Guidance for Industry
`Drug Product
`
`Chemistry, Manufacturing, and Controls Information
`
`DRAFT GUIDANCE
`
`This guidance document is being distributed for comment purposes only.
`
`Comments and suggestions regarding this draft document should be submitted within 150 days
`of publication in the Federal Register of the notice announcing the availability of the draft
`guidance. Submit comments to Dockets Management Branch (HFA-305), Food and Drug
`Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. All comments should be
`identified with the docket number listed in the notice of availability that publishes in the
`Federal Register.
`
`For questions regarding this draft document contact (CDER) Upinder Atwal 301-827-5848 or
`(CBER) Christopher Joneckis 301-435-5681.
`
`U.S. Department of Health and Human Services
`Food and Drug Administration
`Center for Drug Evaluation and Research (CDER)
`Center for Biologics Evaluation and Research (CBER)
`
`January 2003
`CMC
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`Guidance for Industry
`
`Drug Product
`
`Chemistry, Manufacturing, and Controls Information
`
`Additional copies are available from:
`
`Office of Training and Communication
`Division of Drug Information, HFD-240
`Center for Drug Evaluation and Research
`Food and Drug Administration
`5600 Fishers Lane
`Rockville, MD 20857
`(Tel) 301-827-4573
` http://www.fda.gov/cder/guidance/index.htm
`
`and/or
`
` Office of Communication, Training and
`Manufacturers Assistance, HFM-40
`Center for Biologics Evaluation and Research
`
` Food and Drug Administration
`1401 Rockville Pike, Rockville, MD 20852-1448
` http://www.fda.gov/cber/guidelines.htm.
` (Tel) Voice Information System at 800-835-4709 or 301-827-1800
`
`U.S. Department of Health and Human Services
`Food and Drug Administration
`Center for Drug Evaluation and Research (CDER)
`Center for Biologics Evaluation and Research (CBER)
`
`January 2003
`CMC
`
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`Draft — Not for Implementation
`
`TABLE OF CONTENTS 1
`
`INTRODUCTION .................................................................................................................1
`I.
`II. BACKGROUND....................................................................................................................2
`A. The Common Technical Document — Quality (CTD-Q) Format.......................................... 2
`
`1. Format of Drug Product Information in Multiple Related Applications...................................... 3
`2. Format of Drug Product Information for Multiple Product Presentations and/or Manufacturing
`Schemes in One Application........................................................................................................ 3
`B. Content Information Included in an Application.................................................................. 4
`C. Additional Guidance............................................................................................................. 5
`
`D. Drug Master Files................................................................................................................. 6
`
`Environmental Assessments.................................................................................................. 6
`E.
`III. DESCRIPTION AND COMPOSITION OF THE DRUG PRODUCT (P.1)...................6
`A. Description of Dosage Form.................................................................................................. 6
`
`B. Container Closure System .................................................................................................... 7
`C. Composition Statement......................................................................................................... 7
`IV. PHARMACEUTICAL DEVELOPMENT (P.2)...............................................................10
`A. Components of the Drug Product (P.2.1)............................................................................ 11
`
`1. Drug Substance (P.2.1.1)...................................................................................................... 11
`2. Excipients (P.2.1.2) .............................................................................................................. 12
`B. Drug Product (P.2.2) .......................................................................................................... 13
`
`1. Formulation Development (P.2.2.1)....................................................................................... 13
`2. Overages (P.2.2.2) ............................................................................................................... 14
`3. Physicochemical and Biological Properties (P.2.2.3) ............................................................. 14
`C. Manufacturing Process Development (P.2.3) ...................................................................... 15
`D. Container Closure System (P.2.4) ....................................................................................... 16
`
`E. Microbiological Attributes (P.2.5)....................................................................................... 16
`
`F. Compatibility (P.2.6) .......................................................................................................... 17
`V. MANUFACTURE (P.3) ......................................................................................................18
`A. Manufacturer(s) (P.3.1) ...................................................................................................... 18
`
`B. Batch Formula (P.3.2) ........................................................................................................ 19
`C. Description of Manufacturing Process and Process Controls (P.3.3) .................................. 21
`
`1. Flow Diagram...................................................................................................................... 21
`2. Description of Manufacturing Process and Process Controls .................................................. 22
`
`
`1 Alphanumeric designations in parentheses that follow headings show where information should be placed in
`applications that are submitted in Common Technical Document (CTD) format.
