API assessment: Approaches and considerations

1. API assessment: Approaches and considerations Antony Fake WHO Medicines Prequalification Programme

2. Overview • API information is assessed within the PQ programme in two ways: as part of the FPP assessment, or during the APIMF assessment • The new guidance for generic medicines emphasises that the data requirements in either situation are the same. • There is only one standard for the assessment of APIs.

3. Overview (2) • This is a point of interest review of API assessment, it is not a line by line review of technical requirements. • There is a focus on the API starting material (API-SM) and the API starting material for synthesis. • Some requirements are scientific in nature others are regulatory in nature.

4. 3.2.S.1 – General properties • This section summarises information that is already known about the API. • Despite this applicants often do not provide complete information. • Particularly, information on: partition coefficients and solubility. • Optical rotation is sometimes performed using a different solvent or temperature .

5. 3.2.S.1 – General properties An exact chemical and physical description of the API is desired. • Different manufacturers make the same API in different polymorphs, particle sizes, solvates, hydration states. • It is important to understanding the molecule in question. • Unless this information is accurately recorded it is difficult to know in the future whether another API manufacturer is making the exact same molecule. This could potentially lead to bioinequivalence of the FPP.

6. 3.2.S.2 – Manufacture Ensure the unit and block is specified and recorded. • If it is not stated ask. • This affects future variations for changes to the manufacturing facility. • It is needed for GMP inspection purposes.

7. 3.2.S.2 – Manufacture (2) A detailed description of manufacture is required. • Detailed flow diagram of synthesis indicating chemical structures, molecular weights, solvents, reagents. • Detailed narrative of each synthetic step. Types and quantities of reagents and solvents. Reaction conditions, critical steps, in-process controls, yields. • Alternative processes, reprocessing steps or recovery steps should be equally detailed.

8. 3.2.S.2 – Manufacture (3) Choosing the API starting material (APl-SM) API starting material API intermediate(s) Final API intermediate Final API The practise of buying reaction intermediates is common. Increasingly intermediates late in the synthesis are being purchased.

9. 3.2.S.2 – Manufacture (4) Choice of API-SM ASSESSORS Simpler molecules Final API INDUSTRY

10. 3.2.S.2 – Manufacture (5) • The API-SM is the point at which GMP applies to manufacture. • This can be advantageous when API manufacturers buy reaction intermediates from secondary manufacturers with limited GMP experience. API manufacturers prefer to have the API-starting material (API-SM) defined as late in the synthesis as possible because:

11. 3.2.S.2 – Manufacture (6) The problem for assessors is: • Information on the preparation of a complex API from one or two steps makes determination of impurities in the API very difficult. • If the SM is complex it is hard to judge the acceptability of the SM specifications. • The guarantee of quality API is the result of good manufacture and control throughout all the steps. Comprehensive testing of the final API does not replace this. Therefore knowledge of all steps is important.

12. 3.2.S.2 – Manufacture (7) There is a clever compromise, The API starting-material-for-synthesis. • This defines the point in manufacture from which detailed manufacturing information should be provided. • This allows assessors to judge whether the controls on the API-SM are sufficient, without obliging the preparation of the API-SM to be in compliance with GMP regulations.

13. 3.2.S.2 – Manufacture (8) Starting material for synthesis Reaction intermediate(s) API starting material API intermediate(s) Final API intermediate Final API Starting material for synthesis Detailed information provided dossier Reaction intermediate(s) API starting material GMP compliance API intermediate(s) Final API intermediate Final API

14. 3.2.S.2 – Manufacture (9) • Information on the preparation of the API commencing from the API-SM-for-synthesis must be provided in section 3.2.S.2. • However, information on the steps from the API-SM-for-synthesis to the API-SM is usually supplied as an annex. • There is often more than one supplier of API-SM. Each API-SM supplier must provide detailed information.

15. 3.2.S.2 – Manufacture (10) The assessor has to: • Judge whether the choice of API-SM is appropriate. • Judge whether the choice of API-SM-for-synthesis is appropriate. It is subjective, but there is some additional guidance.

16. 3.2.S.2 – Manufacture (11) Choice of API-SM Poorer information provided on the preparation of the API-SM. Simpler molecules Final API Detailed information provided on the preparation of the API-SM.

17. 3.2.S.2 – Manufacture (12) The API-SM for synthesis is a synthetic precursor of one or more synthesis stepsprior to the final API intermediate. Acids, bases, salts, esters and similar derivatives of the API, as well as the racemate of a single enantiomer API, are not considered final intermediates…Be incorporated as a significant structural fragment into the structure of the API. GUIDELINE ON SUBMISSION OF DOCUMENTATION FOR A MULTISOURCE (GENERIC) FINISHED PHARMACEUTICAL PRODUCT (FPP): QUALITY PART

18. 3.2.S.2 – Manufacture (13) A company submission proposes molecule 3 as the AP-SM. Can this be accepted? Crude Nevirapine (2) (3) (1) Nevirapine Proposed API SM

