Quality Assessment and the Assessment Report

1. Quality Assessment and the Assessment Report Lynda Paleshnuik Training workshop: Training workshop on regulatory requirements for registration of Artemisinin based combined medicines and assessment of data submitted to regulatory authorities, February 23-27, 2009, Kampala, Uganda.

2. Creating a Quality Report • Developing the big picture – important aspects • Choosing your battles – where to focus • Digging deeper – when/where to look closer • Keeping the big picture – integrated analysis • Summarizing/Writing good questions • Additional data assessment • Other tips

3. Definition A quality assessment report is an objective, scientific, written analysis of information relevant to prequalification of a dossier. It provides an account of all necessary points, in summary, of studies and findings related to quality. It documents both the applicant’s and reviewer’s evidence-based findings, as well as the decisions taken regarding the dossier. The first assessment and creation of the first assessment report are the most important parts of the review process.

4. Quality Assessment Challenges • Large amounts of data • Short assessment time • Competing demands/interruptions • Focus on assessing/meeting deadlines; little time for research including staying on top of guidance development

5. The Big Picture Why is developing the big picture important? The alternative is to dive into the details. If we do this: - We may review sections that are unnecessary for us to review. - We may be unaware until we are running out of time that an area warrants our close attention.

6. Developing the Big Picture Each item below affects how the dossier assessment should proceed: • Screening/pre-assessment • Biostudy or biowaiver • API/FPP basic research • APIMF and/or CEP • API solubility • FPP form

7. Screening/Pre-Assessment • Confirm all screening criteria are met. In prequalification this takes the form of the Technical Screening Template. • If screening criteria are not met, consult. It is possible that an abbreviated review is required or the dossier may be rejected.

8. Biostudy or Biowaiver • BE report exists? Outcome? • Comparator product: http://healthtech.who.int/pq/info_applicants/info_for_applicants_BE_comparator.htm • Biobatch number/batch size NB: Never weigh in on bioequivalence unless you are quoting a BE report or BE assessor.

9. Biostudy or Biowaiver Where a biostudy/biowaiver has been done, information in the quality assessment report must be with reference to the biobatch. The comparison of biobatch vs proposed production batches is the basis of the quality review. The assessor must establish that the formulation and process (equipment, parameters and controls) are the same or list differences. To this end, the biobatch records must be compared to the blank production manufacturing records. Significant differences must be justified by the applicant. This is necessary to ascertain that the proposed product is representative of the batch which was shown to be bioequivalent/similar to the comparator product. If data on the quality of the product is assessed without reference to the biolot, the conclusions regarding quality data are meaningless.

10. Biowaivers There are various types of biowaivers: Different strengths (Dose-proportionality); Scale-up and post-approval changes; BCS-based biowaivers;

11. Biowaivers BCS-based biowaivers in Prequalification; At this time, only FPP’s containing the following API’s are eligible for biowaivers: ARV’s: lamivudine, stavudine, zidovudine TB’s: ethambutol, isoniazid, levofloxacin, ofloxacin and pyrazinamide

12. Biowaivers BCS-based Biowaiver: The biowaiver includes comparative dissolution between the test product and comparator product in 3 different pH (1.2, 4.5, and 6.8). Requirements include the submission of the batch records for the test product.

13. API/FPP Basic Research • Check the USP dictionary. This provides basic information, including whether the API name may be found under different names in different compendia, eg rifampin/rifampicin. • Check for compendial monographs for both the API and FPP: PhInt, USP, EP/BP • Check standards claimed by the applicant for API and FPP.

14. API/FPP Basic Research • Other sources of information: WHOPARs: http://healthtech.who.int/pq/WHOPAR/WHOPARPRODUCTS/WHOPAR_Index.htm EPARs: http://www.emea.europa.eu/htms/human/epar/a.htm FDA approved drug products: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm Note that these reports can include data on scoring of prequalified/approved products.

15. API: APIMF and/or CEP • Has an APIMF been filed? Assessed? Refer to current guidelines for dossier assessment and APIMF’s. • Does a valid CEP exist? http://www.edqm.eu/site/Databases-10.html • Has CEP been submitted? Check as above that the version submitted is valid. See current guideline for dossier assessment and CEP’s. The presence of APIMF and/or CEP influence how the dossier is assessed.

16. API Solubility • API is highly soluble if listed in the WHO BCS-based biowaiver guideline. • API solubility is not important if the API is fully dissolved during FPP manufacture. • If the API is low solubility (DSV GT 250 mL over the physiological pH range), then particle size and polymorphism must be investigated. Specifications may be required and should be based on the characterization of the API lot used in the biostudy. • Regardless of the solubility of the API, particle size is important for some FPP’s (inhalation products, low dose products (often RH’s)).

