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 quality risk management (for definition, see ICH Q9) 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.

1. ICH Q8
MANSI NARENDRASINH CHAUHAN

2. TOPIC: ICH Q8
COURSE NAME: QUALITY MANAGEMENT SYSTEM
COURSE CODE: MQA102T
Presented By:
Mansi Narendrasinh Chauhan
1st Semester, Master of Pharmacy
Pharmaceutical Quality
Assurance
Guided By:
Dr. Dulendra P. Damahe
Associate Professor
Smt. B.N.B Swaminarayan Pharmacy College, Salvav-Vapi
Department of Pharmaceutical Quality Assurance

3. CONTENTS
1. Introduction
2. Objective & Scope of The Guideline
3. Pharmaceutical Development
3.1 Components of Drug Product
3.1.1 Drug Substances
3.1.2 Excipients
3.2 Drug Product
3.2.1 Formulation Development
3.2.2 Overages
3.2.3 Physiochemical & Biological Properties
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4. CONTENTS
3.3 Manufacturing Process Development
3.4 Container Closure System
3.5 Microbiological Attributes
3.6 Compatibility
4 PART II : PHARMACEUTICAL DEVELOPMENT- ANNEX
4.1 Elements of Pharmaceutical Development
4.1.1 Quality Target Product Profile
4.1.2 Critical Quality Attributes
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5. CONTENTS
4.1.3 Risk Assessments: Linking Material & Process Attributes
4.1.4 Design Space
4.1.5 Control Strategy
4.1.6 Product Lifecycle Management And Continual Improvement
5. SUBMISSION OF PHARMACEUTICAL DEVELOPMENT AND
RELATED INFORMATION IN CTD FORMAT
6. QUESTIONS
7. REFERENCES
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6. 1. INTRODUCTION
• Pharmaceutical development is the identification and evaluation of processes need
to convert an active pharmaceutical ingredient into a drug product suitable for its
intended purpose.
• In the early stages of drug development, this will be for small-scale manufacture
of product to be used in clinical trials.
• If the trials are successful, the process will need to be updated and improved to
make it suitable for manufacture on a commercial scale.
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7. 1. INTRODUCTION
• The pharmaceutical development process begins by measuring the properties of
the drug substance, and identifying the critical quality attributes of the drug
product that is required.
• This process will include checking the absorption and stability profile of the drug,
and the most appropriate route of administration (oral, parenteral or for local
administration).
• Matching the drug substance properties to the formulation needed to meet the
clinical and marketing profile is of great importance.
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8. 1. INTRODUCTION
• Drug substance properties may severely limit the formulations that can be used,
and require extensive study in order to meet the required profile.
• If the clinical development is successful, pharmaceutical development of a
commercial product is needed with build-up of an extensive understanding of the
drug substance and drug product properties, and its manufacturing behavior.
• The final product must be safe, reliable and effective.
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9. 2. OBJECTIVE & SCOPE OF THE GUIDELINE
• This guideline describes the suggested contents for the 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 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 of a product lifecycle.
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10. 3. PHARMACEUTICAL DEVELOPMENT
• 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.
• 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.
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11. 3.1 COMPONENTS OF DRUG PRODUCT
Drug
substances
Excipients
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12. • “The physicochemical and biological properties of the drug substance that can
influence the performance of the drug product and its manufacturability.”
• Solubility
• Water content
• Particle size
• Crystal properties
• Permeability
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3.1.1 Drug Substances
3.1 COMPONENTS OF DRUG PRODUCT

13. 3.1 COMPONENTS OF DRUG PRODUCT
• The excipients chosen, their concentration, and the characteristics that can
influence the drug product performance or manufacturability.
• The compatibility of the drug substance with excipients 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
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3.1.2 Excipients

