|
January 6, 2004
NOTICE
Our file number: 04-100024-856
Release of Draft (Step 2) ICH1Guidance:
Comparability of Biotechnological/Biological Products Subject to Changes
in Their Manufacturing Process (Q5E)
The above referenced draft guidance was released by the ICH Steering
Committee for consultation and is being posted on the Therapeutic Products
Directorate Website2 for information and comment
in accordance with Step 2 of the ICH process.
The Step-2 milestone reached on Q5E represents consensus within the Expert
Working Group with respect to quality issues. Although Q5E has been designated
a Quality Guideline, and most of the issues to be addressed relate to
the evaluation of quality attributes, the intent is that the final version
of the guideline should incorporate non-clinical and clinical considerations
for the demonstration of comparability. Therefore, while the current draft
is being made available for information and public comment, ICH experts
in the areas of safety and efficacy will provide input to the guideline.
A second release for information and public comment, also considered to
be at Step-2, is anticipated once the ICH Experts have reached consensus
on the fully integrated guideline.
Please note that draft guidance documents are only made available in
English until finalized by the ICH. It is also important to note that
amendments to draft documents may occur as a result of regulatory consultations
and subsequent deliberations within the ICH.
All comments forwarded to Health Canada will be transmitted to the ICH
as is, with the disclaimer that they are provided for information and
do not necessarily represent the views of Health Canada, except as specifically
indicated in separate comments.
As appropriate, your organization may alternatively wish to provide comments
to your affiliate association in the U.S., Europe or Japan for their input
directly to ICH.
Comments provided to Health Canada should be submitted no later than
April 30, 2004 in order to allow sufficient time for
their assessment and subsequent transmission to the ICH. Comments should
be directed to:
Anthony Ridgway
Manager
Biotherapeutics Division
Biologics and Genetic Therapies Directorate
Lcdc Building, Tunney's Pasture
A.L. 0603C1
Ottawa, Ontario, K1A 0L2
Tel: (613) 952-3605
Fax: (613) 941-5841
E-mail: anthony_ridgway@hc-sc.gc.ca
1 International Conference on Harmonisation
of Technical Requirements for the Registration of Pharmaceuticals for
Human Use
2 As a PDF file format under Guidelines\ICH\Draft
External Guidelines Out for Comment
INTERNATIONAL CONFERENCE ON HARMONISATION OF TECHNICAL REQUIREMENTS
FOR REGISTRATION OF PHARMACEUTICALS FOR HUMAN USE
DRAFT CONSENSUS GUIDELINE
COMPARABILITY OF BIOTECHNOLOGICAL/BIOLOGICAL PRODUCTS SUBJECT TO CHANGES
IN THEIR MANUFACTURING PROCESS
Q5E
Released for Consultation
at Step 2 of the ICH Process
on 13 November 2003
by the ICH Steering Committee
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.
TABLE OF CONTENTS
1. INTRODUCTION
1.1 Objectives of the Guideline
1.2 Background
1.3 Scope
1.4 General Principles
2. GUIDELINES
2.1 Considerations for the Comparability Exercise
2.2 Quality Considerations
2.2.1 Analytical Techniques
2.2.2 Characterisation
2.2.3 Specifications
2.2.4 Stability
2.3 Manufacturing Process Considerations
2.4 Demonstration of Comparability during Development
3. NONCLINICAL AND CLINICAL CONSIDERATIONS
4. GLOSSARY
5. REFERENCES
Notice to the Reader: Where reference is made to nonclinical and
clinical studies, additional information and modification of these specific
items will be provided by ICH Safety and Efficacy Experts.
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. This guideline is intended to assist in the design and conduct
of studies used to collect the technical information to establish the
comparability of pre-change and post-change products and, thereby, confirm
that the manufacturing process changes did not have an adverse impact
on the quality, safety and efficacy of the drug product.
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 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 pre-change and post-change products,
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 References). This document
builds upon the previous ICH guidelines and provides additional direction
regarding approaches to:
- Compare post-change product to pre-change product following manufacturing
process changes and
- Assess 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.
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 authorization holder (or the developer, if
prior to market authorization).
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.
1.3 Scope
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 characterised using an appropriate
set of analytical procedures;
- Products where 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 products; and
- Products where 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 the drug product produced by a changed manufacturing process
through collection and evaluation of the relevant data to determine whether
there is 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 products 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 might not be 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 post-change
products 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 potential consequences on the product, not just the obvious, should
be performed. Based on this evaluation, acceptance criteria to define
highly similar post-change product can be established. Quality data on
the pre- and post-change products are generated, and a comparison is performed
that integrates and evaluates all data available, e.g., characterisation,
routine batch analyses, stability, in-process control, and process validation/evaluation
data. The comparison of the results to thepredefined acceptance criteria
allows an objective assessment of whether or not the pre- and post-change
products 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 post-change products are highly similar and considered comparable,
i.e. no adverse impact on safety or efficacy profiles is foreseen.
- Although the products appear highly similar, there is doubt concerning
the capability of the analytical procedures to discern relevant differences
that can impact the safety and efficacy of the product. The manufacturer
should consider performing additional nonclinical and/or clinical studies.
- Some differences have been observed in the quality attributes of the
pre-change and post-change products, but it can be justified that no
adverse consequence 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 products can
be considered comparable.
- Although the pre- and post-change products are similar, some differences
have been identified in the comparison of quality attributes and possible
adverse consequences on safety and efficacy profiles cannot be excluded.
In such situations, the generation and analysis of additional data on
quality attributes is unlikely to be sufficient to determine if pre-
and post-change products are comparable. The manufacturer should consider
performing nonclinical and/or clinical studies to reach a definitive
conclusion, taking into account characteristics of the drug product
such as therapeutic window, clinical usage (acute vs. chronic administration),
dosing characteristics, and potential for immunogenic responses.
