under narrow operational ranges in fixed
equipment, an expanded region of operation and an understanding of
multi-parameter interactions may not be achievable from existing
manufacturing data alone and additional studies may be needed to develop
a design space. Sufficient knowledge should be demonstrated and the
design space should be supported experimentally to investigate
interactions and establish parameter/attribute ranges.
6 April
2009
Is there a regulatory expectation to develop a design
space for an existing product?
No, development of design space for existing products is not necessary
unless the applicant has a specific need and desires to use a design space
as a means to achieve a higher degree of product and process
understanding. This may increase manufacturing flexibility and/or
robustness.
7 June
2009
Can a design space be applicable to formulation? Yes, it may be possible to develop formulation (not component but rather
composition) design space consisting of the ranges of excipient amount and
its physicochemical properties (e.g., particle size distribution, substitution
degree of polymer) based on an enhanced knowledge over a wider range of
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Date of
Approval
Question Answer
material attributes. The applicant should justify the rationale for
establishing the design space with respect to quality attributes such as
bioequivalence, stability, manufacturing robustness etc. Formulation
adjustment within the design space depending on material attributes does
not need a submission in a regulatory post approval change.
8 June
2009
Does a set of proven acceptable ranges alone constitute a
design space?
No, a combination of proven acceptable ranges (PARs) developed from
univariate experimentation does not constitute a design space [see Q8(R2),
Section 2.4.5.]. Proven acceptable ranges from only univariate
experimentation may lack an understanding of interactions between the
process parameters and/or material attributes. However proven acceptable
ranges continue to be acceptable from the regulatory perspective but are
not considered a design space [see ICH Q8(R2) Section 2.4.5].
The applicant may elect to use proven acceptable ranges or design space
for different aspects of the manufacturing process.
9 Nov
2010
Should the outer limits of the Design Space be
evaluated during process validation studies at the
commercial scale?
No. There is no need to run the qualification batches at the outer
limits of the design space during process validation studies at
commercial scale. The design space must be sufficiently explored
earlier during development studies (for scale up see also chapter
2.1 Design Space Q02; for life cycle approach see chapter 1.1 for
general clarification Q03).
2.2. Real time release testing 4
Date of
Approval
Question Answer
1 April
2009
How is batch release affected by employing real time
release testing?
Batch release is the final decision to release the product to the market
regardless whether RTR testing or end product testing is employed. End
product testing involves performance of specific analytical procedures on a
defined sample size of the final product after completion of all processing
Date of
Approval
Question Answer
for a given batch of that product. Results of real time release testing are
handled in the same manner as end product testing results in the batch
release decision. Batch release involves an independent review of batch
conformance to predefined criteria through review of testing results and
manufacturing records together with appropriate GMP compliance and
quality system, regardless of which approach is used.
2 April
2009
Does real time release testing mean elimination of end
product testing?
Real time release testing does not necessarily eliminate all end product
testing. For example, an applicant may propose RTR testing for some
attributes only or not all. If all CQAs (relevant for real time release testing)
are assured by in-process monitoring of parameters and/or testing of
materials, then end product testing might not be needed for batch release.
Some product testing will be expected for certain regulatory processes such
as stability studies or regional requirements.
3 April
2009
Is a product specification still necessary in the case of RTR
testing?
Yes, product specifications [see ICH Q6A and Q6B] still need to be
established and met, when tested.
4 April
2009
When using RTR testing, is there a need for stability test
methods?
Even where RTR testing is applied, a stability monitoring protocol that uses
stability indicating methods is required for all products regardless of the
means of release testing. [see ICH Q1A and ICH Q5C].
5 April
2009
What is the relationship between Control Strategy and RTR
testing?
RTR testing, if utilized, is an element of the Control Strategy in which tests
and/or monitoring can be performed as in process testing (in-line, on-line,
at-line) rather than tested on the end product.
6 April
2009
Do traditional sampling approaches apply to RTR testing? No, traditionally sampling plans for in-process and end-product testing
involve a discrete sample size that represents the minimal sampling
expectations. Generally, the use of RTR testing will include more extensive
on-line/in-line measurement. A scientifically sound sampling approach
should be developed, justified, and implemented.
7 April
2009
If RTR testing results fail or trending toward failure, can
end-product testing be used to release the batch?
No, in principle the RTR testing results should be routinely used for the
batch release decisions and not be substituted by end-product testing. Any
failure should be investigated and trending should be followed up
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Date of
Approval
Question Answer
appropriately. However, batch release decisions will need to be made
based on the results of the investigations. The batch release decision needs
to comply with the content of the marketing authorisation and GMP
compliance.
8 June
2009
What is the relationship between in-process testing and
RTR testing?
In-process testing includes any testing that occurs during the
manufacturing process of drug substance and/or finished product. Real
time release testing includes those in-process tests that directly impact the
decision for batch release through evaluation of Critical Quality Attributes.
9 June
2009
What is the difference between ‘real time release’ and ‘real
time release testing’?
The definition of ‘real time release testing’ in Q8(R2) is ‘the ability to
evaluate and ensure the acceptable quality of in-process and/or final
product based on process data, which typically includes a valid combination
of measured material attributes and process controls.
The term ‘Real time release’ in the Q8(R2), Step 2 document was revised
to ‘Real time release testing’ in the final Q8(R2) Part II document to fit the
definition more accurately and thus avoid confusion with batch release.
10 June
2009
Can surrogate measurement be used for RTR testing? Yes, RTR testing can be based on measurement of a surrogate (e.g.,
process parameter, material attribute) that has been demonstrated to
correlate with an in process or end product specification [see ICH Q8(R2);
Section 2.5.].
11 Oct.
2009
What is the relationship between RTR testing and
Parametric Release?
Parametric release is one type of RTR testing. Parametric release is based
on process data (e.g. temperature, pressure, time for terminal sterilization,
physicochemical indicator) rather than the testing of material and/or a
sample for a specific attribute.
5
6
Q8, Q9 and Q10 - questions and answers volume 4
EMA/CHMP/ICH/265145/2009 Page 10/17
2.3. Control strategy 7
8
9
10
11
12
Refer to the definition of control strategy provided in the ICH Q10 glossary: Q10 Control Strategy definition: ‘a planned set of controls, derived from current
product and process understanding that assures process performance and product quality. The controls can include parameters and attributes related to drug
substance and drug product materials and components, facility and equipment operating conditions, in-process controls, finished product specifications, and
the associated methods and frequency of monitoring and control.’
Date of
Approval
Question Answer
1 April
2009
What is the difference in a control strategy for products
developed using the minimal approach vs. ‘quality-by-
design’ approach?
Control strategies are expected irrespective of the development approach.
Control strategy includes different types of control proposed by the
applicant to assure product quality (Section 3.2.1 ICH Q10), such as in-
process testing and end-product testing. For products developed following
the minimal approach, the control strategy is usually derived empirically
and typically relies more on discrete sampling and end product testing.
Under QbD, the control strategy is derived using a systematic science and
risk-based approach. Testing, monitoring or controlling is often shifted
earlier into the process and conducted in-line, on-line or at-line testing.
2 April
2009
Are GMP requirements different for batch release under
QbD?
No, the same GMP requirements apply for batch release under minimal and
QbD approaches.
3 April
2009
What is the relationship between a Design Space and a
Control Strategy?
A control strategy is required for all products. If a Design Space is
developed and approved, the Control Strategy [see ICH Q8(R2), Part II,
Section 4] provides the mechanism to ensure that the manufacturing
process is maintained within the boundaries described by the Design
Space.
4 June
2009
What approaches can be taken in the event of on-line/in-
line/at-line testing or monitoring equipment breakdown?
The control strategy provided in the application should include a proposal
for use of alternative testing or monitoring approaches in cases of
equipment failure. The alternative approach could involve use of end
product testing or other options, while maintaining an acceptable level of
quality. Testing or monitoring equipment breakdown needs to be managed
in the context of a deviation under the Quality System and can be covered
Q8, Q9 and Q10 - questions and answers volume 4
EMA/CHMP/ICH/265145/2009 Page 11/17
Date of
Approval
Question Answer
by GMP inspection.
5 Oct.
2009
Are product specifications different for minimal versus
QbD approaches?
In principle no, the same product specifications are needed for minimal and
QbD approaches. For a QbD approach, the control strategy may allow
achieving the end product specifications via real time release testing
approaches [see ICH Q8(R2), Appendix 1]. Product must meet
specification, when tested.
3. Pharmaceutical quality system 13
Date of
Approval
Question Answer
1 April
2009
What are the benefits of implementing a Pharmaceutical
Quality System (in accordance with ICH Q10)?
The benefits are:
Facilitated robustness of the manufacturing process, through facilitation of
continual improvement through science and risk-based post approval
change processes;
Consistency in the global pharmaceutical environment across regions;
Enable transparency of systems, processes, organisational and
management responsibility;
Clearer understanding of the application of a Quality System throughout
product lifecycle;
Further reducing risk of product failure and incidence of complaints and
recalls thereby providing greater assurance of pharmaceutical product
consistency and availability (supply) to the patient;
Better process performance;
Opportunity to increase understanding between industry and regulators
and more optimal use of industry and regulatory resources. Enhance
manufacturer’s and regulators’ confidence in product quality;
Increased compliance with GMPs, which builds confidence in the regulators
and may result in shorter inspections.
Date of
Approval
Question Answer
2 April
2009
How does a company demonstrate implementation of PQS
in accordance with ICH Q10?
When implemented, a company will demonstrate the use of an effective
PQS through its documentation (e.g., policies, standards), its processes, its
training/qualification its management its continual improvement efforts,
and its performance against pre-defined Key Performance Indicators [see
ICH Q10 glossary on ‘Performance indicator’].
A mechanism should be established to demonstrate at a site how the PQS
operates across the product lifecycle, in an easily understandable way for
management, staff and regulatory inspectors, e.g., a quality manual,
documentation, flowcharts, procedures. Companies can implement a
program in which the PQS is routinely audited in-house (i.e., internal audit
program) to ensure that the system is functioning at a high level.
3 April
2009
Is it necessary to describe the PQS in a regulatory
submission?
No, however relevant elements of the PQS, such as quality monitoring
system, change control and deviation management may be referenced as
part of the control strategy as supporting information.
4 April
2009
Will there be certification that the PQS is in accordance
with ICH Q10?
No. There will not be a specific ICH Q10 certification programme.
5 April
2009
How should the implementation of the design space be
evaluated during inspection of the manufacturing site?
Inspection should verify/assess that manufacturing operations are
appropriately carried out within the Design Space. The inspector in
collaboration with the assessor, where appropriate, should also verify
successful manufacturing operations under the Design Space and that
movement within the Design Space is managed within the company’s
change management system [see ICH Q10, Section 3.2. Table III].
6 April
2009
What should be done if manufacturing operations run
inadvertently outside of the Design Space?
This should be handled as a deviation under GMP. For example unplanned
‘one-off‘ excursions occurring as a result of unexpected events, such as
operator error or equipment failure, would be investigated, documented
and dealt with as a deviation in the usual way. The results of the
investigation may contribute to the process knowledge, preventive actions
and continual improvement of the product.
7 June What information and documentation of the development Pharmaceutical development information (e.g., supporting information on
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Date of
Approval
Question Answer
2009 studies should be available at a manufacturing site? design space, chemometric model, risk management,…) is available at the
development site. Pharmaceutical development information which is useful
to ensure the understanding of the basis for the manufacturing process and
control strategy, including the rationale for selection of critical process
parameters and critical quality attributes should be available at the
manufacturing site.
Scientific collaboration and knowledge sharing between pharmaceutical
development and manufacturing is essential to ensure the successful
transfer to production.
8 June
2009
Can process parameters be adjusted throughout the
product lifecycle?
Process parameters are studied and selected during pharmaceutical
development and monitored during commercial manufacturing. Knowledge
gained could be utilized for adjustment of the parameters as part of
continual improvement of the process throughout the lifecycle of the drug
product (see ICH Q10, Section 3.).
4. ICH new quality guidelines’ impact on GMP inspection practices 14
Date of
Approval
Question Answer
1 April
2009
How will product-related inspections differ in an ICH Q8, Q9
and Q10 environment?
In the case of product-related inspection (in particular pre-authorisation)
depending on the complexity of the product and/or process, there could
be a need for greater collaboration between inspectors and assessors for
example for the assessment of development data. The inspection would
normally occur at the proposed commercial manufacturing site and there
is likely to be greater focus on enhanced process understanding and
understanding relationships e.g., Critical Quality Attribute (CQAs), Critical
Process Parameters (CPPs). It will also extend into the application and
implementation of quality risk management principles, as supported by
the Pharmaceutical Quality System (PQS).
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Date of
Approval
Question Answer
2 April
2009
How will system-related inspections differ in an ICH Q8, Q9
and Q10 environment?
The inspection process will remain similar. However upon the
implementation of ICH Q8, Q9 and Q10, inspections will have greater
focus (but not only) on how the PQS facilitates the use of e.g., Quality
Risk Management methods, implementation of design space and change
management [see ICH Q10].
3 Oct.
2009
How is control strategy approved in the application and
evaluated during inspection?
Elements of control strategy submitted in the application will be reviewed
and approved by the regulatory agency. However, additional elements are
subject to inspection (as described in Q10).
5. Knowledge management 15
Date of
Approval
Question Answer
1 April
2009
How has the implementation of ICH Q8, Q9, and Q10
changed the significance and use of knowledge
management?
Q10 defines knowledge management as: ‘Systematic approach to
acquiring, analyzing, storing, and disseminating information related to
products, manufacturing processes and components’.
Knowledge management is not a system; it enables the implementation of
the concepts described in ICH Q8, Q9 and Q10.
Knowledge Management is not a new concept. It is always important
regardless of the development approach. Q10 highlights knowledge
management because it is expected that more complex information
generated by appropriate approaches (e.g., QbD, PAT, real-time data
generation and control monitoring systems) will need to be better
captured, managed and shared during product life-cycle.
In conjunction with Quality Risk Management, Knowledge Management
can facilitate the use of concepts such as prior knowledge (including from
other similar products), development of design space, control strategy,
technology transfer, and continual improvement across the product life
cycle.
Date of
Approval
Question Answer
2 April
2009
Does Q10 suggest an ideal way to manage knowledge? No. Q10 provides a framework and does not prescribe how to implement
knowledge management. Each company decides how to manage
knowledge, including the depth and extent of information assessment
based on their specific needs.
3 April
2009
What are potential sources of information for Knowledge
Management?
Some examples of knowledge sources are:
Prior knowledge based on experience obtained from similar processes
(internal knowledge, industry scientific and technical publications) and
published information (external knowledge: literature and peer-reviewed
publications);
Pharmaceutical development studies;
Mechanism of action;
Structure/function relationships;
Technology transfer activities;
Process validation studies;
Manufacturing experience e.g.
- Internal and Vendor audits;
- Raw material testing data;
Innovation;
Continual improvement;
Change management activities;
Stability reports;
Product Quality Reviews/Annual Product Reviews;
Complaint Reports;
Adverse event reports (Patient safety);
Deviation Reports, Recall Information;
Technical investigations and/or CAPA reports;
Suppliers and Contractors;
Product history and /or manufacturing history;
Ongoing manufacturing processes information (e.g., trends).
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Date of
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Question Answer
Information from the above can be sourced and shared across a site or
company, between companies and suppliers/contractors, products and
across different disciplines (e.g., development, manufacturing,
engineering, quality units).
4 April
2009
Is a specific dedicated computerised information
management system required for the implementation of
knowledge management with respect to ICH Q8, Q9 and
Q10?
No, but such computerised information management systems can be
invaluable in capturing, managing, assessing and sharing complex data
and information.
5 June
2009
Will regulatory agencies expect to see a formal knowledge
management approach during inspections?
No. There is no added regulatory requirement for a formal knowledge
management system. However it is expected that knowledge from
different processes and systems will be appropriately utilised.
Note: ‘formal’ means: it is a structured approach using a recognised
methodology or (IT-) tool, executing and documenting something in a
transparent and detailed manner.
6. Software solutions 16
Date of
Approval
Question Answer
1 April
2009
With the rapid growth of the new science and risk-based
quality paradigm coupled with the IWG efforts to facilitate
globally consistent implementation of Q8, Q9, and Q10, a
number of commercial vendors are now offering products
that are being marketed as 'ICH compliant solutions' or ICH
Q8, 9 & 10 Implementation software, etc. Is it necessary
for a pharmaceutical firm to purchase these products to
achieve a successful implementation of these ICH
No. The ICH Implementation Working Group has not endorsed any
commercial products and does not intend to do so. ICH is not a regulatory
agency with reviewing authority and thus does not have a role in
determining or defining ‘ICH compliance’ for any commercial products.
While there will likely be a continuous proliferation of new products
targeting the implementation of these ICH guidelines, firms will need to
carry out their own evaluation of these products relative to their business
needs.
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Date of
Approval
Question Answer
guidelines within their companies?
17
December 2010
1. Introduction
1.1. For general clarification
2. Quality by design topics
2.1. Design space
2.2. Real time release testing
2.3. Control strategy
3. Pharmaceutical quality system
4. ICH new quality guidelines’ impact on GMP inspection practices
5. Knowledge management
6. Software solutions
04.08.2014
Datei
PD
7 Westferry Circus ● Canary Wharf ● London E14 4HB ● United Kingdom
Telephone +44 (0)20 7418 8400 Facsimile +44 (0)20 7418 8595
E-mail info@ema.europa.eu Website www.ema.europa.eu An agency of the European Union
© European Medicines Agency, 2011. Reproduction is authorised provided the source is acknowledged.
31 January 2011
EMA/INS/GMP/79766/2011
Quality Risk Management (ICH Q9)
The ICH Q9 document on Quality Risk Management was adopted at step 4 at the ICH Steering
Committee meeting on 9 November 2005.
Quality Risk Management can be applied not only in the manufacturing environment, but also in
connection with pharmaceutical development and preparation of the quality part of marketing
authorisation dossiers. The guideline applies also to the regulatory authorities in the fields of
pharmaceutical assessment of the quality part of the marketing authorisation dossier, GMP inspections
and the handling of suspected quality defects. Nevertheless for coherence the text was included within
the GMP Guide as Annex 20 in March 2008. Since the creation of Part III of the GMP Guide it has been
recognised that Part III is a more appropriate location for its publication.
As part of the EU implementation of ICH Q9, an amendment to Chapter 1 of the GMP Guide (Quality
Management) was published in February 2008 which came into force in July 2008. This amendment
incorporated the principles of Quality Risk Management into the Chapter.
The text of this document, formerly Annex 20, remains optional and provides examples of the
processes and applications of Quality Risk Management.
Quality Risk Management (ICH Q9)
EMA/INS/GMP/79766/2011 Page 2/19
Quality Risk Management (ICH Q9)
Table of contents:
1. Introduction ............................................................................................ 3
2. Scope....................................................................................................... 4
3. Principles of quality risk management..................................................... 4
4. General quality risk management process............................................... 4
4.1. Responsibilities ....................................................................................................5
4.2. Initiating a quality risk management process ...........................................................5
4.3. Risk assessment...................................................................................................5
4.4. Risk control .........................................................................................................6
4.5. Risk communication..............................................................................................7
4.6. Risk review..........................................................................................................7
5. Risk management methodology .............................................................. 7
6. Integration of quality risk management into industry and regulatory
operations ................................................................................................... 8
7. Definitions............................................................................................... 9
8. References ............................................................................................ 10
Annex I: Risk management methods and tools.......................................... 11
I.1 Basic risk management facilitation methods..........................................................11
I.2 Failure Mode Effects Analysis (FMEA) ...................................................................11
I.3 Failure Mode, Effects and Criticality Analysis (FMECA) ............................................12
I.4 Fault Tree Analysis (FTA)....................................................................................12
I.5 Hazard Analysis and Critical Control Points (HACCP)...............................................12
I.6 Hazard Operability Analysis (HAZOP) ...................................................................13
I.7 Preliminary Hazard Analysis (PHA).......................................................................13
I.8 Risk ranking and filtering....................................................................................13
I.9 Supporting statistical tools..................................................................................14
Annex II: Potential applications for quality risk management................... 14
II.1 Quality risk management as part of integrated quality management .......................14
II.2 Quality risk management as part of regulatory operations .....................................16
II.3 Quality risk management as part of development .................................................16
II.4 Quality risk management for facilities, equipment and utilities ...............................16
II.5 Quality risk management as part of materials management...................................18
II.6 Quality risk management as part of production ....................................................18
II.7 Quality risk management as part of laboratory control and stability studies .............19
II.8 Quality risk management as part of packaging and labelling ..................................19
Quality Risk Management (ICH Q9)
EMA/INS/GMP/79766/2011 Page 3/19
1. Introduction
Risk management principles are effectively utilized in many areas of business and government
including finance, insurance, occupational safety, public health, pharmacovigilance, and by agencies
regulating these industries. Although there are some examples of the use of quality risk management
in the pharmaceutical industry today, they are limited and do not represent the full contributions that
risk management has to offer. In addition, the importance of quality systems has been recognized in
the pharmaceutical industry and it is becoming evident that quality risk management is a valuable
component of an effective quality system.
It is commonly understood that risk is defined as the combination of the probability of occurrence of
harm and the severity of that harm. However, achieving a shared understanding of the application of
risk management among diverse stakeholders is difficult because each stakeholder might perceive
different potential harms, place a different probability on each harm occurring and attribute different
severities to each harm. In relation to pharmaceuticals, although there are a variety of stakeholders,
including patients and medical practitioners as well as government and industry, the protection of the
patient by managing the risk to quality should be considered of prime importance.
The manufacturing and use of a drug (medicinal) product, including its components, necessarily entail
some degree of risk. The risk to its quality is just one component of the overall risk. It is important to
understand that product quality should be maintained throughout the product lifecycle such that the
attributes that are important to the quality of the drug (medicinal) product remain consistent with
those used in the clinical studies. An effective quality risk management approach can further ensure
the high quality of the drug (medicinal) product to the patient by providing a proactive means to
identify and control potential quality issues during development and manufacturing. Additionally, use of
quality risk management can improve the decision making if a quality problem arises. Effective quality
risk management can facilitate better and more informed decisions, can provide regulators with
greater assurance of a company’s ability to deal with potential risks and can beneficially affect the
extent and level of direct regulatory oversight.
The purpose of this document is to offer a systematic approach to quality risk management. It serves
as a foundation or resource document that is independent of, yet supports, other ICH Quality
documents and complements existing quality practices, requirements, standards, and guidelines within
the pharmaceutical industry and regulatory environment. It specifically provides guidance on the
principles and some of the tools of quality risk management that can enable more effective and
consistent risk based decisions, both by regulators and industry, regarding the quality of drug
substances and drug (medicinal) products across the product lifecycle. It is not intended to create any
new expectations beyond the current regulatory requirements.
It is neither always appropriate nor always necessary to use a formal risk management process (using
recognized tools and/ or internal procedures e.g. standard operating procedures). The use of informal
risk management processes (using empirical tools and/ or internal procedures) can also be considered
acceptable. Appropriate use of quality risk management can facilitate but does not obviate industry’s
obligation to comply with regulatory requirements and does not replace appropriate communications
between industry and regulators.
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2. Scope
This guideline provides principles and examples of tools for quality risk management that can be
applied to different aspects of pharmaceutical quality. These aspects include development,
manufacturing, distribution, and the inspection and submission/review processes throughout the
lifecycle of drug substances, drug (medicinal) products, biological and biotechnological products
(including the use of raw materials, solvents, excipients, packaging and labelling materials in drug
(medicinal) products, biological and biotechnological products).
3. Principles of quality risk management
Two primary principles of quality risk management are:
The evaluation of the risk to quality should be based on scientific knowledge and ultimately link to
the protection of the patient; and
The level of effort, formality and documentation of the quality risk management process should be
commensurate with the level of risk.
