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Sediaan steril [compatibility mode](1)
This document discusses aseptic processing and the manufacturing environment for sterile products. It describes the classification system for clean areas from Grades A to D based on particulate and microbial limits. Grade A is required for high risk aseptic operations like filling. Environmental monitoring includes particulate levels, air pressures between rooms, air changes and velocity. Personnel requirements aim to minimize introduction of contaminants through hygiene, clothing and training standards.
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Sediaan steril [compatibility mode](1)
- 1. 4/18/2010 1 SEDIAAN STERIL Dr.Heni Rachmawati SCHOOLOF PHARMACY - ITB PENDAHULUAN Produksi sediaan steril harus dilakukan di ruang steril. Ruang produksi harus memenuhi standar yang sesuai dan dilengkapi dengan udara yang disterilkan melalui filter khusus (HEPA filter) Ruang steril untuk produksi sediaan steril diklasifikasikan berdasarkan persyaratan lingkungan yang diperlukan Setiap kegiatan produksi memerlukan tingkatp g p g sterilitas yang berbeda untuk meminimalkan resiko kontaminasi partikulat dan mikroorganisme terhadap produk atau bahan baku
- 2. 4/18/2010 2 Maximum permitted numberof particles /m3 Grade At rest In n operation 0.5mm 5mm 0.5mm 5mm A 3500 0 3500 0 B 3500 0 350,000 2000 C 350,000 2,000 3,500,000 20,000 D 3,500,000 20,000 Not defined Not defined
- 3. 4/18/2010 3 METODE PEMBUATAN SEDIAANSTERIL STERILISASI AKHIR STERILISASI DENGAN FILTARSI ASEPTIK PEMBUATAN SECARA ASEPTIK
- 4. 4/18/2010 1 A ti PiAseptic Processing Mrs Robyn Isaacson Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors - Nanjing, November 2009 1 Aseptic Processing - Overview • Certain pharmaceutical products must be sterile injections ophthalmic preparations irrigations– injections, ophthalmic preparations, irrigations solutions, haemodialysis solutions • Two categories of sterile products – those that can be sterilized in final container (terminally sterilized) Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors - Nanjing, November 2009 2 ( y ) – those that cannot be terminally sterilized and must be aseptically prepared
- 5. 4/18/2010 2 Aseptic Processing -Overview Aseptic processing • Objective is to maintain the sterility of a product,j y p , assembled from sterile components • Operating conditions so as to prevent microbial contamination Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors - Nanjing, November 2009 3 Aseptic Processing - Overview Objective • To review specific issues relating to the manufacture of aseptically prepared products:p y p p p – Manufacturing environment • Clean areas • Personnel – Preparation and filtration of solutions – Pre-filtration bioburden – Filter integrity/validation Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors - Nanjing, November 2009 4 Filter integrity/validation – Equipment/container preparation and sterilization – Filling Process – Validation of aseptic processes – Specific issues relating to Isolators, BFS and Bulk
- 6. 4/18/2010 3 Manufacturing Environment Classification ofClean Areas – Comparison of classifications WHO GMP US 209E US Customary ISO/TC (209) ISO 14644 EEC GMP Grade A M 3.5 Class 100 ISO 5 Grade A Grade B M 3.5 Class 100 ISO 5 Grade B Grade C M 5.5 Class 10 000 ISO 7 Grade C G d D M 6 5 Cl 100 000 ISO 8 G d D Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors - Nanjing, November 2009 5 Grade D M 6.5 Class 100 000 ISO 8 Grade D Table 1 Manufacturing Environment Classification of Clean Areas – Classified in terms of airborne particles (Table 2) Grade At rest In operationGrade At rest In operation maximum permitted number of particles/m3 0.5 - 5.0 µm > 5 µm 0.5 - 5.0 µm > 5 µ A 3 500 0 3 500 0 B 3 500 0 350 000 2 000 C 350 000 2 000 3 500 000 20 000 D 3 500 000 20 000 not defined not defined Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors - Nanjing, November 2009 6 “At rest” - production equipment installed and operating “In operation” - Installed equipment functioning in defined operating mode and specified number of personnel present
