FPP assessment: approaches and considerations

1. FPP assessment: approaches and considerations Wondiyfraw Z. Worku Assessors training Copenhagen, January 2011

2. Talk points • Dossier assessment • Why do we assess dossiers • Where does it fit • General assessment approaches • Approaches for specific dossier sections (quality part) • Section by section recommendations • Points to re-emphasize

3. Dossier assessment/evaluation Dossier assessment 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 efficacy, safety quality. It documents both the applicant’s and reviewer’s evidence-based findings, as well as the decisions taken regarding the dossier.

4. Dossier assessment/evaluationContd • At the centre of a medicine regulatory system • Establish the achieved and desired safety, efficacy and quality profile for a certain product • Assumes genuineness of submitted information

5. General approaches for the assessor • Treat assessment as investigative work • To establish the current quality of the product • To help improve the quality further • To ensure consistency/reproducibility • We also need justifications for our comments • Guidance documents • Summarize available data and discuss the background

6. General approaches, contd • Look for details but don't get lost • There is never enough time • Know when and where to go deeply/lightly • Be pragmatic • Avoid nice to knows

7. General approaches, contd • Dossier sections are not isolated to each other • Aim to do the full assessment in one go. Minimize interruptions • Take notes as you go through your assessment • If you are first assessor don't leave decisions to the second assessor. • Any issue you are uncomfortable with, highlight it in the report and seek advice from colleagues and the second assessor

8. General approaches, contd • Don't forget to record in the report of what you have done • Record in the report reference /version numbers of signed and dated documents • Avoid copying too much data from the dossier, better to summarize it in your own words • Any data that looks suspicious, draft a communication to the inspectors

9. General approaches, contd • Need to know the dossier well before you start the actual assessment (assessment preparation) • New/existing applicant • New/existing product for the programme • New/existing product for the applicant • Get available public regulatory information of approved products (eg. EPAR, Drugs @ FDA, National DRA web sites)

10. General approaches, contd • Collect relevant articles • Collect available monographs for the API and FPP including drafts • Check how the API information is submitted • Check screening/preassessment notes • Check the Efficacy/Safety assessment status • Check key API properties: solubility, polymorphism, stability or sensitivity to environmental conditions • Proposed process: complicated/less complicated • Dosage form: complicated/un complicated

11. General approaches, contd • Any known compatibility issues • Whether applicant has already manufactured commercial validation batches and data is part of the submission • Re-familiarize your self with alerts and internal guidelines • In case of additional data assessment, • Majority of the above considerations also work here • Good to quickly go through the previous assessment reports (at minimum the most recent) • Try to understand the rationale behind each question and the requirements thereof

12. General approaches, contd • When ever available, the bio batch, bio waiver or clinical batch is our reference • We need to understand critical attributes of this batch and compare these with those proposed for production batches. • API specification • Formulation • Manufacturing process specifics and controls • FPP specification

13. API specification & retest period • Recommendations • Review the physico-chemical properties of the API • Identify the FPP applicant's specification • Identify your reference specifications • Pharmacopoeial monograph, CEP • APIMF approved specifications • Any additional in-house test that may be needed (example PSD) • Your assessment of the API information (if API assessment is part of the FPP dossier) • Look for COAs for the API batches used in the submission batches (especially the biolot)

14. API specification & retest period, contd • Check methods and consider the need for additional validation: • adopted from the APIMF holder or pharmacopoeia, • in house • Give attention to special notes by the APIMF assessor • Give attention to foot notes • Identify types and sources of reference substances • Retest period: if already assigned by the APIMF assessment, inform the same to the FPP applicant • If FPP manufacturer wants shorter retest period, we accept this

15. Development pharmaceutics • Why do we need it as a regulatory submission? • To ensure that applicant has sufficient understanding of the product attributes and the manufacturing process • To give us better understanding of key product and process attributes (to help the review) • In certain cases, annual product review report may be considered a substitute

16. Development pharmaceutics, contd • Read and understand the whole development report; in the mean time try to answer the following: • What are the target profile/attributes of the product • Which drug substance characteristics affect performance and stability of the FPP • The purpose of each excipient and proposed amounts • Is there evidence of API-excipient compatibility • Why the preferred process over the others • Has the formulation been optimized

17. Development pharmaceutics, contd • What are the critical steps and parameters • How does the desk designed, lab tried and piloted formulation and process translates to a production/commercial manufacturing • Is the proposed dissolution method satisfactory • Is the proposed container closure system suitable and safe • Overages and justifications • Is there a need for tablet scoring and supporting data provided • Microbiologic attributes • Additional considerations for injectables & other dosage forms • etc