4. General quality risk management process
Quality risk management is a systematic process for the assessment, control, communication and
review of risks to the quality of the drug (medicinal) product across the product lifecycle. A model for
quality risk management is outlined in the diagram (Figure 1). Other models could be used. The
emphasis on each component of the framework might differ from case to case but a robust process will
incorporate consideration of all the elements at a level of detail that is commensurate with the specific
risk.
Figure 1: Overview of a typical Quality risk management process
Risk Review
R
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C
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m
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ic
a
ti
o
n
Risk Assessment
Risk Evaluation
unacceptable
Risk Control
Risk Analysis
Risk Reduction
Risk Identification
Review Events
Risk Acceptance
Initiate
Quality Risk Management Process
Output / Result of the
Quality Risk Management Process
R
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a
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a
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e
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e
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to
o
ls
Quality Risk Management (ICH Q9)
EMA/INS/GMP/79766/2011 Page 5/19
Decision nodes are not shown in the diagram above because decisions can occur at any point in the
process. These decisions might be to return to the previous step and seek further information, to
adjust the risk models or even to terminate the risk management process based upon information that
supports such a decision. Note: “unacceptable” in the flowchart does not only refer to statutory,
legislative or regulatory requirements, but also to the need to revisit the risk assessment process.
4.1. Responsibilities
Quality risk management activities are usually, but not always, undertaken by interdisciplinary teams.
When teams are formed, they should include experts from the appropriate areas (e.g. quality unit,
business development, engineering, regulatory affairs, production operations, sales and marketing,
legal, statistics and clinical) in addition to individuals who are knowledgeable about the quality risk
management process.
Decision makers should
take responsibility for coordinating quality risk management across various functions and
departments of their organization; and
assure that a quality risk management process is defined, deployed and reviewed and that
adequate resources are available.
4.2. Initiating a quality risk management process
Quality risk management should include systematic processes designed to coordinate, facilitate and
improve science-based decision making with respect to risk. Possible steps used to initiate and plan a
quality risk management process might include the following:
Define the problem and/or risk question, including pertinent assumptions identifying the potential
for risk
Assemble background information and/ or data on the potential hazard, harm or human health
impact relevant to the risk assessment
Identify a leader and necessary resources
Specify a timeline, deliverables and appropriate level of decision making for the risk management
process
4.3. Risk assessment
Risk assessment consists of the identification of hazards and the analysis and evaluation of risks
associated with exposure to those hazards (as defined below). Quality risk assessments begin with a
well-defined problem description or risk question. When the risk in question is well defined, an
appropriate risk management tool (see examples in section 5) and the types of information needed to
address the risk question will be more readily identifiable. As an aid to clearly defining the risk(s) for
risk assessment purposes, three fundamental questions are often helpful:
1. What might go wrong?
2. What is the likelihood (probability) it will go wrong?
3. What are the consequences (severity)?
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Risk identification is a systematic use of information to identify hazards referring to the risk question
or problem description. Information can include historical data, theoretical analysis, informed opinions,
and the concerns of stakeholders. Risk identification addresses the “What might go wrong?” question,
including identifying the possible consequences. This provides the basis for further steps in the quality
risk management process.
Risk analysis is the estimation of the risk associated with the identified hazards. It is the qualitative
or quantitative process of linking the likelihood of occurrence and severity of harms. In some risk
management tools, the ability to detect the harm (detectability) also factors in the estimation of risk.
Risk evaluation compares the identified and analyzed risk against given risk criteria. Risk evaluations
consider the strength of evidence for all three of the fundamental questions.
In doing an effective risk assessment, the robustness of the data set is important because it
determines the quality of the output. Revealing assumptions and reasonable sources of uncertainty will
enhance confidence in this output and/or help identify its limitations. Uncertainty is due to combination
of incomplete knowledge about a process and its expected or unexpected variability. Typical sources of
uncertainty include gaps in knowledge gaps in pharmaceutical science and process understanding,
sources of harm (e.g., failure modes of a process, sources of variability), and probability of detection of
problems.
The output of a risk assessment is either a quantitative estimate of risk or a qualitative description of a
range of risk. When risk is expressed quantitatively, a numerical probability is used. Alternatively, risk
can be expressed using qualitative descriptors, such as “high”, “medium”, or “low”, which should be
defined in as much detail as possible. Sometimes a "risk score" is used to further define descriptors in
risk ranking. In quantitative risk assessments, a risk estimate provides the likelihood of a specific
consequence, given a set of risk-generating circumstances. Thus, quantitative risk estimation is useful
for one particular consequence at a time. Alternatively, some risk management tools use a relative risk
measure to combine multiple levels of severity and probability into an overall estimate of relative risk.
The intermediate steps within a scoring process can sometimes employ quantitative risk estimation.
4.4. Risk control
Risk control includes decision making to reduce and/or accept risks. The purpose of risk control is to
reduce the risk to an acceptable level. The amount of effort used for risk control should be proportional
to the significance of the risk. Decision makers might use different processes, including benefit-cost
analysis, for understanding the optimal level of risk control.
Risk control might focus on the following questions:
Is the risk above an acceptable level?
What can be done to reduce or eliminate risks?
What is the appropriate balance among benefits, risks and resources?
Are new risks introduced as a result of the identified risks being controlled?
Risk reduction focuses on processes for mitigation or avoidance of quality risk when it exceeds a
specified (acceptable) level (see Fig. 1). Risk reduction might include actions taken to mitigate the
severity and probability of harm. Processes that improve the detectability of hazards and quality risks
might also be used as part of a risk control strategy. The implementation of risk reduction measures
can introduce new risks into the system or increase the significance of other existing risks. Hence, it
might be appropriate to revisit the risk assessment to identify and evaluate any possible change in risk
after implementing a risk reduction process.
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Risk acceptance is a decision to accept risk. Risk acceptance can be a formal decision to accept the
residual risk or it can be a passive decision in which residual risks are not specified. For some types of
harms, even the best quality risk management practices might not entirely eliminate risk. In these
circumstances, it might be agreed that an appropriate quality risk management strategy has been
applied and that quality risk is reduced to a specified (acceptable) level. This (specified) acceptable
level will depend on many parameters and should be decided on a case-by-case basis.
4.5. Risk communication
Risk communication is the sharing of information about risk and risk management between the
decision makers and others. Parties can communicate at any stage of the risk management process
(see Fig. 1: dashed arrows). The output/result of the quality risk management process should be
appropriately communicated and documented (see Fig. 1: solid arrows). Communications might
include those among interested parties; e.g., regulators and industry, industry and the patient, within
a company, industry or regulatory authority, etc. The included information might relate to the
existence, nature, form, probability, severity, acceptability, control, treatment, detectability or other
aspects of risks to quality. Communication need not be carried out for each and every risk acceptance.
Between the industry and regulatory authorities, communication concerning quality risk management
decisions might be effected through existing channels as specified in regulations and guidances.
4.6. Risk review
Risk management should be an ongoing part of the quality management process. A mechanism to
review or monitor events should be implemented.
The output/results of the risk management process should be reviewed to take into account new
knowledge and experience. Once a quality risk management process has been initiated, that process
should continue to be utilized for events that might impact the original quality risk management
decision, whether these events are planned (e.g. results of product review, inspections, audits, change
control) or unplanned (e.g. root cause from failure investigations, recall). The frequency of any review
should be based upon the level of risk. Risk review might include reconsideration of risk acceptance
decisions (section 4.4).
5. Risk management methodology
Quality risk management supports a scientific and practical approach to decision-making. It provides
documented, transparent and reproducible methods to accomplish steps of the quality risk
management process based on current knowledge about assessing the probability, severity and
sometimes detectability of the risk.
Traditionally, risks to quality have been assessed and managed in a variety of informal ways (empirical
and/ or internal procedures) based on, for example, compilation of observations, trends and other
information. Such approaches continue to provide useful information that might support topics such as
handling of complaints, quality defects, deviations and allocation of resources.
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EMA/INS/GMP/79766/2011 Page 8/19
Additionally, the pharmaceutical industry and regulators can assess and manage risk using recognized
risk management tools and/ or internal procedures (e.g., standard operating procedures). Below is a
non-exhaustive list of some of these tools (further details in Annex 1 and chapter 8):
Basic risk management facilitation methods(flowcharts, check sheets etc.)
Failure Mode Effects Analysis (FMEA)
Failure Mode, Effects and Criticality Analysis (FMECA)
Fault Tree Analysis (FTA)
Hazard Analysis and Critical Control Points (HACCP)
Hazard Operability Analysis (HAZOP)
Preliminary Hazard Analysis (PHA)
Risk ranking and filtering
Supporting statistical tools
It might be appropriate to adapt these tools for use in specific areas pertaining to drug substance and
drug (medicinal) product quality. Quality risk management methods and the supporting statistical tools
can be used in combination (e.g. Probabilistic Risk Assessment). Combined use provides flexibility that
can facilitate the application of quality risk management principles.
The degree of rigor and formality of quality risk management should reflect available knowledge and
be commensurate with the complexity and/ or criticality of the issue to be addressed.
6. Integration of quality risk management into industry and
regulatory operations
Quality risk management is a process that supports science-based and practical decisions when
integrated into quality systems (see Annex II). As outlined in the introduction, appropriate use of
quality risk management does not obviate industry’s obligation to comply with regulatory
requirements. However, effective quality risk management can facilitate better and more informed
decisions, can provide regulators with greater assurance of a company’s ability to deal with potential
risks, and might affect the extent and level of direct regulatory oversight. In addition, quality risk
management can facilitate better use of resources by all parties.
Training of both industry and regulatory personnel in quality risk management processes provides for
greater understanding of decision-making processes and builds confidence in quality risk management
outcomes.
Quality risk management should be integrated into existing operations and documented appropriately.
Annex II provides examples of situations in which the use of the quality risk management process
might provide information that could then be used in a variety of pharmaceutical operations. These
examples are provided for illustrative purposes only and should not be considered a definitive or
exhaustive list. These examples are not intended to create any new expectations beyond the
requirements laid out in the current regulations.
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Examples for industry and regulatory operations (see Annex II):
Quality management
Examples for industry operations and activities (see Annex II):
Development
Facility, equipment and utilities
Materials management
Production
Laboratory control and stability testing
Packaging and labelling
Examples for regulatory operations (see Annex II):
Inspection and assessment activities
While regulatory decisions will continue to be taken on a regional basis, a common understanding and
application of quality risk management principles could facilitate mutual confidence and promote more
consistent decisions among regulators on the basis of the same information. This collaboration could
be important in the development of policies and guidelines that integrate and support quality risk
management practices.
7. Definitions
Decision maker(s) – Person(s) with the competence and authority to make appropriate and timely
quality risk management decisions
Detectability - the ability to discover or determine the existence, presence, or fact of a hazard
Harm – damage to health, including the damage that can occur from loss of product quality or
availability
Hazard - the potential source of harm (ISO/IEC Guide 51)
Product Lifecycle – all phases in the life of the product from the initial development through marketing
until the product’s discontinuation
Quality – the degree to which a set of inherent properties of a product, system or process fulfills
requirements (see ICH Q6a definition specifically for "quality" of drug substance and drug (medicinal)
products.)
Quality risk management – a systematic process for the assessment, control, communication and
review of risks to the quality of the drug (medicinal) product across the product lifecycle
Quality system – the sum of all aspects of a system that implements quality policy and ensures that
quality objectives are met
Requirements – the explicit or implicit needs or expectations of the patients or their surrogates (e.g.
health care professionals, regulators and legislators). In this document, “requirements” refers not only
to statutory, legislative, or regulatory requirements, but also to such needs and expectations.
Risk – the combination of the probability of occurrence of harm and the severity of that harm (ISO/IEC
Guide 51)
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Risk acceptance – the decision to accept risk (ISO Guide 73)
Risk analysis – the estimation of the risk associated with the identified hazards
Risk assessment – a systematic process of organizing information to support a risk decision to be made
within a risk management process. It consists of the identification of hazards and the analysis and
evaluation of risks associated with exposure to those hazards.
Risk communication – the sharing of information about risk and risk management between the decision
maker and other stakeholders
Risk control – actions implementing risk management decisions (ISO Guide 73)
Risk evaluation – the comparison of the estimated risk to given risk criteria using a quantitative or
qualitative scale to determine the significance of the risk
Risk identification – the systematic use of information to identify potential sources of harm (hazards)
referring to the risk question or problem description
Risk management – the systematic application of quality management policies, procedures, and
practices to the tasks of assessing, controlling, communicating and reviewing risk
Risk reduction – actions taken to lessen the probability of occurrence of harm and the severity of that
harm
Risk review – review or monitoring of output/results of the risk management process considering (if
appropriate) new knowledge and experience about the risk
Severity – a measure of the possible consequences of a hazard
Stakeholder – any individual, group or organization that can affect, be affected by, or perceive itself to
be affected by a risk. Decision makers might also be stakeholders. For the purposes of this guideline,
the primary stakeholders are the patient, healthcare professional, regulatory authority, and industry
Trend – a statistical term referring to the direction or rate of change of a variable(s)
8. References
ICH Q8 Pharmaceutical development
ISO/IEC Guide 73:2002 - Risk Management - Vocabulary - Guidelines for use in Standards
ISO/IEC Guide 51:1999 - Safety Aspects - Guideline for their inclusion in standards
Process Mapping by the American Productivity & Quality Center 2002, ISBN 1928593739
IEC 61025 - Fault Tree Analysis (FTA)
IEC 60812 Analysis Techniques for system reliability—Procedures for failure mode and effects analysis
(FMEA)
Failure Mode and Effect Analysis, FMEA from Theory to Execution, 2nd Edition 2003, D. H. Stamatis,
ISBN 0873895983
Guidelines for Failure Modes and Effects Analysis (FMEA) for Medical Devices, 2003 Dyadem Press ISBN
0849319102
The Basics of FMEA, Robin McDermott, Raymond J. Mikulak, Michael R. Beauregard 1996 ISBN
0527763209
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WHO Technical Report Series No 908, 2003 Annex 7 Application of Hazard Analysis and Critical Control
Point (HACCP) methodology to pharmaceuticals.
IEC 61882 - Hazard Operability Analysis (HAZOP)
ISO 14971:2000 - Application of Risk Management to Medical Devices
ISO 7870:1993 - Control Charts
ISO 7871:1997 - Cumulative Sum Charts
ISO 7966:1993 - Acceptance Control Charts
ISO 8258:1991 - Shewhart Control Charts
What is Total Quality Control?; The Japanese Way, Kaoru Ishikawa (Translated by David J. Liu, 1985,
ISBN 0139524339
Annex I: Risk management methods and tools
The purpose of this annex is to provide a general overview of and references for some of the primary
tools that might be used in quality risk management by industry and regulators. The references are
included as an aid to gain more knowledge and detail about the particular tool. This is not an
exhaustive list. It is important to note that no one tool or set of tools is applicable to every situation in
which a quality risk management procedure is used.
I.1 Basic risk management facilitation methods
Some of the simple techniques that are commonly used to structure risk management by organizing
data and facilitating decision-making are:
Flowcharts
Check Sheets
Process Mapping
Cause and Effect Diagrams (also called an Ishikawa diagram or fish bone diagram)
I.2 Failure Mode Effects Analysis (FMEA)
FMEA (see IEC 60812) provides for an evaluation of potential failure modes for processes and their
likely effect on outcomes and/or product performance. Once failure modes are established, risk
reduction can be used to eliminate, contain, reduce or control the potential failures. FMEA relies on
product and process understanding. FMEA methodically breaks down the analysis of complex processes
into manageable steps. It is a powerful tool for summarizing the important modes of failure, factors
causing these failures and the likely effects of these failures.
Potential areas of use(s)
FMEA can be used to prioritize risks and monitor the effectiveness of risk control activities.
FMEA can be applied to equipment and facilities and might be used to analyze a manufacturing
operation and its effect on product or process. It identifies elements/operations within the system that
render it vulnerable. The output/ results of FMEA can be used as a basis for design or further analysis
or to guide resource deployment.
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I.3 Failure Mode, Effects and Criticality Analysis (FMECA)
FMEA might be extended to incorporate an investigation of the degree of severity of the consequences,
their respective probabilities of occurrence, and their detectability, thereby becoming a Failure Mode
Effect and Criticality Analysis (FMECA; see IEC 60812). In order for such an analysis to be performed,
the product or process specifications should be established. FMECA can identify places where additional
preventive actions might be appropriate to minimize risks.
Potential areas of use(s)
FMECA application in the pharmaceutical industry should mostly be utilized for failures and risks
associated with manufacturing processes; however, it is not limited to this application. The output of
an FMECA is a relative risk “score” for each failure mode, which is used to rank the modes on a relative
risk basis.
I.4 Fault Tree Analysis (FTA)
The FTA tool (see IEC 61025) is an approach that assumes failure of the functionality of a product or
process. This tool evaluates system (or sub-system) failures one at a time but can combine multiple
causes of failure by identifying causal chains. The results are represented pictorially in the form of a
tree of fault modes. At each level in the tree, combinations of fault modes are described with logical
operators (AND, OR, etc.). FTA relies on the experts’ process understanding to identify causal factors.
Potential areas of use(s)
FTA can be used to establish the pathway to the root cause of the failure. FTA can be used to
investigate complaints or deviations in order to fully understand their root cause and to ensure that
intended improvements will fully resolve the issue and not lead to other issues (i.e. solve one problem
yet cause a different problem). Fault Tree Analysis is an effective tool for evaluating how multiple
factors affect a given issue. The output of an FTA includes a visual representation of failure modes. It is
useful both for risk assessment and in developing monitoring programs.
I.5 Hazard Analysis and Critical Control Points (HACCP)
HACCP is a systematic, proactive, and preventive tool for assuring product quality, reliability, and
safety (see WHO Technical Report Series No 908, 2003 Annex 7). It is a structured approach that
applies technical and scientific principles to analyze, evaluate, prevent, and control the risk or adverse
consequence(s) of hazard(s) due to the design, development, production, and use of products.
HACCP consists of the following seven steps:
(1) conduct a hazard analysis and identify preventive measures for each step of the process;
(2) determine the critical control points;
(3) establish critical limits;
(4) establish a system to monitor the critical control points;
(5) establish the corrective action to be taken when monitoring indicates that the critical control
points are not in a state of control;
(6) establish system to verify that the HACCP system is working effectively;
(7) establish a record-keeping system.
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Potential areas of use(s)
HACCP might be used to identify and manage risks associated with physical, chemical and biological
hazards (including microbiological contamination). HACCP is most useful when product and process
understanding is sufficiently comprehensive to support identification of critical control points. The
output of a HACCP analysis is risk management information that facilitates monitoring of critical points
not only in the manufacturing process but also in other life cycle phases.
I.6 Hazard Operability Analysis (HAZOP)
HAZOP (see IEC 61882) is based on a theory that assumes that risk events are caused by deviations
from the design or operating intentions. It is a systematic brainstorming technique for identifying
hazards using so-called “guide-words”. “Guide-words” (e.g., No, More, Other Than, Part of, etc.) are
applied to relevant parameters (e.g., contamination, temperature) to help identify potential deviations
from normal use or design intentions. It often uses a team of people with expertise covering the design
of the process or product and its application.
Potential areas of use(s)
HAZOP can be applied to manufacturing processes, including outsourced production and formulation as
well as the upstream suppliers, equipment and facilities for drug substances and drug (medicinal)
products. It has also been used primarily in the pharmaceutical industry for evaluating process safety
hazards. As is the case with HACCP, the output of a HAZOP analysis is a list of critical operations for
risk management. This facilitates regular monitoring of critical points in the manufacturing process.
I.7 Preliminary Hazard Analysis (PHA)
PHA is a tool of analysis based on applying prior experience or knowledge of a hazard or failure to
identify future hazards, hazardous situations and events that might cause harm, as well as to estimate
their probability of occurrence for a given activity, facility, product or system. The tool consists of: 1)
the identification of the possibilities that the risk event happens, 2) the qualitative evaluation of the
extent of possible injury or damage to health that could result and 3) a relative ranking of the hazard
using a combination of severity and likelihood of occurrence, and 4) the identification of possible
remedial measures
Potential areas of use(s)
PHA might be useful when analyzing existing systems or prioritizing hazards where circumstances
prevent a more extensive technique from being used. It can be used for product, process and facility
design as well as to evaluate the types of hazards for the general product type, then the product class,
and finally the specific product. PHA is most commonly used early in the development of a project
when there is little information on design details or operating procedures; thus, it will often be a
precursor to further studies. Typically, hazards identified in the PHA are further assessed with other
risk management tools such as those in this section.
I.8 Risk ranking and filtering
Risk ranking and filtering is a tool for comparing and ranking risks. Risk ranking of complex systems
typically requires evaluation of multiple diverse quantitative and qualitative factors for each risk. The
tool involves breaking down a basic risk question into as many components as needed to capture
factors involved in the risk. These factors are combined into a single relative risk score that can then
be used for ranking risks. “Filters,” in the form of weighting factors or cut-offs for risk scores, can be
used to scale or fit the risk ranking to management or policy objectives.
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Potential areas of use(s)
Risk ranking and filtering can be used to prioritize manufacturing sites for inspection/audit by
regulators or industry. Risk ranking methods are particularly helpful in situations in which the portfolio
of risks and the underlying consequences to be managed are diverse and difficult to compare using a
single tool. Risk ranking is useful when management needs to evaluate both quantitatively-assessed
and qualitatively-assessed risks within the same organizational framework.
I.9 Supporting statistical tools
Statistical tools can support and facilitate quality risk management. They can enable effective data
assessment, aid in determining the significance of the data set(s), and facilitate more reliable decision
making. A listing of some of the principal statistical tools commonly used in the pharmaceutical
industry is provided:
Control charts, for example:
Acceptance control charts (see ISO 7966)
Control charts with arithmetic average and warning limits (see ISO 7873)
Cumulative sum charts (see ISO 7871)
Shewhart control charts (see ISO 8258)
Weighted moving average
Design of Experiments (DOE)
Histograms
Pareto charts
Process capability analysis
Annex II: Potential applications for quality risk management
This annex is intended to identify potential uses of quality risk management principles and tools by
industry and regulators. However, the selection of particular risk management tools is completely
dependent upon specific facts and circumstances.
These examples are provided for illustrative purposes and only suggest potential uses of quality risk
management. This Annex is not intended to create any new expectations beyond the current
regulatory requirements.
II.1 Quality risk management as part of integrated quality management
Documentation
To review current interpretations and application of regulatory expectations
To determine the desirability of and/or develop the content for SOPs, guidelines, etc.
Training and education
To determine the appropriateness of initial and/or ongoing training sessions based on education,
experience and working habits of staff, as well as on a periodic assessment of previous training (e.g.,
its effectiveness)
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To identify the training, experience, qualifications and physical abilities that allow personnel to perform
an operation reliably and with no adverse impact on the quality of the product
Quality defects
To provide the basis for identifying, evaluating, and communicating the potential quality impact of a
suspected quality defect, complaint, trend, deviation, investigation, out of specification result, etc.
To facilitate risk communications and determine appropriate action to address significant product
defects, in conjunction with regulatory authorities (e.g., recall)
Auditing / Inspection
To define the frequency and scope of audits, both internal and external, taking into account factors
such as:
Existing legal requirements
Overall compliance status and history of the company or facility
Robustness of a company’s quality risk management activities
Complexity of the site
Complexity of the manufacturing process
Complexity of the product and its therapeutic significance
Number and significance of quality defects (e.g, recall)
Results of previous audits/inspections
Major changes of building, equipment, processes, key personnel
Experience with manufacturing of a product (e.g. frequency, volume, number of batches)
Test results of official control laboratories
Periodic review
To select, evaluate and interpret trend results of data within the product quality review
To interpret monitoring data (e.g., to support an assessment of the appropriateness of revalidation or
changes in sampling)
Change management / Change control
To manage changes based on knowledge and information accumulated in pharmaceutical development
and during manufacturing
To evaluate the impact of the changes on the availability of the final product
To evaluate the impact on product quality of changes to the facility, equipment, material,
manufacturing process or technical transfers
To determine appropriate actions preceding the implementation of a change, e.g., additional testing,
(re)qualification, (re)validation or communication with regulators
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Continual improvement
To facilitate continual improvement in processes throughout the product lifecycle.
