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`European Medicines Agency
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`May 2000
`CPMP/ICH/367/96
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`II
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`ICH Topic Q 6 A
`Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and
`New Drug Products: Chemical Substances
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`II
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`Step 5
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`NOTE FOR GUIDANCE SPECIFICATIONS: TEST PROCEDURES AND
`ACCEPTANCE CRITERIA FOR NEW DRUG SUBSTANCES AND NEW DRUG
`PRODUCTS: CHEMICAL SUBSTANCES
`(CPMP/ICH/367/96)
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` TRANSMISSION TO CPMP
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`TRANSMISSION TO INTERESTED PARTIES
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`DEADLINE FOR COMMENTS
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`FINAL APPROVAL BY CPMP
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`DATE FOR COMING INTO OPERATION
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`September 1997
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`September 1997
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`March 1998
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`November 1999
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`May 2000
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`7 Westferry Circus, Canary Wharf, London, E14 4HB, UK
`Tel. (44-20) 74 18 85 75 Fax (44-20) 75 23 70 40
`E-mail: mail@emea.eu.int http://www.emea.eu.int
`EMEA 2006 Reproduction and/or distribu ion of this document is authorised for non commercial purposes only provided the EMEA is acknowledged
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`SPECIFICATIONS: TEST PROCEDURES AND ACCEPTANCE CRITERIA FOR
`NEW DRUG SUBSTANCES AND NEW DRUG PRODUCTS: CHEMICAL
`SUBSTANCES
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`TABLE OF CONTENTS
`TRANSMISSION TO INTERESTED PARTIES....................................................................1
`1.
`INTRODUCTION.........................................................................................................3
`1.1 OBJECTIVE OF THE GUIDELINE........................................................................................3
`1.2 BACKGROUND................................................................................................................3
`1.3 SCOPE OF THE GUIDELINE...............................................................................................3
`2. GENERAL CONCEPTS...............................................................................................4
`2.1. PERIODIC OR SKIP TESTING.............................................................................................4
`2.2. RELEASE VS. SHELF-LIFE ACCEPTANCE CRITERIA ...........................................................4
`IN-PROCESS TESTS ..........................................................................................................5
`2.3
`2.4. DESIGN AND DEVELOPMENT CONSIDERATIONS...............................................................5
`2.5. LIMITED DATA AVAILABLE AT FILING.............................................................................5
`2.6 PARAMETRIC RELEASE ...................................................................................................5
`2.7 ALTERNATIVE PROCEDURES...........................................................................................6
`2.8 PHARMACOPOEIAL TESTS AND ACCEPTANCE CRITERIA ..................................................6
`2.9 EVOLVING TECHNOLOGIES .............................................................................................6
`IMPACT OF DRUG SUBSTANCE ON DRUG PRODUCT SPECIFICATIONS.............................7
`2.10
`2.11
` REFERENCE STANDARD .................................................................................................7
`3. GUIDELINES ...............................................................................................................7
`3.1 SPECIFICATIONS: DEFINITION AND JUSTIFICATION .........................................................7
`3.1.1. DEFINITION OF SPECIFICATIONS......................................................................................7
`3.1.2. JUSTIFICATION OF SPECIFICATIONS.................................................................................7
`3.2 UNIVERSAL TESTS/CRITERIA ..........................................................................................8
`3.2.1. NEW DRUG SUBSTANCES ................................................................................................8
`3.2.2. NEW DRUG PRODUCTS ....................................................................................................9
`3.3 SPECIFIC TESTS/CRITERIA .................................................................................................10
`3.3.1. NEW DRUG SUBSTANCES ..............................................................................................10
`3.3.2. NEW DRUG PRODUCTS ..................................................................................................12
`4. GLOSSARY (THE FOLLOWING DEFINITIONS ARE PRESENTED FOR THE
`PURPOSE OF THIS GUIDELINE) .....................................................................................19
`5. REFERENCES ...............................................................................................................21
`6. ATTACHMENTS: DECISION TREES #1 THROUGH #8.......................................21
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`1.
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`INTRODUCTION
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`1.1 Objective of the guideline
`This guideline 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, which have not been registered previously in the United States, the European Union, or
`Japan.