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`3. Reprocessing and Reworking ................................................................................................ 24
`D. Controls of Critical Steps and Intermediates (P.3.4)........................................................... 25
`Process Validation and/or Evaluation (P.3.5)...................................................................... 26
`E.
`VI. CONTROL OF EXCIPIENTS (P.4)..................................................................................27
`A.
`Specifications (P.4.1)........................................................................................................... 28
`
`B. Analytical Procedures (P.4.2) ............................................................................................. 29
`C. Validation of Analytical Procedures (P.4.3) ........................................................................ 29
`
`D.
`E.
`
`Justification of Specifications (P.4.4) .................................................................................. 30
`Excipients of Human or Animal Origin (P.4.5)................................................................... 31
`
`F. Novel Excipients (P.4.6)...................................................................................................... 31
`VII. CONTROL OF DRUG PRODUCT (P.5)......................................................................31
`A.
`Specification(s) (P.5.1) ........................................................................................................ 31
`B. Analytical Procedures (P.5.2) ............................................................................................. 35
`
`C. Validation of Analytical Procedures (P.5.3) ........................................................................ 36
`
`D. Batch Analyses (P.5.4) ........................................................................................................ 36
`
`1. Batch Analysis Reports ......................................................................................................... 37
`2. Collated Batch Analyses Data ............................................................................................... 37
`E. Characterization of Impurities (P.5.5) ................................................................................ 38
`
`1. List of Expected Impurities ................................................................................................... 38
`2. Identification of Impurities.................................................................................................... 38
`Justification of Specification(s) (P.5.6)................................................................................ 40
`F.
`VIII. REFERENCE STANDARDS OR MATERIALS (P.6)................................................42
`IX. CONTAINER CLOSURE SYSTEM (P.7)........................................................................43
`X. STABILITY (P.8) ................................................................................................................44
`A.
`Stability Summary and Conclusion (P.8.1) ......................................................................... 44
`B.
`Postapproval Stability Protocol and Stability Commitment (P.8.2) .................................... 44
`
`C.
`
`Stability Data (P.8.3)........................................................................................................... 44
`
`1. Formal Stability Studies ....................................................................................................... 44
`2. Supporting Stability Studies .................................................................................................. 45
`3. Stress Studies....................................................................................................................... 45
`XI. APPENDICES (A) ...............................................................................................................46
`A.
`Facilities and Equipment (A.1) ........................................................................................... 46
`B. Adventitious Agents Safety Evaluation (A.2)...................................................................... 47
`
`1. Nonviral Adventitious Agents ................................................................................................ 48
`2. Viral Adventitious Agents...................................................................................................... 48
`C. Excipients (A.3) .................................................................................................................. 49
`XII. REGIONAL INFORMATION (R) ................................................................................50
`
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`A. Executed Production Records (R.1.P)................................................................................. 50
`
`1. Executed Production Records................................................................................................ 50
`2. Information on Components .................................................................................................. 50
`B. Comparability Protocols (R.2.P)......................................................................................... 51
`
`C. Methods Validation Package (R.3.P) .................................................................................. 51
`XIII. LITERATURE REFERENCES (3.3) ............................................................................51
`ATTACHMENT 1 .......................................................................................................................52
`GLOSSARY.................................................................................................................................58
`
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`Draft — Not for Implementation
`
`Guidance for Industry2
`
`Drug Product
`
`Chemistry, Manufacturing, and Controls Information
`
`This draft guidance, when finalized, will represent 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. An alternative approach may be used if such approach satisfies the requirements
`of the applicable statutes and regulations.
