Guidance for Industry
Q5E Comparability of Biotechnological/Biological Products Subject to
Changes in Their Manufacturing Process
(PDF
version of this document)
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
June 2005
ICH
Guidance for Industry
Q5E Comparability of Biotechnological/Biological Products
Subject to Changes in Their Manufacturing Process
This
guidance represents the Food and Drug Administration's (FDA's)
current thinking on this topic. It does not create or confer any
rights for or on any person and does not operate to bind FDA or
the public. You can use an alternative approach if the approach
satisfies the requirements of the applicable statutes and
regulations. If you want to discuss an alternative approach,
contact the FDA staff responsible for implementing this guidance.
If you cannot identify the appropriate FDA staff, call the
appropriate number listed on the title page of this guidance.
The objective of this document is to provide
principles for assessing the comparability of
biotechnological/biological products before and after changes are
made in the manufacturing process for the drug substance or drug
product. Therefore, this guidance is intended to assist
manufacturers of biotechnological/biological products in the
collection of relevant technical information that serves as evidence
that the manufacturing process changes will not have an adverse
impact on the quality, safety, and efficacy of the drug product.
The document does not prescribe any particular analytical,
nonclinical, or clinical strategy. The main emphasis of the document
is on quality aspects.
FDA's guidance documents, including this
guidance, do not establish legally enforceable responsibilities.
Instead, guidances describe the Agency's current thinking on a topic
and should be viewed only as recommendations, unless specific
regulatory or statutory requirements are cited. The use of the word
should in Agency guidances means that something is suggested
or recommended, but not required.
Manufacturers
of biotechnological/biological products frequently make changes to
manufacturing processes
of products
both during development and after approval. Reasons for such
changes include improving the manufacturing process, increasing
scale, improving product stability, and complying with changes in
regulatory requirements. When changes are made to the manufacturing
process, the manufacturer generally evaluates the relevant quality
attributes of the product to demonstrate that modifications did not
occur that would adversely impact
the safety and efficacy of the drug product. Such an evaluation
should indicate whether or not confirmatory nonclinical or clinical
studies are appropriate.
While ICH documents have not
specifically addressed considerations for demonstrating
comparability between prechange and postchange product, several ICH
documents have provided guidance for technical information and data
to be submitted in marketing applications that can also be useful
for assessing manufacturing process changes (see section IV (4.0)
References). This document builds upon the previous ICH guidances
and provides additional direction regarding approaches to:
·
Comparing postchange product to
prechange product following manufacturing process changes; and
·
Assessing the impact of observed
differences in the quality attributes caused by the manufacturing
process change for a given product as it relates to safety and
efficacy of the product.
The principles adopted and
explained in this document
apply to:
·
Proteins and polypeptides, their
derivatives, and products of which they are components, e.g.,
conjugates. These proteins and polypeptides are produced from
recombinant or non-recombinant cell-culture expression systems and
can be highly purified and characterized using an appropriate set of
analytical procedures;
·
Products where manufacturing
process changes are made by a single manufacturer, including those
made by a contract manufacturer, who can directly compare results
from the analysis of prechange and postchange product; and
·
Products where manufacturing
process changes are made in development or for which a marketing
authorization has been granted.
The principles outlined in
this document might also apply to other product types, such as
proteins and polypeptides isolated from tissues and body fluids.
Manufacturers are advised to consult with the appropriate regional
regulatory authority to determine applicability.
The goal of the
comparability exercise is to ensure the quality, safety, and
efficacy of drug product produced by a changed manufacturing process
through collection and evaluation of the relevant data to determine
whether there might be any adverse impact on the drug product due to
the manufacturing process changes.
The demonstration of
comparability does not necessarily mean that the quality attributes
of the prechange and postchange product are identical, but that they
are highly similar and that the existing knowledge is sufficiently
predictive to ensure that any differences in quality attributes have
no adverse impact upon safety or efficacy of the drug product.