14. 3.2 DRUG PRODUCT
Formulation
development
Overages
Physiochemical
& biological
properties
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15. 3.2.1 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.
• The summary should highlight the evolution of the formulation design from initial
concept up to the final design.
• Information from comparative in vitro studies (e.g., dissolution) or comparative in
vivo studies (e.g., BE) that links clinical formulations to the proposed formulation.
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16. 3.2.2 OVERAGES
• 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:
i. Amount of overage,
ii. Reason for the overage (e.g., to compensate for expected and documented
manufacturing losses),
iii. Justification for the amount of overage.
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17. 3.2.3 PHYSIOCHEMICAL & 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.
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18. 3.3 MANUFACTURING PROCESS DEVELOPMENT
• 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.
• 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.
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19. 3.4 CONTAINER CLOSURE SYSTEM
• The choice for selection of the container closure system for the commercial
product should be discussed.
• The choice of materials for primary packaging and secondary packaging should be
justified.
• A possible interaction between product and container or label should be
considered
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20. 3.5 MICROBIOLOGICALATTRIBUTES
• The selection and effectiveness of preservative systems in products containing
antimicrobial preservative or the antimicrobial effectiveness.
• For sterile products, the integrity of the container closure system as it relates to
preventing microbial contamination.
• The lowest specified concentration of antimicrobial preservative should be
justified in terms of efficacy and safety.
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21. 3.6 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 labeling.
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22. 4 PART II : PHARMACEUTICAL
DEVELOPMENT- ANNEX
• This guideline is an annex to ICH Q8 Pharmaceutical Development and provides
further clarification of key concepts outlined in the core guideline.
• In addition, this annex describes the principles of quality by design(QbD).
• The annex is not intended to establish new standards or to introduce new
regulatory requirements; however, it shows how concepts and tools (e.g., design
space) outlined in the parent Q8 document could be put into practice by the
applicant for all dosage form.
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23. 4 PART II : PHARMACEUTICAL
DEVELOPMENT- ANNEX
Pharmaceutical development should include, at a minimum, the following elements:
• Defining the quality target product profile (QTPP) as it relates to quality, safety
and efficacy, considering e.g., the route of administration, dosage form,
bioavailability, strength, and stability;
• Identifying potential critical quality attributes(CQAs) of the drug product, so that
those product characteristics having an impact on product quality can be studied
and controlled;
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24. 4 PART II : PHARMACEUTICAL
DEVELOPMENT- ANNEX
• Determining the critical quality attributes of the drug substance, Excipients etc.,
and selecting the type and amount of Excipients to deliver drug product of the
desired quality.
• Selecting an appropriate manufacturing process ;
• Defining a control strategy.
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25. 4.1 ELEMENTS OF PHARMACEUTICAL
DEVELOPMENT
Quality Target
Product Profile
Critical quality
attributes
Risk Assessments:
Linking Material &
Process Attributes
Design Space
Control
Strategy
Product Lifecycle
Management &
Continual
Improvement
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26. 4.1.1 QUALITY TARGET PRODUCT
PROFILE
The QTPP forms the basis of design for the development of the product.
Considerations for the QTPP include:
• Intended use in clinical setting, route of administration, dosage form, delivery
systems;
• Dosage strength(s);
• Container closure system;
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27. 4.1.1 QUALITY TARGET PRODUCT
PROFILE
• Therapeutic moiety release or delivery and attributes affecting pharmacokinetic
characteristics (e.g., dissolution, aerodynamic performance).
• Drug product quality criteria (e.g., sterility, purity, stability and drug release)
appropriate for the intended marketed product.
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28. 4.1.2 CRITICAL QUALITY ATTRIBUTES
• Critical Quality Attributes A CQA is a physical, chemical, biological, or
microbiological property or characteristic that should be within an appropriate
limit, range, or distribution to ensure the desired product quality. CQAs are
generally associated with the drug substance, excipients, intermediates (in-process
materials) and drug product.
• CQAs of solid oral dosage forms are typically those aspects affecting product
purity, strength, drug release and stability.
• Potential drug product CQAs derived from the quality target product profile
and/or prior knowledge are used to guide the product and process development.
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29. 4.1.3 RISK ASSESSMENTS: LINKING MATERIAL
& PROCESS ATTRIBUTES
• Risk assessment is a valuable science-based process used in quality risk
