Specification: Test procedure and acceptance criteria

ICH Q6(A) - Specification
Specifications: Test
procedure
and
Acceptance criteria

DEFINITION
 A list of tests, reference to analytical procedures, and acceptance criteria
(numerical limits, ranges or other specific criteria) to which an API or
FPP should conform to considered acceptable for its intended use.
 Confirm the predefined quality, rather than fully characterize the API or
the FPP
 Should focus on those characteristics found to be useful in ensuring the
safety and efficacy of the drug substance and drug product

OBJECTIVE
 To establish harmonized global specification for drug substance and
drug product.
 To provide the guidance on the selection of the test, setting the
acceptance criteria for them along with justification for same.
 To design and propose one part of total control strategy for the drug
substance and drug product to ensure product quality and consistency
and approved by regulatory authorities as conditions of approval .

ICH Q6- SPECIFICATION
Two guidelines addressing the selection of tests and methods and setting
specifications for quality control of API and finished products (chemicals
and biotechnologically derived proteins and polypeptides)

ICH Q6- SPECIFICATION
Q6A - For Chemical substances Q6B - For Biotechnological and biological
products
Applicability Chemically synthesized
• Drug subtance
• Drug products (including
combination products)
• Proteins and polypeptides produced from
recombinant
• proteins and polypeptides produced from non-
recombinant cell-culture expression systems,
their derivatives
• Products of which protein and polypeptides are
components (e.g., conjugates).
May be
applicable
• synthetic and semi-synthetic
antibiotics
• Low molecular weigh synthetic
peptides.
• Proteins and polypeptides isolated from tissues
and body fluids
Not Applicable • Drug substances or drug products
during the clinical research stages of
drug development.
• Antibiotics
• Synthetic peptides, polypeptides and Heparin
• Vitamins, cell metabolites.
• DNA products, allergenic extracts, conventional
vaccines, cells, whole blood, and cellular blood
components

GENERAL CONCEPT:
 Periodic or skip testing :
 Specified tests at release on pre-selected batches and/or at predetermined intervals, rather
than on a batch-to-batch on the basis of product understanding that those batches must
meet the acceptance criteria even if not tested.
 This concept should therefore generally be implemented post-approval.
 Example: Residual solvent and microbiological testing in case of solid oral dosage form.
 Release vs Shelf life acceptance criteria:
 Applicant may choose to have tighter in-house limits at the time of release to provide
increased assurance within the regulatory acceptance criterion throughout its shelf-life.
 In Japan and the US, the regulatory acceptance criteria are the same from release
throughout shelf-life whereas in EU, there is a regulatory requirement for distinct
specifications for release and for shelf-life.

GENERAL CONCEPT:
 In-process Tests:
 Performed during the manufacture of either the drug substance or drug product.
 used for the purpose of adjusting process parameters within an operating range.
 Example: Hardness, friability of core tablet in case of coated tablet.
 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

GENERAL CONCEPT:
 Design and Development Considerations :
 Basis for the setting of specification to propose inclusion and exclusion of the certain
testing during the in-process, release and shelf life.
 Experience and data accumulated during development.
 Scientific consideration by thorough understanding of the manufacturing process of DS and DP.
 Universal test and product specific test considering the region specific regulatory requirement.
 Examples:
 Microbiological testing for drug substances and solid dosage forms which have been shown
during development not to support microbial viability or growth. Refer Decision tree# 6 and 8.
 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.
Refer Decision tree # 7(1) and 7(2).

GENERAL CONCEPT:
 Limited Data Available at Filing:
 Limited amount of data may be available at the time of filing, which can influence the
process of setting acceptance criteria.
 Initially approved tests and acceptance criteria should be reviewed as more information is
collected, with a view towards possible modifications (loosening as well as tightening of
the acceptance criteria)
 The basis for the acceptance criteria at the time of filing should necessarily focus on safety
and efficacy.

GENERAL CONCEPT:
 Parametric release:
 An operational alternative to routine release testing for the drug product in certain cases
when approved by the regulatory authority .
 Example: Sterility testing for terminally sterilized drug products. 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
 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.

GENERAL CONCEPT:
 Alternative procedures 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: use a spectrophotometric procedure for assay during release as opposed to the official
procedure, which is chromatographic method. However the chromatographic procedure should
still be used to demonstrate compliance with the acceptance criteria during the shelf-life of the
product.
 Pharmacopoeial procedures should be utilized wherever found appropriate.
 New analytical technologies, and modifications to existing technology should be used
when they are considered to offer additional assurance of quality, or are otherwise justified.
 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 ICH Q3B

JUSTIFICATION OF SPECIFICATION:
 Justification should be presented for each procedure and each acceptance criterion included
in the specification considering following aspects.
 Product development data
 Pharmacopoeial standards
 Test data for drug substances and drug products used in toxicology and clinical studies.
 Results from accelerated and long term stability studies.
 A reasonable range of expected analytical and manufacturing variability
 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

