1. Common Deficiencies in submissions for Prequalification (Quality part) HUA YIN Prequalification of Medicines Programme QSM / EMP / HSS WHO prequalification programme: Training workshop March 2010, Beijing

2. 2 |2 | Documentation 1.The product submitted for prequalification is NOT in the latest EOI (should be the same API and strength) 2.The cover letter from the applicant did not clearly indicate that the information submitted is true and correct. 3.The PQIF and BTIF are NOT submitted or submitted but Not in word document. 4.The dossier submitted does NOT have (clear) table of contents and the numbering of dossier pages does not follow one sequence. 5.The FPP applicant has made reference to the APIMF, but a copy of the Letter of Access from the APIMF holder is not submitted.

3. WHO prequalification programme: Training workshop March 2010, Beijing 3 |3 | Common Deficiencies Active Pharmaceutical Ingredient (API)

4. WHO prequalification programme: Training workshop March 2010, Beijing 4 |4 | S.1.3 General Properties Water solubility of the API is not characterized: –Quantitatively (over the physiological pH range 1.2- 6.8)* –For a low-solubility API, particle size, polymorphism, should be characterized (based on the lot used in clinical or bioequivalence studies) See decision tree #3, #4 in ICHQ6A

5. WHO prequalification programme: Training workshop March 2010, Beijing 5 |5 | S.2 Manufacture Description of the manufacturing process is not sufficiently  Flow chart and detailed description of the manufacturing of API, operating conditions and materials used, typical batch size should be provided. Specifications of materials used are not complete  When the starting material (SM) is not available commercially or is only one or two steps from the final API, or is not of simple structure, the synthetic route of the SM should be provided, as well as the detailed specifications especially regarding the impurity profile including residual solvents.  solvents, reagents and catalysts used in the process and their specifications, should include as a minimum an identification test and an assay.specification of recovered solvents should be provide

6. WHO prequalification programme: Training workshop March 2010, Beijing 6 |6 | S.3Characterisation Discussion on potential impurities is not sufficient The following information should be provided: –List of impurities including chemical name, structure, and origin (e.g., starting materials, by-products, intermediates, chiral impurities, degradations) –All potential residual solvents should be discussed, and controlled in specifications unless adequately justified. –If catalysts are used in the synthesis, these should be controlled in specifications unless adequate justified –Data on observed impurities in batches used in clinical or BE study –Impurity limits must be suitably qualified (ICHQ3A)

7. WHO prequalification programme: Training workshop March 2010, Beijing 7 |7 | S.4Control of Drug Substance Copy of the compendial monograph is not considered as sufficient The specifications should have tests/limits meeting existing compendial monographs—as minimum requirement. However, –The suitability of the monograph method to determine new impurities due to a new route of synthesis must be demonstrated. If not, propose a new validated method and a qualified limit. –The purity and potency methods should be verified for specificity, precision and accuracy. –The API specification from the manufacturer of the FPP should be provided, including the parameters related to the specific product. It should be dated and signed by authorized personnel.

8. WHO prequalification programme: Training workshop March 2010, Beijing 8 |8 | S.5Reference Standards Information on reference standard is missing –Where a compendial reference standard (RS) exists, this should be the primary standard against which all house standards are qualified. –Where no compendial RS exists, the primary standard should be highly purified and fully characterized. Potency should be based on mass balance. –Whether any additional purification solvents used for the reference standard could result in modified properties (e.g. polymorphism).

9. WHO prequalification programme: Training workshop March 2010, Beijing 9 |9 | S.6 Container Closure System Identification of container-closure/packaging of the API is not done –Identity of materials of construction of primary packaging –Specifications for components in contact with the API should include a specific test (eg IR) for identity. –Container specifications should be provided by API packager, not the packaging supplier. –The packaging should be food and/or pharmaceutical grade

10. WHO prequalification programme: Training workshop March 2010, Beijing 10 | Common Deficiencies Finished Pharmaceutical Product (FPP)

11. WHO prequalification programme: Training workshop March 2010, Beijing 11 | FPP Description and Composition Description of the FPP is incomplete. Good example: White to off white coloured capsule shaped biconvex uncoated tablets with central breakline on one side and debossed with ‘A’ on other side Description of the Packaging is incomplete. Good example: The primary packs are cylindrical, white, opaque, induction- sealed HDPE bottle fitted with a white Non CRC Screw Cap and containing 1 gm Silica gel bag and Rayon Sani coil.

12. WHO prequalification programme: Training workshop March 2010, Beijing 12 | FPP Description and Composition The composition has errors: –Not in agreement with the master production records –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.

13. WHO prequalification programme: Training workshop March 2010, Beijing 13 |

14. WHO prequalification programme: Training workshop March 2010, Beijing 14 | 3.2. Pharmaceutical development Pharmaceutical development is absent or not complete.  Lack of information on physico-chemical characteristics of the API which may have an impact on the manufacturing and performance of the product. such as particle size distribution, bulk/tapped density, polymorphic form  Compatibility of the API with excipients and in case of FDCs compatibility between APIs are not studied or at least not shown in the dossier. –Compatibility studies often report appearance only. Studies should include chromatographic results (potency and impurity). e.g. Rifampicin/Isoniazid  Rationale behind choice of manufacturing process, overages (if any), not given. e.g. Rifampicin

15. WHO prequalification programme: Training workshop March 2010, Beijing 15 | 3.2. Pharmaceutical development Lack of comparative dissolution testing with the innovator/comparator Comparative dissolution testing is a tool  Help in selection of the formulation – compare formulation(s) with innovator product, – a basic strategy in development to maximize the chances of bioequivalence  Comparison of dissolution properties of pivotal batches with future commercial batches, post-approval changes  Setting of dissolution specification For solid dosage forms, it is a requirement to submit comparative dissolution data for the biobatch and innovator/comparator batch used in the bioequivalence. These data can be included in both part quality and bioequivalence study of the dossier.