- Differences are so significant that it is determined that quality
attributes for products are not comparable (i.e., they are not highly
similar). This outcome is not within the scope of this document and
is not discussed further.
2. 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. Therefore, it might be appropriate to collect data on the drug
product to support the determination of comparability even though all
process changes occurred in the manufacture of the drug substance. Comparability
can be deduced from quality studies (partial or comprehensive), but might
sometimes need to be supported by comparability bridging studies. The
extent of the studies that 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, 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 the 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 protein and, hence, potential product-related
substances and product-related impurities;
- Batches used for demonstration of manufacturing consistency;
- Historical batch 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 ability of downstream steps to accommodate
material from a changed cell culture process, as well as the impact
of the process change on the quality of downstream product;
- Adequacy of the in-process controls including critical control points
and in-process testing: In-process controls for the post-change process
should be confirmed, modified, or created, as appropriate, to maintain
the quality of the product;
- Nonclinical or clinical characteristics of the drug product: Clinical
characteristics, such as therapeutic index, clinical use (e.g., acute
vs. chronic administration), dosing, route of administration, and potential
for immunogenic response, of the drug product can be important in planning
the comparability exercise; and
- Each indication for a multi-indication product: The structure-activity
relationships, mechanism of action, safety profile, and toxicities of
the same product can vary with each clinical indication and, if so,
should be addressed for each clinical indication.
2.2 Quality Considerations
2.2.1 Analytical Techniques
The battery of tests for the comparability exercise should be carefully
selected and optimised to the product to maximise the potential of detecting
differences in thequality attributes 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 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 pre-change 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 valid 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 direct result of changes in quality
attributes that the existing methods are not capable of measuring. That
is, when specific changes occur in quality attributes as a result of
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 to establish routine specifications.
The measurement of quality attributes 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 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
products. However, additional characterisation might be indicated in some
cases. 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, the
significance of these alterations should be evaluated.
Each of the following criteria should be considered as a key point in
the conduct of the comparability exercise.
Physiochemical Properties:
The manufacturer should address 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 addressed. 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 serve multiple purposes in the confirmation
of product quality attributes that are useful for characterisation and
batch analysis, and, in some cases, serve as a link to clinical activity.
The manufacturer should recognise 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 completely correlated
with clinical safety or efficacy or if the mechanism of action is not
understood, the manufacturer should confirm that nonclinical or clinical
activity is not compromised in the post-change product.
Immunochemical Properties:
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:
The combination of analytical procedures selected should provide data
to evaluate the change in purity profile 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 determine their impact on safety and efficacy.
Where the change results in theappearance of new impurities, it might
be appropriate to characterise the new impurities, and in some cases,
to conduct appropriate 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.
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 and
should be justified. In some cases, additional tests and acceptance criteria
on the relative abundance 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 post-change 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 many manufacturing process changes even slight modifications of the
production procedures, including those made early in the manufacturing
process for the drug substance, 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 to buffer composition, processing and holding conditions,
and 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; and, in some cases, divalent ions leached from container closure
might change the stability profile because of the activation of trace
proteases not detected in stability studies of the pre-change product.
Generally, therefore, real-time concurrent stability studies on the product
potentially affected by the change should be conducted, 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 products. The results thus obtained might show product
differences that warrant additional evaluation and also identify conditions
indicating that additional controlsshould 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
is necessary to assure 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 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, 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 will not
need to be considered. For example, analysis of process 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 products
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 in-process controls, including
critical control points and in-process testing, should ensurethat 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 end-of-production cells;
- 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 manufacturing process of the pre-change process and the post-change
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 bridge nonclinical and clinical data generated with pre-change to post-change
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
accumulates, 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 andthorough 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. It should be recognised that during development,
analytical procedures 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 development, physicochemical
and biological tests alone might be considered inadequate to determine
comparability, and therefore, repeating elements of the nonclinical or
clinical studies already performed would be considered appropriate.
3. NONCLINICAL AND CLINICAL CONSIDERATIONS
Notice to the Reader: Where reference is made to nonclinical and
clinical studies, additional information and modification of these specific
items will be provided by ICH Safety and Efficacy Experts.
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 outlined in this document.
Additional evidence from nonclinical or clinical studies is appropriate
when quality data are insufficient to establish comparability. The extent
and nature of nonclinical and clinical studies should be determined on
a case-by-case basis in consideration of various factors, which include:
- Quality findings, e.g.,
- The type, nature, and extent of differences between the post-change
product and the pre-change product with respect to quality attributes
including product-related substances and the impurity profile;
- The results of the evaluation/validation studies on the new process
including the results of relevant in-process tests; and
- The capabilities and limitations of tests used for any comparability
studies.
- The nature of the product, e.g., product complexity, therapeutic class;
- Dosing regimen;
- Route of administration;
- The therapeutic window based upon dose ranging studies;
- Chronic vs. acute use;
- Extent of knowledge regarding structure-activity relationships;
- Previous experience with immunogenic events or responses in patients;
- Mechanism of action;
- Patient population;
- Availability of existing nonclinical and clinical data; and
- Knowledge of how a difference in quality attributes might impact on
safety and efficacy.
4. 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 are highly similar before and after manufacturing
process changes and that no adverse impact on the quality, safety, or
efficacy 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 be indicated.
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 the adventitious agent safety, purity, potency, identity,
and stability of the product. Specifications measure a selected subset
of the quality attributes.
5. 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 Guidance for Active Pharmaceutical Ingredients
(Q7A)
Text on Validation of Analytical Procedures (Q2A)
Validation of Analytical Procedures: Methodology (Q2B)
The Common Technical Document (M4Q)
Stability Testing of New Drug Substances and Products Q1A(R)
|