`
`If you plan to submit comments on this draft guidance, to expedite FDA review of your
`comments, please:
`
`•
`
`• Clearly explain each issue/concern and, when appropriate, include a proposed revision and
`the rationale and/or justification for the proposed revision.
`Identify specific comments by line numbers; use the pdf version of the document whenever
`possible.
`If possible, e-mail an electronic copy (Word) of the comments you have submitted to the
`docket to cunninghamp@cder.fda.gov
`
`•
`
`I.
`
`INTRODUCTION
`
`This guidance provides recommendations on the chemistry, manufacturing, and controls (CMC)
`information for drug products that should be submitted in original new drug applications (NDAs)
`and abbreviated new drug applications (ANDAs). The guidance addresses the content of original
`NDAs and ANDAs. The guidance is structured to facilitate the preparation of applications
`submitted in Common Technical Document (CTD) format (see section II.A and B). The
`recommendations apply to all NDAs and ANDAs, although more detailed guidance on the
`content of an application may be available in separate guidance documents for specific types of
`drug products or dosage forms (see section II.C).
`
`This guidance addresses the information to be submitted for marketing approval of drug products
`to ensure continued product quality (i.e., the identity, strength, quality, purity, and potency).
`Recommendations are provided on the information that should be included for (1) description
`and composition of the drug product, (2) manufacture, (3) control of excipients, (4) control of
`drug products, (5) reference standards or materials, (6) container closure systems, and (7)
`
`
`2 This guidance has been prepared by the Drug Product Technical Committee of the Chemistry, Manufacturing, and
`Controls Coordinating Committee (CMC CC) in the Center for Drug Evaluation and Research (CDER) at the Food
`and Drug Administration in collaboration with the Center for Biologics Evaluations and Research (CBER).
`
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`stability. Information is also provided on the type of pharmaceutical development information
`that should be included in an NDA or ANDA.
`
`This guidance, when finalized, will replace the guidance entitled Submitting Documentation for
`the Manufacture of and Controls for Drug Products (February 1987).
`
`II.
`
`BACKGROUND
`
`A.
`
`The Common Technical Document — Quality (CTD-Q) Format
`
`In November 2000, the International Conference on Harmonisation of Technical
`Requirements for Registration of Pharmaceuticals for Human Use issued harmonized
`guidance for the format of drug product applications (i.e., Common Technical Document
`(CTD)). The CTD describes a format for applications that (supplemented with regional
`information) can be used for submission to the regulatory authorities in the United States,
`European Union, and Japan. One focus of this effort was harmonizing the format for
`quality information (i.e., chemistry, manufacturing, and controls) that will be submitted
`in an application. FDA’s guidance on M4Q: The CTD — Quality describes the format
`for the quality information submitted in Module 3 of an application and provides
`additional information on formatting aspects of an application. Applicants can submit
`NDAs and ANDAs using the CTD-Q format. Applicants should review FDA’s guidance
`on M4Q: The CTD — Quality and other related CTD guidance documents for detailed
`formatting recommendations on preparing an application in CTD format.
`
`Module 3 of each application should include the specified CTD sections: Drug Substance
`(3.2.S), Drug Product (3.2.P), Appendices (3.2.A), Regional Information (3.2.R) and
`Literature References (3.3). In some cases, the majority of information to address the
`drug substance sections will be incorporated by reference from a drug master file (DMF).
`However, an applicant should still provide information to address some of the drug
`substance subsections. The content of the drug substance section (3.2.S) of Module 3
`will be the subject of a forthcoming guidance addressing CMC information for drug
`substances (drug substance guidance). The Appendices, Regional Information, and
`Literature References sections include information for both drug substance and drug
`product, as appropriate.