- 7. 4/18/2010 4 Manufacturing Environment Four gradesof 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. Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors - Nanjing, November 2009 7 p p • Grade B (equivalent to Class 100, ISO 5): – Background environment for Grade A zone, eg. cleanroom in which laminar flow workstation is housed. Manufacturing Environment • Grade A (equivalent to Class 100 (US Federal Standard 209E), ISO 5 (ISO 14644-1): – Local zone for high risk operations eg. product filling, t b l i l h dli t il t i lstopper 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 Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors - Nanjing, November 2009 8 – Non-viable particles are defined by the air classification (See Table 2)
- 8. 4/18/2010 5 Manufacturing Environment • Limitsfor viable particles (microbiological contamination) G d Ai l S ttl l t (90 C t t l t Gl i tGrade Air sample (CFU/m3) Settle plates (90mm diameter) (CFU/4hours) Contact plates (55mm diameter) (CFU/plate) Glove print (5 fingers) (CFU/glove) A < 3 < 3 < 3 < 3 B 10 5 5 5 C 100 50 25 - D 200 100 50 - Table 3 Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors - Nanjing, November 2009 9 – 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 Manufacturing Environment Environmental Monitoring • Physical Particulate matter– 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 10
- 9. 4/18/2010 6 Manufacturing Environment Environmental Monitoring- Physical • Particulate matter Particles significant because they can contaminate and– 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) Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors - Nanjing, November 2009 11 powder filling) – Appropriate alert and action limits should be set and corrective actions defined if limits exceeded Manufacturing Environment Environmental Monitoring - Physical • Differential pressures Positive pressure differential of 10-15 Pascals should be– 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 Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors - Nanjing, November 2009 12 – Any deviations should be investigated and effect on environmental quality determined
- 10. 4/18/2010 7 Manufacturing Environment Environmental Monitoring- Physical • Air Changes/Airflow patterns Ai fl iti l h ld b i di ti l– 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 Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors - Nanjing, November 2009 13 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 Manufacturing Environment Environmental Monitoring - Physical • Temperature and Relative Humidity Ambient temperature and humidity should not be– 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 14
- 11. 4/18/2010 8 Manufacturing Environment Personnel • Minimumnumber of personnel in clean areas – especially during aseptic processingp y g p p g • 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 Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors - Nanjing, November 2009 15 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) Manufacturing Environment Personnel (2) • High standards of hygiene and cleanliness – should not enter clean rooms if ill or with openshould 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 Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors - Nanjing, November 2009 16 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
- 12. 4/18/2010 9 Manufacturing Environment Personnel (3) •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 Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors - Nanjing, November 2009 17 – Grade A and B • headgear, beard and moustache covered, masks, gloves • not shedding fibres, and retain particles shed by operators Manufacturing Environment Personnel (4) • Outdoor clothing not in change rooms leading to G d B d CGrade 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 ( hi d t ili ti ) Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors - Nanjing, November 2009 18 (washing and sterilization) • Regular microbiological monitoring of operators
- 13. 4/18/2010 10 Aseptic Processing • Inaseptic 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 Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors - Nanjing, November 2009 19 – 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 Aseptic Processing Preparation and Filtration of Solutions • Solutions to be sterile filtered prepared in a Grade C environmentenvironment • 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 Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors - Nanjing, November 2009 20 – filters remove bacteria and moulds – do not remove all viruses or mycoplasmas • filtration should be carried out under positive pressure
