9/6/2019
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`Q6A Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances | …
`
`GUIDANCE DOCUMENT
`Q6A Specications: Test Procedures and Acceptance Criteria for New
`Drug Substances and New Drug Products: Chemical Substances
`DECEMBER 2000
`
`Final
`
`Issued by:
`(/regulatory-information/search-fda-guidance-documents/q6a-specications-test-procedures-and-acceptance-criteria-new-drug-
`substances-and-new-drug-products)
`Center for Drug Evaluation and Research
`
`[Federal Register: December 29, 2000 (Volume 65, Number 251)]
`
`[Notices]
`
`[Page 83041-83063]
`
`From the Federal Register Online via GPO Access [wais.access.gpo.gov]
`
`[DOCID:fr29de00-84]
`
`-----------------------------------------------------------------------
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`Food and Drug Administration
`
`[Docket No. 97D-0448]
`
`International Conference on Harmonisation; Guidance on Q6A
`
`Specifications: Test Procedures and Acceptance Criteria for New Drug
`
`Substances and New Drug Products: Chemical Substances
`
`AGENCY: Food and Drug Administration, HHS.
`
`ACTION: Notice.
`
`-----------------------------------------------------------------------
`
`SUMMARY: The Food and Drug Administration (FDA) is publishing a
`
`guidance entitled ``Q6A Specifications: Test Procedures and Acceptance
`
`Criteria for New Drug Substances and New Drug Products: Chemical
`
`Substances.'' The guidance was prepared under the auspices of the
`
`International Conference on Harmonisation of Technical Requirements for
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`Registration of Pharmaceuticals for Human Use (ICH). The guidance
`
`describes or provides recommendations concerning the selection of test
`
`procedures and the setting and justification of acceptance criteria for
`
`new chemical drug substances and new drug products produced from them.
`
`The guidance is intended to assist in the establishment of a single set
`
`of global specifications for new drug substances and new drug products.
`
`DATES: Submit written comments by March 29, 2001.
`
`ADDRESSES: Submit written comments on the guidance to the Dockets
`
`Management Branch (HFA-305), Food and Drug Administration, 5630 Fishers
`
`Lane, rm. 1061, Rockville, MD 20852. Copies of the guidance are
`
`available from the Drug Information Branch (HFD-210), Center for Drug
`
`Evaluation and Research, Food and Drug Administration, 5600 Fishers
`
`Lane, Rockville, MD 20857, 301-827-4573.
`
`FOR FURTHER INFORMATION CONTACT:
`
` Regarding the guidance: Eric B. Sheinin, Center for Drug Evaluation
`
`and Research (HFD-003), Food and Drug Administration, 5600 Fishers
`
`Lane, Rockville, MD 20857, 301-594-2847, or Neil D. Goldman, Center for
`
`Biologics Evaluation and Research (HFM-20), Food and Drug
`
`Administration, 1401 Rockville Pike, Rockville, MD 20852, 301-827-0377.
`
` Regarding the ICH: Janet J. Showalter, Office of Health Affairs
`
`(HFY-20), Food and Drug Administration, 5600 Fishers Lane, Rockville,
`
`MD 20857, 301-827-0864.
`
`SUPPLEMENTARY INFORMATION: In recent years, many important initiatives
`
`have been undertaken by regulatory authorities and industry
`
`associations to promote international harmonization of regulatory
`
`requirements. FDA has participated in many meetings designed to enhance
`
`harmonization and is committed to seeking scientifically based
`
`harmonized technical procedures for pharmaceutical development. One of
`
`the goals of harmonization is to identify and then reduce differences
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`in technical requirements for drug development among regulatory
`
`agencies.