A determination of
comparability can be based on a combination of analytical testing,
biological assays, and, in some cases, nonclinical and clinical
data. If a manufacturer can provide assurance of comparability
through analytical studies alone, nonclinical or clinical studies
with the postchange product are not warranted. However, where the
relationship between specific quality attributes and safety and
efficacy has not been established, and differences between quality
attributes of the pre- and postchange product are observed, it might
be appropriate to include a combination of quality, nonclinical,
and/or clinical studies in the comparability exercise.
To identify the impact of a
manufacturing process change, a careful evaluation of all
foreseeable consequences for the product should be performed. In
consideration of this evaluation, appropriate criteria to define
highly similar postchange product can be established. Generally,
quality data on the pre- and postchange product are generated, and a
comparison is performed that integrates and evaluates all data
collected, e.g., routine batch analyses, in-process control, process
validation and/or evaluation data, characterization and stability,
if appropriate. The comparison of the results to the predefined
criteria should allow an objective assessment of whether or not the
pre- and postchange product are comparable.
Following the evaluation of
the quality attributes, the manufacturer could be faced with one of
several outcomes, including:
·
Based on appropriate comparison of
relevant quality attributes, pre- and postchange product are highly
similar and considered comparable, i.e., no adverse impact on safety
or efficacy profiles is foreseen.
·
Although the pre- and postchange
product appear highly similar, the analytical procedures used are
not sufficient to discern relevant differences that can impact the
safety and efficacy of the product. The manufacturer should consider
employing additional testing (e.g., further characterization) or
nonclinical and/or clinical studies to reach a definitive
conclusion.
·
Although the pre- and postchange
product appear highly similar, some differences have been observed
in the quality attributes of the prechange and postchange product;
but it can be justified that no adverse impact on safety or efficacy
profiles is expected, based on the manufacturer’s accumulated
experience, relevant information, and data. In these circumstances,
pre- and postchange product can be considered comparable.
·
Although the pre- and postchange
product appear highly similar, some
differences have been identified in the comparison of quality
attributes and a possible adverse impact on safety and efficacy
profiles cannot be excluded. In such situations, the generation and
analysis of additional data on quality attributes are unlikely to
assist in determining whether pre- and postchange product are
comparable. The manufacturer should consider performing nonclinical
and/or clinical studies.
·
Differences in the quality
attributes are so significant that it is determined that the
products are not highly similar and are therefore not comparable.
This outcome is not within the scope of this document and is not
discussed further.
The goal of the
comparability exercise is to ascertain that pre- and postchange drug
product are comparable in terms of quality, safety, and efficacy.
To meet this goal, the product should be evaluated at the process
step most appropriate to detect a change in the quality attributes.
This may entail evaluating the product at multiple stages of
manufacture. For example, even though all process changes occurred
in the manufacture of the drug substance, in cases where the drug
product could be impacted by the change, it might be appropriate to
collect data on both the drug substance and the drug product to
support the determination of comparability. Comparability can often
be deduced from quality studies alone (limited or comprehensive
analysis, as appropriate), but might sometimes need to be supported
by comparability bridging studies. The extent of the studies
necessary to demonstrate comparability will depend on:
·
The production step where the
changes are introduced;
·
The potential impact of the changes
on the purity as well as on the physicochemical and biological
properties of the product, particularly considering the complexity
and degree of knowledge of the product (e.g., impurities, product-
related substances);
·
The availability of suitable
analytical techniques to detect potential product modifications and
the results of these studies; and
·
The relationship between quality
attributes and safety and efficacy, based on overall nonclinical and
clinical experience.
