Q5 e step4

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INTERNATIONAL CONFERENCE ON HARMONISATION OF TECHNICAL
REQUIREMENTS FOR REGISTRATION OF PHARMACEUTICALS FOR HUMAN
USE

ICH HARMONISED TRIPARTITE GUIDELINE

COMPARABILITY OF BIOTECHNOLOGICAL/BIOLOGICAL
PRODUCTS SUBJECT TO CHANGES IN THEIR MANUFACTURING
ROCESS
PROCESS
Q5E

Current Step 4 version
dated 18 November 2004

This Guideline has been developed by the appropriate ICH Expert Working
Group and has been subject to consultation by the regulatory parties, in
accordance with the ICH Process. At Step 4 of the Process the final draft is
recommended for adoption to the regulatory bodies of the European Union, Japan
and USA.


Q5E
Document History
New
First

History

Codification

Date

Codification
November
2005

Q5E

Approval by the Steering Committee under Step 2 and
release for public consultation.

13

Q5E

November
2003

Current Step 4 version
Q5E

Approval by the Steering Committee under Step 4 and
recommendation for adoption to the three ICH regulatory
bodies.

18
November
2004

Q5E


COMPARABILITY OF BIOTECHNOLOGICAL/BIOLOGICAL PRODUCTS SUBJECT
TO CHANGES IN THEIR MANUFACTURING PROCESS
ICH Harmonised Tripartite Guideline
Having reached Step 4 of the ICH Process at the ICH Steering Committee meeting
on 18 November 2004, this guideline is recommended for
adoption to the three regulatory parties to ICH

TABLE OF CONTENTS
1.

......................................................................................................
................................................................
INTRODUCTION ...................................................................................................... 1

1.1

Objectives of the Guideline ........................................................................................... 1

1.2

Background.................................................................................................................... 1

1.3

Scope .............................................................................................................................. 2

1.4

General Principles ......................................................................................................... 2

2.

GUIDELINES............................................................................................................
GUIDELINES ............................................................................................................ 3
................................................................................................

2.1

Considerations for the Comparability Exercise............................................................ 3

2.2

Quality Considerations.................................................................................................. 4

2.2.1.
2.2.2
2.2.3
2.2.4

Analytical Techniques ..................................................................................... 4
Characterisation .............................................................................................. 5
Specifications ................................................................................................... 7
Stability............................................................................................................ 7

2.3

Manufacturing Process Considerations ........................................................................ 8

2.4

Demonstration of Comparability during Development ................................................ 9

2.5

Nonclinical and Clinical Considerations..................................................................... 10

2.5.1
2.5.2

Factors to be Considered in Planning Nonclinical and Clinical Studies...... 10
Type of Studies............................................................................................... 11

3.

GLOSSARY..............................................................................................................
GLOSSARY.............................................................................................................. 11
................................................................................................

4.

........................................................................................................
................................................................
REFERENCES ........................................................................................................ 12

i


COMPARABILITY OF BIOTECHNOLOGICAL/BIOLOGICAL PRODUCTS
SUBJECT TO CHANGES IN THEIR MANUFACTURING PROCESS
1.

INTRODUCTION

1.1
Objectives of the Guideline
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
guideline is intended to assist in the collection of relevant technical information which
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.
1.2
Background
Manufacturers1 of biotechnological/biological products frequently make changes to
manufacturing processes2 of products3 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 impact4 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 pre-change and post-change 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 4.0 References). This document builds
upon the previous ICH guidelines and provides additional direction regarding
approaches to:
•

Comparing post-change product
manufacturing process changes; and

to

pre-change

product

following

1 For convenience, when the term “manufacturer” is used, it is intended to include any third
party having a contractual arrangement to produce the intermediates, drug substance, or
drug product on behalf of the marketing authorisation holder (or the developer, if prior to
market authorisation).
2 For convenience, when the term “manufacturing process(es)” is used, it also includes
facilities and equipment that might impact on critical processing parameters and, thereby,
on product quality.
3 For convenience, when the term “product” is used without modifiers, it is intended to refer to
the intermediates, drug substance, and drug product.
4 Improvement of product quality is always desirable and encouraged. If the results of the
comparability exercise indicate an improved quality suggesting a significant benefit in
efficacy and/or safety, the pre- and post-change product may not be comparable. However,
this result could be considered acceptable. The manufacturer is advised to consult the
appropriate regional Regulatory Authority.

1


•

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.

1.3
Scope
The principles adopted and explained in this document5 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 characterised 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 pre-change and post-change
product; and

•

Products where manufacturing process changes are made in development or
for which a marketing authorisation 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.
1.4
General Principles
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 pre-change and post-change 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 post-change 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 post-change product can be
established. Generally, quality data on the pre- and post-change product are
5 This document applies to situations in which all three of the bulleted conditions are present.

