Quality Workshop Copenhagen – January 2012

1. Quality WorkshopCopenhagen – January 2012 Assessing specifications: FPP (solid orals)

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 ● Example specifications exercise ● Review tips

4. Specifications  • The set of criteria to which a FPP 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) [ICH Q6A] • Confirm the quality, rather than fully characterize, the FPP

5. Specifications • Specifications should include, at minimum, tests for appearance, identification, assay, purity, performance tests (e.g. dissolution), physical tests (e.g. loss on drying, hardness, friability, particle size), uniformity of dosage units, and as applicable, identification and assay of antimicrobial or chemical preservatives (e.g. antioxidants) and microbial limit tests. • Several guidelines outline tests in addition to those in Q6A, e.g. for other dosage forms:  New WHO PQP quality guideline P.5.1 • Other regulatory guidelines (e.g. HC, EMA) • Pharmacopoeia

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

7. Validation, verification, equivalency, SST(assay and purity methods)  • Validation: full validation required for in-house methods, generally specificity, linearity, accuracy, repeatability, intermediate precision, plus for purity: LOD/LOQ. • Verification: required for most compendialmethods • 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 NB: CU and dissolution are assay methods, residual solvents (organic granulating solvents) is a purity method

8. 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 additionalrequirements (e.g. ICH IT for individual unspecified related compounds) 3. All monograph tests/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 equivalency testing).

9. 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.

10. When in-house standard is claimed  • Generally, the tightest available monograph limits for assay and purity should be adopted (assay) or justified (specified related compounds). Justification is more difficult for the FPP because related compounds are mainly degradants in the monographs (but not always). 2. The available monographs can still be used as a general guideline for requirements

11. 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.

12. When compendial methods are adopted Verification data is required: The compendial methods as published are typically validated based on an API or an FPP originating from a specific manufacturer. Different sources of the same API or FPP 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). The FPP may also contain excipients not present in the FPP(s) for which the the compendial method was developed.

13. When compendial methods are adopted Verification data: Assay method: specificity, accuracy and repeatability (method precision). Related substances method: full validation for any additional (to the monograph) specified related substances and absence of interference from placebo; 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 (usually 0.2%) should be established.

14. 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, equivalency must be demonstrated compared to the compendial method (assay: assaying aliquots of the same samples using the two methods; related compounds: as above, spiking samples with specified related compounds 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

15. Equivalency - note Equivalency is essentially two things: • Ensure the in-house method is not inferior (in which case they should adopt the compendial method) • Ensure the compendial test can be met, if applied. Two samples are sufficient.

16. Question Q: Compendial standard is claimed. The compendial monograph uses a TLC method. The in-house method is HPLC, which is an improvement over TLC. Is the applicant required to provide equivalency testing? A: Demonstrating “equivalency” per se is not so important, but the product must still pass the compendial tests if tested, or they must change to an in-house standard.

17. Example • USP standard claimed for FPP, in-house assay/degradation methods used, plus the USP degradation test is included in specs. • First assessor asks for equivalency data; 2nd says no with the following justification: a)“The in-house assay method is very similar to that of the USP method. The only differences are pH of the buffer soln (2.2 vs 3.3), ratio of the mobile phase to buffer (66:11 vs 88:12), and with respect to diluents used.” • b)“The applicant’s method is same as the draft PhInt (except w.r.t diluent) and has been sufficiently validated including specificity through forced degradation studies.”

18. Example Adjustment of method outside <621> (NMT 0.2 pH units, NMT 10% absolute change in MP%) Similarity to PhInt method is immaterial (plus a draft monograph is referenced)… USP standard is claimed. In this case equivalency is required for the assay method, but not for the degradation method. Why? In the specs the USP degradation method is applied as well as the in-house method. Equivalency is to demonstrate the monograph standards are met if tested. USP testing for degradants will be met.

19. Specification ParametersDescription Description: should be detailed (colour, shape, coating, markings (score, ink, embossing)) A complete description is also required to facilitate the visual identification of spurious/falsely-labelled/falsified/counterfeit (SFFC) medicines. FPPs for which taste is critical (especially paediatrics): dispersible, sublingual/buccal, soluble, effervescent, and chewable tablets, and powders and granules for dispersion/solution or to be used as sprinkles.

