Teknologi Sediaan Steril dan

Aseptik Dispensing

SUTRIYO
 KOMPETENSI MATA AJAR
• Setelah selesai mengikuti perkuliahan mata ajar ini,
mahasiswa diharapkan mampu:
– Mendisain sediaan steril yang baik
– Menentukan metode pembuatan yang paling sesuai sediaan steril
– Menyusun (menulis) prosedur pembuatan sediaan steril yang baik.
– Menginterpretasi dan menganalisa data evaluasi sediaan steril
– menyusun prosedur pencampuran sediaan intra vena/iv admixture
secara aseptik
– menyusun prosedur penanganan/ pencampuran sediaan sitostatika
– menyusun prosedur pencampuran sediaan nutrisi parenteral
 TOPICS
1. CPOB Sterile Product : Area Classification
2. Injeksi
3. Sterilization
 Heat Sterilization: Dry Heat Sterilization
 Heat Sterilization: Wet Heat Sterilization
 Cold Sterilization : Filtration
 Cold Sterilization: Gasses and Radiation Sterilization
4. Packaging : Glass, Plastic and Elastomer
5. Opthalmic dosage forms
6. QC product Sterile
7. Aseptik Dispensing
 IV Admixture
 Handling cytotoxic
 Parenteral Nutrition
 Istilah
STERILITY:
Absence of life or absolute freedom from
biological contamination
STERILIZATION: Inactivation or elimination of all
viable organism and their spores
DISINFECTANT: Substance used on non-living
objects to render them non-infectious; kills
vegetative bacteria, fungi, viruses but Not
Spores
• VEGETATIVE CELL: Bacterial cell capable of
multiplication (as oppose to spore form which
cannot multiply). Less resistant than the spore form.
• SPORE: Body which some species of bacteria form
within their cells which is considerably more resistant
than the vegetative cell
• BACTERICIDE (GERMICIDE): Substance that kills
vegetative bacteria and some spores
• BACTERIOSTAT: Substance which stops growth and
multiplication of bacteria but does not necessarily kill
them
• ANTISEPTIC: Substance used to prevent
multiplication of microorganism when
applied to living systems. An antiseptic is
bacteriostatic in action but not
necessarily bacteriocidal
ASEPTIC TECHNIQUE:
An aseptic technique is one which is designed to
prevent contamination of materials, instruments,
utensils, containers, during handling.
CPOB/GMP
 CARA PEMBUATAN OBAT YANG BAIK
(CPOB)
1. Manajemen Mutu 9. Penanganan Keluhan
2. Personalia Terhadap Produk,
3. Bangunan dan Penarikan Kembali
Fasilitas Produk dan Produk
4. Peralatan Kembalian
5. Sanitasi Dan Higiene 10. Dokumentasi
6. Produksi 11. Pembuatan dan
7. Pengawasan Mutu Analisis Berdasarkan
8. Inspeksi Diri dan Audit Kontrak
Mutu 12. Kualifikasi dan
Validasi
 CPOB
PRINSIP : bertujuan untuk menjamin obat
dibuat secara konsisten, memenuhi
persyaratan yang ditetapkan sesuai dengan
tujuan penggunaan.
 MUTU OBAT
Pada pembuatan obat,
pengendalian menyeluruh
adalah sangat esensial

untuk menjamin bahwa

konsumen menerima
obat yang bermutu tinggi
 MUTU OBAT
Tidaklah cukup bila produk jadi
hanya sekedar lulus dari
serangkaian pengujian, tetapi
yang lebih penting adalah bahwa

mutu harus dibentuk ke dalam

produk tersebut.

Mutu obat tergantung pada bahan awal, bahan

pengemas, proses produksi dan pengendalian
mutu, bangunan, peralatan yang dipakai dan
personil yang terlibat
.
 MUTU OBAT
Pemastian mutu suatu obat tidak
hanya mengandalkan pada
pelaksanaan pengujian tertentu
saja; namun obat hendaklah

dibuat dalam kondisi yang

dikendalikan dan dipantau
secara cermat
 PEMBUATAN PRODUK STERIL
PRINSIP
PRINSIP PRINSIP
Produk steril banyak
dibuat tujuan untuk tergantung
dengan menghilangkan pada
persyaratan jasad renik dan keterampilan,
khusus partikel lain latihan dan
sikap dari
orang yang
terlibat
Specific Points To Minimizing Risks Of
Contamination
1. Pembuatan produk steril hendaklah dilakukan di
area bersih, memasuki area ini hendaklah melalui
ruang penyangga untuk personil dan/atau
peralatan dan bahan. Area bersih hendaklah dijaga
tingkat kebersihannya sesuai standar kebersihan
yang ditetapkan dan dipasok dengan udara yang
telah melewati filter dengan efisiensi yang sesuai
2. Berbagai kegiatan persiapan komponen, pembuatan
produk dan pengisian hendaklah dilakukan di ruang
terpisah di dalam area bersih
3. Area bersih untuk pembuatan produk steril
digolongkan berdasarkan karakteristik lingkungan
yang dipersyaratkan. Tiap kegiatan pembuatan
membutuhkan tingkat kebersihan ruangan yang
sesuai dalam keadaan operasional untuk
meminimalkan risiko pencemaran oleh partikulat
dan/atau mikroba pada produk dan/atau bahan
yang ditangani.
 Kelas A
• Zona untuk kegiatan yang berisiko tinggi, misalnya
zona pengisian, wadah tutup karet, ampul dan vial
terbuka, penyambungan secara aseptik.
• kondisi ini dicapai dengan memasang unit aliran
udara laminar (laminar air flow) di tempat kerja.
• Sistem udara laminar hendaklah mengalirkan udara
dengan kecepatan merata berkisar 0,36 – 0,54
m/detik (nilai acuan) pada posisi kerja dalam ruang
bersih terbuka.
• Kelas B: Untuk pembuatan dan pengisian
secara aseptik, kelas ini adalah lingkungan
latar belakang untuk zona kelas A.
• Kelas C dan D: Area bersih untuk melakukan
tahap pembuatan produk steril dengan tingkat
risiko lebih rendah
 Airborne Particulate Classification
WHO GMP US 209E US Customary ISO/TC (209) 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

