INTRODUCTION
The
Pharmaceutical Development section provides an opportunity to present the
knowledge gained through the application of scientific approaches and 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 guideline 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.
PHARMACEUTICAL DEVELOPMENT
The
aim of pharmaceutical development is to design a quality product and its the 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 the establishment of the design space. Similarly, the 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 post approval 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 a 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 an 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 this section provides an
opportunity to demonstrate a higher degree of understanding of the material
attributes, manufacturing processes and their controls. This scientific
understanding facilitates the 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 post-approval submissions;
•
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,
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 prioritising the additional
pharmaceutical development studies to collect such knowledge.
A.
Components of the Drug Product
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., solid state properties),
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 interrelated and might need to 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.
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. 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).
B.
Drug Product
1.
Formulation Development
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).
2.
Overages
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),
3)
justification for the amount of overage. The overage should be included in the
amount of drug substance listed in the batch formula.
3.
Physicochemical and Biological Properties
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
assure drug release, and the development and suitability of the chosen test,
could be provided in this section.
C.
Manufacturing Process Development
The
selection, the control, and any improvement of the manufacturing process (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. The manufacturing process
development programme or process improvement programme 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 should be discussed. The discussion should summarise the
influence of the differences on the performance, manufacturability and quality
of the product.
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.
D.
Container Closure System
The
choice and rationale for selection of the container closure system for the
commercial product 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 which, as
far as possible, simulate the use of the product.
E.
Microbiological Attributes
Where
appropriate, the microbiological attributes of the drug product should be
discussed. 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.
F.
Compatibility
The
compatibility of the drug product with reconstitution diluents (e.g.,
precipitation, 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. Similarly, admixture or dilution of
products prior to administration (e.g., product added to large volume infusion
containers) might need to be addressed.
Reference: ICH Q8 R2 Guidelines
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