19. 3.2.S.2 – Manufacture (14) First identify the final intermediate, as logically the API-SM and API-SM-for-synthesis must occur prior to this molecule. Crude Nevirapine (2) (1) (3) Nevirapine Proposed API-SM

20. 3.2.S.2 – Manufacture (15) Conversion of the crude nevirapine (2) to nevirapine(1) is not a synthetic step. Therefore, crude nevirapine (2)is not the final intermediate. Crude Nevirapine (2) (1) (3) Nevirapine Proposed SM

21. 3.2.S.2 – Manufacture (16) The conversion of precursor 3 to crude nevirapine (2) is a synthetic step. Therefore, precursor 3 is the final intermediate. Further information on how molecule 3 is prepared is required. (2) (1) (3) Final intermediate Proposed SM

22. 3.2.S.2 – Manufacture (17) The applicant states that molecule 3 is prepared from molecule 4. Molecule 4 can be assigned as the API-SM, but as it is a complex molecule further information on its preparation is required. API Starting material (4) (2) (3) (1) Final intermediate

23. 3.2.S.2 – Manufacture (18) Molecules 5 and 6 can be accepted as the API-SM-for-synthesis. Each are significant structural fragments of the final API and commercially available. API Starting material (2) (4) + (5) (6) (3) Starting materials for synthesis Final intermediate Nevirapine

24. 3.2.S.2 – Manufacture (19) • Controls on the API-SM should typically include identity, assay and impurity content. • The controls should take into account the API-SM preparation. • Controls on reaction intermediates should typically include identity, assay and impurity content, but will vary depending on the length of synthesis and controls placed on subsequent intermediates.

25. 3.2.S.3 Characterisation • It would be rare that the manufacturer has synthesised a completely different molecule. Even the wrong enantiomer or diastereomer. • It’s more a question of verification than being truly worried, but you never know! And, the consequences could be complete therapeutic failure, or worse.

26. 3.2.S.3 Characterisation (2) • For non-pharmacopoeial substances a range of different techniques can and should be used. UV, IR, 1H and 13C 19F, 31P NMR, elemental analysis, HRMS, MS. • For pharmacopoeial substances comparison to the pharmacopoeial reference standard is desirable. Comparative IR is suggested, however, proton NMR wouldn’t hurt either. • Comparative IR will not address the question of enantiomers (maybe not even diastereomers), or particle size. It may address polymorphism.

27. 3.2.S.3 Characterisation (3) If the molecule can exhibit stereoisomerism • Ensure the techniques used can distinguish these. • Optical rotation comparisons to a reference standard is simplest. • Through-space proton NMR (NOE, NOESY, ROESY) experiments are increasingly used in larger organisations, but its really just showing off.

28. 3.2.S.3 Characterisation (4) Polymorphism • pXRD and DSC can be used to distinguish polymorphs. • Comparative IR is often used, but IR may not always be able to distinguish all polymorphs, or mixtures of polymorphs. • The use of IR must be validated by suitable experiments. Literature can be used for this purpose.

29. 3.2.S.3.2 Impurities This is covered in another talk, but: • Always look at the method of preparation. • Pharmacopoeial monographs are not magic, they may not control all potential impurities. • If the test method can’t detect the impurity, you will never see it!

30. 3.2.S.4.1 Specifications • Do the tests cover all the applicable physical and chemical tests? • Compliance with a pharmacopoeial monograph may not be sufficient control, especially for impurities. • If a pharmacopoeial standard is claimed then the API specifications must meet the monograph requirements. • A one sentence statement in the report about compliance, or not, with a specific monograph is useful. • Microbial quality is not an issue unless the API is sterile.

31. 3.2.S.4.1 Specifications (2) • It is important that the manufacturer provides a signed, dated and version-numbered specification. This is to ensure traceability of testing requirements in case of GMP audits and future variations. Skip testing • Often manufacturers will propose the elimination of certain tests based upon batch manufacturing data. • It is best to retain the test in specifications as a non-routine test, with a comment that the test is to be performed if there is a change to to manufacture, material suppliers etc.

32. 3.2.S.4.1 Specifications (3) • API specifications should be provided from the FPP manufacturer and from all of the API manufacturers. • The FPP manufacturer should have one API specification, even if there are multiple API suppliers. • The FPP manufacturer’s specifications may be a compilation of all the API manufacturers‘ specifications.

33. 3.2.S.4.1 Specifications (4) • if one API supplier controls the API to the EP monograph, plus an additional impurity, • the FPP must also control for the additional impurity. Adoption of the EP monograph only is not acceptable. The FPP manufacturer's specifications should take into account those of the API manufacturers. Therefore,

34. 3.2.S.4.2 Analytical Procedures • Non-pharmacopoeial test methods should be explicitly described, and numbered. • In an APIMF it is the API manufacturer’s procedures that are described. • In an FPP dossier it is the FPP manufacturer’s API test methods that are described.

35. 3.2.S.4.3 Validation of Analytical Procedures • The provision of validation data for pharmacopoeial methods is not usually required. • If an in-house method is used when claiming a pharmacopoeial standard, equivalence of the in-house and pharmacopoeial methods must be demonstrated.