Grade D M 6.5 Class 100 000 ISO 8 Grade D

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
 Jumlah partikulat di udara
Non-operasional Operasional
Jumlah maksimum partilkel /m³ yang diperbolehkan
KELAS
untuk kelas setara atau lebih tinggi dari
0,5 µm 5 µm 0,5 µm 5 µm
A 3.500 1 3.500 1
B 3.500 1 350.000 2.000
C 350.000 2.000 3.500.000 20.000
D 3.500.000 20.000 Tidak ditetapkan Tidak ditetapkan
Non operasional : kondisi di mana fasilitas telah terpasang dan beroperasi,
lengkap dengan peralatan produksi tetapi tidak ada personil.
Operasional : kondisi di mana fasilitas dalam keadaan jalan sesuai modus
pengoperasian yang ditetapkan dengan sejumlah tertentu personil yang sedang
bekerja
 Jumlah cemaran mikroba
Batas yang disarankan untuk cemaran mikroba *
KELAS Sampel udara Cawan papar Cawan kontak Sarung tangan
3
cfu/m ( 90 mm) ( 55 mm) 5 jari
cfu/4 jam** cfu/plate cfu/sarung tangan
A <1 <1 <1 <1
B 10 5 5 5
C 100 50 25 -
D 200 100 50 -
(*) Ini adalah nilai rata-rata.
(**) Cawan papar dapat dipaparkan kurang dari 4 jam
Airborne Particulate Classification

Class Limits

Class Name 0.5 µm (micron) 5 µm (micron)

Volume Units Volume Units

SI English (m3) (ft3) (m3) (ft3)

M 3.5 100 3,530 100 - -

M 4.5 1,000 35,300 1,000 247 7.00

M 5.5 10,000 353,000 10,000 2,470 7.00

M 6.5 100,000 3,530,000 100,000 24,700 700

 Airborne Particulate Classification
Klasifikasi Batas Konsentrasi Maksimum (partikel/m3) udara
ISO  0,1 µm  0,2 µm  0,3 µm  0,5 µm  1 µm  5 µm
ISO Class 1 10 2
ISO Class 2 100 24 10 4
ISO Class 3 10.000 237 102 35 8
ISO Class 4 100.000 2.370 1.020 352 83
ISO Class 5 1.000.000 23.700 10.200 3.520 832 29
ISO Class 6 237.000 102.000 35.200 8.320 293
ISO Class 7 352.000 83.200 2.930
ISO Class 8 3.520.000 832.000 29.300
ISO Class 9 35.200.000 8.320.000 293.000
 AIRBORNE CLASSIFICATION
EU GMP
Jumlah Maksimum (partikel/m3) udara
Grade
At rest (b) In operation
 0,5µm  5 µm  0,5µm  5 µm
A 3.500 0 3.500 0
B (a) 3.500 0 350.000 2.000
C (a) 350.000 2.000 3.500.000 20.000
D (a) 3.500.000 20.000 Not defined (c) Not defined (c)
 Recommended limits for Microbial
Contamination
Air sample Settle Plates Contact Plates Glove Print
Grade (cfu/m3) ( 90 mm), ( 55 mm), 5 Fingers
cfu/4 hours cfu/plate Cfu/glove
A <1 <1 <1 <1
B 10 5 5 5
C 100 50 25 -
D 200 100 50 -

(a) nilai rata-rata

(b) masing-masing plate diekspose kurang dari 4 jam
 BANGUNAN DAN FASILITAS
• Area kelas B didesain sehingga semua kegiatan dapat
diamati dari luar
• Di area bersih, semua permukaan yang terpapar
hendaklah halus, kedap air dan tidak retak untuk
mengurangi pelepasan atau akumulasi partikel atau
mikroba dan untuk memungkinkan penggunaan
berulang bahan pembersih dan bahan disinfektan.
• tidak ada bagian yang sukar dibersihkan
• lis yang menonjol, rak, lemari dan peralatan dalam
jumlah terbatas.
• Pintu didesain untuk menghindarkan bagian
yang tersembunyi dan sukar dibersihkan;
pintu geser/sorong tidak boleh digunakan
• area kelas C, B dan A tidak boleh ada bak cuci
dan drainase.
a. Production in clean areas
b. Appropriate standard of cleanliness
c. Filtered air supplied
d. Airlocks for entry
– personnel and/or equipment
– materials
e. Separate areas for operations
– component preparation (containers and
closures)
– product preparation
– filling, sterilization, etc
Clean Areas
all exposed surfaces
• smooth, impervious (tahan), unbroken
• minimize shedding and accumulation of
particles, microorganisms
• permit cleaning and disinfection
• no uncleanable recesses (wadah), ledges
(tepi), shelves (rak), cupboards (lemari),
equipment (peralatan)
• sliding doors undesirable
• false ceilings sealed
 Changing Rooms
 designed as airlocks
 effective flushing with filtered air
 separate rooms for entry and exit desirable
 hand washing facilities
 interlocking system for doors
 visual and/or audible warning system