- 14. 4/18/2010 11 Aseptic Processing Preparation andFiltration of Solutions (2) • consideration should be given to complementing filtration process with some form of heat treatmentfiltration 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 Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors - Nanjing, November 2009 21 • If bulk product is stored in sealed vessels, pressure release outlets should have hydrophobic microbial retentive air filters Aseptic Processing Preparation and Filtration of Solutions (3) • Time limits should be established for each phase of processing, e.g.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 t t l ti f d t filt ti t t i Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors - Nanjing, November 2009 22 – 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)
- 15. 4/18/2010 12 Aseptic Processing Preparation andFiltration of Solutions (4) • Filling of solution may be followed by lyophilization (freeze drying)(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 23 Aseptic Processing Prefiltration Bioburden (natural microbial load) • Limits should be stated and testing should be carried out on each batchout 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 Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors - Nanjing, November 2009 24 • Limits should reasonably reflect bioburden routinely achieved
- 16. 4/18/2010 13 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 Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors - Nanjing, November 2009 25 • Excessive bioburden can have adverse effect on the quality of the product and cause excessive levels of endotoxins/pyrogens Aseptic Processing Filter integrity • Filters of 0.22µm or less should be used for filtration of liquids and gasses (if applicable)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 Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors - Nanjing, November 2009 26 – pressure hold – forward flow • methods are defined by filter manufacturers and limits determined during filter validation
- 17. 4/18/2010 14 Aseptic Processing Filter Validaton •Filter must be validated to demonstrate ability to remove bacteriaremove 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 f f Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors - Nanjing, November 2009 27 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 Aseptic Processing Filter validation (2) – if the product is bactericidal, product should be passed through the filter first followed by modified productthrough 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 Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors - Nanjing, November 2009 28 g validation
- 18. 4/18/2010 15 Aseptic Processing Equipment/container preparationand sterilization • All equipment (including lyophilizers) and productq p ( g y p ) p 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 Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors - Nanjing, November 2009 29 during vacuum stage of sterilization process – equipment wrapped and loaded to facilitate air removal – particular attention to filters, housings and tubing 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 Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors - Nanjing, November 2009 30 – need to consider speed of conveyor – validation of depyrogenation (3 logs endotoxin units) • worst case locations – tunnel supplied with HEPA filtered air
- 19. 4/18/2010 16 Aseptic Processing Equipment/container preparationand sterilization (2) • equipment should be designed to be easily assembled and• 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) Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors - Nanjing, November 2009 31 g ( p p py g ) • 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) Aseptic Processing Process Validation • Not possible to define a sterility assurance level for aseptic processingfor 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 Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors - Nanjing, November 2009 32 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
