1. Module 13Slide 1 of 48 WHO - EDM Part Three Basic Principles of GMP Sterile Production

2. Module 13Slide 2 of 48 WHO - EDM Sterile Production Objectives l To review basic GMP requirements in the manufacture of sterile products l To review air classifications for activities related to the manufacture of sterile products l To review the different types of sterilisation methods l To review quality assurance aspects in the manufacture and control of sterile products l To consider current issues applicable in your country.

3. Module 13Slide 3 of 48 WHO - EDM Sterile Production Types of sterile products l Terminally sterilised ä prepared, filled and sterilised l Sterilised by filtration l Aseptic preparation

4. Module 13Slide 4 of 48 WHO - EDM Sterile Production GMP Requirements for Sterile Products l Additional rather than replacement l Specific points relating to minimizing risks of contamination ä microbiological ä particulate matter ä pyrogen

5. Module 13Slide 5 of 48 WHO - EDM Sterile Production General Requirements l Production in clean areas l Airlocks for entry ä personnel ä goods l Separate areas for operations ä component preparation ä product preparation ä filling etc l Level of cleanliness l Filtered air

6. Module 13Slide 6 of 48 WHO - EDM Sterile Production General Requirements (contd) l Air classification: Grade A, B, C and D l Laminar air flow: ä air speed (horizontal versus vertical flow) ä number of air changes ä air samples l Conformity to standards l Work station and environment l Barrier technology and automated systems

7. Module 13Slide 7 of 48 WHO - EDM Sterile Production Manufacture of sterile preparations l Terminally sterilised ä preparation: – Grade C: then immediate filtration and sterilisation – Grade D: Closed vessels – Grade A: Filling (Grade C environment) of parenterals – Grade C: Filling of ointments, suspensions etc

8. Module 13Slide 8 of 48 WHO - EDM Part Three 17.5.1 Sterile Production Classifications - I Terminally Sterilized Products

9. Module 13Slide 9 of 48 WHO - EDM Sterile Production Manufacture of sterile preparations l Sterilisation by filtration ä Handling of starting materials – Grade C – Grade D: Closed vessels – Sterile filtration into containers: Class A (in Class B environment) or Class B (in Class C environment)

10. Module 13Slide 10 of 48 WHO - EDM Part Three 17.5.2 Sterile Production Classifications - II Sterile Filtered Products

11. Module 13Slide 11 of 48 WHO - EDM Part Three 17.5.3 Sterile Production Classifications - III Products produced from Sterile Materials

12. Module 13Slide 12 of 48 WHO - EDM Sterile Production Manufacture of sterile preparations l Aseptic preparation ä Handling of materials ä All processing ä Grade A in Grade B environment or ä Grade B in Grade C environment

13. Module 13Slide 13 of 48 WHO - EDM Part Three 17.16 - 17.21 Sterile Production Premises l Design ä avoid unnecessary entry l Clean areas ä smooth, impervious, unbroken surfaces ä permit cleaning ä no uncleanable recesses, ledges, cupboards, equipment ä no sliding doors ä ceilings ä pipes and ducts ä sinks and drains

14. Module 13Slide 14 of 48 WHO - EDM Part Three 17.22 - 17.23 Sterile Production Premises l Changing rooms ä designed as airlocks ä flushed with filtered air ä separate for entry and exit desirable ä hand washing facilities ä interlocking system ä visual and/or audible warning system

15. Module 13Slide 15 of 48 WHO - EDM Part Three 17.34 - 17.37 Sterile Production Sanitation l Clean areas ä frequency ä SOP l Disinfectants ä periodic alterations ä monitor microbial contamination ä dilutions, storage and topping-up l Fumigation l Monitoring ä micro and particulate matter

16. Module 13Slide 16 of 48 WHO - EDM Air Classification System Sterile Production

17. Module 13Slide 17 of 48 WHO - EDM Comparison of Various Codes Sterile Production

18. Module 13Slide 18 of 48 WHO - EDM Part Three 17.10 - 17.15 Sterile Production Personnel l Outdoor clothing l Appropriate to air grade ä Grade D – hair, beard and shoes ä Grade C – hair and beard – suit covering wrists, neck – no fibres ä Grade B – masks, gloves l Laundry and changes

19. Module 13Slide 19 of 48 WHO - EDM Part Three 17.6 - 17.8 Sterile Production Personnel l Minimum number in clean areas ä aseptic processing ä inspection and control l Regular training ä manufacture ä hygiene ä microbiology ä outside staff l Animal tissue and cultures of micro-organisms