Pressure differential approximately 10 to 15 Pascals

 Personnel
1. Minimum number of personnel in clean areas
– especially during aseptic processing
2. Inspections and controls from outside
3. Training to all including cleaning and maintenance
staff
– initial and regular
– manufacturing, hygiene, microbiology
4. Special cases
– decontamination procedures (e.g. staff who
worked with animal tissue materials)
 Personnel
5. High standards of hygiene and cleanliness
6. Periodic health checks
7. No shedding of particles
8. No introduction of microbiological hazards
9. No outdoor clothing
10.Changing and washing procedure
11.No watches, jewellery and cosmetics
Clothing of appropriate quality
1. Grade D : hair, beard, moustache covered
protective clothing and shoes
2. Grade C : hair, beard, moustache covered
single or 2-piece suit (covering wrists, high
neck), shoes no fibres
3. Grade A and B: headgear, beard and moustache
covered, masks, gloves, not shedding fibres, and
retain particles shed by operators
• Outdoor clothing not in change rooms leading to
Grade B and C rooms
• Change at every working session, or once a day (if
supportive data)
• Change gloves and masks at every working session
• Disinfect gloves during operations
• Washing of garments – separate laundry facility
• No damage, and according to validated
procedures
 JENIS PRODUK STERIL
Menurut cara produksi, produk steril dapat
digolongkan dalam dua kategori utama yaitu
1. yang harus diproses dengan cara aseptik pada
semua tahap dan
2. yang disterilkan dalam wadah akhir yang disebut
dengan sterilisasi akhir (terminal sterilization/Na
steril)
Bila mungkin semua produk steril disterilisasi
akhir
 PRODUK YANG DISTERILISASI AKHIR
• Penyiapan komponen dan sebagian besar produk,
yang memungkinkan untuk disaring dan disterilisasi,
hendaklah dilakukan di lingkungan minimal kelas D
untuk mengurangi risiko cemaran mikroba dan
partikulat.
• Bila ada risiko terhadap produk yang di luar
kebiasaan yaitu karena cemaran mikroba, misalnya,
produk yang secara aktif mendukung pertumbuhan
mikroba atau harus didiamkan selama beberapa saat
sebelum sterilisasi atau terpaksa diproses dalam
tangki tidak tertutup, maka penyiapan hendaklah
dilakukan di lingkungan kelas C.
• Pengisian produk yang akan disterilisasi akhir
hendaklah dilakukan di lingkungan minimal kelas C.
• Bila ada risiko terhadap produk yang di luar
kebiasaan yaitu karena cemaran dari lingkungan,
misalnya karena kegiatan pengisian berjalan lambat
atau wadah berleher-lebar atau terpaksa terpapar
lebih dari beberapa detik sebelum ditutup, pengisian
hendaklah dilakukan di zona kelas A dengan latar
belakang minimal kelas C.
 Terminal Sterilization

Product containers are filled and sealed under high-quality

environmental conditions designed to minimize contamination,
but not to guarantee sterility

Product in its final container is subject to a

sterilization process such as heat or
irradiation.

Sterile Product
 Terminal Sterilization
Drug
Product

Container Sterilization
/ Closure
Process Sterile Drug Product !

Excipiants
 PEMBUATAN SECARA ASEPTIK
• Komponen setelah dicuci hendaklah ditangani di
lingkungan minimal kelas D.
• Penanganan bahan awal dan komponen steril,
dilakukan di lingkungan kelas A dengan latar
belakang kelas B.
• Proses pembuatan larutan yang akan disterilisasi
secara filtrasi dilakukan di lingkungan kelas C;
• bila tidak dilakukan filtrasi, penyiapan bahan dan
produk hendaklah dilakukan di lingkungan kelas A
dengan latar belakang kelas B.
• Penanganan dan pengisian produk yang dibuat secara
aseptik dilakukan di lingkungan kelas A dengan latar
belakang kelas B.
• Transfer wadah setengah-tertutup, yang akan digunakan
dalam proses beku-kering (freeze drying) hendaklah,
sebelum proses penutupan dengan stopper selesai,
dilakukan di lingkungan kelas A dengan latar belakang kelas
B atau dalam nampan (tray) transfer yang tertutup di
lingkungan kelas B.
• Pembuatan dan pengisian salep, krim, suspensi dan emulsi
dilakukan di lingkungan kelas A dengan latar belakang kelas
B, apabila produk terpapar dan tidak akan disaring
 PERSONIL
• Hanya personil dalam jumlah terbatas yang diperlukan
boleh berada di area bersih
• Personil yang bekerja di area bersih dan steril dapat
diandalkan untuk bekerja dengan penuh disiplin dan
tidak mengidap suatu penyakit atau dalam kondisi
kesehatan yang dapat menimbulkan bahaya pencemaran
mikrobiologis terhadap produk.
• Semua personil yang akan bekerja di area tersebut
hendaklah mendapat pelatihan teratur dalam bidang
yang berkaitan dengan pembuatan produk steril yang
benar, termasuk mengenai higiene dan pengetahuan
dasar mikrobiologi.
 Aseptic Processing

Drug product, container, and closure are subject

to sterilization separately, and then brought
together

no process to sterilize the product in its final

container, it is critical that containers be filled and
sealed in an extremely high –quality environment

Sterile Product
 Aseptic Processing

Drug
Sterile
Sterilization
Product Process
Drug
Product

Container Sterilization Sterile

Process
Container

Aseptic Sterile Drug

Sterile
Closure Sterilization Processing Product !
Process Closure

Sterile
Excipient Sterilization
Process Excipient
Types of Contamination
Viable particles
• Bacteria
• Endotoxin
• Viruses

Nonviable particles
• dust,
• fibers, or suspended in the air

• other material
Sources Of Contamination
Personnel

Equipment

Air/liquids

Drug product

Outside environment

Containers/closures
 Personnel
• Over 200 different species of bacteria are
found associated with humans.
• Bacteria are found in the intestines, eyes,
nares, mouth, hair and skin.
• Dry skin can have 1000’s of microbes / mm2
• As operator activities increase in an aseptic
processing operation, the risk to finished
product sterility also increases
The skin is home to a virtual zoo of bacteria
• Avoid clean rooms when ill
• Frequent bathing and shampooing
• Avoid getting sunburned
• Avoid cosmetics such as face powder, hair
sprays, perfumes and aftershave
• Clothing should be clean, non frayed ( usang)
and nonlinting
• Avoid smoking
http://www.rit.edu/

