Sediaan Steril (Compatibility Mode) PDF

4/18/2010
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 diperlukan
Setiapp kegiatan
g produksi
p memerlukan tingkat
g
sterilitas 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 ASEPTIK
STERILISASI DENGAN FILTARSI
PEMBUATAN SECARA ASEPTIK
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A
Aseptic
ti Processing
P i
Mrs Robyn Isaacson
1 Manufacture of sterile medicines – Advanced workshop for SFDA GMP

inspectors - Nanjing, November 2009
Aseptic Processing - Overview

• Certain pharmaceutical products must be
sterile
– injections
injections, ophthalmic preparations
preparations, irrigations
solutions, haemodialysis solutions
• Two categories of sterile products

– those that can be sterilized in final container
((terminally
y sterilized))
– those that cannot be terminally sterilized and
must be aseptically prepared

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Aseptic processing
• Objective
j is to maintain the sterility
y of a p
product,,
assembled from sterile components
• Operating conditions so as to prevent microbial
contamination


Objective
• To review specific issues relating to the
p yp
manufacture of aseptically prepared
p products:
p
– Manufacturing environment
• Clean areas
• Personnel
– Preparation and filtration of solutions
– Pre-filtration bioburden
– Filter integrity/validation
– Equipment/container preparation and sterilization
– Filling Process
– Validation of aseptic processes
– Specific issues relating to Isolators, BFS and Bulk
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Manufacturing Environment
Classification of Clean Areas
– Comparison of classifications
WHO GMP US 209E US Customary ISO/TC (209) EEC GMP

ISO 14644
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
Grade M 6.5
65 Cl
Class 100 000 ISO 8 G d D
Grade
Table 1

Classification of Clean Areas
– Classified in terms of airborne particles (Table 2)
Grade At rest In operation
maximum permitted number of particles/m3

0.5 - 5.0 µm > 5 µm 0.5 - 5.0 µm >5µ
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
“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
p p of solutions to be filtered.
• Grade B (equivalent to Class 100, ISO 5):
– Background environment for Grade A zone, eg.
cleanroom in which laminar flow workstation is housed.

• Grade A (equivalent to Class 100 (US Federal
Standard 209E), ISO 5 (ISO 14644-1):
– Local zone for high risk operations eg. product filling,
stopper
t bowls,
b l open vials,i l handling
h dli sterile
t il materials,
t i l
aseptic connections, transfer of partially stoppered
containers to be lyophilized.
– Conditions usually provided by laminar air flow
workstation.
• Each grade of cleanroom has specifications for
viable and non-viable particles
– Non-viable particles are defined by the air classification
(See Table 2)

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• Limits for viable particles (microbiological
contamination)
G d
Grade Air sample
Ai l Settle
S ttl plates
l t (90mm
(90 Contact
C t t plates
l t Glove print
Gl i t
(CFU/m3) diameter) (55mm (5 fingers)
(CFU/4hours) diameter) (CFU/glove)
(CFU/plate)
A <3 <3 <3 <3
B 10 5 5 5
C 100 50 25 -
D 200 100 50 -
Table 3
– These are average values
– Individual settle plates may be exposed for less than 4 hours
• Values are for guidance only - not intended to represent specifications
• Levels (limits) of detection of microbiological contamination should be
established for alert and action purposes and for monitoring trends of air
quality in the facility
Environmental Monitoring
• Physical
– Particulate matter
– Differential pressures
– Air changes, airflow patterns
– Clean up time/recovery
– Temperature and relative humidity
– Airflow velocity

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

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

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

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

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Personnel
• Minimum number of personnel in clean areas
– especially
p y during
g aseptic
p processing
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
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 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,
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
• 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 and
Grade d C rooms
• Change at every working session, or once a day (if
supportive data)
• Change gloves and masks at every working session
• Frequent disinfection of gloves during operations
• Washing of garments – separate laundry facility
– No damage, and according to validated procedures
(
(washing
hi andd sterilization)
t ili ti )
• 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
– 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
environment
• If not to be filtered, preparation should be prepared in
a Grade A environment with Grade B background (e.g.
ointments, creams, suspensions and emulsions)
• Prepared solutions filtered through a sterile 0.22µm
(or less) membrane filter into a previously sterilized
container
– filters remove bacteria and moulds
– do not remove all viruses or mycoplasmas
• filtration should be carried out under positive
pressure

