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Q6 guidelines

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Brief explanation of ICH Q6 guideline

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Q6 guidelines

  2. 2. Quality Q6 Guidelines can be categorized into two sections Q6A Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances Q6B Specifications: Test Procedures and Acceptance Criteria for Biotechnological/Biological products
  3. 3. 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.
  4. 4. GENERAL CONCEPTS 1. Periodic or Skip Testing 2. Release vs. Shelf-life Acceptance Criteria 3. In-process Tests 4. Design and Development Considerations 5. Limited Data Available at Filing 6. Parametric Release 7. Alternative Procedures 8.Pharmacopoeial Tests and Acceptance Criteria 9. Evolving Technologies 10. Impact of Drug Substance on Drug Product Specifications 11. Reference Standard
  5. 5. 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 concept may be applicable to, for example, residual solvents and microbiological testing, for solid oral dosage forms. 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.
  6. 6. In-process Tests 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. 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 ,particle size testing
  7. 7. 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. 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. 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.
  8. 8. 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. Pharmacopoeial Tests and Acceptance Criteria References to certain procedures are found in pharmacopoeias in each region.
  9. 9. 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. 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.
  10. 10. 1. Specifications: Definition and Justification 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.
  11. 11. 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. 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. Presentation of test results in graphic format may be helpful in justifying individual acceptance criteria, particularly for assay values and impurity levels.
  12. 12. 2. Universal Tests / Criteria 2.1 New Drug Substances The following tests and acceptance criteria are considered generally applicable to all new drug substances. a) Identification: eg; IR , HPLC , HPTLC , GC ,GC/MS etc. b) Description: properties like color , odour , state, etc. can be determined c) Assay: content uniformity d) Impurities : organic & inorganic impurites ,residual solvents 2.2 New Drug Products 3. Specific Tests / Criteria 3.1 New Drug Substances a) Physicochemical properties: pH of an aqueous solution, melting point / range, and refractive index
  13. 13. b) Particle size: solid or suspension drug products c) Polymorphic form : Polymorphism may also include solvation or hydration products (also known as pseudopolymorphs) and amorphous forms. Differences in these forms could, in some cases, affect the quality or performance of the new drug products. Physicochemical measurements and techniques are commonly used to determine whether multiple forms exist. Examples of these procedures are: melting point (including hot-stage microscopy), solid state IR, X-ray powder diffraction, thermal analysis procedures (like DSC, TGA and DTA), Raman spectroscopy, optical microscopy, and solid state NMR.
  14. 14. d) Tests for chiral new drug substances: identity tests, impurity tests, and assays may be needed for both new drug substances and new drug products, according to the following concepts:  Drug Substance :1. Impurities 2. Assay 3. Identity  Drug Product: 1. Degradation products 2. Assay 3. Identity e) Water content: This test is important in cases where the new drug substance is known to be hygroscopic or degraded by moisture. e.g., Karl Fischer titration
  15. 15. f) Inorganic impurities: may be determined by other appropriate procedures, e.g., atomic absorption spectroscopy. g) Microbial limits: There may be a need to specify the total count of aerobic microorganism, the total count of yeasts and molds, and the absence of specific objectionable bacteria (e.g., Staphylococcus aureus, Escherichia coli, Salmonella, Pseudomonas aeruginosa). These should be suitably determined using pharmacopoeial procedures. 3.2 New Drug Products  3.2.1 The following tests are applicable to tablets (coated and uncoated) and hard capsules. One or more of these tests may also be applicable to soft capsules and granules. a) Dissolution b) Disintegration
  16. 16. c) Hardness/friability d) Uniformity of dosage units e) Water content f) Microbial limits 3.2.2 Oral liquids a) Uniformity of dosage units b) pH c) Microbial limits d) Antimicrobial preservative content e) Extractables: f) Alcohol content g) Dissolution h) Particle size distribution i) Redispersibility
  17. 17. j) Rheological properties k) Reconstitution time m)Water content 3.2.3 Parenteral Drug Products a) Uniformity of dosage units b) pH c) Sterility d) Endotoxins/Pyrogens e) Particulate matter f) Water content g) Antimicrobial preservative content h) Extractables i) Antioxidant preservative content
  18. 18. j) Functionality testing of delivery systems k) Osmolarity l) Particle size distribution m) Redispersibility n) Reconstitution time
  19. 19. Objective This guidance document provides general principles on the setting and justification, to the extent possible, of a uniform set of international specifications for biotechnological and biological products to support new marketing applications. PRINCIPLES FOR CONSIDERATION IN SETTING SPECIFICATIONS 1. Characterization a) Physicochemical properties b) Biological activity
  20. 20. Examples of procedures used to measure biological activity include:  Animal-based biological assays, which measure an organism's biological response to the product;  Cell culture-based biological assays, which measure biochemical or physiological response at the cellular level;  Biochemical assays, which measure biological activities such as enzymatic reaction rates or biological responses induced by immunological interactions. c) Immunochemical properties e.g., ELISA, Western-blot
  21. 21. d) Purity, impurities and contaminants e) Quantity 2. Analytical Considerations 2.1 Reference standards and reference materials 2.2 Validation of analytical procedures 3. Process Controls 3.1 Process-related considerations Adequate design of a process and knowledge of its capability are part of the strategy used to develop a manufacturing process which is controlled and reproducible, yielding a drug substance or drug product that meets specifications.
  22. 22. 3.2 In-process acceptance criteria and action limits The results of in-process testing may be recorded as action limits or reported as acceptance criteria. Performing such testing may eliminate the need for testing of the drug substance or drug product. 3.3 Raw materials and excipient specifications The quality of the raw materials used in the production of the drug substance (or drug product) should meet standards, appropriate for their intended use. The quality of the excipients used in the drug product formulation (and in some cases, in the drug substance), as well as the container/closure systems, should meet pharmacopoeial standards, where available and appropriate.
  23. 23. 3.4. Pharmacopoeial Specifications 3.5. Release Limits vs. Shelf-life Limits This concept pertains to the establishment of limits which are tighter for the release than for the shelf-life of the drug substance or drug product. Examples where this may be applicable include potency and degradation products. 3.6. Statistical Concepts Appropriate statistical analysis should be applied, when necessary, to quantitative data reported. 2. JUSTIFICATION OF THE SPECIFICATION The following points should be taken into consideration when establishing scientifically justifiable specifications.  Specifications are linked to a manufacturing process.  Specifications should account for the stability of drug substance and drug product.
  24. 24.  Specifications are linked to preclinical and clinical studies.  Specifications are linked to analytical procedures.  Specifications should account for the stability of drug substance and drug product. 3. SPECIFICATIONS 3.1 Drug Substance Specification Generally, the following tests and acceptance criteria are considered applicable to all drug substances o Appearance and description o Identity o Purity and impurities o Potency o Quantity
  25. 25. 3.2 Drug Product Specification Generally, the following tests and acceptance criteria are considered applicable to all drug products. o Appearance and description o Identity o Purity and impurities o Potency o Quantity o General tests o Additional testing for unique dosage forms
  26. 26. THANKYOU