Sediaan Steril (Compatibility Mode)

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
Setiap
p kegiatan
g
produksi
p
memerlukan tingkat
g
sterilitas yang berbeda untuk meminimalkan resiko
kontaminasi partikulat dan mikroorganisme terhadap
produk atau bahan baku
4/18/2010
Maximum permitted number of particles /m3

Grade
At rest
In n operation
0.5mm
5mm
0.5mm
5mm
3500
3500
3500
350,000
2000
350,000
2,000
3,500,000
20,000
3,500,000
20,000
Not defined
Not defined
4/18/2010
METODE PEMBUATAN SEDIAAN STERIL
STERILISASI AKHIR
ASEPTIK
STERILISASI DENGAN FILTARSI
PEMBUATAN SECARA ASEPTIK
4/18/2010
A
Aseptic
ti Processing
P
i
Mrs Robyn Isaacson
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

4/18/2010

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
prepared
p
products:
p
manufacture of aseptically
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

4/18/2010
Manufacturing Environment
Classification of Clean Areas
Comparison of classifications
WHO GMP
Grade A
Grade B
Grade C
G d D
Grade
US 209E
US Customary
M 3.5
M 3.5
M 5.5
M 6.5
65
Class 100
Class 100
Class 10 000
Cl
Class
100 000
ISO/TC (209)
ISO 14644
ISO 5
ISO 5
ISO 7
ISO 8
EEC GMP
Grade A
Grade B
Grade C
G d D
Grade
Table 1
5

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 m
> 5 m
0.5 - 5.0 m
>5
3 500
3 500
3 500
350 000
2 000
350 000
2 000
3 500 000
20 000
3 500 000
not defined
20 000
not defined
At rest - production equipment installed and operating

In operation - Installed equipment functioning in defined
operating mode and specified number of personnel present
6

4/18/2010
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)

4/18/2010
Limits for viable particles (microbiological
contamination)
G d
Grade
A
B
C
D
Air sample
Ai
l
(CFU/m3)
Settle
S
ttl plates
l t
(90mm
(90
Contact
C
t t plates
l t
diameter)
(55mm
(CFU/4hours)
diameter)
(CFU/plate)
<3
10
100
200
<3
5
50
100
<3
5
25
50
Glove print
Gl
i t
(5 fingers)
(CFU/glove)
<3
5
-
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
9

Environmental Monitoring
Physical
Particulate matter
Differential pressures
Air changes, airflow patterns
Clean up time/recovery
Temperature and relative humidity
Airflow velocity
10

4/18/2010
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
11

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
12

4/18/2010
Air Changes/Airflow patterns
Ai
Air fl
flow over critical
iti l areas should
h ld be
b 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
13

Temperature and Relative Humidity
Ambient temperature and humidity should not be
uncomfortably high (could cause operators to
generate particles) (18C)
Airflow velocity
Laminar airflow workstation air speed of approx
0.45m/s 20% at working position (guidance value)
14

4/18/2010
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)
15

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
16

4/18/2010
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
17

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 and
d sterilization)
t ili ti )
Regular microbiological monitoring of operators
18

4/18/2010
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
19

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 0.22m
(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
20

10
4/18/2010
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
21

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)
22

11
4/18/2010
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
23

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
24

12
4/18/2010
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 inprocess 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
25

Aseptic Processing
Filter integrity
Filters of 0.22m 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
26

13
4/18/2010
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
27

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
28

14
4/18/2010
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
29

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

30

15
4/18/2010
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)
31

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
32

16
4/18/2010
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
33

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
34

17
4/18/2010
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

35
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
36

18
4/18/2010
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
37

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)
38

19
4/18/2010
Aseptic Processing
Incubation, Examination
In the range 20-35
20-35C
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
39

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
40

20
4/18/2010
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
41

Aseptic Processing
Batch Record Review
Process and environmental control activities
should be included in batch records and reviewed
as part of batch release
42
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

21
4/18/2010
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
43

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
44

22
4/18/2010
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.
45

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
46

23
4/18/2010
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
47
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

24
4/18/2010
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.
4/18/2010
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 sterilisasi uap
- Kering sterilisasi panas kering
2. Sterilisasi dengan cara filtrasi
3. Sterilisasi dengan gas
4 Sterilisasi
St ilis si dengan
d
di si
4.
radiasi
Volume sediaan
Karakteristik sediaan (stabilitas)
Lolos uji sterilitas
4/18/2010
STERILISASI PANAS :
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
sediaan larutan dalam kemasan, ruahan larutan, alatalat 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
4/18/2010
9 Faktor kritis yang mempengaruhi keberhasilan

ster l sas
sterilisasi:
Suhu
Waktu sterilisasi
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
10
15
20
Suhu
115.5
121.5
126.5
Waktu
30
20
15
Tekanan suhu waktu
4/18/2010
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:

Ukuran produk/sediaan
Jenis produk/sediaan
Jenis kemasan produk/sediaan
Karakteristik distribusi panas
Volume sekecil mungkin

