1. Module 1, Part 3: Process validation Slide 1 of 22 © WHO – EDM – 12/2001 Validation Part 3: Process validation Supplementary Training Modules on Good Manufacturing Practices

2. Module 1, Part 3: Process validation Slide 2 of 22 © WHO – EDM – 12/2001 Validation Objectives To review: l Validation, risk analysis, and critical steps of processing l Points to consider in process validation of: ä solid dose mixing ä tablet compression ä sterilization l Finalization of validation

3. Module 1, Part 3: Process validation Slide 3 of 22 © WHO – EDM – 12/2001 Introduction Validation

4. Module 1, Part 3: Process validation Slide 4 of 22 © WHO – EDM – 12/2001 Validation Reliable, repeatable, under control l At least first 3 consecutive batches - repeatable l Must investigate failures l The rationale should be documented if experimental method is changed  document deviations, decisions and reasoning l Does not improve processes l Should not validate bad processes

5. Module 1, Part 3: Process validation Slide 5 of 22 © WHO – EDM – 12/2001 Validation Design user or process requirements Install installation qualification Operate operational qualification Validate performance qualification and process validation Review periodically (+ change control) DQ, IQ, OQ and PQ

6. Module 1, Part 3: Process validation Slide 6 of 22 © WHO – EDM – 12/2001 Validation Critical factors or parameters l Need to be determined l Need to be monitored during validation l May affect the quality of the product

7. Module 1, Part 3: Process validation Slide 7 of 22 © WHO – EDM – 12/2001 Validation Setting Limits l Marketing authorization limits ä stability specifications l Release specification l Validation limits Batch release limits Marketing authorisation limits based on stability specifications Validation limits

8. Module 1, Part 3: Process validation Slide 8 of 22 © WHO – EDM – 12/2001 Determining critical control point example of a tablet granulation process l Particle size distribution of the active(s) l Blending time for the powder l Granulating time and speed, l Amount of granulating fluid-binder concentration l Drying time - final moisture content, granule particle size distribution l Granule active content and homogeneity, blending time of external phase Validation

9. Module 1, Part 3: Process validation Slide 9 of 22 © WHO – EDM – 12/2001 Validation Determining critical control points

10. Module 1, Part 3: Process validation Slide 10 of 22 © WHO – EDM – 12/2001 Solid dose mixing (1) Homogeneity in blending – the key to quality! l Sampling strategy l Sample site, label, container l Storage l Transport l Sample thief Validation

11. Module 1, Part 3: Process validation Slide 11 of 22 © WHO – EDM – 12/2001 Solid dose mixing (2) l In situ analysis l Methods of analysis l Statistical analysis ä inter-batch ä intra-batch ä within-sample-site Validation

12. Module 1, Part 3: Process validation Slide 12 of 22 © WHO – EDM – 12/2001 Validation Tablet compression variables l Fill volume l Pre-compression force, compression force l Turntable speed l Dwell time l Granule size and feed l Ejection force, lubrication

13. Module 1, Part 3: Process validation Slide 13 of 22 © WHO – EDM – 12/2001 Validation Tablet compression parameters l Mass l Hardness l Moisture l Friability l Disintegration l Dissolution l Thickness Tablet coating variables l Spray rate l Inlet and outlet air temp l Coating weight

14. Module 1, Part 3: Process validation Slide 14 of 22 © WHO – EDM – 12/2001 Validation l Lethality of cycle l D value l Z value l F value l F o value min 8 Moist heat sterilization “Z”

15. Module 1, Part 3: Process validation Slide 15 of 22 © WHO – EDM – 12/2001 Validation Sterilization validation (1) l Sterility test l Physical measurements l Chemical and biological indicators l Loading patterns

16. Module 1, Part 3: Process validation Slide 16 of 22 © WHO – EDM – 12/2001 Validation Sterilization validation (2) l Cooling fluid or gas l Automated process l Leak tests l Control instrumentation l Steam quality l Heat distribution

17. Module 1, Part 3: Process validation Slide 17 of 22 © WHO – EDM – 12/2001 Validation Dry heat sterilization l Parameters l Air circulation, positive air pressure, HEPA filter l Advantages ä microorganisms destroyed ä depyrogenation possible l Disadvantages ä poor heat transfer ä higher temperatures for long periods

18. Module 1, Part 3: Process validation Slide 18 of 22 © WHO – EDM – 12/2001 Validation Process variation Controllable causes of variation may include: l Temperature, humidity l Variations in electrical supply l Vibration l Environmental contaminants l Light l Human factors l Variability of materials l Wear and tear of equipment

19. Module 1, Part 3: Process validation Slide 19 of 22 © WHO – EDM – 12/2001 Validation Change control l Must be a review procedure for validated processes l From time to time changes may be necessary l Documented change control procedure needed l “Like for like" changes do not require re-validation

20. Module 1, Part 3: Process validation Slide 20 of 22 © WHO – EDM – 12/2001 Mixing validation liquid and solid dose change control and scale up l Mixer type and size l Batch size l Pilot study scale up l Limit on the proportion of the scale up Validation

21. Module 1, Part 3: Process validation Slide 21 of 22 © WHO – EDM – 12/2001 Validation Finalization of validation process l Final report required l Summarize and reference protocols and results l Conclusion required: “Is the process valid” l Final report should be reviewed and approved by ä the validation team ä “authorized person”

22. Module 1, Part 3: Process validation Slide 22 of 22 © WHO – EDM – 12/2001 Validation Group Session l You are given a tablet manufacturing flow chart to study l List the critical steps that are required to be validated l List the critical equipment required to be qualified l Identify the variables and construct a table as directed