Quality Workshop Copenhagen – May 2014

1. Quality WorkshopCopenhagen – May 2014 Specifications Hua YIN

2. Outline • Specification • Example specification exercise • Compendial Vs Non-compendial (In-house) standards • Deficiencies • Review tips

3. Information Source • ICH Q6A Specifications: Test procedures and acceptance criteria for new drug substances and new drug products: Chemical substances • ICH Q3A - Q3D: Impurities • Ph Int, USP, BP, EP, JP (recognized standards in PQP) • PQP Generic Guideline – Quality Part • Other regulatory guidelines • Assessing specifications: Lynda Paleshnuik, PQP Quality Workshop, Copenhagen – January 2012

4. Specifications • A list of tests, reference to analytical procedures, and acceptance criteria (numerical limits, ranges or other criteria), to which an API or FPP should conform • Confirm the 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

5. SpecificationsUniversal tests/criteria For both API and FPP • Description /appearance • Identification (IR, HPLC/UV diode array, etc.) • Assay • Impurities

6. Specificationsspecific tests/criteria API BCS low solubility APIs (DSV > 250ml) • Polymorphism should be investigated. If polymorphism is a factor, a test is required in specs --ICH Q6 decision tree #4 • PSD limits (d10, d50, d90) are required in the API specs, based on the results of the lot used in biostudies. --ICH Q6 decision tree #3 • Must be representative of the biolot characteristics.

7. Specificationsspecific tests/criteria API • Physico-chemical properties: pH, melting point • Water content (KF preferred) • Inorganic impurities, Heavy metals • Microbial limits

8. Specificationsspecific tests/criteria FPP • Performance tests: e.g. dissolution, disintegration (where applicable) • Uniformity of dosage units: mass or content uniformity, fill volume • Physical tests: e.g. LOD/water content, pH, friability, hardness, particle size • Content of preservatives • Microbial contamination • Sterility, bacterial endotoxins, particulate matter(parenteral)

9. Specification Parameters - Description Description: should be detailed (colour, shape, coating, markings (score, ink, embossing)) A complete description is required to facilitate the visual identification of spurious/falsely-labelled/falsified/counterfeit (SFFC) medicines. It is also important to distinguishing the look of different strengths

10. Specification Parameters - Description 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. 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).

11. Specification Parameters - Identification • Identification should be specific to the API, i.e. should be able to discriminate between compounds of closely related structure (Q6A)—IR spectroscopy for API, not always applicable to FPP • A single HPLC retention time is not regarded as being specific. Two chromatographic procedures, where the separation is based on different principles (HPLC + TLC) , or combination of tests into a single procedure is generally acceptable, such as HPLC/UV diode array, HPLC/MS, or GC/MS. (Q6A)

12. Specification Parameters - Assay • Assay: should be stability indicating. May be non-specific, e.g. titration, but need to achieve overall specificity, e.g. non-specific assay plus suitable related substances test. • The assay in the release specifications of FPP is ± 5% of the label claim (i.e. 95.0-105.0%)..

13. Specification Parameters - Related substances • Related compounds: need limits on • specified (identified and unidentified *), • unspecified (individual unknowns), and • total related compounds. *specified unidentified = structurally unidentified. It is identified in the specs by means of e.g. RRT (relative retention time). Limits must be suitably justified/qualified. ICH Q3A, Q3B Thresholds for Reporting, Identification, and qualification

14. Thresholds for impurities in API

15. Thresholds for degradation products in FPP

16. Thresholds for degradation products in FPP

17. Specification Parameters - Related substances Any impurity • > reporting threshold should be reported • > Identification Thresholds (IT) should be Specified • Unspecified (individual unknowns) ≤ Identification Thresholds (IT) • >Qualification Thresholds (QT) should be qualified

18. Specification Parameters - Related substances Qualification of limits: adopt limit  QT, or qualify: • Level present in a product used in safety and/or clinical studies (ICH Q3) • If a limit refers to a significant metabolite, it is considered qualified (confirm it is a metabolite, e.g. WHOPAR, EPAR, SmPC). • Literature i.e. Pharmacopoeial (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

