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`
`83041
`
`evaluating the quality and reliability of
`information and data for use in
`developing the VADS system contents;
`(3) apply the principles of
`pharmacology in constructing
`therapeutic regimens for use when
`approved antimicrobial products are not
`effective as labeled; (4) design a
`relational database allowing a user to
`efficiently search the VADS system for
`label and extralabel regimens based on
`therapeutic applications, and to then
`review regulatory and food safety
`information applicable to these
`regimens; and (5) subject the VADS
`system content to review prior to release
`and then constantly upgrade the content
`on the basis of new information and
`review by users.
`II. Eligible Applicants
`Assistance may only be provided to
`Iowa State University because of the
`following:
`1. Iowa State University is the only
`organization that submitted an
`unsolicited application for the purpose
`stated above.
`2. The project proposed by the
`applicant is unique and innovative in
`that pharmacokinetic,
`pharmacodynamic, clinical trial, and
`pathogen susceptibility information will
`be interpreted by clinical
`pharmacologists and reviewed by other
`experts in the appropriate fields prior to
`inclusion in the system. Users may
`either use the information as provided
`or examine the transparent development
`process used in constructing the system.
`In addition, by compiling available
`information to support prudent
`antimicrobial use, the VADS system will
`emphasize what information is not
`available, thereby aiding researchers in
`targeting research goals.
`3. The team assembled to carry out
`the proposed work is uniquely qualified
`to achieve the goals of this application.
`Their combined experience
`encompasses practice in academic,
`general, and specialized production
`medicine settings as well as
`demonstrated competence in the
`application of clinical pharmacology
`and informatics in veterinary medicine.
`Support for the research team and the
`VADS system project has already been
`expressed in the form of start up
`funding provided by veterinary and
`producer organizations.
`III. Funding
`We anticipate that approximately
`$250,000 may be made available in
`fiscal year (FY) 2001 to support this
`project. If funded the award will begin
`sometime in FY 2001 and will be made
`for a 12-month budget period within a
`
`project period of up to 5 years. Funding
`estimates may change. Continuation
`awards within an approved project
`period will be made on the basis of
`satisfactory progress as evidenced by
`required reports and the availability of
`funds.
`Dated: December 22, 2000.
`Margaret M. Dotzel,
`Associate Commissioner for Policy.
`[FR Doc. 00–33372 Filed 12–28–01; 8:45 am]
`BILLING CODE: 4160–01–S
`
`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 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 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
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`
`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 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
`at http://www.fda.gov/cder/guidance/
`index.htm or at http://www.fda.gov/
`cber/publications.htm.
`The text of the guidance follows:
`
`Q6A Specifications: Test Procedures
`and Acceptance Criteria for New Drug
`Substances and New Drug Products:
`Chemical Substances 1
`
`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
`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
`
`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.
`
`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
`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
`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
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`83043
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`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, 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-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 product.
`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.
`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.
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`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 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 that the
`procedures and acceptance criteria from
`all three pharmacopeias are considered
`equivalent and are, therefore,
`interchangeable.
`Since the overall value of this
`guidance is linked to the extent of
`harmonization of the analytical
`procedures and acceptance criteria of
`the pharmacopeias, it is agreed by the
`members of the Q6A expert working
`group that none of the three
`pharmacopeias should change a
`harmonized monograph unilaterally.
`According to the PDG procedure for the
`revision of harmonized monographs and
`chapters, ‘‘no pharmacopoeia shall
`revise unilaterally any monograph or
`chapter after sign-off or after
`publication.’’
`2.9 Evolving Technologies
`New analytical technologies, and
`modifications to existing technology, are
`continually being developed. Such
`technologies should be used when they
`are considered to offer additional
`assurance of quality, or are otherwise
`justified.
`2.10 Impact of Drug Substance on Drug
`Product Specifications
`In general, it should not be necessary
`to test the drug product for quality
`attributes uniquely associated with the
`drug substance. Example: It is normally
`not considered necessary to test the
`drug product for synthesis impurities
`that are controlled in the drug substance
`and are not degradation products. Refer
`to the ICH guidance on ‘‘Q3B Impurities
`
`in New Drug Products’’ for detailed
`information.
`2.11 Reference Standard
`A reference standard, or reference
`material, is a substance prepared for use
`as the standard in an assay,
`identification, or purity test. It should
`have a quality appropriate to its use. It
`is often characterized and evaluated for
`its intended purpose by additional
`procedures other than those used in
`routine testing. For new drug substance
`reference standards intended for use in
`assays, the impurities should be
`adequately identified and/or controlled,
`and purity should be measured by a
`quantitative procedure.
`3. Guidance
`3.1 Specifications: Definition and
`Justification
`3.1.1 Definition of Specifications
`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 new drug substance or new 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 manufacturer and
`approved by regulatory authorities as
`conditions of approval.