When considering the
comparability of products, the manufacturer should evaluate, for
example:
·
Relevant physicochemical and
biological characterization data regarding quality attributes;
·
Results from analysis of relevant
samples from the appropriate stages of the manufacturing process
(e.g., intermediate, drug substance, and drug product);
·
The need for stability data,
including those generated from accelerated or stress conditions, to
provide insight into potential product differences in the
degradation pathways of the product and, hence, potential
differences in product-related substances and product-related
impurities;
·
Batches used for demonstration of
manufacturing consistency;
·
Historical data that provide
insight into potential “drift” of quality attributes with respect to
safety and efficacy, following either a single or a series of
manufacturing process changes. That is, the manufacturer should
consider the impact of changes over time to confirm that an
unacceptable impact on safety and efficacy profiles has not
occurred.
In addition to evaluating
the data, manufacturers should also consider:
·
Critical control points in the
manufacturing process that affect product characteristics, e.g., the
impact of the process change on the quality of in-process
materials, as well as the ability of downstream steps to accommodate
material from a changed cell culture process;
·
Adequacy of the in-process controls
including critical control points and in-process testing:
In-process controls for the postchange process should be confirmed,
modified, or created, as appropriate, to maintain the quality of the
product;
·
Nonclinical or clinical
characteristics of the drug product and its therapeutic indications
(see section II.E (2.5) of this guidance.
The battery of tests for the comparability
exercise should be carefully selected and optimized to maximize the
potential for detecting relevant differences in the quality
attributes of the product that might result from the proposed
manufacturing process change. To address the full range of
physicochemical properties or biological activities, it might be
appropriate to apply more than one analytical procedure to evaluate
the same quality attribute (e.g., molecular weight, impurities,
secondary/tertiary structures). In such cases, each method should
employ different physicochemical or biological principles to collect
data for the same parameter to maximize the possibility that
differences in the product caused by a change in the manufacturing
process might be detected.
It can be difficult to ensure that the chosen
set of analytical procedures for the prechange product will be able
to detect modifications of the product due to (1) the limitations of
the assays (e.g., precision, specificity, and detection limit) and
(2) the complexity of some products due to molecular heterogeneity.
Consequently, the manufacturer should determine:
·
Whether or not existing tests
remain appropriate for their intended use or should be modified.
For example, when the manufacturing process change gives rise to a
different impurity profile in the host cell proteins, manufacturers
should confirm that the test used to quantitate these impurities is
still suitable for its intended purpose. It might be appropriate to
modify the existing test to detect the new impurities;
·
The need to add new tests as a
result of changes in quality attributes that the existing methods
are not capable of measuring. That is, when specific changes in
quality attributes are expected as a result of a process change
(e.g., following addition of a new raw material or modification of a
chromatographic purification step), it might be appropriate to
develop new analytical procedures, i.e., to employ additional
analytical techniques above and beyond those used previously for
characterization or routine testing.
The measurement of quality attributes in
characterization studies does not necessarily entail the use of
validated assays, but the assays should be scientifically sound and
provide results that are reliable. Those methods used to measure
quality attributes for batch release should be validated in
accordance with ICH guidances (ICH Q2A, Q2B, Q5C, Q6B), as
appropriate.
Characterization of a
biotechnological/biological product by appropriate techniques, as
described in ICH Q6B, includes the determination of physicochemical
properties, biological activity, immunochemical properties (if any),
purity, impurities, contaminants, and quantity.
When a manufacturing process change has been
made that has the potential to have an impact on quality attributes,
a complete or limited (but rationalized) repetition of the
characterization activity conducted for the market application is
generally warranted to directly compare the prechange and postchange
product. However, additional characterization might be indicated in
some cases. For example, when process changes result in a product
characterization profile that differs from that observed in the
material used during nonclinical and clinical studies or other
appropriate representative materials (e.g., reference materials,
marketed batches), the significance of these alterations should be
evaluated. Results of comprehensive
characterization of the material used in pivotal clinical trials
could provide a useful point of reference for subsequent
comparability exercises.
