Aseptic Process

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Aseptic Process:

Aseptic Process Srikanth Asst prof JPNES Mahabub Naga r

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Overview; Certain pharmaceutical products must be sterile injections, ophthalmic preparations, irrigations solutions, haemodialysis solutions Two categories of sterile products those that can be sterilized in final container (terminally sterilized) Those that cannot be terminally sterilized and must be aseptically prepared

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Aseptic process; Objective is to maintain the sterility of a product, assembled from sterile components Operating conditions so as to prevent microbial contamination Objective To review specific issues relating to the manufacture of aseptically prepared products: Manufacturing environment Clean areas Personnel Preparation and filtration of solutions Pre-filtration bioburden Filter integrity/validation Equipment/container preparation and sterilization Filling Process Validation of aseptic processes Specific issues relating to Isolators, BFS and Bulk

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Manufacturing Environment Environmental Monitoring; Physical Particulate matter Differential pressures Air changes, airflow patterns Clean up time/recovery Temperature and relative humidity Airflow velocity

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Environmental Monitoring - Physical Particulate matter Particles significant because they can contaminate and also carry organisms Critical environment should be measured not more than 30cm from worksite, within airflow and during filling/closing operations Preferably a remote probe that monitors continuously Difficulties when process itself generates particles (e.g. powder filling) Appropriate alert and action limits should be set and corrective actions defined if limits exceeded

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Environmental Monitoring - Physical Differential pressures Positive pressure differential of 10-15 Pascals should be maintained between adjacent rooms of different classification (with door closed) Most critical area should have the highest pressure Pressures should be continuously monitored and frequently recorded. Alarms should sound if pressures deviate Any deviations should be investigated and effect on environmental quality determined

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Environmental Monitoring - Physical Air Changes/Airflow patterns; Air flow over critical areas should be uni-directional (laminar flow) at a velocity sufficient to sweep particles away from filling/closing area for B, C and D rooms at least 20 changes per hour are ususally required Clean up time/recovery; Particulate levels for the Grade A “at rest” state should be achieved after a short “clean-up” period of 20 minutes after completion of operations (guidance value) Particle counts for Grade A “in operation” state should be maintained whenever product or open container is exposed

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Environmental Monitoring - Physical Temperature and Relative Humidity Ambient temperature and humidity should not be uncomfortably high (could cause operators to generate particles) (18°C) Airflow velocity Laminar airflow workstation air speed of approx 0.45m/s ± 20% at working position (guidance value)

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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 should be formally validated and authorized to enter aseptic area Special cases supervision in case of outside staff decontamination procedures (e.g. staff who worked with animal tissue materials)

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Personnel; High standards of hygiene and cleanliness Should not enter clean rooms if ill or with open wounds Periodic health checks No shedding of particles, movement slow and controlled No introduction of microbiological hazards No outdoor clothing brought into clean areas, should be clad in factory clothing Changing and washing procedure No watches, jewellery and cosmetics Eye checks if involved in visual inspection

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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/overshoes No fibres/particles to be shed Grade A and B headgear, beard and moustache covered, masks, gloves not shedding fibres, and retain particles shed by operators

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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 Frequent disinfection of gloves during operations Washing of garments – separate laundry facility No damage, and according to validated procedures (washing and sterilization) Regular microbiological monitoring of operators

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In aseptic processing, each component is individually sterilised, or several components are combined with the resulting mixture sterilized. Most common is preparation of a solution which is filtered through a sterilizing filter then filled into sterile containers (e.g active and excipients dissolved in Water for Injection) May involve aseptic compounding of previously sterilized components which is filled into sterile containers May involve filling of previously sterilized powder sterilized by dry heat/irradiation produced from a sterile filtered solution which is then aseptically crystallized and precipitated requires more handling and manipulation with higher potential for contamination during processing

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Preparation and Filtration of Solutions Solutions to be sterile filtered prepared in a Grade C environment If not to be filtered, preparation should be prepared in a Grade A environment with Grade B background (e.g. ointments, creams, suspensions and emulsions) Prepared solutions filtered through a sterile 0.22μm (or less) membrane filter into a previously sterilized container filters remove bacteria and moulds do not remove all viruses or mycoplasmas filtration should be carried out under positive pressure

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consideration should be given to complementing filtration process with some form of heat treatment Double filter or second filter at point of fill advisable Fitlers should not shed particles, asbestos containing filters should not be used Same filter should not be used for more than one day unless validated If bulk product is stored in sealed vessels, pressure release outlets should have hydrophobic microbial retentive air filters

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Time limits should be established for each phase of processing, e.g. maximum period between start of bulk product compounding and sterilization (filtration) maximum permitted holding time of bulk if held after filtration prior to filling product exposure on processing line storage of sterilized containers/components total time for product filtration to prevent organisms from penetrating filter maximum time for upstream filters used for clarification or particle removal (can support microbial attachment)

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Equipment/container preparation and sterilization All equipment (including lyophilizers) and product containers/closures should be sterilized using validated cycles Same requirements apply for equipment sterilization that apply to terminally sterilized product Particular attention to stoppers - should not be tightly packed as may clump together and affect air removal during vacuum stage of sterilization process Equipment wrapped and loaded to facilitate air removal particular attention to filters, housings and tubing

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Equipment/container preparation and sterilization CIP/SIP processes Particular attention to deadlegs - different orientation requirements for CIP and SIP Heat tunnels often used for sterilization/depyrogenation of glass vials/bottles Usually high temperature for short period of time need to consider speed of conveyor Validation of depyrogenation (3 logs endotoxin units) worst case locations Tunnel supplied with HEPA filtered air

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Equipment/container preparation and sterilization Equipment should be designed to be easily assembled and disassembled, cleaned, sanitised and/or sterilized Equipment should be appropriately cleaned - O-rings and gaskets should be removed to prevent build up of dirt or residues Rinse water should be WFI grade Equipment should be left dry unless sterilized immediately after cleaning (to prevent build up of pyrogens) Washing of glass containers and rubber stoppers should be validated for endotoxin removal Should be defined storage period between sterilization and use (period should be justified)

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Thank you

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