20. Module 13Slide 20 of 48 WHO - EDM Part Three 17.9,17.11 - 17.12 Sterile Production Personnel l Hygiene and cleanliness ä contaminants ä health checks l SOPs : Changing and washing l Jewellery and cosmetics

21. Module 13Slide 21 of 48 WHO - EDM Part Three 17.24 - 17.33 Sterile Production Equipment l Air supply:(HVAC) ä Generation and supply of filtered air under positive pressure ä Airflow patterns ä Failure of air supply ä Pressure differentials monitored and recorded l Conveyer belts l Effective sterilisation of equipment l Maintenance and repairs l Planned maintenance, validation and monitoring l Water treatment plants

22. Module 13Slide 22 of 48 WHO - EDM Sterile Production Environmental Monitoring - I Microbiological l Air l Surfaces l Personnel

23. Module 13Slide 23 of 48 WHO - EDM Sterile Production Environmental Monitoring - II Physical l Particulates l Differential pressures l Air changes l Filter integrity l Temperature/humidity

24. Module 13Slide 24 of 48 WHO - EDM Part Three 17.38-39, 17.42-43 Sterile Production Processing l Minimise contamination l No unsuitable materials e.g. live microbiological organisms l Minimise activities ä staff movement l Temperature and humidity l Water sources and systems ä monitoring ä records ä action taken

25. Module 13Slide 25 of 48 WHO - EDM Part Three 17.44-47; 17.50-17.51 Sterile Production Processing l Bio-burden determination ä raw materials ä in-process materials – LVP : filtered immediately before sterilisation – sealed vessels: pressure-released outlets l Components, materials and containers ä fibre generation ä no re-contamination after cleaning ä stage identified ä sterilised when used in aseptic areas l Gas through a sterilising filter

26. Module 13Slide 26 of 48 WHO - EDM Part Three 17.52, 17.40 Sterile Production Processing l Validation ä new processes ä re-validation: Periodic and after change l Aseptic process: Sterile media fill (“broth fills”) ä simulate actual operation ä appropriate medium/media ä sufficient number of units – acceptable limit – investigations ä revalidation: periodic and after change

27. Module 13Slide 27 of 48 WHO - EDM Part Three 17.47,17.48 Sterile Production Processing l Time intervals: Components, containers, equipment ä washing, drying and sterilisation ä sterilisation and use – time limit and validated storage conditions l Time intervals: Product preparation ä preparation and sterilisation ä short as possible ä maximum time for each product

28. Module 13Slide 28 of 48 WHO - EDM Sterile Production Finishing of products l Validated closing process l Checks for integrity l Maintenance of vacuum (where applicable) checked l Parenteral products: Individual inspection ä illumination and background ä eyesight checks ä breaks ä validation

29. Module 13Slide 29 of 48 WHO - EDM Sterile Production Group session 1 l You are asked to visit a factory producing the following product lines: ä Injections in ampoules and vials, including insulin, vaccines and heat-stable pharmaceuticals. ä Sterile eye ointment l Describe the type of facility you would expect to find. l List the typical rooms, their purpose and air classification

30. Module 13Slide 30 of 48 WHO - EDM Sterile Production Possible Issues l Poor design of the building l Poor design of the systems e.g. water, HVAC l Flow of personnel l Flow of material l No validation or qualification l Old facilities not complying with current requirements

31. Module 13Slide 31 of 48 WHO - EDM Sterile Production Possible Issues(contd) l Particulate levels/micro-organisms l Differential pressures l Air changes l Temperature/humidity

32. Module 13Slide 32 of 48 WHO - EDM Part Three 17.53 - 17.55 Sterile Production Sterilization l Methods of sterilization ä heat sterilization: Method of choice l Validation ä all processes ä non-pharmacopoeia ä non-aqueous or oily solutions l Suitability and efficacy ä part of load ä type of load ä repeated: annually and after change

33. Module 13Slide 33 of 48 WHO - EDM Part Three 17.56 - 17.57 Sterile Production Sterilization l Biological indicators l Differentiation between sterilized and not-sterilized products ä labelling ä autoclave tape