`
` ICH was organized to provide an opportunity for tripartite
`
`harmonization initiatives to be developed with input from both
`
`regulatory and industry representatives. FDA also seeks input from
`
`consumer representatives and others. ICH is concerned with
`
`harmonization of technical requirements for the registration of
`
`pharmaceutical products among three regions: The European Union, Japan,
`
`and the United States. The six ICH sponsors are the European
`
`Commission, the European Federation of Pharmaceutical Industries
`
`Associations, the Japanese Ministry of Health and Welfare, the Japanese
`
`Pharmaceutical Manufacturers Association, the Centers for Drug
`
`Evaluation and Research and Biologics Evaluation and Research, FDA, and
`
`the Pharmaceutical Research and Manufacturers of America. The ICH
`
`Secretariat, which coordinates the preparation of documentation, is
`
`provided by the International Federation of Pharmaceutical
`
`Manufacturers Associations (IFPMA).
`
` The ICH Steering Committee includes representatives from each of
`
`the ICH sponsors and the IFPMA, as well as observers from the World
`
`Health Organization, the Canadian Health Protection Branch, and the
`
`European Free Trade Area.
`
` In the Federal Register of November 25, 1997 (62 FR 62890), FDA
`
`published a draft tripartite guidance entitled ``Q6A Specifications:
`
`Test Procedures and
`
`[Page 83042]
`
`Acceptance Criteria for New Drug Substances and New Drug Products:
`
`Chemical Substances.'' The notice gave interested persons an
`
`opportunity to submit comments by January 26, 1998.
`
` After consideration of the comments received and revisions to the
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`guidance, a final draft of the guidance was submitted to the ICH
`
`Steering Committee and endorsed by the three participating regulatory
`
`agencies on October 6, 1999.
`
` In accordance with FDA's good guidance practices regulation (65 FR
`
`56468, September 19, 2000), this document has been designated a
`
`guidance, rather than a guideline.
`
` The guidance provides recommendations on the selection of test
`
`procedures and the setting and justification of acceptance criteria for
`
`new drug substances of synthetic chemical origin, and new drug products
`
`produced from them, that have not been registered previously in the
`
`United States, the European Union, or Japan. This guidance is intended
`
`to assist in the establishment of a single set of global specifications
`
`for new drug substances and new drug products.
`
` This guidance represents the agency's current thinking on the
`
`selection of tests procedures and the setting and justification of
`
`acceptance criteria for new chemical drug substances and new drug
`
`products. 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.
`
` Interested persons may submit to the Dockets Management Branch
`
`(address above) written comments on the guidance at any time. Two
`
`copies of any comments are to be submitted, except that individuals may
`
`submit one copy. Comments are to be identified with the docket number
`
`found in brackets in the heading of this document. The guidance and
`
`received comments may be seen in the Dockets Management Branch between
`
`9 a.m. and 4 p.m., Monday through Friday. An electronic version of this
`
`guidance is available on the Internet.
`
` The text of the guidance follows:
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`Q6A Specifications: Test Procedures and Acceptance Criteria for New
`
`Drug Substances and New Drug Products: Chemical Substances \1\
`
`---------------------------------------------------------------------------
`
` \1\ This guidance represents the Food and Drug Administration'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.
`
`Table of Contents
`
`1. Introduction
`
` 1.1 Objective of the Guidance
`
` 1.2 Background
`
` 1.3 Scope of the Guidance
`
`2. General Concepts
`
` 2.1 Periodic or Skip Testing
`
` 2.2 Release vs. Shelf-Life Acceptance Criteria
`
` 2.3 In-Process Tests
`
` 2.4 Design and Development Considerations
`
` 2.5 Limited Data Available at Filing
`
` 2.6 Parametric Release
`
` 2.7 Alternative Procedures
`
` 2.8 Pharmacopeial Tests and Acceptance Criteria
`
` 2.9 Evolving Technologies
`
` 2.10 Impact of Drug Substance on Drug Product Specifications
`
` 2.11 Reference Standard
`
`3. Guidance
`
` 3.1 Specifications: Definition and Justification
`
` 3.1.1 Definition of Specifications
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` 3.1.2 Justification of Specifications
`
` 3.2 Universal Tests/Criteria
`
` 3.2.1 New Drug Substances
`
` 3.2.2 New Drug Products
`
` 3.3 Specific Tests/Criteria
`
` 3.3.1 New Drug Substances
`
` 3.3.2 New Drug Products
`
`4. Glossary
`
`5. References
`
`6. Attachments: Decision Trees #1 Through #8
`
`1. Introduction
`
`1.1 Objective of the Guidance
`
` This guidance is intended to assist, to the extent possible, in the
`
`establishment of a single set of global specifications for new drug
`
`substances and new drug products. It provides guidance on the setting
`
`and justification of acceptance criteria and the selection of test
`
`procedures for new drug substances of synthetic chemical origin, and
`
`new drug products produced from them, that have not been registered
`
`previously in the United States, the European Union, or Japan.