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Aseptic Processing
Preparation and Filtration of Solutions (2)
• consideration should be given to complementing
filtration process with some form of heat treatment
• Double filter or second filter at point of fill advisable
• Fitlers should not shed particles, asbestos containing
filters should not be used
• Same filter should not be used for more than one day
unless validated
• If bulk product is stored in sealed vessels,
vessels pressure
release outlets should have hydrophobic microbial
retentive air filters

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

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Aseptic Processing
• Filling of solution may be followed by lyophilization
(freeze drying)
– stoppers partially seated, product transferred to
lyophilizer (Grade A/B conditions)
– Release of air/nitrogen into lyophilizer chamber at
completion of process should be through sterilizing
filter

Aseptic Processing
Prefiltration Bioburden (natural microbial load)
• Limits should be stated and testing should be carried
out on each batch
• Frequency may be reduced after satisfactory history
is established
– and biobuden testing performed on components
• Should include action and alert limits (usually differ
by a factor of 10) and action taken if limits are
exceeded
• Limits should reasonably reflect bioburden routinely
achieved

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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
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)
– filters for gasses that may be used for purging or
overlaying of filled containers or to release vacuum in
lyphilization chamber
• filter intergrity shoud be verified before filtration and
confirmed after filtration
– bubble point
– pressure hold
– forward flow
• methods are defined by filter manufacturers and limits
determined during filter validation

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Aseptic Processing
Filter Validaton
• Filter must be validated to demonstrate ability to
remove bacteria
– most common method is to show that filter can retain a
microbiological challenge of 107 CFU of Brevundimonas
diminuta per cm2 of the filter surface
– a bioburden isolate may be more appropriate for filter
retention studies than Brevundimonas diminuta
– Challenge concentration is intended to provide a margin
off safety
f 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 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 g filter
validation

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Aseptic Processing
Equipment/container preparation and
sterilization
• All equipment
q p (including
( g lyophilizers)
y p ) and product
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
– equipment wrapped and loaded to facilitate air removal
– particular attention to filters, housings and tubing

Aseptic Processing

sterilization (2)
• CIP/SIP processes
– particular attention to deadlegs - different orientation
requirements for CIP and SIP
• heat tunnels often used for
sterilization/depyrogenation of glass vials/bottles
– usually high temperature for short period of time
– need to consider speed of conveyor
– validation of depyrogenation (3 logs endotoxin units)
• worst case locations
– tunnel supplied with HEPA filtered air

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Aseptic Processing
sterilization (2)
• equipment should be designed to be easily assembled and
disassembled, cleaned, sanitised and/or sterilized
– equipment should be appropriately cleaned - O-rings and
gaskets should be removed to prevent build up of dirt or
residues
• rinse water should be WFI grade
• equipment should be left dry unless sterilized immediately
after cleaning
g (to
( prevent
p build up
p of pyrogens)
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 processing
• Process is validated by simulating the
manufacturing process using microbiological
growth medium (media fill)
– Process simulation includes formulation
(compounding), filtration and filling with suitable media
using the same processes involved in manufacture of
the product
– modifications must be made for different dosage
formats e.g. lyophilized products, ointments, sterile
bulks, eye drops filled into semi-transparent/opaque
containers, biological products

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Aseptic Processing
Process Validation (2)
• Media fill program should include worst case
activities
– Factors associated with longest permitted run (e.g.
operator fatigue)
– Representative number, type, and complexity of
normal interventions, non-routine interventions
and events (e.g. maintenance, stoppages, etc)
– Lyophilisation
yop sat o
– Aseptic equipment assembly

Aseptic Processing
• Worst case activities (cont)
– No of personnel and their activities,
activities shift changes,
changes
breaks, gown changes
– Representative number of aseptic additions (e.g.
charging containers, closures, sterile ingredients)
or transfers
– Aseptic equipment connections/disconnections
– Aseptic sample collections
– Line speed and configuration

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Aseptic Processing

• Worst case activities (cont)
– Weight checks
– Container closure systems
– Specific provisions in processing instructions
• Written batch record documenting conditions and
activities
• Should not be used to justify risky practices

Aseptic Processing

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
– 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
• Frequency and Number
– Three
Th iinitial,
iti l consecutive
ti per shift
hift
– Subsequently semi-annual per shift and process
– All personnel should participate at least annually,
consistent with routine duties
– Changes should be assessed and revalidation
carried out as required
• Line Speed
– Speed depends on type of process

