Basic Principles of GMP

Basic Principles of GMP Sterile Pharmaceutical Products Annex 6. TRS 902, 2002

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

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

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

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

Sterile Production Premises (continued) • 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.

Sterile Production Premises (continued) • 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 Pascals • Zone of greatest risk – immediate environment 9.7 – 9.9

Sterile Production Premises (continued) • 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

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

Sterile Production Equipment (continued) • 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

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

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

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

Sterile Production Sanitation (continued) • 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

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

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

Sterile Production Personnel (continued) • 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

Sterile Production Personnel (continued) • 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 • not shedding fibres, and retain particles shed by operators 8.7

Sterile Production Personnel (continued) • 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

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

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

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

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

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" • (That is "completed installation, equipment installed and operating, but no operating personnel present") 4.1

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

Sterile Production Air Classification System 3.1

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.

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

Sterile Production Airborne particulate classification 4.1

Sterile Production Processing • Minimize 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

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

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

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

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

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

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

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

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

Sterile Production Sterilization • Validation • all sterilization processes • special attention when non-pharmacopoeial 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

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

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

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

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

Sterile Production Terminal Sterilization Sterilization by moist heat (heating in an autoclave) • Water-wettable 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

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

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

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

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 6.14 – 6.20

Sterile Production Terminal Sterilization • Monitoring of each cycle with biological indicators • time, pressure • temperature, humidity • gas concentration 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

Sterile Production Terminally sterilized products 4.6 – 4.7

Basic Principles of GMP