Farmasetika II (Teknologi

Sediaan Steril)
Karakteristik khusus sediaan
parenteral :
1. Aman secara toksikologi
2. Steril
3. Bebas dari kontaminasi bahan pirogenik
4. Bebas partikel partikulat asing
5. Stabil , tidak hanya secara fisika dan
kimia tapi juga secara mikrobiologi
6. Isotonis
7. Kompatibel dengan obat lain , jika
diberikan dalam bentuk intravena
admixture

Tantangan Umum :
Relatif hanya sedikit eksipien yang dapat
diterima dalam formulasi dan dapat digunakan
untuk sediaan injeksi
Selama proses pembuatan sediaan injeksi ,
produk hrs dilindungi dari kontaminasi
personil .
Kebanyakan sediaan injeksi diberikan oleh
para profesional (dokter dan perawat).

Tantangan Mikroorganisme dan

kontaminasi lain
Kontaminasi mikroba dapat berasal dari bahan
baku dan eksipien. Mikroba dapat memasuki
sediaan selama proses manufaktur (peralatan,
operator, udara dan material pengemas), selama
penyimpanan dan penggunaan. Untuk bahan
baku dicantumkan dalam USP microbial limit
test
Sediaan injeksi (terutama voleme besar) harus
bebas pirogen dan endotoksin. Pengujian
pirogen secara in vivo dan in vitro.
Sediaan injeksi jika disuntikkan dalam bentuk
larutan harus bebas dari partikel partikulat.

Tantangan Stabilitas
Sediaan injeksi biasanya diberikan dalam
bentuk larutan
air dan sistem dispersi
(suspensi, emulsi, liposom atau sistem
partikulat lain). Secara umum sediaan injeksi
bermasalah dalam hal stabilitas kimia, fisika
dan mikrobiologi.
Kimia : hidrolisis, oksidasi, rasemasi dan
fotolisis
Fisika : pada sediaan injeksi protein, cendrung
terbentuk self- aggregate yang selanjutnya
akan mengendap,
kekeruhan, penurunan
kelarutan dan pertumbuhan kristal.

Stabilitas
mikrobiologi
:
kontaminasi
mikrorganisme selama proses pembuatan dan
penyimpanan.
Dpt diatasi dengan pengunaan
kemasan yang tepat dan penambahan bahan
pengawet.

Pengujian kompatibilitas anatara sediaan injeksi

dengan kombinasi cairan sediaan intravena lain
(NaCl, dektrosa dan laktat ringeri) atau sediaan
injeksi lain diperlukan untuk mencegah hal yang
tidak diinginkan pada pasien pengguna sediaan .

Tantangan kelarutan
Kebanyakan senyawa obat
yang terbatas dalam air,
fenitoin, diazepam dan
kelarutan dapat diatasi
cara :

memiliki
seperti ;
digoksin.
dengan

kelarutan
steroide,
Masalah
beberapa

1. Pembentukan garam
2. Pengaturan pH
3. Penggunaan kosolven
4. Penambahan surfaktan
5. Pembentukan kompleks inclusi dengan beta
cyclodextrin
6. Formulasi sediaan mikroemulsi, liposom,
mixed miccele

Tantanagan Kemasan
Formulasi sediaan injeksi harus kompatibel dengan
sistem kemasan dan penutup kemasan .
Kemasan yg paling luas digunakan vial gelas dan
penutup karet.
Kriteria penutup karet sangat penting diperhatikan
krn dapat mengadsorpsi bahan aktif dan bahan
eksipien. Atau leaching material pengemas ke
dalam larutan injeksi

PIROGEN

PYROGEN BERASAL DARI KATA PYRO = KEADAAN ATAU

BENTUK YANG BERHUBUNGAN DENGAN PANAS, GEN =
MENGHASILKAN
PIROGEN : SUATU PRODUK MIKROORGANISME, TERUTAMA
BAKTERI GRAM NEGATIF DAN DAPAT BERUPA ENDOTOKSIN
DARI BAKTERI INI. ENDOTOKSIN INI TERDIRI ATAS SENYAWA
KOMPLEKS YANG MERUPAKAN SUATU SENYAWA
LIPOPOLISAKARIDA