`
`This Drug Product guidance has been organized in a format conforming to Module 3 of
`the CTD, and it provides CMC content recommendations specific to drug product,
`including recommendations for the Appendices, Regional Information, and Literature
`References sections. Alphanumeric designations in parentheses corresponding to the
`CTD format follow relevant headings and text to show where information is to be placed
`in the CTD.3 Recommendations specific to drug substance, including recommendations
`
`
`3 Arabic numbers have been assigned to specific sections of the CTD. For example, the designation 3.2 before S, P,
`A, and R indicates Module 3, Body of Data section 2. Where this guidance discusses Module 3, Body of Data
`section 2, for brevity, the initial designation 3.2 is not repeated throughout the rest of the guidance (e.g., 3.2.P.3.1
`reads P.3.1).
`
`2
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`for the Appendices, Regional Information and Literature References sections, will be
`provided in the drug substance guidance.
`
`1.
`
`Format of Drug Product Information in Multiple Related Applications
`
`In general, when separate applications are submitted for drug products, each application
`should contain stand-alone drug product information even when the applications are
`related (e.g., tablet and oral solution with the same active ingredient submitted at the
`same time). In some rare cases, quality information can be incorporated by reference
`from a related application (e.g., co-marketing agreements). It is recommended that an
`applicant discuss cross-referencing of drug product quality information with the
`appropriate review division before submitting an application that uses cross-references.
`Information on when separate applications should be submitted is available in the
`following guidances:
`
`• Submitting Separate Marketing Applications and Clinical Data for Purposes of
`Assessing User Fees4
`
`• Variations in Drug Products that May Be Included in a Single ANDA
`
`2.
`
`Format of Drug Product Information for Multiple Product Presentations and/or
`Manufacturing Schemes in One Application
`
`Under certain circumstances (see guidances cited in II.A.1), different product
`presentations (e.g., strengths, container closure configurations, formulations) and/or
`manufacturing schemes (e.g., aseptic and terminal sterilization) can be submitted in the
`same application. In general, when a single application can be submitted, information for
`each of the product presentations and manufacturing schemes should be combined and
`presented together in one Drug Product (P) section with information provided in the
`Appendices, Regional Information, and Literature References sections for each of the
`product presentations and manufacturing schemes, as warranted. For example, if 100
`milligram (mg) tablets will be marketed in a bottle and a unit-dose blister package, the
`information should be presented in one P section. The majority of the CMC information
`would be identical for the two products. The information that differs between the two
`would be presented together in the appropriate subsections (e.g., P.7 — Container
`Closure System, P.8 — Stability), but would be physically or electronically separated
`within the subsection.
`
`However, there are cases when it is more appropriate and logical to have information
`presented separately for product presentations or manufacturing schemes that can be
`included in a single application. Information presented separately means one complete P
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`4 In February 2001 (66 FR 11175), the Agency made available a draft version of this guidance.
`
`3
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`section followed by other complete P sections.5 Information should be presented
`separately when a single application can be and is submitted for:6
`
`• A drug product that consists of two different formulated products. Separate P
`sections for each of the formulated products should be provided. For example,
`information on the drug product and reconstitution diluent should be presented in
`separate P sections for a drug product supplied with a reconstitution diluent. 7
`Similarly, separate P sections should be provided for an oral contraceptive with active
`and placebo tablets.
`
`• Parenteral drug products with different formulations (e.g., lyophilized, liquid,
`preserved, nonpreserved). Each formulation should be presented in a separate
`section. However, different strengths, fills, and container closure configurations can
`be included in the same P sections. For example, if an application includes a
`nonpreserved formulation packaged in two sizes of unit dose vials and a prefilled
`syringe and a preserved formulation packaged in a multidose vial, two separate P
`sections should be provided. One P section will include the information on the
`nonpreserved formulation and the other P section would include the information on
`the preserved product.