`It is possible that, in addition to
`release tests, a specification may list in-
`process tests as defined in section 2.3,
`periodic or skip tests, and other tests
`that are not always conducted on a
`batch-by-batch basis. In such cases the
`applicant should specify which tests are
`routinely conducted batch by batch, and
`which tests are not, with an indication
`and justification of the actual testing
`frequency. In this situation, the drug
`substance and/or drug product should
`meet the acceptance criteria if tested.
`It should be noted that changes in the
`specification after approval of the
`application may need prior approval by
`the regulatory authority.
`3.1.2 Justification of Specifications
`When a specification is first proposed,
`justification should be presented for
`each procedure and each acceptance
`criterion included. The justification
`should refer to relevant development
`data, pharmacopeial standards, test data
`for drug substances and drug products
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`Federal Register / Vol. 65, No. 251 / Friday, December 29, 2000 / Notices
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`83045
`
`used in toxicology and clinical studies,
`and results from accelerated and long-
`term stability studies, as appropriate.
`Additionally, a reasonable range of
`expected analytical and manufacturing
`variability should be considered. It is
`important to consider all of this
`information.
`Approaches other than those set forth
`in this guidance may be applicable and
`acceptable. The applicant should justify
`alternative approaches. Such
`justification should be based on data
`derived from the new drug substance
`synthesis and/or the new drug product
`manufacturing process. This
`justification may consider theoretical
`tolerances for a given procedure or
`acceptance criterion, but the actual
`results obtained should form the
`primary basis for whatever approach is
`taken.
`Test results from stability and
`scaleup/validation batches, with
`emphasis on the primary stability
`batches, should be considered in setting
`and justifying specifications. If multiple
`manufacturing sites are planned, it may
`be valuable to consider data from these
`sites in establishing the initial tests and
`acceptance criteria. This is particularly
`true when there is limited initial
`experience with the manufacture of the
`drug substance or drug product at any
`particular site. If data from a single
`representative manufacturing site are
`used in setting tests and acceptance
`criteria, product manufactured at all
`sites should still comply with these
`criteria.
`Presentation of test results in graphic
`format may be helpful in justifying
`individual acceptance criteria,
`particularly for assay values and
`impurity levels. Data from development
`work should be included in such a
`presentation, along with stability data
`available for new drug substance or new
`drug product batches manufactured by
`the proposed commercial processes.
`Justification for proposing exclusion of
`a test from the specification should be
`based on development data and on
`process validation data (where
`appropriate).
`3.2 Universal Tests/Criteria
`Implementation of the
`recommendations in the following
`section should take into account the ICH
`guidances ‘‘Q2A Text on Validation of
`Analytical Procedures’’ and ‘‘Q2B
`Validation of Analytical Procedures:
`Methodology.’’
`3.2.1 New Drug Substances
`The following tests and acceptance
`criteria are considered generally
`applicable to all new drug substances.
`
`(a) Description: A qualitative
`statement about the state (e.g., solid,
`liquid) and color of the new drug
`substance. If any of these characteristics
`change during storage, this change
`should be investigated and appropriate
`action taken.
`(b) Identification: Identification
`testing should optimally be able to
`discriminate between compounds of
`closely related structure that are likely
`to be present. Identification tests should
`be specific for the new drug substance,
`e.g., infrared spectroscopy (IR).
`Identification solely by a single
`chromatographic retention time, for
`example, is not regarded as being
`specific. However, the use of two
`chromatographic procedures, where the
`separation is based on different
`principles or a combination of tests into
`a single procedure, such as HPLC (high-
`pressure liquid chromatography)/UV
`(ultraviolet) diode array, HPLC/MS
`(mass spectroscopy), or GC (gas
`chromatography)/MS is generally
`acceptable. If the new drug substance is
`a salt, identification testing should be
`specific for the individual ions. An
`identification test that is specific for the
`salt itself should suffice.
`New drug substances that are
`optically active may also need specific
`identification testing or performance of
`a chiral assay. Please refer to section
`3.3.1(d) in this guidance for further
`discussion of this topic.
`(c) Assay: A specific, stability-
`indicating procedure should be
`included to determine the content of the
`new drug substance. In many cases it is
`possible to employ the same procedure
`(e.g., HPLC) for both assay of the new
`drug substance and quantitation of
`impurities.
`In cases where use of a nonspecific
`assay is justified, other supporting
`analytical procedures should be used to
`achieve overall specificity. For example,
`where titration is adopted to assay the
`drug substance, the combination of the
`assay and a suitable test for impurities
`should be used.
`(d) Impurities: Organic and inorganic
`impurities and residual solvents are
`included in this category. Refer to the
`ICH guidances on ‘‘Q3A Impurities in
`New Drug Substances’’ and ‘‘Q3C
`Impurities: Residual Solvents’’ for
`det