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)
May 2006
ICH
Guidance
for Industry
Q8 Pharmaceutical Development
Additional copies are
available from:
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Food and Drug Administration
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http://www.fda.gov/cder/guidance/index.htm
Office of Communication,
Training and
Manufacturers Assistance, HFM-40
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Food and Drug Administration
1401 Rockville Pike, Rockville, MD 20852-1448
http://www.fda.gov/cber/guidelines.htm
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)
May 2006
ICH
Guidance for Industry
Q8 Pharmaceutical Development
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.
This guidance describes the suggested
contents for the 3.2.P.2 (Pharmaceutical Development) section of a
regulatory submission in the ICH M4 Common Technical Document (CTD)
format.
The Pharmaceutical
Development section provides an opportunity to present the
knowledge gained through the application of scientific approaches
and quality risk management (for definition, see ICH Q9 Quality
Risk Management) to the development of a product and its
manufacturing process. It is first produced for the original
marketing application and can be updated to support new knowledge
gained over the lifecycle
of a product. The Pharmaceutical Development section is intended
to provide a comprehensive understanding of the product and
manufacturing process for reviewers and inspectors. The guidance
also indicates areas where the demonstration of greater
understanding of pharmaceutical and manufacturing sciences can
create a basis for flexible regulatory approaches. The degree of
regulatory flexibility is predicated on the level of relevant
scientific knowledge provided.
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.
Scope (1.2)
This guidance is intended
to provide guidance on the contents of section 3.2.P.2
(Pharmaceutical Development) for drug products as defined in the
scope of Module 3 of the Common Technical Document (ICH M4:
Common Technical Document for the Registration of
Pharmaceuticals for Human Use). The
guidance does not apply to contents of submissions for drug
products during the clinical research stages of drug development.
However, the principles in this guidance are important to consider
during those stages as well. This guidance might also be
appropriate for other types of products. To determine the
applicability of this guidance to a particular type of product,
applicants can consult with the appropriate regulatory
authorities.
II. Pharmaceutical Development (2)
The aim of pharmaceutical
development is to design a quality product and its manufacturing
process to consistently deliver the intended performance of the
product. The information and knowledge gained from pharmaceutical
development studies and manufacturing experience provide
scientific understanding to support the establishment of the
design space, specifications, and manufacturing
controls.
Information from
pharmaceutical development studies can be a basis for quality risk
management. It is important to recognize that quality
cannot be tested into products, i.e., quality should be built in
by design. Changes in formulation and manufacturing processes
during development and lifecycle management should be looked upon
as opportunities to gain additional knowledge and further support
establishment of the design space. Similarly,
inclusion of relevant knowledge gained from
experiments giving unexpected results can also be useful.
Design space is proposed by the applicant and is subject to
regulatory assessment and approval. Working within the design
space is not considered as a change. Movement out of the design
space is considered to be a change and would normally initiate a
regulatory postapproval change process.
The Pharmaceutical
Development section should describe the knowledge that establishes
that the type of dosage form selected and the formulation proposed
are suitable for the intended use. This section should include
sufficient information in each part to provide an understanding of
the development of the drug product and its manufacturing process.
Summary tables and graphs are encouraged where they add clarity
and facilitate review.
At a minimum, those
aspects of drug substances, excipients, container closure systems,
and manufacturing processes that are critical to product quality
should be determined and control strategies justified. Critical
formulation attributes and process parameters are generally
identified through an assessment of the extent to which their
variation can have impact on the quality of the drug product.
In addition, the applicant
can choose to conduct pharmaceutical development studies that can
lead to an enhanced knowledge of product performance over a wider
range of material attributes, processing options and process
parameters. Inclusion of this additional information in the
Pharmaceutical Development section provides an opportunity to
demonstrate a higher degree of understanding of material
attributes, manufacturing processes, and their controls. This
scientific understanding facilitates establishment of an expanded
design space. In these situations, opportunities exist to develop
more flexible regulatory approaches, for example, to facilitate:
·
risk-based regulatory decisions
(reviews and inspections)
·
manufacturing process
improvements, within the approved design space described in the
dossier, without further regulatory review
·
reduction of postapproval
submissions
·
real-time quality control,
leading to a reduction of end-product release testing
To realize this
flexibility, the applicant should demonstrate an enhanced
knowledge of product performance over a range of material
attributes, manufacturing process options and process parameters.
