Sediaan steril [compatibility mode](1)

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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)


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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


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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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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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• 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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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


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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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


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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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)


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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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


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”

Sediaan steril [compatibility mode](1)

Documents

Transcript of Sediaan steril [compatibility mode](1)