20. Specification ParametersDescription Palatability (including taste) should be demonstrated as part of pharmaceutical development. Taste may exceptionally be part of specs if an artificial taster is available. (Ideally would be in shelf-life specs). Descriptions in compendial monographs: “Statements given under this heading are not to be interpreted in a strict sense and are not to be regarded as analytical requirements.” [PhInt, BP, EP etc]

21. Specification ParametersIdentification • Identification - establish the identity of the API(s) in the FPP and discriminate between compounds of closely related structure which are likely to be present. Identity tests should be specific for the API, e.g., IR spectroscopy. [stated for FPP as well as API in Q6A, although rarely seen in FPP specs] • 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. (Q6A)

22. Specification ParametersIdentification • Note that for PQP, we have recently removed the requirement to include a test for the identification of colourant(s) in specifications. • [This is no longer in the Q guideline.]

23. Specification ParametersIdentification • Q: When might identification of the salt in the FPP be a critical parameter? • A: When there is a risk of in-situ conversion during FPP manufacture. [Beware of bicarbonates and hydroxides (K, Na) in the formulation, except in minor amounts to adjust pH.] • Pharmaceutical equivalence definitions are about the API form “contained” in a product, not what it is “formulated with”.

24. Specification ParametersAssay and Related Compounds • Assay: may be non-specific, e.g. titration, but need to achieve overall specificity, e.g. non-specific assay plus suitable related substances test. • Limits should be 95.0-105.0% at release, may be 90.0-110.0% in shelf-life specs if justified by stability results. • Related compounds: need limits on specified (identified and unidentified), unspecified (individual unknowns) and total related compounds. Limits must be suitably qualified. • Limits may be in S specs only, but only if there is no significant degradation observed in stability studies. Otherwise, need R limits which are tighter than S limits.

25. Related 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 Q3B) • Literature i.e. ORC 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. • An enantiomer is excluded from ICH ITs and QTs (Q6A)

26. Related compounds Note that unlike the API impurities, the FPP specified related compounds are degradants. Therefore if the means of qualification are inadequate, there is an additional consideration: reducing the degradant to below the QT. A more protective container closure system may be investigated. Watch for organic solvents used as granulating fluids (e.g. ethanol, isopropyl alcohol). Such solvents require a limit in the specifications (no skip testing, no justification for removal of test).

27. Specification Parameters Microbial limits (solid orals) Microbial limits test: a general test is required for solid orals unless justified by the submission of acceptable results for 5 production batches. If justified, skip test parameters should be in the specs: At minimum every 10th batch, at least one batch annually [R], and at release and shelf-life [S]. • PhEur limits are generally acceptable: 5.1.4 • Generally: include limit on total count of aerobic microorganisms, total count of yeast and molds, and absence of objectionable bacteria (e.g. E. coli). (Q6A)

28. Specification ParametersUniformity of Dosage Units PQP requirements are newly harmonized with the PhInt: Mass uniformity: for the API(s) present at 5 mg and5% of the weight of the dosage unit, a test and limit for weight variation may be established in lieu of content uniformity testing; Content uniformity: a test and limit for content uniformity is required for each API present in the FPP at < 5 mg or < 5% of the weight of the dosage unit Criteria for application as above, otherwise, the ICH PDG harmonized text is used, i.e. limits e.g. AV NMT 15%.

29. Specification ParametersUniformity of dosage units – scored tablets • Uniformity of split portions: content uniformity requirement applies to tablets containing < 5mg or 5% of API per portion. What this effectively means: e.g. for a single breakline, tablets must be 10 mg or more for weight uniformity testing.

30. Specification ParametersDissolution Dissolution is considered product-specific. The method and limits should be appropriate for the proposed product. Surfactant use should be exceptional and appropriate. Dissolution specs at release and shelf-life should be identical. It is useful to have the parameters (medium, apparatus, speed) in specs. Some accepted specifications can be checked e.g. FDA site “Dissolution Methods for Drug Products” www.accessdata.fda.gov/scripts/cder/dissolution/ Careful consideration is required for dissolution specifications when a biowaiver was accepted (see “BE considerations for quality” talk).

