1. Supplementary Training Modules on Good Manufacturing Practice Sterile Pharmaceutical Products Annex 6. TRS 902, 2002

2. Sterile Production Objectives • To review basic GMP requirements in the manufacture of sterile pharmaceutical products • To review air classifications for activities related to the manufacture of sterile products • To review the different types of sterilization methods • To review quality assurance aspects in the manufacture and control of sterile products • To consider current issues applicable in your country

3. Sterile Production GMP Requirements for Sterile Products • Additional rather than replacement • Specific points relating to minimizing risks of contamination • microbiological • particulate matter • pyrogen

4. Sterile Production General Considerations • Production in clean areas • Appropriate standard of cleanliness • Filtered air supplied • Airlocks for entry • Personnel and/or equipment • Materials • Separate areas for operations • component preparation (containers and closures) • product preparation, filling, sterilization, etc. 1.1 – 1-2

5. Sterile Production Premises • Design • Avoid unnecessary entry of supervisors and control personnel • Operations observed from outside • In clean areas, all exposed surfaces: • Smooth, impervious, unbroken • Minimize shedding and accumulation of particles, microorganisms • Permit cleaning and disinfection • No uncleanable recesses, ledges, shelves, cupboards, equipment • Sliding doors undesirable • False ceilings sealed 9.1 – 9.6

6. Sterile Production Premises • In clean areas, all exposed surfaces (2): • Proper installation of pipes and ducts, no recesses, no unsealed openings • Sinks and drains avoided, and excluded in Grade A and B areas • Where installed, design, location, maintenance • Effective cleanable traps • Air breaks preventing backflow • Floor channels open and easily cleanable 9.6.

7. Sterile Production Premises • Changing rooms • Designed as airlocks • Effective flushing with filtered air • Separate rooms for entry and exit desirable • Hand washing facilities • Interlocking system for doors • Visual and/or audible warning system • Use filtered air supply to maintain pressure cascade • Pressure differential approximately 10 to 15 Pascales • Zone of greatest risk – immediate environment 9.7 – 9.9

8. Sterile Production Premises • Pathogenic, highly toxic, radioactive materials • Pressure cascade may be different • Decontamination procedures – air, equipment, garments • Qualification including airflow patterns • No risk to the product • Warning system to indicate failure in air supply • Pressure indicators – results regularly recorded • Restricted access – e.g. use of barriers 9.9 – 9.12

9. Sterile Production Equipment • Conveyer belts • Effective sterilization of equipment • Maintenance and repairs from outside the clean area • If taken apart, resterilized before use • Use clean instruments and tools • Planned maintenance, validation and monitoring • Equipment, air filtration systems, sterilizers, water treatment systems 10.1 – 10.5

10. Sterile Production Equipment • Water treatment plants and distribution system • Design, construction, maintenance • Operation and design capacity • Testing programme • Water for Injection (WFI) • Produced, stored, distributed – prevention of growth of microorganisms • Constant circulation at temperature above 70, or not more than 4 degrees Celsius 10.6

11. Sterile Production Environmental Monitoring - I Microbiological • Air samples • Surface swabs • Personnel swabs

12. Sterile Production Environmental Monitoring - II Physical • Particulate matter • Differential pressures • Air changes, airflow patterns • Clean-up time/recovery • Filter integrity • Temperature and relative humidity • Airflow velocity

13. Sterile Production Sanitation • Frequent, thorough cleaning of areas necessary • Written programme • Regular monitoring to detect resistant strains of microorganisms • Chemical disinfection • Monitoring of disinfectants and detergents • Dilutions • Clean containers, stored for defined periods of time • Sterilized before use, when used in Grade A or B areas 3.1 – 3.2

14. Sterile Production Sanitation • Monitoring of clean areas • Monitoring of personnel and surfaces after critical operations • Frequent monitoring in areas where aseptic operations are carried out • Settle plates, volumetric air samples, surface sampling (swabs and contact plates) • Sampling methods should not contaminate the area • Results considered when batch release is done 3.3

15. Sterile Production Sanitation • Limits of detection established • Alert and action, and monitoring trends of air quality Table 1. Limits for microbial contamination (Information only) 3.4

16. Sterile Production Personnel • Minimum number of personnel in clean areas • Especially during aseptic processing • Inspections and controls from outside • Training to all including cleaning and maintenance staff • Initial and regular • Manufacturing, hygiene, microbiology • Special cases • Supervision in case of outside staff • Decontamination procedures (e.g. staff who worked with animal tissue materials) 8.1 – 8.3

17. Sterile Production Personnel • High standards of hygiene and cleanliness • Periodic health checks • No shedding of particles • No introduction of microbiological hazards • No outdoor clothing • Changing and washing procedure • No watches, jewellery and cosmetics 8.4 – 8.6