`
`1.2 Background
`
` A specification is defined as a list of tests, references to
`
`analytical procedures, and appropriate acceptance criteria that are
`
`numerical limits, ranges, or other criteria for the tests described. It
`
`establishes the set of criteria to which a drug substance or drug
`
`product should conform to be considered acceptable for its intended
`
`use. ``Conformance to specifications'' means that the drug substance
`
`and/or drug product, when tested according to the listed analytical
`
`procedures, will meet the listed acceptance criteria. Specifications
`
`are critical quality standards that are proposed and justified by the
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`manufacturer and approved by regulatory authorities as conditions of
`
`approval.
`
` Specifications are one part of a total control strategy for the
`
`drug substance and drug product designed to ensure product quality and
`
`consistency. Other parts of this strategy include thorough product
`
`characterization during development, upon which specifications are
`
`based, and adherence to good manufacturing practices (GMP's), e.g.,
`
`suitable facilities, a validated manufacturing process, validated test
`
`procedures, raw materials testing, in-process testing, stability
`
`testing.
`
` Specifications are chosen to confirm the quality of the drug
`
`substance and drug product rather than to establish full
`
`characterization, and should focus on those characteristics found to be
`
`useful in ensuring the safety and efficacy of the drug substance and
`
`drug product.
`
`1.3 Scope of the Guidance
`
` The quality of drug substances and drug products is determined by
`
`their design, development, in-process controls, GMP controls, process
`
`validation, and by specifications applied to them throughout
`
`development and manufacture. This guidance addresses specifications,
`
`i.e., those tests, procedures, and acceptance criteria that play a
`
`major role in assuring the quality of the new drug substance and new
`
`drug product at release and during shelf life. Specifications are an
`
`important component of quality assurance, but are not its only
`
`component. All of the factors listed above are considered necessary to
`
`ensure consistent production of drug substances and drug products of
`
`high quality.
`
` This guidance addresses only the marketing approval of new drug
`
`products (including combination products) and, where applicable, new
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`drug substances; it does not address drug substances or drug products
`
`during the clinical research stages of drug development. This guidance
`
`may be applicable to synthetic and semisynthetic antibiotics and
`
`synthetic peptides of low molecular weight; however, it is not
`
`sufficient to
`
`[Page 83043]
`
`adequately describe specifications of higher molecular weight peptides
`
`and polypeptides, and biotechnological/biological products. The ICH
`
`guidance on ``Q6B Specifications: Test Procedures and Acceptance
`
`Criteria for Biotechnological/Biological Products'' addresses guidance
`
`specifications, tests, and procedures for biotechnological/biological
`
`products. Radiopharmaceuticals, products of fermentation,
`
`oligonucleotides, herbal products, and crude products of animal or
`
`plant origin are similarly not covered.
`
` Guidance is provided with regard to acceptance criteria that should
`
`be established for all new drug substances and new drug products, i.e.,
`
`universal acceptance criteria, and those that are considered specific
`
`to individual drug substances and/or dosage forms. This guidance should
`
`not be considered all encompassing. New analytical technologies, and
`
`modifications to existing technology, are continually being developed.
`
`Such technologies should be used when justified.
`
` Dosage forms addressed in this guidance include solid oral dosage
`
`forms, liquid oral dosage forms, and parenterals (small and large
`
`volume). This is not meant to be an all-inclusive list, or to limit the
`
`number of dosage forms to which this guidance applies. The dosage forms
`
`presented serve as models that may be applicable to other dosage forms
`
`that have not been discussed. The extended application of the concepts
`
`in this guidance to other dosage forms, e.g., to inhalation dosage
`
`forms (powders, solutions, etc.), to topical formulations (creams,
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`ointments, gels), and to transdermal systems, is encouraged.
