INTERNATIONAL CONFERENCE ON HARMONISATION OF TECHNICAL
`REQUIREMENTS FOR REGISTRATION OF PHARMACEUTICALS FOR HUMAN
`USE
`
`
`
`ICH HARMONISED TRIPARTITE GUIDELINE
`
`SPECIFICATIONS: TEST PROCEDURES AND ACCEPTANCE CRITERIA
`FOR NEW DRUG SUBSTANCES AND NEW DRUG PRODUCTS:
`CHEMICAL SUBSTANCES
`Q6A
`
`
`
`
`
`
`
`Current Step 4 version
`dated 6 October 1999
`
`
`
`
`This Guideline has been developed by the appropriate ICH Expert Working Group and
`has been subject to consultation by the regulatory parties, in accordance with the ICH
`Process. At Step 4 of the Process the final draft is recommended for adoption to the
`regulatory bodies of the European Union, Japan and USA.
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`Q6A
`Document History
`
`History
`
`
`
`First
`Codification
`
`Q6A
`
`Approval by the Steering Committee under Step 2
`and release for public consultation.
`
`New
`Codification
`November
`2005
`
`Q6A
`
`Date
`
`18
`July
`1997
`
`Q6A
`
`Current Step 4 version
`Approval by the Steering Committee under Step 4 and
`recommendation
`for adoption to the three ICH
`regulatory bodies.
`
`6
`October
`1999
`
`Q6A
`
`
`
`
`
`
`
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`SPECIFICATIONS: TEST PROCEDURES AND ACCEPTANCE CRITERIA
`FOR NEW DRUG SUBSTANCES AND NEW DRUG PRODUCTS:
`CHEMICAL SUBSTANCES
`
`ICH Harmonised Tripartite Guideline
`Having reached Step 4 of the ICH Process at the ICH Steering Committee meeting
`on 6 October 1999, this guideline is recommended for
`adoption to the three regulatory parties to ICH
`
`
`TABLE OF CONTENTS
`
`1. INTRODUCTION ...................................................................................................... 1
`1.1
`Objective of the Guideline .............................................................................. 1
`1.2
`Background ..................................................................................................... 1
`1.3
`Scope of the Guideline .................................................................................... 1
`
`
`2. GENERAL CONCEPTS ........................................................................................... 2
`2.1
`Periodic or Skip Testing ................................................................................. 2
`2.2
`Release vs. Shelf-life Acceptance Criteria ..................................................... 2
`2.3
`In-process Tests .............................................................................................. 3
`2.4
`Design and Development Considerations ..................................................... 3
`2.5
`Limited Data Available at Filing ................................................................... 3
`2.6
`Parametric Release ......................................................................................... 4
`2.7
`Alternative Procedures ................................................................................... 4
`2.8
`Pharmacopoeial Tests and Acceptance Criteria ........................................... 4
`2.9
`Evolving Technologies .................................................................................... 5
`2.10
`Impact of Drug Substance on Drug Product Specifications ......................... 5
`2.11 Reference Standard ........................................................................................ 5
`
`
`3. GUIDELINES ............................................................................................................ 5
`3.1
`Specifications: Definition and Justification .................................................. 5
`Definition of Specifications ............................................................. 5
`3.1.1
`3.1.2
`Justification of Specifications ......................................................... 6
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`Specifications: New Chemical Drug Substances and Products
`
`
`
`3.2 Universal Tests / Criteria .............................................................................. 6
`New Drug Substances .................................................................... 6
`3.2.1
`3.2.2
`New Drug Products ........................................................................ 7
`Specific Tests / Criteria .................................................................................. 8
`New Drug Substances .................................................................... 8
`3.3.1
`3.3.2
`New Drug Products ...................................................................... 10
`
`3.3
`
`
`4. GLOSSARY .............................................................................................................. 18
`
`5. REFERENCES ........................................................................................................ 20
`
`6. ATTACHMENTS .................................................................................................... 20
`
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`SPECIFICATIONS: TEST PROCEDURES AND ACCEPTANCE CRITERIA
`FOR NEW DRUG SUBSTANCES AND NEW DRUG PRODUCTS:
`CHEMICAL SUBSTANCES
`
`
`1. INTRODUCTION
`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.
`
`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.
`
`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
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`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.
`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.
`
`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.
`
`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.
`
`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
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`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.
`
`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.
`
`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)).
`
`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
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`possible modification. This could involve loosening, as well as tightening, acceptance
`criteria as appropriate.
`
`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 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.
`
`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.
`
`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.
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`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.”
`
`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 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.
`
`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. 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.
`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).
`
`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.
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`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.
`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)
`
`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.
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`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 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)
`
`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