18. Sterile Production Personnel • Clothing of appropriate quality: • Grade D • hair, beard, moustache covered • Protective clothing and shoes • Grade C • Hair, beard, moustache covered • Single or 2-piece suit (covering wrists, high neck), shoes • no fibres to be shed • Grade A and B • Headgear, beard and moustache covered, masks, gloves • No shedding of fibres, and retain particles shed by operators 8.7

19. Sterile Production Personnel • Outdoor clothing not in change rooms leading to grade B and C rooms • Change at every working session, or once a day (if supportive data) • Change gloves and masks at every working session • Disinfect gloves during operations • Washing of garments – separate laundry facility • No damage, and according to validated procedures 8.8 – 8.9

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

21. Sterile Production Possible Issues • Poor design of the building • Poor design of the systems, e.g. water, HVAC • Flow of personnel • Flow of material • No validation or qualification • Old facilities not complying with current requirements

22. Sterile Production Possible Issues (continued) • Particulate levels/microorganisms • Differential pressures • Air changes • Temperature/humidity

23. Sterile Production Two categories of manufacturing operations: • Terminally sterilized • prepared, filled and sterilized • Aseptic preparation • some or all stages 1.3

24. Sterile Production Manufacture of sterile preparations • Classification of clean areas • Manufacturing operation in an appropriate environment cleanliness level • Minimize risks – particulate and microbiological contamination – product and material • Meet classification "at rest" • (i.e. "completed installation, equipment installed and operating, but no operating personnel present"). 4.1

25. Sterile Production Manufacture of sterile preparations • For sterile pharmaceutical preparations: • Grade A • Local zone, high risk operations, e.g. filling, aseptic connections • Usually UDAF systems used • Grade B • Background environment to grade A (in case of aseptic preparation and filling) • Grade C and Grade D • Clean areas for less critical operations 4.1

26. Sterile Production Air Classification System 3.1

27. Sterile Production Manufacture of sterile preparations • To reach Grade B, C and D, the number of air changes should be appropriate to the size of the area, number of personnel, equipment present • Minimum of 20 air changes per hour • Clean up time about 15-20 minutes • Good airflow pattern in the area • HEPA-filtered air • Suitable methods to determine particulate matter and micro- • e.g. EU, ISO, Japan, USA 4.1 – 4.2.

28. Sterile Production Manufacture of sterile preparations • Control particulate during operation • Monitoring during operation • Alert and action limits for particulate and micro • Action taken when exceeded • Area grades should be proven (e.g. validation runs, media fills, environment, time limits – based on microbiological contamination/bioburden found) 4.3 – 4.5

29. Sterile Production Airborne particulate classification 4.1

30. Sterile Production Processing • Minimise contamination – all stages including before sterilization and during processing • No unsuitable materials, e.g. live microbiological organisms • Minimize activities • staff movement controlled and methodical • avoid shedding of particles • Temperature and humidity comfortable • Containers and materials in the area 4.15 – 4.16, 4.20 – 4.21

31. Sterile Production Processing • Validation – should not compromise the processes • Aseptic process validation: Sterile media fill (“broth fills”) • Simulate actual operation – intimate as closely as possible • Simulate worst expected condition • Use appropriate medium/media • Sufficient number of units - e.g. equal to batch size (small batches) • acceptable limit • investigations • Revalidation: periodic and after change • New processing procedures validated • Revalidation after significant changes • And regular intervals 4.17, 4.18, 4.28

32. Sterile Production Processing • Water sources, water treatment systems and treated water • Monitored regularly • Chemicals • Biological contamination • Endotoxin • Water specification • Records of results and action taken 4.19

33. Sterile Production Processing • Components, bulk product containers and equipment • fibre generation • no recontamination after final cleaning • stage properly identified • sterilized when used in aseptic areas • Used in clean areas, passed through double-ended sterilizers or use triple wrapping • Gas used to purge solution or blanket a product – passed through a sterilizing filter 4.22 – 4.23

34. Sterile Production Processing • Bioburden monitored • Products: Before sterilization • Working limits established • Solutions to be filtered before filling (especially LVP) • Pressure release outlets – hydrophobic microbiological air filters • Starting materials – microbiological contamination should be minimal • Monitored as per specification 4.26, 5.3

35. Sterile Production Processing • Time intervals: Components, bulk containers, equipment • Washing and drying and sterilization; and sterilization and use • As short as possible • Time limit validated • Time intervals: Product • Start of preparation of solution and sterilization (filtration) • As short as possible • Maximum time set for each product 4.23 - 4.24

36. Sterile Production Group session 2 • Considering the same factory as in the previous group session, discuss the process of sterilization. • List all the items that will need to be sterilized (and indicate the choice of sterilization process). • What are the key features you should find in each sterilization situation? • Discuss the relevance, need, and the extent of qualification and validation required.