Aseptic Processing

• Environmental conditions
– Representative of actual production conditions (no. of
personnel, activity levels etc) - no special precautions (not
including adjustment of HVAC)
– if nitrogen used for overlaying/purging need to substitute with
air
• Media
– Anaerobic media should be considered under certain
circumstances
– Should be tested for growth promoting properties (including
factory isolates)

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Aseptic Processing
• Incubation, Examination
– In the range 20-35
20-35ºC
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
consistent with routine practices (although
incubation would give information regarding risk of
intervention)
– Batch reconciliation
Aseptic Processing
• 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
revalidation,
lid ti following
f ll i investigation
i ti ti
– 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

• Interpretation of Results
– Media fills should be observed by QC and
contaminated units reconcilable with time and
activity being simulated (Video may help)
– Ideally - no contamination. Any contamination
should be investigated.
– Any organisms isolated should be identified to
species level (genotypic identification)
– Invalidation of a media fill run should be rare

Aseptic Processing

• Batch Record Review
– Process and environmental control activities
should be included in batch records and reviewed
as part of batch release
• In-process and laboratory control results
• Environmental and personnel monitoring data
• Output from support systems(HEPA/HVAC, WFI, steam
generator)
• Equipment function (batch alarm reports, filter integrity)
• Interventions, Deviations, Stoppages - duration and
associated time
• Written instructions regarding need for line clearances
• Disruptions to power supply

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Aseptic Processing
Additional issues specific to Isolator and
BFS Technologies
• Isolators
– Decontamination process requires a 4-6 log
reduction of appropriate Biological Indicator (BI)
– Minimum 6 log reduction of BI if surface is to be
free of viable organisms
– Significant focus on glove integrity - daily checks,
second pair of gloves inside isolator glove
– Traditional aseptic vigilance should be maintained

Aseptic Processing
• Blow-Fill-Seal (BFS)
– Located in a Grade D environment
– Critial zone should meet Grade A (microbiological)
requirements (particle count requirements may be
difficult to meet in operation)
– Operators meet Grade C garment requirements
– Validation of extrusion process should
demonstrate destruction of endotoxin and spore
challenges in the polymeric material
– Final inspection should be capable of detecting
leakers

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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
manufacturing
f t i process.
• Entire aseptic process should be subject to process
simulation studies under worst case conditions
(maximum duration of "open" operations, maximum no
of operators)
• Process simulations should incorporate storage and
transport of bulk.
• Multiple uses of the same bulk with storage in between
should also be included in process simulations
• Assurance of bulk vessel integrity for specified holding
times.

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.
(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 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
Part 5: Sterilization-In-Place
S ili i I Pl
– Part 6: Isolator Systems

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MACAM SEDIAAN STERIL
1. Injeksi
9 Larutan obat dalam pembawa yang sesuai dengan
atau tanpa zat tambahan, dimaksudkan untuk
pemberian secara parenteral
9 Dapat sebagai single dose dan multiple dose
2. Infus
Cairan yang diberikan melalui intravena: nutrisi
(dekstrosa) menjaga keseimbangan elektrolit (larutan
(dekstrosa),
ringer), untuk cairan pengganti (kombinasi dekstrosa
dan NaCl), dan untuk tujuan khusus (hiperalimentasi
parenteral)
3. Solid
Misalnya sediaan parenteral rekonstitusi
4. Suspensi
Ob t tersuspensi
Obat t i dalam
d l pembawa
b yang sesuaii untuk
t k
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 rad
radiasi,
as , dan sebag
sebagian
an d
dibuat
buat dengan cara
aseptik. Sediaan ini harus dikemas dalam wadah tertutup
dan bebas partikel logam.
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6. Larutan untuk irigasi

Larutan yang digunakan untuk mandi atau mencuci luka
terbuka.
Larutan digunakan
di unakan secara topikal
t pikal
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 Î sterilisasi uap
- Kering Î sterilisasi panas kering
2. Sterilisasi dengan cara filtrasi
3. Sterilisasi dengan gas
4 Sterilisasi
4. St ilis si dengan
d di si
radiasi
Volume sediaan Lolos uji sterilitas

Karakteristik sediaan (stabilitas)
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STERILISASI PANAS :
Î digunakan untuk membunuh mikroorganisme
Wet heat (otoklaf)/panas basah