19. Case study 1 Zidovudine 300mg tablets, Maximum daily dose is 600mg. Int.Ph: Imp A, B, C, D are identified. Imp C is a degradant Monograph limits of zidovudine tablets: • imp C ≤ 3.0%; • any other imp ≤ 1.0%; • total ≤ 4.0% The applicant claims the same method and limits as Int.Ph. Is it acceptable? Note: RT= 0.1% ; IT= 0.2%; QT= 0.2%

20. Case study 1 cont'd • imp C ≤ 3.0% √ qualified • any other imp ≤ 1.0%; × • A, B, D ≤ 1.0%, but • any other unknown individual should be ≤ 0.2% • total ≤ 4.0% √ may be tightened as per the real results of primary batches

21. Specification Parameters - Dissolution • Dissolution is considered product-specific. The method and limits should be appropriate for the proposed product. • 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/ • Surfactant use should be exceptional and appropriate.—not exceed 2% normally

22. Specification Parameters - Dissolution • 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. • For products containing water insoluble APIs, it is recommended to have a two tire dissolution limit. For example Artemether dissolution: NLT 40% in 1 hour and NLT 60% at the 3rd hour • It should be ascertained that the dissolution limits are not overly wide, compared to the actual results (even for an ORC limit). ORC: officially recognized compendial

23. Specification Parameters - Dissolution ICH Q6A decision trees #7 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: highly soluble and very rapidly dissolving, plus 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.

24. Specification Parameters - Dissolution Additional considerations are required when there is a BCS-based biowaiver: • 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.

25. Case study 2 • Ethambutol hydrochloride 400mg tablets. The applicant claimed USP standard for the product. • Bioequivalent of the product is accepted as per BCS class 3 based biowavier • The applicant set the dissolution limits as below: • NLT 80% (Q) in 45min at release • NLT 75% (Q) in 45min at shelf life, which is in line with the requirement of USP monograph. • Is it acceptable? What limits should be applied?

26. Case study 2 cont'd Answer: not acceptable • The dissolution limits at release and shelf life should be the same. • A limit of NLT 80% (Q) in 15min should be set for both release and shelf life as for the BCS class 3 biowaiver.

27. Specification ParametersUniformity of Dosage Units PQP requirements are harmonized with the Ph Int: 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 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;

28. 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. -– on a one-time basis and does not need to be added to the specifications. For example, 10mg tablets • split into 2 portions, each portion contains 5mg -- mass uniformity • into 4 portions, each protion contains 2.5mg – content uniformity

29. Fixed-dose combination FPPs • distinguish each API in the presence of the other API(s) , • acceptance criteria for degradation products should be established with reference to the API they are derived from. • if an impurity results from a chemical reaction between two or more APIs, its acceptance limits should be calculated with reference to the worst case (the API with the smaller area under the curve). • when one API is present at less than 5 mg or less than 5% of the weight of the dosage unit, a test and limit for content uniformity is required for this API in the FPP

30. Specification(s) • Monographs of Ph. Int., USP, BP are acceptable+ additional in-house controls, e.g. • Specific impurity related to the route of synthesis • Individual unspecified impurity • Residual solvents • Particle size distribution, polymorphism form • Those standard for the type of dosage form (e.g. friability, tablet hardness, uniformity of dosage units, viscosity) • Microbial limits • ID and assay of preservatives • If non-pharmacopoeial monograph, note for guidance ICHQ6A applicable • For FPP : two set of specifications, i.e. Release and Shelf life are required

31. When compendial standard is claimed • Generally, the monograph tests and limits should be adopted. • The monograph is the minimum standard; the authority can impose additional requirements (e.g. ICH IT for individual unspecified related compounds) • May use in-house methods • 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).

32. When in-house standard is claimed • Generally, the tightest available monograph limits for assay and purity should be adopted or justified. • The available monographs can still be used as a general guideline for requirements

33. When compendial methods are claimed…(purity and assay methods) • Ensure the same compendial method is adopted. 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 limits for EP and USP methods. If these methods are adopted, the SST requirements should apply.

