Manufacturing Process

1. Manufacturing Process Rutendo Kuwana Technical Officer, WHO, Geneva Training workshop: Training workshop on regulatory requirements for registration of Artemisinin based combined medicines and assessment of data submitted to regulatory authorities, February 23-27, 2009, Kampala, Uganda.

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 • 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. Manufacturing Process • Flow chart with indication of each step showing where materials enter the process. Indication of critical steps and 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, temperature, pH) • Environmental conditions, e.g. relative humidity for hygroscopic FPPs., area class for sterile FPPs

5. Manufacturing process (cont.) • 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 including plan of sampling and acceptance limits). • Data for 3 full scale batches to support achievement of predetermined specifications.

6. Manufacturing Process Controls of Critical steps and Intermediates • Identification of critical steps with test methods and justified acceptance criteria • Information on quality of isolated intermediates, test methods and justified acceptance criteria to control them

7. 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.

8. 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”

9. 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

10. 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

11. Critical Steps to Validate (Example)

12. Critical Steps to Validate (Example)

13. Critical Steps to Validate (Example)

14. Identification of some CQAs (Tablets)

15. Process Validation and Evaluation Details required 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

16. Other requirements • Concurrent validation carried out during normal production on the first 3 consecutive production batches OR • For well-established processesprocess data, in-process controls and quality controls on a total of 10- 25 batches to present a statistically significant picture

17. 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.

18. Validation Protocol • Objective, Scope and Rationale • Brief description of the process with summary of critical steps and parameters to be followed during validation, process flow chart • specifications and analytical methods of the FPP at release, • details of analytical procedures and limits, • List of equipment to be used • sampling plan and acceptance criteria • Defined CPPs to be monitored and CQAs to be tested • proposed timeframe Validation report when submitted should include results for each batch, certificates of analysis, batch production records, report on unusual findings, modifications, observations and conclusions

19. Validation Report Outline – Each Batch • Objective • Scope • Validation Batch Information • Deviation report • Critical Quality Attributes (CQAs) Test Data • Statistical Evaluation of CQAs • Conclusion NB: One batch, One Report

20. Validation Report Outline – Final • Objective • Scope • Validation Batch Information Summary • Summary on CQAs and Test Data evaluated • Overall Conclusion • Recommendation NB:Three Batches, One Report