II.2 Quality risk management as part of regulatory operations
Inspection and assessment activities
To assist with resource allocation including, for example, inspection planning and frequency, and
inspection and assessment intensity (see "Auditing" section in Annex II.1)
To evaluate the significance of, for example, quality defects, potential recalls and inspectional findings
To determine the appropriateness and type of post-inspection regulatory follow-up
To evaluate information submitted by industry including pharmaceutical development information
To evaluate impact of proposed variations or changes
To identify risks which should be communicated between inspectors and assessors to facilitate better
understanding of how risks can be or are controlled (e.g., parametric release, Process Analytical
Technology (PAT)).
II.3 Quality risk management as part of development
To design a quality product and its manufacturing process to consistently deliver the intended
performance of the product (see ICH Q8)
To enhance knowledge of product performance over a wide range of material attributes (e.g. particle
size distribution, moisture content, flow properties), processing options and process parameters
To assess the critical attributes of raw materials, solvents, Active Pharmaceutical Ingredient (API)
starting materials, APIs, excipients, or packaging materials
To establish appropriate specifications, identify critical process parameters and establish manufacturing
controls (e.g., using information from pharmaceutical development studies regarding the clinical
significance of quality attributes and the ability to control them during processing)
To decrease variability of quality attributes:
reduce product and material defects
reduce manufacturing defects
To assess the need for additional studies (e.g., bioequivalence, stability) relating to scale up and
technology transfer
To make use of the “design space” concept (see ICH Q8)
II.4 Quality risk management for facilities, equipment and utilities
Design of facility / Equipment
To determine appropriate zones when designing buildings and facilities, e.g.,
flow of material and personnel
minimize contamination
pest control measures
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prevention of mix-ups
open versus closed equipment
clean rooms versus isolator technologies
dedicated or segregated facilities / equipment
To determine appropriate product contact materials for equipment and containers (e.g., selection of
stainless steel grade, gaskets, lubricants)
To determine appropriate utilities (e.g., steam, gases, power source, compressed air, heating,
ventilation and air conditioning (HVAC), water)
To determine appropriate preventive maintenance for associated equipment (e.g., inventory of
necessary spare parts)
Hygiene aspects in facilities
To protect the product from environmental hazards, including chemical, microbiological, and physical
hazards (e.g., determining appropriate clothing and gowning, hygiene concerns)
To protect the environment (e.g., personnel, potential for cross-contamination) from hazards related to
the product being manufactured
Qualification of facility / Equipment / Utilities
To determine the scope and extent of qualification of facilities, buildings, and production equipment
and/or laboratory instruments (including proper calibration methods)
Cleaning of equipment and environmental control
To differentiate efforts and decisions based on the intended use (e.g., multi- versus single-purpose,
batch versus continuous production)
To determine acceptable (specified) cleaning validation limits
Calibration / Preventive maintenance
To set appropriate calibration and maintenance schedules
Computer systems and computer controlled equipment
To select the design of computer hardware and software (e.g., modular, structured, fault tolerance)
To determine the extent of validation, e.g..
identification of critical performance parameters
selection of the requirements and design
code review
the extent of testing and test methods
reliability of electronic records and signatures
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II.5 Quality risk management as part of materials management
Assessment and evaluation of suppliers and contract manufacturers
To provide a comprehensive evaluation of suppliers and contract manufacturers (e.g., auditing,
supplier quality agreements)
Starting material
To assess differences and possible quality risks associated with variability in starting materials (e.g.,
age, route of synthesis).
Use of materials
To determine whether it is appropriate to use material under quarantine (e.g., for further internal
processing)
To determine appropriateness of reprocessing, reworking, use of returned goods
Storage, logistics and distribution conditions
To assess the adequacy of arrangements to ensure maintenance of appropriate storage and transport
conditions (e.g., temperature, humidity, container design)
To determine the effect on product quality of discrepancies in storage or transport conditions (e.g. cold
chain management) in conjunction with other ICH guidelines
To maintain infrastructure (e.g. capacity to ensure proper shipping conditions, interim storage,
handling of hazardous materials and controlled substances, customs clearance)
To provide information for ensuring the availability of pharmaceuticals (e.g., ranking risks to the
supply chain).
II.6 Quality risk management as part of production
Validation
To identify the scope and extent of verification, qualification and validation activities (e.g., analytical
methods, processes, equipment and cleaning methods
To determine the extent for follow-up activities (e.g., sampling, monitoring and re-validation)
To distinguish between critical and non-critical process steps to facilitate design of a validation study
In-process sampling & testing
To evaluate the frequency and extent of in-process control testing (e.g., to justify reduced testing
under conditions of proven control)
To evaluate and justify the use of process analytical technologies (PAT) in conjunction with parametric
and real time release
Production planning
To determine appropriate production planning (e.g., dedicated, campaign and concurrent production
process sequences).
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II.7 Quality risk management as part of laboratory control and stability
studies
Out of specification results
To identify potential root causes and corrective actions during the investigation of out of specification
results
Retest period / Expiration date
To evaluate adequacy of storage and testing of intermediates, excipients and starting materials
II.8 Quality risk management as part of packaging and labelling
Design of packages
To design the secondary package for the protection of primary packaged product (e.g., to ensure
product authenticity, label legibility)
Selection of container closure system
To determine the critical parameters of the container closure system
Label controls
To design label control procedures based on the potential for mix-ups involving different product
labels, including different versions of the same label
Quality Risk Management.doc
Table of contents: 1. Introduction 3 2. Scope 4 3. Principles of quality risk management 4 4. General quality risk management process 4 4.1. Responsibilities 5 4.2. Initiating a quality risk management process 5 4.3. Risk assessment 5 4.4. Risk control 6 4.5. Risk communication 7 4.6. Risk review 7 5. Risk management methodology 7 6. Integration of quality risk management into industry and regulatory operations 8 7. Definitions 9 8. References 10 Annex I: Risk management methods and tools 12 I.1 Basic risk management facilitation methods 12 I.2 Failure Mode Effects Analysis (FMEA) 12 I.3 Failure Mode, Effects and Criticality Analysis (FMECA) 12 I.4 Fault Tree Analysis (FTA) 13 I.5 Hazard Analysis and Critical Control Points (HACCP) 13 I.6 Hazard Operability Analysis (HAZOP) 14 I.7 Preliminary Hazard Analysis (PHA) 14 I.8 Risk ranking and filtering 14 I.9 Supporting statistical tools 15 Annex II: Potential applications for quality risk management 16 II.1 Quality risk management as part of integrated quality m
Introduction
Scope
Principles of quality risk management
General quality risk management process
Responsibilities
Initiating a quality risk management process
Risk assessment
Risk control
Risk communication
Risk review
Risk management methodology
Integration of quality risk management into industry and regulatory operations
Definitions
References
Annex I: Risk management methods and tools
I.1 Basic risk management facilitation methods
I.2 Failure Mode Effects Analysis (FMEA)
I.3 Failure Mode, Effects and Criticality Analysis (FMECA)
I.4 Fault Tree Analysis (FTA)
I.5 Hazard Analysis and Critical Control Points (HACCP)
I.6 Hazard Operability Analysis (HAZOP)
I.7 Preliminary Hazard Analysis (PHA)
I.8 Risk ranking and filtering
I.9 Supporting statistical tools
Annex II: Potential applications for quality risk management
II.1 Quality risk management as part of integrated quality management
II.2 Quality risk management as part of regulatory operations
II.3 Quality risk management as part of development
II.4 Quality risk management for facilities, equipment and utilities
II.5 Quality risk management as part of materials management
II.6 Quality risk management as part of production
II.7 Quality risk management as part of laboratory control and stability studies
II.8 Quality risk management as part of packaging and labelling
04.08.2014
Datei
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E-mail info@ema.europa.eu Website www.ema.europa.eu An agency of the European Union
© European Medicines Agency, 2011. Reproduction is authorised provided the source is acknowledged.
31 January 2011
EMA/INS/GMP/79818/2011
Pharmaceutical Quality System (ICH Q10)
The ICH Q10 document on Pharmaceutical Quality System was adopted at Step 4 at the ICH Steering
Committee meeting in June 2008.
By virtue of Article 6 of Directive 2003/94/EC and Directive 91/412/EEC manufacturing authorisation
holders are already obliged to establish and implement an effective pharmaceutical quality assurance
system in order to comply with Good Manufacturing Practice (GMP) and guidance is provided in
Chapter 1 of the GMP Guide.
ICH Q10 provides an example of a pharmaceutical quality system designed for the entire product
lifecycle and therefore goes beyond current GMP requirements, which with the exception of the
manufacture of investigational medicinal products for human use, do not apply to the development
part of the lifecycle. At the time of the EU implementation of ICH Q10 it was also recognised that
Chapters 1, 2 and 7 of the GMP Guide should be updated to align with the terminology and concepts
utilised in ICH Q10.
The content of ICH Q10 that is additional to the scope of GMP is optional. Its use should facilitate
innovation, continual improvement and strengthen the link between pharmaceutical development and
manufacturing activities.
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Pharmaceutical Quality System (ICH Q10)
ICH harmonised tripartite guideline
Table of contents
1. Pharmaceutical quality system................................................................ 3
1.1. Introduction.........................................................................................................3
1.2. Scope .................................................................................................................3
1.3. Relationship of ICH Q10 to regional GMP requirements, ISO standards and ICH Q7 ......4
1.4. Relationship of ICH Q10 to regulatory approaches ....................................................4
1.5. ICH Q10 objectives...............................................................................................5
1.6. Enablers: knowledge management and quality risk management ...............................5
1.7. Design and content considerations .........................................................................6
1.8. Quality manual ....................................................................................................6
2. Management responsibility...................................................................... 6
2.1. Management commitment .....................................................................................6
2.2. Quality policy.......................................................................................................7
2.3. Quality planning...................................................................................................7
2.4. Resource management..........................................................................................8
2.5. Internal communication ........................................................................................8
2.6. Management review .............................................................................................8
2.7. Management of outsourced activities and purchased materials...................................8
2.8. Management of change in product ownership...........................................................9
3. Continual improvement of process performance and product quality ...... 9
3.1. Lifecycle stage goals .............................................................................................9
3.2. Pharmaceutical quality system elements ...............................................................10
4. Continual improvement of the pharmaceutical quality system .............. 13
4.1. Management review of the pharmaceutical quality system.......................................14
4.2. Monitoring of internal and external factors impacting the pharmaceutical quality system
..............................................................................................................................14
4.3. Outcomes of management review and monitoring ..................................................14
5. Glossary ................................................................................................ 14
Annex 1 ..................................................................................................... 17
Annex 2 ..................................................................................................... 18
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1. Pharmaceutical quality system
1.1. Introduction
This document establishes a new ICH tripartite guideline describing a model for an effective quality
management system for the pharmaceutical industry, referred to as the Pharmaceutical Quality
System. Throughout this guideline, the term “pharmaceutical quality system” refers to the ICH Q10
model.
ICH Q10 describes one comprehensive model for an effective pharmaceutical quality system that is
based on International Standards Organisation (ISO) quality concepts, includes applicable Good
Manufacturing Practice (GMP) regulations and complements ICH Q8 “Pharmaceutical Development” and
ICH Q9 “Quality Risk Management”. ICH Q10 is a model for a pharmaceutical quality system that can
be implemented throughout the different stages of a product lifecycle. Much of the content of ICH Q10
applicable to manufacturing sites is currently specified by regional GMP requirements. ICH Q10 is not
intended to create any new expectations beyond current regulatory requirements. Consequently, the
content of ICH Q10 that is additional to current regional GMP requirements is optional.
ICH Q10 demonstrates industry and regulatory authorities’ support of an effective pharmaceutical
quality system to enhance the quality and availability of medicines around the world in the interest of
public health. Implementation of ICH Q10 throughout the product lifecycle should facilitate innovation
and continual improvement and strengthen the link between pharmaceutical development and
manufacturing activities.
1.2. Scope
This guideline applies to the systems supporting the development and manufacture of pharmaceutical
drug substances (i.e., API) and drug products, including biotechnology and biological products,
throughout the product lifecycle.
The elements of ICH Q10 should be applied in a manner that is appropriate and proportionate to each
of the product lifecycle stages, recognising the differences among, and the different goals of each
stage (see Section 3).
For the purposes of this guideline, the product lifecycle includes the following technical activities for
new and existing products:
Pharmaceutical Development
Drug substance development;
Formulation development (including container/closure system);
Manufacture of investigational products;
Delivery system development (where relevant);
Manufacturing process development and scale-up;
Analytical method development.
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Technology transfer
New product transfers during development through manufacturing;
Transfers within or between manufacturing and testing sites for marketed products.
Commercial manufacturing
Acquisition and control of materials;
Provision of facilities, utilities, and equipment;
Production (including packaging and labelling);
Quality control and assurance;
Release;
Storage;
Distribution (excluding wholesaler activities).
Product discontinuation
Retention of documentation;
Sample retention;
Continued product assessment and reporting.
1.3. Relationship of ICH Q10 to regional GMP requirements, ISO standards
and ICH Q7
Regional GMP requirements, the ICH Q7 Guideline, “Good Manufacturing Practice Guide for Active
Pharmaceutical Ingredients”, and ISO quality management system guidelines form the foundation for
ICH Q10. To meet the objectives described below, ICH Q10 augments GMP by describing specific
quality system elements and management responsibilities. ICH Q10 provides a harmonised model for a
pharmaceutical quality system throughout the lifecycle of a product and is intended to be used
together with regional GMP requirements.
The regional GMPs do not explicitly address all stages of the product lifecycle (e.g., Development). The
quality system elements and management responsibilities described in this guideline are intended to
encourage the use of science and risk based approaches at each lifecycle stage, thereby promoting
continual improvement across the entire product lifecycle.
1.4. Relationship of ICH Q10 to regulatory approaches
Regulatory approaches for a specific product or manufacturing facility should be commensurate with
the level of product and process understanding, the results of quality risk management, and the
effectiveness of the pharmaceutical quality system. When implemented, the effectiveness of the
pharmaceutical quality system can normally be evaluated during a regulatory inspection at the
manufacturing site. Potential opportunities to enhance science and risk based regulatory approaches
are identified in Annex 1. Regulatory processes will be determined by region.
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1.5. ICH Q10 objectives
Implementation of the Q10 model should result in achievement of three main objectives which
complement or enhance regional GMP requirements.
1.5.1. Achieve product realisation
To establish, implement and maintain a system that allows the delivery of products with the quality
attributes appropriate to meet the needs of patients, health care professionals, regulatory authorities
(including compliance with approved regulatory filings) and other internal and external customers.
1.5.2. Establish and maintain a state of control
To develop and use effective monitoring and control systems for process performance and product
quality, thereby providing assurance of continued suitability and capability of processes. Quality risk
management can be useful in identifying the monitoring and control systems.
1.5.3. Facilitate continual improvement
To identify and implement appropriate product quality improvements, process improvements,
variability reduction, innovations and pharmaceutical quality system enhancements, thereby increasing
the ability to fulfill quality needs consistently. Quality risk management can be useful for identifying
and prioritising areas for continual improvement.
1.6. Enablers: knowledge management and quality risk management
Use of knowledge management and quality risk management will enable a company to implement ICH
Q10 effectively and successfully. These enablers will facilitate achievement of the objectives described
in Section 1.5 above by providing the means for science and risk based decisions related to product
quality.
1.6.1. Knowledge management
Product and process knowledge should be managed from development through the commercial life of
the product up to and including product discontinuation. For example, development activities using
scientific approaches provide knowledge for product and process understanding. Knowledge
management is a systematic approach to acquiring, analysing, storing and disseminating information
related to products, manufacturing processes and components. Sources of knowledge include, but are
not limited to prior knowledge (public domain or internally documented); pharmaceutical development
studies; technology transfer activities; process validation studies over the product lifecycle;
manufacturing experience; innovation; continual improvement; and change management activities.
1.6.2. Quality risk management
Quality risk management is integral to an effective pharmaceutical quality system. It can provide a
proactive approach to identifying, scientifically evaluating and controlling potential risks to quality. It
facilitates continual improvement of process performance and product quality throughout the product
lifecycle. ICH Q9 provides principles and examples of tools for quality risk management that can be
applied to different aspects of pharmaceutical quality.
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1.7. Design and content considerations
(a) The design, organisation and documentation of the pharmaceutical quality system should be
well structured and clear to facilitate common understanding and consistent application.
(b) The elements of ICH Q10 should be applied in a manner that is appropriate and proportionate
to each of the product lifecycle stages, recognising the different goals and knowledge available for each
stage.
(c) The size and complexity of the company’s activities should be taken into consideration when
developing a new pharmaceutical quality system or modifying an existing one. The design of the
pharmaceutical quality system should incorporate appropriate risk management principles. While some
aspects of the pharmaceutical quality system can be company-wide and others site-specific, the
effectiveness of the pharmaceutical quality system is normally demonstrated at the site level.
(d) The pharmaceutical quality system should include appropriate processes, resources and
responsibilities to provide assurance of the quality of outsourced activities and purchased materials as
described in Section 2.7.
(e) Management responsibilities, as described in Section 2, should be identified within the
pharmaceutical quality system.
(f) The pharmaceutical quality system should include the following elements, as described in
Section 3: process performance and product quality monitoring, corrective and preventive action,
change management and management review.
(g) Performance indicators, as described in Section 4, should be identified and used to monitor the
effectiveness of processes within the pharmaceutical quality system.
1.8. Quality manual
A Quality Manual or equivalent documentation approach should be established and should contain the
description of the pharmaceutical quality system. The description should include:
(a) The quality policy (see Section 2);
(b) The scope of the pharmaceutical quality system;
(c) Identification of the pharmaceutical quality system processes, as well as their sequences,
linkages and interdependencies. Process maps and flow charts can be useful tools to facilitate depicting
pharmaceutical quality system processes in a visual manner;
(d) Management responsibilities within the pharmaceutical quality system (see Section 2).
2. Management responsibility
Leadership is essential to establish and maintain a company-wide commitment to quality and for the
performance of the pharmaceutical quality system.
2.1. Management commitment
(a) Senior management has the ultimate responsibility to ensure an effective pharmaceutical
quality system is in place to achieve the quality objectives, and that roles, responsibilities, and
authorities are defined, communicated and implemented throughout the company.
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(b) Management should:
(1) Participate in the design, implementation, monitoring and maintenance of an effective
pharmaceutical quality system;
(2) Demonstrate strong and visible support for the pharmaceutical quality system and
ensure its implementation throughout their organisation;
(3) Ensure a timely and effective communication and escalation process exists to raise
quality issues to the appropriate levels of management;
(4) Define individual and collective roles, responsibilities, authorities and inter-relationships
of all organisational units related to the pharmaceutical quality system. Ensure these interactions
are communicated and understood at all levels of the organisation. An independent quality
unit/structure with authority to fulfill certain pharmaceutical quality system responsibilities is
required by regional regulations;
(5) Conduct management reviews of process performance and product quality and of the
pharmaceutical quality system;
(6) Advocate continual improvement;
(7) Commit appropriate resources.
2.2. Quality policy
(a) Senior management should establish a quality policy that describes the overall intentions and
direction of the company related to quality.
(b) The quality policy should include an expectation to comply with applicable regulatory
requirements and should facilitate continual improvement of the pharmaceutical quality system.
(c) The quality policy should be communicated to and understood by personnel at all levels in the
company.
(d) The quality policy should be reviewed periodically for continuing effectiveness.
2.3. Quality planning
(a) Senior management should ensure the quality objectives needed to implement the quality
policy are defined and communicated.
(b) Quality objectives should be supported by all relevant levels of the company.
(c) Quality objectives should align with the company’s strategies and be consistent with the quality
policy.
(d) Management should provide the appropriate resources and training to achieve the quality
objectives.
(e) Performance indicators that measure progress against quality objectives should be established,
monitored, communicated regularly and acted upon as appropriate as described in Section 4.1 of this
document.
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2.4. Resource management
(a) Management should determine and provide adequate and appropriate resources (human,
financial, materials, facilities and equipment) to implement and maintain the pharmaceutical quality
system and continually improve its effectiveness.
(b) Management should ensure that resources are appropriately applied to a specific product,
process or site.
2.5. Internal communication
(a) Management should ensure appropriate communication processes are established and
implemented within the organisation.
(b) Communications processes should ensure the flow of appropriate information between all
levels of the company.
(c) Communication processes should ensure the appropriate and timely escalation of certain
product quality and pharmaceutical quality system issues.
2.6. Management review
(a) Senior management should be responsible for pharmaceutical quality system governance
through management review to ensure its continuing suitability and effectiveness.
(b) Management should assess the conclusions of periodic reviews of process performance and
product quality and of the pharmaceutical quality system, as described in Sections 3 and 4.
2.7. Management of outsourced activities and purchased materials
The pharmaceutical quality system, including the management responsibilities described in this
section, extends to the control and review of any outsourced activities and quality of purchased
materials. The pharmaceutical company is ultimately responsible to ensure processes are in place to
assure the control of outsourced activities and quality of purchased materials. These processes should
incorporate quality risk management and include:
(a) Assessing prior to outsourcing operations or selecting material suppliers, the suitability and
competence of the other party to carry out the activity or provide the material using a defined supply
chain (e.g., audits, material evaluations, qualification);
(b) Defining the responsibilities and communication processes for quality-related activities of the
involved parties. For outsourced activities, this should be included in a written agreement between the
contract giver and contract acceptor;
(c) Monitoring and review of the performance of the contract acceptor or the quality of the
material from the provider, and the identification and implementation of any needed improvements;
(d) Monitoring incoming ingredients and materials to ensure they are from approved sources using
the agreed supply chain.
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2.8. Management of change in product ownership
When product ownership changes, (e.g., through acquisitions) management should consider the
complexity of this and ensure:
(a) The ongoing responsibilities are defined for each company involved;
(b) The necessary information is transferred.
3. Continual improvement of process performance and
product quality
This section describes the lifecycle stage goals and the four specific pharmaceutical quality system
elements that augment regional requirements to achieve the ICH Q10 objectives, as defined in Section
1.5. It does not restate all regional GMP requirements.
3.1. Lifecycle stage goals
The goals of each product lifecycle stage are described below.
3.1.1. Pharmaceutical development
The goal of pharmaceutical development activities is to design a product and its manufacturing process
to consistently deliver the intended performance and meet the needs of patients and healthcare
professionals, and regulatory authorities and internal customers’ requirements. Approaches to
pharmaceutical development are described in ICH Q8. The results of exploratory and clinical
development studies, while outside the scope of this guidance, are inputs to pharmaceutical
development.
3.1.2. Technology transfer
The goal of technology transfer activities is to transfer product and process knowledge between
development and manufacturing, and within or between manufacturing sites to achieve product
realisation. This knowledge forms the basis for the manufacturing process, control strategy, process
validation approach and ongoing continual improvement.
3.1.3. Commercial manufacturing
The goals of manufacturing activities include achieving product realisation, establishing and
maintaining a state of control and facilitating continual improvement. The pharmaceutical quality
system should assure that the desired product quality is routinely met, suitable process performance is
achieved, the set of controls are appropriate, improvement opportunities are identified and evaluated,
and the body of knowledge is continually expanded.
