MANUFACTURING PROCESS AND VALIDATION

1. MANUFACTURING PROCESS AND VALIDATION Rutendo Kuwana Training workshop: Assessment of Interchangeable Multisource Medicines, Kenya, August 2009

2. Finished Pharmaceutical Product Manufacturing Manufacturing and marketing authorization Pharmaceutical development Formulation Sites of manufacture Manufacturing process Manufacturing process controls of Critical steps and intermediates Process validation and Evaluation

3. Manufacturing site(s) Name and street address of each facility where any aspect of manufacture occurs including production, sterilisation, packaging and quality control Blocks and Units should be clearly stated Including any alternative manufacturers Certificate issued by the Competent DRA according to WHO Certification scheme for each site where a major step of manufacturing is performed Valid GMP certificate (may not insist if inspected by WHO)

4. Development of manufacturing process Pre- formulation Formulation Pilot manufacture Industrial Scale 4

5. Development of manufacturing process Relationship between method of manufacture and process validation data Process should address the need and value of in process controls Process evaluation and validation should justify reduction of some tests from routine 5

6. Development of manufacturing process Scale Up Data Used to generate information from laboratory through pilot to production scale batch Evidence that scale up will not result in loss in quality Should show that variations in batch size will not adversely alter FPP characteristics 6

7. Manufacturing processInformation required Flow diagram critical steps – in-process controls Description of manufacturing/packaging, including Scale Equipment by type (e.g. tumble blender) & working capacity Process parameters for steps, e.g. time, temp, pH Environmental conditions, e.g. rel. humidity for hygroscopic FPPs. 7

8. Manufacturing process (2) Proposal for reprocessing – justified with data Copy of master formula Batch manufacturing record – real batch Sterile products – sterilisation steps and / or aseptic procedures Description of in-process tests Data for ≥ 3 full scale batches to show achievement of predetermined specifications 8

9. Manufacturing processControls of critical steps and intermediates Critical steps Acceptance criteria (justified) Test methods (cross reference acceptable) Intermediates isolated during process e.g tablet cores in film-coated tablet production Acceptance criteria (justified if not Compendial) Test methods (cross reference acceptable) 9

10. ManufacturingProcessControls of Criticalsteps and Intermediates

11. ManufacturingProcessControls of Criticalsteps and Intermediates

12. Process Validation and Evaluation WHO validation definition The documented act of proving that any procedure, process, equipment, material, activity, or system actually leads to the expected results. Process validation is the collection and evaluation of data, from process design stage throughout production, which establishes scientific evidence that a process is capable of consistently delivering quality products US FDA

13. Process validation & evaluation Differentiate between the following generics: New FPPs(new for manufacturer, not marketed yet) FPPs that have been newly developed by the manufacturer, though it will be a generic Full validation required Established FPPs The manufacturer has manufactured & marketed this FPP for quite some time Submit review of report for ≥ 10 recent consecutive batches Manufactured within the preceding year. If less than 10 batches, may extend the period to 3 years result/trend/statistical analysis & discussion Rejected batches excluded - submit failure investigation 13

14. What should be validated ? “Any aspect of operation, including significant changes to the premises, facilities, equipment or processes, which may affect the quality of the product, directly or indirectly, should be qualified and validated”

15. Purpose of Process Validation Process validation is intended to establish that the proposed manufacturing process is a suitable one and yields consistently a product of the desired quality.i.e. that the process is suitable and under control

16. Process Validation and Evaluation Validation is mandatory for processes including all critical steps The aim is to show that critical steps are under control and lead continuously to the desirable quality Examples of critical steps (list non exhaustive) mixing, coating, granulation, emulsification, non-standard sterilisation

17. Process Validation and EvaluationDetailsrequired on first 3 production batches Batches batch number batch size place and date of manufacture batch number of API(s) yield batch purpose (validation, stability, clinical trial …) Process equipment process parameters validation protocol. Results critical steps in process control finished product specification

18. Validation “new” productConcurrent / prospective validation (1) Concurrent validation Carried out during normal production First 3 production batches (prospective validation) In-process controls are set on outcome of validation Extensive sampling and testing during process, for example (tablets) planned sampling on mixing / granulation stages for content uniformity (low-dose FPPs & FDCs !) A large number of tablets for mass and/or content uniformity, hardness, friability and even dissolution Sampled according to plan during process Statistical analysis of results with conclusions To be within acceptance criteria 18

19. Validation “new” productConcurrent / prospective validation (2) Parenteral products, aseptically filled (if terminal sterilization is not possible) Filling ampoules with culture media, then Incubation and control of microbial growth Level of contamination: ≤ 0.1% Challenge experiments to determine robustness of process effect of material variations, such as particle size can be carried out on experimental batches e.g. stability of granulate over time Effect in case of unplanned stoppage 19

20. Validation “new” productConcurrent / prospective validation (4) Laboratory scale batches (small size), To support e.g. formulation and packaging development Pilot batches Used e.g. in stability and safety/efficacy studies Size for oral solid dosage forms: the largest of 10% of production scale or 100,000 units Productions scale For full validation and stability studies Scale-up / scale down after registration Up to10-fold compared to the original batch size (minor amendment/change) 20

21. Process Validation Data Compliance with FPP specifications alone inadequate to demonstrate validation of processes and control over process Manufacturer may not have completed formal validation on production scale batches Important to link development and evaluation of laboratory and pilot scale batches, process development and optimisation 21

22. Development of manufacturing processProcess Validation Scheme/Protocol To be used for applications where production scale batches not yet produced To outline the formal validation process to be conducted on production scale batches (at least 3 consecutive batches) Data should be available for verification post - registration 22

23. Development of manufacturing processProcess Validation Scheme/Protocol (2) Information required - short description of the process including critical processing steps or parameters to be monitored - FPP release specifications - Details of analytical methods - IPC proposed and acceptance criteria - additional testing and analytical validation - sampling plan – where, when and how samples are taken - details of methods for recording and evaluating of results - proposed timeframe 23

24. Development of manufacturing processProcess Validation Report After validation Batch analytical data Certificates of analysis Batch manufacturing records Report on unusual findings, modifications or changes found necessary with appropriate rationale Conclusions Significant deviations to be informed to DRA and regulatory approval required before implementation 24

25. Other requirements For well-established processes/productfor the manufacturer – report on review of NLT 10 batches manufactured in the past 12 months

26. Review report for established FPP should contain at least the following • List of reviewed batches - batch numbers, manufacturing dates and batch size. Any differences from the prequalified/approved batch size should be clarified. • Review of starting materials (active pharmaceutical ingredients (APIs) and excipients) – list of sources (API), compliance with specifications • Review of primary packing materials used in the FPP, including reference to those from new sources. • A tabulation of Batch Analysis data (including in-process test results and finished product quality control results) together with statistical and trend analysis where appropriate. • A review of all out-of-specification and related investigations, with indication of batches that failed to meet specification(s) • A review of all deviations. • All changes carried out • Quality-related returns, complaints and recalls.

27. Alternatives If validation data (on production scale batches) are not available submit validation protocol, commitment that validation report will be submitted later for evaluation, commitment that data will be available in case of inspection, commitment that WHO will be informed of any significant deviation.

28. Analytical Methods Process knowledge depends on accurate and precise measuring techniques on starting material, intermediates and finished product. For data to be of value the analytical tests must be scientifically sound Validated analytical methods are not required during product and process development activities. The methods should however be scientifically sound (e.g. specific, sensitive, accurate), suitable and reliable for the specified purpose.

29. Use of analytical methods - generics