Each of the following criteria should be
considered as a key point in the conduct of the comparability
exercise:
- Physicochemical Properties
The manufacturer should consider the concept of
the desired product (and its variants) as defined in ICH Q6B when
designing and conducting a comparability exercise. The complexity
of the molecular entity with respect to the degree of molecular
heterogeneity should also be considered. Following a manufacturing
process change, manufacturers should attempt to determine that
higher order structure (secondary, tertiary, and quaternary
structure) is maintained in the product. If the appropriate higher
order structural information cannot be obtained, a relevant
biological activity assay (see biological activity below) could
indicate a correct conformational structure.
Biological assay results can serve multiple
purposes in the confirmation of product quality attributes that are
useful for characterization and batch analysis, and, in some cases,
could serve as a link to clinical activity. The manufacturer should
consider the limitations of biological assays, such as high
variability, that might prevent detection of differences that occur
as a result of a manufacturing process change.
In cases where the biological assay also serves
as a complement to physicochemical analysis (e.g., as a surrogate
assay for higher order structure), the use of a relevant biological
assay with appropriate precision and accuracy might provide a
suitable approach to confirm that change in specific higher order
structure has not occurred following manufacturing process changes.
Where physicochemical or biological assays are not considered
adequate to confirm that the higher order structure is maintained,
it might be appropriate to conduct a nonclinical or clinical study.
When changes are made to a product with
multiple biological activities, manufacturers should consider
performing a set of relevant functional assays designed to evaluate
the range of activities. For example, certain proteins possess
multiple functional domains that express enzymatic and receptor
mediated activities. In such situations, manufacturers should
consider evaluating all relevant functional activities.
Where one or more of the multiple activities
are not sufficiently correlated with clinical safety or efficacy or
if the mechanism of action is not understood, the manufacturer
should justify that nonclinical or clinical activity is not
compromised in the postchange product.
- Immunochemical Properties
When immunochemical properties are part of the
characterization (e.g., for antibodies or antibody-based products),
the manufacturer should confirm that postchange product is
comparable in terms of the specific properties.
- Purity, Impurities, and Contaminants
The combination of analytical procedures
selected should provide data to evaluate whether a change in purity
profile has occurred in terms of the desired product.
If differences are observed in the purity and
impurity profiles of the postchange product relative to the
prechange product, the differences should be evaluated to assess
their potential impact on safety and efficacy. Where the change
results in the appearance of new impurities, the new impurities
should be identified and characterized when possible. Depending on
the impurity type and amount, it might be appropriate to conduct
nonclinical or clinical studies to confirm that there is no adverse
impact on safety or efficacy of the drug product.
Contaminants should be strictly avoided and/or
suitably controlled with appropriate in-process acceptance criteria
or action limits for drug substance or drug product.
New
contaminants should be evaluated to assess their potential impact on
the quality, safety and efficacy of the product.
The tests and analytical
procedures chosen to define drug substance or drug product
specifications alone are generally not considered adequate to assess
the impact of manufacturing process changes since they are chosen to
confirm the routine quality of the product rather than to fully
characterize it. The manufacturer should confirm that the
specifications after the process change are appropriate to ensure
product quality. Results within the established acceptance criteria,
but outside historical manufacturing control trends, might suggest
product differences that warrant additional study or analysis.
Modification, elimination, or addition of a test (i.e., in the
specification) might be indicated where data suggest that the
previous test is no longer relevant for routine batch analysis of
the postchange product. For example, the elimination of bovine
serum from the cell culture process would remove the need for
related analyses. However, a widening of the acceptance criteria is
generally not considered appropriate unless justified. In some
cases, additional tests and acceptance criteria on the relative
amount of specific new impurities might be appropriate if the
impurity profile is different following the manufacturing process
changes. When evaluating both the test methods and acceptance
criteria for the postchange product, it is important to consider the
general principles for setting specifications as defined in Q6B,
i.e., the impact of the changes on the validated manufacturing
process, characterization studies, batch analysis data, stability
data, and nonclinical and clinical experience.