3.1.4. Product discontinuation
The goal of product discontinuation activities is to manage the terminal stage of the product lifecycle
effectively. For product discontinuation, a pre-defined approach should be used to manage activities
such as retention of documentation and samples and continued product assessment (e.g., complaint
handling and stability) and reporting in accordance with regulatory requirements.
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3.2. Pharmaceutical quality system elements
The elements described below might be, required in part under regional GMP regulations. However, the
Q10 model’s intent is to enhance these elements in order to promote the lifecycle approach to product
quality. These four elements are:
Process performance and product quality monitoring system;
Corrective action and preventive action (CAPA) system;
Change management system;
Management review of process performance and product quality.
These elements should be applied in a manner that is appropriate and proportionate to each of the
product lifecycle stages, recognising the differences among, and the different goals of, each stage.
Throughout the product lifecycle, companies are encouraged to evaluate opportunities for innovative
approaches to improve product quality.
Each element is followed by a table of example applications of the element to the stages of the
pharmaceutical lifecycle.
3.2.1. Process performance and product quality monitoring system
Pharmaceutical companies should plan and execute a system for the monitoring of process
performance and product quality to ensure a state of control is maintained. An effective monitoring
system provides assurance of the continued capability of processes and controls to produce a product
of desired quality and to identify areas for continual improvement. The process performance and
product quality monitoring system should:
(a) Use quality risk management to establish the control strategy. This can include parameters and
attributes related to drug substance and drug product materials and components, facility and
equipment operating conditions, in-process controls, finished product specifications, and the associated
methods and frequency of monitoring and control. The control strategy should facilitate timely
feedback/feed-forward and appropriate corrective action and preventive action;
(b) Provide the tools for measurement and analysis of parameters and attributes identified in the
control strategy (e.g., data management and statistical tools);
(c) Analyse parameters and attributes identified in the control strategy to verify continued
operation within a state of control;
(d) Identify sources of variation affecting process performance and product quality for potential
continual improvement activities to reduce or control variation;
(e) Include feedback on product quality from both internal and external sources, e.g., complaints,
product rejections, non-conformances, recalls, deviations, audits and regulatory inspections and
findings;
(f) Provide knowledge to enhance process understanding, enrich the design space (where
established), and enable innovative approaches to process validation.
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Table I: Application of process performance and product quality monitoring system
throughout the product lifecycle
Pharmaceutical
development
Technology transfer Commercial
manufacturing
Product
discontinuation
Process and product
knowledge generated
and process and
product monitoring
conducted throughout
development can be
used to establish a
control strategy for
manufacturing.
Monitoring during
scale-up activities can
provide a preliminary
indication of process
performance and the
successful integration
into manufacturing.
Knowledge obtained
during transfer and
scale up activities can
be useful in further
developing the control
strategy.
A well-defined system
for process
performance and
product quality
monitoring should be
applied to assure
performance within a
state of control and to
identify improvement
areas.
Once manufacturing
ceases, monitoring
such as stability testing
should continue to
completion of the
studies. Appropriate
action on marketed
product should continue
to be executed
according to regional
regulations.
3.2.2. Corrective Action and Preventive Action (CAPA) system
The pharmaceutical company should have a system for implementing corrective actions and preventive
actions resulting from the investigation of complaints, product rejections, non-conformances, recalls,
deviations, audits, regulatory inspections and findings, and trends from process performance and
product quality monitoring. A structured approach to the investigation process should be used with the
objective of determining the root cause. The level of effort, formality, and documentation of the
investigation should be commensurate with the level of risk, in line with ICH Q9. CAPA methodology
should result in product and process improvements and enhanced product and process understanding.
Table II: Application of corrective action and preventive action system throughout the
product lifecycle
Pharmaceutical
development
Technology transfer Commercial
manufacturing
Product
discontinuation
Product or process
variability is explored.
CAPA methodology is
useful where corrective
actions and preventive
actions are incorporated
into the iterative design
and development
process.
CAPA can be used as an
effective system for
feedback, feed-forward
and continual
improvement.
CAPA should be used
and the effectiveness of
the actions should be
evaluated.
CAPA should continue
after the product is
discontinued. The
impact on product
remaining on the
market should be
considered as well as
other products which
might be impacted.
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3.2.3. Change management system
Innovation, continual improvement, the outputs of process performance and product quality
monitoring and CAPA drive change. In order to evaluate, approve and implement these changes
properly, a company should have an effective change management system. There is generally a
difference in formality of change management processes prior to the initial regulatory submission and
after submission, where changes to the regulatory filing might be required under regional
requirements.
The change management system ensures continual improvement is undertaken in a timely and
effective manner. It should provide a high degree of assurance there are no unintended consequences
of the change.
The change management system should include the following, as appropriate for the stage of the
lifecycle:
(a) Quality risk management should be utilised to evaluate proposed changes. The level of effort
and formality of the evaluation should be commensurate with the level of risk;
(b) Proposed changes should be evaluated relative to the marketing authorisation, including design
space, where established, and/or current product and process understanding. There should be an
assessment to determine whether a change to the regulatory filing is required under regional
requirements. As stated in ICH Q8, working within the design space is not considered a change (from
a regulatory filing perspective). However, from a pharmaceutical quality system standpoint, all
changes should be evaluated by a company’s change management system;
(c) Proposed changes should be evaluated by expert teams contributing the appropriate expertise
and knowledge from relevant areas (e.g., Pharmaceutical Development, Manufacturing, Quality,
Regulatory Affairs and Medical), to ensure the change is technically justified. Prospective evaluation
criteria for a proposed change should be set;
(d) After implementation, an evaluation of the change should be undertaken to confirm the change
objectives were achieved and that there was no deleterious impact on product quality.
Table III: Application of change management system throughout the product lifecycle
Pharmaceutical
development
Technology transfer Commercial
manufacturing
Product
discontinuation
Change is an inherent
part of the development
process and should be
documented; the
formality of the change
management process
should be consistent
with the stage of
pharmaceutical
development.
The change
management system
should provide
management and
documentation of
adjustments made to
the process during
technology transfer
activities.
A formal change
management system
should be in place for
commercial
manufacturing.
Oversight by the quality
unit should provide
assurance of
appropriate science and
risk based
assessments.
Any changes after
product discontinuation
should go through an
appropriate change
management system.
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3.2.4. Management review of process performance and product quality
Management review should provide assurance that process performance and product quality are
managed over the lifecycle. Depending on the size and complexity of the company, management
review can be a series of reviews at various levels of management and should include a timely and
effective communication and escalation process to raise appropriate quality issues to senior levels of
management for review.
(a) The management review system should include:
(1) The results of regulatory inspections and findings, audits and other assessments, and
commitments made to regulatory authorities;
(2) Periodic quality reviews, that can include:
(i) Measures of customer satisfaction such as product quality complaints and recalls;
(ii) Conclusions of process performance and product quality monitoring;
(iii) The effectiveness of process and product changes including those arising from
corrective action and preventive actions.
(3) Any follow-up actions from previous management reviews.
(b) The management review system should identify appropriate actions, such as:
(1) Improvements to manufacturing processes and products;
(2) Provision, training and/or realignment of resources;
(3) Capture and dissemination of knowledge.
Table IV: Application of management review of process performance and product quality
throughout the product lifecycle
Pharmaceutical
development
Technology transfer Commercial
manufacturing
Product
discontinuation
Aspects of management
review can be
performed to ensure
adequacy of the
product and process
design.
Aspects of management
review should be
performed to ensure
the developed product
and process can be
manufactured at
commercial scale.
Management review
should be a structured
system, as described
above, and should
support continual
improvement.
Management review
should include such
items as product
stability and product
quality complaints.
4. Continual improvement of the pharmaceutical quality
system
This section describes activities that should be conducted to manage and continually improve the
pharmaceutical quality system.
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4.1. Management review of the pharmaceutical quality system
Management should have a formal process for reviewing the pharmaceutical quality system on a
periodic basis. The review should include:
(a) Measurement of achievement of pharmaceutical quality system objectives;
(b) Assessment of performance indicators that can be used to monitor the effectiveness of
processes within the pharmaceutical quality system, such as:
(1) Complaint, deviation, CAPA and change management processes;
(2) Feedback on outsourced activities;
(3) Self-assessment processes including risk assessments, trending, and audits;
(4) External assessments such as regulatory inspections and findings and customer audits.
4.2. Monitoring of internal and external factors impacting the
pharmaceutical quality system
Factors monitored by management can include:
(a) Emerging regulations, guidance and quality issues that can impact the Pharmaceutical Quality
System;
(b) Innovations that might enhance the pharmaceutical quality system;
(c) Changes in business environment and objectives;
(d) Changes in product ownership.
4.3. Outcomes of management review and monitoring
The outcome of management review of the pharmaceutical quality system and monitoring of internal
and external factors can include:
(a) Improvements to the pharmaceutical quality system and related processes;
(b) Allocation or reallocation of resources and/or personnel training;
(c) Revisions to quality policy and quality objectives;
(d) Documentation and timely and effective communication of the results of the management
review and actions, including escalation of appropriate issues to senior management.
5. Glossary
ICH and ISO definitions are used in ICH Q10 where they exist. For the purpose of ICH Q10, where the
words “requirement”, “requirements” or “necessary” appear in an ISO definition, they do not
necessarily reflect a regulatory requirement. The source of the definition is identified in parentheses
after the definition. Where no appropriate ICH or ISO definition was available, an ICH Q10 definition
was developed.
Pharmaceutical Quality System (ICH Q10)
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Capability of a process:
Ability of a process to realise a product that will fulfill the requirements of that product. The concept of
process capability can also be defined in statistical terms. (ISO 9000:2005)
Change management:
A systematic approach to proposing, evaluating, approving, implementing and reviewing changes. (ICH
Q10)
Continual improvement:
Recurring activity to increase the ability to fulfill requirements. (ISO 9000:2005)
Control strategy:
A planned set of controls, derived from current product and process understanding that assures
process performance and product quality. The controls can include parameters and attributes related
to drug substance and drug product materials and components, facility and equipment operating
conditions, in-process controls, finished product specifications, and the associated methods and
frequency of monitoring and control. (ICH Q10)
Corrective action:
Action to eliminate the cause of a detected non-conformity or other undesirable situation. NOTE:
Corrective action is taken to prevent recurrence whereas preventive action is taken to prevent
occurrence. (ISO 9000:2005)
Design space:
The multidimensional combination and interaction of input variables (e.g., material attributes) and
process parameters that have been demonstrated to provide assurance of quality. (ICH Q8)
Enabler:
A tool or process which provides the means to achieve an objective. (ICH Q10)
Feedback / Feed-forward:
Feedback: The modification or control of a process or system by its results or effects.
Feed-forward: The modification or control of a process using its anticipated results or effects. (Oxford
Dictionary of English by Oxford University Press, 2003)
Feedback/ feed-forward can be applied technically in process control strategies and conceptually in
quality management. (ICH Q10)
Innovation:
The introduction of new technologies or methodologies. (ICH Q10)
Knowledge management:
Systematic approach to acquiring, analysing, storing, and disseminating information related to
products, manufacturing processes and components. (ICH Q10)
Outsourced activities:
Activities conducted by a contract acceptor under a written agreement with a contract giver. (ICH Q10)
Pharmaceutical Quality System (ICH Q10)
EMA/INS/GMP/79818/2011 Page 16/18
Performance indicators:
Measurable values used to quantify quality objectives to reflect the performance of an organisation,
process or system, also known as “performance metrics” in some regions. (ICH Q10)
Pharmaceutical Quality System (PQS):
Management system to direct and control a pharmaceutical company with regard to quality. (ICH Q10
based upon ISO 9000:2005)
Preventive action:
Action to eliminate the cause of a potential non-conformity or other undesirable potential situation.
NOTE: Preventive action is taken to prevent occurrence whereas corrective action is taken to prevent
recurrence. (ISO 9000:2005)
Product realisation:
Achievement of a product with the quality attributes appropriate to meet the needs of patients, health
care professionals, and regulatory authorities (including compliance with marketing authorisation) and
internal customers’ requirements. (ICH Q10)
Quality:
The degree to which a set of inherent properties of a product, system or process fulfils requirements.
(ICH Q9)
Quality manual:
Document specifying the quality management system of an organisation. (ISO 9000:2005)
Quality Objectives:
A means to translate the quality policy and strategies into measurable activities. (ICH Q10)
Quality planning:
Part of quality management focused on setting quality objectives and specifying necessary operational
processes and related resources to fulfill the quality objectives. (ISO 9000:2005)
Quality policy:
Overall intentions and direction of an organisation related to quality as formally expressed by senior
management. (ISO 9000:2005)
Quality risk management:
A systematic process for the assessment, control, communication and review of risks to the quality of
the drug (medicinal) product across the product lifecycle. (ICH Q9)
Senior management:
Person(s) who direct and control a company or site at the highest levels with the authority and
responsibility to mobilise resources within the company or site. (ICH Q10 based in part on ISO
9000:2005)
State of control:
A condition in which the set of controls consistently provides assurance of continued process
performance and product quality. (ICH Q10)
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Annex 1
Potential opportunities to enhance science and risk based regulatory approaches *
*Note: This annex reflects potential opportunities to enhance regulatory approaches. The actual
regulatory process will be determined by region.
Scenario Potential opportunity
1. Comply with GMPs Compliance – status quo
2. Demonstrate effective pharmaceutical
quality system, including effective use of quality
risk management principles (e.g., ICH Q9 and ICH
Q10).
Opportunity to:
increase use of risk based approaches for
regulatory inspections.
3. Demonstrate product and process
understanding, including effective use of quality
risk management principles (e.g., ICH Q8 and ICH
Q9).
Opportunity to:
facilitate science based pharmaceutical quality
assessment;
enable innovative approaches to process
validation;
establish real-time release mechanisms.
4. Demonstrate effective pharmaceutical
quality system and product and process
understanding, including the use of quality risk
management principles (e.g., ICH Q8, ICH Q9 and
ICH Q10).
Opportunity to:
increase use of risk based approaches for
regulatory inspections;
facilitate science based pharmaceutical quality
assessment;
optimise science and risk based post-approval
change processes to maximise benefits from
innovation and continual improvement;
enable innovative approaches to process
validation;
establish real-time release mechanisms.
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Annex 2
GMP
ICH Q10 Pharmaceutical Quality System
Pharmaceutical
Development
Commercial
Manufacturing
Product
Discontinuation
Technology
Transfer
Investigational products
Management Responsibilities
Process Performance & Product Quality Monitoring System
Corrective Action / Preventive Action (CAPA) System
Change Management System
Management Review
PQS
elements
Knowledge Management
Quality Risk Management
Enablers
Annex 2
Diagram of the ICH Q10 Pharmaceutical Quality System Model
This diagram illustrates the major features of the ICH Q10 Pharmaceutical Quality System (PQS)
model. The PQS covers the entire lifecycle of a product including pharmaceutical development,
technology transfer, commercial manufacturing, and product discontinuation as illustrated by the upper
portion of the diagram. The PQS augments regional GMPs as illustrated in the diagram. The diagram
also illustrates that regional GMPs apply to the manufacture of investigational products.
The next horizontal bar illustrates the importance of management responsibilities explained in Section
2 to all stages of the product lifecycle. The following horizontal bar lists the PQS elements which serve
as the major pillars under the PQS model. These elements should be applied appropriately and
proportionally to each lifecycle stage recognising opportunities to identify areas for continual
improvement.
The bottom set of horizontal bars illustrates the enablers: knowledge management and quality risk
management, which are applicable throughout the lifecycle stages. These enablers support the PQS
goals of achieving product realisation, establishing and maintaining a state of control, and facilitating
continual improvement.
Pharmaceutical Quality System.doc
Table of contents
Pharmaceutical quality system
Introduction
Scope
Relationship of ICH Q10 to regional GMP requirements, ISO standards and ICH Q7
Relationship of ICH Q10 to regulatory approaches
ICH Q10 objectives
Achieve product realisation
Establish and maintain a state of control
Facilitate continual improvement
Enablers: knowledge management and quality risk management
Knowledge management
Quality risk management
Design and content considerations
Quality manual
Management responsibility
Management commitment
Quality policy
Quality planning
Resource management
Internal communication
Management review
Management of outsourced activities and purchased materials
Management of change in product ownership
Continual improvement of process performance and product quality
Lifecycle stage goals
Pharmaceutical development
Technology transfer
Commercial manufacturing
Product discontinuation
Pharmaceutical quality system elements
Process performance and product quality monitoring system
Corrective Action and Preventive Action (CAPA) system
Change management system
Management review of process performance and product quality
Continual improvement of the pharmaceutical quality system
Management review of the pharmaceutical quality system
Monitoring of internal and external factors impacting the pharmaceutical quality system
Outcomes of management review and monitoring
Glossary
Annex 1
Annex 2
04.08.2014
Datei
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May 2011
EMA/CHMP/ICH/425213/2011
ICH/ Committee for medicinal products for human use (CHMP)
ICH guideline Q11 on development and manufacture of
drug substances (chemical entities and
biotechnological/biological entities)
Step 3
Transmission to CHMP May 2011
Adoption by CHMP for release for consultation May 2011
End of consultation (deadline for comments) September 2011
Comments should be provided using this template. The completed comments form should be sent to
ICH@ema.europa.eu
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ICH guideline Q11 on development and manufacture of drug substances (chemical
entities and biotechnological/biological entities)
EMA/CHMP/ICH/425213/2011 Page 2/27
ICH guideline Q11 on development and manufacture of
drug substances (chemical entities and
biotechnological/biological entities)
Table of contents
1. Introduction ............................................................................................ 4
2. Scope....................................................................................................... 4
3. Manufacturing Process Development....................................................... 4
3.1. General Principles .............................................................................................. 4
3.1.1. Drug Substance Quality Link to Drug Product ...................................................... 4
3.1.2. Process Development Tools............................................................................... 5
3.1.3. Approaches to Development.............................................................................. 5
3.1.4. Drug Substance Critical Quality Attributes ........................................................... 6
3.1.5. Linking Material Attributes and Process Parameters to Drug Substance CQAs ........... 6
3.1.6. Design Space.................................................................................................. 7
3.2. Submission of Manufacturing Process Development Information................................ 8
3.2.1. Overall Process Development Summary.............................................................. 8
3.2.2. Drug Substance CQAs ...................................................................................... 8
3.2.3. Manufacturing Process History........................................................................... 8
3.2.4. Manufacturing Developmental Studies ................................................................ 9
4. Description of Manufacturing Process and Process Controls.................... 9
5. Selection of Starting Materials and Source Materials............................. 10
5.1. General Principles ............................................................................................ 10
5.1.1. Selection of Starting Materials for Synthetic Drug Substances .............................. 10
5.1.2. Selection of Starting Materials for Semi-synthetic Drug Substances ...................... 11
5.1.3. Selection of Source Materials for Biotechnological/Biological Products.................... 11
5.2. Submission of Information for Starting Material or Source Material .......................... 11
5.2.1. Justification of Starting Material Selection for Synthetic Drug Substances .............. 11
5.2.2. Justification of Starting Material Selection for Semi-Synthetic Drug Substances ...... 12
5.2.3. Qualification of Source Materials for Biotechnological/Biological Products ............... 12
6. Control Strategy .................................................................................... 12
6.1. General Principles ............................................................................................ 12
6.1.1. Approaches to Developing a Control Strategy .................................................... 12
6.1.2. Considerations in Developing a Control Strategy ................................................ 13
6.2. Submission of Control Strategy Information ......................................................... 13
7. Process Validation/Evaluation............................................................... 13
7.1. General Principles ............................................................................................ 13
7.2. Principles Specific to Biotechnological/Biological Products....................................... 14
ICH guideline Q11 on development and manufacture of drug substances (chemical
entities and biotechnological/biological entities)
EMA/CHMP/ICH/425213/2011 Page 3/27
8. Submission of Manufacturing Process Development and Related
Information In Common Technical Documents (CTD) Format ................... 15
8.1. Quality Risk Management and Process Development.............................................. 15
8.2. Critical Quality Attributes (CQAs)........................................................................ 15
8.3. Design Space .................................................................................................. 15
8.4. Control Strategy .............................................................................................. 15
9. Lifecycle Management ........................................................................... 16
10. Illustrative Examples........................................................................... 17
10.1. Example 1: Linking Material Attributes and Process Parameters to Drug Substance
CQAs - Chemical Entity............................................................................................ 17
10.2. Example 2: Use of Quality Risk Management to Support Lifecycle Management of
Process Parameters ................................................................................................ 20
10.3. Example 3: Presentation of a Design Space for a Biotechnological Product Unit
Operation .............................................................................................................. 21
10.4. Example 4: Selecting an Appropriate Starting Material ......................................... 22
10.5. Example 5: Summary of Control Elements for select CQAs ................................... 23
11. Glossary .............................................................................................. 27
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1. Introduction
This guideline describes approaches to developing process and drug substance understanding and also
provides guidance on what information should be provided in CTD sections 3.2.S.2.2 – 3.2.S.2.6. It
provides further clarification on the principles and concepts described in ICH guidelines on
Pharmaceutical Development (Q8), Quality Risk Management (Q9) and Pharmaceutical Quality
Systems (Q10) as they pertain to the development and manufacture of drug substance.
A company can choose to follow different approaches in developing a drug substance. For the purpose
of this guideline, the terms “traditional” and “enhanced” are used to differentiate two possible
approaches. In a traditional approach, set points and operating ranges for process parameters are
defined and the drug substance control strategy is typically based on demonstration of process
reproducibility and testing to meet established acceptance criteria. In an enhanced approach, risk
management and more extensive scientific knowledge are used to select process parameters and unit
operations that impact critical quality attributes (CQAs) for evaluation in further studies to establish
any design space(s) and control strategies applicable over the lifecycle of the drug substance. As
discussed in ICH Q8 for drug product, a greater understanding of the drug substance and its
manufacturing process can create the basis for more flexible regulatory approaches. The degree of
regulatory flexibility is generally predicated on the level of relevant scientific knowledge provided in the
application for marketing authorisation.
Traditional and enhanced approaches are not mutually exclusive. A company can use either a
traditional approach or an enhanced approach to drug substance development, or a combination of
both.
2. Scope
This guideline is applicable to drug substances as defined in the Scope sections of ICH Guidelines Q6A
and Q6B, but might also be appropriate for other types of products following consultation with the
appropriate regulatory authorities. It is particularly relevant to the preparation and organisation of the
contents of sections 3.2.S.2.2 – 3.2.S.2.6 of Module 3 of the Common Technical Document (ICH M4Q).
The guideline does not apply to contents of submissions during the clinical research stages of drug
development. Nevertheless, the development principles presented in this guideline are important to
consider during the investigational stages.
Regional requirements for post-approval changes are not covered by this guideline.
3. Manufacturing Process Development
3.1. General Principles
The goal of manufacturing process development for the drug substance is to establish a commercial
manufacturing process capable of consistently producing drug substance of the intended quality.
3.1.1. Drug Substance Quality Link to Drug Product
The intended quality of the drug substance should be determined through consideration of its use in
the drug product as well as from knowledge and understanding of its physical, chemical, biological, and
microbiological properties or characteristics, which can influence the development of the drug product
(e.g., the solubility of the drug substance can affect the choice of dosage form). The Quality Target
Product Profile (QTPP) and potential CQAs of the drug product (as defined in ICH Q8) can help identify
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potential CQAs of the drug substance. Knowledge and understanding of the CQAs can evolve during
the course of development.
3.1.2. Process Development Tools
Quality Risk Management (QRM, as described in ICH Q9) can be used in a variety of activities including
assessing options for the design of the manufacturing process, assessing quality attributes and
manufacturing process parameters, and increasing the assurance of routinely achieving acceptable
quality results. Risk assessments can be carried out early in the development process and repeated as
greater knowledge and understanding become available. It is neither always appropriate nor always
necessary to use a formal risk management process (using recognised tools and/or internal
procedures, e.g., standard operating procedures). The use of informal risk management processes
(using empirical tools and/or internal procedures) can also be considered acceptable.