18. Formulation, manufacturing process and controls • To ensure that the formulation and mfg process for the commercial batches • are sufficiently detailed regarding inputs, processing sequence, process parameters, equipment details and other factors which may affect batch to batch reproducibility/consistency • are inline with the ones developed and used in the production of the clinical/bioequivalence/biowaiver batch/es • Any difference should be known and justified

19. Formulation, Mfg and controls-contd • Recommendations: • Go through the batch record for the clinical batch and take note of key process parameters, equipment types, in process results • Demand further details if necessary, example: granulation parameters • Take the proposed blank master production record, ensure equivalence of composition, excipient grades, details of the process, as described above, may be by page to page comparison • Any difference should be understood and justified in light of reproducibility; consider variation and SUPAC requirements as necessary • Also discuss differences with 2nd assessor and possibly bio assessors

20. Formulation, Mfg and controls-contd • If required comment on a need for revision of the master record • Also check that the narrative and process flow charts provided in the dossier are reflective of what's provided in the BMRs • Highlight the reference observations in the assessment report (to help the subsequent assessment) • Check if proposed controls including frequencies are satisfactory • If the bio study has been rejected, request for batch record of the new bio/clinical batch

21. Initial proposed • Wet granulation

22. Comment to the applicant

23. Revised

24. Process validation • If available at the time of assessment, preliminary process validation data provides further assurance to the assessor that proposed mfg method can provide reproducible batches as the clinical batch. • confirms what is already known • A good validation exercise supplemented with robustness studies provides additional assurance that the manufacturer has good understanding and control of the product and its attributes. • Should be pushed to the “edge of failure”

25. Process valdn-contd • Recommendations • Ensure that process parameters and other variabilities are representative of those proposed for production batches • Provide particular attention to the specific steps where sampling and testing is made • Not all specific step needs to be evaluated by sample analysis but at least the process parameters should have been monitored and understood as these will affect the down stream results

26. Process valdn-contd • Ensure extensive sampling than normally required for in process testing • Try to interpret and understand reported results • Consider improvements to the protocol, such as the need for • additional sampling points, • Individual vs composite sample testing • robustness studies • Where applicable for comparative dissolution profile studies

27. Example-tablet Manufacturing steps Process monitoring Sampling and testing stages Dispensing Weight checks Sifting and dry mixing Sifting and mixing parameters Granulation Wet and dry granulation parameters Drying Tray or FBD parameters Content uniformity on individual samples Blending Blending parameters and equipment Content uniformity on individual and composite samples, blend properties, LOD Lubrication Lubrication parameters & equipment In process (including robustness studies) and pooled sample testing Compression Compression parameters and equipment In process and pooled sample testing including dissolution profile Coating Coating parameters and equipments Uniformity of drying

28. Excipients • Need to have good quality and safety as the API • Most are well established • For the purpose of PQ, we have clearly stated in our guideline that novel excipients are not acceptable • Recommendations • Ensure presence of specifications for every excipient used • For colourants, ensure that these are permitted • For proprietary coating materials, ensure that qualitative composition is provided

29. Excipients, contd • For flavours, ensure that these are permitted and a qualitative composition is provided • For excipients of animal or plant origin ensure that the necessary TSE/BSE free certification/declaration is provided • Depending on the dosage form and formulation requirement, consider the need for additional in house tests (example, MLT, endotoxin, particle size, bulk density)

30. Finished product specification • Just one of the control mechanisms • Quality by design • Control of raw materials • Process monitoring and in process testing • Final product testing • etc • Should be relevant and realistic • Should be signed and dated • Can be viewed as a contractual agreement

31. Finished product spec, contd • Recommendations • Remind your self of the product attributes • Visit your notes from previous sections • Outline common and specific additional tests • Identity, potency, purity, performance and microbiologic tests • Consider a need for additional identification test for the API • Identification test for non active excipients but which may have safety importance such as colours • Identification and potency tests for preservatives, antioxidants • Limit tests for residual solvents

32. Finished product spec, contd • Check all available pharmacopoeial monographs (including drafts), identify additional tests that may need to be considered • Identify release, shelf/regulatory and/or stability specifications • Identify periodic testing proposals and ensure that the necessary support is provided • If additional data, compare the spec against the previous version (to identify any unsolicited changes)

33. Finished product spec, contd • For related substances, • if pharmacopoeial, ensure that all the specified and unspecified degradants are controlled by the applicant's specification/analytical methods • If non pharmacopoeial, try to identify potential identified impurities that need to be controlled and ensure that the analytical method is demonstrated as capable of controlling these degradants • Acceptance limits • If pharmacopoeial ensure that the product meets the requirements of your recognized pharmacopoeia (including the general monograph requirements)