9 Metode sterilisasi yang digunakan untuk
destruksi semua mikroorganisme hidup
9 Dilakukan dalam otoklaf dengan menggunakan
panas pada suhu 121C dan uap jenuh dengan
tekanan 15 psi, selama 30-40 menit
9 Adanya uap menyebabkan protein
mikroorganisme terkoagulasi dan rusak pada
suhu yang lebih rendah dibandingkan jika tidak
ada uap
APLIKASI STERILISASI UAP
UNTUK:
Semua sediaan dan bahan yang tahan terhadap panas

pada suhu yang digunakan dan uap dapat berpenetrasi
Î 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
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9 Faktor kritis yang mempengaruhi keberhasilan

ster l sas
sterilisasi:
¾ Suhu
¾ Waktu sterilisasi
¾ Kesempurnaan pergantian udara dengan uap
(tidak boleh ada udara yang terjerap)
9 Efektif
f f terhadap
p semua jjenis mikroorganisme
g
termasuk spora
9 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 Ç Î suhu Ç Î waktu È
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STERILISASI PANAS KERING
Umumnya dilakukan di oven, baik dengan sistem pemanas gas

atau listrik dengan suhu terkontrol
9 Sterilisasi dengan cara panas kering kurang efisien

dibandingkan dengan cara basah sehingga:
9 Memerlukan waktu yang lebih lama (2-4 jam)
9 Memerlukan panas yang lebih tinggi (160-170C)
Suhu dan waktu bergantung pada: Volume sekecil mungkin

Alat pensteril
Ukuran produk/sediaan mensirkulasi panas
Jenis produk/sediaan secara bebas dan
Jenis kemasan produk/sediaan menyeluruh
Karakteristik distribusi panas
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APLIKASI STERILISASI PANAS KERING
y
Minyak
Gliserin
Petrolatum
Parafin
Serbuk tahan panas (ZnO)
Alat-alat gelas
Perlengkapan operasi
STERILISASI FILTRASI
Penghilangan mikroorganisme dilakukan dengan

cara adsorpsi
p pada
p medium
m m filter
f atau mekanisme
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
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JENIS-JENIS FILTER
1. Filter berbentuk tabung reaksi Æ filter candles,

terbuat dari mineral yang dikompres (Berkefeld
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
Ukuran porii (paling
( li penting)
ti )
Muatan listrik filter dan mikroba
pH larutan
Suhu
Tekanan
10
4/18/2010
KEUNTUNGAN VS KERUGIAN METODE FILTRASI
KEUNTUNGAN
Cepat (terutama untuk volum kecil)
Menjaga
M j stabilitas
t bilit produk/bahan
d k/b h
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
Biasanya dikombinasi
mbin si den
dengan
n otoklaf:
t kl f: autoclave-
ut cl ve
ethylene oxide sterilizer dan perlu pertimbangan:
waktu, suhu, konsentrasi gas dan kelembapan:
Ç Kelembapan sampai 60% dan suhu (50 dan 60C)

dapat È t sterilisasi
Bahan yang tidak tahan lembap dan panas
memerlukan t sterilisasi lebih lama
Contoh gas pensteril: Etilen oksidandan propilen

oksida
11
4/18/2010
ETILEN OKSIDA
Sterilisasi dengan cara mengganggu metabolisme sel bakteri
9 Digunakan untuk sterilisasi produk yang tidak dapat

disterilkan dengan
g uap p
9 Berupa gas tidak berwarna
9 Mudah terbakar dan meledak
9 Pemakaiannya terbatas
9 Keuntungan:
9 Dapat digunakan untuk sterilisasi bahan yang sensitif
terhadap panas dan lembap (perlengkapan operasi, senyawa
enzim, antibiotik) karena kemampuan penetrasinya yang baik
9 Kerugian:
9 Memerlukan waktu lama (4-16 jam)
9 Mahal
9 Berbahaya untuk pasien dan pekerja
9 Perlu pengecekan setelah sterilisasi untuk menjamin tidak
terjadinya reaksi kimia dan penguaraian pada bahan
Toksisitas metode sterilisasi dengan gas ETO
12
4/18/2010
STERILISASI DENGAN RADIASI
Sterilisasi menggunakan 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
9 Terbatas pada permukaan bahan karena UV tidak

dapat berpenetrasi ke dalam gelas,
elas air,
air lapisan dan
zat lain
9 Sudah digunakan untuk pengolahan air
13
4/18/2010
STERILISASI DENGAN PELARUT ORGANIK
Fenol
Alkohol
Formaldehid
14
4/18/2010
15
4/18/2010
NILAI F
Untuk mengkuantifikasi efektivitas proses sterilisasi
panas digunakan bilangan F (time of thermal death) Æ
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 awal