Knowledge management (as described in ICH Q10) can also facilitate manufacturing process
development. In this context, potential sources of information can include prior knowledge and
development studies. Prior knowledge can include established biological, chemical and engineering
principles and applied manufacturing experience. Data derived from relevant prior knowledge,
including platform manufacturing (see glossary) can be leveraged to support development of the
commercial process and expedite scientific understanding.
3.1.3. Approaches to Development
ICH Q8 recognises that “Strategies for product development vary from company to company and from
product to product. The approach to, and extent of, development can also vary and should be outlined
in the submission.” These concepts apply equally to the development of the drug substance
manufacturing process. An applicant can choose either a traditional approach or an enhanced approach
to drug substance development, or a combination of both.
Manufacturing process development should include, at a minimum, the following elements:
Identifying potential CQAs associated with the drug substance so that those characteristics having an
impact on product quality can be studied and controlled;
Defining an appropriate manufacturing process;
Defining a control strategy to ensure process performance and drug substance quality (see Section 6
on Control Strategy).
An enhanced approach to manufacturing process development would additionally include the following
elements:
A systematic evaluation, understanding and refining of the manufacturing process, including;
Identifying, through e.g. prior knowledge, experimentation and risk assessment, the material
attributes and process parameters that can have an effect on drug substance CQAs;
Determining the functional relationships that link material attributes and process parameters to drug
substance CQAs;
Using the enhanced approach in combination with QRM to establish an appropriate control strategy
which can, for example, include a proposal for a design space(s) and/or real-time release testing
(RTRT).
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The increased knowledge and understanding obtained from taking an enhanced approach could
facilitate continual improvement and innovation throughout the product lifecycle (see ICH Q10).
3.1.4. Drug Substance Critical Quality Attributes
A CQA is a physical, chemical, biological, or microbiological property or characteristic that should be
within an appropriate limit, range, or distribution to ensure the desired product quality. Potential drug
substance CQAs are used to guide process development. The list of potential CQAs can be modified as
drug substance knowledge and process understanding increase.
Drug substance CQAs typically include those properties or characteristics that affect identity, purity,
biological activity and stability. When physical properties are important with respect to in vivo
performance or drug product manufacture, these can be designated as CQAs. In the case of
biotechnological/biological products, most of the CQAs of the drug product are associated with the drug
substance and thus are a direct result of the design of the drug substance or its manufacturing
process.
Impurities are an important class of potential drug substance CQAs because of their potential impact
on drug product safety. For chemical entities, impurities can include organic impurities (including
potential genotoxic impurities), inorganic impurities, for example metal residues, and residual solvents
(see ICH Q6A, Q3A, and Q3C). For biotechnological/biological products, impurities may be process-
related or product-related (see ICH Q6B). Process-related impurities include: cell substrate-derived
impurities (e.g., Host Cell Proteins and DNA); cell culture-derived impurities (e.g., media components);
and downstream-derived impurities (e.g., column leachables). CQAs for biotechnology/biological
products should also include consideration of contaminants, as defined in Q6B, including all
adventitiously introduced materials not intended to be part of the manufacturing process (e.g.,
adventitious viral, bacterial, or mycoplasma contamination).
The identification of CQAs for complex products can be challenging. Biotechnological/biological
products, for example, typically possess such a large number of quality attributes that it might not be
possible to fully evaluate the impact on safety and efficacy of each one. Risk assessments can be
performed to rank or prioritise quality attributes. Prior knowledge can be used at the beginning of
development and assessments can be iteratively updated with development data (including data from
non-clinical and clinical studies) during the lifecycle. Knowledge regarding mechanism of action and
biological characterisation, such as studies evaluating structure-function relationships, can contribute
to the assessment of risk for some product attributes.
3.1.5. Linking Material Attributes and Process Parameters to Drug
Substance CQAs
The manufacturing process development program should identify which material attributes (e.g., of
raw materials, starting materials, reagents, solvents, process aids, intermediates) and process
parameters should be controlled. Risk assessment can help identify the material attributes and process
parameters with the potential for having an effect on drug substance CQAs. Those material attributes
and process parameters that are found to be important to drug substance quality should be addressed
by the control strategy.
The risk assessment to define the control strategy of materials upstream from the drug substance can
include an assessment of manufacturing process capability, attribute detectability, and severity of
impact as they relate to drug substance quality. For example, when assessing the link between an
impurity in a raw material or intermediate and drug substance CQAs, the ability of the drug substance
manufacturing process to remove that impurity should be considered in the assessment. The risk
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related to impurities can usually be controlled by specifications for raw material/intermediates and/or
robust purification capability in downstream steps. The risk assessment can also identify material
attributes for which there are inherent limitations in detectability (e.g., viral safety) or inadequate
purification capability. In these cases, such upstream material attributes should be considered drug
substance CQAs.
Using a traditional approach, material specifications and process parameter ranges can be based
primarily on batch process history and univariate experiments. An enhanced approach can lead to a
more thorough understanding of the relationship of material attributes and process parameters to
CQAs and the effect of interactions. Example 1 illustrates the development of process parameters using
prior knowledge and chemistry first principles.
Risk assessment can be used during development to identify those parts of the process likely to impact
potential CQAs. Further risk assessments can be used to focus development work in areas where
better understanding of the link between process and quality is needed. Using an enhanced approach,
the determination of appropriate material specifications and process parameter ranges could follow a
sequence such as the one shown below:
Identify potential sources of process variability;
Identify the material attributes and process parameters likely to have the greatest impact on drug
substance quality. This can be based on prior knowledge and risk assessment tools;
Design and conduct experiments and/or mechanistic studies (e.g., multivariate design of experiments,
simulations, modelling) to identify and confirm the links and relationships of material attributes and
process parameters to drug substance CQAs;
Analysis and assessment of the data to establish appropriate ranges, including establishment of a
design space if desired.
Small-scale models can be developed and used to support process development studies. The
development of a model should account for scale effects and be representative of the proposed
commercial process. A scientifically justified model can enable a prediction of product quality, and can
be used to support the extrapolation of operating conditions across multiple scales and equipment.
3.1.6. Design Space
The considerations for design space addressed in ICH Q8 for an enhanced approach to the
development of the drug product are equally applicable to drug substance. The ability to accurately
assess the significance and effect of the variability of material attributes and process parameters on
drug substance CQAs, and hence the limits of a design space, depends on the extent of process and
product understanding. In some cases, prior knowledge can be used to support development of a
design space. Irrespective of whether the manufacturing process of a product has been developed
using prior knowledge the manufacturing process should be appropriately validated (see Process
Validation/Evaluation Section 7).
For chemical entity design space development, a major focus is knowledge of formation, fate, and
purge of impurities through every step of a manufacturing process. It is important to understand the
formation, fate (whether the impurity reacts and changes its chemical structure), and purge (whether
the impurity is removed via crystallisation, extraction, etc.) as well as their relationship to the resulting
impurities that end up in the drug substance as CQAs. All steps (or unit operations) should be
evaluated to establish appropriate acceptance criteria for impurities as they progress through multiple
process operations.
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3.2. Submission of Manufacturing Process Development Information
The information provided on the development of the drug substance manufacturing process (primarily
in section 3.2.S.2.6 of the application) should identify significant changes during process development,
link relevant drug substance batches with the developmental stage of the manufacturing process used
to prepare them, and explain how prior knowledge, risk assessments, and experimental studies (e.g.,
modelling, simulations, engineering and scientific principles) were used to establish important aspects
of the manufacturing process and control strategy. The significance of a drug substance manufacturing
change during development should be assessed by evaluating its potential to impact the quality of the
drug substance (and/or intermediate, if appropriate). Process development information should be
logically organised and easy to understand. Manufacturers can present process development
information in a number of different ways, but some specific recommendations are provided below for
consideration.
3.2.1. Overall Process Development Summary
It is recommended that the manufacturing process development section begin with a narrative
summary that describes important milestones in the development of the process and explains how
they are linked to assuring that the intended quality of the drug substance is achieved. The following
should be included in the summary:
List of drug substance CQAs;
Brief description of the stages in the evolution of the manufacturing process and control strategy;
Brief description of the material attributes and process parameters that impact drug substance CQAs;
Brief description of the development of any design spaces.
Following the Overall Process Development Summary, the manufacturing process development section
should include more comprehensive information, as recommended below.
3.2.2. Drug Substance CQAs
The CQAs of the drug substance should be listed, and the rationale for designating these properties or
characteristics as CQAs should be provided. In some cases, it might be appropriate to explain why
other properties or characteristics that might be considered potential CQAs are not included in the list
of CQAs. Links or references should be provided to information submitted elsewhere in the submission
(e.g., 3.2.S.3.1, Elucidation of Structure and other Characteristics) that supports the designation of
these properties or characteristics as CQAs. Some discussion of drug substance CQAs as they relate to
drug product CQAs can be appropriate in the pharmaceutical development section of the application
(e.g., 3.2.P.2.1, Components of the Drug Product).
3.2.3. Manufacturing Process History
A description and discussion should be provided of significant changes made to the manufacturing
process or site of manufacture of drug substance batches used in support of the marketing application
(e.g., those used in nonclinical or clinical studies or stability studies in support of a marketing
authorisation) and, if available, production-scale batches. The description should follow a chronological
sequence ending with the proposed commercial process.
The reason for each significant change should be explained, together with an assessment of its
potential to impact the quality of the drug substance (and/or intermediate, if appropriate). Batch
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information (batch size or scale, site and date of manufacture, route and process used, and intended
purpose (e.g., in a specified toxicology or clinical study)) and supporting data from comparative
analytical testing on relevant drug substance batches should be provided or referenced (e.g., batch
analysis section 3.2.S.4.4).
For biotechnological/biological products, the manufacturing process history section should include a
discussion of comparability during development as described in ICH Q5E. A discussion of the data,
including a justification for selection of the tests and assessment of results, should be included.
Testing used to assess the impact of manufacturing changes on the drug substance and the
corresponding drug product can also include nonclinical and clinical studies. Cross-reference to the
location of these studies in other modules of the submission should be included.
3.2.4. Manufacturing Developmental Studies
The studies and risk assessments used to establish important aspects of the commercial manufacturing
process and control strategy cited in the application should be listed (e.g., in tabular form). The
purpose or end use of each cited study or risk assessment should be provided.
Each cited study or risk assessment should be summarised with a level of detail sufficient to convey an
understanding of the purpose of the study, the data collected, how it was analysed, the conclusions
reached, and the impact of the study on the manufacturing process or further development of the
manufacturing process. The particular parameters and ranges studied should be described and
discussed in relation to the proposed operating conditions for the commercial manufacturing process
(as described in 3.2.S.2.2). The risk assessment tools and study results on which a design space is
based should be adequately described. Example 2 shows a possible communication tool for risk ranking
of parameters. Where development refers to specific prior knowledge, the relevant information and
data should be provided and, where appropriate, the relevance to the particular drug substance should
be justified.
Small-scale models used to support process development studies should be described.
4. Description of Manufacturing Process and Process
Controls
The description of the drug substance manufacturing process represents the applicant’s commitment
for the manufacture of the drug substance. Information should be provided to adequately describe the
manufacturing process and process controls (see ICH M4Q (3.2.S.2.2).
The description of the manufacturing process should be provided in the form of a flow diagram and
sequential procedural narrative. The in-process controls for each step or stage of the process should be
indicated in the description. Scaling factors should be included for manufacturing steps intended to
span multiple operational scales when the process step is scale dependent. Any design spaces in the
manufacturing process should be included as part of the manufacturing process description. Example 3
gives an example of the presentation of a design space for a biotechnological product.
To facilitate the approval of a design space for a complex product, such as a biotechnological/biological
product, an applicant can choose to provide information on how movements within the design space
will be managed post approval. This could help the reviewer understand how residual risk will be
managed.
Many biotechnological/biological products have complex upstream processes and use splitting and
pooling to create a drug substance. An explanation of how batches of drug substance are defined by
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the manufacturer (e.g., splitting and pooling of harvests or intermediates), should be provided. Details
of batch size or scale and batch numbering should be included.
5. Selection of Starting Materials and Source Materials
5.1. General Principles
5.1.1. Selection of Starting Materials for Synthetic Drug Substances
The following general principles should be considered in determining where the drug substance
manufacturing process begins (i.e., in selecting starting materials).
In general, changes in material attributes or operating conditions that occur near the beginning of the
manufacturing process have lower potential to impact the quality of the drug substance;
The relationship between risk and number of steps from the end of the manufacturing process is the
result of two factors, one concerning the physical properties of the drug substance and the other
concerning the formation, fate, and purge of impurities. The physical properties of a drug substance
are determined during the final crystallisation step and subsequent operations (e.g., milling,
micronising, transport), all of which occur at the end of the manufacturing process. Impurities
introduced or created early in the manufacturing process typically have more opportunities to be
removed in purification operations (e.g., washing, crystallisation of isolated intermediates) than
impurities generated late in the manufacturing process, and are therefore less likely to be carried into
the drug substance. However, in some cases (e.g., when peptides or oligonucleotides are synthesised
on a solid support), there is a more limited relationship between risk and number of steps from the end
of the manufacturing process;
Regulatory authorities assess whether the controls on the drug substance and drug substance
manufacturing process can be considered adequate, including whether there are appropriate controls
for impurities. To conduct this assessment, enough of the drug substance manufacturing process
should be described in the application for regulatory authorities to understand how impurities are
formed in the process, how changes in the process could affect the formation, fate, and purge of
impurities, and why the proposed control strategy is suitable for the drug substance manufacturing
process. This will typically include a description of multiple chemical transformation steps;
Manufacturing steps that impact the impurity profile of the drug substance should normally be included
in the manufacturing process described in section 3.2.S.2.2 of the application;
Each branch of a convergent drug substance manufacturing process begins with one or more starting
materials. The GMP provisions described in ICH Q7 apply to each branch beginning with the first use of
a starting material. Performing manufacturing steps under GMP together with an appropriate control
strategy provides assurance of quality of the drug substance;
A starting material should be a substance of defined chemical properties and structure. Non-isolated
intermediates are usually not considered appropriate starting materials;
A starting material is incorporated as a significant structural fragment into the structure of the drug
substance. “Significant structural fragment” in this context is intended to distinguish starting materials
from reagents, solvents, or other raw materials. Commonly available chemicals used to create salts,
esters or other simple derivatives should be considered reagents.
All the general principles above should be considered in selecting Starting Material(s), rather than
strictly applying each general principle in isolation (see Example 4).
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5.1.2. Selection of Starting Materials for Semi-synthetic Drug Substances
For purposes of this guideline, a semi-synthetic drug substance is one in which the structural
constituents have been introduced by a combination of chemical synthesis and elements of biological
origin (e.g., obtained from fermentation or by extraction from botanical material). In some cases, it
might be appropriate for the applicant to describe the manufacturing process starting from the source
material (microorganism or botanical material). However, if it can be demonstrated that one of the
isolated intermediates in the synthetic process complies with the principles outlined above for the
selection of starting materials for synthetic drug substances, that isolated intermediate can be
proposed as the starting material. The applicant should specifically evaluate whether it is possible to
analytically characterise the proposed starting material, including its impurity profile, and whether the
fermentation or botanical material and extraction process impact the impurity profile of the drug
substance. Risks from microbial and other contamination should also be addressed.
5.1.3. Selection of Source Materials for Biotechnological/Biological
Products
Cell banks are the starting point for manufacture of biotechnological/biologics products. Guidance
appropriate for cell banks is contained in ICH Q5A, Q5B, and Q5D.
5.2. Submission of Information for Starting Material or Source Material
Applicants should identify all proposed starting materials or source materials and provide appropriate
specifications. Proposed starting materials should be justified.
5.2.1. Justification of Starting Material Selection for Synthetic Drug
Substances
The applicant should provide a justification for how each proposed starting material is appropriate in
light of the general principles for the selection of starting materials outlined above in Section 5.1.1.
This can include information on:
The ability of analytical procedures to detect impurities in the starting material;
The fate and purge of those impurities and their derivatives in subsequent processing steps;
How the proposed specification for each starting material will contribute to the control strategy;
The applicant should provide, as part of the justification, a flow diagram outlining the current synthetic
route(s) for the manufacture of the drug substance, with the proposed starting materials clearly
indicated. Changes to the starting material specification and to the synthetic route from the starting
material to final drug substance are subject to regional, post-approval change requirements. In
addition, regional requirements concerning starting material suppliers may also be applicable.
An applicant generally need not justify the use of a commercially available chemical as a starting
material. A commercially available chemical is usually one that is sold as a commodity in a pre-
existing, non-pharmaceutical market in addition to its proposed use as starting material. Chemicals
produced by custom syntheses are not considered to be commercially available. If a chemical from a
custom synthesis is proposed as a starting material, it should be justified in accordance with the
general principles for the selection of starting materials outlined above in Section 5.1.1.
In some instances, additional purification steps might be called for to ensure the consistent quality of a
commercially available starting material. In these instances, the additional purification steps should be
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included as part of the description of the drug substance manufacturing process. Specifications should
normally be provided for both incoming and purified starting material.
5.2.2. Justification of Starting Material Selection for Semi-Synthetic Drug
Substances
If an isolated intermediate is proposed as the starting material for a semi-synthetic drug substance,
the applicant should provide a justification that explains how the proposed starting material complies
with the general principles for the selection of starting materials outlined above in Section 5.1.1.
Otherwise, the applicant should describe the manufacturing process starting from the source material
(microorganism or botanical material) and the source materials should be appropriately qualified.
5.2.3. Qualification of Source Materials for Biotechnological/Biological
Products
Guidance is contained in ICH Q5A, Q5B and Q5D.
6. Control Strategy
6.1. General Principles
A control strategy is a planned set of controls, derived from current product and process understanding
that assures process performance and product quality (ICH Q10). Every drug substance manufacturing
process, whether developed through a traditional or an enhanced approach (or some combination
thereof), has an associated control strategy.
A control strategy can include, but is not limited to, the following:
Controls on material attributes (including raw materials, starting materials, intermediates, reagents,
primary packaging materials for the drug substance, etc.);
Controls implicit in the design of the manufacturing process (e.g., sequence of purification steps
(Biotechnological/Biological Products), or order of addition of reagents (Chemical Products));
In-process controls (including in-process tests and process parameters);
Controls on drug substance (e.g., release testing).
6.1.1. Approaches to Developing a Control Strategy
A control strategy can be developed through a combination of approaches, utilising the traditional
approach for some CQAs, steps, or unit operations, and a more enhanced approach for others.
In a traditional approach to developing a manufacturing process and control strategy, set points and
operating ranges are typically set narrowly based on the observed data to ensure consistency of
manufacture. More emphasis is placed on assessment of CQAs at the stage of the drug substance (i.e.,
end-product testing). The traditional approach provides limited flexibility in the operating ranges to
address variability (e.g., in raw materials).
An enhanced approach to manufacturing process development generates better process and product
understanding than the traditional approach, so sources of variability can be identified in a more
systematic way. This allows for the development of more meaningful and efficient parametric,
attribute, and procedural controls. The control strategy might be developed through several iterations
as the level of process understanding increases during the product lifecycle. A control strategy based
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on an enhanced approach can provide for flexibility in the operating ranges for process parameters to
address variability (e.g., in raw materials).
6.1.2. Considerations in Developing a Control Strategy
In either the traditional or enhanced approach, the control strategy can include an in-process
determination that a CQA is within an appropriate limit, range or distribution in lieu of testing the final
drug substance. Any approach other than testing the final drug substance should provide at least the
same level of assurance of drug substance quality. When considering such an approach, applicants
should determine whether there are any downstream factors that might impact the quality of the drug
substance, such as temperature changes, oxidative conditions, light, ionic content, and shear.
When developing a control strategy, a manufacturer can consider implementing single or multiple
points of control for a specific CQA, depending on the risk associated with the CQA and the ability of
individual controls to detect a potential problem. For example, with sterilised drug substances or
biotechnological/biological products, there is an inherent limitation in the ability to detect low levels of
bacterial or viral contamination in the drug substance. In these cases, end-product testing is
considered to provide inadequate assurance of quality, so additional points of control (e.g., attribute
and in-process controls) are incorporated into the control strategy.
The quality of each raw material used in the manufacturing process should be appropriate for its
intended use. Raw materials used in operations near the end of the manufacturing process have a
greater potential to introduce impurities into the drug substance than raw materials used upstream.
Therefore, manufacturers should evaluate whether the quality of such materials should be more tightly
controlled than similar materials used upstream.
6.2. Submission of Control Strategy Information
The information provided on the control strategy should include detailed descriptions of the individual
elements of the control strategy plus, when appropriate, a summary of the overall drug substance
control strategy. The summary of the overall control strategy can be presented in a tabular format as
well as in a diagrammatic format, to aid visualisation and understanding (see Example 5 for example of
a Control Strategy Summary in tabular form). Ideally, the summary should explain how the individual
elements of the control strategy work together to assure drug substance quality.
ICH M4Q recommends that the individual elements of the control strategy reported in an application be
provided in the appropriate sections of a submission, including:
Description of Manufacturing Process and Process Controls (3.2.S.2.2);
Control of Materials (3.2.S.2.3);
Controls of Critical Steps and Intermediates (3.2.S.2.4);
Container Closure System (3.2.S.6);
Control of Drug Substance (3.2.S.4).
7. Process Validation/Evaluation
7.1. General Principles
Process Validation (PV) is the documented evidence that the process, operated within established
parameters, can perform effectively and reproducibly to produce a drug substance or intermediate
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meeting its predetermined specifications and quality attributes (ICH Q7). Process validation involves
the collection and evaluation of data, from the process design stage throughout production, that
establish scientific evidence that a process is capable of consistently delivering a quality drug
substance.
The drug substance manufacturing process should be validated before commercial distribution of
resulting drug product. For biotechnological processes, or for aseptic processing and sterilisation
process steps for drug substances, the data provided in support of process validation is included as
part of the marketing application (3.2.S.2.5). For non-sterile drug substance processes, results of
process validation studies are not normally included in the dossier.
Generally, process validation includes the collection of data on an appropriate number of production
batches (see ICH Q7, Section 12.5). The number of batches can depend on several factors including
but not limited to: (1) the complexity of the process being validated; (2) the level of process
variability; and (3) the amount of experimental data and/or process knowledge available on the
specific process.
As an alternative to the traditional process validation, continuous process verification (ICH Q8) can be
utilised in process validation protocols for the initial commercial production and for manufacturing
process changes for the continual improvement throughout the remainder of the product lifecycle.
7.2. Principles Specific to Biotechnological/Biological Products
For biotechnological/biological products, the information provided in the dossier in support of process
validation usually contains both commercial-scale process validation studies and small-scale studies.
Process validation batches should be representative of the commercial process, taking into account the
batch definition as detailed in the process description
The contribution of data from small-scale studies to the overall validation package will depend upon
demonstration that the small-scale model is an appropriate representation of the proposed commercial
scale. Data should be provided demonstrating that the model is scalable and representative of the
proposed commercial process. Successful demonstration of the suitability of the small-scale model can
enable manufacturers to propose process validation with reduced dependence on testing of
commercial-scale batches. Data derived from commercial-scale batches should confirm results
obtained from small scale studies used to generate data in support of process validation. Scientific
grounds, or reference to guidelines which do not require or specifically exclude such studies, can be an
appropriate justification to conduct certain studies only at small scale (e.g. viral removal).
Studies should be conducted to demonstrate the ability of the process to remove product-related
impurities, process-related impurities (ICH Q6B) and potential contaminants (such as viruses in
processes using material from human or animal origin, see ICH Q5A). Studies carried out to
demonstrate the lifetime of chromatography columns can include experimental studies carried out in
small-scale models but should be confirmed during commercial-scale production.