34. Finished product spec, contd • Ensure that your specific requirements are met, e.g. Assay at release • For additional tests (such as related substances and residual solvents) apply ICH requirements • For tests whose limits can be justified by batch analysis/stability results (except those for which the pharmacopoeial monograph includes specific limits), check if proposed limits are reflective of the observed results • Dissolution, metabolite impurities, water content/LOD, antioxidants, preservatives

35. Analytical methods and validation • Most of the data in the dossier depends on reliability and reproducibility of the analytical methods • Recommendations: • before proceeding with the validation details go through the proposed method & try to understand • how standard and sample solutions are processed • take note of concentrations of sample and standard solutions • if pharmacopoeial compare with the appropriate monograph • see how analytes particularly impurities are determined

36. Analytical methods and Valdn, contd • As you evaluate the validation data, • Check if sample/std concentrations taken are relevant to the method being validated • Check if results were correctly determined, eg RRF • If method is in-house while a pharmacopoeial monograph is available, check if the method is demonstrated as capable of controlling all potential degradants specified in the pharmacopoeia

37. Analytical methods and Valdn, contd • Check the supporting/representative chromatograms • Check if there is a need to include in the method details a precautionary note to the analyst • Check if proposed SS criteria are adequate • see whether the RRT and RF values of the specified degradants included in the method are appropriate

38. Reference standards • To ensure validity of the standard used to produce the dossier data and for future use • When there is no official RS, applicant may receive the standard from the API supplier or may prepare one in-house (qualification) • If official RS exists then check if the WS has been qualified against the official RS (calibration)

39. Reference standards, contd • Recommendations • Try to establish the type and source of the standard • Check the characterization/qualification data preferably for lots of the standard lots used in the validation studies • Establsih Identity, potency and purity • Other details better be left for the inspectors

40. Container closure system • One of the major product attributes • Recommendations • We need to understand the components and establish • Components in immediate contact with the product (Primary components) • Secondary functional components • Measuring devices • Secondary components • ensure that specifications are inline with general pharmacopoeial monograph requirements (depending on the dosage form).

41. Container closure system, contd • consider further aspects depending on the dosage form and stability concerns (which may have been partly addressed as part of development pharmaceutics) • Extractables/leachables • Moisture and air permeation • Biological activity tests • Contaminants (for rubber elastomers) • Dose reproducibility for measuring devices

42. Stability data • To ensure that the product quality as achieved at release can also be maintained throughout a reasonable product shelf life • Recommendations: • Start with the protocol • specification and analytical methods • batch type and packaging • testing plan • future plans (ongoing and stability on production batches)

43. Stability data, contd • While assessing the stability data • Check if all reported results are within acceptable limits • Try to visualize any visible trend or variability (intra and inter batch) • Summarize the data indicating any trend, variability of OOS • When there are trends, variabilities, or OOS go back to the relevant other sections of the dossier • Conclude if the data is sufficient to support a shelf life • When ever appropriate ask for updated data instead of communicating an extrapolated shelf life • Consider if there is a need for revision of the protocol for commitment batches

44. Samples and product labelling • Submitted samples are primarily for visual evaluation of the product and its labels • ensure that these are representative of the product as presented in the dossier • As quality assessors, we only need to comment on quality related aspects of the labels, • Section 1.0, 2.0, 3.0 and 6.0 • Occasionally also section 4.2(posology and administration) • WHOPAR • Make sure that in your assessment reports/QIS, information vital for WHOPAR preparation are clearly spelled out, e.g. ink composition for capsules shell

45. Example 1 • Assume that you are preparing to start an assessment of a new application (quality part). As part of your preparation you have noticed that the BE data submitted had already been assessed and considered not acceptable. What does this tells you and how will this affect your assessment? Would you start a full assessment of the dossier?

46. Example 2 • Assume that you are assessing an API specification as used by an FPP manufacturer. The APIMF approved specification is based on a BP/EP monograph, while the FPP manufacturer's specification is based on USP monograph • As FPP assessors what issues do you need to consider?

47. Example 3 • Assume that you are assessing control of degradation products of a certain FPP (as part of the FPP specification). It's noted that applicant is using an in-house developed method for control of degradants while a monograph exists in one of the recognized pharmacopoeias. Please describe your approaches in determining acceptability or non acceptability of the proposed controls.

48. Some points to re-emphasize • We are always under time pressure • We need to be pragmatic • Biobatch/clinical batch records • heart of the quality assessment • Process details and end points • Example: Wet granulation • API/FPP specifications and other signed records • Should be clear and changes should be known • Always re-familiarize your self with requirements, alerts, and internal guidance

49. Additional material • Presentation on • Quality assessment and the assessment report • by Lynda Paleshnuik • On PQ web site, under trainings (Kampala Uganda, 23-27 February 2009) • FDA's Q and A guide on question based review (QbR)

50. Thank you