http://www.imi.org.uk/
GOWNING
 Material NOT permitted in a
Cleanroom
• Fiber-shedding materials such as cardboard and paper
– Cardboard packaging must be removed and items placed into non-
cardboard containers.
• Wood (i.e. wooden pallets)
 RUANGAN BERSIH
• Ruangan bersih untuk pelaksanaan kegiatan bersih
tidak harus steril.
• Daerah itu digunakan juga untuk persiapan
komponen dan pembuatan larutan .
• Produk yang akan disterilkan akhir dapat dikerjakan
di ruang ini.
• Ruangan tidak boleh mengandung lebih dari
3.500.000 partikel berukuran 0,5 mikron atau lebih
besar dan tidak lebih dari 500 jasad renik per meter
kubik udara
 RUANGAN STERIL
• Ruangan steril dipergunakan untuk kegiatan steril.
• Karyawan masuk ke daerah ini melalui suatu ruang
penyangga udara atau cara lain yang sesuai
• Ruangan steril tidak boleh mengandung lebih dari 350.000
partikel berukuran 0,5 mikron atau lebih besar dan tidak
lebih dari 100 jasad renik per meter kubik udara.
• Daerah di bawah aliran udara laminar dalam ruangan steril
tidak boleh mengandung lebih dari 3.500 partikel
berukuran 0,5 mikron atau lebih besar dan tidak lebih dari
5 jasad renik per meter kubik udara.
LAYOUT RUANG PRODUKSI
STERILISASI AKHIR
LAYOUT RUANG PRODUKSI
ASEPTIS
CLEAN ROOM PASS THROUGH
PASS BOX
CLEAN ROOM BANCHES
LAMINAR AIR FLOW WORKBENCH
LAMINAR AIR FLOW WORKBENCH
CLEAN ROOM FLOORS
 Facilities: General Cleanroom Design
• HEPA/ULPA filters on ceiling
• Exhaust vents on floor
• Drains in aseptic processing areas are inappropriate
• Airlocks and interlocking doors to control air balance
• Lantai halus/mulus dan tanpa sudut (Seamless and rounded
floor to wall junctions)
• Sudut mudah diakses (Readily accessible corners)
• Floors, walls, and ceilings constructed of smooth hard
surfaces that can be easily cleaned
• Limited equipment, fixtures and personnel
• Layout of equipment to optimize comfort and movement of
operators
 HEPA Filters
High Efficiency Particulate Air
Minimum particle collection efficiency:
99.97% for 0.3µm diameter particles.
Disposable
Filter made of pleated borosilicate glass
HEPA Filters
CLEAN ROOM
 four main microbiological environmental
monitoring methods
• active air sampling
• passive air sampling (settle plates)
• surface sampling
• personnel sampling
 Active Air Sampling
1. The “traditional” active air sampler
2. A second type of active sampler is the Reuter
Centrifugal Sampler (RCS).
3. Filtration is the third means of active air
sampling
4. At least three variants of another type of air
sampler exist
• The FDA defines two areas in aseptic
processing that are of particular importance
to drug product quality. These are the
– critical area and
– The controlled area
 A ‘critical area’
• ‘one in which the sterilized dosage form,
containers, and closures are exposed to the
environment. Activities that are conducted in
this area include manipulations of these
sterilized materials/product prior to and
during filling/ closing operations
• Air in the immediate proximity of expossetde rilized containers/closures
and filling/closing operations is of acceptable particulate quality when it
has a per-cubic-foot particle count of no more than 100 in a size range of
0.5 micron and larger (Class 100) when measured not more than one foot
away from the work site, and upstream of the air pow, during
filling/closing operations. The agency recognizes that some powder filling
operations may generate high levels of powder particulates which, by their
nature, do not pose a risk of product contamination. It may not, in these
cases, be feasible to measure air quality within the one foot distance and
still differentiate "background noise'' levels of powder particles from air
contaminants which can impeach product quality. In these instances, it is
nonetheless important to sample the air in a manner, which to the extent
possible characterises the true level of extrinsic particulate contamination
to which the product is exposed.
• Air in critical areas should be supplied at the point of use as HEPA $1-tered
laminar flow air, having a velocity suficient to sweep particulate matter
away from the$lling/closing area. Normally, a velocity of90 feet per
minute, plus or minus 20%, is adequate, although higher velocities may be
needed where the operations generate high levels ofparticulates or where
equipment configuration disrupts laminarflow.
• Air should also be of a high microbial quality. An incidence of no more
than one colony forming unit per IO cubic feet is considered as attainable
and desirable.
• Critical areas should have a positive pressure dlfferential relative to
adjacent less clean areas; a pressure dtfferential of 0.05 inch of water is
acceptable'
 controlled area
• ‘an area in which it is important to control the
environment, is the area where unsterilized product,
in-process materials, and container/closures are
prepared. This includes areas where components are
compounded, and where components, in-process
materials, drug products and drug product contact
surfaces of equipment, containers, and closures, after
final rinse of such surfaces, are exposedt o the
planetn vironment’.
• 'Air in controlled areas is generally of acceptable particulate quality if it
has a per-cubic-foot particle count of not more than 100,000 in a size
range of 0.5 micron and larger (Class 100,000) when measured in the
vicinity of the exposed articles during periods of activity. With regard to
microbial quality, an incidence of no more than 25 colony forming units per
10 cubic feet is acceptable.
• In order to maintain air quality in controlled areas, it is important to
achieve a suficient air jlow and a positive pressure differential relative to
adjacent uncontrolled areas. In this regard, an airflow suficienf to achieve
at least 20 air changes per hour and, in general, a pressure dtferential of a
t least 0.05 inch of water (with all doors closed), are acceptable. When
doors are open, outward airflow should be suflcient to minimize ingress of
contamination
Laminar Air Flow And Isolator
 Facilities: Air Lock
Permits the passage of objects and
people into a cleanroom.

Consists of two airtight doors in series

which do not open simultaneously.