- 20. 4/18/2010 17 Aseptic Processing Process Validation(2) • Media fill program should include worst case activitiesactivities – 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 Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors - Nanjing, November 2009 33 yop sat o – Aseptic equipment assembly Aseptic Processing Process Validation (3) • Worst case activities (cont) No of personnel and their activities shift changes– 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 Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors - Nanjing, November 2009 34 Aseptic sample collections – Line speed and configuration
- 21. 4/18/2010 18 Aseptic Processing Process Validation(4) • Worst case activities (cont)• Worst case activities (cont) – Weight checks – Container closure systems – Specific provisions in processing instructions • Written batch record documenting conditions and activities Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors - Nanjing, November 2009 35 • Should not be used to justify risky practices Aseptic Processing Process Validation (5) Duration – 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 Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors - Nanjing, November 2009 36 – 5000 - 10000 generally acceptable or batch size if <5000 – For manually intensive processes larger numbers should be filled – Lower numbers can be filled for isolators
- 22. 4/18/2010 19 Aseptic Processing Process Validation(6) • Frequency and Number Th i iti l ti hift– 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 Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors - Nanjing, November 2009 37 • Line Speed – Speed depends on type of process 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 Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors - Nanjing, November 2009 38 – Anaerobic media should be considered under certain circumstances – Should be tested for growth promoting properties (including factory isolates)
- 23. 4/18/2010 20 Aseptic Processing Process Validation(8) • Incubation, Examination In the range 20-35ºC– In the range 20-35 C. – 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 Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors - Nanjing, November 2009 39 Units removed (and not incubated) should be consistent with routine practices (although incubation would give information regarding risk of intervention) – Batch reconciliation 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 5000-10000 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 lid ti f ll i i ti ti Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors - Nanjing, November 2009 40 revalidation, following investigation – When filling more than 10000 units • One (1) contaminated unit should result in an investigation • Two (2) contaminated units are considered cause for revalidation, following investigation
- 24. 4/18/2010 21 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) Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors - Nanjing, November 2009 41 species level (genotypic identification) – Invalidation of a media fill run should be rare 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) Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors - Nanjing, November 2009 42 • 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
- 25. 4/18/2010 22 Aseptic Processing Additional issuesspecific to Isolator and BFS Technologies • Isolators• 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 Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors - Nanjing, November 2009 43 second pair of gloves inside isolator glove – Traditional aseptic vigilance should be maintained Aseptic Processing • Blow-Fill-Seal (BFS) – Located in a Grade D environment – Critial zone should meet Grade A (microbiological)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 Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors - Nanjing, November 2009 44 – Final inspection should be capable of detecting leakers
- 26. 4/18/2010 23 Aseptic Processing • Issuesrelating to Aseptic Bulk Processing • Applies to products which can not be filtered at point of fill and require aseptic processing throughout entire f t imanufacturing 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 Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors - Nanjing, November 2009 45 • 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. 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) Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors - Nanjing, November 2009 46 – microscopic examination (e.g. gram stain) – endotoxin testing
