Sterile products

nullSupplementary Training Modules on Good Manufacturing PracticeSupplementary Training Modules on Good Manufacturing Practice Sterile Pharmaceutical ProductsAnnex 6. TRS 902, 2002Sterile ProductionSterile ProductionObjectives 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 countrySterile Production Sterile Production GMP Requirements for Sterile Products Additional rather than replacement Specific points relating to minimizing risks of contamination microbiological particulate matter pyrogen Sterile ProductionSterile 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 – 1-2Sterile ProductionSterile ProductionPremises 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 sealed9.1 – 9.6Sterile ProductionSterile ProductionPremises 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 cleanable9.6.Sterile ProductionSterile ProductionPremises 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 environment9.7 – 9.9Sterile ProductionSterile ProductionPremises 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 barriers9.9 – 9.12Sterile ProductionSterile ProductionEquipment 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 systems10.1 – 10.5Sterile ProductionSterile ProductionEquipment 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 Celsius10.6Sterile ProductionSterile ProductionEnvironmental Monitoring - I Microbiological Air samples Surface swabs Personnel swabsSterile ProductionSterile ProductionEnvironmental Monitoring - II Physical Particulate matter Differential pressures Air changes, airflow patterns Clean-up time/recovery Filter integrity Temperature and relative humidity Airflow velocitySterile ProductionSterile ProductionSanitation 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 areas3.1 – 3.2Sterile ProductionSterile ProductionSanitation 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 done3.3Sterile ProductionSterile ProductionSanitation Limits of detection established Alert and action, and monitoring trends of air quality Table 1. Limits for microbial contamination (Information only)3.4Sterile ProductionSterile ProductionPersonnel 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 – 8.3Sterile ProductionSterile ProductionPersonnel 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 cosmetics8.4 – 8.6Sterile ProductionSterile ProductionPersonnel 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 operators8.7Sterile ProductionSterile ProductionPersonnel 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 procedures8.8 – 8.9Sterile ProductionSterile ProductionGroup 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 classificationSterile ProductionSterile ProductionPossible 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 requirementsSterile ProductionSterile ProductionPossible Issues (continued) Particulate levels/microorganisms Differential pressures Air changes Temperature/humidity Sterile ProductionSterile ProductionTwo categories of manufacturing operations: Terminally sterilized prepared, filled and sterilized Aseptic preparation some or all stages 1.3Sterile ProductionSterile ProductionManufacture 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").4.1Sterile ProductionSterile ProductionManufacture 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 operations4.1Sterile ProductionSterile ProductionAir Classification System3.1Sterile ProductionSterile ProductionManufacture 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, USA4.1 – 4.2.Sterile ProductionSterile ProductionManufacture 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 – 4.5Sterile ProductionSterile ProductionAirborne particulate classification4.1Sterile ProductionSterile ProductionProcessing 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 area4.15 – 4.16, 4.20 – 4.21 Sterile ProductionSterile ProductionProcessing 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 intervals4.17, 4.18, 4.28Sterile ProductionSterile ProductionProcessing Water sources, water treatment systems and treated water Monitored regularly Chemicals Biological contamination Endotoxin Water specification Records of results and action taken4.19Sterile ProductionSterile ProductionProcessing 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 filter4.22 – 4.23Sterile ProductionSterile ProductionProcessing 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 specification4.26, 5.3Sterile ProductionSterile ProductionProcessing 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 product4.23 - 4.24Sterile ProductionSterile ProductionGroup 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 ProductionSterile ProductionPossible 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 regularlySterile ProductionSterile ProductionSterilization 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 choice5.1 – 5. 2Sterile ProductionSterile ProductionSterilization 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 maintained5.4 – 5.5Sterile ProductionSterile ProductionSterilization 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 contamination5.6 - 5.7Sterile ProductionSterile ProductionSterilization 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 procedure5.8 - 5.9Sterile ProductionSterile ProductionTerminal Sterilization Sterilization by heat Sterilization by moist heat Sterilization by dry heat Sterilization by radiation Sterilization by gases and fumigants6Sterile ProductionSterile ProductionTerminal 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 – 6.3Sterile ProductionSterile ProductionTerminal 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 contamination6.4 – 6.6Sterile ProductionSterile ProductionTerminal 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)6.7Sterile ProductionSterile ProductionTerminal 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 discs6.8 – 6.10Sterile ProductionSterile ProductionTerminal 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 time6.10 – 6.13Sterile ProductionSterile ProductionTerminal 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 concentration6.14 – 6.20Sterile ProductionSterile ProductionTerminal 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 6.21Sterile ProductionSterile ProductionTerminally sterilized products 4.6 – 4.7Sterile ProductionSterile ProductionTerminally sterilized products 4.8 – 4.9Sterile ProductionSterile ProductionAseptic processing and sterilization by filtration Aseptic processing Objective is to maintain the sterility of a product, assembled from sterile components Operating conditions so as to prevent microbial contamination What do you think are the aspects that require careful attention?7.1 – 7.2Sterile ProductionSterile ProductionAseptic processing and sterilization by filtration Aseptic processing (2) Careful attention to: Environment Personnel Critical surfaces Container/closure sterilization Transfer procedures Maximum holding period before filling7.3Sterile ProductionSterile ProductionAseptic preparation 4.10, 4.11, 4.14Sterile ProductionSterile ProductionAseptic preparation 4.10 – 4.13Sterile ProductionSterile ProductionSterilization by filtration Through a sterile filter of 0,22 µm or less, into previously sterilized containers remove bacteria and moulds not all viruses or mycoplasmas Consider complementing with some degree of heat treatment Double filter layer or second filtration advisable, just before filling - no fibre shedding or asbestos filters Filter integrity testing immediately after use also before use if possible7.4 – 7.7Sterile ProductionSterile ProductionSterilization by Filtration (2) Validation to include Time taken to filter a known volume Pressure difference to be used across the filter Significant differences to be noted and investigated, recorded in batch records Integrity of gas and air vent filters checked after use, other filters at appropriate intervals 7.7Sterile ProductionSterile ProductionSterilization by Filtration (3) Same filter not used for more than one working day, unless validated No filter interaction with product, e.g. removal of ingredients releasing substances into product 7.8 – 7.9Sterile ProductionSterile ProductionQuality Control Samples for sterility testing should be representative From parts of the batch, most at risk Aseptic filling – at beginning and end of batch filling, and after interruptions Heat sterilized – coolest part of the load Sterility of the batch ensured through validation Validated sterilization cycle Media fill Sterility test procedure as per pharmacopoeia, and validated for each product Batch processing records, sterility testing records, environmental records should be reviewed2.1 -2.2Sterile ProductionSterile ProductionQuality Control Endotoxin testing for injectable products Water for injection, intermediate and finished product Always for large volume infusion solutions Pharmacopoeia method, validated for each product Failure of the test – investigation Corrective action2.3Sterile ProductionSterile ProductionFinishing of products Containers closed by means of validated methods Samples checked for integrity Maintenance of vacuum (where applicable) checked Parenteral products inspected individually Visual inspection under suitable and controlled conditions: illumination and background eyesight checks of operators allowed frequent breaks Other methods: validated, and equipment performance checked at intervals results recorded11.1 – 11.3Sterile ProductionSterile ProductionGroup session 3 Considering the same factory as in the previous group sessions, devise a plan for monitoring of the facility. List the parameters to be tested, tests to be used, acceptance criteria and f