JUSTIFICATION OF SPECIFICATION:
 Test results from stability and scale-up / validation batches, with emphasis on the primary
stability batches, should be considered in setting and justifying specifications.
 It may be valuable to consider data from multiple sites in establishing the initial tests and
acceptance criteria in case of multiple sites are planned.
 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.
 Justification for proposing exclusion of a test from the specification should be based on
development data and on process validation data (where appropriate)

UNIVERSAL TESTS/CRITERIA (FOR DS AND DP)
Following test and criteria applicable to all drug substance and drug product.
 Description/Appearance – state, colon, size, shape
 Identification
 Must be specific for drug substance (e.g., Infrared spectroscopy)
 Identification solely by a single chromatographic retention time is not considered as specific.
 Combination of tests, such as HPLC/UV diode array, HPLC/MS, or GC/MS is generally acceptable .
 Identification testing should be specific for the individual ions, in case of DS is salt.
 Specific identification testing or performance of a chiral isomer required in case of optically active DS.
 Assay
 Specific, stability-indicating procedure to determine the potency/strength.
 Use of a non-specific assay method should be justified using other explored analytical procedures to demonstrate
overall specificity.
 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.

UNIVERSAL TESTS/CRITERIA (FOR DS AND DP)
 Impurities (Organic, inorganic, residual solvent and elements)
 Organic and inorganic impurities and residual solvents are included in the drug substance.(Q3A,C and D)
 Organic and inorganic impurities (degradation products) and residual solvents are included in the drug
product.(Q3B)
 Organic impurities arising from degradation of the DS and impurities that arise during the manufacturing process
for the drug product should be monitored in the new drug product.
 Process impurities from the new drug substance synthesis are not included in total impurities.
 Specific, stability-indicating procedure must be used.
 Degradation product testing may be reduced or eliminated upon approval by the regulatory authorities, in case of
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.
 Reporting of the impurities should be inline to ICH Q3 guidance.
 ICH Q6 decision tree #1 for establishing the impurity limit in drug substance.
 ICH Q6 decision tree #2 for establishing the impurity limit in drug product.

SPECIFIC TESTS/CRITERIA – DRUG SUBSTANCE :
 Solubility:
 Qualitative solubility should be part of specification.
 BCS solubility should be known for the drug product development.
 Particle size
 Particle size distribution should be carried out using an appropriate procedure, and acceptance criteria should be
provided incase Particle size of drug substance can have a significant effect on dissolution rates, bioavailability,
and / or stability.
 ICH Q6 Decision tree # 3 for additional guidance on when PSD should be considered.
 Polymorphism
 Polymorphism should be investigated. If polymorphism is a factor, a test is required in specs
 ICH Q6 decision tree #4 for guidance on when, and how, polymorphic forms should be monitored and
controlled.
 A surrogate test can generally used to monitor product performance as technically it is difficult to measure
polymorphic changes in the drug product.
 Polymorph content should only be used as a test and acceptance criterion of last resort

 Physicochemical properties
 Physical nature of the new drug substance and by its intended use (i.e. pH, melting point / range, and refractive
index)
 Procedures usually unique and do not need much elaboration.
 Water content
 Important in cases of hygroscopic substance or degraded by moisture or known to be a stoichiometric hydrate.
 Acceptance criteria may be justified with data on the effects of hydration or moisture absorption.
 Loss on Drying procedure may be considered adequate; however, a detection procedure that is specific for water
(e.g., Karl Fischer titration) is preferred.
 Inorganic impurities ,elements
 Need for inclusion of organic impurities to evaluated based on the knowledge of manufacturing process.
 ICH Q3D to be taken in to consideration for elemental impurities.

 Test for chiral drug substances:
 Chiral isomers should be considered in the same manner as for other impurities.
 An enantioselective determination of the drug substance should be part of the specification (e.g. Chiral assay or
Achiral assay and other appropriate control of enantiomeric impurity)
 A stereospecific identity test is not generally needed in the drug product release specification when racemization
is insignificant during process and storage.
 ICH Decision Tree# 5 for when and if chiral identity tests, impurity tests, and assays may be needed for both new
drug substances and new drug products.
 Microbial Limits:
 Microbiological testing for drug substances and solid dosage forms which have been shown during development
not to support microbial viability or growth.
 ICH Decision tree #6 for microbiological quality attributes of drug substance and excipient.
 ICH Decision tree #8 for microbial attributes of non-sterile drug products

SPECIFIC TESTS/CRITERIA – DRUG PRODUCT :
 Performance test (e.g. dissolution, disintegration test)
 Uniformity of dosage units – Mass, content uniformity, fill volume
 Physical test – LOD/Water, pH, friability, hardness, particle size
 Preservative content
 Microbial contamination
 Sterility, bacterial endotoxins, particulate matter