Spray down materials with 70% IPA

before placing in the airlock

http://news.thomasnet.com/images/large/451/451402.jpg
 Pressure Differentials
• Used to maintain airflow in the
direction of higher cleanliness
to adjacent less clean areas
• A minimum of 10-15 Pascals
should be maintained between
the aseptic area and an
adjacent rooms with differing
cleanroom classifications
(doors open)
 Environmental Monitoring
1. Microbiological
– Air samples
– Surface swabs
– Personnel swabs
2. Physical
– Particulate matter
– Differential pressures
– Air changes, airflow patterns
– Clean up time/recovery
– Filter integrity
– Temperature and relative humidity
– Airflow velocity
Environmental Monitoring
Particulate Air Monitoring
 Surface Monitoring

Touch or Contact plates

- RODAC Plates

http://www.blood.co.uk/hospitals/services/Micro/Bact2.htm

Swabs
Viable Microbial Air Monitoring

Active Air Monitoring RCS Plus

Passive Air Monitoring

Settling Plates
Environmental Monitoring/Control
 Limits for microbial contamination

Grade Air sample Settle plates Contact plates Glove print

(CFU/m3) (90mm diameter) (55mm diameter) (5 fingers)
(CFU/4hours) (CFU/plate) (CFU/glove)
A <3 <3 <3 <3
B 10 5 5 5
C 100 50 25 -
D 200 100 50 -
 PRODUK STERIL
Parenteral : para/disamping & enteral/usus
• INJEKSI :
– Volume : Kecil : SVPs; Besar : LVPs,
– Bentuk :
• Cairan : Larutan (air ; minyak); suspensi; emulsi
• Padat : Serbuk
• SALEP DAN TETES MATA
• Gauze
• VAKSIN
• IMPLANT
 PRODUK STERIL

Eye ointment Eye drops

Gauze

Vaccine

LVPs

SVPs
Advantages of parenteral formulations
• An immediate physiological response may be achieved (usually by the IV
route). This is important in acute medical situations, e.g. cardiac arrest,
anaphylactic shock, asthma.
• essential for drugs that offer poor bioavailability or those that are rapidly
degraded within the gastrointestinal tract (e.g. insulin and other
peptides).
• method to administration drugs to patients who are unconscious or
uncooperative or for patients with nausea and vomiting (and additionally
dysphagia).
• Local effects may be achieved using parenteral formulations, e.g. local
anaesthesia.
• Parenteral formulations may be readily formulated to offer a wide range of
drug release profiles, including:
– rapidly acting formulations (generally drug solutions that are administered IV)
– long-acting formulations (
• In patients who cannot consume food, total parenteral nutrition offers a
means by which nutrition may be provided using specially formulated
solutions that are infused into the patient.
PARENTERAL NUTRITION
 Disadvantages
• The manufacturing process is more complicated
• requirement for aseptic technique.
• The level of training of staff is high
• Skill of administration is required to ensure that the
dosage form is administered by the correct route..
• Parenteral formulations are associated with pain on
administration.
• If the patient is allergic to the formulation (the therapeutic
agents and/or the excipients), parenteral administration
will result in both rapid and intense allergic reactions.
• It is difficult to reverse the effects of drugs that have been
administered parenterally
 Clinical Hazards of Parenteral Administration

• Air Emboli: Result principally from IV infusions, Small

amounts of air are not harmful, 10 ml could be fatal,
causing occlusions in cerebral or coronary arteries
• Bleeding: Usually related to patient’s condition
(platelet deficiency, hemophilia
• Fever and Toxicity: Caused by sterile abscesses
produced from IM injections, injection of poorly
soluble drug, pyrogenic material, or hypersensitivity
reaction
• Hypersenitivity;
• Incompatibilities; Precipitates cause platelet
aggregation in the vascular compartment
• Infiltration and Extravasation; Infusion of substance
into tissue. Leakage of blood into surrounding tissue
• Overdosage; Toxic reaction, pulmonary edema
• Particulate matter; Can cuase foreign body reaction
during IV, IA administration
• Phlebitis; Usually with long term IV,
sometimes associated with infection and/or
thrombosis
• Sepsis:
Caused by microbial contamination from the
product, the patient’s skin or the delivery
system.
 PARENTERAL PRODUCT
• Small Volume Parenterals (SVPs)
• Large Volume Parenterals (SVPs)
• Optalmics Preparations
• Vaccine
• Small-volume intravenous injection: is applied
to an injection that is packaged in containers
labeled as containing 100 ml or less
• Large-volume intravenous solution: is a single
dose injection that is intended for iv use and is
packaged in container labeled as containing
more than 100 ml
INJECTIONS
 Parenteral Routes of Administration
Most Common:1. Subcutaneous (SC; SQ ;Sub Q)
2. Intramuscular (IM)
3. Intravenous (IV)

Others: 4. Intra-arterial (IA)

5. Intrathecal
6. Intraarticular
7. Intrapleural
8. Intracardial
9. Intradermal (Diagnostic)
RUTE INJEKSI
 Subcutaneous (21) Intravenous (21)

Intramuscular (20)
Intradermal (23)
Intra arterial (20-22)