For certain manufacturing
process changes, even slight modifications of the production
procedures might cause changes in the stability of the postchange
product. Any change with the potential to alter protein structure
or purity and impurity profiles should be evaluated for its impact
on stability, since proteins are frequently sensitive to changes,
such as those made to buffer composition, processing and holding
conditions, and the use of organic solvents. Furthermore, stability
studies might be able to detect subtle differences that are not
readily detectable by the characterization studies. For example,
the presence of trace amounts of a protease might only be detected
by product degradation that occurs over an extended time period; or,
in some cases, divalent ions leached from the container closure
system might change the stability profile because of the activation
of trace proteases not detected in stability studies of the
prechange product. Therefore, real-time/real temperature stability
studies on the product potentially affected by the change should be
initiated, as appropriate.
Accelerated and stress
stability studies are often useful tools to establish degradation
profiles and provide a further direct comparison of prechange and
postchange product. The results thus obtained might show product
differences that warrant additional evaluation and also identify
conditions indicating that additional controls should be employed in
the manufacturing process and during storage to eliminate these
unexpected differences. Appropriate studies should be considered to
confirm that suitable storage conditions and controls are selected.
ICH Q5C and Q1A(R) should be
consulted to determine the conditions for stability studies that
provide relevant data to be compared before and after a change.
A well-defined manufacturing
process with its associated process controls ensures that acceptable
product is produced on a consistent basis. Approaches to
determining the impact of any process change will vary with respect
to the specific process, the product, the extent of the
manufacturer’s knowledge of and experience with the process, and
development data generated. The manufacturer should confirm that
the process controls in the modified process provide at least
similar or more effective control of the product quality, compared
to those of the original process.
A careful consideration of
potential effects of the planned change on steps downstream and
quality parameters related to these steps is extremely important
(e.g., for acceptance criteria, in-process specification, in-process
tests, in-process hold times, operating limits, and
validation/evaluation, if appropriate). This analysis will help
identify which tests should be performed during the comparability
exercise, which in-process or batch release acceptance criteria or
analytical procedures should be reevaluated, and which steps should
not be impacted by the proposed change. For example, analysis of
intermediates might suggest potential differences that should be
evaluated to determine the suitability of existing tests to detect
these differences in the product. The rationale for excluding parts
of the process from this consideration should be justified.
While the process will
change and the associated controls might be redefined, the
manufacturer should confirm that prechange and postchange product
are comparable. To support the comparison, it is often useful to
demonstrate, for example, that specific intermediates are comparable
or that the modified process has the capability to provide
appropriate levels of removal for process- and product-related
impurities, including those newly introduced by the process change.
To support process changes for approved products, data from
commercial-scale batches are generally indicated.
The process assessment
should consider such factors as the criticality of the process step
and proposed change, the location of the change and potential for
effects on other process steps, and the type and extent of change.
Information that can aid this assessment is generally available from
several sources. The sources can include knowledge from process
development studies, small scale evaluation/validation studies,
experience with earlier process changes, experience with equipment
in similar operations, changes in similar manufacturing processes
with similar products, and literature. Although information from
external sources is useful to some extent, it is within the context
of the specific manufacturing process and specific product that the
change should be assessed.
When
changes are made to a process, the manufacturer should demonstrate
that the associated process controls, including any new ones,
provide assurance that the modified process will also be capable of
providing comparable product. The
modified process steps should be reevaluated and/or revalidated, as
appropriate. The in-process controls, including critical control
points and in-process testing, should ensure that
the postchange process is well controlled
and maintains the quality of the product.
Typically, reevaluation/revalidation
activities for a simple change might be limited to the affected
process step if there is no evidence to indicate that there is an
impact on the performance of subsequent (downstream) process steps
or on the quality of the intermediates resulting from the subsequent
steps. When the change considered affects more than a single step,
more extensive analysis of the change and resultant validation might
be appropriate.
