6 th CPH assessment training workshop May 2014

1. Process validation 6th CPH assessment training workshopMay 2014 Wondiyfraw Worku, Assessor

2. Talk points • Objectives of review of quality(CMC) data- reminder • Process validation, definition and current approaches • Role of dossier assessment in process validation • Risk assessment as part of process validation • Validation scheme: Monitoring and Sampling • Specific topics: Blend uniformity and validation of compression step • Process validation: other dosage forms • Process validation commitment • Retrospective validation • Summary: How to review protocol and report

3. Reminder • Objectives of assessment of quality part • To provide the highest assurance that all production batches (unit doses) will be consistentlyefficaciousas the clinical batch(es) • To reduce risk to safety via the highest assurance of acceptable andconsistentquality of the product and its components Process validation

4. Process validation • The collection and evaluation of data, from the process design stage through commercial production, which establishes scientific evidence that a process is capable of consistently delivering quality products. (FDA) • Documented evidence which provides a high degree of assurance that a specific process will consistently result in a product that meets predetermined specifications and quality characteristics. (WHO) • The documented evidence that the process, operated within established parameters, can perform effectively and reproducibly to produce a medicinal product meeting its predetermined specifications and quality attributes.(EMA)

5. Process validationTraditional vs new paradigm ICH Q8, QbD Development- Basic Enhanced-Development and process qualification Pilot batch manufacturing Post approval changes/change controls/risk analysis Process validation- 3 batches Continuous and extensive monitoring of CQAs and CPPs for each production batch Control Strategy ICH Q9 and Q10

6. Latest guidelines

7. Types of process validation and dossier requirements

8. Process validation- Role of assessment Process validation Operational qualification Performance qualification Design qualification Dossier GMP

9. Process validation phases Includes demonstration of content uniformity of the clinical batch Pre-validation phase Protocol Preparation Information from primary/clinical manufacturing (scale up information) Process risk assessment information (identification of critical steps) Validation phase Protocol execution Information from product development studies (identification of critical attributes) Post valdn phase: Review of process, deviations, failures, need for improvement, scale up etc…

10. Risk assessment • Part of process development and protocol preparation • Risk matrix- usually as part of process development • Critical quality attributes (CQA) vs processing stages, e.g. dissolution vs granulation • CQA vs critical process parameters, e.g., dissolution vs kneading time • Failure mode analysis- usually as part of process validation • To identify critical attributes, processes and parameters • Informed validation • To establish control strategy

11. Example: risk matrix for low dose capsule (CQA vs process stages)

12. Process steps to be validated • All steps that are generally considered critical (medium and high risk steps) should be monitored/scrutinized • by summarizing actual process parameters applied and observations recorded • e.g. sifting stage, wet and dry granulation stages • observations serve as feedback for future refinement of process parameters • In addition, where feasible, sampling and testing should be performed • e.g. drying, mixing steps, compression, filling • results measure effectiveness and consistency of the immediate as well as preceding steps- e.g. final blend characteristics are mainly shaped by wet/dry granulation process

13. Validation scheme- example

14. Monitoring- Example:Compaction • Any comment vis à vis the difference between BMR set range and actual applied inputs?

15. Example: Monitoring and sampling:Drying

16. Blend uniformity • Early check for content uniformity of the final dosage form Uniform blend with good flow and compressibility characteristics Compression with optimum conditions Tablets meeting criteria for uniformity of dosage units Note: Blend uniformity is a routine test for low dose products (i.e. active load <=5% or 5mg)

17. Blend uniformity- Sampling location and method • Sampling location -usually predetermined as part of qualification of the mixer (i.e. mostly GMP issue) • But, in the dossier, we at least check if periphery, center positions and various other positions are considered • Samples from each location are usually taken in triplicate • Samples should also be taken from the blend container- to evaluate impact of transfer • important for low dose products and particularly for DC processed blend • Sampling should be done consistently and in away that does not disturb the bulk blend state – such aspects (e.g. type of sampling thief used) are better addressed at the time of inspection

18. Blend uniformity- Sample size • What is an acceptable amount for samples taken at each location? • Normally 1-3 time of the FPP unit dose weight C. Morten, PIAT programme, University of Manchester

19. Blend uniformity- acceptance criteria • Commonly used criteria • Individual assays: 90.0-110.0% of label claim, RSD NMT 5.0% • Less common • Individual assays:90.0-110.0% of the mean value, RSD NMT 5.0% • In this case, setting mean = 95.0-105.0% of the label claim appears reasonable • Rarely (in case of very low dose products) • Individual assays: 85.0-105.0% of the label claim/mean value, RSD: NMT 5.0% • May be acceptable provided that uniformity of dosage units is satisfactorily demonstrated on tablets/capsules manufactured from blend lot with close to limit blend uniformity results

20. Sampling and testing plan- Lubrication- example What are the minimum tests we expect to see in blend spec? Do you agree with the acceptance criteria? missing parameter? Acceptable?