Epidermis

Dermis

Vein
Subcutaneous Artery
tissue

Muscle
 Intravenous
• into a vein,
• 1 inch ,19 to 20 gauge needle
• rapid and predictable response.
• 100% drug bioavailability.
• Both large- (up to 500 ml) and small- (up to 10 ml) volume formulations may be
administered intravenously.
• Large volumes are infused into the vein at a controlled rate, e.g. total parenteral
nutrition, infusion of solutions of electrolytes/nutrients either containing or devoid
of drugs.
• Formulations are usually solutions or emulsions
• Suspensions (or solutions that precipitate within the blood stream) must not be
administered IV due to disruption of blood flow.
• Care must be taken regarding the rate of administration of the parenteral
formulation.
– 1ml/ 10 sec. for volume up to 5 ml & 1 ml/ 20 sec. for volume more than 5 ml.
• Given: Aqueous solutions, Hydro alcoholic solutions , Emulsions, Liposome
 Subcutaneous
• This involves administration into the subcutaneous tissue, a
layer of fat located below the dermis.
• There is a slower onset of action and sometimes less total
absorption of therapeutic agents when compared to the IV
or IM routes of administration
• Viscous formulations are not generally administered
subcutaneously.
• Need to be isotonic , Upto 2 ml , Using ½ to 1 inch 23 gauge
needle or smaller needle
• Typical sites include the arms, legs and abdomen.
• SC administration is the route of choice for the
administration of insulin.
– Ex. Vaccines ,Scopolamine ,Epinephrine
• into a muscle, usually the gluteal
(buttocks), vastus lateralis (lateral Intramuscular
thigh) or deltoid (upper arm) muscles.
• The volume of injection is small,
usually 1–3 ml or up to 10 ml in
divided doses. 1 to 1.5 inch & 19 to 22
gauge needle is used
• Faulty injection technique may lead to
local muscle damage.
• IM injection results in relatively rapid
absorption,.
• Drug absorption from aqueous
solutions is greater than from
aqueous suspension or non-aqueous
(oil-based) solutions of drugs.
• IM injections are usually used for
controlled-release formulations.
• Preferably isotonic
• Given: Solutions, Emulsions, Oils, Suspension
 Official Types of Injections
1. Obat atau larutan atau emulsi yang digunakan untuk injeksi (Solutions of Medicinal) ditandai
dengan nama
 Injeksi ................. (drug injection)
 Contoh : Injeksi kodein fosfat (Codeine Phosphate Injection);
2. Sediaan padat kering atau cairan pekat , tidak mengandung dapar, pengencer atau bahan
tambahan lain dan larutan yang diperoleh setelah penambahan pelarut yang sesuai memenuhi
persyaratan injeksi, (Dry solids or liquid concentrate does not contain diluents etc.) ditandai
dengan nama :
 ................... Steril (sterile drug)
 Contoh Sodium ampisillin steril ( Sterile Ampicillin Sodium)
3. Sediaan seperti no 2, tetapi mengandung satu atau lebih dapar, pengencer atau bahan tambahan
lain (If diluents present) ditandai dengan nama
 .................... Untuk Injeksi (drug for injection)
 Contoh : Sodium metisillin untuk injeksi (Methicillin Sodium for injection)
4. Sediaan berupa suspensi serbuk dalam medium cair yang sesuai dan tidak disuntikkan secara
intra vena (IV) atau ke dalam saluran spinal (Suspensions) ditandai dengan nama :
 Suspensi .......................... Steril (Sterile drug Suspension)
 Contoh : Suspensi deksametason asetat steril. (Sterile Dexamethasone Acetate Suspension)
5. Sediaan padat kering dengan bahan pembawa yang sesuai membentuk larutan yang memenuhi
semua persyaratan untuk suspensi steril, setelah penambahan bahan pembawa yang sesuai (Dry
solids, which upon the addition of suitable vehicles yield preparations containing in all respects
to the requirements for sterile suspensions) ditandai dengan nama :
 ......................... Steril untuk suspensi ( Sterile drug for Suspension)\
 Contoh : Ampisillin steril untuk suspensi (Sterile Ampicillin for Suspension)
 Requirement of Injections
1. Sterility (must)
2. Pyrogen free (should / must)
3. Free from particulate matter (must)
4. Clarity (must for solution)
5. Stability (must)
6. Isotonicity (should)
7. Isohidris (should)
8. Syringability ( partikel  1/3 ID needle,
suspensi)
9. globul size  0.5 µm (emulsion)
 Pyrogen
Endotoxin: a pyrogenic (fever inducing) substance (e.g. lipopolysaccharide)
present in the bacterial cell wall. Endotoxin reactions range from fever to death.

http://www.arches.uga.edu/~kristenc/cellwall.html
PYROGEN TEST

Limulus Amebocyte Lysate

(LAL) test
Cells in an isotonic solution
 Cells in a hypotonic solution

In a hypotonic solution, water

enters a cell by osmosis, causing Plant cells swell beyond their
the cell to swell. normal size as pressure increases.
Cells in a hypertonic solution

In a hypertonic solution, water

leaves a cell by osmosis, causing
the cell to shrink
 OSMOLARITY

OSMOLARITY (mOsmol/L) TONICITY

> 350 Hipertonis
329 - 350 Agak hipertonis
270 - 328 ISOTONIS
250 - 269 Agak hipotonis
< 249 Hipotonis
 WHITE-VINCENT EQUATION

V={ (W × E) } 111,1
V = volume larutan isotonis yang disiapkan
E = ekivalen NaCl
W = banyaknya zat (gram)
111,1 = tetapan yang diambil dari volume (ml) larutan
isotonis yang dibuat dengan melarutkan 1 gram
NaCl dalam air
R/ Atropin SO4 1 %
NaCl qs ad isotonicity
Steril water for injections ad 30,0 mL

𝑉 = ෍ 𝑤𝑎𝑡𝑟𝑜𝑝𝑖𝑛 𝑠𝑢𝑙𝑓𝑎𝑡 × 𝐸𝑎𝑡𝑟𝑜𝑝𝑖𝑛 𝑠𝑢𝑙𝑓𝑎𝑡 + 𝑊𝑁𝑎𝐶𝑙 × 𝐸𝑁𝑎𝐶𝑙 × 111,1

30 = σ 0,3 × 0,13 + 𝑊𝑁𝑎𝐶𝑙 × 1 × 111,1

30
=0,039 +W NaCl
111,1

𝑊𝑁𝑎𝐶𝑙 = 0,27 − 0,039

W NaCl = 0,231 𝑔
 Formulation of Parenteral

• Vitamin C
Drug • Diazepam
• Water
Vehicles • Water miscible vehicles
• Non- aqueous vehicles
Added • Antimicrobials, Antioxidants, Buffers, Bulking agents
• Chelating agents, Protectants,
substances • Solubilizing agents, Surfactants
 General steps involved
1. Cleaning

2. Preparation of bulk products

3. Filtration

4. Filling of solution in or product in ampoule or vial

5.Sealing

6. Sterilization

7. Tests for Quality control

 Solvents

Non-irritating
Non-toxic
Non-sensitizing

No pharmacological activity
Not affect activity of medicinal
Vehicles for Injection
Aqueous vehicles