The limit of in vitro cell age for commercial production should be assessed. ICH documents Q5B and
Q5D provide further guidance for relevant products.
When platform manufacturing experience is utilised, the suitability of the control strategy should be
demonstrated and the drug substance manufacturing process should be appropriately validated at the
time of marketing authorisation application. Full scale validation studies should include data derived
from the final manufacturing process and site(s) used to produce the product to be commercialised.
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8. Submission of Manufacturing Process Development and
Related Information In Common Technical Documents
(CTD) Format
The use of an enhanced approach to process development results in the generation of information for
which a location in the CTD is not defined. Process development information should usually be
submitted in Section 3.2.S.2.6 of the CTD. Other information resulting from development studies could
be accommodated by the CTD format in a number of different ways and some specific suggestions are
provided below. The applicant should clearly indicate where the different information is located. In
addition to what is submitted in the application, certain aspects (e.g., lifecycle management, continual
improvement) of this guideline are handled under the applicant’s pharmaceutical quality system (see
ICH Q10).
8.1. Quality Risk Management and Process Development
Quality risk management can be used at different stages during process development and
manufacturing implementation. The assessments used to guide and justify development decisions
(e.g., risk analyses and functional relationships linking material attributes and process parameters to
drug substance CQAs) can be summarised in section 3.2.S.2.6.
8.2. Critical Quality Attributes (CQAs)
The CQAs of the drug substance should be listed, and the rationale for designating these properties or
characteristics as CQAs should be provided in the manufacturing process development section of the
application (3.2.S.2.6). However, detailed information about structural characterisation studies that
supports the designation of these properties or characteristics as CQAs should be provided in the
appropriate CTD format sections (e.g., 3.2.S.3.1, Elucidation of Structure and other Characteristics,
3.2.S.7 Stability). Some discussion of drug substance CQAs as they relate to drug product CQAs can be
appropriate in the pharmaceutical development section of the application (3.2.P.2.1, Components of
the Drug Product).
8.3. Design Space
As an element of the proposed manufacturing process, the design space(s) can be described in the
section of the application that includes the description of the manufacturing process and process
controls (3.2.S.2.2). If appropriate, additional information can be provided in the section of the
application that addresses the controls of critical steps and intermediates (3.2.S.2.4). The
manufacturing process development section of the application (3.2.S.2.6) is the appropriate place to
summarise and describe process development studies that provide the basis for the design space(s).
The relationship of the design space(s) to the overall control strategy can be discussed in the section of
the application that includes the justification of the drug substance specification (3.2.S.4.5).
8.4. Control Strategy
The section of the application that includes the justification of the drug substance specification
(3.2.S.4.5) is a good place to summarise the overall drug substance control strategy. However,
detailed information about input material controls, process controls, and control of drug substance
should still be provided in the appropriate CTD format sections (e.g., description of manufacturing
process and process controls (3.2.S.2.2), control of materials (3.2.S.2.3), controls of critical steps and
intermediates (3.2.S.2.4), drug substance specification (3.2.S.4.1)). The evolution of the control
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strategy should be described in the manufacturing process development section of the application
(3.2.S.2.6).
9. Lifecycle Management
The quality system elements and management responsibilities described in ICH Q10 are intended to
encourage the use of science-based and risk-based approaches at each lifecycle stage, thereby
promoting continual improvement across the entire product lifecycle. Product and process knowledge
should be managed from development through the commercial life of the product up to and including
product discontinuation.
The development and improvement of a drug substance manufacturing process usually continues over
its lifecycle. Manufacturing process performance, including the effectiveness of the control strategy and
suitability of any design spaces, should be periodically evaluated. This can be done as part of the
Product Quality Review described in ICH Q7 Section 2.5. Knowledge gained from this product quality
review, as well as from the manufacturing of the drug substance for commercial supply, can be used to
further improve process understanding and process performance and to adjust the control strategy to
ensure drug substance quality. Knowledge gained from other products, or from new innovative
technologies, can also contribute to these goals. Continual improvement and successful process
validation, or continuous process verification, call for an appropriate and effective control strategy.
There should be a systematic approach to managing knowledge related to both drug substance and its
manufacturing process throughout the lifecycle. This knowledge management should include but not be
limited to process development activities, technology transfer activities to internal sites and contract
manufacturers, process validation studies over the lifecycle of the drug substance, and change
management activities. The knowledge and process understanding should be shared across all sites
involved in manufacturing the drug substance (ICH Q10 1.6.1).
An applicant can include in the original submission a proposal for how specific future changes will be
managed during the product lifecycle. For an example of how process parameters can be managed for
a biotechnological product, see Example 2.
Any proposed change to the manufacturing process should be evaluated for the impact on the quality
of drug substance and, when appropriate, drug product. This evaluation should be based on scientific
understanding of the manufacturing process and should determine appropriate testing to analyse the
impact of the proposed change. For chemical entities the appropriate testing to analyse the impact of
the proposed change could, for example, be on an intermediate or drug substance. For process
changes for biotechnological/biological products, see also ICH Q5E.
All changes should be subject to internal change management processes as part of the overall Quality
System. This includes movements within the Design Space, which do not require approval by regional
regulatory authorities.
Changes to information filed and approved in a dossier should be reported to regulatory authorities in
accordance with regional regulations and guidelines.
10. Illustrative Examples
These examples are provided for illustrative purposes and only suggest potential uses. This Appendix is
not intended to create any new expectations beyond the current regulatory requirements.
10.1. Example 1: Linking Material Attributes and Process Parameters to
Drug Substance CQAs - Chemical Entity
This example illustrates development of a design space using prior knowledge and chemistry first
principles. It depicts both a traditional and enhanced approach to determination of the ranges for
parameters controlling the formation of a hydrolysis impurity during Step 5 of the following reaction
scheme (Also used in Example 4).
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After the formation of intermediate F in Step 5, the mixture is heated to reflux. During reflux an
impurity is formed through hydrolysis of intermediate F.
For the purpose of this simplified example, this is the only reaction of intermediate F that occurs during
this reflux. The following assumptions where used in the design of the process:
The concentration of intermediate F remains approximately constant.
Temperature remains constant.
The acceptance criterion for the hydrolysis impurity in Intermediate F is 0.30%. (This is based on the
CQA in the drug substance and the demonstrated capacity of the subsequent steps to purge the
impurity.)
The initial amount of water in the reflux mixture depends on the amount of water in Intermediate E,
which can be controlled by drying.
Time of reflux and water concentration were identified as the most important parameters affecting the
hydrolysis of intermediate F. Other potential factors were determined to be insignificant based on prior
knowledge and risk assessment.
The reaction was expected to follow second-order kinetics according to the equation below:
FOHk
dt
impurityhydrolysisd
2
_
A
Final Drug
Substance
R3
R4
R1
D
E
Step 1 Step 2
Step 5 Step 6
Step 4
R3
R2
1
(B)
“Crude”
Drug
R3
R4
R1Purification
Step 3
C
F
Where refers to the concentration of intermediate F. F
Through simple experimentation the following graph linking the extent of hydrolysis to time and the
water content of intermediate E can be generated:
Hydrolysis Degradation at Reflux
0.6
0.5
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Traditional Approach:
In a traditional approach this information would be used to set a proven acceptable range for % water
and time that achieves the acceptance criteria for the hydrolysis impurity of 0.30% in intermediate F.
This is typically done by setting a target value and maximum such as:
Dry Intermediate E to a maximum water content of 1.0%
Target reflux time of 1.5 hours and a maximum reflux time of 4 hours
Enhanced Approach:
The 2nd order rate equation can be integrated and solved explicitly (Chemical Reaction Engineering,
Levenspiel 2nd Edition, 1972).
ktFOH
XM
XM
oo
F
F
21
ln
Where:
oF refers to the initial concentration of intermediate F,
oOH 2 refers to the initial concentration of water,
oo OHFM 2 refers to the ratio of the initial concentration of intermediate F to the
0.0
0.1
0.2
0.3
0.4
0 1 2 3
Reflux Time (hours)H
y
d
o
ly
si
s
Im
p
u
ri
ty
(
%
)
in
I
n
te
rm
e
d
ia
te
F
2.0% water
1.0% water
0.5% water
0.1% water
4 5
initial concentration of water, and
XF refers to the time-dependent concentration of the hydrolysis
degradant of intermediate F.
Solving this equation for time (t) permits the calculation of the maximum allowable reflux time for any
combination of initial water content and target level for the hydrolysis impurity. (The initial
concentration of intermediate F in the reflux mixture will essentially be constant from batch to batch.)
The following graph shows the combination of conditions required to ensure that the hydrolysis
impurity remains below 0.30% in intermediate F.
Interdependence of Reflux Time and Water Content in
the Formation of Hydrolysis Impurity
0.0
1.0
2.0
3.0
4.0
5.0
6.0
7.0
8.0
0.0 1.0 2.0 3.0 4.0 5.0
Water Content (%) in Intermediate E
R
ef
lu
x
T
im
e
(h
ou
rs
)
Conditions that produce a level
of 0.30% of the hydrolysis
impurity
Operating above the line will
produce more than 0.30% of
the hydrolysis impurity
The area below the line in the plot above could be proposed as the design space.
Summary:
While both the traditional and enhanced approach provide ranges of water content and time to control
the formation of the hydrolysis impurity, the enhanced approach allows more manufacturing flexibility.
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10.2. Example 2: Use of Quality Risk Management to Support Lifecycle
Management of Process Parameters
This example illustrates how results from an iterative quality risk assessment can be used to
communicate the rationale for classification and proposed future management of changes to process
parameters. Relevant parameters for establishment of a design space for a Q-anion exchange column
are shown in this Risk Ranking Histogram. The histogram showing the ranking of parameters is
intended for illustrative purposes only and is not all inclusive, nor is it meant to be applicable to all
products that may use ion exchange chromatography.
Initial Filing
A quality risk assessment utilising prior knowledge and development studies can be used to rank
process parameters based on their relative potential to have an effect on product quality if parameter
ranges were changed. The histogram shows the potential impact to quality for future changes to
parameter ranges based on the knowledge and understanding at the time of submission. Process
development studies and interaction studies were conducted to establish design space boundaries for
each of the higher risk parameters (parameters A-F) that impact CQAs. Parameters G, H and I were
also challenged in the development studies and shown not to impact CQAs under the conditions
studied. Changes to the ranges of these parameters could still carry residual risk (based on prior
knowledge/uncertainties, including potential scale sensitivity). Parameters J-T were considered lower
risk parameters based on documented prior knowledge, and therefore an impact on quality attributes
is not anticipated. The ranking of parameters from the quality risk assessment can be used to
communicate with regulators regarding a lifecycle management approach to assure continual
improvement throughout the product lifecycle.
Lifecycle Management Options
Risk should be reassessed throughout the lifecycle as process understanding increases.
Recommendations regarding lifecycle management changes can be found in the Pharmaceutical Quality
System (PQS) as described in ICH Q10.
Working within the design space is not considered as a change. Movement out of the design space is
considered to be a change and consequently any extension of ranges for higher risk parameters (i.e.
parameters A-F) would normally initiate a regulatory post approval change process.
An applicant can include in the original submission a proposal for how specific future changes to
parameters G, H, and I will be managed during the product lifecycle. Extension of ranges for lower
risk parameters (J-T) does not require prior regulatory approval, although notification may be called
for depending on regional regulatory requirements and guidance. If it is determined subsequently to
the filing that there is a change in the risk ranking, such that an extension of ranges for a parameter
represents a higher risk, this change should be appropriately filed through the regional regulatory
process.
10.3. Example 3: Presentation of a Design Space for a Biotechnological
Product Unit Operation
This example is based on a design space for a drug substance purification unit operation (Q-anion
exchange column run for a monoclonal antibody in flow-through mode), determined from the common
region of successful operating ranges for multiple CQAs. This figure illustrates a potential depiction of a
design space based on successful operating ranges for three CQAs and the use of prior knowledge
(platform manufacturing) in developing a design space. The ranges represented here indicate areas of
successful operation and not edges of failure.
Viral clearance and host cell protein (HCP) ranges were derived from multivariate experimentation (see
ICH Q8). The successful operating range for DNA was derived from prior knowledge (platform
manufacturing) which in turn was derived from results of multivariate studies performed on related
products. The successful operating range for HCP lies within the viral clearance and DNA successful
operating ranges. In this example, the diagrams below show how HCP limits the unit operation design
space compared to viral safety and DNA. Consideration of additional input variables, process
parameters, or CQAs could limit design space further.
The design space is applicable only within specified conditions, including
Appropriately defined quality criteria for input materials;
Appropriately selected CQAs and process parameters.
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10.4. Example 4: Selecting an Appropriate Starting Material
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This example illustrates the importance of considering all general principles described in section 5.1.1
when selecting an appropriate starting material, rather than applying each general principle in
isolation. The example is fictional, based on a linear synthesis for a relatively simple molecule, and is
not intended to convey any particular meaning in relation to the number of steps.
The desired stereochemical configuration in the drug substance results from the synthesis of compound
B in step 1 from a commercially available achiral precursor A and a stereo-selective reagent. A small
amount of the opposite enantiomer of compound B is also formed in step 1. Once formed, both
A
Final Drug
Substance
R3
R4
R1
D
E
Step 1 Step 2
Step 5 Step 6
Step 4
R3
R2
1
(B)
“Crude”
Drug
Substance
R3
R4
R1Purification
Step 3
C
F
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stereochemical configurations persist through the synthetic steps that follow, so the drug substance
also contains a small amount of its undesired enantiomer as a specified impurity. In accordance with
the principle that manufacturing steps that impact the drug substance impurity profile should normally
be included in the manufacturing process described in section 3.2.S.2.2 of the application, it could be
concluded that step 1 should be described in 3.2.S.2.2, and that A should be considered the starting
material.
However, for this manufacturing process, it is also known that all of the significant impurities in the
drug substance (other than opposite enantiomer) arise from steps 4, 5, and 6. Steps 2 and 3 have no
impact on the drug substance impurity profile, and the only impact from step 1 is with regard to the
enantiomeric impurity. Furthermore, it is also known that the stereocentre first formed in step 1 is
stable to the manufacturing conditions in all of the steps that follow (i.e., no racemisation occurs or is
ever likely to occur), and that a suitable analytical procedure exists for measuring the amount of the
opposite enantiomer in compound D. Therefore, as compound D is in accordance with most of the
other general principles described in section 5.1.1, it would be reasonable to propose D as the starting
material instead of A in accordance with the principle that early steps in the manufacturing process
tend to have a lower potential to impact drug substance quality than later steps. In this example, the
only impact of step 1 is on the amount of the enantiomeric impurity in the drug substance, and this
could alternatively be controlled through an appropriate limit on the amount of the opposite
enantiomer in compound D. Information on steps 1-3 would be made available to regulatory
authorities in order to justify such a proposal as per regional expectations.
A similar argument could be made if the stereocentre in the drug substance originated in the
commercially available precursor A instead of being created in step 1.
10.5. Example 5: Summary of Control Elements for select CQAs
This example illustrates how part of a drug substance control strategy might be summarised in tabular
form. The tables show how an applicant can communicate information on multiple elements of a drug
substance control strategy and guide the reviewer to sections of the CTD where detailed elements of
the control strategy are described or justified. Such control strategy summary tables should not
contain the rationale or justification for the controls but should simply indicate where the information
can be found in the application for marketing authorisation.
There are multiple ways of presenting this information, and two are shown below. One table shows
more detail than the other to illustrate that there is a range of possibilities for presenting this
information. The amount of detail included in a control strategy summary table is up to the applicant
and is not related to the type of drug substance. CQAs and control elements shown in the tables below
are only examples and are not intended to be a comprehensive representation of all elements of a drug
substance control strategy. The tables should not be considered templates. The section of the
application that includes the justification of the drug substance specification (3.2.S.4.5) is a good place
to summarise the overall drug substance control strategy.
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5a. Example of a Possible Control Strategy Summary – Biotechnological Products
Drug
Substance
CQA
Control Strategy for drug substance CQA
Section(s) in
CTD where
detailed
information is
located
Summaries of viral safety information for
biologically-sourced materials
3.2.S.2.3 Contaminants in
biologically
sourced
materials
(Viral Safety)
Detailed information including for materials of
biological origin, testing at appropriate stages of
production and viral clearance studies
3.2.A.2
Design Space for an individual unit operation
(e.g. see Example 3)
3.2.S.2.2
Target range for consistent removal assured by
validation
3.2.S.2.5
Residual Host
Cell Proteins
Analytical procedures and their validation 3.2.S.4.2 and
3.2.S.4.3
Controls implicit in the design of the
manufacturing process including a summary of
process control steps (e.g. cell culture
conditions, downstream purification, holding
conditions etc.)
3.2.S.2.2
Characterisation to justify classification as CQA
(cross reference to non-clinical/clinical sections if
relevant)
3.2.S.3.1
Control of Critical Steps, Testing program and
specifications
3.2.S.2.4 and/or
3.2.S.4.1
Justification of specification 3.2.S.4.5
Specific
Glycoforms
Stability 3.2.S.7
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5b. Example of a possible Control Strategy Summary – Chemical Entity.
Type of
Control
Drug -→
Substance
CQA (3.2.S.2.6)
/ Limit in Drug
Substance↓
In process
Controls (including
In-process testing
and process
parameters)
Controls on
material
attributes
(raw
materials/startin
g materials
/intermediates)
Impact of
Manufacturing
Process
Design
Is CQA tested
on drug
substance/
included in
Drug
Substance
specification
(3.2.S.4.1)
Organic Purity
Impurity X
NMT 0.15%
Design space of the reflux unit operation
composed of a combination of %water in
Intermediate E and the reflux time in step 5
that delivers Intermediate F with Hydrolysis
Impurity ≤0.30% (3.2.S.2.2)
Yes/Yes
Impurity Y
NMT 0.20%
Process parameters
step 4 (3.2.S.2.2)
p(H2) ≥2 barg
T <50°C
In-process test step
4 (3.2.S.2.4)
Impurity Y ≤0.50%
Yes/Yes
Any individual
unspecified
impurity
NMT 0.10%
Specs for starting
material D
(3.2.S.2.3)
Yes/Yes
Total impurities
NMT 0.50%
Yes/Yes
Enantiomeric
purity
S-enantiomer
NMT 0.50%
Spec for starting
material D
(3.2.S.2.3)
S-enantiomer
≤0.50%
Stereocentre is
shown not to
racemize;
(3.2.S.2.6)
No/No
Residual Solvent
Ethanol
NMT 5000 ppm
In-process test
during drying after
final purification step
(3.2.S.2.4)
LOD ≤0.40 %
In-process
results
correlated to
test results on
drug substance.
No/Yes
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Type of
Control
Drug -→
Substance
CQA (3.2.S.2.6)
/ Limit in Drug
Substance↓
In process
Controls (including
In-process testing
and process
parameters)
Controls on
material
attributes
(raw
materials/startin
g materials
/intermediates)
Impact of
Manufacturing
Process
Design
Is CQA tested
on drug
substance/
included in
Drug
Substance
specification
(3.2.S.4.1)
(3.2.S.2.6)
Toluene
NMT 890 ppm
In-process test step
4 (3.2.S.2.4)
≤2000 ppm by G.C
Process steps
after step 4 are
shown to purge
toluene to levels
significantly
below (less than
10%) that
indicated in ICH
Q3C
(3.2.S.2.6).
No/No1
1This approach could be acceptable as part of a control strategy when justified by submission of
relevant process data that confirms the adequacy of the process design and control. The
manufacturing process should be periodically evaluated under the firm's quality system to verify
removal of the solvent.
Notes concerning Table 5b
The above table is based on the route of synthesis presented in Example 1. The Control for
enantiomeric impurity is based on Decision Tree 5 from ICH guideline Q6A, which allows for control of
chiral quality to be established by applying limits to appropriate starting materials or intermediates
when justified from development studies. In order for this approach to be acceptable data would need
to be provided in 3.2.S.2.6 to demonstrate the stability of the stereocentre under the proposed
manufacturing conditions.
The table summarises only a portion of the control strategy that would be presented at the time of
initial submission and does not include all CQAs of the drug substance. The example control strategy
provides for control of some CQAs at stages in the process prior to the drug substance. The elements
of the proposed control strategy described in the application would be justified by the applicant in
3.2.S.4.5 and subject to regulatory assessment and approval.
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11. Glossary
Chemical Transformation Step
For Chemical Entities, a step involved in the synthesis of the chemical structure of the drug substance
from precursor molecular fragments. Typically it involves C-X or C-C bond formation or breaking.
Continuous Process Verification: An alternative approach to process validation in which manufacturing
process performance is continuously monitored and evaluated. (ICH Q8)
Control Strategy: A planned set of controls, derived from current product and process understanding,
that assures process performance and product quality. The controls can include parameters and
attributes related to drug substance and drug product materials and components, facility and
equipment operating conditions, in-process controls, finished product specifications, and the associated
methods and frequency of monitoring and control. (ICH Q10)
Critical Quality Attribute (CQA): A physical, chemical, biological or microbiological property or
characteristic that should be within an appropriate limit, range, or distribution to ensure the desired
product quality. (ICH Q8)
Design Space: The multidimensional combination and interaction of input variables (e.g., material
attributes) and process parameters that have been demonstrated to provide assurance of quality.
Working within the design space is not considered as a change. Movement out of the design space is
considered to be a change and would normally initiate a regulatory post approval change process.
Design space is proposed by the applicant and is subject to regulatory assessment and approval. (ICH
Q8)
Intermediate: See ICH Q7, ICH Q3a, and ICH Q5c
Impurity: See ICH Q6A and ICH Q6B
Lifecycle: All phases in the life of a product from the initial development through marketing until the
product’s discontinuation (ICH Q8).
Platform Manufacturing: The approach of developing a production strategy for a new drug starting
from manufacturing processes similar to those used by the same applicant to manufacture other drugs
of the same type (e.g., as in the production of monoclonal antibodies using predefined host cell, cell
culture, and purification processes, for which there already exists considerable experience)
Process Robustness: Ability of a process to tolerate variability of materials and changes of the process
and equipment without negative impact on quality. (ICH Q8)
Quality Risk Management (QRM): A systematic process for the assessment, control, communication
and review of risks to the quality of the drug (medicinal) product across the product lifecycle. (ICH Q9)
Quality Target Product Profile (QTPP): A prospective summary of the quality characteristics of a drug
product that ideally will be achieved to ensure the desired quality, taking into account safety and
efficacy of the drug product. (ICH Q8)
Real Time Release Testing: The ability to evaluate and ensure the quality of in-process and/or final
product based on process data, which typically include a valid combination of measured material
attributes and process controls. (ICH Q8)
1. Introduction
2. Scope
3. Manufacturing Process Development
3.1. General Principles
3.1.1. Drug Substance Quality Link to Drug Product
3.1.2. Process Development Tools
3.1.3. Approaches to Development
3.1.4. Drug Substance Critical Quality Attributes
3.1.5. Linking Material Attributes and Process Parameters to Drug Substance CQAs
3.1.6. Design Space
3.2. Submission of Manufacturing Process Development Information
3.2.1. Overall Process Development Summary
3.2.2. Drug Substance CQAs
3.2.3. Manufacturing Process History
3.2.4. Manufacturing Developmental Studies
4. Description of Manufacturing Process and Process Controls
5. Selection of Starting Materials and Source Materials
5.1. General Principles
5.1.1. Selection of Starting Materials for Synthetic Drug Substances
5.1.2. Selection of Starting Materials for Semi-synthetic Drug Substances
5.1.3. Selection of Source Materials for Biotechnological/Biological Products
5.2. Submission of Information for Starting Material or Source Material
5.2.1. Justification of Starting Material Selection for Synthetic Drug Substances
5.2.2. Justification of Starting Material Selection for Semi-Synthetic Drug Substances
5.2.3. Qualification of Source Materials for Biotechnological/Biological Products
6. Control Strategy
6.1. General Principles
6.1.1. Approaches to Developing a Control Strategy
6.1.2. Considerations in Developing a Control Strategy
6.2. Submission of Control Strategy Information
7. Process Validation/Evaluation
7.1. General Principles
7.2. Principles Specific to Biotechnological/Biological Products
8. Submission of Manufacturing Process Development and Related Information In Common Technical Documents (CTD) Format
8.1. Quality Risk Management and Process Development
8.2. Critical Quality Attributes (CQAs)
8.3. Design Space
8.4. Control Strategy
9. Lifecycle Management
10. Illustrative Examples
10.1. Example 1: Linking Material Attributes and Process Parameters to Drug Substance CQAs - Chemical Entity
10.2. Example 2: Use of Quality Risk Management to Support Lifecycle Management of Process Parameters
10.3. Example 3: Presentation of a Design Space for a Biotechnological Product Unit Operation
10.4. Example 4: Selecting an Appropriate Starting Material
10.5. Example 5: Summary of Control Elements for select CQAs
11. Glossary
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[image: image1.png]
Association Européenne des Spécialités Pharmaceutiques Grand Public
Association of the European Self-Medication Industry
Europäischer Verband der Arzneimittel-Hersteller
2010 QUESTIONNAIRE ON IMPLEMENTATION OF THE EMEA Q&A ON
GMP COMPLIANCE FOR ATYPICAL ACTIVES
Atypical actives are pharmaceutical active ingredients primarily used for other categories of goods (e.g. food, cosmetics), for which GMP qualified suppliers are not available. A non-exclusive list of atypical actives is provided in the annex for illustration purposes.