`
`2. General Concepts
`
` The following concepts are important in the development and setting
`
`of harmonized specifications. They are not universally applicable, but
`
`each should be considered in particular circumstances. This guidance
`
`presents a brief definition of each concept and an indication of the
`
`circumstances under which it may be applicable. Generally, proposals to
`
`implement these concepts should be justified by the applicant and
`
`approved by the appropriate regulatory authority before being put into
`
`effect.
`
`2.1 Periodic or Skip Testing
`
` Periodic or skip testing is the performance of specified tests at
`
`release on preselected batches and/or at predetermined intervals,
`
`rather than on a batch-by-batch basis, with the understanding that
`
`those batches not being tested still meet all acceptance criteria
`
`established for that product. This represents a less than full schedule
`
`of testing and should therefore be justified and presented to and
`
`approved by the regulatory authority prior to implementation. This
`
`concept may be applicable to, for example, residual solvents and
`
`microbiological testing for solid oral dosage forms. It is recognized
`
`that only limited data may be available at the time of submission of an
`
`application (see section 2.5). This concept should therefore generally
`
`be implemented postapproval. When tested, any failure to meet
`
`acceptance criteria established for the periodic test should be handled
`
`by proper notification of the appropriate regulatory authority(ies). If
`
`these data demonstrate a need to restore routine testing, then batch-
`
`by-batch release testing should be reinstated.
`
`2.2 Release vs. Shelf-Life Acceptance Criteria
`
` The concept of different acceptance criteria for release vs. shelf-
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`life specifications applies to drug products only; it pertains to the
`
`establishment of more restrictive criteria for the release of a drug
`
`product than are applied to the shelf life. Examples where this may be
`
`applicable include assay and impurity (degradation product) levels. In
`
`Japan and the United States, this concept may only be applicable to in-
`
`house criteria, and not to the regulatory release criteria. Thus, in
`
`these regions, the regulatory acceptance criteria are the same from
`
`release throughout shelf life; however, an applicant may choose to have
`
`tighter in-house limits at the time of release to provide increased
`
`assurance to the applicant that the product will remain within the
`
`regulatory acceptance criteria throughout its shelf life. In the
`
`European Union there is a regulatory requirement for distinct
`
`specifications for release and for shelf life where different.
`
`2.3 In-Process Tests
`
` In-process tests, as presented in this guidance, are tests that may
`
`be performed during the manufacture of either the drug substance or
`
`drug product, rather than as part of the formal battery of tests that
`
`are conducted prior to release.
`
` In-process tests that are only used for the purpose of adjusting
`
`process parameters within an operating range, e.g., hardness and
`
`friability of tablet cores that will be coated and individual tablet
`
`weights, are not included in the specification.
`
` Certain tests conducted during the manufacturing process, where the
`
`acceptance criterion is identical to or tighter than the release
`
`requirement, (e.g., pH (hydrogen-ion concentration) of a solution) may
`
`be sufficient to satisfy specification requirements when the test is
`
`included in the specification. However, this approach should be
`
`validated to show that test results or product performance
`
`characteristics do not change from the in-process stage to finished
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`product.
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`Q6A Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances | …
`
`2.4 Design and Development Considerations
`
` The experience and data accumulated during the development of a new
`
`drug substance or product should form the basis for the setting of
`
`specifications. It may be possible to propose excluding or replacing
`
`certain tests on this basis. Some examples are:
`
` Microbiological testing for drug substances and solid
`
`dosage forms that have been shown during development not to support
`
`microbial viability or growth (see Decision Trees #6 and #8).
`
` Extractables from product containers where it has been
`
`reproducibly shown that either no extractables are found in the drug
`
`product or the levels meet accepted standards for safety.
`
` Particle size testing may fall into this category, may be
`
`performed as an in-process test, or may be performed as a release test,
`
`depending on its relevance to product performance.