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`1.2 Background
`A specification is defined as a list of tests, references to analytical procedures, and appropriate
`acceptance criteria, which 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 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; e.g., suitable facilities, a validated
`manufacturing process, validated test procedure, raw material testing, in-process testing,
`stability testing, etc.
`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.
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`1.3 Scope of the guideline
`The quality of drug substances and drug products is determined by their design, development,
`in-process controls, GMP controls, and process validation, and by specifications applied to
`them throughout development and manufacture. This guideline addresses specifications, i.e.,
`those tests, procedures, and acceptance criteria which 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 considerations listed above are necessary to ensure consistent
`production of drug substances and drug products of high quality.
`This guideline 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
`guideline may be applicable to synthetic and semi-synthetic antibiotics and synthetic peptides
`of low molecular weight; however, it is not sufficient to adequately describe specifications of
`higher molecular weight peptides and polypeptides, and biotechnological/biological products.
`The ICH Guideline Specifications: Test Procedures and Acceptance Criteria for
`Biotechnological/Biological Products addresses guideline 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.
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`Guidance is provided with regard to acceptance criteria which 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 guideline
`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 guideline 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 guideline applies. The dosage forms
`presented serve as models, which may be applicable to other dosage forms which have not
`been discussed. The extended application of the concepts in this guideline 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.
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`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 guideline 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.
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`2.1. Periodic or skip testing
`Periodic or skip testing is the performance of specified tests at release on pre-selected batches
`and / or at predetermined intervals, rather than on a batch-to-batch basis with the
`understanding that those batches not being tested still must 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 post-approval. 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.
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`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 criterion throughout its shelf-life. In the European Union there is a
`regulatory requirement for distinct specifications for release and for shelf-life where different.
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`2.3 In-process tests
`In-process tests, as presented in this guideline, are tests which may be performed during the
`manufacture of either the drug substance or drug product, rather than as part of the formal
`battery of tests which are conducted prior to release.
`In-process tests which are only used for the purpose of adjusting process parameters within an
`operating range, e.g., hardness and friability of tablet cores which 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 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.
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`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 which 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)).
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`•
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`•
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`•
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`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,
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`and time during the terminal sterilization phase(s) of drug product manufacturing. These
`parameters can generally be more accurately controlled and measured, so that 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 which is indirectly controlled (e.g., sterility), together with a reference to the
`associated test procedure, still should be included in the specifications.
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`2.7 Alternative procedures
`Alternative procedures are those which 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.
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`2.8 Pharmacopoeial tests and acceptance criteria
`References to certain procedures are found in pharmacopoeias in each region. Wherever they
`are appropriate, pharmacopoeial procedures should be utilized. Whereas differences in
`pharmacopoeial 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 Guideline is dependent on the successful completion of harmonization
`of pharmacopoeial 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 Pharmacopoeia, the Japanese Pharmacopoeia, 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, are considered acceptable for
`registration in all three regions. To signify the harmonized status of these procedures, the
`pharmacopoeias have agreed to include a statement in their respective texts which indicates
`that the procedures and acceptance criteria from all three pharmacopoeias are considered
`equivalent and are, therefore, interchangeable.
`Since the overall value of this Guideline is linked to the extent of harmonization of the
`analytical procedures and acceptance criteria of the pharmacopoeias, it is agreed by the
`members of the Q6A expert working group that none of the three pharmacopoeias 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.”
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`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.
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`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 which are controlled in the drug substance and are
`not degradation products. Refer to the ICH Guideline Impurities in New Drug Products for
`detailed information.
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`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.
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`3. GUIDELINES
`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 which 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 2.3, periodic (skip) tests, and other tests which 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.
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`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, pharmacopoeial standards, test data for drug substances and drug products 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 guideline 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.
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`Test results from stability and scale-up / 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).
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`3.2 Universal tests/criteria
`Implementation of the recommendations in the following section should take into account the
`ICH Guidelines Text on Validation of Analytical Procedures and 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 which are likely to be present. Identification tests
`should be specific for the new drug substance, e.g., infrared spectroscopy. 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/UV
`diode array, HPLC/MS, or GC/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 which are optically active may also need specific identification testing
`or performance of a chiral assay. Please refer to 3.3.1.d) in this Guideline 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 non-specific 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 Guidelines Impurities in New Drug Substances and Residual
`Solvents in Pharmaceuticals for detailed information.