- 27. 4/18/2010 24 Useful Publications • PIC/SRecommendation on the Validation of Aseptic Processes • FDA Guidance for Industry- Sterile Drug Products Produced by Aseptic Processing Current Good Manufacturingby Aseptic Processing - Current Good Manufacturing Process • ISO 13408 Aseptic Processing of Health Care Products – Part 1: General Requirements – Part 2: Filtration – Part 3: Lyophilization – Part 4: Clean-In-Place Technologies P S ili i I Pl Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors - Nanjing, November 2009 47 – Part 5: Sterilization-In-Place – Part 6: Isolator Systems
- 28. 4/18/2010 4 MACAM SEDIAAN STERIL 1.Injeksi Larutan obat dalam pembawa yang sesuai denganLarutan obat dalam pembawa yang sesuai dengan atau tanpa zat tambahan, dimaksudkan untuk pemberian secara parenteral Dapat sebagai single dose dan multiple dose 2. Infus Cairan yang diberikan melalui intravena: nutrisi (dekstrosa) menjaga keseimbangan elektrolit (larutan(dekstrosa), menjaga keseimbangan elektrolit (larutan ringer), untuk cairan pengganti (kombinasi dekstrosa dan NaCl), dan untuk tujuan khusus (hiperalimentasi parenteral) 3. Solid Misalnya sediaan parenteral rekonstitusi 4. Suspensi Ob t t i d l b i t kObat tersuspensi dalam pembawa yang sesuai untuk parenteral . 5. Obat mata (larutan, suspensi, dan salep) Khusus untuk salep mata, zat aktif baik dalam bentuk terlarut atau serbuk tersuspensi halus dimasukkan ke dalam basis salep yang non iritan. Salep disterilkan dengan cara panas atau radiasi, dan sebagian dibuat dengan caracara panas atau rad as , dan sebag an d buat dengan cara aseptik. Sediaan ini harus dikemas dalam wadah tertutup dan bebas partikel logam.
- 29. 4/18/2010 5 6. Larutan untukirigasi Larutan yang digunakan untuk mandi atau mencuci luka terbuka. Larutan di unakan secara t pikalLarutan digunakan secara topikal METODE STERILISASI Dalam bidang farmasi sterilisasi berarti destruksi sempurna organisme hidup dan sporanya atau pemusnahan mikroorganisme secara sempurna dari suatu sediaan Ada 4 metode utama untuk sterilisasi produk farmasi: 1. Sterilisasi panas - Basah sterilisasi uap - Kering sterilisasi panas kering 2. Sterilisasi dengan cara filtrasi 3. Sterilisasi dengan gas 4 St ilis si d di si4. Sterilisasi dengan radiasi Volume sediaan Karakteristik sediaan (stabilitas) Lolos uji sterilitas
- 30. 4/18/2010 6 STERILISASI PANAS : digunakanuntuk membunuh mikroorganisme Wet heat (otoklaf)/panas basah Metode sterilisasi yang digunakan untukMetode sterilisasi yang digunakan untuk destruksi semua mikroorganisme hidup Dilakukan dalam otoklaf dengan menggunakan panas pada suhu 121C dan uap jenuh dengan tekanan 15 psi, selama 30-40 menit Adanya uap menyebabkan protein mikroorganisme terkoagulasi dan rusak pada suhu yang lebih rendah dibandingkan jika tidaksuhu yang lebih rendah dibandingkan jika tidak ada uap APLIKASI STERILISASI UAP UNTUK: Semua sediaan dan bahan yang tahan terhadap panasSemua sediaan dan bahan yang tahan terhadap panas pada suhu yang digunakan dan uap dapat berpenetrasi sediaan larutan dalam kemasan, ruahan larutan, alat- alat gelas, pakaian operasi dan peralatan operasi TIDAK UNTUK: Minyak, lemak, sediaan mengandung lemak, dan lain-lain yang tidak bisa dipenetrasi oleh uap Sediaan solid yang rusak oleh adanya lembap
- 31. 4/18/2010 7 Faktor kritis yangmempengaruhi keberhasilan sterilisasi:ster l sas Suhu Waktu sterilisasi Kesempurnaan pergantian udara dengan uap (tidak boleh ada udara yang terjerap) Efektif terhadap semua jenis mikroorganismef f p j g termasuk spora Menguraikan asam nukleat, protein dan membran TEKANAN VS SUHU VS WAKTU Tekanan Suhu Waktu 10 115.5 30 15 121.5 20 20 126.5 15 Tekanan suhu waktu
- 32. 4/18/2010 8 STERILISASI PANAS KERING Umumnyadilakukan di oven, baik dengan sistem pemanas gas atau listrik dengan suhu terkontrol Sterilisasi dengan cara panas kering kurang efisien dibandingkan dengan cara basah sehingga: Memerlukan waktu yang lebih lama (2-4 jam) Memerlukan panas yang lebih tinggi (160-170C) Suhu dan waktu bergantung pada: Ukuran produk/sediaan Jenis produk/sediaan Jenis kemasan produk/sediaan Karakteristik distribusi panas Volume sekecil mungkin Alat pensteril mensirkulasi panas secara bebas dan menyeluruh
