Quality Workshop Copenhagen – January 2012

1. Quality WorkshopCopenhagen – January 2012 Biobatch Considerations for Quality Assessment

2. Overview Biobatch basics (biowaiver vs bioequivalence study, size) Biowaivers and their considerations for quality (Q) assessors Formulation of the proposed product Dissolution API lot, formulation and method of manufacture Biobatch uniformity

3. Biobatch basics • The biobatch is a key component of the quality assessment, regardless of whether there is:  a biowaiver (BW) supported by dissolution studies and a formulation comparison, or A bioequivalence (BE) study • When there is a BW, this does not mean there is no biobatch, or that its importance is lessened. The biobatch (BW or BE batch) is of prime importance to support the dossier.

4. Biobatch basics • The size of the biobatch must be adequate to represent the production batch size, i.e. no scale up beyond ten times. • This applies throughout the life of the product, not just before PQ/approval. Scale up beyond ten times should be supported with a new biobatch/BW data to support the new size (possible exception for low-risk cases if well-defined). • A biobatch should be the greater of 100,000 units, or not less than 1/10th the proposed production size. • A biobatch of < 100,000 units may be accepted, but then no scale-up is allowed. This should be clearly indicated in reports for the product, as it affects allowable variations.

5. Biowaivers • Familiarity with the BW policies is useful for Q assessors. • BE/BW is done by bio assessors; quality assessors in PQP should not comment on the BE studies. But an awareness of the quality-related issues is helpful. • There are two general quality considerations for BWs: 1) formulation, and 2) dissolution considerations

6. BCS-based biowaivers Currently the dossiers with the following APIs are eligible for BCS-based biowaiver: ARV’s: lamivudine, stavudine, zidovudine (+ abacavir sulfate, emtricitabine added November 2011) TB’s: ethambutol, isoniazid, levofloxacin, ofloxacin and pyrazinamide The new BCS-based BW doc now also makes reference to FDCs. (Difficult to envision due to formulation restrictions and lack of FDC comparators).

7. Biowaiver considerations for Q assessorsFormulation Formulation considerations for BCS-based BWs: BCS Class 1 APIs • Similar amounts (to comparator) of the same excipients are encouraged. • “Well-established excipients in usual amounts should be employed” (generally required in PQP, not just for BWs) • Excipients that may affect bioavailability of the API (e.g. mannitol, sorbitol, surfactants) should be Q&Q with the comparator (qualitatively and quantitatively the same)

8. Biowaiver considerations for Q assessorsFormulation Formulation considerations for BCS-based BWs: BCS Class 3 APIs • Excipients must be qualitatively the same and quantitatively very similar to the comparator. Very similar defined as level 1 SUPAC changes. • Excipients that may affect bioavailability of the API (e.g. mannitol, sorbitol, surfactants) should be Q&Q with the comparator (qualitatively and quantitatively the same) • For isoniazid-containing products, lactose and other reducing sugars should be Q&Q with the comparator.

9. Biowaiver considerations for Q assessorsFormulation Other formulation considerations: Bioequivalence studies are not considered necessary for certain categories of products, e.g. aqueous parenterals, solutions for oral use (e.g. syrups, elixirs, tinctures), powders for oral solution, gases, aqueous otic/ophthalmic products, aqueous topicals or aqueous inhaler products when the products meet certain formulation conditions (see TRS 937 Section 4).

10. Consider the form

11. Biowaiver considerations for Q assessorsFormulation • Proportional strength biowaivers: formulations are either exactly proportional (e.g. common granulation) or same total weight with the difference in API made up with diluent (see TRS 937 Section 9.3) • Very minor quantitative differences may be accepted (e.g. SUPAC level 1). Be cautious with regard to the limitations of the SUPAC guides (multi-functional excipients not considered, and some combined groups, e.g. simple and super-disintegrants, missing groups e.g. surfactants) • Ensure diluent is used to make up API amount in second scenario (not stated in TRS 937)

12. Biowaiver considerations for Q assessorsDissolution BCS Class 1: • The test and comparator products must be at least rapidly dissolving. (NLT 85% in 30 minutes) BCS Class 3: • The test and comparator products must be very rapidly dissolving (NLT 85% in 15 minutes). Criteria in both cases applies to behaviourin all 3 media.