management that can aid in identifying which material attributes and process
parameters potentially have an effect on product CQAs.
• Risk assessment is typically performed early in the pharmaceutical development
process and is repeated as more information becomes available
• Risk assessment tools can be used to identify and rank parameters (e.g., process,
equipment, input materials) with potential to have an impact on product quality.
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30. 4.1.4 DESIGN SPACE
• The relationship between the process inputs (material attributes and process
parameters) and the CQAs can be described in the design space
A) Selection of Variables:
• The risk assessment and process development experiments described in Section
3.1.3 can lead to an understanding of the linkage and effect of process parameters
and material attributes on product CQAs, and also help identify the variables and
their ranges within which consistent quality can be achieved.
• These process parameters and material attributes can thus be selected for inclusion
in the design space.
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31. 4.1.4 DESIGN SPACE
B) Describing a Design Space in a Submission:
• A design space can be described in terms of ranges of material attributes and
process parameters, or through more complex mathematical relationships.
• It is possible to describe a design space as a time dependent function (e.g.,
temperature and pressure cycle of a lyophilization cycle), or as a combination of
variables such as components of a multivariate model.
C) Unit Operation Design Space(s):
• The applicant can choose to establish independent design spaces for one or more
unit operations, or to establish a single design space that spans multiple operations
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32. 4.1.4 DESIGN SPACE
D) Relationship of Design Space to Scale and Equipment:
• A design space can be developed at any scale.
• The applicant should justify the relevance of a design space developed at small or
pilot scale to the proposed production scale manufacturing process and discuss the
potential risks in the scale-up operation.
E) Design Space Versus Proven Acceptable Ranges:
• A combination of proven acceptable ranges does not constitute a design space.
• However, proven acceptable ranges based on univariate experimentation can
provide useful knowledge about the process.
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33. 4.1.4 DESIGN SPACE
F) Design Space and Edge of Failure:
• It can be helpful to determine the edge of failure for process parameters or
material attributes, beyond which the relevant quality attributes cannot be met.
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34. 4.1.5 CONTROL STRATEGY
A control strategy is designed to ensure that a product of required quality will be
produced consistently. A control strategy can include,
• Control of input material attributes (e.g., drug substance, excipients, ) based on an
understanding of their impact on product quality;
• Product specification;
• Controls for unit operations that have an impact on product quality;
• In-process testing in lieu of end-product testing (e.g. measurement and control of
CQAs during processing);
• A monitoring program (e.g., full product testing at regular intervals).
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35. 4.1.6 PRODUCT LIFECYCLE MANAGEMENT
AND CONTINUAL IMPROVEMENT
• Throughout the product lifecycle, companies have opportunities to evaluate
innovative approaches to improve product quality .
• Process performance can be monitored to ensure that it is working as anticipated
to deliver product quality attributes as predicted by the design space.
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36. 5. SUBMISSION OF PHARMACEUTICAL
DEVELOPMENT AND RELATED INFORMATION IN
CTD FORMAT
• Pharmaceutical development information is submitted in Section P.2 of the CTD.
Other information resulting from pharmaceutical development studies could be
accommodated by the CTD format in a number of different ways and some
specific suggestions are provided below. However, the applicant should clearly
indicate where the different information is located. In addition to what is
submitted in the application, certain aspects (e.g., product lifecycle management,
continual improvement) of this guideline are handled under the applicant’s
pharmaceutical quality system
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37. 5. SUBMISSION OF PHARMACEUTICAL
DEVELOPMENT AND RELATED INFORMATION IN
CTD FORMAT
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38. 6. QUESTION
1) Describe the scope of ICH Q8 guidelines. Explain the terms critical Quality
Attributes, Design space and control strategy with respect to guideline. (8M)
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39. 7. REFERENCES
1. Gamlen M., & Cummings P. Pharmaceutical Development: The Textbook of
Pharmaceutical Medicine; 2013. pp 32–41.
2. Vohora, Divya, and Gursharan Singh, eds. Pharmaceutical Medicine and
Translational Clinical Research. Academic Press, 2018.
3. Pramod, Kannissery, et al, "Pharmaceutical product development: A quality by
design approach." International Journal Of Pharmaceutical Investigation. 2016
6.3, 129.
4. ICH Q8(R2): “Pharmaceutical Development.” 2009
https://database.ich.org/sites/default/files/Q8_R2_Guideline.pdf Accessed 14/12/2021; 22:29 pm
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