16. WHO prequalification programme: Training workshop March 2010, Beijing 16 | 3.5 Manufacturing Process  Missing of typical commercial batch size  Batch manufacturing records are not included  Poor description of manufacturing process –In-process testing should be specified. –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; –Equipment should, at minimum, be identified by type (e.g., tumble blender, in-line homogeniser) and working capacity –process parameters such as time, temperature, speed should be indicated

17. WHO prequalification programme: Training workshop March 2010, Beijing 17 | 3.7 Process Validation and Evaluation Process validation protocol is not adequacy –Description of the manufacturing process & Flow diagram –identification of critical steps and process parameters to be monitored –equipments to be used in the process –sampling plans i.e. location, time and method –Proposed in-process controls with acceptance criteria –The frequency of in-process testing –Finished product release specification – Evaluation of results Confirmation/commitment that three consecutive, production-scale batches of this drug product will be subjected to prospective validation.

18. WHO prequalification programme: Training workshop March 2010, Beijing 18 | 3.9. Control of the FPP –The specification should include a reference number, version, date, and appropriate standard, (e.g. Int.Ph+ In-house) –The specification should be dated and signed by authorized personnel –Details of specifications and test methods should be provided sufficiently. –information for reference standard –justification of specifications

19. WHO prequalification programme: Training workshop March 2010, Beijing 19 | 3.9. Control of the FPP –Validation of analytical methods and/or demonstration of applicability for pharmacopoeial methods –The FPP is a pharmacopoeial product and the pharmacopoeial method is used but a minimum validation is not performed. –The pharmacopoeial monograph cannot cover all the formulations for a FPP. As a minimum, the selectivity of the pharmacopoeial method towards a specific formulation should be demonstrated, in terms of specificity, precision and accuracy. –If the tablet contains a score (justified), a one-time study of uniformity of tablet halves should be provided. refer to TABLETS, Subdivision of tablets (EP, 5.5, p. 4166)

20. WHO prequalification programme: Training workshop March 2010, Beijing 20 | 3.11 Stability testing Incomplete stability to meet the requirements as stimulated in the regulations & guidelines –three batches, at least pilot scale. Batch No., B.size –in the claimed commercial packaging –6 months accelerate (40°C / 75% RH) + 12 months long term data + commitment to continue Unless otherwise justified, 30°C / 75% RH is the recommended storage condition for Prequalification

21. WHO prequalification programme: Training workshop March 2010, Beijing 21 | 3.11 Stability testing Lack of discussion and evaluation of the results Variation in analytical results, Example –Stability specificaiton limit of API : 92.5-105.0% –Stability data: 102.0% at initial→95.0% at end of 24 months (Within spec), But, loss in potency: 7.0% –Disscuss: is it a real trend of decrease in assay or due to method variability? Investigation of the Out of Specification (OOS) results. Investigation of known/unknown degradation products Justification of the shelf life specification –widening of the acceptance criteria at the end of shelf-life is possible for some parameters with justification, such as degradants and assay –but unacceptable for some other, such as dissolution

22. WHO prequalification programme: Training workshop March 2010, Beijing 22 | 3.11 Stability testing In-use stability testing is not provided –To provide information for the labelling on the preparation, storage conditions and utilization period of multidose products after opening, reconstitution or dilution of a solution, such as powder for oral solution/suspension –The test should be designed to simulate the use of the FPP in practice, –Monitor the physical, chemical and microbial properties of the FPP susceptible to change during storage. Although there is no control of impurities in monograph, degradation should be monitored in stability studies—products contain rifampicin. –A minimum of two batches, at least pilot-scale –At least one of these batches should be chosen towards the endof its shelf-life, or at the final point of the submitted stability studies

23. WHO prequalification programme: Training workshop March 2010, Beijing 23 | Documentation in English Original documents to be submitted with translation –Certificates, Manufacturing license, MA, GMP, TSE –Manufacturing process documentation  Batch manufacturing record  Validation reports  Specifications and CoAs

24. WHO prequalification programme: Training workshop March 2010, Beijing 24 | Documentation in English Terms of specification: essential to be correct. Example: IR/UV absorption chromatogram does not exist. it should be spectrum Moisture: is not equal to Water in a molecule with two moles of water of crystallization. It should be water content Calculated on “dehydrated products” is not an acceptable term for “anhydrous basis.” Tips: use pharmacopoeia Int Ph/USP/BP terms

25. WHO prequalification programme: Training workshop March 2010, Beijing 25 | Other sources of information: refer to the drug information of innorvators, approved generics for SmPC, FPP description, packaging information, etc. 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

26. WHO prequalification programme: Training workshop March 2010, Beijing 26 | Thank you