`
` Dissolution testing for immediate release solid oral drug
`
`products made from highly water soluble drug substances may be replaced
`
`by disintegration testing, if these products have been demonstrated
`
`during development to have consistently rapid drug release
`
`characteristics (see Decision Trees #7(1) through #7(2)).
`
`2.5 Limited Data Available at Filing
`
` It is recognized that only a limited amount of data may be
`
`available at the time of filing, which can influence the process of
`
`setting acceptance criteria. As a result, it may be necessary to
`
`propose revised acceptance criteria as additional experience is gained
`
`with the manufacture of a particular drug substance or drug product
`
`(example: acceptance limits for a specific impurity). The basis for the
`
`acceptance criteria at the time of filing should necessarily focus on
`
`safety and efficacy.
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` When only limited data are available, the initially approved tests
`
`and acceptance criteria should be reviewed as more information is
`
`collected, with a view towards possible modification. This could
`
`involve loosening, as well as tightening, acceptance criteria, as
`
`appropriate.
`
`[Page 83044]
`
`2.6 Parametric Release
`
` Parametric release can be used as an operational alternative to
`
`routine release testing for the drug product in certain cases, when
`
`approved by the regulatory authority. Sterility testing for terminally
`
`sterilized drug products is one example. In this case, the release of
`
`each batch is based on satisfactory results from monitoring specific
`
`parameters, e.g., temperature, pressure, and time during the terminal
`
`sterilization phase(s) of drug product manufacturing. These parameters
`
`can generally be more accurately controlled and measured, so they are
`
`more reliable in predicting sterility assurance than is end-product
`
`sterility testing. Appropriate laboratory tests (e.g., chemical or
`
`physical indicator) may be included in the parametric release program.
`
`It is important to note that the sterilization process should be
`
`adequately validated before parametric release is proposed, and
`
`maintenance of a validated state should be demonstrated by revalidation
`
`at established intervals. When parametric release is performed, the
`
`attribute that is indirectly controlled (e.g., sterility), together
`
`with a reference to the associated test procedure, still should be
`
`included in the specifications.
`
`2.7 Alternative Procedures
`
` Alternative procedures are those that may be used to measure an
`
`attribute when such procedures control the quality of the drug
`
`substance or drug product to an extent that is comparable or superior
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`to the official procedure. Example: For tablets that have been shown
`
`not to degrade during manufacture, it may be permissible to use a
`
`spectrophotometric procedure for release as opposed to the official
`
`procedure, which is chromatographic. However, the chromatographic
`
`procedure should still be used to demonstrate compliance with the
`
`acceptance criteria during the shelf life of the product.
`
`2.8 Pharmacopeial Tests and Acceptance Criteria
`
` References to certain procedures are found in pharmacopeias in each
`
`region. Wherever they are appropriate, pharmacopeial procedures should
`
`be used. Whereas differences in pharmacopeial procedures and/or
`
`acceptance criteria have existed among the regions, a harmonized
`
`specification is possible only if the procedures and acceptance
`
`criteria defined are acceptable to regulatory authorities in all
`
`regions.
`
` The full utility of this guidance is dependent on the successful
`
`completion of harmonization of pharmacopeial procedures for several
`
`attributes commonly considered in the specification for new drug
`
`substances or new drug products. The Pharmacopoeial Discussion Group
`
`(PDG) of the European Pharmacopeia, the Japanese Pharmacopoeia (JP),
`
`and the United States Pharmacopeia has expressed a commitment to
`
`achieving harmonization of the procedures in a timely fashion.
`
` Where harmonization has been achieved, an appropriate reference to
`
`the harmonized procedure and acceptance criteria is considered
`
`acceptable for a specification in all three regions. For example, after
`
`harmonization, sterility data generated using the JP procedure, as well
`
`as the JP procedure itself and its acceptance criteria, will be
`
`considered acceptable for registration in all three regions. To signify
`
`the harmonized status of these procedures, the pharmacopeias have
`
`agreed to include a statement in their respective texts that indicates
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`that the procedures and acceptance criteria from all three
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`pharmacopeias are considered equivalent and are, therefore,
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`interchangeable.