Demonstration of state of
control with the modified/changed manufacturing process might include, but is not limited to, such items as:
·
Establishment of modified
specifications for raw, source and starting materials, and reagents;
·
Appropriate bioburden and/or viral
safety testing of the postchange cell banks and cells at the limit
of in vitro cell age for production;
·
Adventitious agent clearance;
·
Removal of product- or
process-related impurities, such as residual host cell DNA and
proteins; and
·
Maintenance of the purity level.
For approved products, an
appropriate number of postchange batches should be analyzed to
demonstrate consistent performance of the process.
To support the analysis of
the changes and the control strategy, the manufacturer should
prepare a description of the change that summarizes the prechange
and the postchange manufacturing process and that clearly highlights
modifications of the process and changes in controls in a
side-by-side format.
During product development,
it is expected that multiple changes in the manufacturing process
will occur that could impact drug product quality, safety, and
efficacy. Comparability exercises are generally performed to
demonstrate that nonclinical and clinical data generated with
prechange product are applicable to postchange product in order to
facilitate further development and, ultimately, to support the
marketing authorization. Comparability studies conducted for
products in development are influenced by factors such as the stage
of product development, the availability of validated analytical
procedures, and the extent of product and process knowledge, which
are limited at times due to the available experience that the
manufacturer has with the process.
Where changes are introduced in development
before nonclinical studies, the issue of assessing comparability is
not generally raised because the manufacturer subsequently conducts
nonclinical and clinical studies using the postchange product as
part of the development process. During early phases of nonclinical
and clinical studies, comparability testing is generally not as
extensive as for an approved product. As knowledge and information
accumulate, and the analytical tools develop, the comparability
exercise should utilize available information and will generally
become more comprehensive. Where process changes are introduced in
late stages of development and no additional clinical studies are
planned to support the marketing authorization, the comparability
exercise should be as comprehensive and thorough as one conducted
for an approved product. Some outcomes of the comparability studies
on quality attributes can lead to additional nonclinical or clinical
studies.
In order for a comparability
exercise to occur during development, appropriate assessment tools
should be used. Analytical procedures used during development might
not be validated, but should always be scientifically sound and
provide results that are reliable and reproducible. Due to the
limitations of the analytical tools in early clinical development,
physicochemical and biological tests alone might be considered
inadequate to determine comparability; therefore, bridging
nonclinical and/or clinical studies, as appropriate, might be
needed.
Determinations of product
comparability can be based solely on quality considerations (see
section 2.2) if the manufacturer can provide assurance of
comparability through analytical studies as suggested in this
document. Additional evidence from nonclinical or clinical studies
is considered appropriate when quality data are insufficient to
establish comparability. The extent and nature of nonclinical and
clinical studies will be determined on a case-by-case basis in
consideration of various factors, which include among others:
Quality findings
·
Drug product — The type, nature,
and extent of differences between the postchange product and the
prechange product with respect to quality attributes including
product-related substances, the impurity profile, stability, and
excipients.
For example, new impurities could warrant toxicological studies for
qualification;
·
Results of the
evaluation/validation studies on the new process including the
results of relevant in-process tests;
·
Availability, capabilities, and
limitations of tests used for any comparability studies.
The nature and the level of knowledge of the product
·
Product complexity, including
heterogeneity and higher order structure — Physicochemical and in
vitro biological assays might not be able to detect all differences
in structure and/or function;
·
Structure-activity relationship and
strength of the association of quality attributes with safety and
efficacy;
·
Relationship between the
therapeutic protein and endogenous proteins and the consequences for
immunogenicity;
·
Mode(s) of action (unknown vs.
known, single vs. multiple active sites).
