1. FPP Assessment and Deficiencies Lynda Paleshnuik Training workshop: Assessment of Interchangeable Multisource Medicines, Kenya, August 2009

2. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 2 |2 | Overview FPP = Finished Pharmaceutical Product CTD organization of the FPP Common deficiencies on a section-by-section basis Dossier assessment tips (FPP)

3. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 3 |3 | CTD Structure of FPP Sections 2.3.PDRUG PRODUCT 2.3.PDRUG PRODUCT 2.3.P.1Description and Composition of the Drug Product 2.3.P.1Description and Composition of the Drug Product 2.3.P.2Pharmaceutical Development 2.3.P.2Pharmaceutical Development 2.3.P.3Manufacture 2.3.P.3Manufacture 2.3.P.4Control of Excipients 2.3.P.4Control of Excipients 2.3.P.5Control of Drug Product 2.3.P.5Control of Drug Product 2.3.P.6Reference Standards or Materials 2.3.P.6Reference Standards or Materials 2.3.P.7Container Closure System 2.3.P.7Container Closure System 2.3.P.8Stability 2.3.P.8Stability

4. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 4 |4 | P.1 Description and Composition Provide description and composition of the FPP, including: Composition, i.e., list of all components of the dosage form, and their amount on a per-unit basis (including any overages), the function of components, and their quality standards (e.g., compendial or manufacturer’s specifications) Description of accompanying reconstitution diluent(s); and Type of container and closure used for the dosage form and accompanying reconstitution diluent, if applicable.

5. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 5 |5 | P.1 Common Deficiencies Description is incomplete (should be as in FPP specifications) and/or is not in agreement with sample. The composition has errors: –Not in agreement with the master production records –Totals don’t add up –Solvents should be listed in the table, but amounts per unit should not be included or added to the totals –All components used in manufacture should be listed, eg Nitrogen The qualitative composition of mixtures, such as Opadry colourants, capsule shells, printing ink, is not provided.

6. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 6 |6 | P.2 Pharmaceutical Development This section should: - contain information on the development studies conducted to establish that the dosage form, the formulation, manufacturing process, container closure system, microbiological attributes and usage instructions are appropriate for the purpose specified in the application. - CQA/CPP: identify and describe the formulation and process attributes (critical parameters) that can influence batch reproducibility, product performance and drug product quality.

7. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 7 |7 | P.2.1 Components of the Drug Product P.2.1.1Drug Substance The compatibility of the API with excipients should be discussed. Additionally, key physicochemical characteristics (e.g., water content, solubility, particle size distribution, polymorphic or solid state form) of the API that can influence the performance of the FPP should be discussed. For combination products, discuss API-API compatibility. P.2.1.2Excipients Discuss the choice of excipients, their concentration, and characteristics that can influence the FPP performance.

8. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 8 |8 | P.2.1 Common Deficiencies API-excipient compatibility: note that if an excipient is in the comparator, the compatibility of that excipient may be considered established. The applicant should therefore include in the dossier the qualitative composition of the comparator product(s). Guidance on study design is provided in TRS 929 appendix 3 Table A.1 (2005) and Supplement 2 (2006). Compatibility studies often report appearance only. Studies should include chromatographic results (potency and impurity).

9. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 9 |9 | P.2.2 Drug Product P.2.2.1Formulation Development - A brief summary describing the development of the drug product - Differences between clinical/BE formulations and the proposed formulation should be discussed. - Results from comparative in vitro studies (e.g., dissolution) should be discussed. P.2.2.2Overages – justify any overages P.2.2.3 Physicochemical and Biological Properties Parameters relevant to the performance of the drug product, such as pH, ionic strength, dissolution, redispersion, reconstitution, particle size distribution, aggregation, polymorphism, rheological properties should be addressed.

10. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 10 | P.2.2 Common Deficiencies Overages are only acceptable for the API. Overage of the API in order to extend the shelf-life is unacceptable. The acceptable justification for an overage of the API is loss of API during manufacture. This can be justified by showing that batches containing an overage have a potency value of close to 100% at release.

11. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 11 | P.2.2 Common Deficiencies, Cont’d Justification for the presence, choice and amount of preservative is absent. From WHO Generics guideline: “Usually, in this phase the microbial challenge test could be performed to establish and justify the amount of the antimicrobial preservatives to be used. For this purpose, the drug product should be formulated with different concentrations of preservatives and a microbial challenge test on each of the formulations will give the answer on the “least necessary” but still effective concentration.”

12. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 12 | P.2.3 Manufacturing Process Development The selection and optimisation of the manufacturing process, in particular its critical aspects, should be explained. Where relevant, the method of sterilisation should be explained and justified. Differences between the manufacturing process(es) used to produce the BE batch and the proposed process should be discussed and justified, where differences may influence the performance of the product.

13. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 13 | P.2.3 Common Deficiencies Differences between the manufacturing process(es) used to produce the BE batch and the proposed process were not discussed and justified. This is a significant issue, as the proposed manufacturing process must be representative of that used to manufacture the biolot. For this reason, a comparison of the executed records of the biolot, and proposed master records should be performed.

14. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 14 | P.2.4 Container Closure System The suitability of the container closure system used for the storage, transportation (shipping) and use of the drug product should be discussed, including: - choice of materials, - protection from moisture and light, - compatibility of the materials with the FPP (including sorption to container and leaching), - performance (such as reproducibility of the dose delivery from the device when presented as part of the drug product).

15. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 15 | P.2.4 Common Deficiencies It must be clear whether the FPP is manufactured and packaged at the same site. If not, shipping of bulk product is required, and this should be validated: –Studies in the bulk container, representative of shipping conditions –Information on the container components for bulk shipping

16. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 16 | P.2.5 Microbiological Attributes Where appropriate, the microbiological attributes of the dosage form should be discussed, including, for example, the rationale for not performing microbial limits testing for non-sterile products and the selection and effectiveness of preservative systems in products containing antimicrobial preservatives. For sterile products, the integrity of the container closure system to prevent microbial contamination should be addressed.

17. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 17 | P.2.5 Common Deficiencies For solid orals, skip testing for microbial limits may be acceptable if the negative results of at least 5 production batches are submitted.

18. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 18 | P.2.6 Compatibility The compatibility of the drug product with reconstitution diluent(s) or dosage devices (e.g., precipitation of drug substance in solution, sorption on injection vessels, stability) should be addressed to provide appropriate and supportive information for the labeling.

19. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 19 | P.2.6 Common Deficiencies This section includes data only on compatibility with reconstitution diluents, or devices. Data on API-excipient, and API-API compatibility should be in section P.2.1.1.

20. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 20 | P.3 Manufacture P.3.1Manufacturer(s) The name, address, and responsibility of each manufacturer, including contractors, and each proposed production site or facility involved in manufacturing and testing should be provided. P.3.2Batch Formula A batch formula should be provided that includes a list of all components of the FPP to be used in the manufacturing process, their amounts on a per batch basis, including overages, and a reference to their quality standards.

21. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 21 | P.3 Manufacture P.3.3Description of Manufacturing Process and Process Controls A flow diagram giving the steps of the process and where materials enter the process. The critical steps and points at which process controls, intermediate tests or final product controls are conducted should be identified. A narrative description of the manufacturing process should be provided. Novel processes or technologies and packaging operations that directly affect product quality should be described with a greater level of detail. Appropriate process parameters such as time, temperature, or pH should be identified. In certain cases, environmental conditions (e.g., low humidity for an effervescent product) should be stated.

22. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 22 | P.3.3 Common Deficiencies Equipment should, at minimum, be identified by type (e.g., tumble blender, in-line homogeniser) and working capacity, where relevant. Proposals for the reprocessing of materials should be justified. Information should be confirmed to be in agreement with the proposed master production records.

23. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 23 | P.3 Manufacture P.3.4Controls of Critical Steps and Intermediates Critical Steps: Tests and acceptance criteria should be provided (with justification, including experimental data) performed at the critical steps of the manufacturing process, to ensure that the process is controlled. Intermediates: quality and control of isolated intermediates should be provided. 3.2.P.3.5Process Validation and/or Evaluation Description, documentation, and results of the validation and/or evaluation studies should be provided for critical steps or critical assays used in the manufacturing process (e.g., validation of the sterilisation process or aseptic processing or filling).

24. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 24 | P.3.4 Common Deficiencies The frequency of in-process testing should be specified. Process controls should be appropriate: - granulations: moisture (range), blend uniformity, as necessary: bulk and tapped densities, particle size distribution; - tablet cores: average weight, weight variation, hardness, thickness, friability, disintegration - coated tablets: weight gain during coating;

25. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 25 | P.3.5 Common Deficiencies adequacy of process validation protocol: - identification of critical equipment and process parameters, - definition of testing parameters, -sampling plans, -analytical procedures, - acceptance criteria, - confirmation that three consecutive, production-scale batches of this drug product will be subjected to prospective validation, or, for sterile products, adequacy of results provided.

26. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 26 | P.4 Control of Excipients P.4.1Specifications P.4.2Analytical Procedures P.4.3Validation of Analytical Procedures P.4.4Justification of Specifications P.4.5Excipients of Human or Animal Origin For excipients of human or animal origin, information should be provided regarding adventitious agents (e.g., sources, specifications; description of the testing performed; viral safety data). (Details in 3.2.A.2).

27. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 27 | P.4 Control of Excipients P.4.6Novel Excipients (name, dosage form) For excipient(s) used for the first time in a drug product or by a new route of administration, full details of manufacture, characterisation, and controls, with cross references to supporting safety data (nonclinical and/or clinical) should be provided according to the drug substance format. (Details in 3.2.A.3).

28. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 28 | P.4 Common Deficiencies Specifications should be those of the FPP manufacturer. Reference to a compendial monograph may be accepted if compendial standard with no additional tests. All components of the manufacture, whether they appear in the final product, should be discussed (eg nitrogen, solvents) Excipients from natural sources should have adequate microbial tests and limits

29. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 29 | P.4 Common Deficiencies Cont’d For certain excipients, declarations with respect to the BSE/TSE risk are required from the suppliers where the excipients are of human/animal origin: Stearic acid, Magnesium stearate and other stearates –If from plant origin, a statement to this effect will suffice Gelatin Phosphates from animal origin (eg should be asked for dibasic calcium phosphate) (Lactose is exempted from this requirement.)

30. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 30 | P.4 Common Deficiencies Cont’d Attestation (eg for API): You are requested to provide an attestation that your API is not manufactured from reagents obtained from sources that are at risk of transmitting Bovine Spongiform Encephalopathy(BSE)/Transmissible Spongiform Encephalopathy(TSE) agents.

31. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 31 | P.5 Control of Drug Product P.5.1Specification(s) P.5.2Analytical Procedures P.5.3Validation of Analytical Procedures P.5.4Batch Analyses A description of batches and results of batch analyses should be provided. P.5.5Characterisation of Impurities Information on impurities if not provided in "3.2.S.3.2 Impurities". P.5.6Justification of Specification(s)

32. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 32 | P.5 Common Deficiencies The FPP specification provided should be from the company responsible for release testing The specification should include a reference number, version, date, and appropriate standard The specification should be dated and signed by authorized personnel (i.e., the person in charge of the Quality Control department)

33. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 33 | P.5 Common Deficiencies Cont’d The specification should include all standard drug product tests and limits for that dosage form - Solid orals: description, identity, uniformity of dosage units, potency, related compounds, dissolution, microbial limits... If the tablet contains a score (justified), a one-time study of uniformity of tablet halves should be provided.

34. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 34 | P.5 Common Deficiencies Cont’d Methods and Validation Copies of the House analytical procedures (and accompanying validation) should be provided, Adequate system suitability tests should be included. Results of studies justifying the choice of in vitro dissolution or drug release conditions (apparatus, rotation speed, medium) and demonstrating its sensitivity to any changes in the product that would result in a change in one or more of the pharmacokinetic parameters.

35. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 35 | P.6 Reference Standards Information on the reference standards or reference materials used for testing of the drug product should be provided, if not previously provided in "3.2.S.5 Reference Standards or Materials".

36. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 36 | P.7 Container Closure System A description of the container closure systems should be provided, including the identity of materials of construction of each primary packaging component and its specification. The specifications should include description and identification (and critical dimensions, with drawings where appropriate). Non-compendial methods (with validation) should be included where appropriate. For non-functional secondary packaging components (e.g., those that neither provide additional protection nor serve to deliver the product), only a brief description should be provided. For functional secondary packaging components, additional information should be provided. Suitability information should be located in 3.2.P.2.

37. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 37 | P.7 Common Deficiencies Specifications (from manufacturer/packager, not supplier) should include identity (IR) of materials in contact with the drug. Plastics should meet USP tests (one-time study). Other requirements depending on the FPP form.

38. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 38 | P.8 Stability P.8.1Stability Summary and Conclusion Summary of the types of studies conducted, protocols used, and the results of the studies. The summary should include conclusions with respect to storage conditions and shelf-life, and if applicable, in-use storage conditions and shelf-life. P.8.2Post-approval Stability Protocol and Stability Commitment The post-approval stability protocol and stability commitment should be provided. P.8.3Stability Data Results of the stability studies should be presented (e.g. tabular, graphical, narrative). Information on the methods and validation if different from P.5.

39. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 39 | Dossier Assessment - FPP Each item below affects how the dossier assessment should proceed: Screening/pre-assessment FPP basic research Biostudy or biowaiver FPP form

40. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 40 | 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.

41. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 41 | FPP Basic Research Check for compendial monographs for the FPP: - PhInt, USP, BP Check standards claimed by the applicant for FPP.

42. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 42 | FPP Basic Research Other sources of information: WHOPARs: http://healthtech.who.int/pq/WHOPAR/WHOPARPRODUCTS/WHO PAR_Index.htm http://healthtech.who.int/pq/WHOPAR/WHOPARPRODUCTS/WHO PAR_Index.htm EPARs: http://www.emea.europa.eu/htms/human/epar/a.htmhttp://www.emea.europa.eu/htms/human/epar/a.htm FDA approved drug products: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm Note that these reports can include data on scoring of prequalified/approved products.

43. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 43 | 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.

44. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 44 | 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.

45. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 45 | Biowaivers There are various types of biowaivers: Different strengths (Dose-proportionality); Scale-up and post-approval changes; BCS-based biowaivers;

46. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 46 | 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

47. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 47 | 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.

48. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 48 | 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.

49. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 49 | FPP Form Sources of information International Pharmacopeia: http://www.who.int/phint/en/p/docf/ BP 2009 index: http://www.pharmacopoeia.co.uk/pdf/2009_index.pdf EDQM Knowledge Database: http://www.edqm.eu/site/Databases-10.html

50. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 50 | 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

51. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 51 | Where to Focus Sections FPP (CTD sections): P.2 Pharmaceutical Development P.3 Manufacture P.5 Specifications P.8 Stability

52. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 52 | Where to Focus Documents Certain official documents comprise the heart of the dossier. For the FPP these are mainly: Master production documents and executed records (biobatch). Process validation protocol/report or annual report. Signed FPP specifications. Signed stability protocol.

53. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 53 | Where to Focus Documents It must be stated clearly in the assessment report that the official signed documents such as specifications were reviewed, and not just the summarized data (data in summary such as PQIF/QOS). For example, under the specifications tables in the report, 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.

54. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 54 | Where to Focus Documents When referring to signed documents, it is important to include the document code including version number. Whenever updated 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).

55. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 55 | Thank you