13. Dissolution Considerations The dissolution of the biobatch (test product) should always be fully characterized in the dossier (both for when BE and BW). • Dissolution should be run on the tablets as they are required for the BE study: e.g. whole chewable tablets when they “may be swallowed whole”…. Dissolution testing of chewable tablets should normally be the same as non-chewables (including using whole tablets) even when they should always be chewed. • If the dossier is supported by a biowaiver, there are specific requirements regarding dissolution. Dissolution limits in specifications should meet the requirements on the previous page, i.e. 85% in 15 or 30min.

14. Dissolution Considerations • Process validation protocol for production batches should include comparative dissolution (single medium, i.e. proposed medium) against biobatch data. The comparison can be against biobatch data, as the batch may be expired. • Yet another reason why the data on the dissolution profile of the biobatch is so important to be provided and reviewed in the original report. If the absence is noted in the first review, the data is usually available before the biobatch expires. Time points are also important, as future comparative studies must use the same time points for the test products.

15. Biolot dissolution comment Biolot dissolution data was not requested in the first report. Now the biolot is expired: We note that the biobatch has expired and that dissolution profile data for this batch in the other media (other than the release) is not available. Please note that the biobatch should always be fully characterized for its dissolution characteristics in multiple media, and this is an expected part of every dossier. The multimedia dissolution profiles established for the biobatch in this regard will be used as reference profiles for any future variation applications that may require submission of comparative dissolution profile data. As a result, you are requested to take note and confirm that for future applications, the biobatch dissolution profile will be established in at least the three usual pH buffer media (pH 1.2, pH 4.5 and pH 6.8) including the release medium. Continues next slide…

16. Biolot dissolution comment • For the current application, you are requested to submit the required multimedia multipoint dissolution study on the remaining process validation batch of the proposed batch size of 120,000 tablets. [If the data is unavailable on the biolot, data should be provided for a lot which is the same as the biolot (as much as possible).]

17. Dissolution Considerations • Q: The process validation protocol for a solid oral product normally must include comparative dissolution profiles against the biolot. For a product containing only BCS class 3 API(s) with acceptable biowaiver, the process validation protocol does not need to include this requirement for comparative dissolution profiles against the biolot. What is the reason for this exception? • A: Because the FPP specifications must include dissolution with limits of at least NLT 85% in 15 minutes (don’t assume, make sure). The criteria is met by meeting the release specifications, which are part of process validation.

18. Quality assessmentAPI lot used in the biobatch The API lot used in the biobatch is of critical importance in the quality review. • API specs should be based on the results of primary lots, especially the lot used in the biobatch. All subsequent lots of the API should be representative of the lot used in the biobatch. For a BCS low solubility API, particle size (PDS) and polymorphism specifications should reflect the results of the API lot used in the biostudy

19. Quality assessmentAPI lot used in the biobatch What does this mean for multiple API suppliers, or a change in API supplier? • The FPP manufacturer should have a single set of API specs that applies to API from each proposed supplier (there may be different requirements for a single parameter, e.g. residual solvents.) • It is not a requirement to have FPP batches manufactured with API from each supplier, prior to PQ

20. Quality assessmentAPI lot used in the biobatch Demonstrated similar quality of API from each supplier:  COAs from each supplier showing equivalent or superior quality to the API lot used in the biolot  The purity profile need not be identical for suppliers, but the impurities must be adequately controlled for each (qualified limits).  For BSC low solubility APIs, API from each supplier should have the same polymorphic form*/similar PSD to that of the API used in the biolot. *unless equivalent stability/solubility of the alternate form is demonstrated

21. Quality assessmentFundamental importance of the biobatch There was one biobatch, demonstrated to be bioequivalent (BE) or similar (BW) to the comparator product. The biolot should be representative of all future production batches. = …

22. Quality assessmentBiobatch formulation and method of manufacture • A key aspect of the Q assessment: comparison of the biobatch records to the master production records for the largest intended production size • Ensure first that the biolot is within 10x the largest proposed production size. If not, this is unacceptable.

23. Biobatch formulation and method of manufacture Elements of the comparison: ● Formulation (including excipients, their grades and amounts) • Generally no differences allowed but minor quantitative differences may be justified ● Manufacturing process (equipment, processing parameters and controls) • Some provision made for changes to equipment due to scale-up • Differences should be justified

24. Biobatch uniformity • Why is uniformity of the biobatch necessary? Biobatch size 100,000 tablets Tablets used in the average study: ≈ 100 • Previously part of the process validation of primary lots. If not part of above, need uniformity demonstration: • Either an in-process demonstration of the uniformity of the final blend, or equivalent sampling during compression or (more likely) after packaging, e.g. at least 100 total units sampled from at least 5 points or containers.

