1. Slide 1 of 19D.K. Mubangizi, Dar Es Salaam Sept. 2007 Training Workshop for Evaluators from National Medicines Regulatory Authorities in East African Community Dar Es Salaam, Tanzania Date: 10 to 14 September 2007 Evaluation of Quality and Interchangeability of Medicinal Products

2. Slide 2 of 19D.K. Mubangizi, Dar Es Salaam Sept. 2007 Evaluation of Quality and Interchangeability of Medicinal Products Finished Pharmaceutical Products  Manufacturing process and in-process controls  Process validation  Compliance with GMP Presenter: Deus K. Mubangizi, pharmacist, MSc(Pharm.) deuskm@yahoo.co.ukdeuskm@yahoo.co.uk, dmubangizi@nda.or.ugdmubangizi@nda.or.ug Chief Inspector of Drugs, National Drug Authority WHO expert

3. Slide 3 of 19D.K. Mubangizi, Dar Es Salaam Sept. 2007 Quality dossier / Section 3 Finished Pharmaceutical Product (FPP) 3.1.Manufacturing and marketing authorization 3.2.Pharmaceutical development 3.3.Formulation 3.4.Sites of manufacture 3.5.Manufacturing process 3.6. Manufacturing process controls of Critical steps and intermediates 3.7.Process validation and Evaluation 3.8. Specifications for excipients 3.9. Control of the FPP 3.10. Container/closure system (s) and other packaging 3.11. Stability testing

4. Slide 4 of 19D.K. Mubangizi, Dar Es Salaam Sept. 2007 Quality dossier / Section 3 Finished Pharmaceutical Product (FPP) 3.12. Container labelling 3.13.Product information for health professionals 3.14.Patient information and package leaflet 3.15.Justification for any differences to the product in the country or countries issuing the submitted WHO-type certificate(s)

5. Slide 5 of 19D.K. Mubangizi, Dar Es Salaam Sept. 2007 3.4. Manufacturing sites  Name and street address of each facility where any aspect of manufacture occurs including production, sterilisation, packaging and quality control – Include 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  Submit a valid GMP certificate (may not insist if inspected by WHO)

6. Slide 6 of 19D.K. Mubangizi, Dar Es Salaam Sept. 2007 3.5. 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

7. Slide 7 of 19D.K. Mubangizi, Dar Es Salaam Sept. 2007 3.5. 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.

8. Slide 8 of 19D.K. Mubangizi, Dar Es Salaam Sept. 2007 3.6. 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

9. Slide 9 of 19D.K. Mubangizi, Dar Es Salaam Sept. 2007 3.7. 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.

10. Slide 10 of 19D.K. Mubangizi, Dar Es Salaam Sept. 2007 3.7. Process Validation and Evaluation 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”

11. Slide 11 of 19D.K. Mubangizi, Dar Es Salaam Sept. 2007 3.7. Process Validation and Evaluation Purpose of 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

12. Slide 12 of 19D.K. Mubangizi, Dar Es Salaam Sept. 2007 3.7. Process Validation and Evaluation Validation mandatory for processes including a critical step 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

13. Slide 13 of 19D.K. Mubangizi, Dar Es Salaam Sept. 2007 3.7. Process Validation and Evaluation 3.7. Process Validation and Evaluation (details 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

14. Slide 14 of 19D.K. Mubangizi, Dar Es Salaam Sept. 2007 3.7. Process Validation and Evaluation  Concurrent validation carried out during normal production on the first 3 production batches OR  For well-established processes process data, in-process controls and quality controls on a total of 10- 25 batches to present a statistically significant picture

15. Slide 15 of 19D.K. Mubangizi, Dar Es Salaam Sept. 2007 3.7. Process Validation and Evaluation 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.

16. Slide 16 of 19D.K. Mubangizi, Dar Es Salaam Sept. 2007 3.7. Process Validation and Evaluation Validation protocol should include  brief description of the process with summary of critical steps and parameters to be followed during validation,  specifications of the FPP at release,  details of analytical procedures and limits,  sampling plan,  unifromity of dosage units essential for FDCs,  proposed timeframe Validation report when submitted should include results for each batch, certificates of analysis, batch production records, report on usual findings, modifications, observations and conclusions

17. Slide 17 of 19D.K. Mubangizi, Dar Es Salaam Sept. 2007 THANK YOU