Quality Workshop Copenhagen – January 2012

1. Quality WorkshopCopenhagen – January 2012 Assessing specifications: API

2. Outline Compendial versus in-house standards: ● When compendial standard is claimed ● When in-house standard is claimed ● When compendial methods are used ● When in-house methods are used but compendial standard is claimed

3. Outline ● Specific parameters in brief ● Unnecessary tests in specifications ● Exceptions to full testing (reduced testing, retesting, skip testing) ● Example specifications exercise ● Review tips

4. Specifications • The set of criteria to which an API should conform to be considered acceptable for its intended use. • A list of tests, reference to analytical procedures, and acceptance criteria (numerical limits, ranges or other criteria) • Confirm the quality, rather than fully characterize, the API [ICH Q6A]

5. Officially recognized pharmacopoeia • PhInt, USP, BP, EP, JP are recognized standards in PQP PhInt S2 available as CD-ROM or on-line

6. Compendial Standards • Other compendia which may be referenced for information: WHO Index of pharmacopoeias (next page) Korean Pharmacopoeia now added to the list of freely available pharmacopoeia (Argentina removed as was up for comment only.)

7. Pharmacopoeias With Free Access

8. Validation, verification, equivalency, SST(assay and purity methods) • Validation: full validation required for in-house methods (impurities, assay, residual solvents), generally specificity, linearity, accuracy, repeatability, intermediate precision, plus for purity: LOD/LOQ. • Verification: required for most compendial methods • Equivalency: required for an in-house method, when compendial standard is claimed • SST: part of methodology, parameters determined via robustness; tested every time the method is run to ensure adequate performance

9. When compendial standard is claimed 1. Generally, the monograph tests and limits should be adopted. 2. The monograph is the minimum standard; the authority can impose additional requirements (e.g. ICH IT for individual unspecified impurities) 3. All monograph methods, tests and limits need not be included in specifications. (may use in-house methods, provide justification for not including certain parameters) But…The product must comply with the monograph, if tested (see equivalence testing).

10. When compendial standard is claimed • BP “Official Standards” and EP “General Statements”: An article is not of pharmacopoeial quality unless it meets all monograph requirements. However, performance of all tests is not necessarily required to assess compliance before release. Assurance of pharmacopoeial quality may instead be obtained from validation studies of the manufacturing process and from IPCs.

11. When in-house standard is claimed 1. Generally, the tightest available monograph limits for assay and purity should be adopted (assay) or justified (specified impurities). • Exception: monograph titration vs in-house HPLC assay Available monographs can still be used as as a general guideline for requirements

12. When compendial methods are claimed…(purity and assay methods) • Ensure they have really adopted the method as is. If not: • Check the deviations against published accepted deviations: • USP <621> Chromatography • EP 2.2.46 Chromatographic separation techniques • Note that there are specific SST RSD limits for EP and USP methods. If these methods are adopted, so should be the SST requirements.

13. When compendial methods are adopted Full validation is not required, but verification data is required: The compendial methods as published are typically validated based on an API originating from a specific manufacturer. Different sources of the same API can contain impurities and/or degradation products that were not considered during the development of the monograph. Therefore the monograph and compendial method should be demonstrated suitable to control the impurity profile of the API from the intended source(s).

14. When compendial methods are adopted(purity and assay) Verification data: • Assay method: generally not required for API assay methods but may require specificity if additional (to the monograph) impurities are specified • Impurity method: full validation for any additional (to the monograph) specified impurities. If there is no monograph limit on individual unknowns (or it is higher than the IT/acceptable limit), repeatability of the API at the limit for unknowns (or LOQ of API) should be established.

15. Compendial standard claimed, but in-house method used • Full validation is required for an in-house purity/assay method. • In addition, if compendial standard is claimed, equivalence must be demonstrated compared to the compendial method (assay: assaying aliquots of the same samples using the two methods; impurities: as above, spiking samples with specified impurities at the limits) • If they can not demonstrate this, they may claim in-house standard but not compendial standard • Note that a compendial method becomes an in-house method when adjustments are made outside the allowable adjustments

16. Specification Parameters The solubility of the API is the most important API CQA. For BCS low solubility APIs (DSV > 250 mL): • Polymorphism and particle size distribution are critical parameters, and must be representative of the biolot characteristics. • Polymorphism should be investigated. If no data is found in a literature search, the applicant should perform screening studies. If polymorphism is a factor, a test is required in specs. • PSD limits (d10, d50, d90) are required in the API specs, based on the results of the lot used in biostudies.

17. Specification Parameters Polymorphism Q: A common oversight: polymorphism has been found to be a critical parameter. The API specs include an XRD comparison to reference standard (RS). What else needs to be considered for this test to be sufficient? A: Before the RS lot serves as reference for polymorphism, it needs to be ascertained that the polymorphic form of the RS lot (or at least the primary standard, against which in-house standards are qualified) is the same as that of the lot in the biobatch.

18. Specification Parameters Assay and Related Compounds • Assay: may be tested using a non-specific method, e.g. titration, but need to achieve overall specificity, e.g. non-specific assay plus suitable impurity test. • Related compounds: need limits on specified (identified and unidentified*), unspecified (individual unknowns) and total impurities. Limits must be suitably qualified. *specified unidentified = structurally unidentified. It is identified in the specs by means of e.g. RT. The specifications should have a key identifying impurities.

