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Supplementary Training Modules on Good Manufacturing Practice

Supplementary Training Modules on Good Manufacturing Practice. Sterile Pharmaceutical Products. Annex 6. TRS 902, 2002. Sterile Production. Objectives To review basic GMP requirements in the manufacture of sterile pharmaceutical products

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Supplementary Training Modules on Good Manufacturing Practice

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  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

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