In September 2008, the following Q&A prepared by the GMP/GDP inspectorates (GMDP) was published on the EMEA website to address the issues of GMP compliance for ‘atypical actives’:
“The Notice to Applicants requires the submission of a declaration signed by the Qualified Person that the active substance used is manufactured in accordance with GMP. The active substance in my product is widely used, but not normally as a pharmaceutical active substance, and I am having some difficulty in confirming compliance. What should I do to furnish the required declaration?
Answer:
Full compliance with GMP for finished products and active substances is a legal obligation for Manufacturing Authorisation holders. It is recognised that for a small number of medicinal products the primary use of the active substance is not in a medicinal product and the producer may therefore not be aiming to meet the specific requirements of pharmaceutical customers that represent an insignificant volume of business. Alternative sources should normally be sought but in exceptional circumstances the manufacturing authorisation holder should assess and document to which extent GMP is complied with and provide a risk-based justification for the acceptance of any derogation. The declaration provided by the Qualified Person should set out in detail the basis for declaring that the standards applied provide the same level of assurance as GMP. EMEA will collect experience with this approach which can be used as a basis for discussion on related amendments to guidelines in the future. “
In 2009, AESGP collected industry experience on the implementation and use of this Q&A across the EU. Feedback received was limited (a little over 10 questionnaires were returned) but was overall positive. To continue monitoring the implementation and use of this Q&A, AESGP is inviting Marketing authorisation holders and manufacturing authorisation holders to provide their recent company’s experience by answering the following questions.
Your feedback is instrumental and will help us analyse whether the EMEA Q&A fulfils its intended use and if not, your comments will serve as a basis for the development of proposals for improvement.
Completed questionnaire should be returned to Christelle Anquez-Traxler, AESGP, at: C.Anquez@aesgp.be BEFORE 31 August 2010.
Data collected will be made anonymous and compiled by the AESGP office and the results will be presented at the GMDP-interested parties meeting at the end of 2010.
In advance, we thank you for your response.
1. Do you own any manufacturing/marketing authorisation for any products containing atypical actives (see examples listed in the enclosed annex)?
FORMCHECKBOX
YES
(if so, please go to the following questions)
FORMCHECKBOX
NO
(if not, skip the remaining questions and return the questionnaire as such)
2. If you are the Marketing authorisation holder (MAH):
2.1 Did you submit application(s) for a new license, line extension, renewal, or variation concerning a so-called ‘atypical active’ in the past 12 months?
FORMCHECKBOX
YES
FORMCHECKBOX
NO
If so, could you please tell us the Member State(s) to which the application was submitted, the atypical active involved, and the type of application (new license, line extension, renewal, variation):
Member State(s):
Type of application:
Atypical active (optional):
2.2 What was your company’s experience on the construction of a risk-based approach, as recommended in the Q&A?
2.3 To support the quality of your atypical active ingredient did you submit (a) a “general” QA declaration, (b) a full risk assessment, (c) other (please specify).....
2.4 What was the reaction of the national competent authority with regard to the QP declaration on the atypical active as mentioned at 2.3?
Were there any further questions asked?
2.5 Had the national authority to which you submitted the application published an official statement endorsing the use Q&A?
Were there additional guidance published?
3. If you are the Manufacturing authorisation holder, did you experience any issues concerning the atypical active during a GMP inspection by a national competent authority?
FORMCHECKBOX
YES
FORMCHECKBOX
NO
If so, which issues?
Were they mentioned in the inspection report?
FORMCHECKBOX
YES
FORMCHECKBOX
NO
4. Any comments and/or suggestions you would like to add?
ANNEX
Non-exhaustive list of ‘atypical actives’, substances provided as illustration
Alginic acid
Aluminium oxid
Ammonium (acetate, chloride)
Amylmetacresol
Avobenzone
Benzoyl peroxide
Benzylic alcohol
Borax
Butanediol (1,3 – butandiol)
Caffeine
Calcium carbonate
Camphor
Chaolin [or kaolin]
Charcoal (Carbo vegetalis, Beech wood)
Chlorhexidine digluconate
Chloroxylenol
Chloride
Choline hydrogentartrate
Chromium
Coal tar (extract)
Coenzyme A
Coenzyme Q10 [or Ubidecarenon]
Copper (acetate, sulphate)
Citric acid
Ethanol
Formic acid
Glucose
Glycerol
Honey
Hydrotalcite
Iodine
Iron
Lactic acid
Lanolin
Lemon juice
Magnesium salts
Manganese
Menthol
Nitric acid
Oxybenzone
Padimate O
Paraffin
n-Pentane
Phenol
Phosphoric acid
Phosphorus
Polyethylene glycol
Potassium salts
Propan-1-ol
Propan-2-ol
Resorcinol [or resorcin]
Silica
Simethicone
Sodium (bicarbonate, carbonate, chloride, citrate)
Sodium Pyrrolidone Carboxylate
Starch (from rice)
Sulphur
Tartaric acid
Terpine hydrate
Treacle [or molasses]
Triclosane
Turpentine
Urea
Vaseline
Zinc oxide
Essential oils (e.g. Lavender essential oil, eucalyptus essential oil, etc.)
Vegetable oils
Fish oils
Vitamins
Minerals
7, avenue de Tervuren ( B-1040 Brussels ( Belgium ( Tel.: + 32 (0)2 735 51 30 ( Fax: + 32 (0)2 735 52 22
E-mail: info@aesgp.be ( http://www.aesgp.be
PAGE
2
2010.04.23
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letzte Änderung in Kraft getreten am: 12.06.2014
1
Anlage VII zum Abschnitt M der Arzneimittel-Richtlinie
Hinweise zur Austauschbarkeit von Darreichungsformen (aut idem) gemäß § 129 Abs. 1a
SGB V
Die nach der Liste der Standard Terms des European Directorate for the Quality of
Medicines & Health Care (EDQM) bezeichneten Darreichungsformen sind nach den in dieser
Anlage zusammengestellten Hinweisen im Sinne des § 129 Absatz 1 Satz 1 Nummer 1
SGB V in Verbindung mit § 4 Absatz 1 d) zweiter Spiegelstrich des Rahmenvertrags über die
Arzneimittelversorgung nach § 129 Absatz 2 SGB V austauschbar.
Weitere, in der Anlage nicht aufgeführte Bezeichnungen von Darreichungsformen sind von
dieser Regelung erfasst, soweit sie den definitorischen Voraussetzungen der in der Anlage
aufgeführten Standard Terms entsprechen.
Wirkstoff Wirkstoffbasen
im Verhältnis
austauschbare Darreichungsformen
Acebutolol
Acebutolol hydrochlorid
Filmtabletten
Tabletten
Acemetacin Hartkapseln
Acetylcystein Filmtabletten, dispers
Kapseln
Tabletten
Lutschtabletten
Acetylcystein Brausetabletten
Granulat im Beutel, fluessige Anwendung
Pulver im Beutel, fluessige Anwendung
Trinktabletten
Acetylcystein Lösung zum Einnehmen
Lösung zur Herstellung eines Sirups
Acetylsalicylsäure Kautabletten
Tabletten
Tabletten, magensaftresistent
Granulat im Beutel
Acetylsalicylsäure
Acetylsalicylsäure
DL-Lysin(acetylsalicylat)/DL-
Lysin(acetoxybenzoat)
Brausetabletten
Pulver im Beutel, fluessige Anwendung
Aciclovir Filmtabletten
Tabletten
Aescin
Rosskastaniensamen-
Trockenextrakt
Retardkapseln
Retardtabletten
Alendronsäure Filmtabletten
Tabletten
letzte Änderung in Kraft getreten am: 12.06.2014
2
Wirkstoff Wirkstoffbasen
im Verhältnis
austauschbare Darreichungsformen
Allopurinol überzogene Tabletten
Filmtabletten
Tabletten
Allopurinol +
Benzbromaron
1/0,2 Filmtabletten
Tabletten
Alpha-Liponsäure Filmtabletten
Kapseln
Ambroxol
Ambroxol hydrochlorid
Filmtabletten
Lutschpastillen
Pastillen
Tabletten
Lutschtabletten
Ambroxol
Ambroxol hydrochlorid
Retardkapseln
Retardtabletten
Ambroxol
Ambroxol hydrochlorid
Brausetabletten
Pulver im Beutel, fluessige Anwendung
Trinktabletten
Ambroxol
Ambroxol hydrochlorid
Lösung
Saft
Sirup
Tropfen
Tropflösung
Amisulprid Tabletten
Filmtabletten
Amitriptylin
Amitriptylinoxid
Amitriptylin hydrochlorid
überzogene Tabletten
Filmtabletten
Tabletten
Amitriptylin
Amitriptylinoxid
Amitriptylin hydrochlorid
Retardfilmtabletten
Retardkapseln
Retardtabletten
Amoxicillin
Amoxicillin-3-Wasser
Filmtabletten
Oblongtabletten
Tabletten
Amoxicillin
Amoxicillin-3-Wasser
Brausetabletten
Granulat im Beutel, fluessige Anwendung
Trinktabletten
Amoxicillin
Amoxicillin-3-Wasser
Saft
Suspension
Trockensaft
Trockensaft aus Granulat
Pulver zur Herstellung einer Suspension zum
Einnehmen
Amoxicillin + Clavulansäure Pulver zur Herstellung einer Suspension zum
Einnehmen
Amoxicillin + Clavulansäure Tabletten
Filmtabletten
letzte Änderung in Kraft getreten am: 12.06.2014
3
Wirkstoff Wirkstoffbasen
im Verhältnis
austauschbare Darreichungsformen
Ampicillin
Ampicillin-3-Wasser
Filmtabletten
Tabletten
Atenolol Filmtabletten
Tabletten
Azathioprin Tabletten
Filmtabletten
Azithromycin Pulver zur Herstellung einer Suspension zum
Einnehmen
Benzbromaron überzogene Tabletten
Tabletten
Bezafibrat überzogene Tabletten
Filmtabletten
Bezafibrat Retarddragees
Retardfilmtabletten
Retardtabletten
Bisoprolol
Bisoprolol hemifumarat
Filmtabletten
Lacktabletten
Tabletten
Bisoprolol +
Hydrochlorothiazid
Bisoprolol hemifumarat
1/2,95 Filmtabletten
Tabletten
Bromhexin
Bromhexin hydrochlorid
überzogene Tabletten
Tabletten
Bromhexin
Bromhexin hydrochlorid
Lösung
Saft
Tropfen
Tropflösung
Butylscopolaminium
Butylscopolaminiumbromid
überzogene Tabletten
Filmtabletten
Tabletten
Calciumcarbonat + Colecalciferol Kautabletten
Brausetabletten
Brausegranulat
Filmtabletten
Calcium dobesilat
Calcium dobesilat
Calcium dobesilat-Monohydrat
Kapseln
Tabletten
Captopril +
Hydrochlorothiazid
1/0,5 Filmtabletten
Tabletten
Captopril +
Hydrochlorothiazid
1/1 Filmtabletten
Tabletten
Carbamazepin Suspension zum Einnehmen
Carbimazol Filmtabletten
Tabletten
letzte Änderung in Kraft getreten am: 12.06.2014
4
Wirkstoff Wirkstoffbasen
im Verhältnis
austauschbare Darreichungsformen
Carvedilol Tabletten
Filmtabletten
Cefaclor Pulver zur Herstellung einer Suspension zum
Einnehmen
Granulat zur Herstellung einer Suspension zum
Einnehmen
Cefaclor Filmtabletten
Hartkapseln
Cefadroxil
Cefadroxil-1-Wasser
Tabletten
Filmtabletten
Cefalexin
Cefalexin
Cefalexin-1-Wasser
Filmtabletten
Tabletten
Cefixim Filmtabletten
Tablette zur Herstellung einer Suspension zum
Einnehmen
Cefixim Granulat zur Herstellung einer Suspension zum
Einnehmen
Cefpodoxim Pulver zur Herstellung einer Suspension zum
Einnehmen
Granulat zur Herstellung einer Suspension zum
Einnehmen
Cefuroxim Pulver zur Herstellung einer Suspension zum
Einnehmen
Granulat zur Herstellung einer Suspension zum
Einnehmen
Cefuroxim
Cefuroxim axetil
Filmtabletten
Tabletten
überzogene Tabletten
Cetirizin Lösung zum Einnehmen
Sirup
Cetirizin Tropfen zum Einnehmen, Lösung
Cetirizin
Cetirizin dihydrochlorid
Filmtabletten
Tabletten
Chlordiazepoxid überzogene Tabletten
Filmtabletten
Tabletten
Chloroquin
Chloroquin phosphat
Filmtabletten
Tabletten
Chlorprothixen
Chlorprothixen hydrochlorid
überzogene Tabletten
Filmtabletten
Cimetidin Filmtabletten
Tabletten
Cinnarizin Kapseln
Tabletten
letzte Änderung in Kraft getreten am: 12.06.2014
5
Wirkstoff Wirkstoffbasen
im Verhältnis
austauschbare Darreichungsformen
Clarithromycin Granulat zur Herstellung einer Suspension zum
Einnehmen
Clindamycin
Filmtabletten
Hartkapseln
Clodronsäure,
Dinatriumsalz
Clodronsäure, Dinatriumsalz-4-
Wasser
Filmtabletten
Kapseln
Clomipramin
Clomipramin hydrochlorid
überzogene Tabletten
Filmtabletten
Tabletten
Clonidin
Clonidin hydrochlorid
überzogene Tabletten
Kapseln
Tabletten
Clonidin
Clonidin hydrochlorid
Depotperlongetten
Retardkapseln
Codein Tropfen zum Einnehmen, Lösung
Colestyramin Granulat im Beutel, fluessige Anwendung
Pulver im Beutel, fluessige Anwendung
Cromoglicinsäure
Cromoglicinsäure, Dinatriumsalz
Granulat im Beutel, fluessige Anwendung
Pulver im Beutel, fluessige Anwendung
Cyproteronacetat + Ethinylestradiol Filmtabletten
überzogene Tabletten
Desloratadin Filmtabletten
Schmelztabletten
Tabletten
Desloratadin Lösung zum Einnehmen
Diclofenac Tropfen zum Einnehmen, Lösung
Diclofenac
Diclofenac natrium
Retarddragees
Retardkapseln
Retardkapseln, schnell
SL-Retardkapseln
Retardtabletten
Retardtabletten, schnell
Diclofenac Brausetabletten
Filmtabletten
Hartkapseln
magensaftresistente Hartkapseln
magensaftresistente Tabletten
Pulver zur Herstellung einer Lösung zum
Einnehmen
Tabletten zur Herstellung einer Suspension zum
Einnehmen
überzogene Tabletten
Weichkapseln
letzte Änderung in Kraft getreten am: 12.06.2014
6
Wirkstoff Wirkstoffbasen
im Verhältnis
austauschbare Darreichungsformen
Dienogest + Ethinylestradiol Filmtabletten
Tabletten
überzogene Tabletten
Dihydralazin
Dihydralazin sulfat
Dihydralazin sulfat-2,5-Wasser
Filmtabletten
Tabletten
Dihydroergotamin
Dihydroergotamin mesilat
Retardkapseln
Retardtabletten
Dihydroergotamin
Dihydroergotamin mesilat
Lösung
Tropfen
Tropflösung
Dihydroergotoxin mesilat Filmtabletten
Tabletten
Dihydroergotoxin mesilat Retardkapseln
Retardtabletten
Dihydroergotoxin mesilat
Dihydroergotoxinmethansulfonat
Co-dergocrinmesilat
Lösung
Tropfen
Tropflösung
Diltiazem
Diltiazem hydrochlorid
Filmtabletten
Tabletten
Diltiazem
Diltiazem hydrochlorid
Retardfilmtabletten
Retardkapseln
Retardtabletten
Dimenhydrinat überzogene Tabletten
Filmtabletten
Kapseln
Kaudragees
Tabletten
Kaugummi
Diphenhydramin
Diphenhydramin hydrochlorid
überzogene Tabletten
Filmtabletten
Kapseln
Tabletten
Dipyridamol überzogene Tabletten
Filmtabletten
Disopyramid
Disopyramid
Disopyramid dihydrogenphosphat
Retardkapseln
Retardtabletten
Domperidon
Domperidon maleat
Filmtabletten
Tabletten
Doxepin
Doxepin hydrochlorid
Filmtabletten
Kapseln
Tabletten
überzogene Tabletten
Doxycyclin
Doxycyclin-1-Wasser
Doxycyclin hyclat
Filmtabletten
Kapseln
Tabletten
letzte Änderung in Kraft getreten am: 12.06.2014
7
Wirkstoff Wirkstoffbasen
im Verhältnis
austauschbare Darreichungsformen
Doxylamin
Doxylamin succinat
Filmtabletten
Tabletten
Eisen(II)sulfat Filmtabletten
Hartkapseln
magensaftresistente Hartkapseln
Weichkapseln
überzogene Tabletten
Erythromycin
Erythromycin
Erythromycin stinoprat
Kapseln, magensaftresistent
Tabletten mit Stinoprat
Erythromycin
Erythromycin ethylsuccinat
Saft
Suspension
Trockensaft
Tropfen
Esomeprazol magensaftresistente Hartkapseln
magensaftresistente Tabletten
Estradiol Tabletten
Filmtabletten
überzogene Tabletten
Estriol überzogene Tabletten
Tabletten
Ethambutol
Ethambutol dihydrochlorid
Filmtabletten
Tabletten
Etilefrin
Etilefrin hydrochlorid
Kapseln
Tabletten
Etilefrin
Etilefrin hydrochlorid
Retardkapseln
Retardtabletten
Etilefrin
Etilefrin hydrochlorid
Lösung
Tropfen
Tropflösung
Exemestan Filmtabletten
überzogene Tabletten
Famotidin Filmtabletten
Plaettchen
Tabletten
Fenofibrat Filmtabletten mit modifizierter
Wirkstofffreisetzung
Kapseln
Kapseln, mikronisiert
Kapseln mit modifizierter Wirkstofffreisetzung
Hartkapseln, mikronisiert
Filmtabletten
Fluconazol Hartkapseln
Flunitrazepam Filmtabletten
Tabletten
letzte Änderung in Kraft getreten am: 12.06.2014
8
Wirkstoff Wirkstoffbasen
im Verhältnis
austauschbare Darreichungsformen
Fluoxetin
Filmtabletten
Hartkapseln
Tabletten
Tabletten zur Herstellung einer Suspension zum
Einnehmen
Fluphenazin
Fluphenazin dihydrochlorid
überzogene Tabletten
Filmtabletten
Tabletten
Flurazepam
Flurazepam
Flurazepam monohydrochlorid
Kapseln
Lacktabletten
Tabletten
Fluvastatin Hartkapseln
Folsäure Kapseln
Tabletten
Furosemid Hartkapseln, retardiert
Furosemid +
Spironolacton
1/2,5 Filmtabletten
Kapseln
Lacktabletten
Tabletten
Furosemid +
Spironolacton
1/5 Filmtabletten
Kapseln
Lacktabletten
Tabletten
Gabapentin Filmtabletten
Hartkapseln
Haloperidol Lösung zum Einnehmen
Tropfen zum Einnehmen, Lösung
Hydromorphon Retardtabletten
Hartkapseln, retardiert
(Applikationshäufigkeit 2 x täglich)
Hydrotalcit Kautabletten
Pastillen
Hydroxyzin
Hydroxyzin dihydrochlorid
Filmtabletten
Tabletten
Hymecromon überzogene Tabletten
Tabletten
Ibuprofen
Ibuprofen
Ibuprofen lysin
Filmtabletten
Kautabletten
Tabletten
Weichgelatinekapseln
Kapseln
überzogene Tabletten
Schmelztabletten
Ibuprofen
Ibuprofen
Ibuprofen lysin
Brausetabletten
Granulat im Beutel, fluessige Anwendung
Trinktabletten
letzte Änderung in Kraft getreten am: 12.06.2014
9
Wirkstoff Wirkstoffbasen
im Verhältnis
austauschbare Darreichungsformen
Ibuprofen Retardfilmtabletten
Retardkapseln
SL-Retardkapseln
Retardtabletten
Ibuprofen Suspension zum Einnehmen
Sirup
Imipramin
Imipramin hydrochlorid
überzogene Tabletten
Filmtabletten
Indapamid
Indapamid-0,5-Wasser
Filmtabletten
Kapseln
Indometacin Retardkapseln
Retardtabletten
Isosorbid dinitrat Tabletten
Sublingualtabletten
Isosorbid dinitrat Retarddragees
Retardkapseln
Retardtabletten
Isosorbid mononitrat Retarddragees
Retardkapseln
Retardtabletten
Isotretinoin Kapseln
Weichkapseln
Itraconazol Hartkapseln
Ketoprofen Filmtabletten
Kapseln
Tabletten
Ketoprofen Retardkapseln
Retardtabletten
SL-Retardtabletten
Ketotifen
Filmtabletten
Hartkapseln
Tabletten
Lactulose Granulat im Beutel, fluessige Anwendung
Pulver im Beutel, fluessige Anwendung
Brausetabletten
Trinktabletten
Lamotrigin Tabletten
Tablette zur Herstellung einer Suspension zum
Einnehmen
Lansoprazol magensaftresistente Hartkapseln
Levetiracetam Lösung zum Einnehmen
Levodopa + Benserazid Tabletten
Hartkapseln
Levomepromazin
Levomepromazin maleat
Filmtabletten
Tabletten
letzte Änderung in Kraft getreten am: 12.06.2014
10
Wirkstoff Wirkstoffbasen
im Verhältnis
austauschbare Darreichungsformen
Lisinopril
Lisinopril-2-Wasser
Filmtabletten
Tabletten
Loperamid Hartkapseln
Kautabletten
Schmelztabletten
Tabletten
Weichkapseln
Loperamid
Lösung zum Einnehmen
Tropfen zum Einnehmen, Lösung
Loratadin Filmtabletten
Tabletten
Lorazepam Expidettäfelchen
Tabletten
Lormetazepam Kapseln
Tabletten
Magaldrat
Kautabletten
Lutschtabletten
Tabletten
Magaldrat Gel im Beutel
Gel im Beutel, Stick-Pack
Suspension im Beutel
Mebeverin
Mebeverin hydrochlorid
überzogene Tabletten
Filmtabletten
Meclozin
Meclozin dihydrochlorid
überzogene Tabletten
Tabletten