- 33. 4/18/2010 9 APLIKASI STERILISASI PANASKERING Minyaky Gliserin Petrolatum Parafin Serbuk tahan panas (ZnO) Alat-alat gelas Perlengkapan operasi STERILISASI FILTRASI Penghilangan mikroorganisme dilakukan dengan cara adsorpsi pada medium filter atau mekanismep p m m f m m penapisan Digunakan untuk produk atau bahan yang sensitif terhadap panas, dan hanya untuk LARUTAN Efektivitas sterilisasi dipengaruhi oleh jumlah kandungan mikroba dalam larutan
- 34. 4/18/2010 10 JENIS-JENIS FILTER 1. Filterberbentuk tabung reaksi filter candles, terbuat dari mineral yang dikompres (Berkefeld dan Mandler)dan Mandler) 2. Filter candles dari porselin (Pasteur-Chamberland, Doulton, Selas) 3. Filter keping terbuat dari asbes yang dikompres (Seitz dan Swinney) 4. Buchner 5. Millipore (terbaru) FAKTOR PENTING DALAM FILTRASI Uk i ( li ti )Ukuran pori (paling penting) Muatan listrik filter dan mikroba pH larutan Suhu TekananTekanan
- 35. 4/18/2010 11 KEUNTUNGAN VS KERUGIANMETODE FILTRASI Cepat (terutama untuk volum kecil) M j t bilit d k/b h KEUNTUNGAN Menjaga stabilitas produk/bahan Relatif murah Sifat penghilangan mikroba dan partikulat lainnya sempurna KERUGIAN Sifat adsorpsi zat tertentu (zat aktif) yang tidak diinginkan terutama yang jumlahnya kecil Terbatas penggunaannya untuk larutan-larutan viskus STERILISASI GAS Digunakan terutama untuk bahan yang tidak tahan panas dan lembap Bi s n dik mbin si den n t kl f: ut cl veBiasanya dikombinasi dengan otoklaf: autoclave- ethylene oxide sterilizer dan perlu pertimbangan: waktu, suhu, konsentrasi gas dan kelembapan: Kelembapan sampai 60% dan suhu (50 dan 60C) dapat t sterilisasi Bahan yang tidak tahan lembap dan panasBahan yang tidak tahan lembap dan panas memerlukan t sterilisasi lebih lama Contoh gas pensteril: Etilen oksidandan propilen oksida
- 36. 4/18/2010 12 ETILEN OKSIDA Sterilisasi dengancara mengganggu metabolisme sel bakteri Digunakan untuk sterilisasi produk yang tidak dapat disterilkan dengan uapg p Berupa gas tidak berwarna Mudah terbakar dan meledak Pemakaiannya terbatas Keuntungan: Dapat digunakan untuk sterilisasi bahan yang sensitif terhadap panas dan lembap (perlengkapan operasi, senyawa enzim, antibiotik) karena kemampuan penetrasinya yang baik Kerugian:Kerugian: Memerlukan waktu lama (4-16 jam) Mahal Berbahaya untuk pasien dan pekerja Perlu pengecekan setelah sterilisasi untuk menjamin tidak terjadinya reaksi kimia dan penguaraian pada bahan Toksisitas metode sterilisasi dengan gas ETO
- 37. 4/18/2010 13 STERILISASI DENGAN RADIASI Sterilisasimenggunakan sinar gamma dan radiasi katoda Mekanisme kerja sterilisasi dengan radiasi belum diketahui secara pasti, teori menyebutkan terjadinya perubahan kimia destruktif pada mikroba yang dapat merusak sel secara sempurna dan ireversibel RADIASI UV Terbatas pada permukaan bahan karena UV tidak dapat berpenetrasi ke dalam elas air lapisan dandapat berpenetrasi ke dalam gelas, air, lapisan dan zat lain Sudah digunakan untuk pengolahan air
- 38. 4/18/2010 14 STERILISASI DENGAN PELARUTORGANIK Fenol Alkohol Formaldehid
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- 40. 4/18/2010 16 NILAI F Untuk mengkuantifikasiefektivitas proses sterilisasi panas digunakan bilangan F (time of thermal death) yaitu waktu yang diperlukan untuk membunuhyaitu waktu yang diperlukan untuk membunuh organisme tertentu pada suatu kondisi Nilai F dihitung dari data biologi yang diturunkan dari kecepatan destruksi dari sejumlah mikroba, dengan persamaan: Fo = D121 (Log A – Log B) A : populasi mikroba awal B : jumlah mikroba yang hidup setelah waktu pemanasan tertentu PIROGEN DAN UJI PIROGEN PIROGEN : senyawa organik yang dapat menimbulkan demam berasal dari kontaminasi mikrobademam, berasal dari kontaminasi mikroba Materi penyebabnya adalah LPS dari dinding luar sel bakteri dan endotoksin Pirogen termasuk senyawa yang termostabil sehingga kemungkinan masih tertinggal dalam sediaan larutankemungkinan masih tertinggal dalam sediaan larutan setelah proses sterilisasi dengan otoklaf maupun filtrasi
- 41. 4/18/2010 17 PEMBEBASAN PIROGEN DAN UJIPIROGEN Pirogen (dalam air pro injeksi) dihilangkan dengan adsorpsi menggunakan karbon aktif carip m gg f prosedurnya! Uji pirogen menurut USP dilakukan pada hewan kelinci cari prosedurnya! PENGEMBANGAN SEDIAAN STERIL LIQUID SEMI SOLID SOLID Suspensi Emulsi Larutan bebas partikulat- bebas partikulat - isotonis, terutama untuk volume besar dan intravena - isohidris, idem (kapasitas dapar rendah) - Bebas pirogen (terutama iv volume > 10 ml)