19. Specification parametersRelated compounds Qualification of limits: adopt limit  QT, or qualify: • If a limit refers to a significant metabolite, it is considered qualified (confirm it is a metabolite, e.g. WHOPAR, EPAR, SmPC). • Level used in safety studies and/or clinical studies (ICH Q3A) • Literature i.e. ORP limits for specified related compounds are considered qualified; an unspecified/unknown limit in a monograph is not qualified. • Limit is similar to levels found in unstressed innovator product.

20. Specification Parameters Residual Solvents • ICH Q3C limits are acceptable. • When EtOH, MeOH, toluene or acetone are used (especially last two steps), benzene may be present (often used as an azeotropic agent to remove water). A limit should be included in specs (API or intermediate) unless shown to be absent. In PQP, this may be conditionally included in specs eg as a skip test, to be re-established in case of (for e.g.) change in supplier.

21. Specification Parameters Identification Identification should be specific to the API, i.e. should be able to discriminate between compounds of closely related structure (Q6A) Identification tests in pharmacopoeia sometimes gives clues as to whether polymorphism may be a factor for the API (sample prep).

22. Specification Parameters Identification Caution regarding pharmacopoeial identity testing: First and second identification: • “Second identification” is intended only for pharmacies and only under certain circumstances (API is fully traceable to a batch certified to meet all other monograph requirements). • Issue: if “2nd id” tests are allowed in specifications as the routine tests for an API, when they do periodic/reduced testing where they test a batch only for identification, they will be using non-specific testing.

23. Specification Parameters Identification When the API is present as a salt, the salt moiety must be included in the specifications: Example identity test: (e.g. abacavir (as sulfate) PhInt): A 10 mg/ml solution yields reaction A described under2.1 General identification tests, as characteristic of sulfates. Example identity test: (e.g. bupropion HCl USP): IDENTIFICATION TESTS—GENERAL,CHLORIDE 191 : Meets the requirements for the silver nitrate precipitate test

24. Specification Parameters Identification • The applicant’s API specifications for bupropion HCl don’t include the chloride identification. What to check for before posing the question? • Check if specs include an assay of the salt. Example content of chloride: Not less than 12.6% and not more than 13.1% of chloride, calculated on the anhydrous basis [Physical method, USP monograph]. Generally acceptable to have identification or assay.

25. “Minor” Tests • ROI (USP)/Sulfated Ash (EP/BP): • The Residue on Ignition/Sulfated Ash test measures the amount of residual substance (usually inorg imps in an org substance) not volatilized from a sample when the sample is ignited in the presence of sulfuric acid. • Not universally required, should be looked at case-by-case, e.g. an inorganic reagent (e.g. NaBH4) was used to prepare the API • When required (above), compendial limits can be accepted (usually 0.1%).

26. “Minor” tests Heavy Metalsvs a specific test for a residual metal: Substances that typically will respond to this test are lead, mercury, bismuth, arsenic, antimony, tin, cadmium, silver, copper, and molybdenum. But it is not specific to any of these metals. In the case of environmental contamination through exposure to reaction vessels etc, this risk exists for almost all API preparations and every API specification should include a test for heavy metal content, even if the monograph does not specify one. Generally NMT 10 ppm (insoluble API) or 20 ppm (soluble API).

27. “Minor” tests Heavy Metals vs a specific test for a residual metal: • Where a specific metal is used in the manufacturing process (e.g. as catalyst), EMA guidance on the control of metal residues of specific metals should be followed • Note that ICH Q3D is also under development (now at step 1) Special cases: organo tin compounds – watch for this with valsartan, losartan (tetrazole group)

28. “Minor” tests Water versus LOD • LOD is adequate to control class 3 residual solvents (if NMT 0.5%) • Water (KF) is specific to the determination of water.

29. Unnecessary tests in specifications • Solubility – critical to know this about the API, but not necessary in specs • Characters or Characteristics items in a EP/BP monograph appearance (description is an important parameter, but the appearance need not be exactly as in the monograph)  e.g. solubility, decomposition point, odour, melting point polymorphism may be stated for information only, e.g. “it shows polymorphism”; whether a test is necessary depends on API solubility

30. Exceptions to full testing • Reduced testing – test results taken from the API manufacturer’s COA Generally not accepted but there are situations where this may be acceptable. • Retesting parameters • Skip testing In all cases, the API should meet the full specifications if tested. Note: specific tests may also be contracted out, but the contract test site(s) must be GMP compliant

31. Example specifications • See separate handout. Full result slides will be provided after the workshop.

32. Review tips • Focus review time on the important elements:  Low solubility APIs: PSD, polymorphism All APIs: assay, purity, residual solvents • When reviewing method validation, the validation protocol is of much less importance than the validation study results • Ensure the API specs you review for the dossier are those of the FPP manufacturer (particularly when the API supplier and FPP manufacturer are from the same corporate structure but different sites)

33. Review tips • Updated specs should always be compared to the previous version submitted, or at minimum the change history should be reviewed. The result of the comparison must be in the report, with a discussion of the acceptability of any solicited and unsolicited changes.

34. Thank you