Existing nonclinical and clinical data relevant
to the product, aspects of product use, and product class
·
Therapeutic indications/target
patient groups — The impact of possible differences can vary between
patient groups, e.g., risk for unintended immunogenicity. It may be
appropriate to consider the consequences separately for each
indication;
·
Posology, e.g., dosing regimen,
route of administration — The risk of certain possible consequences
of a difference, such as immunogenicity, could be higher with
chronic administration as compared to short-term administration;
subcutaneous administration might induce immunogenicity more often
than intravenous administration;
·
The therapeutic
window/dose-response curve — The impact of a certain change could be
different for products that have a wide therapeutic window as
compared to those with a more narrow window. The safety or efficacy
of products with a steep or a bell-shaped dose-response curve can be
affected by minor changes in pharmacokinetics or receptor-binding;
·
Previous experience, e.g.,
immunogenicity, safety — The experience with the original product or
with other products in the same class can be relevant, especially
with regard to rare adverse effects, e.g., knowledge about the
consequences of immunogenicity;
·
Pharmacokinetic (PK)/pharmacodynamic
(PD) relation, distribution, clearance.
The nonclinical and clinical
studies referred to in this document might include, depending on the
situation, PK studies, PD studies, PK/PD studies, clinical efficacy
studies, specific safety studies, immunogenicity studies, and
pharmacovigilance studies. The purpose of these studies is to enable
comparison of pre- and postchange product. Where appropriate, these
studies should be direct comparative studies.
Comparability Bridging Study: A study
performed to provide nonclinical or clinical data that allows
extrapolation of the existing data from the drug product produced by
the current process to the drug product from the changed process.
Comparable: A conclusion that products
have highly similar quality attributes before and after
manufacturing process changes and that no adverse impact on the
safety or efficacy, including immunogenicity, of the drug product
occurred. This conclusion can be based on an analysis of product
quality attributes. In some cases, nonclinical or clinical data
might contribute to the conclusion.
Comparability Exercise: The activities,
including study design, conduct of studies, and evaluation of data,
that are designed to investigate whether the products are
comparable.
Quality Attribute: A molecular or
product characteristic that is selected for its ability to help
indicate the quality of the product. Collectively, the quality
attributes define identity, purity, potency, and stability of the
product, and safety with respect to adventitious agents.
Specifications measure a selected subset of the quality attributes.
Viral Safety Evaluation of
Biotechnology Products Derived From Cell Lines of Human or Animal
Origin (Q5A).
Quality of Biotechnological
Products: Analysis of the Expression Construct in Cells Used for
Production of r-DNA Derived Protein Products (Q5B).
Quality of Biotechnological
Products: Stability Testing of Biotechnological/Biological Products
(Q5C).
Quality of Biotechnological
Products: Derivation and Characterization of Cell Substrates Used
for Production of Biotechnological/Biological Products (Q5D).
Specifications: Test
Procedures and Acceptance Criteria for Biotechnological/Biological
Products (Q6B).
Good Manufacturing Practice
Guidance for Active Pharmaceutical Ingredients (Q7A).
Text on Validation of
Analytical Procedures (Q2A).
Validation of Analytical
Procedures: Methodology (Q2B).
Common Technical Document
for the Registration of Pharmaceuticals for Human Use (M4Q).
Stability Testing of New
Drug Substances and Products (Q1AR).
Preclinical Safety
Evaluation of Biotechnology-Derived Pharmaceuticals (S6).
Statistical Principles for
Clinical Trials (E9).
Choice of Control Group and
Related Issues in Clinical Trials (E10).
This guidance was developed
within the Expert Working Group (Quality) of the International
Conference on Harmonisation of Technical Requirements for
Registration of Pharmaceuticals for Human Use (ICH) and has been
subject to consultation by the regulatory parties, in accordance
with the ICH process. This document has been endorsed by the
ICH Steering Committee at Step 4 of the ICH process,
November 2004. At Step 4 of the process, the final draft
is recommended for adoption to the regulatory bodies of the
European Union, Japan, and the United States.
Arabic numbers reflect the
organizational breakdown in the document endorsed by the ICH
Steering Committee at Step 4 of the ICH process, November 2004.
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Date created: June 29, 2005 |