SUBSTAN DAN PREPARAT YANG HARUS BEBAS PIROGEN :

1.AIR UNTUK INJEKSI
2.LARUTAN INFUS
3.ANTIBIOTIKA
4.GARAM ASAM ORGANIK
5.PRODUK-PRODUK HEWANI : CHORIONIC GONADOTROPIN,
GELATIN DAN HEPARIN
6.OBAT TETES DAN SUBSTAN LAIN, YANG DIBERIKAN I.V
UNTUK MAKSUD DIAGNOSTIK, INULIN, INDIGOCARMIN
7.PRODUK-PRODUK DARAH ; HUMAN ALBUMIN

1923 SEIBERT MEMBUKTIKAN BAHWA PIROGEN ADALAH

SUBSTANCE YANG BERSIFAT :
TIDAK TERSARING
THERSTABIL
NON VOLATILE

SUMBER PIROGEN :
PELARUT OBAT SUNTIK
OBAT ITU SENDIRI
PERALATAN
CARA PENYIMPANAN

ADANYA PIROGEN DALAM LARUTAN INJEKSI BISA MENJADI HAL

SERIUS JIKA OBAT SUNTIK DALAM JUMLAH BESAR (MISAL
INFUS), INI DISEBABKAN KARENA :
1.INJEKSI VOLUME BESAR AKAN MENGANDUNG PIROGEN YANG
BANYAK PULA
2.INJEKSI VOLUME BESAR , BIASANYA DIBERIKAN INTRAVENA,
AKIBATNYA PIROGEN AKAN MEMBERIKAN EFEK YANG CEPAT
3.PASIEN YANG MENERIMA CAIRAN INFUS INI BIASANYA PASIEN
GAWAT, BILA TERJADIKENAIKAN TEMPERATUS TUBUH BISA
BERAKIBAT FATAL.
OLEH KARENA ITU, LARUTAN INFUS (INJEKSI VOLUME BESAR)
HARUS BEBAS PIROGEN, BPC MENSYARATKAN VOLUME OBAT
SUNTIK YANG LEBIH BESAR DARI 10 ML HARUS BEBAS PIROGEN

SIFAR SIFAT PIROGEN :

1.THERMOSTABIL, UNTUK MENGHANCURKAN PIROGEN
DIBUTUHKAN TEMPERATUR YANG LEBIH TINGGI DARI
TEMPERATUR BIASA, YANG DIGUNAKAN UNTUK PROSES
STERILISASI (> 200 O C)
2.LARUT DALAM AIR, TIDAK DAPAT DIHILANGKAN DENGAN
PENYARING BAKTERI
3.TIDAK DIPENGARUHI OLEH BAKTERISIDA YANG BIASA
4.TIDAK MENGUAP
5.BERAT MOLEKUL ANTARA 15.000 4.000.000 DA
6.UKURAN UMUMNYA 1 -50 MIKRON, YANG DAPAT
DITENTUKAN SECARA DIALISA