25. Biostudy acceptability • When dossier review is near completion (few issues remain, or ready for QA), the assessor should check that: • A) the biostudy was accepted, (check final BE report) and • B) if the biostudy report was completed long after the initial quality review, check whether the biolot batch # has changed.

26. Biostudy acceptability • Situation: the quality assessment is almost complete (most issues have been resolved). The above check was done and it was noted that the original BE study was rejected/failed, and at some point in the assessment process a new biostudy was submitted. Need to know: • Did the new study include a new biolot? • Was this ever communicated to the quality assessors? Were biobatch records and other relevant data submitted/assessed? NOTE: This change may also be observed when the SOQR is sent for confirmation or the QIS is updated (correction to biobatch #)

27. New biolot question (1) Due to the new biostudy submitted for product X, (new biobatch Y), the following information is required to be submitted for quality review.  The current blank master production records for the largest proposed production size, if more recent than the previously submitted version. Your response should include the change history since the previous version submitted.

28. New biolot question (2)  The executed records of the biobatch, with a tabulated comparison of the formulation and manufacturing process compared to the proposed production batches, including formulation, equipment, process parameters and controls as outlined in current master production documents.  The COA of the biobatch, and the COA of the API lot used to manufacture the Biobatch.

29. New biolot question (3)  Data to demonstrate the dissolution profile of the Biobatch in three media across the physiological pH range.  Data to demonstrate the uniformity of the biobatch. Note that when the response is received, the report should include a discussion of all points above.

30. Examples • Ofloxacin solubility: a dossier indicates it may not be soluble over the physiological pH range. It’s listed as one of the BW APIs as BCS class 1. • What to do? • Solubility data is always important. If it is contradictory, at minimum this should be discussed, including a BE consult. • Note that the BCS classifications for solubility in TRS 937 are error-prone (based on limited data). Data on solubility should always be discussed and highlighted in the Q report.

31. Example • No blank production records provided. How best to ask the question? • You are requested to provide blank master production records for the largest proposed production batch size. With your response you should provide a detailed comparison of differences in formulation and manufacture (equipment, processing parameters and controls) between the production batch manufacture and the biobatch.

32. Example There are two important elements to the above question: • The largest proposed size is important. • The reference to comparison to the biolot may save the assessors work and serves as reminder to those reviewing the response. Example where this was not included in the question, the assessment of the response was: “The applicant provided the blank master production records and it is ok.”

33. Biolot as referenceExample questions The biolot serves as the primary reference whenever possible. Example: the granulation was not fully characterized in master documents. IF there is little or no scale-up to production size, the actual parameters (rather than instructions) used to make the biolot should be the basis of the granulation details in production records. 1. “Granulation should be characterized by addition of defined amount(s) of water, with mixing over specified period(s) of time at defined speed, based on the actual processing of the batch used in biostudies.”

34. Example questions 2. “You are requested to revise the master production records to include a range for the ampere reading used to determine the end-point of the granulation of each sublot. Based on the results observed for the batches used in biowaiver studies, a limit of 005-009 amperes would be considered acceptable.” 3. [proposed limit 25 amp] “The added limit on amperage for the granulation steps should be revised to include an upper limit. The highest value observed for the Biobatch was 27.4 amp, therefore a limit of 25-30 amp would be acceptable at this time. It is understood that this limit may be further optimized with additional manufacturing experience.”

35. Example questions 4. “You are requested to submit a revised MPD and a process validation protocol for the 400,000 tablet commercial batch size that include full characterization of the granulation process or a tentative granulation endpoint established based on your available pharmaceutical development/scale up data and manufacturing experience from the biolot, since the latter must be representative of the proposed commercial product.It is understood that this endpoint will be further optimized during the production of the first three production scale validation batches.”

36. Conclusion The assessment of the biobatch is a key component of the quality assessment, whether there is a BW or BE study. If the dossier is supported by a biowaiver, there are considerations for quality assessors regarding formulation and dissolution. The API lot, formulation and method of manufacture of the biolot require careful consideration and should be the primary reference for the assessor regarding the proposed production product.