17. FPP Form • There are different considerations based on the final dosage form. It is wise to check the general chapters for the dosage form to be familiar with the kind of tests/issues associated with this form. As noted with API solubility, an issue with the FPP (eg. PSD for inhalation products) may affect the assessment of the API. • Assemble pertinent guidance documents, such as specific dosage form documents.

18. FPP Form Sources of information International Pharmacopeia: http://www.who.int/phint/en/p/docf/ BP 2008 index: http://www.pharmacopoeia.co.uk/2007/pdfs/BP%202008%20Index.pdf EDQM Knowledge Database: http://www.edqm.eu/site/Databases-10.html

19. Choosing Your Battles:Where to Focus We can always delve deeper. A good assessor also knows where to go lightly. We can always argue for the importance of any given area. With limited time, our approach must be pragmatic and based on risk/benefit. We cannot treat everything with equal importance. Focusing on: • Sections and Documents

20. Where to FocusSections API (CTD sections): S.1.3/S.3.1 General properties S.2 Manufacture S.3.2 Impurities S.4 Specifications S.7 Stability

21. Where to FocusSections FPP (CTD sections): P.2 Pharmaceutical Development P.3 Manufacture P.5 Specifications P.8 Stability

22. Where to FocusDocuments Certain official documents comprise the heart of the dossier: Master production documents and executed records (biobatch). Process validation protocol/report or annual report. Signed API and FPP specifications. Signed stability protocol.

23. Where to FocusDocuments • It must be stated clearly in the assessment report that the official signed documents such as specifications and blank manufacturing records were reviewed, and not just the summarized data (data in summary such as PQIF/QOS). • For example, under the specifications tables the assessor must state that the tests/methods are in agreement with information in signed documents, or differences should be listed and clarified. • If this is not done, it is not clear if the official documents were reviewed and it is possible that the most important deficiencies are overlooked.

24. Where to FocusDocuments • When assessing the batch formula (kg/batch) and mg/unit table (if possible), reference should be made to both the master production documents and the executed documents for the biobatch, ie the summary information should be confirmed to be representative of both. In the case of kg/batch data, the values should be proportional to the biobatch values, and the production batch size should be NMT 10x the biobatch size.

25. Where to FocusDocuments • When referring to signed documents, it is important to include the document code including version number. Whenever updated API/FPP specifications are submitted, scanning the updated version into the report is very helpful for subsequent reviews and creating the final approval letter (SOQR for PQP). Note that for the FPP dossier, it is the applicant’s or FPP manufacturer’s API specifications that are the official specifications of the dossier and are to be assessed. This should be ascertained at the beginning, and is also important to remember when reviewing A/D. (The original reviews may include both supplier’s and applicant’s specificatons.)

26. Where to FocusCapturing Key Data Specifications: Include in report: - Codes as above - Method types (eg HPLC) - Dissolution parameters (medium, apparatus, speed) - Confirmation statements (see next slide) Check for presence of, and assess/summarize: - Methodology for all non-compendial methods - Validation reports for all non-compendial purity/potency/residual solvent/dissolution methods - Verification reports for all compendial purity/potency/dissolution methods

27. Where to FocusCapturing Key Data Confirmation statements: • Provide vital information. • Let the current and next assessors know what has been verified/assessed. Examples regarding specifications: • “Specifications (in PQIF/QOS) were compared to signed applicant specs and are in agreement with the exception of…” • “Specifications include all those of the (PhInt/USP/BP/EP) monograph, with the exception of x, plus additional tests for y, z.” • “The applicant claims adoption of (PhInt/USP/etc) purity/potency/dissolution methods. This was confirmed.”

28. Digging Deeper Recognizing problem areas that warrant a closer look/more questions: - inconsistencies: data in one section contradicts that in another. Could be sloppiness, or negligence/sign of serious problems. - unknown applicant or applicant with history of poor dossier quality; good review history for a given applicant gives some confidence, however confidence can be lost on any given dossier

29. Keeping the Big Picture Integrated analysis – remember that everything is inter-related. Data in one section will influence assessment of other sections. Eg ICH M4Q (CTD) Q&A lists where polymorphism, particle size, and impurity data may be located. For polymorphism, this data may be located in 12 sections of the QOS.

30. Keeping the Big Picture Example: API solubility As noted previously, information such as whether the API is dissolved during FPP manufacture should be discovered up front for a low solubility API. If fully dissolved during manufacture, time is saved because analysis of polymorphism and particle size data is unnecessary. (Together polymorphism/PSD data is located in 21 different QOS sections, M4Q.)

31. Summarizing Making it all come together When finalizing a dossier, do it in one sitting (minimize interruptions) so that comments are comprehensive (everything is considered together) and concise (nothing is repeated or contradictory). This is another time when it is important to see the dossier as a whole, as well as a collection of individual issues.

