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Aseptic Processing Mrs Robyn Isaacson

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1 Aseptic Processing Mrs Robyn Isaacson
Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors - Nanjing, November 2009

2 Aseptic Processing - 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 Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors - Nanjing, November 2009

3 Aseptic Processing - Overview
Objective is to maintain the sterility of a product, assembled from sterile components Operating conditions so as to prevent microbial contamination Aseptic processing and sterilization by filtration Aseptic processing We have already discussed the fact that terminal sterilization of a product is preferable as it reduces the risk of and provides more assurance of sterility. However, for some types of products, this is not possible. Another method to prepare a sterile products then is to maintain the sterility of a product, assembled from sterile components. All operating conditions should be such to prevent microbial contamination. What do you think are the aspects that require careful attention? Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors - Nanjing, November 2009

4 Aseptic Processing - Overview
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 Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors - Nanjing, November 2009

5 Manufacturing Environment
Classification of Clean Areas Comparison of classifications Table 1 Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors - Nanjing, November 2009

6 Manufacturing Environment
Classification of Clean Areas Classified in terms of airborne particles (Table 2) “At rest” - production equipment installed and operating “In operation” - Installed equipment functioning in defined operating mode and specified number of personnel present Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors - Nanjing, November 2009

7 Manufacturing Environment
Four grades of clean areas: Grade D (equivalent to Class 100,000, ISO 8): Clean area for carrying out less critical stages in manufacture of aseptically prepared products eg. handling of components after washing. Grade C (equivalent to Class 10,000, ISO 7): Clean area for carrying out less critical stages in manufacture of aseptically prepared products eg. preparation of solutions to be filtered. Grade B (equivalent to Class 100, ISO 5): Background environment for Grade A zone, eg. cleanroom in which laminar flow workstation is housed. Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors - Nanjing, November 2009

8 Manufacturing Environment
Grade A (equivalent to Class 100 (US Federal Standard 209E), ISO 5 (ISO ): Local zone for high risk operations eg. product filling, stopper bowls, open vials, handling sterile materials, aseptic connections, transfer of partially stoppered containers to be lyophilized. Conditions usually provided by laminar air flow workstation. Each grade of cleanroom has specifications for viable and non-viable particles Non-viable particles are defined by the air classification (See Table 2) Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors - Nanjing, November 2009

9 Manufacturing Environment
Limits for viable particles (microbiological contamination) Table 3 These are average values Individual settle plates may be exposed for less than 4 hours Values are for guidance only - not intended to represent specifications Levels (limits) of detection of microbiological contamination should be established for alert and action purposes and for monitoring trends of air quality in the facility Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors - Nanjing, November 2009

10 Manufacturing Environment
Environmental Monitoring Physical Particulate matter Differential pressures Air changes, airflow patterns Clean up time/recovery Temperature and relative humidity Airflow velocity Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors - Nanjing, November 2009

11 Manufacturing Environment
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 Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors - Nanjing, November 2009

12 Manufacturing Environment
Environmental Monitoring - Physical Differential pressures Positive pressure differential of 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 Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors - Nanjing, November 2009

13 Manufacturing Environment
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 Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors - Nanjing, November 2009

14 Manufacturing Environment
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) Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors - Nanjing, November 2009

15 Manufacturing Environment
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) Personnel play an important part in ensuring the quality of manufacture. It is also relevant (perhaps in particular) in the manufacture of sterile products. Only a minimum number of personnel should work in clean areas, especially during aseptic processing. As far as possible, all inspections and controls should be done from outside the production rooms. Training should be given to all including cleaning and maintenance staff, and should include initial and regular training on manufacturing, hygiene, and microbiology. Look at the procedure for training, training program, training material and assessment of the personnel. In special cases, when outside staff have to enter the clean areas, they should be supervised. Remember also the previous discussion on decontamination procedures (e.g. staff who worked with animal tissue materials). Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors - Nanjing, November 2009

16 Manufacturing Environment
Personnel (2) 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 Personnel working in clean areas should maintain high standards of hygiene and cleanliness. They should undergo periodic health checks, wear clothing that do not shed particles, and should take care not to introduce microbiological contaminants in the areas. No outdoor clothing should be brought into clean change rooms. Personnel should follow changing and washing procedures, wear no watches, jewellery and cosmetics Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors - Nanjing, November 2009

17 Manufacturing Environment
Personnel (3) Clothing of appropriate quality: Grade D hair, beard, moustache covered protective clothing and shoes Grade C 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 The WHO GMP text specifies the type of clothing that is appropriate for the different grades of rooms. Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors - Nanjing, November 2009