Water-miscible vehicles

Nonaqueous vehicles
 Aqueous vehicles
• Frequently, isotonic (to blood) to which drug
may be added at time of use.
• Types of water:
1. Purified water
2. Sterile Purified water
3. Sterile water for injection
4. Bacteriostatic water for Injection
5. Sterile water for inhalation
6. Sterile water for Irrigation
 Purified water, USP
a. may not contain other substances
b. meets standard for the presence of total
solids
c. is used in the preparation of some bulk
pharmaceutical chemicals,
d. do not use purified water in preparations
intended for parenteral administration.
e. Must be protected from microbial
proliferation.
 Water for Injection, USP
a. is purified by distillation or by reverse osmosis.
b. not required to be sterilized, it must be pyrogen
free.
c. is intended for use in the preparation of parenteral
solutions and in the preparation of some bulk
pharmaceutical chemicals.
d. It must be protected from microbial contamination.
e. It meets the requirements of all of the tests under
purified water + Bacterial Endotoxin Test.
Sterile Water for Injection, USP
• is water for injection which has
been sterilized and packaged in
single-dose containers of not
greater than I L size.
• as water for Injection, it must be
pyrogen free and may not
contain an anti-microbial agent
or other added substance.
Example: benzyl alcohol -
not good for neonates and the
toxicity of the bacteriostat.
Bacteriostatic Water for Injection, USP

• is sterile water for injection which

contain one or more suitable
antimicrobial agents.
• It is intended to be used as diluent
for parenteral products.
• it is packaged in pre-filled syringes or
in vials containing not more than 30
mL of the water. Label must state,
“Not for Use in Newborns”.
• Example: benzyl alcohol - not good
for neonates and the toxicity of
the bacteriostat.
 Sterile water for inhalation
• Is intended for use in inhalators and in the
preparation of inhalation solutions.
• Not use for parenteral administration.
• Bacterial Endotoxin Test.
Sterile water for irrigation
• It contains no antimicrobial
agent.
• For irrigation only, Not for
injection.
• Wash wounds, surgical
incisions or body tissue
• Packaged in single-dose
containers of larger than 1-
liter size.
 Water-miscible Vehicles
portion of the vehicle in the formulation used primarily to effect solubility
of drugs and/or reduce hydrolysis

1 Ethyl alcohol Lanoxin 

2 Propylene glycol Valium 
3 Glycerin Regular Iletin 
4 Polyethylene glycols Robaxin 
 Nonaqueous Vehicles
free fatty acid content) used in fixed oils (vegetable origin, liquid, and
rancid-resistance, unsaturation

1 Corn Oil
2 Cottonseed seed Oil
3 Peanut Oil
4 Sesame Oil
5 Castor Oil and Olive Oil
(occasion)
6 Ethyl oleate
7 Isopropyl myristate
 Minyak Untuk Injeksi
Harus jernih pada suhu 10C
Tidak berbau asing atau tengik
Bilangan asam 0,2 – 0,9
Bilangan iodium 79 – 128
Bilangan penyabunan 185 – 200
Harus bebas minyak mineral
 ACID VALUE
(or neutralization number or acid number or acidity)

• is the mass of potassium hydroxide (KOH) in

miligrams that is required to neutralize one
gram of chemical substance.
• The acid number is a measure of the amount
of carboxylic acid groups in a chemical
compound, such as a fatty acid, or in a
mixture of compounds
 THE IODINE VALUE
(or iodine adsorption value or iodine number or iodine index)

• in chemistry is the mass of iodine in grams that is

consumed by 100 grams of a chemical substance
• One application of the iodine number is the
determination of the amount of unsaturation
contained in fatty acids.
• This unsaturation is in the form of double bonds
which react with iodine compounds.
• The higher the iodine number, the more unsaturated
fatty acid bonds are present in a fat
 SAPONIFICATION VALUE
(or saponification number/Koettstorfer number)