This understanding can be gained by application of, for example,
formal experimental designs, process
analytical technology (PAT), and/or prior knowledge.
Appropriate use of quality risk management principles can be
helpful in prioritizing the additional pharmaceutical development
studies to collect such knowledge.
The design and conduct of
pharmaceutical development studies should be consistent with their
intended scientific purpose. It should be recognized that the
level of knowledge gained, and not the volume of data, provides
the basis for science-based submissions and their regulatory
evaluation.
The physicochemical and
biological properties of the drug substance that can influence the
performance of the drug product and its manufacturability, or were
specifically designed into the drug substance (e.g., solid state
properties), should be identified and discussed. Examples of
physicochemical and biological properties that should be examined,
as appropriate, include solubility, water content, particle size,
crystal properties, biological activity, and permeability. These
properties could be interrelated and, when appropriate, should be
considered in combination.
To evaluate the potential
effect of drug substance physicochemical properties on the
performance of the drug product, studies on drug product might be
warranted. For example, ICH Q6A Specifications: Test Procedures
and Acceptance Criteria for New Drug Substances and New Drug
Products: Chemical Substances describes some of the
circumstances in which drug product studies are recommended (e.g.,
Decision Trees #3 and #4 (Part 2)). This approach applies equally
for ICH Q6B Specifications: Test Procedures and Acceptance
Criteria for Biotechnology/Biological Products. The knowledge
gained from the studies investigating the potential effect of drug
substance properties on drug product performance can be used, as
appropriate, to justify elements of the drug substance
specification (3.2.S.4.5).
The compatibility of the
drug substance with excipients listed in 3.2.P.1 should be
evaluated. For products that contain more than one drug substance,
the compatibility of the drug substances with each other should
also be evaluated.
The excipients chosen,
their concentration, and the characteristics that can influence
the drug product performance (e.g., stability, bioavailability) or
manufacturability should be discussed relative to the respective
function of each excipient. This should include all substances
used in the manufacture of the drug product, whether they appear
in the finished product or not (e.g., processing aids).
Compatibility of excipients with other excipients, where relevant
(for example, combination of preservatives in a dual preservative
system), should be established. The ability of excipients (e.g.,
antioxidants, penetration enhancers, disintegrants, release
controlling agents) to provide their intended functionality and to
perform throughout the intended drug product shelf life should
also be demonstrated. The information on excipient performance can
be used, as appropriate, to justify the choice and quality
attributes of the excipient and to support the justification of
the drug product specification (3.2.P.5.6).
Information to support the
safety of excipients, when appropriate, should be cross-referenced
(3.2.P.4.6).
A summary should be provided describing the
development of the formulation, including identification of those
attributes that are critical to the quality of the drug product,
taking into consideration intended usage and route of
administration. Information from formal experimental designs can
be useful in identifying critical or interacting variables that
might be important to ensure the quality of the drug product.
The summary should highlight the evolution of
the formulation design from initial concept up to the final
design. This summary should also take into consideration the
choice of drug product components (e.g., the properties of the
drug substance, excipients, container closure system, any relevant
dosing device), the manufacturing process, and, if appropriate,
knowledge gained from the development of similar drug product(s).
Any excipient ranges included in the batch
formula (3.2.P.3.2) should be justified in the Pharmaceutical
Development section of the application; this justification can
often be based on the experience gained during development or
manufacture.
A summary of formulations used in clinical
safety and efficacy and in any relevant bioavailability or
bioequivalence studies should be provided. Any changes between the
proposed commercial formulation and those formulations used in
pivotal clinical batches and primary stability batches should be
clearly described and the rationale for the changes provided.
