sediaan steril [compatibility mode](1)
TRANSCRIPT
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SEDIAAN STERIL
Dr.Heni Rachmawati
SCHOOL OF 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 diperlukanSetiap kegiatan produksi memerlukan tingkat p g p gsterilitas yang berbeda untuk meminimalkan resiko kontaminasi partikulat dan mikroorganisme terhadap produk atau bahan baku
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Maximum permitted number of 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
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METODE PEMBUATAN SEDIAAN STERIL
STERILISASI AKHIR
STERILISASI DENGAN FILTARSI
ASEPTIK
PEMBUATAN SECARA ASEPTIK
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A ti P iAseptic Processing
Mrs Robyn Isaacson
Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors - Nanjing, November 2009
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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
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( y )– those that cannot be terminally sterilized and
must be aseptically prepared
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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
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Aseptic Processing - OverviewObjective• 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
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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
Classification of Clean 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
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Grade D M 6.5 Class 100 000 ISO 8 Grade D
Table 1
Manufacturing EnvironmentClassification 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
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“At rest” - production equipment installed and operating
“In operation” - Installed equipment functioning in defined operating mode and specified number of personnel present
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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.
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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
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– Non-viable particles are defined by the air classification (See Table 2)
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Manufacturing Environment
• Limits for 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
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– 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 EnvironmentEnvironmental Monitoring• Physical
Particulate matter– Particulate matter – Differential pressures– Air changes, airflow patterns– Clean up time/recovery– Temperature and relative humidity– Airflow velocity
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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)
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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
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– Any deviations should be investigated and effect on environmental quality determined
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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
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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)
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Manufacturing Environment
Personnel• Minimum number 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
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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
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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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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
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– 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 )
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(washing and sterilization)• Regular microbiological monitoring of operators
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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
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– 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
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– filters remove bacteria and moulds– do not remove all viruses or mycoplasmas
• filtration should be carried out under positive pressure
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Aseptic Processing
Preparation and Filtration 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
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• 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
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– 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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Aseptic Processing
Preparation and Filtration 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
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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
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• Limits should reasonably reflect bioburden routinely achieved
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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
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• 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
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– pressure hold– forward flow
• methods are defined by filter manufacturers and limits determined during filter validation
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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
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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
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gvalidation
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Aseptic ProcessingEquipment/container preparation and
sterilization• All equipment (including lyophilizers) and product q 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
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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
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– 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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Aseptic Processing
Equipment/container preparation and 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)
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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
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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
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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
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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
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Aseptic sample collections– Line speed and configuration
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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
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• 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 timeSize
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– 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
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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
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• 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
• MediaAnaerobic media should be considered under certain
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– Anaerobic media should be considered under certain circumstances
– Should be tested for growth promoting properties (including factory isolates)
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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
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Units removed (and not incubated) should be consistent with routine practices (although incubation would give information regarding risk of intervention)
– Batch reconciliation
Aseptic ProcessingProcess 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
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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
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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)
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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)
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• 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
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Aseptic Processing
Additional issues specific 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
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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
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– Final inspection should be capable of detecting leakers
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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
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
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• 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 intermediatesmicroscopic examination (e g gram stain)
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– microscopic examination (e.g. gram stain)– endotoxin testing
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Useful Publications• PIC/S Recommendation 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
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– Part 5: Sterilization-In-Place– Part 6: Isolator Systems
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MACAM SEDIAAN STERIL
1. InjeksiLarutan obat dalam pembawa yang sesuai denganLarutan obat dalam pembawa yang sesuai denganatau tanpa zat tambahan, dimaksudkan untukpemberian secara parenteralDapat sebagai single dose dan multiple dose
2. InfusCairan yang diberikan melalui intravena: nutrisi(dekstrosa) menjaga keseimbangan elektrolit (larutan(dekstrosa), menjaga keseimbangan elektrolit (larutanringer), untuk cairan pengganti (kombinasi dekstrosadan NaCl), dan untuk tujuan khusus (hiperalimentasiparenteral)
3. SolidMisalnya sediaan parenteral rekonstitusi
4. SuspensiOb t t i d l b i t kObat tersuspensi dalam pembawa yang sesuai untukparenteral .
5. Obat mata (larutan, suspensi, dan salep)Khusus untuk salep mata, zat aktif baik dalam bentukterlarut atau serbuk tersuspensi halus dimasukkan kedalam basis salep yang non iritan. Salep disterilkan dengancara panas atau radiasi, dan sebagian dibuat dengan caracara panas atau rad as , dan sebag an d buat dengan caraaseptik. Sediaan ini harus dikemas dalam wadah tertutupdan bebas partikel logam.
