Guidance for Industry
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`Q8(R2) Pharmaceutical
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`Development
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`U.S. Department of Health and Human Services
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`Food and Drug Administration
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`Center for Drug Evaluation and Research (CDER)
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`Center for Biologics Evaluation and Research (CBER)
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`November 2009
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`ICH
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`Revision 2
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`Guidance for Industry
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`Q8(R2) Pharmaceutical
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`Development
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`Additional copies are available from:
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`Office of Communications
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`Division of Drug Information, WO51, Room 2201
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`10903 New Hampshire Ave.
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`Silver Spring, MD 20993
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`Phone: 301-796-3400; Fax: 301-847-8714
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`druginfo@fda.hhs.gov
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`http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm
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`Office of Communication, Outreach and Development, HFM-40
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`Center for Biologics Evaluation and Research
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`Food and Drug Administration
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`1401 Rockville Pike, Rockville, MD 20852-1448
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`(Tel) 800-835-4709 or 301-827-1800
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`http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm
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`U.S. Department of Health and Human Services
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`Food and Drug Administration
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`Center for Drug Evaluation and Research (CDER)
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`Center for Biologics Evaluation and Research (CBER)
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`November 2009
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`ICH
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`Revision 2
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`TABLE OF CONTENTS
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`PHARMACEUTICAL DEVELOPMENT — PARENT GUIDANCE
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`INTRODUCTION (1, 1.1)................................................................................................ 1
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`I.
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`PHARMACEUTICAL DEVELOPMENT (2) ............................................................... 2
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`II.
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`A. Components of the Drug Product (2.1) ........................................................................................4
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`1. Drug Substance (2.1.1) ....................................................................................................................4
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`2. Excipients (2.1.2) .............................................................................................................................4
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`B. Drug Product (2.2) .........................................................................................................................5
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`1. Formulation Development (2.2.1)....................................................................................................5
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`2. Overages (2.2.2) ..............................................................................................................................5
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`3. Physicochemical and Biological Properties (2.2.3) ........................................................................6
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`C. Manufacturing Process Development (2.3)..................................................................................6
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`D. Container Closure System (2.4)....................................................................................................7
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`E. Microbiological Attributes (2.5) ...................................................................................................7
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`F. Compatibility (2.6) .........................................................................................................................8
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`III. GLOSSARY (3)................................................................................................................. 9
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`PHARMACEUTICAL DEVELOPMENT — ANNEX
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`1.
`INTRODUCTION (1)..................................................................................................... 10
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`ELEMENTS OF PHARMACEUTICAL DEVELOPMENT (2)................................ 11
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`II.
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`A. Quality Target Product Profile (2.1) ..........................................................................................11
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`B. Critical Quality Attributes (2.2) .................................................................................................12
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`C. Risk Assessment: Linking Material Attributes and Process Parameters to Drug Product
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`CQAs (2.3) ....................................................................................................................................12
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`D. Design Space (2.4) ........................................................................................................................13
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`1. Selection of Variables (2.4.1).........................................................................................................13
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`2. Describing a Design Space in a Submission (2.4.2)......................................................................13
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`3. Unit Operation Design Space(s) (2.4.3) ........................................................................................13
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`4. Relationship of Design Space to Scale and Equipment (2.4.4)......................................................14
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`5. Design Space Versus Proven Acceptable Ranges (2.4.5) ..............................................................14
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`6. Design Space and Edge of Failure (2.4.6).....................................................................................14
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`E. Control Strategy (2.5) ..................................................................................................................14
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`F. Product Lifecycle Management and Continual Improvement (2.6)........................................15
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`III.
`SUBMISSION OF PHARMACEUTICAL DEVELOPMENT AND RELATED
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`INFORMATION IN COMMON TECHNICAL DOCUMENT (CTD)
`FORMAT (3) ................................................................................................................... 16
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`A. Quality Risk Management and Product and Process Development (3.1)...............................16
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`B. Design Space (3.2) ........................................................................................................................16
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`C. Control Strategy (3.3) ..................................................................................................................16
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`D. Drug Substance Related Information (3.4)................................................................................17
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`IV. GLOSSARY (4)............................................................................................................... 18
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`Appendix 1. Differing Approaches to Pharmaceutical Development..........................................19
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`Illustrative Examples...................................................................................................20
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`Appendix 2.
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`Contains Nonbinding Recommendations
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` Guidance for Industry1
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`Q8(R2) Pharmaceutical Development
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`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.
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`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.