• the number of milligrams of potassium hydroxide or

sodium hydroxide required to saponify 1g of fat
under the conditions specified.
• It is a measure of the average molecular weight (or
chain length) of all the fatty acids present
• The long chain fatty acids found in fats have low
saponification value because they have a relatively
fewer number of carboxylic functional groups per
unit mass of the fat as compared to short chain fatty
acids
 Added Substances
a. Antibacterial Agents
b. Antioxidants
c. Buffers
d. Tonicity Contributors
e. Other:
 Solubilizers,
 wetting agents,
 emulsifiers,
Should not cause precipitation, hydrolysis,
complexation,
 Antibacterial Agents
• Required to prevent microorganism growth
• Limited concentration of agents
• Preservatives are incorporated into parenteral
formulations whenever:
– The product is a multidose preparation
– Aseptic processing
• Preservatives are not incorporated into
parenteral formulations whenever:
– The product has not been terminally sterilised, e.g. by
irradiation or heat and packed single dose
– Volume > 10 mL
 Examples of preservatives
• esters of para hydroxy benzoic acid, e.g.
• methyl and propyl para hydroxy benzoic acid are
often used in combination in a ratio of 9:1. The
concentration is usually circa 0.2% w/v
– phenolic compounds, e.g. phenol (0.25–0.5% w/v)
or chlorocresol (0.1–0.3% w/v).
– Phenylmercuric nitrate and Thimersol 0.01%
– Benzethonium chloride and benzalkonium
chloride 0.01%
– Chlorobutanol 0.5%
 Effectiveness varies with formulation
– e.g., Binding of p-hydroxybenzoic acid with
macromolecules (by increasing the
concentration of preservative (generally up to
0.25% w/v).
 Antioxidants
• Prevent oxidization by being oxidized faster
than the drug or by blocking oxidization
• Water soluble:
ascorbic acid,
sodium bisulfite,
sodium metabisulfite,
sodium sulfite.
• Oil-soluble:
butylated hydroxytoluene (BHT),
butylated hydroxyanisole (BHA)
 CHELATING AGENT
MATERIAL %
EDTA 0.1
CITRIC ACID 0.02 - 1
TARTARIC ACID 0.002 - 1
PHOSPHORIC ACID 0.02 - 1
GLYCERIN 20
SORBITOL > 30
 Buffers
• Added to maintain pH
• Results in stability
• Not overwhelmed by physiological buffer
• Effective range, concentration, chemical effect
• Examples:
– sodium citrate and citric acid
– sodium acetate and acetic acid
– sodium benzoate and benzoic acid
– sodium tartrate and tartaric acid
– sodium phosphate (monobasic NaH2PO4 and dibasic
Na2HPO4)
– sodium bicarbonate
 Tonicity Agents
• Reduce pain of injection
sodium chloride
potassium chloride
dextrose
mannitol
sorbitol
lactose
 ISOTONICITY
1. Freezing point depression method
2. NaCl equivalent method
3. White Vincent method
4. Sprowl method
5. Molecules concentration method
6. Graphical method on vapor pressure and
freezing point determinatio
 Other Prenteral Adjuncts
• Suspending or Viscosity Increasing Agents
– sodium carboxymethyl cellulose (Bicillin L.A. R - Wyeth)
– gelatin (Acthar GelR - Armor)
– polyvinylpyrrolidone (CrysticillinR - Squibb)
– methylcellulose
• Surfactants (Emulsifying, Solubilizing, Wetting Agents)
– egg yolk phospholipids (IntralipidR)
– polysorbate 20, 60, 80 (MVIR)
– lecithin (Bicillin L.A. R - Wyeth)
– Pluronic F-68R (Oxypropylene Polymer) (experimental)
– PEG-400 Castor Oil (AquaphytonR - MSD) (MonistatR -
Janssen)
• Chelating Agents
– ethylenediamine tetraacetic acid
• Inert Gases
– N2 (gentamicin sulfate injection)
– CO2 (sodium bicarbonate injection)
• Enhanced Drug Targeting Effect
– vasoconstrictor in local anesthetic)
• Administration Aids
– local anesthetics; benzyl alcohol, xylocaine HCl, procaine
HCl
– anti-inflammatory agents; hydrocortisone
– anti-clotting agents; heparin
– vaso-constrictors (prolong action); epinephrine
– increase tissue permeability; hyaluronidase (enzyme)
 Adjuncts Influencing Solubility
• barbiturates, antihistamines, cardiac glycosides
• creatnine to solubilize the free hydrocortisone
precipitate in a hydrocortisone phosphate
product
• niacinamide to solubilize riboflavin before
riboflavin phosphate became available
• sodium benzoate to solubilize caffeine
• ethylene diamine to solubilize theophylline
• toxicity specifications of solvent, e.g. instability of
polyethylene glycol 300 results in toxic
decomposition products
 PARENTERAL SUSPENSION
• The suspension is easily drawn through a
needle into a syringe (syringability),
• It is injected without the use of excessive force
(injectability).
• It is not irritating to the tissue into which it is
injected.
• The suspension is both physically and
chemically stable over the shelf life of the
product
• Colloidal dispersions are suspensions in which the
– particle size is small enough that
– the suspended phase
– does not settle under the force of gravity;
• The particle size in a colloidal dispersion ranges from
about 1nm to an upper limit of about 1 mm
• coarse suspensions typically contain dispersed solid
particles in the size range of about 1 to about 50 mm
• Parenteral suspensions are typically
administered intramuscularly, subcutaneously,
intra-articularly, or intradermally.
• Coarse suspensions should never be
administered intravenously or intra-arterially ,
since the particles in a coarse suspension are
usually larger than the diameter of capillaries
 Parenteral suspensions
a. the drug has limited aqueous solubility, and
attempts to solubilize the drug would
compromise safety,
b. sustained release of the drug is needed, or
c. when a local effect is needed.
• Sustained release formulations typically are
either aqueous or oil-based suspensions
administered intramuscularly or
subcutaneously
 Excipients
• Buffers
• Wetting
• Suspending Agents
• Tonicity Adjusting Agents
• Antimicrobial Preservative
 Particle Size Reduction
• Air micronization
• Spray drying
• Colloid mill
• Supercritical fluids
PARENTERAL SUSPENSION
DOSAGE FORMS
 DLVO THEORY
• Derjaguin, Landau, Verwey, and Overbeek, the
scientists who published the original theory of
colloidal stability in the 1940s
• Colloidal stability is determined by a balance
between electrical double layer repulsion,
which increases exponentially with decreasing
distance between particles, and van der Waals
forces of attraction
 DLVO THEORY
1. ionic strength of the vehicle is a dominant
factor controlling flocculation of the system,
and
2. adsorption of polymers can be used to
sterically stabilize a suspension by preventing
two particles from approaching closely
enough to aggregate in the primary minimum
DLVO THEORY
 DLVO THEORY
• Addition of a flocculating agent, such as an
electrolyte, causes a reduction in zeta
potential, which causes changes in sediment
volume.
• In the region where the sediment volume is
maximized, there should be minimum
probability of caking.
• Note that too much added electrolyte can
result in over flocculation and subsequent
caking
 PARENTERAL EMULSIAON
• An emulsion is a heterogeneous mixture of
two or more immiscible liquids, with a third
component (emulsifier) used to stabilize the
dispersed phase droplets.
• Co-emulsifiers and other additives are often
used to improve stability.
• The most commonly used parenteral emulsion
system is for parenteral nutrition (PN)
Parenteral emulsiaon
Physical Changes

Creaming

Flocculation

Coalescence
 Physical changes possible in a lipid
emulsion
A. freshly prepared lipid emulsion;
B. Creaming—readily reversible,
slow flotation of lipid droplets on
more dense aqueous phase;
C. Flocculation—aggregated
droplets are not readily
redispersed by agitation;
D. Coalescence—irreversible
merging of smaller droplets;
E. Rapid creaming of coalesced
emulsion;
F. Rapid Creaming of flocculated
emulsion;
G. Broken Emulsion—separation of
oil and water phases
 TUGAS MAKALAH
1. Sterilisasi Panas lembab/uap
2. Sterilisasi Gas
3. Sterilisasi Radiasi
4. Uji Sterilitas
5. Uji Pyrogen
6. Uji Partikulat dan Kebocoran
7. Wadah Gelas
8. Wadah Plastik
9. Tutup Elastomer