32. Summarizing This is also often a time when other considerations will become apparent and we need to go back and check certain aspects. Summarizing/finalizing properly takes time for this reason. Summarizing/finalizing is one of the most important stages of the assessment process. Give yourself time to summarize properly.

33. Summarizing Conclusions, including concurrence with applicant’s conclusions, should be substantiated, eg “The information is considered acceptable, based on…”.

34. Writing Good Questions • Be direct, address the applicant: “You are requested to…” • Be specific • Include deficiency • Include requirements • Include declarative statements

35. Writing Good Questions • Be specific: Example: packaging specifications were not provided for HDPE bottles. The minimum requirement is that specifications (from the FPP packager – generally the applicant or FPP manufacturer) include a specific test for identification. A vague question will result in a vague/incomplete response. The ideal question will result in a response that is complete the first time.

36. Writing Good Questions Poor question: You are requested to provide packaging specifications for the HDPE bottles. Usual Response to this question: Applicant provides specifications but these are supplier specifications, and/or don’t include proper identification testing. A follow-up question is necessary.

37. Writing Good Questions • Proper question: You are requested to provide [FPP packager] packaging specifications for the HDPE bottles. Specifications should include a test for identification by a specific method such as IR. • If we would not accept a response without some key element, make sure that element is included in the question. This is particularly important when the requirement is not spelt out in the guidance documents. • This also helps the next assessor review the response.

38. Writing Good Questions • Include all elements in the question: Example: results for parameter x are requested for several batches. The comment should include the request, plus: Your response should include analytical methodology, validation data and analytical results.

39. Writing Good Questions Example: Question: An identification test for the colourant should be included in tablet specifications. Skip testing may be allowed. The question should include the requirements of skip testing, ie: Skip testing can be justified by the submission of results for five batches. (Without the second part, they will indicate skip testing and a second question will be required for justification.)

40. Writing Good Questions • Avoid questions where unacceptable answers may result: • Example: Identity testing is not in COA’s but was in packaging specifications, are these tests excluded from testing upon receipt of material? • An affirmative response is unacceptable, so it should not be presented as an option. The question should be worded so that the applicant confirms that testing is done upon receipt as per specifications.

41. Writing Good Questions Declarative statements: • Include declarative statements when revised documents are requested, for example when we are asking for revised methodology, blank production records, stability protocols, etc: “Your response should include the revised document with an itemization of changes or a statement that no other changes have been made.” - Puts the onus on the applicant, saves us time, avoids unsolicited changes sneaking in.

42. Writing Good Questions • Whenever possible, include references to WHO published guidelines.

43. Writing Good Questions Justification Be able to justify your questions. The reason should be in the question (data is missing, data is incomplete, clarify confusing data, data suggests a related quality issue, etc). A long and/or complicated reason should be clearly stated in the assessment report.

44. Additional Data Assessment • Need to know for each question/response: - what the deficiency was, - what the requirement is, - what was provided in the response, - does it meet the requirements

45. Additional Data Assessment Before you begin: • Have the previous report(s) on hand. • Make sure the questions are from the letter to the applicant, not just the applicant’s repeating of the question.

46. Additional Data AssessmentElements • Understanding the question. • Keeping the focus on the questions Two pitfalls: • Recreating the wheel, re-reviewing data covered by previous reviews • Getting sidetracked from the question • Key data to include • The assessor’s discussion

47. Additional Data AssessmentUnderstanding the Question Make sure the question is a) correct and b) understood before the response is assessed. For a), check this is the question in the WHO letter or previous assessment report. For b), check the original intent of the question by reference to the previous review(s). This should provide details on what we want in response. Discuss with previous assessors when in doubt and when possible.

48. Additional Data Assessment • Staying focused on the questions: - Don’t redo previous assessments unless there is a significant reason for concern, eg new data suggests a significant new issue or issue was overlooked. - Don’t get sidetracked. Example: request for results for some parameter in several batches. Response includes COAs. Assessor reviews the COAs as if they are the current specifications and proposes numerous questions about the tests and limits. If the requested parameter was reported as requested, and there are no issues with the results or the method used, COA limits are not relevant. Official specifications are reviewed elsewhere, COA’s may be an earlier version.

49. Additional Data Assessment • Key data to include: When revised official documents are requested/provided, they must be compared to the previous version as the applicant has often introduced unsolicited changes. (Exception is larger documents such as master production records where the declarative statements are included as above).

50. Additional Data Assessment Example: revised specifications provided When reviewing the response, include in your discussion: a) the code and date of revised specifications, b) confirmation that the requested change is reflected in revised specifications c) a comparison of the revised specifications with the previous version of specifications; discuss the acceptability of any unsolicited changes. Item c) is very important. If unsolicited changes have been added, the version submitted is the version we have stated we have assessed and considered acceptable.