18 Manufacturing Environment
Personnel (4) 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 Garments should be changed at every working session, or once a day (if supportive data exist through validation studies). Gloves and masks should be changes at every working session Personnel should disinfect their gloves frequently during operations to prevent possible introduction of contaminants (micro) into the areas where they work or touch. Arrangements must be in place for the laundering and sterilization of clean-room clothing. This should be carried out in a controlled environment. If fibres are damaged due to inappropriate cleaning or sterilization, an increased risk for contamination may develop as clothing could shed particles. The use of contract laundries for this purpose, requires an audit by the company to ensure that appropriate procedures are in place. Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors - Nanjing, November 2009

19 Aseptic Processing 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 Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors - Nanjing, November 2009

20 Aseptic Processing 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 Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors - Nanjing, November 2009

21 Aseptic Processing Preparation and Filtration of Solutions (2)
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 Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors - Nanjing, November 2009

22 Aseptic Processing Preparation and Filtration of Solutions (3)
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) Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors - Nanjing, November 2009

23 Aseptic Processing Preparation and Filtration of Solutions (4)
Filling of solution may be followed by lyophilization (freeze drying) stoppers partially seated, product transferred to lyophilizer (Grade A/B conditions) Release of air/nitrogen into lyophilizer chamber at completion of process should be through sterilizing filter Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors - Nanjing, November 2009

24 Aseptic Processing Prefiltration Bioburden (natural microbial load)
Limits should be stated and testing should be carried out on each batch Frequency may be reduced after satisfactory history is established and biobuden testing performed on components Should include action and alert limits (usually differ by a factor of 10) and action taken if limits are exceeded Limits should reasonably reflect bioburden routinely achieved Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors - Nanjing, November 2009

25 Aseptic Processing Prefiltation Bioburden (2)
No defined “maximum” limit but the limit should not exceed the validated retention capability of the filter Bioburden controls should also be included in “in-process” controls particularly when product supports microbial growth and/or manufacturing process involves use of culture media Excessive bioburden can have adverse effect on the quality of the product and cause excessive levels of endotoxins/pyrogens Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors - Nanjing, November 2009

26 Aseptic Processing Filter integrity
Filters of 0.22μm or less should be used for filtration of liquids and gasses (if applicable) filters for gasses that may be used for purging or overlaying of filled containers or to release vacuum in lyphilization chamber filter intergrity shoud be verified before filtration and confirmed after filtration bubble point pressure hold forward flow methods are defined by filter manufacturers and limits determined during filter validation Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors - Nanjing, November 2009

27 Aseptic Processing Filter Validaton
Filter must be validated to demonstrate ability to remove bacteria most common method is to show that filter can retain a microbiological challenge of 107 CFU of Brevundimonas diminuta per cm2 of the filter surface a bioburden isolate may be more appropriate for filter retention studies than Brevundimonas diminuta Challenge concentration is intended to provide a margin of safety well beyond what would be expected in production preferably the microbial challenge is added to the fully formulated product which is then passed through the filter Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors - Nanjing, November 2009

28 Aseptic Processing Filter validation (2)
if the product is bactericidal, product should be passed through the filter first followed by modified product containing the microbial challenge (after removing any bactericidal activity remaining on the filter) filter validation should be carried out under worst case conditions e.g. maximum allowed filtration time and maximum pressure integrity testing specification for routine filtration should correlate with that identified during filter validation Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors - Nanjing, November 2009

29 Aseptic Processing 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 Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors - Nanjing, November 2009

30 Aseptic Processing Equipment/container preparation and sterilization (2) 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 Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors - Nanjing, November 2009

31 Aseptic Processing Equipment/container preparation and sterilization (2) 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) Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors - Nanjing, November 2009

32 Aseptic Processing Process Validation
Not possible to define a sterility assurance level for aseptic processing Process is validated by simulating the manufacturing process using microbiological growth medium (media fill) Process simulation includes formulation (compounding), filtration and filling with suitable media using the same processes involved in manufacture of the product modifications must be made for different dosage formats e.g. lyophilized products, ointments, sterile bulks, eye drops filled into semi-transparent/opaque containers, biological products Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors - Nanjing, November 2009

33 Aseptic Processing Process Validation (2)
Media fill program should include worst case activities Factors associated with longest permitted run (e.g. operator fatigue) Representative number, type, and complexity of normal interventions, non-routine interventions and events (e.g. maintenance, stoppages, etc) Lyophilisation Aseptic equipment assembly Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors - Nanjing, November 2009

34 Aseptic Processing Process Validation (3) Worst case activities (cont)
No of personnel and their activities, shift changes, breaks, gown changes Representative number of aseptic additions (e.g. charging containers, closures, sterile ingredients) or transfers Aseptic equipment connections/disconnections Aseptic sample collections Line speed and configuration Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors - Nanjing, November 2009

35 Aseptic Processing Process Validation (4) Worst case activities (cont)
Weight checks Container closure systems Specific provisions in processing instructions Written batch record documenting conditions and activities Should not be used to justify risky practices Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors - Nanjing, November 2009