PENENTUAN PIROGEN

PENENTUAN KWANTITATIF PIROGEN SECARA FISIKO

KIMIA :
1.DENGAN FOTOKOLORIMETRI
2.POLAROGRAFI
3.ELEKTROFORESA
4.SPEKTROFOTOMETRI

PENENTUAN SECARA KWALITATIF SECARA

BIOLOGIS :
PENGUKURAN TEMPERATUR BADDAN HEWAN PERCOBAAN :
HEWAN PERCOBAAN YANG DIGUNAKAN : KELINCI , KARENA
KELINCI ADALAH HEWAN YANG SANGAT PEKA TERHADAP
PIROGEN
PRINSIP : MENGUKUR KENAIKAN TEMPERATUR TUBUH
KELINCI, BILA DIINJEKSIKAN DENGAN LARUTAN OBAT SUNTIK
YANG
MENGANDUNG
PIROGEN
SECARA
INTRAVENA
DITELINGA KELINCI , PENGUKURAN TEMPERATUS TUBUH
DILAKUKAN
PADA
DAERAH
DUBUR.KELINCI
YANG
DIGUNAKAN, HARUSLAH SELAMA SEMINGGU SEBELUM
PENGUJIAN TIDAK MENUNJUKKAN PENURUNAN BERAT
BADAN.
ALAT : TERMOMETER DENGAN KETELITIAN 0,1 DERAJAT DAN
DAPAT DIMASUKKAN KE DALAM DUBUR SEDALAM LEBIH
KURANG 5 CM.

SEDIAAN UJI : ZAT UJI DILARUTKAN ATAU DIENCERKAN DENGAN

LARUTAN NATRIUM KLORIDA P. STERIL BEBA S PIROGEN

PERHITUNGAN SEL DARAH PUTIH

INJEKSI LARUTAN OBAT SUNTIK YANG MENGANDUNG PIROGEN
PADA PEMBULUH DARAH BALIK KELINCI AKAN MENYEBABKAN
TERJADINYA PERUBAHAN SEL-SEL DARAH PUTIH. EX. PENURUNAN
LIMFOSIT DAN MENAIKAN NETROFIL.

TEST LIMULUS
PRINSIP : LYMULUS AMOBOCYTES LYSATE YANG BERUPA
EKSTRAK CAIR SEL-SEL DARAH KEPITING LADAM KUDA
(LIMULUS POLYPHEMUS) AKAN MENGGUMPAL (MEMBENTUK
GEL) DENGAN ADANYA PIROGEN

CAIRAAN LIMFA DAN DARAH KEPITING INI MENGANDUNG

AMOEBOCYTEN (MENGANDUNG PROTEIN YANG DAPAT
MENGGUMPAL /PROCOAGULANTIN) = LAL ( LIMULUS
AMOBOCYTES LYSATE)

BAKTERI GRAM NEGATIF BEREAKSI DENGAN EKSTRAK SEL DARAH

KEPITING LIMULUS POLYPHEMUS.

METODE LAL SANGAT SENSITIF DAN AKURAT UNTUK

PENGUJIAN PIROGEN SECARA KWALITATIF ; BAGIAN LIPID A
DARI MOLEKUL ENDOTOKSIN DAPAT BEREKSI MENJADI
PENGGUMPALAN (GEL)DENGAN LIMULUS LYSATE .

Penghilangan Pirogen
Ada beberapa metode untuk menghilangkan pirogen :
1. Cara Penyulingan :
biasanya digunakan untuk membebaskan pirogen dari air.
Dilakukan penyulingan bertingkat, dengan alat destilasi tertutup.
Pada saat penyulingan dapat ditambahkan bahan kimia dan
absorbensia ex. 0,5 % KMnO4, atau dengan bubuk pemutih .

2. Cara pemanasan
larutan : waktu dibutuhkan 6-8 jam, suhu 120 derajat, 30 menit 1
jam suhu 140 derajat. (autoclave)
dalam keadaan kering : untuk alat dan bahan yang tahan
pemanasan : selama 30 menit 250 derajat, 2 jam 200 derajat.

3. Cara Penyerapan
pirogen dapat dihilangkan dg cara adsorpsi dengan menggunakan f
ilter asbes aktif atau karbon aktif. Pirogen dapat diserap secara kimia
dan fisika.
Bentuk saringan : asbes aktif dan norit aktif (0,1 0,3 %)
Bentuk bubuk : carbo adsorben, asbes aktif (1 %)

Small Volume Parenteral : Sterile, pyrogen free injectable

product which are packaged in volume s up to 100 ml
(Avis et al. 1984).
SVP product can be classified into one or
more of the following categories :
a. Pharmaceutical product (solution, suspension, emulsion,
freeze dried product for reconstitution or powder for
constitution).
b. Biological product (vaccines, toxoid, biological extracts).
c. Diagnostic agent are used to diagnose clinical condition (xray contrast media, dyes)
d. Allergenic extracts
e. Radiopharmaceutical products
f. Dental product (local anesthetics)

Market Inventory and Projected Sales. A combination

of product inventory and projected sales determine in
large measure when and how much the product is to
be made by a production department.