- 42. 4/18/2010 18 OBAT SUNTIK S dib l t l i t i d l iSediaan berupa larutan, emulsi atau suspensi dalam air atau pembawa lain yang sesuai, steril dan digunakan secara parenteral Berdasarkan volumnya dibagi menjadi 2: 1. Volume kecil (berupa larutan atau suspensi, <10 ml) 2 Volume besar (berupa larutan >=100 ml diberikan2. Volume besar (berupa larutan >=100 ml, diberikan sebagai infus intravena) Contoh produk: “pharmaceutical dosage forms & dds” LARGE VOLUME PARENTERAL (LVP) Diberikan umumnya untuk penggantian cairan tubuh, elektrolit atau nutrisi; terapi perawatan, ; p p w paska operasi, pasien tidak sadar dan tidak bisa menerima cairan, elektrolit dan nutrisi melalui rute oral Volume >= 100 ml per hari secara infus iv, dengan atau tanpa kontrol kecepatan pemberian Karena volumenya yang besar sediaan tidakKarena volumenya yang besar, sediaan tidak boleh mengandung pengawet (bakteriostatik) atau zat tambahan lain Kemasan umumnya single dose next: lihat “Pharmaceutical dosage forms & DDS”
- 43. 4/18/2010 19 KLASIFIKASI OBAT SUNTIK 1.Bentuk sediaan Larutan sejati pembawa air Larutan sejati pembawa minyak Larutan sejati pembawa pelarut campur Suspensi steril pembawa air Suspensi steril pembawa minyak Serbuk rekonstitusi Emulsi steril 2. Rute pemberian Iv, im, sk, ik, ip, dan lain-lain, , , , p,
- 44. 4/18/2010 20 BAHAN PEMBAWA OBATSUNTIK 1. AIR Ai i j k iAir pro injeksi Aquabidest dengan pH tertentu, tidak mengandung logam berat, tidak mengandung ion Ca, Cl, NO3, SO4, Nh4, NO2 dan CO3 Harus steril, penggunaan dalam jumlah besar harus bebas pirogen Nilai tahanan spesifik sebesar 500.000 ohm/cm, jik il i h k tid k b l h di kjika nilainya separuhnya maka tidak boleh digunakan Aqua demineralisata tidak boleh digunakan sebagai pembawa obat suntik Air pro injeksi bebas CO2 Dibuat dengan cara mendidihkan air pro injeksi selama 20-30 menit, lalu dialiri gas N2 sambil didinginkan Air pro injeksi bebas O2 Dibuat dengan cara mendidihkan air pro injeksi selama 20-30 menit, jika dibutuhkan dalam jumlah besar maka dialiri N2 sambil didinginkandidinginkan Digunakan untuk melarutkan zat aktif yang mudah teroksidasi (klorpromazin, prometazin, klorfeniramin, sulfamidin, dan lain-lain)
- 45. 4/18/2010 21 2. Non air Digunakanjika: Zat aktif tidak larut dalam pembawa air k f d l bZat aktif terurai dalam pembawa air Diinginkan kerja depo dari sediaan Minyak tumbuhan Mudah tengik karena mengandung asam lemak bebas (+ antioksidan) Tidak boleh mengandung minyak mineral atau parafin cair karena tidak bisa dimetabolisme dalam tubuh, karsinogenik, dan memberikan reaksi terhadap jaringan Sering menimbulkan rasa nyeri sehingga perlu penambahan benzil alkohol 5% untuk anestesi lokal Jenis minyak tumbuhan yang digunakan: Ol. Arachidis Ol. SesamiOl. Sesami Ol.Gossypii Ol. Olivarum netral Ol Terebintinae Ol.Maidis Ol.Amygdalarumyg
- 46. 4/18/2010 22 Minyak semi sintesis Esterasam lemak AlkoholAlkohol Memiliki aktivitas fisiologis, menimbulkan rasa nyeri dan kerusakan jaringan pada penggunaannya sehingga pemberiannya secara iv tidak disarankan FAKTOR YANG MEMPENGARUHI ABSORPSI OBAT SUNTIK Rute pemberian (iv > im > sk)Rute pemberian (iv > im > sk) Ukuran partikel zat aktif (makin halus makin cepat) Polimorfisma (amorf > kristal) Bentuk sediaan (larutan > emulsi > suspensi) Pembawa (air > minyak)( y ) pH (untuk rute im dan sk isohidrisitas sangat penting, iv tidak karena volume darah yang besar dengan kapasitas dapar mampu menetralkan)
- 47. 4/18/2010 23 TONISITAS LARUTAN OBAT SUNTIK ISOTONIS Jikasuatu larutan konsentrasinya sama dengan konsentrasiJika suatu larutan konsentrasinya sama dengan konsentrasi dalam sel darah merah sehingga tidak terjadi pertukaran cairan diantara keduanya ISOOSMOTIK Jika suatu larutan mempunyai tekanan osmotik yang sama dengan tekanan osmotik serum HIPOTONIS Jika tekanan osmosis sediaan lebih rendah dari tekanan osmosis serum darah, menyebabkan air akan melintasi membran sel darah merah yang semipermeabel memperbesar volume menyebabkan peningkatan tekanan dalam sel pecah hemolisis HIPERTONI Jika tekanan osmosis sediaan lebih besar dari tekanan serum darah, menyebabkan air keluar dari sel darah merah melintasi membran semipermeabel mengakibatkan penciutan sel-sel darah merah plasmolisism p m TONISITAS MODIFIER NaCl Glukosa Sukrosa KNO3 NaNO3
- 48. 4/18/2010 24 PERHITUNGAN ISOTONISITAS “Pharmaceutical dosageform and drug delivery systems”