Alat pensteril
mensirkulasi panas
secara bebas dan
menyeluruh
4/18/2010
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
4/18/2010
JENIS-JENIS FILTER
1. Filter berbentuk tabung reaksi 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
stabilitas
M j
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: autoclaveut cl ve
ethylene oxide sterilizer dan perlu pertimbangan:
waktu, suhu, konsentrasi gas dan kelembapan:
Kelembapan sampai 60% dan suhu (50 dan 60C)
dapat t sterilisasi
Bahan yang tidak tahan lembap dan 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)
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
B
: populasi mikroba awal

: 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 cari
prosedurnya!
Uji pirogen menurut USP dilakukan pada hewan
kelinci 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
Sediaan
S di
b
berupa llarutan,
t
emulsi
l i atau
t suspensii d
dalam
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
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
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
Jika suatu larutan konsentrasinya sama dengan konsentrasi
dalam sel darah merah sehingga tidak terjadi pertukaran
cairan diantara keduanya
ISOOSMOTIK
Jika suatu larutan mempunyai tekanan osmotik yang sama
dengan tekanan osmotik serum
HIPOTONIS
Jika tekanan osmosis sediaan lebih rendah dari tekanan
osmosis serum darah, menyebabkan air akan melintasi
membran sel darah merah yang semipermeabel memperbesar
volume menyebabkan peningkatan tekanan dalam sel pecah
hemolisis
HIPERTONI
Jika tekanan osmosis sediaan lebih besar dari tekanan serum
darah, menyebabkan air keluar dari sel darah merah melintasi
membran semipermeabel mengakibatkan penciutan sel-sel
darah m
merah p
plasmolisis
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

Sediaan Steril (Compatibility Mode)

Uploaded by

Document Information

Original Description:

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Sediaan Steril (Compatibility Mode)

Uploaded by

Copyright:

Available Formats

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 DENGAN FILTARSI

PEMBUATAN SECARA ASEPTIK

Manufacture of sterile medicines Advanced workshop for SFDA GMP

Aseptic Processing - Overview

Two categories of sterile products

Manufacture of sterile medicines Advanced workshop for SFDA GMP

Aseptic Processing - Overview

Manufacture of sterile medicines Advanced workshop for SFDA GMP

Aseptic Processing - Overview

Preparation and filtration of solutions

Manufacture of sterile medicines Advanced workshop for SFDA GMP

Manufacture of sterile medicines Advanced workshop for SFDA GMP

maximum permitted number of particles/m3

At rest - production equipment installed and operating

Manufacture of sterile medicines Advanced workshop for SFDA GMP

Grade C (equivalent to Class 10,000, ISO 7):

Grade B (equivalent to Class 100, ISO 5):

Manufacture of sterile medicines Advanced workshop for SFDA GMP

Each grade of cleanroom has specifications for

Manufacture of sterile medicines Advanced workshop for SFDA GMP

Manufacture of sterile medicines Advanced workshop for SFDA GMP

Manufacture of sterile medicines Advanced workshop for SFDA GMP

Manufacture of sterile medicines Advanced workshop for SFDA GMP

Manufacture of sterile medicines Advanced workshop for SFDA GMP

Manufacture of sterile medicines Advanced workshop for SFDA GMP

Manufacture of sterile medicines Advanced workshop for SFDA GMP

Inspections and controls from outside

Manufacture of sterile medicines Advanced workshop for SFDA GMP

Periodic health checks

Manufacture of sterile medicines Advanced workshop for SFDA GMP

Manufacture of sterile medicines Advanced workshop for SFDA GMP

Regular microbiological monitoring of operators

Manufacture of sterile medicines Advanced workshop for SFDA GMP

Manufacture of sterile medicines Advanced workshop for SFDA GMP

filtration should be carried out under positive

Manufacture of sterile medicines Advanced workshop for SFDA GMP

Manufacture of sterile medicines Advanced workshop for SFDA GMP

Manufacture of sterile medicines Advanced workshop for SFDA GMP

Manufacture of sterile medicines Advanced workshop for SFDA GMP

Should include action and alert limits (usually differ

Manufacture of sterile medicines Advanced workshop for SFDA GMP

Excessive bioburden can have adverse effect on the

Manufacture of sterile medicines Advanced workshop for SFDA GMP

filter intergrity shoud be verified before filtration and

methods are defined by filter manufacturers and limits

Manufacture of sterile medicines Advanced workshop for SFDA GMP

Manufacture of sterile medicines Advanced workshop for SFDA GMP

Manufacture of sterile medicines Advanced workshop for SFDA GMP

Manufacture of sterile medicines Advanced workshop for SFDA GMP

heat tunnels often used for

tunnel supplied with HEPA filtered air

Manufacture of sterile medicines Advanced workshop for SFDA GMP

rinse water should be WFI grade

Manufacture of sterile medicines Advanced workshop for SFDA GMP

Manufacture of sterile medicines Advanced workshop for SFDA GMP

Manufacture of sterile medicines Advanced workshop for SFDA GMP

Manufacture of sterile medicines Advanced workshop for SFDA GMP