B : jumlah mikroba yang hidup setelah waktu
pemanasan tertentu
PIROGEN DAN UJI PIROGEN
PIROGEN : senyawa organik yang dapat menimbulkan

demam berasal dari kontaminasi mikroba
demam,
Materi penyebabnya adalah LPS dari dinding luar sel

bakteri dan endotoksin
Pirogen termasuk senyawa yang termostabil sehingga

kemungkinan masih tertinggal dalam sediaan larutan
setelah proses sterilisasi dengan otoklaf maupun filtrasi
16
4/18/2010
PEMBEBASAN PIROGEN
DAN UJI PIROGEN
Pirogen (dalam air pro injeksi) dihilangkan dengan

adsorpsi
p menggunakan
m gg karbon aktif f Æ cari
prosedurnya!
Uji pirogen menurut USP dilakukan pada hewan

kelinci Æ cari prosedurnya!
PENGEMBANGAN SEDIAAN STERIL
LIQUID SEMI SOLID SOLID
Suspensi
Emulsi
Larutan
- bebas partikulat
- isotonis, terutama untuk volume besar dan intravena
- isohidris, idem (kapasitas dapar rendah)
- Bebas pirogen (terutama iv volume > 10 ml)
17
4/18/2010
OBAT SUNTIK
Î Sediaan
S di b
berupa llarutan,
t emulsi
l i atau
t suspensii ddalam
l air
i
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,
2. 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
p perawatan
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
besar, sediaan tidak
boleh mengandung pengawet (bakteriostatik)
atau zat tambahan lain
Kemasan umumnya single dose
Î next: lihat “Pharmaceutical dosage forms & DDS”
18
4/18/2010
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
Î Iv,, im,, sk,, ik,, ip,

p, dan lain-lain
19
4/18/2010
BAHAN PEMBAWA OBAT SUNTIK
1. AIR
Air
Ai pro iinjeksi
j k i
9 Aquabidest dengan pH tertentu, tidak mengandung
logam berat, tidak mengandung ion Ca, Cl, NO3,
SO4, Nh4, NO2 dan CO3
9 Harus steril, penggunaan dalam jumlah besar harus
bebas pirogen
9 Nilai tahanan spesifik sebesar 500.000 ohm/cm,
jik nilainya
jika il i separuhnya
h maka
k tidak
tid k b
boleh
l h di
digunakan
k
9 Aqua demineralisata tidak boleh digunakan sebagai
pembawa obat suntik
Air pro injeksi bebas CO2

9 Dibuat dengan cara mendidihkan air pro
injeksi selama 20-30 menit, lalu dialiri gas
N2 sambil didinginkan
Air pro injeksi bebas O2
9Dibuat dengan cara mendidihkan air pro

injeksi selama 20-30 menit, jika dibutuhkan
dalam jumlah besar maka dialiri N2 sambil
didinginkan
9Digunakan untuk melarutkan zat aktif yang
mudah teroksidasi (klorpromazin,
prometazin, klorfeniramin, sulfamidin, dan
lain-lain)
20
4/18/2010
2. Non air
Digunakan jika:
9 Zat aktif tidak larut dalam pembawa air
9 Zat aktif
k f terurai d
dalam
l pembawa
b air
9 Diinginkan kerja depo dari sediaan
Minyak tumbuhan
9 Mudah tengik karena mengandung asam lemak
bebas (+ antioksidan)
9 Tidak boleh mengandung minyak mineral atau
parafin cair karena tidak bisa dimetabolisme
dalam tubuh, karsinogenik, dan memberikan
reaksi terhadap jaringan
9 Sering menimbulkan rasa nyeri sehingga perlu
penambahan benzil alkohol 5% untuk anestesi
lokal
Jenis minyak tumbuhan yang digunakan:

9 Ol. Arachidis
9 Ol. Sesami
9 Ol.Gossypii
9 Ol. Olivarum netral
9 Ol Terebintinae
9 Ol.Maidis
9 Ol.Amygdalarum
yg
21
4/18/2010
Minyak semi sintesis

Ester asam lemak
Alkohol
9 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)

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)
22
4/18/2010
TONISITAS LARUTAN
OBAT SUNTIK
ISOTONIS
Î Jika suatu larutan konsentrasinya sama dengan konsentrasi
dalam sel darah merah sehingga tidak terjadi pertukaran
cairan diantara keduanya
ISOOSMOTIK
Î 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 Î pecah
Î 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 m
merah Î pplasmolisis
m
TONISITAS MODIFIER
9 NaCl
9 Glukosa
9 Sukrosa
9 KNO3
9 NaNO3
23
4/18/2010
PERHITUNGAN ISOTONISITAS
“Pharmaceutical dosage form and drug delivery systems”
24

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4/18/2010

SCHOOL OF PHARMACY - ITB

Produksi sediaan steril harus dilakukan di ruang steril.

