1. Introduction
1.1 Objective of the Guideline
This guideline 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 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 guideline also indicates areas where the
provision of greater understanding of pharmaceutical and manufacturing sciences
can create a basis for flexible regulatory approaches. The Pharmaceutical
Development section is intended to provide a more comprehensive understanding
of the product and manufacturing process for reviewers and inspectors.
1.2 Background
During the
July 2003 ICH meeting in Brussels, agreement was reached on a common vision and
approach for developing an international plan for a harmonized pharmaceutical
quality system that would be applicable across the life cycle of a product.
This plan emphasizes an integrated approach to review (assessment) and
inspection based on scientific risk management. Several actions were outlined
to implement this vision. An expert-working group (EWG) was established to
develop guidance for pharmaceutical development, which will cover the lifecycle
of a product.
1.3 Scope
This
guideline 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 topic M4). The guideline does
not apply to contents of submissions for drug products during the clinical
research stages of drug development. However the principles in this guideline
are important to consider during these stages.
This guideline might also be appropriate for other types of
products. To determine the applicability
of this guideline for a particular type of product, applicants should consult
with the appropriate regulatory authorities.
2. Pharmaceutical
Development
The aim of
pharmaceutical development is to design a quality*
product and the manufacturing process to deliver the product in a reproducible
manner. The information and knowledge gained from pharmaceutical development
studies provide scientific understanding to support the establishing of
specifications and manufacturing controls.
Information
from pharmaceutical development studies is a basis for 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 should be looked upon as opportunities to gain
additional knowledge and further support establishment of the design space. Inclusion of knowledge gained from
experiments giving negative results also can be useful in supporting the
selected product and its manufacturing process.
The
Pharmaceutical Development section should describe the knowledge that
establishes that the type of dosage form selected and the formulation proposed
are satisfactory for the purpose specified in the application. 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.
At a
minimum, those aspects of drug substances, excipients, and manufacturing
processes that are critical and that present a significant risk* to product
quality, and therefore should be monitored or otherwise controlled, should be
identified and discussed. These 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 other 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 this section provides an
opportunity to demonstrate a higher degree of understanding of manufacturing
processes and process controls. This
scientific understanding establishes the 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;
·
“real time” quality control, leading to a reduction of end-product release
testing.
To realise
this flexibility, the applicant should demonstrate an enhanced knowledge of
product performance over a range of material attributes (e.g. particle size
distribution, moisture content, flow properties), processing options and
process parameters. This knowledge can be gained by, for example, application
of formal experimental designs* or PAT*. Appropriate use of risk management
principles can be helpful in prioritising the additional pharmaceutical
development studies to collect such knowledge.
The design
and conduct of the pharmaceutical development studies should be consistent with
their intended scientific purpose and the stage of the development of the
product. 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.
2.1 Components of the Drug Product
2.1.1 Drug Substance
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., crystal engineering), should be identified and discussed. Examples of physicochemical and biological properties that might need to be examined include solubility, water content, particle size, crystal properties, biological activity, and permeability. These properties could be inter-related and might need to be considered in combination. Some of these properties can change with time and might be supplier dependent.
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, the 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
Tree #3 and #4 (Part 2)). 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
discussed. For products that contain
more than one drug substance, the compatibility of the drug substances with
each other should also be discussed.
2.1.2 Excipients
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. 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).
2.2 Drug
Product
2.2.1 Formulation
Development
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, experiences gained from the development of
similar drug product(s).
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. Any excipient ranges included in the batch
formula (3.2.P.3.2) should be justified in this section of the application:
this justification can often be based on the experience gained during the
development of the formulation and manufacturing process.
A summary of all formulations used
in clinical safety and efficacy, 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 this
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)
should be identified and a rationale provided for their use. Information to
support the appropriateness of such features should be provided.
2.2.2 Overages
The use of overages
of drug substance(s) in drug products is discouraged.
An overage is a fixed amount of the drug substance added to the
formulation in excess of the label claim. 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 representative batch formula
(3.2.P.3.2).