Planning and scheduling activities are the key to the

successful production of small volume parenterals.

Materials Management
This group of personnel is responsible for providing
the materials necessary to manufacture the product.
Materials management
activities :

personnel

coordinate

the

chemical stock, package component warehouse,

printing, and purchasing so that there are sufficient
supplies of chemicals, package components, and
printed components to keep up with the needs of
production, and makes certain that these supplies are
available in a timely manner.

Personnel Management
The key factor in the large-scale manufacturing of highquality products is a properly motivated production staff .

Documentation Control
Documentation is the control and verification of the critical
activities in a pharmaceutical process production and
control cycle.

The elements of good documentation include

the following:
a.Master file
b.Batch records
c.Process logs
d.Material Iogs
e.Distribution records
f. ComPlaint files
g.Retained sample storage area records
h.Return good records

The master file is a perpetual record of the

production and control cycles on all batches of a
particular product.
The batch record is the complete record of the
manufacture, control, and distributiott of a single
batch of a product.
Process logs are written verification by a
responsible person that the facilities and equipment
used during a pharmaceutical process have been
cleaned, maintained,calibrated, and/or operated in
an acceptable manner.

Material logs are a verification that the raw materials used in a

pharmaceutical process are acceptable
Distribution records are maintained so that the manufacturer can
determine the location of all manufactured products at all times.
In addition, a complaint file is maintained as a backup to in-house
monitoring of product performance. Complaint files include
inquiries or complaints on product and,/or package defects or
adverse product reactions.
A retained sample storage area is maintained as a comparative
reference source to assist in the reply to product inquiries and
complaints.
The returned goods record is a record of products returned to the
manufacturer as a result of complaints or products exceeding their
shelf life before being consumed. In any case, returned goods are
an important indicator of product market demand and acceptance
of a product.

The majority of formulation fall into three

pharmaceutical products :
I.Solution
II.Suspensions/dispersions
III.Solid for constitution
Sterile solution is the most common small volume
parenteral dosage forms.

Composition of a sterile solution :

a.Soluble drug
b.Osmotic pressure adjusters (sodium
chloride or mannitol)
c.Bacteriostatic agents (required for
multiple dose containers such as benzyl
alcohol)
d.Buffering agents (phosphates, acetate and
citrate salt)
e.pH adjausters (such as sodium hydroxide
and hydrochloric acid)

Dosage
10 mg

Soluble drug

Active drug

8,3 mg

Sodium phosphate Buffering agent

mono basic

11,29 mg

Sodium phosphate Buffering agent

dibasic

9,0 mg

Benzyl alcohol

Parenteral
preservative

Qs pH 6,8 - 7

Sodium hydroxide

pH adjuster

Ad 1 ml

Water for injection

Solvent

Figure I : operation I Nonsterile Formulation

I.Place WFI (in excess of 10 % of the final volume) into stainless
steel tank
II.Heat WFI (121 C 20 min), cool to 60 C
III.Remove and place WFI (30 %) in separate container, save for final
volume adjustment
IV.Dissolve with stirring the buffering agent with remaining WFI (60
C)
V.Allow the solution to cool (at room temperature 25 30 C),
dissolve active drug and preservative, check the pH of the solution,
if required, adjust with 1 N sodium hydroxide solution
VI.Bring the bulk to final volume with WFI and mix well.