Maximum permitted number of particles /m3

METODE PEMBUATAN SEDIAAN STERIL

STERILISASI AKHIR ASEPTIK

STERILISASI DENGAN FILTARSI

PEMBUATAN SECARA ASEPTIK

Mrs Robyn Isaacson

1 Manufacture of sterile medicines – Advanced workshop for SFDA GMP

Aseptic Processing - Overview

• Two categories of sterile products

2 Manufacture of sterile medicines – Advanced workshop for SFDA GMP

Aseptic Processing - Overview

3 Manufacture of sterile medicines – Advanced workshop for SFDA GMP

Aseptic Processing - Overview

WHO GMP US 209E US Customary ISO/TC (209) EEC GMP

5 Manufacture of sterile medicines – Advanced workshop for SFDA GMP

maximum permitted number of particles/m3

“At rest” - production equipment installed and operating

6 Manufacture of sterile medicines – Advanced workshop for SFDA GMP

Four grades of clean areas:

7 Manufacture of sterile medicines – Advanced workshop for SFDA GMP

8 Manufacture of sterile medicines – Advanced workshop for SFDA GMP

10 Manufacture of sterile medicines – Advanced workshop for SFDA GMP

11 Manufacture of sterile medicines – Advanced workshop for SFDA GMP

12 Manufacture of sterile medicines – Advanced workshop for SFDA GMP

13 Manufacture of sterile medicines – Advanced workshop for SFDA GMP

14 Manufacture of sterile medicines – Advanced workshop for SFDA GMP

17 Manufacture of sterile medicines – Advanced workshop for SFDA GMP

18 Manufacture of sterile medicines – Advanced workshop for SFDA GMP

20 Manufacture of sterile medicines – Advanced workshop for SFDA GMP

21 Manufacture of sterile medicines – Advanced workshop for SFDA GMP

22 Manufacture of sterile medicines – Advanced workshop for SFDA GMP

23 Manufacture of sterile medicines – Advanced workshop for SFDA GMP

24 Manufacture of sterile medicines – Advanced workshop for SFDA GMP

Prefiltation Bioburden (2)

25 Manufacture of sterile medicines – Advanced workshop for SFDA GMP

26 Manufacture of sterile medicines – Advanced workshop for SFDA GMP

27 Manufacture of sterile medicines – Advanced workshop for SFDA GMP

28 Manufacture of sterile medicines – Advanced workshop for SFDA GMP

29 Manufacture of sterile medicines – Advanced workshop for SFDA GMP

Equipment/container preparation and

30 Manufacture of sterile medicines – Advanced workshop for SFDA GMP

31 Manufacture of sterile medicines – Advanced workshop for SFDA GMP

32 Manufacture of sterile medicines – Advanced workshop for SFDA GMP

33 Manufacture of sterile medicines – Advanced workshop for SFDA GMP

34 Manufacture of sterile medicines – Advanced workshop for SFDA GMP

Process Validation (4)

35 Manufacture of sterile medicines – Advanced workshop for SFDA GMP

Process Validation (5)

36 Manufacture of sterile medicines – Advanced workshop for SFDA GMP

37 Manufacture of sterile medicines – Advanced workshop for SFDA GMP

Process Validation (7)

38 Manufacture of sterile medicines – Advanced workshop for SFDA GMP

40 Manufacture of sterile medicines – Advanced workshop for SFDA GMP

Process Validation (10)

41 Manufacture of sterile medicines – Advanced workshop for SFDA GMP

Process Validation (11)

42 Manufacture of sterile medicines – Advanced workshop for SFDA GMP

43 Manufacture of sterile medicines – Advanced workshop for SFDA GMP

44 Manufacture of sterile medicines – Advanced workshop for SFDA GMP

45 Manufacture of sterile medicines – Advanced workshop for SFDA GMP