Most frequent GMP deficiencies observed in sterile production facilities

1. Most frequent GMP deficiencies observed in sterile production facilities Ian Thrussell, MHRA, UK Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors, Nanjing, November 2009

2. Session Outline • Inspection Findings - Aseptic Processing • Inspection Findings – Terminally sterilised Products • Questions

3. Poorly designed processes Materials transferred into Aseptic area with insufficient sterility assurance Poor transfer of partially stoppered vials to lyophiliser Excessive holding times for sterile equipment or filtered solutions Personnel Validated processes Procedures Raw Materials Equipment PackingMaterials Environment Premises

4. Poorly designed processes Single filtration Filtration not performed as close as practicable to the filling point Inadequate response to leaking containers – no limits set to prompt an investigation Personnel Validated processes Procedures Raw Materials Equipment PackingMaterials Environment Premises

5. What happened when these filters are vented!

6. Poorly designed processes Raw material suppliers not audited but acceptance of side samples e.g. sterile API side samples accepted with no justification Prefilled syringe assembly sterilisation sites never audited Personnel Validated processes Procedures Raw Materials Equipment Packing Materials Environment Premises

7. Poor clean room and aseptic practices Filling needles installed & left unprotected while remainder of line set up still taking place Not routinely recorded/documented No monitoring during equipment set up Allowed interventions into aseptic zone are not derived from risk based process review Systems/Procedures not clear what to do upon intervention Interventions not linked to batch release process Personnel Validated processes Procedures Raw Materials Equipment PackingMaterials Environment Premises

8. Poor clean room and aseptic practices Interventions not linked to batch release process Excessive numbers of manipulations Excessive numbers of people People routinely located in the class A zone Failure to use isolation and closed techniques Personnel Validated processes Procedures Raw Materials Equipment PackingMaterials Environment Premises

9. “Any intervention or stoppage during an aseptic process can increase the risk of contamination.  The design of equipment used in aseptic processing should limit the number and complexity of aseptic interventions by personnel.”  • “Even successfully qualified systems can be compromised by poor operational, maintenance, or personnel practices.”

10. Aseptic processing operator touches floor when picking up settle plates, sanitizes hands, and then performs intervention immediately afterward • Operator removes sterile forceps from aseptic processing zone (Class 100), carries them through the surrounding Class 10,000 area, and places them on a trolley in the class 10,000 room. These were the only sterile forceps sterilized and available for aseptic manipulations. Later, the operator retrieves forceps and uses them again at the aseptic processing line to manipulate sterile product.

11. Poorly designed or maintained equipment Viewing ports on sterilising tunnels not adequately sealed Lyophilisers not sterilisable or not sterilised sufficiently frequently Vial capping performed under uncontrolled conditions Personnel Validated processes Procedures Raw Materials Equipment PackingMaterials Environment Premises

12. Construction activities • Major construction in cleanroom next to personnel entry airlock (e.g., gowning). • Construction occurred over approximately one-month period and coincided with continued production • Media Fill Failure 2 weeks later • Construction not considered to be the cause. Root causes identified by investigation considered corrected. • New Media Fill performed • Second Media Fill Failure Occurred • Contamination attributed to construction

13. Examples of misplaced stoppers from real case lines

14. Vision systems for raised stopper detection

15. Poorly designed or maintained equipmentBlow fill seal machine Cooling water Chills mold plates used to form the container-closure into which the sterile drug is filled. Demineralized potable water. Held in tank, chilled (when sampled, yields very high microbial counts) Sterility failure and media fill failure Pseudomonas, sp. and Acinetobacter, sp. found in media fill Stenotrophomonas maltophilia identified as Sterility Failure isolate Several lots rejected Both the sterility failure and media fill failure attributed to cooling water contamination Root cause of non-sterility was leak/s/ in aseptic filling machine’s mold plates. Cooling water directly contaminated product. CAPA Issue: Exact date of problem occurrence unknown. Personnel Validated processes Procedures Raw Materials Equipment PackingMaterials Environment Premises

16. Poorly designed or executed PM monitoring Samples points inappropriately positioned Alarm systems do not feedback to filling operators. Alarms and procedures unclear and confused Personnel Validated processes Procedures Raw Materials Equipment PackingMaterials Environment Premises

17. Poorly designed or executed PM monitoring Length of tubing to particle counter too long & even kinked! PMS data not reviewed as part of batch release process Overseas-use of manifold systems and no 5 micron monitoring Personnel Validated processes Procedures Raw Materials Equipment PackingMaterials Environment Premises

18. Poorly designed or executed PM monitoring Reliance on the use of contact plates and no use of swabs Reliance on active air monitoring and inadequate use of settle plates “Averaging into compliance” – inadequate attention to the individual high count Acceptance of “good pattern” of very low contamination and failure to evaluate whether the programme is effective. Personnel Validated processes Procedures Raw Materials Equipment PackingMaterials Environment Premises

19. Poorly designed or executed micro monitoring Viable sample points not close to point of fill The whole process is not monitored Viable sampling does not cover all key areas under Grade A e.g. vial turntable, stopper hopper Monitoring is not risked based and “too routine” High pre-filtration bioburden not adequately investigated and bioburden limits >> 10cfu/100ml and no justification Personnel Validated processes Procedures Raw Materials Equipment PackingMaterials Environment Premises