Melperon Lösung zum Einnehmen
Melperon
Melperon hydrochlorid
überzogene Tabletten
Filmtabletten
Memantin Lösung zum Einnehmen
Meprobamat überzogene Tabletten
Tabletten
Mesalazin Retardgranulat im Beutel
Retardgranulat im Beutel,
magensaftresistent
Retardtabletten
Metamizol
Metamizol natrium
Metamizol natrium-1-Wasser
Filmtabletten
Tabletten
Metamizol Lösung zum Einnehmen
Tropfen zum Einnehmen, Lösung
Metformin
Metformin hydrochlorid
Filmtabletten
Tabletten
Methyldopa Filmtabletten
Tabletten
letzte Änderung in Kraft getreten am: 12.06.2014
11
Wirkstoff Wirkstoffbasen
im Verhältnis
austauschbare Darreichungsformen
Methylergometrin
Methylergometrin hydrogenmaleat
Liquidum
Lösung
Tropfen
Tropflösung
Metoclopramid
Metoclopramid dihydrochlorid-1-
Wasser
Metoclopramid hydrochlorid
Metoclopramid hydrochlorid-1-
Wasser
Filmtabletten
Kapseln
Tabletten
Metoclopramid
Lösung zum Einnehmen
Tropfen zum Einnehmen, Lösung
Metoprolol
Metoprolol tartrat
Filmtabletten
Lacktabletten
Tabletten
Metronidazol überzogene Tabletten
Filmtabletten
Kapseln
Tabletten
Minocyclin
Minocyclin hydrochlorid
Minocyclin hydrochlorid-2-Wasser
Filmtabletten
Kapseln
Mirtazapin Filmtabletten
Schmelztabletten
Moclobemid Filmtabletten
Tabletten
Montelukast Filmtabletten
Tabletten
Morphin Hartkapseln
Filmtabletten
Morphin Retardtabletten
Hartkapseln, retardiert
(Applikationshäufigkeit 2 x täglich)
Mycophenolatmofetil Filmtabletten
Tabletten
Naftidrofuryl
Naftidrofuryl hydrogenoxalat
Filmtabletten
Kapseln
Retarddragees
Retardkapseln
Naproxen
Naproxen
Naproxen natrium
Filmtabletten
Tabletten
Tabletten, magensaftresistent
Nicergolin überzogene Tabletten
Filmtabletten
Kapseln
Tabletten
letzte Änderung in Kraft getreten am: 12.06.2014
12
Wirkstoff Wirkstoffbasen
im Verhältnis
austauschbare Darreichungsformen
Nifedipin Manteltabletten
Retardkapseln
SL-Retardkapseln
Retardtabletten
Rapid-Retardtabletten
SL-Retardtabletten
Nifedipin überzogene Tabletten
Filmtabletten
Weichkapseln
Nitrendipin Filmtabletten
Tabletten
Nitrofurantoin überzogene Tabletten
Kapseln
Tabletten
Norethisteron
Norethisteron acetat
überzogene Tabletten
Filmtabletten
Tabletten
Norfenefrin
Norfenefrin hydrochlorid
Retarddragees
Retardtabletten
Norfenefrin
Norfenefrin hydrochlorid
Liquidum
Lösung
Tropfen
Tropflösung
Nystatin überzogene Tabletten
Filmtabletten
Kapseln
Tabletten
Olanzapin Filmtabletten
Schmelztabletten
Tabletten
überzogene Tabletten
Omeprazol
Omeprazol
Omeprazol magnesium
Hartkapseln, magensaftresistent
Kapseln
Kapseln, magensaftresistent
Magensaftresistente Pellets in Kapseln
Tabletten, magensaftresistent
Ondansetron Filmtabletten
Schmelztabletten
Opipramol Filmtabletten
überzogene Tabletten
Paracetamol Kapseln
Tabletten
Paracetamol Brausetabletten
Granulat im Beutel, fluessige Anwendung
Pulver im Beutel, fluessige Anwendung
Paracetamol Lösung zum Einnehmen
Sirup
letzte Änderung in Kraft getreten am: 12.06.2014
13
Wirkstoff Wirkstoffbasen
im Verhältnis
austauschbare Darreichungsformen
Paroxetin
Paroxetin hydrochlorid
Paroxetin hydrochlorid-Anhydrat
Paroxetin hydrochlorid-Hemihydrat
Paroxetin mesilat
Filmtabletten
Tabletten
Penicillamin Filmtabletten
Kapseln
Pentaerythrityl tetranitrat überzogene Tabletten
Tabletten
Pentoxifyllin überzogene Tabletten
Tabletten
Pentoxifyllin Retarddragees
Retardkapseln
Retardtabletten
Retardfilmtabletten
Perazin
Perazin dimalonat
überzogene Tabletten
Filmtabletten
Tabletten
Phenoxymethylpenicillin
Phenoxymethylpeniclillin kalium
Filmtabletten
Tabletten
Phenoxymethylpenicillin Kalium Granulat zur Herstellung einer Lösung zum
Einnehmen
Granulat zur Herstellung einer Suspension zum
Einnehmen
Granulat
Pulver zur Herstellung einer Lösung zum
Einnehmen
Pulver zur Herstellung einer Suspension zum
Einnehmen
Suspension zum Einnehmen
Phenprocoumon Tabletten
Filmtabletten
Phenylbutazon überzogene Tabletten
Filmtabletten
Pilocarpin
Pilocarpin hydrochlorid
Pilocarpin nitrat
Augengel
Augensalbe
Piracetam Filmtabletten
Kapseln
Tabletten
Piracetam Granulat im Beutel, fluessige Anwendung
Trinkampullen
Piroxicam
Hartkapseln
Tabletten
Piroxicam
Piroxicam betadex
Brausetabletten
Granulat im Beutel, fluessige Anwendung
Trinktabletten
letzte Änderung in Kraft getreten am: 12.06.2014
14
Wirkstoff Wirkstoffbasen
im Verhältnis
austauschbare Darreichungsformen
Pravastatin Tabletten
Filmtabletten
Promethazin
Promethazin teoclat
Promethazin hydrochlorid
überzogene Tabletten
Filmtabletten
Tabletten
Propafenon
Propafenon hydrochlorid
überzogene Tabletten
Filmtabletten
Tabletten
Propiverin Filmtabletten
überzogene Tabletten
Propranolol
Propranolol hydrochlorid
Filmtabletten
Lacktabletten
Tabletten
Propranolol
Propranolol hydrochlorid
Retardkapseln
Retardtabletten
Propyphenazon Lacktabletten
Tabletten
Pyrazinamid Filmtabletten
Lacktabletten
Tabletten
Pyridostigmin bromid überzogene Tabletten
Tabletten
Pyridoxin
Pyridoxin hydrochlorid
überzogene Tabletten
Filmtabletten
Tabletten
Ramipril Filmtabletten
Hartkapseln
Kapseln
Tabletten
Ramipril + Hydrochlorothiazid Filmtabletten
Tabletten
Ranitidin
Ranitidin hydrochlorid
Filmtabletten
Tabletten
Ribavirin Filmtabletten,
Hartkapseln
Rifampicin überzogene Tabletten
Filmtabletten
Kapseln
Risperidon
Filmtabletten
Schmelztabletten
Risperidon Lösung zum Einnehmen
Rivastigmin Hartkapseln
Roxithromycin Filmtabletten
Tabletten
letzte Änderung in Kraft getreten am: 12.06.2014
15
Wirkstoff Wirkstoffbasen
im Verhältnis
austauschbare Darreichungsformen
Salbutamol
Salbutamol sulfat
Retardkapseln
Retardtabletten
Selegilin
Selegilin hydrochlorid
Tabletten
Schmelztabletten
Simvastatin Filmtabletten
Tabletten
Sotalol
Sotalol hydrochlorid
Filmtabletten
Tabletten
Spironolacton überzogene Tabletten
Filmtabletten
Kapseln
Tabletten
Sucralfat Kautabletten
Tabletten
Sucralfat
Aluminium Ion
Granulat im Beutel, fluessige Anwendung
Suspension im Beutel
Sulfamethoxazol + Trimethoprim Suspension zum Einnehmen
Sulfasalazin Filmtabletten
Tabletten
Tabletten, magensaftresistent
Sulpirid Filmtabletten
Kapseln
Tabletten
Sumatriptan Filmtabletten
Tabletten
überzogene Tabletten
Tamoxifen
Tamoxifen dihydrogencitrat
Filmtabletten
Tabletten
Tamsulosin Retardtabletten
Hartkapseln, retardiert
Hartkapsel mit veränderter Wirkstofffreisetzung
Terbutalin
Terbutalin sulfat
Retardkapseln
Retardtabletten
Tetracyclin
Tetracyclin hydrochlorid
Filmtabletten
Kapseln
Tetrazepam Filmtabletten
Tabletten
Theophyllin Retardtabletten
Hartkapseln, retardiert
Thiamazol Filmtabletten
Tabletten
Thioridazin
Thioridazin hydrochlorid
überzogene Tabletten
Filmtabletten
Tiaprid Tabletten
Filmtabletten
letzte Änderung in Kraft getreten am: 12.06.2014
16
Wirkstoff Wirkstoffbasen
im Verhältnis
austauschbare Darreichungsformen
Ticlopidin
Ticlopidin hydrochlorid
Filmtabletten
Tabletten
Tilidin + Naloxon Lösung zum Einnehmen
Tropfen zum Einnehmen, Lösung
Topiramat Filmtabletten
Hartkapseln
Tramadol Lösung zum Einnehmen
Tropfen zum Einnehmen, Lösung
Tramadol
Hartkapseln, retardiert
Retardtabletten
(Applikationshäufigkeit 2 x täglich)
Tramadol
Hartkapseln, retardiert
Retardtabletten
(Applikationshäufigkeit 1 x täglich)
Tramadol
Filmtabletten
Hartkapseln
Tabletten
Tramadol
Tramadol hydrochlorid
Brausetabletten
Trinktabletten
Triacylglycerollipase
Pankreas-Pulver (Schwein)
Magensaftresistente, polydisperse Mikrotabletten
in Kapseln
Magensaftresistente, polydisperse Pellets in
Beuteln
Magensaftresistente, polydisperse Pellets in
Kapseln
Magensaftresistentes, polydisperses Granulat in
Beuteln
Triacylglycerollipase
Pankreas-Pulver (Schwein)
Magensaftresistente, monolithische Dragees
Magensaftresistente, monolithische Filmtabletten
Triacylglycerollipase
Pankreas-Pulver (Schwein)
überzogene Tabletten
Filmtabletten
Granulat im Beutel
Triamteren + Hydrochlorothiazid 1/0,5 Filmtabletten
Kapseln
Tabletten
Trimethoprim +
Sulfamethoxazol
Synonym: Co-trimoxazol
1/5 Saft
Sirup
Suspension
Trimethoprim +
Sulfamethoxazol
Synonym: Co-trimoxazol
1/5 Filmtabletten
Tabletten
Trimipramin
Trimipramin hydrogenmaleat
Filmtabletten
Tabletten
Trimipramin Lösung zum Einnehmen
Tropfen zum Einnehmen, Lösung
letzte Änderung in Kraft getreten am: 12.06.2014
17
Wirkstoff Wirkstoffbasen
im Verhältnis
austauschbare Darreichungsformen
Trospium chlorid überzogene Tabletten
Filmtabletten
Tabletten
Troxerutin überzogene Tabletten
Filmtabletten
Kapseln
Tryptophan Filmtabletten
Tabletten
Ursodeoxycholsäure Filmtabletten
Kapseln
Tabletten
Venlafaxin Hartkapseln, retardiert
Retardtabletten
Venlafaxin Tabletten
Filmtabletten
Verapamil
Verapamil hydrochlorid
Filmtabletten
Lacktabletten
überzogene Tabletten
Verapamil
Verapamil hydrochlorid
Retardkapseln
Retardtabletten
Vincamin Retarddragees
Retardkapseln
Retardtabletten
Xantinol nicotinat Retarddragees
Retardfilmtabletten
Retardkapseln
Retardtabletten
Xylometazolin
Xylometazolin hydrochlorid
Eindosispipetten
Nasendosierspray
Nasengel
Nasenloesung
Nasenspray
Nasentropfen
Zopiclon Filmtabletten
Tabletten
Die nach der Liste der Standard Terms des European Directorate for the Quality of Medicines & Health Care (EDQM) bezeichneten Darreichungsformen sind nach den in dieser Anlage zusammengestellten Hinweisen im Sinne des § 129 Absatz 1 Satz 1 Nummer 1 SG...
Weitere, in der Anlage nicht aufgeführte Bezeichnungen von Darreichungsformen sind von dieser Regelung erfasst, soweit sie den definitorischen Voraussetzungen der in der Anlage aufgeführten Standard Terms entsprechen.
05.08.2014
Datei
PD
Beschluss
des Gemeinsamen Bundesausschusses
über eine Änderung der Arzneimittel-Richtlinie
(AM-RL): Anlage VII - Hinweise zur
Austauschbarkeit von Darreichungsformen
(aut idem) gemäß § 129 Abs. 1a SGB V:
Ergänzung neuer Gruppen austauschbarer
Darreichungsformen mit den Wirkstoffen
Irbesartan und Telmisartan
Vom 19. Juni 2014
Der Gemeinsame Bundesausschuss hat in seiner Sitzung am 19. Juni 2014 beschlossen,
die Richtlinie über die Verordnung von Arzneimitteln in der vertragsärztlichen Versorgung
(Arzneimittel-Richtlinie) in der Fassung vom 18. Dezember 2008 / 22. Januar 2009 (BAnz.
Nr. 49a vom 31. März 2009), zuletzt geändert am T. Monat JJJJ BAnz AT TT.MM.JJJJ B, wie
folgt zu ändern:
I. In der Tabelle in Anlage VII werden entsprechend der alphabetischen Reihenfolge
folgende Zeilen eingefügt:
Wirkstoff Wirkstoffbasen
im Verhältnis
austauschbare Darreichungsformen
„Irbesartan Filmtabletten
Tabletten“
„Telmisartan Filmtabletten
Tabletten“
II. Die Änderungen der Richtlinie treten am Tag nach der Veröffentlichung im
Bundesanzeiger in Kraft.
2
Die Tragenden Gründe zu diesem Beschluss werden auf den Internetseiten des
Gemeinsamen Bundesausschusses unter www.g-ba.de veröffentlicht.
Berlin, den 19. Juni 2014
Gemeinsamer Bundesausschuss
gemäß § 91 SGB V
Der Vorsitzende
Hecken
http://www.g-ba.de/
austauschbare Darreichungsformen
Wirkstoff
05.08.2014
Datei
PD
Tragende Gründe
zum Beschluss des Gemeinsamen
Bundesausschusses
über eine Änderung der Arzneimittel-Richtlinie
(AM-RL): Anlage VII - Hinweise zur
Austauschbarkeit von Darreichungsformen (aut
idem) gemäß § 129 Abs. 1a SGB V:
Ergänzung neuer Gruppen austauschbarer
Darreichungsformen mit den Wirkstoffen
Irbesartan und Telmisartan
Vom 19. Juni 2014
Inhalt
1. Rechtsgrundlage .......................................................................................................... 2
2. Eckpunkte der Entscheidung ...................................................................................... 2
3. Bürokratiekosten .......................................................................................................... 2
4. Verfahrensablauf .......................................................................................................... 2
5. Dokumentation des gesetzlich vorgeschriebenen
Stellungnahmeverfahrens ........................................................................................... 4
5.1 Unterlagen des Stellungnahmeverfahrens .................................................................. 6
5.2 Übersicht der eingegangen Stellungnahmen ............................................................ 16
2
1. Rechtsgrundlage
Nach § 129 Abs. 1a Satz 1 SGB V gibt der Gemeinsame Bundesausschuss (G-BA) in den
Richtlinien nach § 92 Abs. 1 Satz 2 Nr. 6 Hinweise zur Austauschbarkeit von
Darreichungsformen unter Berücksichtigung ihrer therapeutischen Vergleichbarkeit.
2. Eckpunkte der Entscheidung
Mit dem vorliegenden Richtlinienentwurf werden die bestehenden Hinweise zur
Austauschbarkeit von Darreichungsformen in Anlage VII der AM-RL ergänzt und damit
aktualisiert.
Gemäß 4. Kapitel § 48 Satz 1 der Verfahrensordnung des G-BA (VerfO) legt der G-BA zur
Bezeichnung der Darreichungsformen die Standard Terms der Europäischen Arzneibuch-
Kommission (nach European Directorate for the Quality of Medicines & Health Care) in der
zum gegenwärtigen Zeitpunkt aktuellen Fassung zugrunde.
Die Anlage VII wird entsprechend der alphabetischen Reihenfolge um die folgenden
Hinweise zur Austauschbarkeit von Darreichungsformen ergänzt:
Wirkstoff Wirkstoffbasen
im Verhältnis
austauschbare Darreichungsformen
„Irbesartan Filmtabletten
Tabletten“
„Telmisartan Filmtabletten
Tabletten“
Der Unterausschuss Arzneimittel ist auf Basis der ihm vorliegenden Unterlagen wie den
entsprechenden Fachinformationen zu der Auffassung gekommen, dass die in den
jeweiligen Gruppen aufgeführten Darreichungsformen therapeutisch vergleichbar und damit
austauschbar sind. Weitere Bezeichnungen von Darreichungsformen, die definitorisch
diesen Standard Terms zuzuordnen sind, sind von der Austauschbarkeit umfasst.
3. Bürokratiekosten
Durch den vorgesehenen Beschluss entstehen keine neuen bzw. geänderten
Informationspflichten für Leistungserbringer im Sinne von Anlage II zum 1. Kapitel VerfO und
dementsprechend keine Bürokratiekosten.
4. Verfahrensablauf
Der Geschäftsstelle lagen Schreiben pharmazeutischer Unternehmer mit Hinweisen zur
Ergänzung von Gruppen austauschbarer Darreichungsformen vor. Diese Schreiben wurden
in der Sitzung einer Arbeitsgruppe beraten, die sich aus den von den Spitzenorganisationen
3
der Leistungserbringer benannten Mitgliedern, den vom GKV-Spitzenverband benannten
Mitgliedern sowie den Vertretern/Vertreterinnen der Patientenorganisationen
zusammensetzt. Diese Arbeitsgruppe hat in ihrer Sitzung am 16. Dezember 2013 über die
Aktualisierung der Anlage VII beraten.
Der Beschlussentwurf zur Einleitung eines Stellungnahmeverfahrens wurde in der Sitzung
des Unterausschusses Arzneimittel am 11. Februar 2014 konsentiert. Der Unterausschuss
hat in der Sitzung am 11. Februar 2014 nach 1. Kapitel § 10 Abs. 1 VerfO die Einleitung des
Stellungnahmeverfahrens einstimmig beschlossen.
Es sind keine Stellungnahmen eingegangen. Demzufolge war eine mündliche Anhörung
nach § 91 Abs. 9 S. 1 SGB V i. V. m. 1. Kapitel § 12 Abs. 1 VerfO des G-BA nicht
durchzuführen. Insofern stellen die vorliegenden Tragenden Gründe den aktuellen Stand der
Zusammenfassenden Dokumentation dar.
Der Unterausschuss Arzneimittel hat in seiner Sitzung am 13. Mai 2014 den
Beschlussentwurf zur Änderung Anlage VII ohne weitere Änderungen konsentiert.
Das Plenum hat in seiner Sitzung am 19. Juni 2014 die Änderung der AM-RL in Anlage VII
beschlossen.
Zeitlicher Beratungsverlauf
Sitzung der AG/ UA Datum Beratungsgegenstand
AG
Nutzenbewertung
16. Dezember 2013 Beratung über Vorschläge pharmazeutischer
Unternehmer zur Ergänzung der AM-RL in
Anlage VII
UA Arzneimittel 11. Februar 2014 Konsentierung der Beschlussvorlage und
Beschluss zur Einleitung des
Stellungnahmeverfahrens zur Änderung der
Arzneimittel-Richtlinie
UA Arzneimittel 13. Mai 2014 Beratung und Konsentierung der
Beschlussvorlage zur Änderung der
Arzneimittel-Richtlinie
Plenum 19. Juni 2014 Beschlussfassung
Berlin, den 19. Juni 2014
Gemeinsamer Bundesausschuss
gemäß § 91 SGB V
Der Vorsitzende
Hecken
4
5. Dokumentation des gesetzlich vorgeschriebenen Stellungnahmeverfahrens
Gemäß § 92 Abs. 3a SGB V wird den Sachverständigen der medizinischen und
pharmazeutischen Wissenschaft und Praxis sowie den für die Wahrnehmung der
wirtschaftlichen Interessen gebildeten maßgeblichen Spitzenorganisationen der
pharmazeutischen Unternehmer, den betroffenen pharmazeutischen Unternehmern, den
Berufsvertretungen der Apotheker und den maßgeblichen Dachverbänden der
Ärztegesellschaften der besonderen Therapierichtungen auf Bundesebene Gelegenheit zur
Stellungnahme zu geben.
Folgende Organisationen wurden angeschrieben:
Organisation Straße Ort
Bundesverband der
Pharmazeutischen Industrie (BPI)
Friedrichstr. 148 10117 Berlin
Verband Forschender
Arzneimittelhersteller
Hausvogteiplatz 13 10117 Berlin
Deutscher Zentralverein
Homöopathischer Ärzte e.V.
Reinhardtstraße 37 10117 Berlin
Bundesverband der
Arzneimittel-Importeure e.V. (BAI)
EurimPark 8 83416 Saaldorf-
Surheim
Bundesverband der
Arzneimittel-Hersteller e.V. (BAH)
Ubierstraße 73 53173 Bonn
Gesellschaft für Phytotherapie e.V. Postfach 10 08 88 18055 Rostock
Pro Generika e.V. Unter den Linden 32 - 34 10117 Berlin
Gesellschaft Anthroposophischer
Ärzte e.V.
Roggenstraße 82 70794 Filderstadt
Arzneimittelkommission der
Deutschen Ärzteschaft (AkdÄ)
Herbert-Lewin-Platz 1 10623 Berlin
Bundesvereinigung Deutscher
Apothekerverbände (ABDA)
Deutsches Apothekerhaus
Jägerstraße 49/50
10117 Berlin
Arzneimittelkommission der
Deutschen Zahnärzteschaft (AK-Z)
c/o Bundeszahnärztekammer
Chausseestr. 13 10115 Berlin
Darüber hinaus wird die Einleitung des Stellungnahmeverfahrens im Bundesanzeiger
bekanntgemacht (BAnz AT 06.03.2014 B1).
5
6
5.1 Unterlagen des Stellungnahmeverfahrens
7
8
9
Stellungnahmeverfahren zum Thema aut idem,
Ergänzung neuer Gruppen austauschbarer Darreichungsformen mit den
Wirkstoffen Irbesartan und Telmisartan
Literaturliste [Hier Institution / Firma eingeben]
Nr. Feldbezeichnung Text
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5.2 Übersicht der eingegangen Stellungnahmen
Es sind keine Stellungnahmen eingegangen.
1. Rechtsgrundlage
2. Eckpunkte der Entscheidung
3. Bürokratiekosten
4. Verfahrensablauf
5. Dokumentation des gesetzlich vorgeschriebenen Stellungnahmeverfahrens
5.1 Unterlagen des Stellungnahmeverfahrens
5.2 Übersicht der eingegangen Stellungnahmen
05.08.2014
Datei
PD