2


generated, and a comparison is performed that integrates and evaluates all data
collected, e.g., routine batch analyses, in-process control, process validation/evaluation
data, characterisation 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 post-change product are comparable.
Following the evaluation of the quality attributes, the manufacturer could be faced
with one of several outcomes, including:
•

•

Although the pre- and post change 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 characterisation) or
nonclinical and/or clinical studies to reach a definitive conclusion;

•

Although the pre- and post-change product appear highly similar, some
differences have been observed in the quality attributes of the pre-change and
post-change 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
post-change product can be considered comparable;

•

Although the pre- and post-change 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 post-change
product are comparable. The manufacturer should consider performing
nonclinical and/or clinical studies;

•

2.

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;

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.
GUIDELINES

2.1
Considerations for the Comparability Exercise
The goal of the comparability exercise is to ascertain that pre- and post-change drug
product is 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:

3


•

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 characterisation 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:
•

•

Adequacy of the in-process controls including critical control points and inprocess testing: In-process controls for the post-change process should be
confirmed, modified, or created, as appropriate, to maintain the quality of the
product;

•
2.2

Critical control points in the manufacturing process that affect product
characteristics, e.g., the impact of the process change on the quality of inprocess materials, as well as the ability of downstream steps to accommodate
material from a changed cell culture process;

Nonclinical or clinical characteristics of the drug product and its therapeutic
indications (see section 2.5).
Quality Considerations

2.2.1. Analytical Techniques
The battery of tests for the comparability exercise should be carefully selected and
optimised to maximise 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

4


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
maximise 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 the
limitations of the assays (e.g., precision, specificity, and detection limit) and 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 characterisation or routine testing.

The measurement of quality attributes in characterisation 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 guidelines
(ICH Q2A, Q2B, Q5C, Q6B), as appropriate.

2.2.2 Characterisation
Characterisation 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 rationalised) repetition of
the characterisation activity conducted for the market application is generally
warranted to directly compare the pre-change and post-change product. However,
additional characterisation might be indicated in some cases. For example, when
process changes result in a product characterisation 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
characterisation of the material used in pivotal clinicial trials could provide a useful
point of reference for subsequent comparability excercises.
Each of the following criteria should be considered as a key point in the conduct of the
comparability exercise:

5


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 Activity
Biological assay results can serve multiple purposes in the confirmation of product
quality attributes that are useful for characterisation 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 post-change product.

Immunochemical Properties
Immunochemical
When immunochemical properties are part of the characterisation (e.g., for antibodies
or antibody-based products), the manufacturer should confirm that post-change
product is comparable in terms of the specific properties.

Purity, Impurities, and Contaminants
Impurities,
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 post-change
product relative to the pre-change 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

6


characterised 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.

2.2.3 Specifications
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 characterise 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 post-change 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, characterisation studies, batch analysis data, stability data,
and nonclinical and clinical experience.

2.2.4 Stability
For certain manufacturing process changes, even slight modifications of the
production procedures might cause changes in the stability of the post-change
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 characterisation 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 pre-change 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 pre-change and post-change
product. The results thus obtained might show product differences that warrant
additional evaluation, and also identify conditions indicating that additional controls

7


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.
2.3
Manufacturing Process Considerations
A well-defined manufacturing process with its associated process controls assures
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 re-evaluated 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 pre-change and post-change 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 re-evaluated and/or re-validated, as appropriate. The inprocess controls, including critical control points and in-process testing, should ensure

8


that the post-change process is well controlled and maintains the quality of the
product. Typically, re-evaluation/re-validation activities for a simple change might be
limited to the affected process step, if there is no evidence to indicate that there is
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 post-change 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 post-change batches should be
analysed 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 summarises the pre-change and the
post-change manufacturing process and that clearly highlights modifications of the
process and changes in controls in a side-by-side format.
2.4
Demonstration of Comparability during Development
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 pre-change product are applicable to postchange product in order to facilitate further development and, ultimately, to support
the marketing authorisation. 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 post-change 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 utilise 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
authorisation, the comparability exercise should be as comprehensive and thorough as

9


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, and therefore, bridging nonclinical
and/or clinical studies, as appropriate, might be needed.
2.5

Nonclinical and Clinical Considerations

2.5.1
2.5.1 Factors to be Considered in Planning Nonclinical and Clinical Studies
Nonc
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 pre-change 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

10


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 bellshaped 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;

•

PK/PD relation, distribution, clearance.

2.5.2 Type of Studies
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 post-change
product. Where appropriate, these studies should be direct comparative studies.
3.

GLOSSARY

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.
Exercise:
Comparability Exercise:
The activities, including study design, conduct of studies, and evaluation of data, that
are designed to investigate whether the products are comparable.

11


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.
4.

REFERENCES

Viral Safety Evaluation of Biotechnology Products Derived From Cell Lines of Human
or Animal Origin (Q5A).
Analysis of the Expression Construct in Cells Used for Production of r-DNA Derived
Protein Products (Q5B).
Stability Testing of Biotechnological/Biological Products (Q5C).
Derivation and Characterisation 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 Guide for Active Pharmaceutical Ingredients (Q7A).
Validation of Analytical Procedures (Q2A).
Validation of Analytical Procedures: Methodology (Q2B).
Common Technical Document (M4Q).
Stability Testing of New Drug Substances and Products (Q1A) (Second Revision).
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).

12

Q5 e step4

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