`
`• Modified release products with different release mechanisms or release rates (e.g., 1-
`day and 7-day transdermal drug delivery system). Each release mechanism or release
`rate should be presented separately.
`
`B.
`
`Content Information Included in an Application
`
`The application should include information in every P subsection for each of the product
`presentations (e.g., strengths, container closure configurations, formulations) and
`manufacturing schemes (e.g., alternative processes, drug substance source, manufacturing
`site) intended for approval under the application. There may be circumstances in which
`specific documentation (e.g., batch release data or certificate of analysis, executed
`production record, stability data) on a presentation or manufacturing scheme need not be
`included, such as when the intermediate strengths or container sizes are omitted in a
`bracketed stability study or when site specific stability studies are not needed
`preapproval. Although specific documentation might not be needed in some
`circumstances, the application should still include the remaining information on the
`product presentation or manufacturing scheme.
`
`
`5 See FDA’s guidance on M4Q: The CTD — Quality for additional guidance on formatting separate P sections.
`6 An applicant should refer to the guidances cited in section II.A.1 for information on when a single application can
`be submitted. For NDAs, the Agency may, for administrative reasons, choose to file separate NDAs for a
`submission that is eligible to be filed in a single NDA. When separate NDAs are filed, the recommendations in
`II.A.1 apply.
`7 If the diluent is the subject of a Center for Devices and Radiological Health (CDRH) 510k application or premarket
`approval application (PMA), only a citation to that application need be provided. Citations can be provided to
`approved applications in other situations when appropriate (e.g., devices).
`
`4
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`If information is not provided in a P subsection at all or for a particular product
`presentation or manufacturing scheme, this should be stated in the application and a
`reason given. Information should be provided in the Appendices, Regional Information,
`and Literature References sections for each of the product presentations and
`manufacturing schemes, as appropriate. If an Appendices or Regional Information
`subsection or the Literature References section is not applicable, this should be stated in
`the application.
`
`Before preparing an application, an applicant can discuss with CDER or CBER questions
`about providing less than full information on each of the product presentation and
`manufacturing schemes included in an application. This advance discussion can preclude
`expending time and effort in preparing an application that CDER or CBER might later
`determine to be incomplete.
`
`C.
`
`Additional Guidance
`
`This Drug Product guidance and the forthcoming drug substance guidance, when
`finalized, will be the primary content guidances for NDA and ANDA applicants. For
`quality, the general format guidance is M4Q: The CTD — Quality. These are the first
`guidances an applicant should consider when preparing the quality section (i.e.,
`chemistry, manufacturing, and controls) of an NDA or ANDA (Module 3).
`
`This guidance references ICH guidance documents cited in the CTD-Q and FDA’s
`guidances on general technical topics (i.e., stability, container closure systems, analytical
`procedures and methods validation, sterilization process validation, drug master files, and
`environmental assessments) rather than incorporating this detailed information. These
`guidances are referenced in the text and/or listed at the end of a section. An applicant
`should refer to these guidances for recommendations on the detailed information that
`should be included in the application to address the general technical topic.
`
`Finally, an applicant should consider guidances that are available for specific technical
`issues, dosage forms, or drug product types when preparing its NDA or ANDA. These
`guidances provide additional recommendations on unique scientific and technical aspects
`of the topic. Some references to these types of guidances are included in this guidance.
`However, the references are given only as examples, and the list is not meant to be all-
`inclusive. Some examples of these types of guidance are:
`
`• Nasal Spray and Inhalation Solution, Suspension, and Spray Drug Products
`
`• The Sourcing and Processing of Gelatin to Reduce the Potential Risk Posed by
`Bovine Spongiform Encephalopathy (BSE) in FDA-Regulated Products for Human
`Use
`
`• ANDAs: Impurities in Drug Products (under development)
`
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`• Submission of Chemistry, Manufacturing and Controls Information for a Therapeutic
`Recombinant DNA-Derived Product or a Monoclonal Antibody Product for In Vivo
`Use, CBER/CDER (under development)
`
`CDER and CBER continue to update existing and publish new guidance documents. An
`applicant should use current guidance when preparing an NDA or ANDA submission.