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6. Larutan untuk irigasiLarutan yang digunakan untuk mandi atau mencuci lukaterbuka.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 filtrasi3. Sterilisasi dengan gas4 St ilis si d di si4. Sterilisasi dengan radiasi
Volume sediaanKarakteristik sediaan (stabilitas)
Lolos uji sterilitas
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STERILISASI PANAS : digunakan untuk membunuh mikroorganisme
Wet heat (otoklaf)/panas basahMetode sterilisasi yang digunakan untukMetode sterilisasi yang digunakan untukdestruksi semua mikroorganisme hidupDilakukan dalam otoklaf dengan menggunakanpanas pada suhu 121C dan uap jenuh dengantekanan 15 psi, selama 30-40 menitAdanya uap menyebabkan protein mikroorganisme terkoagulasi dan rusak padasuhu yang lebih rendah dibandingkan jika tidaksuhu yang lebih rendah dibandingkan jika tidakada uap
APLIKASI STERILISASI UAP
UNTUK:
Semua sediaan dan bahan yang tahan terhadap panas Semua 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 uapSediaan solid yang rusak oleh adanya lembap
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Faktor kritis yang mempengaruhi keberhasilansterilisasi:ster l sas
SuhuWaktu sterilisasiKesempurnaan pergantian udara dengan uap(tidak boleh ada udara yang terjerap)
Efektif terhadap semua jenis mikroorganismef f p j gtermasuk sporaMenguraikan asam nukleat, protein danmembran
TEKANAN VS SUHU VS WAKTU
Tekanan Suhu Waktu
10 115.5 3015 121.5 2020 126.5 15
Tekanan suhu waktu
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STERILISASI PANAS KERING
Umumnya dilakukan di oven, baik dengan sistem pemanas gas atau listrik dengan suhu terkontrol
Sterilisasi dengan cara panas kering kurang efisiendibandingkan 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/sediaanJenis produk/sediaanJenis kemasan produk/sediaanKarakteristik distribusi panas
Volume sekecil mungkinAlat pensteril mensirkulasi panas secara bebas dan menyeluruh
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APLIKASI STERILISASI PANAS KERING
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 mpenapisan
Digunakan untuk produk atau bahan yang sensitifterhadap panas, dan hanya untuk LARUTAN
Efektivitas sterilisasi dipengaruhi oleh jumlahkandungan mikroba dalam larutan
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JENIS-JENIS FILTER
1. Filter berbentuk tabung reaksi filter candles,terbuat dari mineral yang dikompres (Berkefelddan Mandler)dan Mandler)
2. Filter candles dari porselin (Pasteur-Chamberland,Doulton, Selas)
3. Filter keping terbuat dari asbes yang dikompres(Seitz dan Swinney)
4. Buchner5. Millipore (terbaru)
FAKTOR PENTING DALAM FILTRASI
Uk i ( li ti )Ukuran pori (paling penting)
Muatan listrik filter dan mikroba
pH larutan
Suhu
TekananTekanan
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KEUNTUNGAN VS KERUGIAN METODE FILTRASI
Cepat (terutama untuk volum kecil)M j t bilit d k/b h
KEUNTUNGAN
Menjaga stabilitas produk/bahanRelatif murahSifat penghilangan mikroba dan partikulat lainnyasempurna
KERUGIAN
Sifat adsorpsi zat tertentu (zat aktif) yang tidak diinginkan terutama yang jumlahnya kecilTerbatas penggunaannya untuk larutan-larutan viskus
STERILISASI GAS
Digunakan terutama untuk bahan yang tidak tahan panas dan lembapBi 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 sterilisasiBahan yang tidak tahan lembap dan panas Bahan yang tidak tahan lembap dan panas memerlukan t sterilisasi lebih lama
Contoh gas pensteril: Etilen oksidandan propilen oksida
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ETILEN OKSIDA
Sterilisasi dengan cara mengganggu metabolisme sel bakteri
Digunakan untuk sterilisasi produk yang tidak dapatdisterilkan dengan uapg pBerupa gas tidak berwarnaMudah terbakar dan meledakPemakaiannya terbatasKeuntungan:Dapat digunakan untuk sterilisasi bahan yang sensitifterhadap panas dan lembap (perlengkapan operasi, senyawaenzim, antibiotik) karena kemampuan penetrasinya yang baikKerugian:Kerugian:Memerlukan waktu lama (4-16 jam)MahalBerbahaya untuk pasien dan pekerjaPerlu pengecekan setelah sterilisasi untuk menjamin tidakterjadinya reaksi kimia dan penguaraian pada bahan
Toksisitas metode sterilisasi dengan gas ETO
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STERILISASI DENGAN RADIASI
Sterilisasi menggunakan sinar gamma dan radiasi katoda
Mekanisme kerja sterilisasi dengan radiasi belumdiketahui secara pasti, teori menyebutkan terjadinya perubahan kimia destruktif pada mikrobayang dapat merusak sel secara sempurna danireversibel
RADIASI UV
Terbatas pada permukaan bahan karena UV tidakdapat berpenetrasi ke dalam elas air lapisan dandapat berpenetrasi ke dalam gelas, air, lapisan danzat lainSudah digunakan untuk pengolahan air
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STERILISASI DENGAN PELARUT ORGANIK
Fenol
Alkohol
Formaldehid
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NILAI F
Untuk mengkuantifikasi efektivitas proses sterilisasi panas digunakan bilangan F (time of thermal death) yaitu waktu yang diperlukan untuk membunuh yaitu 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 awalB : jumlah mikroba yang hidup setelah waktu
pemanasan tertentu
PIROGEN DAN UJI PIROGEN
PIROGEN : senyawa organik yang dapat menimbulkandemam 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 larutan kemungkinan masih tertinggal dalam sediaan larutan setelah proses sterilisasi dengan otoklaf maupun filtrasi
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PEMBEBASAN PIROGENDAN UJI PIROGEN
Pirogen (dalam air pro injeksi) dihilangkan dengan adsorpsi menggunakan karbon aktif cari p m gg fprosedurnya!