36. 3.2.S.4.4 Batch Analyses • Batch analysis should be provided for at least two pilot scale batches from each API supplier. • This should include the API batch used in the manufacture of the biobatch. • The size, manufacturing site and manufacturing date for each batch should be identified. • If testing was not to proposed specifications, a justification should be provided. • Certificates of Analysis from the API and FPP manufacturer should be provided for each batch.

37. 3.2.S.5 Reference Standards • The primary and secondary reference standards used in the tests for assay, impurities and identification should be stated. • Primary reference standards obtained from the Ph.Int., BP, EP or USP should be used if possible. • If a pharmacopoeial standard is claimed then the primary reference standard of that pharmacopoeia should be used.

38. 3.2.S.6 Container Closure System • Copies of the specifications for the primary packaging should be provided. • The materials used in the construction of the primary packaging must be suitable for use with pharmaceuticals • It should be verified that the proposed packaging is that used in the stability studies.

39. 3.S.7.1 Stability data This will be covered in detail in a further talk, but… • If the drug substance assessment is occurring as part of the FPP dossier assessment the drug substance stability data must be assessed for each API manufacturer. • Long-term storage conditions.

40. 3.S.7.1 Stability data (3) Are the primary stability studies conducted at 30ºC/65%RH or 30ºC/75%RH? • They should be unless it has been demonstrated that the API is inherently unstable at 30ºC/65%RH or 30ºC/75%RH. • Instability during accelerated stability trials is not acceptable evidence of instability.

41. 3.S.7.1 Stability data (4) • If the API is stable at 30ºC/65%RH or 30ºC/75%RH to 24 months then a lower storage condition is not really justified. • If the API is unstable at 30ºC/65%RH. studies at 25ºC/60%RH should be attempted. 2ºC - 8ºC is not the next logical storage condition.

42. 3.S.7.1 Stability data (5) If there is no data available at 30ºC/65%RH or 30ºC/75%RH then the API manufacturer should: • commit to initiating long-term stability trials on the next two batches (pilot scale or greater) manufactured at either 30ºC/65%RH or 30ºC/75%RH. • provide a signed, authorised stability protocol for the new stability studies. • specify a date when they will submit an APIMF amendment or FPP variation to change the recommended storage conditions to stored below 30ºC.

43. Questions 1.  Does the APIMF need to be in the CTD format? Yes, it should be. The question is why wouldn't it be? 2.  If the API manufacturers have DMF in the US-DMF format, will it be acceptable? Do they need to convert to the CTD format, or can the applicant submit it as it is, as annex to 3.2.S and fill the sections S.1 – S.7 in the PD accordingly?   This course of action is not encouraged! But I would rather have a DMF than not

44. Questions 3. If we use US-DMF or EDMF that already got reviewed by the USFDA or European authority, will the WHO review it again? Yes, unless the evaluation report can be provided. In which case a peer review of the report will be conducted. 4. If the DMF is old (e.g. >5 years ago) but can still meet the current requirements, will it be acceptable? Does the WHO have restriction on that, or require additional data e.g. annual product review, ongoing stability data? No there are no specific requirements on the age of the APIMF. But be honest, will a 5 year old APIMF really meet current requirements? Or, accurately reflect current manufacture and control?

45. Questions 5. Can the WHO share the names of API manufacturers or APIMF holders that were already passed the review by the WHO as part of the prequalified FPP? This can help the FPP manufacturer knows the good source of API that can meet the WHO requirements and in turn reduce the WHO workload in reviewing the DMF. No. Not at this time. But, the names and details of Prequalified APIs will be published for this very purpose. 

46. Questions Variations: 1. When the manufacture of an API is scaled up, a variation needs to be introduced to the WHO. This is the responsibility of the API manufacturer and not the FPP manufacturer. May be the FPP manufacturer could have a “quality agreement” with the API manufacturer asking for this commitment. Nevertheless when an API has a CEP is this required?

47. Questions • When there is an API related change and there is an APIMF then an APIMF amendment should first be submitted by the APIMF holder. Once the amendment is accepted then a variation from the FPP manufacturer maybe required, depending on the change involved. • If there is a CEP involved, no notification to the WHO is required unless the CEP is reissued. • If there is no APIMF or CEP supporting the FPP then the FPP manufacturer should submit a variation for all API related changes.

48. Questions 2.  Will the reduction in number of batches for stability study affect the variations? For example, if some changes require stability of 3 pilot lots, will it be reduced to 2 pilot lots as per the new guideline?  It should, yes, but not for requirements that concern production lots.

49. Questions Revised stability requirements for generic FPPs were introduced to the PQ programme as part of the new guidance document for generic FPPs Therefore, when stability data is required to support a variation, the following requirements apply: • For uncomplicated FPPs (e.g. immediate release solid oral dose forms) the minimum number of FPP batches required to establish the shelf-life is now two, of which one batch must be at least pilot scale. • For complicated FPPs the minimum number of FPP batches required to establish the shelf life is now two, both of which must be pilot scale or larger.