34. Validation, verification, equivalency • Validation: full validation required for in-house methods, generally specificity, linearity, accuracy, repeatability, intermediate precision, plus for purity: LOD/LOQ--ICH Q2 • Verification: required for most compendial methods • Equivalency: required for an in-house method, when compendial standard is claimed Refer to : Assessing specifications: Lynda Paleshnuik, PQP Quality Workshop, Copenhagen – January 2012

35. Case Study 3 • pH of mobile phase: 3.3 Vs 2.2 (USP)= non USP method • Ratio of the mobile phase 86:14 Vs 88:12 (USP) = USP method <621>: NMT 0.2 pH units, NMT 10% absolute change in MP% • Detector wavelength 254nm Vs 277nm (USP) = non USP method • Dissolution test uses apparatus II Vs USP apparatus I = non USP method Non pharmacopoeial method → full validation required Non pharmacopoeial method → equivalent to be demonstrated if pharmacopeial standard is claimed

36. 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, Zinc 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

37. Periodic /Skip Testing • Specified tests on pre-selected batches and /or at predetermined intervals. e.g. • Polymorphic form (e.g API) • Genotoxic impurity (e.g. API) • Residual solvents (e.g. solid dosage form) • Microbiological testing (e.g. solid dosage form) • Dissolution (high water soluble, ICH decision tree #7)-- carefully justified • Justified by supportive results for five production batches.

38. Periodic /Skip Testing • If justified, skip test parameters should be in the specs: At minimum every 10th batch, at least one batch annually, and at release and shelf-life. • Full testing must be reinstated as soon as any batch failure is observed or conditions under which reduced/skip testing was approved are no longer met. • In all cases, the API or FPP should meet the full specifications if tested • This concept may be implemented post approval in accordance with GMP, if sufficient data are available. E.g test results taken from the API manufacturer's COA

39. Case study 4 The supplier's specification of Zidovudine includes the control of : • Methyl methane sulfonate content (by GC-MS): NMT 2.5ppm • Methyl-4-toluene sulfonate content (by HPLC) : NMT 2.5ppm • Sum of Methyl methane sulfonate and Methyl-4-toluene sulfonate content : NMT 2.5ppm • to be performed every 10th individual batch and first individual batch of every campaign: The FPP manufacturer's specification of Zidovudine does not contain the above test. Is it acceptable?

40. Case study 4 cont'd • Answer: no • The FPP manufacturer is requested to include that the same control of above genotoxic impurities in the specification of Zidovudine (include the same skip testing is acceptable).

41. Common Deficiencies • The specification should include a reference number, version, date, and appropriate standard • The specification should be dated and signed by authorized personnel • Any differences between release and shelf-life tests and acceptance criteria should be clearly indicated and justified. • If an officially recognized compendial standard exists and an in-house method is used, compliance to compendial requirements should be demonstrated unless otherwise justified.

42. Common Deficiencies Cont’d • The specification should include all standard drug product tests and limits for that dosage form E.g. solid orals: description, identity, uniformity of dosage units (CU or MU), assay, related compounds, dissolution, microbial limits...

43. Review of API specification Impurity MDD CEP/ API-PQ/ APIMF FPP manufacturer’s API specification User specific tests monograph RoS Specific tests ICH Q6A ICH Q3 Generic Guidance QIS

44. Review of FPP specification FPP manufacturer’s Signed and dated specification • Review as per • Compendial monograph • generic guide • ICH Q6A, Q3B Compare the summary in QIS comment • Review the • Specific dosage form • specific test as per the manufacturing process

45. Summary and Key Advice • Control of drug product and establishment of specifications key areas in the marketing dossier • 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. • Major concerns around impurities/degradation products and safety for the patient • Confirm the sameness to compendial methods if compendial standard is claimed, when applicable • Review QIS and confirm with the submitted dossier

46. Any questions?