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` Since the overall value of this guidance is linked to the extent of
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`harmonization of the analytical procedures and acceptance criteria of
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`the pharmacopeias, it is agreed by the members of the Q6A expert
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`working group that none of the three pharmacopeias should change a
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`harmonized monograph unilaterally. According to the PDG procedure for
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`the revision of harmonized monographs and chapters, ``no pharmacopoeia
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`shall revise unilaterally any monograph or chapter after sign-off or
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`after publication.''
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`2.9 Evolving Technologies
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` New analytical technologies, and modifications to existing
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`technology, are continually being developed. Such technologies should
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`be used when they are considered to offer additional assurance of
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`quality, or are otherwise justified.
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`2.10 Impact of Drug Substance on Drug Product Specifications
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` In general, it should not be necessary to test the drug product for
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`quality attributes uniquely associated with the drug substance.
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`Example: It is normally not considered necessary to test the drug
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`product for synthesis impurities that are controlled in the drug
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`substance and are not degradation products. Refer to the ICH guidance
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`on ``Q3B Impurities in New Drug Products'' for detailed information.
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`2.11 Reference Standard
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` A reference standard, or reference material, is a substance
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`prepared for use as the standard in an assay, identification, or purity
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`test. It should have a quality appropriate to its use. It is often
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`characterized and evaluated for its intended purpose by additional
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`procedures other than those used in routine testing. For new drug
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`substance reference standards intended for use in assays, the
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`impurities should be adequately identified and/or controlled, and
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`purity should be measured by a quantitative procedure.
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`3. Guidance
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`3.1 Specifications: Definition and Justification
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`3.1.1 Definition of Specifications
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` A specification is defined as a list of tests, references to
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`analytical procedures, and appropriate acceptance criteria that are
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`numerical limits, ranges, or other criteria for the tests described. It
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`establishes the set of criteria to which a new drug substance or new
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`drug product should conform to be considered acceptable for its
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`intended use. ``Conformance to specifications'' means that the drug
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`substance and/or drug product, when tested according to the listed
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`analytical procedures, will meet the listed acceptance criteria.
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`Specifications are critical quality standards that are proposed and
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`justified by the manufacturer and approved by regulatory authorities as
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`conditions of approval.
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` It is possible that, in addition to release tests, a specification
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`may list in-process tests as defined in section 2.3, periodic or skip
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`tests, and other tests that are not always conducted on a batch-by-
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`batch basis. In such cases the applicant should specify which tests are
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`routinely conducted batch by batch, and which tests are not, with an
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`indication and justification of the actual testing frequency. In this
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`situation, the drug substance and/or drug product should meet the
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`acceptance criteria if tested.
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` It should be noted that changes in the specification after approval
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`of the application may need prior approval by the regulatory authority.
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`3.1.2 Justification of Specifications
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` When a specification is first proposed, justification should be
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`presented for each procedure and each acceptance criterion included.
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`The justification should refer to relevant development data,
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`pharmacopeial standards, test data for drug substances and drug
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`products
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`[Page 83045]
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`used in toxicology and clinical studies, and results from accelerated
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`and long-term stability studies, as appropriate. Additionally, a
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`reasonable range of expected analytical and manufacturing variability
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`should be considered. It is important to consider all of this
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`information.
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` Approaches other than those set forth in this guidance may be
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`applicable and acceptable. The applicant should justify alternative
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`approaches. Such justification should be based on data derived from the
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`new drug substance synthesis and/or the new drug product manufacturing
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`process. This justification may consider theoretical tolerances for a
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`given procedure or acceptance criterion, but the actual results
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`obtained should form the primary basis for whatever approach is taken.
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` Test results from stability and scaleup/validation batches, with
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`emphasis on the primary stability batches, should be considered in
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`setting and justifying specifications. If multiple manufacturing sites
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`are planned, it may be valuable to consider data from these sites in
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`establishing the initial tests and acceptance criteria. This is
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`particularly true when there is limited initial experience with the
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`manufacture of the drug substance or drug product at any particular
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`site. If data from a single