`Current guidance documents are available on the Internet at
`http://www.fda.gov/cder/guidance/index.htm and
`http://www.fda.gov/cber/guidelines.htm .
`
`D.
`
`Drug Master Files
`
`Under FDA's regulations, an application may incorporate by reference all or part of the
`contents of any drug master file (DMF) to address particular drug product issues if the
`DMF holder provides written authorization to the applicant and the authorization is
`included in the application (Module 1). The authorization must describe the incorporated
`material by name, reference number, volume and page number of the DMF (21 CFR
`314.420). See CDER’s Drug Master Files guidance for more information.
`
`E.
`
`Environmental Assessments
`
`All NDAs and ANDAs must include either an environmental assessment (EA) or claim
`of categorical exclusion from the requirement to provide an environmental assessment
`(21 CFR 25.15(a)). Although included in Module 1 of the CTD, this information is
`considered part of the chemistry, manufacturing, and controls documentation in the
`United States. Applicants should refer to 21 CFR part 25 and the guidance for industry
`Environmental Assessment of Human Drug and Biologics Applications for additional
`information on environmental assessments.
`
`III.
`
`DESCRIPTION AND COMPOSITION OF THE DRUG PRODUCT (P.1)
`
`A brief description of the dosage form and container closure system and a statement of the
`composition of the drug product should be provided.
`
`A.
`
`Description of Dosage Form8
`
`A brief description of the dosage form should be provided. For CDER products, the
`description should use standard dosage form terminology found in the CDER Data
`Standards Manual (http://www.fda.gov/cder/dsm).9
`
`
`8 Headings that are not followed by alphanumeric designations (i.e., non-CTD-Q headings) are included in this
`document for ease of providing recommendations on the information that should be included under a CTD-Q
`heading (in this instance Description and Composition of the Drug Product (P.1)). An application submitted in
`CTD-Q format need not include these non-CTD-Q headings. An applicant can physically or electronically separate
`information under a CTD-Q heading as it chooses. However, once a particular approach is adopted, the same
`approach should be used throughout the life of the application.
`
`6
`
` PFIZER, INC. v. NOVO NORDISK A/S - IPR2020-01252, Ex. 1029, p. 11 of 66
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`Draft — Not for Implementation
`
`B.
`
`Container Closure System
`
`A brief description of the container closure systems proposed for marketing should be
`provided. If an overfill (see section IV.B.1) is used, the amount of overfill in each
`container should be identified. Information on the suitability of the container closure
`systems should be provided in P.2.4. A full description of the container closure systems
`and their specifications should be provided in P.7.
`
`C.
`
`Composition Statement
`
`The composition statement describes the qualitative and quantitative formulation of the
`drug product intended for commercial distribution. The composition statement must
`contain a list of all components used in the manufacture of the drug product regardless of
`whether or not they appear in the finished drug product (21 CFR 314.50(d)(1)(ii)(a)).
`Furthermore, the statement should include: (1) reference to the quality standards used, (2)
`the function of the component, (3) the amount of the component on a per unit basis, (4)
`the total weight, volume or other appropriate measure of the unit, and (5) any explanatory
`notes.
`
`In some instances, the composition of distinct subformulations (e.g., cores, coating) of
`the drug product should be listed separately in the composition statement. For example,
`some modified release products (1) contain a mixture of immediate release and extended
`release beads within a capsule shell or (2) are formulated with the drug substance
`apportioned between a modified release core and an immediate release coating. In these
`cases, the composition of the immediate release and extended release portions of the drug
`product should be listed separately.
`
`Additional guidance on each element of the composition statement is provided below.
`An illustrative example of a composition statement is provided in Table 1.
`
`• Components
`
`Compon