Uji pirogen menurut USP dilakukan pada hewan kelinci cari prosedurnya!
PENGEMBANGAN SEDIAAN STERIL
LIQUID SEMI SOLID SOLID
SuspensiEmulsiLarutan
bebas partikulat- bebas partikulat- isotonis, terutama untuk volume besar dan intravena- isohidris, idem (kapasitas dapar rendah)- Bebas pirogen (terutama iv volume > 10 ml)
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OBAT SUNTIK
S di b l t l i t i d l i Sediaan 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 diberikan 2. 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 wpaska operasi, pasien tidak sadar dan tidak bisamenerima cairan, elektrolit dan nutrisi melalui rute oralVolume >= 100 ml per hari secara infus iv, dengan atau tanpa kontrol kecepatan pemberianKarena volumenya yang besar sediaan tidakKarena volumenya yang besar, sediaan tidakboleh mengandung pengawet (bakteriostatik)atau zat tambahan lainKemasan umumnya single dose
next: lihat “Pharmaceutical dosage forms & DDS”
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KLASIFIKASI OBAT SUNTIK
1. Bentuk sediaan
Larutan sejati pembawa airLarutan sejati pembawa minyakLarutan sejati pembawa pelarut campurSuspensi steril pembawa airSuspensi steril pembawa minyakSerbuk rekonstitusiEmulsi steril
2. Rute pemberian
Iv, im, sk, ik, ip, dan lain-lain, , , , p,
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BAHAN PEMBAWA OBAT SUNTIK
1. AIR
Ai i j k iAir pro injeksiAquabidest dengan pH tertentu, tidak mengandung logam berat, tidak mengandung ion Ca, Cl, NO3, SO4, Nh4, NO2 dan CO3Harus steril, penggunaan dalam jumlah besar harus bebas pirogenNilai tahanan spesifik sebesar 500.000 ohm/cm, jik il i h k tid k b l h di kjika nilainya separuhnya maka tidak boleh digunakanAqua demineralisata tidak boleh digunakan sebagai pembawa obat suntik
Air pro injeksi bebas CO2Dibuat 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 didinginkandidinginkanDigunakan untuk melarutkan zat aktif yang mudah teroksidasi (klorpromazin, prometazin, klorfeniramin, sulfamidin, dan lain-lain)
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2. Non air
Digunakan jika:Zat aktif tidak larut dalam pembawa air
k f d l bZat aktif terurai dalam pembawa airDiinginkan kerja depo dari sediaan
Minyak tumbuhanMudah 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 jaringanSering menimbulkan rasa nyeri sehingga perlu penambahan benzil alkohol 5% untuk anestesi lokal
Jenis minyak tumbuhan yang digunakan:Ol. ArachidisOl. SesamiOl. SesamiOl.GossypiiOl. Olivarum netralOl TerebintinaeOl.MaidisOl.Amygdalarumyg
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Minyak semi sintesisEster asam lemakAlkoholAlkohol
Memiliki aktivitas fisiologis, menimbulkanrasa nyeri dan kerusakan jaringan padapenggunaannya sehingga pemberiannyasecara iv tidak disarankan
FAKTOR YANG MEMPENGARUHIABSORPSI 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)
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TONISITAS LARUTANOBAT SUNTIK
ISOTONISJika suatu larutan konsentrasinya sama dengan konsentrasiJika suatu larutan konsentrasinya sama dengan konsentrasidalam sel darah merah sehingga tidak terjadi pertukarancairan diantara keduanya
ISOOSMOTIKJika suatu larutan mempunyai tekanan osmotik yang sama
dengan tekanan osmotik serum
HIPOTONISJika 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
NaClGlukosaSukrosaKNO3NaNO3
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PERHITUNGAN ISOTONISITAS
“Pharmaceutical dosage form and drug delivery systems”