36 Aseptic Processing Process Validation (5) Duration Size
Depends on type of operation BFS, Isolator processes - sufficient time to include manipulations and interventions For conventional operations should include the total filling time Size generally acceptable or batch size if <5000 For manually intensive processes larger numbers should be filled Lower numbers can be filled for isolators Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors - Nanjing, November 2009

37 Aseptic Processing Process Validation (6) Frequency and Number
Three initial, consecutive per shift Subsequently semi-annual per shift and process All personnel should participate at least annually, consistent with routine duties Changes should be assessed and revalidation carried out as required Line Speed Speed depends on type of process Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors - Nanjing, November 2009

38 Aseptic Processing Process Validation (7) Environmental conditions
Representative of actual production conditions (no. of personnel, activity levels etc) - no special precautions (not including adjustment of HVAC) if nitrogen used for overlaying/purging need to substitute with air Media Anaerobic media should be considered under certain circumstances Should be tested for growth promoting properties (including factory isolates) Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors - Nanjing, November 2009

39 Aseptic Processing Process Validation (8) Incubation, Examination
In the range 20-35ºC. If two temperatures are used, lower temperature first Inspection by qualified personnel. All integral units should be incubated. Should be justification for any units not incubated. Units removed (and not incubated) should be consistent with routine practices (although incubation would give information regarding risk of intervention) Batch reconciliation Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors - Nanjing, November 2009

40 Aseptic Processing Process Validation (9) Interpretation of Results
When filling fewer than 5000 units: no contaminated units should be detected One (1) contaminated unit is considered cause for revalidation, following an investigation When filling from units One (1) contaminated unit should result in an investigation, including consideration of a repeat media fill Two (2) contaminated units are considered cause for revalidation, following investigation When filling more than units One (1) contaminated unit should result in an investigation Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors - Nanjing, November 2009

41 Aseptic Processing Process Validation (10) Interpretation of Results
Media fills should be observed by QC and contaminated units reconcilable with time and activity being simulated (Video may help) Ideally - no contamination. Any contamination should be investigated. Any organisms isolated should be identified to species level (genotypic identification) Invalidation of a media fill run should be rare Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors - Nanjing, November 2009

42 Aseptic Processing Process Validation (11) Batch Record Review
Process and environmental control activities should be included in batch records and reviewed as part of batch release In-process and laboratory control results Environmental and personnel monitoring data Output from support systems(HEPA/HVAC, WFI, steam generator) Equipment function (batch alarm reports, filter integrity) Interventions, Deviations, Stoppages - duration and associated time Written instructions regarding need for line clearances Disruptions to power supply Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors - Nanjing, November 2009

43 Aseptic Processing Additional issues specific to Isolator and BFS Technologies Isolators Decontamination process requires a 4-6 log reduction of appropriate Biological Indicator (BI) Minimum 6 log reduction of BI if surface is to be free of viable organisms Significant focus on glove integrity - daily checks, second pair of gloves inside isolator glove Traditional aseptic vigilance should be maintained Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors - Nanjing, November 2009

44 Aseptic Processing Blow-Fill-Seal (BFS)
Located in a Grade D environment Critial zone should meet Grade A (microbiological) requirements (particle count requirements may be difficult to meet in operation) Operators meet Grade C garment requirements Validation of extrusion process should demonstrate destruction of endotoxin and spore challenges in the polymeric material Final inspection should be capable of detecting leakers Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors - Nanjing, November 2009

45 Aseptic Processing Issues relating to Aseptic Bulk Processing
Applies to products which can not be filtered at point of fill and require aseptic processing throughout entire manufacturing process. Entire aseptic process should be subject to process simulation studies under worst case conditions (maximum duration of "open" operations, maximum no of operators) Process simulations should incorporate storage and transport of bulk. Multiple uses of the same bulk with storage in between should also be included in process simulations Assurance of bulk vessel integrity for specified holding times. Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors - Nanjing, November 2009

46 Aseptic Processing Bulk Processing (2)
Process simulation for formulation stage should be performed at least twice per year. Cellular therapies, cell derived products etc products released before results of sterility tests known (also TPNs, radioactive preps, cytotoxics) should be manufactured in a closed system Additional testing sterility testing of intermediates microscopic examination (e.g. gram stain) endotoxin testing Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors - Nanjing, November 2009

47 Useful Publications PIC/S Recommendation on the Validation of Aseptic Processes FDA Guidance for Industry- Sterile Drug Products Produced by Aseptic Processing - Current Good Manufacturing Process ISO Aseptic Processing of Health Care Products Part 1: General Requirements Part 2: Filtration Part 3: Lyophilization Part 4: Clean-In-Place Technologies Part 5: Sterilization-In-Place Part 6: Isolator Systems Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors - Nanjing, November 2009


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