2.2.3 Physicochemical and Biological Properties
A summary of the development studies
that were carried out to investigate the potential impacts of the
physicochemical and biological properties of the drug product and the
appropriateness of the drug product acceptance criteria should be reported in
this section of the application (3.2.P.2.2.3). These studies could include, for
example, the development of a dissolution or drug release test, or the
development of a test for respirable fraction of an inhaled product, where
appropriate. Physiological implications of drug substance and formulation
attributes should be addressed. For
example, information could be provided from studies to investigate whether
acceptance criteria for polymorphism should be included in the drug product
specification. Similarly, information to support the robustness of the
formulation and manufacturing process with respect to the selection of
dissolution versus disintegration testing, or other means to assure drug
release, 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).
2.3 Manufacturing Process Development
The
selection, the control, and any optimisation 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 (e.g.,
dry granulation vs. wet granulation, terminal sterilisation vs. aseptic
processing), in order to address the selection of the manufacturing process and
confirm the appropriateness of the components (i.e., excipients).
Appropriateness of the equipment used for the intended products should be
discussed. Process development studies should provide the basis for process
optimisation, process validation and 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). 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) should be
provided.
The manufacturing process development programme
should identify the 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 the clinical safety and efficacy,
bioavailability, bioequivalence, or primary stability batches and the process
described in 3.2.P.3.3 should be discussed. The discussion should summarise the
influence of the differences on the performance and manufacturability 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 using the specified
equipment (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 optimisation, when describing the
development of the manufacturing process, it is useful to describe any
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 controls that provide process adjustment
capabilities to ensure control of all critical attributes should be
described. These provide a means for a
risk control strategy.
An assessment of process robustness can be useful in risk assessment and risk
reduction*, to support future manufacturing and
process optimisation, especially in conjunction with the use of structured risk
management tools.
2.4 Container Closure System
The choice and rationale for selection of the container closure system(s)
for the commercial product(s) (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(s) or label should be considered. This applies also to
admixture or dilution of products prior to administration e.g. product added to
large volume infusion containers.
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.
If a dosing
device is used (e.g., dropper pipette, pen injection device), it is important
to demonstrate that a reproducible and accurate dose of the product is
delivered under testing conditions which, as far as possible, simulate the use
of the product.
2.5 Microbiological Attributes
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
nonsterile 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)
·
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.
2.6 Compatibility
The compatibility of
the drug product with reconstitution diluent(s) or dosage devices (e.g.,
precipitation of drug substance in solution, sorption on injection vessels,
stability) should be addressed to provide appropriate and supportive
information for the labelling. This information should cover the recommended
in-use shelf life, at the recommended storage temperature and at the likely
extremes of concentration. Where the label recommends dilution or mixing of
solid dose forms (for example with drinks) prior to administration, appropriate
compatibility studies should be described.
3. Glossary
Design Space: the design space is the established range of
process parameters that has been demonstrated to provide assurance of quality.
In some cases design space can also be applicable to formulation attributes.
Working within the design space is not generally considered as a change of the
approved ranges for process parameters and formulation attributes. Movement out
of the design space is considered to be a change and would normally initiate a
regulatory post approval change process.
Formal
Experimental Design: a
structured, organized method for determining the relationship between factors
(Xs) affecting a process and the output of that process (Y). Also known as “Design of
Experiments”.
Lifecycle:
all phases in
the life of a product from the initial development through pre- and
post-approval until the product’s discontinuation.
PAT: Process Analytical Technologies - 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 assuring final product
quality.
Quality: degree to which a set of inherent properties
of a product, system or process fulfils requirements
Risk: the combination of the probability of occurrence of harm and the severity of that harm (from ISO/IEC Guide 51)
Risk
Management: systematic application of
quality management policies, procedures, and practices
to the tasks of assessing, controlling and communicating risk.
Risk
Reduction: actions taken to lessen the probability of occurrence of harm and
the severity of that harm