34. Module 13Slide 34 of 48 WHO - EDM Part Three 17.58 - 17.60 Sterile Production Sterilization by Heat l Recording of each cycle, e.g. time and temperature ä validated coolest part ä second independent probe ä indicators l Heating phase ä each load determined l Cooling phase ä no contamination ä leaking containers

35. Module 13Slide 35 of 48 WHO - EDM Part Three 17.61- 17.63 Sterile Production Moist Heat Sterilization l Water wettable materials l Temperature, time and pressure monitored l Recorder and controller independent l Independent indicator l Drain and leak test l Removal of air l Penetration of steam, quality of steam l All parts of the load: Contact, time, temperature

36. Module 13Slide 36 of 48 WHO - EDM Part Three 17.64 Sterile Production Dry Heat Sterilization l Air circulation and positive pressure in chamber l Filtered air l Temperature and time must be recorded l Removes pyrogens ä validation (challenge tests with endotoxins)

37. Module 13Slide 37 of 48 WHO - EDM Part Three 17.65 - 17.67 Sterile Production Sterilization by Radiation l Suitable for heat sensitive materials and products ä confirm suitability of method for material ä ultraviolet irradiation not acceptable l Contracting service l Measurement of dose l Dosimeters ä quantitative measurement ä number, location and calibration l Biological indicators l Colour discs

38. Module 13Slide 38 of 48 WHO - EDM Part Three 17.67 - 17.70 Sterile Production Sterilization by Radiation l Batch record l Validation ä density of packages l Mix-ups: Irradiated and non-irradiated materials l Dose: Predetermined time span

39. Module 13Slide 39 of 48 WHO - EDM Part Three 17.71 - 17.76 Sterile Production Sterilization by Ethylene Oxide Gas l Only when no other method is practicable l Effect of gas on the product l Degassing (specified limits) l Direct contact with microbial cells ä Nature and quantity of packaging materials l Humidity and temperature equilibrium l Monitoring of each cycle ä time, pressure ä temperature, humidity ä gas concentration

40. Module 13Slide 40 of 48 WHO - EDM Part Three 17.77 Sterile Production Sterilization by Ethylene Oxide Gas l Post-sterilization storage ä ventilation ä defined limit of residual gas ä validated process l Safety and toxicity issues

41. Module 13Slide 41 of 48 WHO - EDM Sterile Production Sterilization by Filtration l Previously sterilized containers l Nominal pore size 0.22 µm or less ä remove bacteria and moulds ä not viruses or mycoplasmas l Double filter layer or second filtration l No fibre shedding or asbestos filters l Filter integrity testing l Time taken and pressure difference validated

42. Module 13Slide 42 of 48 WHO - EDM Sterile Production Sterilization by Filtration l Length of use ä one working day ä or validated l Filter interaction with product ä removal of ingredients ä releasing substances

43. Module 13Slide 43 of 48 WHO - EDM Sterile Production Group session 2 l Considering the same factory as in the previous group session, discuss the process of sterilization. l List all the items that will need to be sterilized. l What are the key features you should find in each sterilization situation? l Which aspects would be subject to validation?

44. Module 13Slide 44 of 48 WHO - EDM Sterile Production Possible Issues l Autoclave - no pressure gauge l Autoclave - no temperature recorder l Autoclave - superheated steam l Clean room - pressure differentials l Exposure for settle plates l Interlocks turned off l Rusty Laminar airflow cabinets l HEPA filters not checked regularly

45. Module 13Slide 45 of 48 WHO - EDM Sterile Production Quality Control l Environmental monitoring l Sterility testing l Endotoxin testing

46. Module 13Slide 46 of 48 WHO - EDM Sterile Production Sterility Testing l Samples representative of the batch ä aseptic fill – beginning, and end of batch, or interruption ä heat sterilization – coolest part of the load l Last of series of control measures l Adequate testing facility (e.g. Class A in B environment) l Test failure: Second test subject to ä investigation: – type of organism – batch records, environmental monitoring records

47. Module 13Slide 47 of 48 WHO - EDM Sterile Production Pyrogen Testing l Rabbit method l LAL test (endotoxin monitoring) l Injectable products ä water, intermediate, finished product ä validated pharmacopoeia method for each type of product ä always for water and intermediates l Test failures ä cause investigated ä remedial action

48. Module 13Slide 48 of 48 WHO - EDM Sterile Production Group session 3 l Considering the same factory as in the previous group sessions, devise a plan for monitoring of the facility. l List the parameters to be tested, tests to be used, acceptance criteria and frequency of testing.