37. Sterile Production Possible Issues • Autoclave - no pressure gauge • Autoclave - no temperature recorder • Autoclave - superheated steam • Clean room - pressure differentials • Exposure for settle plates • Interlocks turned off • Rusty Laminar airflow cabinets • HEPA filters not checked regularly

38. Sterile Production Sterilization • Methods of sterilization: • Moist or dry heat • Irradiation (ionizing radiation) • Sterilizing gaseous agents (e.g. ethylene oxide) • Filtration with subsequent aseptic filling • Whenever possible: Terminal sterilization by heat in their final container - method of choice 5.1 – 5. 2

39. Sterile Production Sterilization • Validation • All sterilization processes • Special attention when non-pharmacopoeia methods are used • Non-aqueous or oily solutions • Before the method is adopted – its suitability and efficacy demonstrated with desired conditions: • All parts of the load • Each type of load • Physical measurements and biological indicators (where appropriate) • Verified at least annually and after change • Records maintained 5.4 – 5.5

40. Sterile Production Sterilization • For effective sterilization: • Whole of the material subjected to the treatment • Biological indicators: • Additional method of monitoring • Storage and use, quality checked through positive control • Risk of contamination 5.6 - 5.7

41. Sterile Production Sterilization • Differentiation between sterilized and not-yet-sterilized products • Each basket/tray or other carrier, properly labelled • Name of material • Batch number • Sterilization status • Use of autoclave tape • Sterilization records for each run – approved as part of the batch release procedure 5.8 - 5.9

42. Sterile Production Terminal Sterilization • Sterilization by heat • Sterilization by moist heat • Sterilization by dry heat • Sterilization by radiation • Sterilization by gases and fumigants 6

43. Sterile Production Terminal Sterilization Sterilization by heat • Recording of each cycle, e.g. time and temperature chart • Temperature: validated coolest part • Check from second independent probe • Additional chemical or biological indicators • Heating phase: Sufficient time for the whole load • Determined for each load • Cooling phase: After sterilization cycle • Precautions to prevent contamination • Sterilized cooling fluid/gas 6.2 – 6.3

44. Sterile Production Terminal Sterilization Sterilization by moist heat (heating in an autoclave) • Water-wetable materials only, and aqueous formulations • Temperature, time and pressure monitored • Temperature recorder independent of the controller • Independent temperature indicator • Drain – temperature recorded from this position • Regular leak test when vacuum is part of the cycle • Material allows for removal of air and penetration of steam • All parts of the load in contact with steam • Quality of the steam – no contamination 6.4 – 6.6

45. Sterile Production Terminal Sterilization Sterilization by dry heat • For non-aqueous liquids, dry powders • Air circulation in the chamber • Positive pressure in chamber to prevent entry of non-sterile air • HEPA filtered air supplied • When removing pyrogens, challenge tests • validation (using endotoxins) 6.7

46. Sterile Production Terminal Sterilization Sterilization by radiation • Suitable for heat-sensitive materials and products • confirm suitability of method for material • ultraviolet irradiation not acceptable • Contracting service – ensure validation status, responsibilities • Measurement of dose during procedure • Dosimeters independent of dose rate • quantitative measurement • number, location and calibration time-limit • Biological indicators only as additional control • Radiation sensitive colour discs 6.8 – 6.10

47. Sterile Production Terminal Sterilization Sterilization by radiation (2) • Information forms part of the batch record • Validation to cover effects of variation in density of packages • Handling procedures to prevent misidentification of irradiated and non-irradiated materials • Each package to have a radiation-sensitive indicator • Total radiation dose administered within a predetermined period of time 6.10 – 6.13

48. Sterile Production Terminal Sterilization Sterilization by gases and fumigants • Only when no other method is suitable • e.g. ethylene oxide, hydrogen peroxide vapour • Validation: Also prove the gas has no damaging effect on product • Time and conditions for degassing (specified limits) - residue • Direct contact with microbial cells essential • Nature and quantity of packaging materials • Humidity and temperature equilibrium • Monitoring of each cycle with biological indicators • time, pressure • temperature, humidity and gas concentration 6.14 – 6.20

49. Sterile Production Terminal Sterilization Sterilization by gases and fumigants (2) • Post-sterilization storage – controlled manner • Ventilated conditions • Defined limit of residual gas • Validated process • Safety and toxicity issues 6.21

50. Sterile Production Terminally sterilized products 4.6 – 4.7