21. Compression • Good compression outcome is a measure of (it depends on):- • Granule/powder mix properties • bulk and tapped density-granulation • particle size and particle size distribution-granulation • moisture content- drying • extent of lubrication- lubrication time • Machine and tooling attributes • appropriate selection and adequate lubrication of punches and dye • machine speed • applied compression pressure

22. Compression – Sampling frequency and size • depends on the length of the run time/ batch size • we expect frequent sampling than the normal IPQC frequency • the number of tablets/capsules taken should be greater than those taken during a normal IPQC sampling

23. Compression- Challenge studies • Certain variations in compression speed and hardness than the target set points may happen • what would be the impact of such variations? • speed affects dwell time- which intern affects several tablet parameters (thickness, hardness, as well as weight variation) • Therefore, robustness should be demonstrated C. Morten, PIAT programme, University of Manchester

24. Extensive sampling- example(there are several other approaches)

25. How to demonstrate consistency? 3 sigma process e.g. 4 sigma process

26. Process validation-oral solutions • Validation focuses on • mixing time and conditions to clear solution, if deemed relevant • bulk liquids: pH, specific gravity, clarity of solutions; assay • filling process • filled units:- Volume/Wt variation and as per FPP specs • Protocol with commitment is acceptable at the time of review

27. Process Validation- Oral suspensions • Focuses on • API micronization processes (if applicable) • colloidal milling process (as applicable), • homogenization • filling • Viscosity, fill volume/weight variation, • Other critical attribute that may be affected by filling process? • Other parameters as per FPP spec including, PSD, pH, dissolution, • Protocol with commitment is acceptable at the time of review

28. Process validation- sterile products

29. Process validation- sterile products-Contd

30. Dissolution profile comparison with clinical/BE batch- solids and suspensions (as part of process validation) • A good check point to verify performance relative to the biobatch • All validation batches should be profiled in the routine media on 12 units, using time points as used for biobatch • Comparison with historical biobatch profile, with calculation of f2 (as necessary), should be performed and results discussed • Check if the protocol includes adequate instruction/provision

31. Matrixing/bracketing approach • Multiple strengths of same product (common blend) • until stages of final granules: 3 consecutive batches of the common blend (instead of 3 separate blend batches for each strength) • compression: 3 consecutive batches of each strength • Primary packaging of tablet/capsule products • blistering of hygroscopic or moisture sensitive products however should always be individually validated

32. Process validation- commitment • As described in Annex 4, TRS 970, applicants are not expected to have process validation data before PQ • In this case satisfactory PV protocol (PVP) and appropriately worded commitment are essential • PVP or signed commitment letter should clearly indicate the need for prospective validation as finalized on three consecutive production batches, unless other wise justified.

33. Retrospective validation for established products • Generally acceptable if condition described in Annex 4, TRS 970 (generic guide), are met. • Tries to demonstrate process effectiveness and consistency via trend analysis: • extent of deviations • extent of OOSor OOT • extent of batch rejection • extent of product complains • extent of changes/ improvements introduced • See Appendix 2 of Annex 4, TRS 970

34. Review of protocol- main aspects to check • Scope of the validation (type, batch size, reason)- do they reflect the planned validation? Highest batch size to be validated? • Major equipments identified (in line with BMR) and a provision for recording their Q status included? • Reference to current master production record included? • Summary of critical steps identified? is this convincing ? • Monitoring and sampling plan provided?- Do you agree with the steps monitored/sampled? • Sampling schedule, schematics, tests and acceptance criteria, as well as current specification codes included ? Are these acceptable?

35. Review of protocol- main aspects to check-contd • For solid orals: final blending, compression/encapsulation, coating stages must be adequately sampled and tested. Are these being reflected? • Blend uniformity: Sampling schemes and blend uniformity acceptance criteria specified? Are these acceptable? • Compression/encapsulation at lower, target and upper speeds included? • Provision for performance of dissolution profile testing and comparison with the biobatch included? • Appropriate commitment (prospective validation on first three consecutive batches mentioned) provided? • Protocol reference and version number included in QIS?

36. Review of validation report • Is the reported data relevant for the proposed manufacturing process and scale • equipment used, process parameters applied • All critical steps adequately monitored/sampled? • Level of sampling and size are acceptable? • All results within acceptable limits? Particular trend? • Deviations appropriately evaluated and discussed? • Is the overall process in sufficient control? Is there any thing that should be improved or refined for future production batches

37. Thank you, Questions?