Information from comparative in vitro studies
(e.g., dissolution) or comparative in vivo studies (e.g.,
bioequivalence) that links clinical formulations to the proposed
commercial formulation described in 3.2.P.1 should be summarized,
and a cross-reference to the studies (with study numbers) should
be provided. Where attempts have been made to establish an in
vitro/in vivo correlation, the results of those studies and a
cross-reference to the studies (with study numbers) should be
provided in the Pharmaceutical Development section. A successful
correlation can assist in the selection of appropriate dissolution
acceptance criteria and can potentially reduce the need for
further bioequivalence studies following changes to the product or
its manufacturing process.
Any special design features of the drug product
(e.g., tablet score line, overfill, anti-counterfeiting measure as
it affects the drug product) should be identified and a rationale
provided for their use.
In general, use of an overage of a drug
substance to compensate for degradation during manufacture or a
product’s shelf life, or to extend shelf life, is discouraged.
Any overages in the manufacture of the drug
product, whether they appear in the final formulated product or
not, should be justified considering the safety and efficacy of
the product. Information should be provided on the (1) amount of
overage, (2) reason for the overage (e.g., to compensate for
expected and documented manufacturing losses), and (3)
justification for the amount of overage. The overage should be
included in the amount of drug substance listed in the batch
formula (3.2.P.3.2).
The physicochemical and biological properties
relevant to the safety, performance, or manufacturability of the
drug product should be identified and discussed. This includes the
physiological implications of drug substance and formulation
attributes. Studies could include, for example, the development of
a test for respirable fraction of an inhaled product. Similarly,
information supporting the selection of dissolution vs.
disintegration testing (or other means to ensure drug release) and
the development and suitability of the chosen test could be
provided in this section. See also ICH Q6A Specifications: Test
Procedures and Acceptance Criteria for New Drug Substances and New
Drug Products: Chemical Substances, Decision Tree #4 (Part 3)
and Decision Tree #7 (Part 1) or ICH Q6B Specifications: Test
Procedures and Acceptance Criteria for Biotechnology/Biological
Products. The discussion should cross-reference any relevant
stability data in 3.2.P.8.3.
The selection, the
control, and any improvement of the manufacturing process
described in 3.2.P.3.3 (i.e., intended for commercial production
batches) should be explained. It is important to consider the
critical formulation attributes, together with the available
manufacturing process options, in order to address the selection
of the manufacturing process and confirm the appropriateness of
the components. Appropriateness of the equipment used for the
intended products should be discussed. Process development studies
should provide the basis for process improvement, process
validation, continuous process verification (where
applicable), and any process control requirements. Where
appropriate, such studies should address microbiological as well
as physical and chemical attributes. The knowledge gained from
process development studies can be used, as appropriate, to
justify the drug product specification (3.2.P.5.6).
The manufacturing process
development program or process improvement program should identify
any critical process parameters that should be monitored or
controlled (e.g., granulation end point) to ensure that the
product is of the desired quality.
For those products
intended to be sterile, an appropriate method of sterilization for
the drug product and primary packaging material should be chosen
and the choice justified.
Significant differences
between the manufacturing processes used to produce batches for
pivotal clinical trials (safety, efficacy, bioavailability,
bioequivalence) or primary stability studies and the process
described in 3.2.P.3.3 should be discussed. The discussion should
summarize the influence of the differences on the performance,
manufacturability, and quality of the product. The information
should be presented in a way that facilitates comparison of the
processes and the corresponding batch analyses information
(3.2.P.5.4). The information should include, for example, (1) the
identity (e.g., batch number) and use of the batches produced
(e.g., bioequivalence study batch number), (2) the manufacturing
site, (3) the batch size, and (4) any significant equipment
differences (e.g., different design, operating principle, size).
In order to provide
flexibility for future process improvement, when describing the
development of the manufacturing process, it is useful to describe
measurement systems that allow monitoring of critical attributes
or process end-points. Collection of process monitoring data
during the development of the manufacturing process can provide
useful information to enhance process understanding. The process
control strategies that provide process adjustment capabilities to
ensure control of all critical attributes should be described.