31. Specification ParametersDissolution • The limits should be expressed as “Q”, which also implies three stage testing as per harmonized texts. Ideally the stages are expressed in the specs (i.e. S1 all individual values  Q+5%) • There should be a discussion if the time is > 45 minutes. • It should be ascertained that the dissolution limits are not overly wide, compared to the actual results (even for an ORC limit). • Especially for a modified release tablet, the method should be demonstrated to be discriminatory (sensitive to changes e.g. qualitative and/or quantitative difference in excipients, API particle size, process parameters or have different in-process test specifications for hardness, coating thickness etc.

32. Specification ParametersDissolution ICH Q6A decision trees 7(1) to 7 (3) can be used to assess the proposed dissolution criteria, however: • For considering accepting DT in place of dissolution: all the considerations should be carefully assessed (not just highly soluble and rapidly dissolving: accepted rarely and only with significant supporting development data – including when DT is more discriminating or has a demonstrated relationship to dissolution, robustness of the formulation/manufacturing process have been demonstrated wrt DT, etc.) • Some terms are not in agreement with established definitions, e.g. rapidly dissolving (80% in 15 min vs 85% in 30 min)

33. Specification ParametersDissolution • Additional considerations are required when there is a BCS-based biowaiver (see BE considerations for Q assessment talk): BCS Class 1 (e.g. emtricitabine, stavudine, zidovudine, levofloxacin, ofloxacin): The test and comparator products must be at least rapidly dissolving. (NLT 85% in 30 minutes) BCS Class 3 (e.g. abacavir sulfate, lamivudine, ethambutol, isoniazid, pyrazinamide):The test and comparator products must be very rapidly dissolving (NLT 85% in 15 minutes). • Dissolution limits must meet the biowaiver requirements.

34. Specification ParametersWater • Water content should be included in specs when appropriate. Specs may be justified by data on the effects of hydration or absorption on the FPP. Q6A • LOD may be considered adequate, but a water test (i.e. specific detection procedure such as Karl Fischer titration) is preferred. • If a product is to be stored in semi-permeable blisters (i.e. not Al/Al), then water should be included in stability specs.

35. Dosage form – specific testsfor specific solid oral dosage forms Chewabletablets: hardness and friability are critical (Q6A) Effervescent tablets: it is critical to control moisture throughout manufacture and storage Dispersible tablets: DT (NMT 3 min), fineness of dispersion (a type of palatability test)

36. Dosage form – specific tests Scored tablets: Q: When might you require breakability in the release specs? A: When a score has been added but no scored batch has been manufactured. The test may be removed once uniformity of split portions has been ascertained. Q: When might you require breakability in the stability specs? A: When there is known to be significant change in tablet hardness during storage. [See EMA Quality of Medicines Q&A document]

37. Unnecessary tests in specifications • In-process tests: used for the purpose of adjusting process parameters within an operating range; e.g. hardness, friability (see exception for chewable tabs), individual tablet weight • Impurities from the API synthesis which are not degradants; not normally controlled in FPP testing, and not included in the total impurities limit. Note that the enantiomer should be controlled. (Q6A) • Shelf-life specifications do not need to include tests that are not stability-indicating, such as identity and content uniformity. • Redundant tests: e.g. MU when CU is required and included

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

39. Review tips • Specifications should have been developed based on the results of the primary batches, primarily the biolot. • A comparison of the specs to the biolot results should result in questions or further considerations when the specs are much wider than, or are not representative of, the results. • 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 solicited and unsolicited changes.

40. Review tips Scanning specs into reports:  Always include page tops (including e.g. “page 1 of 5” and specifications codes/versions)  Always include page bottoms (so it is clear the full specs were included)  Always include the final page, even if “only” footnotes. The footnotes and related compound names are a critical part of specs! (Names should be conducive to knowing structure, ie EP impurity A or 6-ethinyl estradiol)