SPECIFIC TESTS/CRITERIA – DRUG PRODUCT : DISSOLUTION
 In-vitro release of active from drug product.
 Dissolution test is product specific. Method and limit should be appropriate for proposed drug product.
 Release and shelf-life specification should be identical.
 Single-point measurements for IR dosage forms, two-stages for DR dosage forms, multiple time point testing for
extended-release dosage forms.
 Acceptance criteria should be set to reject batches with unacceptable bioavailability, in case of affects on
bioavailability
 In vitro / in vivo correlation may be used to establish acceptance criteria, if BA data available for different release
rate.
 Permitted variability in mean release rate at any given time point should not exceed a total numerical difference of
+/-10% of the labeled content of drug substance unless wider range supported by BE study.
 Develop test conditions which can distinguish batches with unacceptable bioavailability, where changes in
dissolution rate have been demonstrated to significantly affect bioavailability .
 Appropriate to adopt dissolution test conditions which can distinguish changes in formulation or process variables
in case of changes are not controlled by another aspect of the specification.
 ICH decision tree # 7 For setting acceptance criteria for drug product dissolution.

SPECIFIC TESTS/CRITERIA – DRUG PRODUCT : DISINTEGRATION
 May be acceptance for DT in place of dissolution:
 Rapidly dissolving product containing high soluble drugs
 Supported via development data
 Relationship to dissolution has been established
 Disintegration is shown to be more discriminating than dissolution
 Robustness of the formulation and manufacturing process with respect to the selection of dissolution
vs. disintegration testing

UNIVERSAL TESTS/CRITERIA:
 Test results from stability and scale-up / validation batches, with emphasis on the primary
stability batches, should be considered in setting and justifying specifications.

 Microbial limits:
 Control of the other enantiomer should be considered in the same manner as for other impurities.
 An enantioselective determination of the drug substance should be part of the specification. considered
acceptable for this to be achieved either through use of a chiral assay procedure or by the combination of an
achiral assay together with appropriate methods of controlling the enantiomeric impurity.
 Control of the other enantiomer in a drug product is considered necessary unless racemization has been shown to
be insignificant during manufacture of the dosage form, and on storage.
 A stereospecific identity test is not generally needed in the drug product release specification when racemization
is insignificant during process and storage.
 Refer Decision Tree#5 for when and if chiral identity tests, impurity tests, and assays may be needed for both new
drug substances and new drug products.
 Inorganic impurities:
 Need for inclusion of organic impurities to evaluated based on the knowledge of manufacturing process.
 ICH Q3D to be taken in to consideration for elemental impurities.

DEFINITION:
 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.
 A specification 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 instead of complete
characterisation.
 Specifications are critical quality standards that are proposed and justified by the
manufacturer and approved by regulatory authorities as conditions of approval.
 Changes in the specification after approval of the application may need prior approval by the
regulatory authority.
 Focused on the specific characteristics requires to ensure safety and efficacy of the DS and DP.

GENERAL CONCEPT
 Periodic/Skip testing:
 Specified tests at release on pre-selected batches and / or at predetermined intervals, rather than on a batch-to-batch.(e.g. residual solvents and microbiological
testing, for solid oral dosage forms)
 Only one batch testing required if product is clearly Photostable or Photolabile.
 Additional two batches testing required if results are equivocal.
 If immediate pack is completely impenetrable to light, such as aluminium tubes or cans, testing should only be conducted on directly
exposed drug product.
 It may be appropriate to test certain products such as infusion liquids, dermal creams, etc., to support their photostability in-use. The
extent of this testing should depend on and relate to the directions for use, and is left to the applicant’s discretion.
 The samples should be positioned to provide maximum area of exposure to the light source. For example, tablets, capsules, etc.,
should be spread in a single layer.
 A 2 per cent weight/volume aqueous solution of quinine monohydrochloride dihydrate is use for calibrating ultraviolet radiation
intensity in light-stability testing of pharmaceuticals.
 If direct exposure is not practical (e.g., due to oxidation of a product), the sample should be placed in a suitable protective inert
transparent container (e.g., quartz).
 Depending on the extent of change special labeling or packaging may be needed to mitigate exposure to light. c

DECISION TREE#1 (ESTABLISHING ACCEPTANCE CRITERION FOR SPECIFIED IMPURITY IN DRUG SUBSTANCE)

DECISION TREE#2 (ESTABLISHING ACCEPTANCE CRITERION FOR SPECIFIED IMPURITY IN DRUG PRODUCT)

DECISION TREE#3 SETTING ACCEPTANCE CRITERION FOR PARTICLE SIZE DISTRIBUTION IN DRUG SUBSTANCE)

DECISION TREE#4(1) INVESTIGATING THE NEED TO SET ACCEPTANCE CRITERIA FOR POLYMORPHISM IN DS AND DP.

DECISION TREE#5 ESTABLISHING NVESTIGATING THE NEED TO SET ACCEPTANCE CRITERIA FOR POLYMORPHISM IN DS
AND DP.

Specification: Test procedure and acceptance criteria

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