An
assessment of the ability of the process to reliably produce a
product of the intended quality (e.g., the performance of the
manufacturing process under different operating conditions, at
different scales, or with different equipment) can be provided. An
understanding of process robustness
can be useful in risk assessment and risk
reduction (see ICH Q9 Quality Risk Management glossary for
definition) and to support future manufacturing and process
improvement, especially in conjunction with the use of risk
management tools (see ICH Q9 Quality Risk Management).
The choice and rationale
for selection of the container closure system for the commercial
product (described in 3.2.P.7) should be discussed. Consideration
should be given to the intended use of the drug product and the
suitability of the container closure system for storage and
transportation (shipping), including the storage and shipping
container for bulk drug product, where appropriate.
The
choice of materials for primary packaging should be justified. The
discussion should describe studies performed to demonstrate the
integrity of the container and closure. A possible interaction
between product and container or label
should be considered.
The choice of primary packaging materials
should consider, e.g., choice of materials, protection from
moisture and light, compatibility of the materials of construction
with the dosage form (including sorption to container and
leaching), and safety of materials of construction. Justification
for secondary packaging materials should be included, when
relevant.
If a dosing device is used
(e.g., dropper pipette, pen injection device, dry powder inhaler),
it is important to demonstrate that a reproducible and accurate
dose of the product is delivered under testing conditions that, as
far as possible, simulate the use of the product.
Where appropriate, the
microbiological attributes of the drug product should be discussed
in this section (3.2.P.2.5). The discussion should include, for
example:
·
The rationale for performing or
not performing microbial limits testing for non sterile drug
products (e.g., Decision Tree #8 in ICH Q6A Specifications:
Test Procedures and Acceptance Criteria for New Drug Substances
and New Drug Products: Chemical Substances and ICH Q6B
Specifications: Test Procedures and Acceptance Criteria for
Biotechnology/Biological Products)
·
The selection and effectiveness
of preservative systems in products containing antimicrobial
preservative or the antimicrobial effectiveness of products that
are inherently antimicrobial
·
For sterile products, the
integrity of the container closure system as it relates to
preventing microbial contamination
Although chemical testing for preservative
content is the attribute normally included in the drug product
specification, antimicrobial preservative effectiveness should be
demonstrated during development. The lowest specified
concentration of antimicrobial preservative should be demonstrated
to be effective in controlling microorganisms by using an
antimicrobial preservative effectiveness test. The concentration
used should be justified in terms of efficacy and safety, such
that the minimum concentration of preservative that gives the
required level of efficacy throughout the intended shelf life of
the product is used. Where relevant, microbial challenge testing
under testing conditions that, as far as possible, simulate
patient use should be performed during development and documented
in this section.
The compatibility of the drug product with
reconstitution diluents (e.g., precipitation, stability) should be
addressed to provide appropriate and supportive information for
the labeling. This information should cover the recommended in-use
shelf life, at the recommended storage temperature and at the
likely extremes of concentration. Similarly, admixture or dilution
of products prior to administration (e.g., product added to large
volume infusion containers) should be addressed.
Continuous Process
Verification: An alternative
approach to process validation in which manufacturing process
performance is continuously monitored and evaluated.
Design Space: The multidimensional
combination and interaction of input variables (e.g., material
attributes) and process parameters that have been demonstrated to
provide assurance of quality. Working within the design space is
not considered as a change. Movement out of the design space is
considered to be a change and would normally initiate a regulatory
postapproval change process. Design space is proposed by the
applicant and is subject to regulatory assessment and approval.
Formal Experimental
Design: A structured,
organized method for determining the relationship between factors
affecting a process and the output of that process.
Also known as “Design of Experiments.”
Process Analytical
Technology (PAT): A system for
designing, analyzing, and controlling manufacturing through timely
measurements (i.e., during processing) of critical quality and
performance attributes of raw and in-process materials and
processes with the goal of ensuring final product quality.
Quality:
The suitability of either a drug substance or drug product for
its intended use. This term includes such attributes as the
identity, strength, and purity (from ICH Q6A
Specifications: Test Procedures and Acceptance
Criteria for New Drug Substances and New Drug Products: Chemical
Substances).
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 2005. 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.