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`Decision tree #1 addresses the extrapolation of meaningful limits on impurities from the body
`of data generated during development. At the time of filing it is unlikely that sufficient data
`will be available to assess process consistency. Therefore it is considered inappropriate to
`establish acceptance criteria which tightly encompass the batch data at the time of filing. (see
`section 2.5)
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`3.2.2. New drug products
`The following tests and acceptance criteria are considered generally applicable to all new drug
`products:
`a) Description: A qualitative description of the dosage form should be provided (e.g., size,
`shape, and color). If any of these characteristics change during manufacture or storage, this
`change should be investigated and appropriate action taken. The acceptance criteria should
`include the final acceptable appearance. If color changes during storage, a quantitative
`procedure may be appropriate.
`b) Identification: Identification testing should establish the identity of the new drug
`substance(s) in the new drug product and should be able to discriminate between compounds
`of closely related structure which are likely to be present. Identity tests should be specific for
`the new drug substance, e.g., infrared spectroscopy. 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 combination of tests into a single procedure, such as HPLC/UV diode array, HPLC/MS, or
`GC/MS, is generally acceptable.
`c) Assay: A specific, stability-indicating assay to determine strength (content) should be
`included for all new drug products. 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. Results
`of content uniformity testing for new drug products can be used for quantitation of drug
`product strength, if the methods used for content uniformity are also appropriate as assays.
`In cases where use of a non-specific 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 for release, the combination of the assay and a suitable test for impurities
`can be used. A specific procedure should be used when there is evidence of excipient
`interference with the non-specific assay.
`d) Impurities: Organic and inorganic impurities (degradation products) and residual solvents
`are included in this category. Refer to the ICH Guidelines Impurities in New Drug Products
`and Residual Solvents for detailed information.
`Organic impurities arising from degradation of the new drug substance and impurities that
`arise during the manufacturing process for the drug product should be monitored in the new
`drug product. Acceptance limits should be stated for individual specified degradation
`products, which may include both identified and unidentified degradation products as
`appropriate, and total degradation products. Process impurities from the new drug substance
`synthesis are normally controlled during drug substance testing, and therefore are not included
`in the total impurities limit. However, when a synthesis impurity is also a degradation
`product, its level should be monitored and included in the total degradation product limit.
`When it has been conclusively demonstrated via appropriate analytical methodology, that the
`drug substance does not degrade in the specific formulation, and under the specific storage
`conditions proposed in the new drug application, degradation product testing may be reduced
`or eliminated upon approval by the regulatory authorities.
`Decision tree #2 addresses the extrapolation of meaningful limits on degradation products
`from the body of data generated during development. At the time of filing it is unlikely that
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`sufficient data will be available to assess process consistency. Therefore it is considered
`inappropriate to establish acceptance criteria which tightly encompass the batch data at the
`time of filing. (see section 2.5)
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`3.3 Specific tests/criteria
`In addition to the universal tests listed above, the following tests may be considered on a case
`by case basis for drug substances and/or drug products. Individual tests/criteria should be
`included in the specification when the tests have an impact on the quality of the drug
`substance and drug product for batch control. Tests other than those listed below may be
`needed in particular situations or as new information becomes available.
`3.3.1. New drug substances
`a) Physicochemical properties: These are properties such as pH of an aqueous solution,
`melting point / range, and refractive index. The procedures used for the measurement of these
`properties are usually unique and do not need much elaboration, e.g., capillary melting point,
`Abbé refractometry. The tests performed in this category should be determined by the
`physical nature of the new drug substance and by its intended use.
`b) Particle size: For some new drug substances intended for use in solid or suspension drug
`products, particle size can have a significant effect on dissolution rates, bioavailability, and /
`or stability. In such instances, testing for particle size distribution should be carried out using
`an appropriate procedure, and acceptance criteria should be provided.
`Decision tree #3 pro