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`
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`This guidance is a revision of the ICH guidance Q8 Pharmaceutical Development (Q8 parent
`guidance) that published in May 2006. In June 2009, the Q8 parent guidance was revised to add
`an annex, which provides further clarification of the key concepts outlined in the May 2006
`guidance and describes the principles of quality by design (QbD). The Q8(R1) document issued
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`in June 2009 includes the Q8 parent guidance and the annex. This second revision, Q8(R2),
`provides corrected captions for figures 2a and 2b in Appendix 2, section C.
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`I.
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`The Q8 parent 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.
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`The Pharmaceutical Development section provides an opportunity to present the knowledge
`gained through the application of scientific approaches and quality risk management (for
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`INTRODUCTION (1, 1.1)2
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` 1 This guidance was developed within the Expert Working Group (Quality) of the International Conference on
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` Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) and has been
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` subject to consultation by the regulatory parties, in accordance with the ICH process. This guidance includes an
` annex to Q8 Pharmaceutical Development (the Q8 parent guidance). The annex has been endorsed by the ICH
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` Steering Committee at Step 4 of the ICH process, November 2008. 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. Following
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`the addition of the annex to the Q8 parent guidance, ICH recoded the guidance Q8(R1). In August 2009, ICH
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`issued Q8(R2) with corrected captions for figures 2a and 2b in Appendix 2, section C.
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`2 Arabic numbers reflect the organizational breakdown of the Q8 parent guidance endorsed by the ICH Steering
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`Committee at Step 4 of the ICH process, November 2005.
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`definition, see ICH Q9 Quality Risk Management)3 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 lifecycle4 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
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`recommended, but not required.
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`Scope (1.2)
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`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.
`
`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
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`PHARMACEUTICAL DEVELOPMENT (2)
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` 3 Available on the Internet, on the CDER guidance page, at
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`http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm. We update
`
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`
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`guidances periodically. To make sure you have the most recent version of a guidance, check the CDER guidance
`page.
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`4 Terms that appear in bold italic type in this guidance are defined in the glossary, section III (3).
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`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.
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`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.
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`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.
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`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:
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`•
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`risk-based regulatory decisions (reviews and inspections)
`• manufacturing process improvements, within the approved design space described in the
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`dossier, without further regulatory review
`reduction of postapproval submissions
`real-time quality control, leading to a reduction of end-product release testing
`
`•
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`•
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`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.
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`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.
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`Components of the Drug Product (2.1)
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`A.
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`1.
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`Drug Substance (2.1.1)
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`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.
`
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`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.
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`2.
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`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).
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`Information to support the safety of excipients, when appropriate, should be cross-referenced
`(3.2.P.4.6).
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`Excipients (2.1.2)
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`B.
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`Drug Product (2.2)
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`1.
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`Formulation Development (2.2.1)
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`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.
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`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
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`relevant dosing device), the manufacturing process, and, if appropriate, knowledge gained from
`the development of similar drug product(s).
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`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.
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`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.
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`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.
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`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.
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`2.
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`Overages (2.2.2)
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`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.
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`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.
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`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).
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`3.
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`Physicochemical and Biological Properties (2.2.3)
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`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
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`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.
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`C. Manufacturing Process Development (2.3)
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`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
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`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).
`
`
`D.
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`Container Closure System (2.4)
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`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
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`interaction between product and container or label should be considered.
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`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
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`(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.
`
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`E. Microbiological Attributes (2.5)
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`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:
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`• The rationale for performing or not performing microbial limits testing for non sterile drug
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`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)
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`• The selection and effectiveness of preservative systems in products containing antimicrobial
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`preservative or the antimicrobial effectiveness of products that are inherently antimicrobial
`
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`• For sterile products, the integrity of the container closure system as it relates to preventing
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`microbial contamination
`
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`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.
`
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`F.
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`Compatibility (2.6)
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`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.
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`III. GLOSSARY (3)
`
`
`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.”
`
`Lifecycle: All phases in the life of a product from the initial development through marketing
`until the product’s discontinuation.
`
`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.
`
`Process Robustness: Ability of a process to tolerate variability of materials and changes of the
`process and equipment without negative impact on 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).
`
`
`
`9
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`Eton Ex. 1018
`13 of 29
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`

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`Contains Nonbinding Recommendations
`
`PHARMACEUTICAL DEVELOPMENT — ANNEX
`
`INTRODUCTION (1)
`
`
`1.
`
`This annex provides further clarification of key concepts outlined in Q8 Pharmaceutical
`Development (the Q8 parent guidance). In addition, this annex describes the principles o