20. Media fills! The belief that some contamination is OK! Acceptance criteria does not meet Annex 1 & allows 1 failure to be accepted with no effective investigation Poor practices accepted as covered & justified by “passing” Media Fills! Good history does not mean failures/growth need not be investigated Implications to batches on the market or in stock subsequent to failures are not always considered fully Personnel Validated processes Procedures Raw Materials Equipment PackingMaterials Environment Premises

21. Media fills! Interventions allowed in procedures but not covered by simulations Excessive interventions not prohibited Personnel Validated processes Procedures Raw Materials Equipment PackingMaterials Environment Premises

22. Steam Sterilisation! Leak test/Bowie Dick test not performed sufficiently frequently on equipment sterilisers and failures fully investigated. Poor control of checking acceptability of autoclave cycles Engineering work not recorded No trial runs after major breakdowns to show autoclave still meets validated parameters Personnel Validated processes Procedures Raw Materials Equipment PackingMaterials Environment Premises

23. Steam Sterilisation! Long heat times during validation not investigated as no limits for heat up times = potential sterility issues Personnel Validated processes Procedures Raw Materials Equipment PackingMaterials Environment Premises

24. When sterilising equipment and components - there is just one objective • TO KNOW UNEQUIVOCALLY THAT ALL PARTS OF THE LOAD ARE SUBJECT TO DRY SATURATED STEAM AT THE REQUIRED TEMPERATURE FOR THE REQUIRED TIME.

25. Gravity Displacement Process A sterilization process based on the principle that cold air within the chamber is heavier than the steam entering and will sink to the bottom of the chamber. As steam enters the chamber, air is pushed out the bottom drain and exits, with the condensate, through a steam trap.

26. Equilibration Time The equilibration time is the period that elapses between attainment of the minimum specified sterilizing temperature in the chamber (chamber reference temperature - typically in the drain) and attainment of the minimum specified sterilization temperature in the load, as measured by the slowest-to-heat penetration probe. This period is an indication of the ability to properly condition the load through air removal and load heating.

27. Sterilization Process Development Equilibration Time

28. 1 Prevacuum - Tyvek WrappedMaterials l

29. Short equilibration times can be achieved with appropriate pre-vacuums to pre-condition (remove air and heat) the load. • With appropriate load preconditioning, any surface temperature measurement method should yield acceptable results. • With minimal load pre-conditioning, the heat penetration probes covered with autoclave tape were influenced the most.

30. Pre-vacuum Process • A sterilization process in which air is removed from the chamber using a vacuum pump or other mechanical system before the exposure phase begins.  This method is particularly suited to load items that can trap air such as tubing, filters and filling machine assemblies.

31. Steam Sterilisation & SIP systems! Air removal from equipment not adequately considered Steam quality not assessed adequately Non-condensable gases Wet steam (Dryness fraction) Superheat Clean steam quality tests are not performed at distal points of the distribution system. Steam quality test not performed following modifications Personnel Validated processes Procedures Raw Materials Equipment PackingMaterials Environment Premises

32. Oven designs! No overpressure in hot air ovens No HEPA filters on the exhaust side of the oven Personnel Validated processes Procedures Raw Materials Equipment PackingMaterials Environment Premises

33. Packaging and post sterilisation damage! Failure to meet GMP: Rough handling of bulk finished vials resulted in difficult to detect and hairline cracks in bottle. “Washdown” of vials with potable water was apparent contamination source. Patients Infected: multiple blood cultures yield Enterobacter cloacae. At least one lot “directly implicated” in septicemia Over 25 Septicemia Reports naming the lot or “unknown” Class 1 Recall: Eleven Lots (“strong likelihood that product will cause serious adverse health consequences or death”) Cultures of unopened vials grew Enterobacter cloacae Several water samples collected at firm from the water hose/sink found Enterobacter cloacae Personnel Validated processes Procedures Raw Materials Equipment Packing Materials Environment Premises

34. Sterile API – unacceptable process design! Huge Grade A/B rooms-poor differential pressures Masses of pipe work Redundant equipment Cracks, crevices, ledges……. Sterility starts here! Personnel Validated processes Procedures Raw Materials Equipment PackingMaterials Environment Premises

35. Bulk lyophilisation

36. Risk of contamination • Extent of human manipulation of sterilised filtrate and lyophilisate during loading and unloading of the large number of trays typically used in these processes. • Extent of exposure of sterilised filtrate to controlled environmental conditions during filling, lyophilisation and unloading of lyophiliser compared to lyophilisation in the final container. • Extent of aseptic operations subsequent to the sterilisation step at both drug substance and finished product manufacturer in the ‘open tray’ process compared to lyophilisation in the final container.

37. Orchid Video • E:\Training Materials\Bulk Lyophilisation Videos\Bulk Lyophilisation\Orchid videos\LYO Unloading - 3 (Frames 21-26).mpg • Qilu Video • E:\MHRA BAck ups\MHRA Laptop back ups\16_11_09\MHRA Documents\Qilu Autoloading\Video for unloading-20081210160000[4].dav