Figure I : operation II Sterilization

I.Sterilize the bulk solution by filtration method
II.Collect the sterile filtrate
Figure I : operation III Sterile Subdivision
Aseptically subdivide the sterile bulk into appropriate sterile
container
Aseptically apply sterilized closure systems to the container and
seal
Inspect for sterility and volume fill check during filling operation
Inspect all units for defect and particulate matter
Submit samples to the quality control laboratory for release assays

The blue zone (Dan Buettner, 2008)

Figure 2 : operation I nonsterile formulation of the

vehicle
I.Place WFI (in excess of 10 % of the final volume)
into stainless steel tank
II.Heat WFI (121 C 20 min), cool to 60 C
III.Remove and place WFI (30 %) in separate
container, save for final volume adjustment
IV.Dissolve with stirring the buffering agent with
remaining WFI (60 C)
V.Seal the tank for autoclaving

Figure 2. Operation II thermal sterilization of the vehicle

Autoclave both of the vessel from operation I for 30 min at 121 C
Figure 2. Operation III aseptic formulation of the active and
preservative
I.Cool the sterile vessel from OP II to room temperature, aseptically
add and dissolve active drug and preservative
II.Aseptically check and adjust the pH 6,8 7 if required
III.Aseptically bring the bulk to final volume with WFI
Figure 2. operation IV Filtration
Figure 2. operation V sterile subdivision

Formulation for a sterile injectable suspension

Dosage
800 mg
O,2 mg

Insoluble drug
Polysorbate 80 USP

Active drug
Surface active

6,67 mg

Sodium Chloride

agent
Tonicity adjuster

5,0 mg

USP
Sodium

Viscosity

Carboxymethyl

building agent

cellulose
Benzyl alcohol

Parenteral

Water for injection

preservative
Solvent

9,0
Ad 1 ml

Sterile suspensions for injection are more

complicated in composition than a sterile solutions.
Consequently, they are more difficult to process and
sterilize than solutions.

Solid active ingredient may be sterilized prior to

compounding into a suspensions in a numer of
ways , dry heat, autoclave, radiation, sterile
precipitation or crystallization.

Dry heat sterilization

; low melting point , heat
sensitivity of active drug.
Autoclaving of suspensions : increased solubility
of active drug , induce degradation and
recrystallization when is cooled.
Alter the crystal form , habits, or sizes of solid drug

Ethylene oxide : residuals of toxic gas, react with

the active drug

Radiation : radiation energy can break chemical bonds

and or form a new one.
The most practical method of preparing a sterile solid
for suspension : sterile crystallization and
precipitation .
Active drug dissolve in a solvent (organic solvent and
co-solvent), then sterilized by filtration through a
sterilizing membran with porosity 0,2 mikron or less,
Collected in a sterile vessel containing a sterile liquid
in which the dug is insoluble.
The active drug precipitates as crystalline or
amorphous mass.

Some sterile solids may have to be aseptically milled

to reduce particle size or break up hard aggregates of
solid if the crystallizing or precipitation pro
cess does not produce a uniform particle size

Preparation of Packaging
Components

Sterile package consist of :

I. Primary packaging component (ampuls, vial,
syringes, rubber or plastic stopper
II. Secondary packaging component (Box and
shrink wrap)
Preparation and sterilization of primary packaging component
for parenteral and other sterile products are very important
steps in the overall manufacturing process.
Primary component must be clean and sterile

Rubber
Components

Vial stoppers, syringe parts, opthalmic

dropper bulbs
FIFO inventory inventory control for packaging component are
critical.

Processing of rubber component involves the

following operations :
I.Washing
II.Sterilization
III.Siliconization

Rubber component are generally sterilized by

autoclaving (moist heat) because of the rapid heat
penetration (121 C 30-60 min)

Siliconization of rubber component

is usually
necessary to facilitate insertion of the rubber
component into container openings via high speed
automatic filling and sealing machine.
Silicon oil is used to siliconize SVP rubber
component.

Glass Component
Vials , ampuls, bottles , syringe are chemically stable than
rubber component and therefore may be stored at higher
temperature and high humidities for s longer period of time.

Processing :
I.Washing
II.Sterilization
III.Siliconization

Glass component are sterilized by dry heat, dry heat is the process of
choice for sterilizing glass component.