Drs.

Pramono Abdullah Apt

2013
 Tujuan Dari Modul ini

1. Mengenal air yg dipakai dalam farmasi .

2. Sumber dan jenis air yg dapat dipakai untuk

farmasi.
3. Menyimpanan air sebelum dan sesudah
dilakukan treatment .
4. Proses pembuatan Aqua Pro Injeksi
Dasar Pemikiran .
Air untuk di farmasi harus diperlakukan
sebagai bahan baku yg lain, harus memenuhi
syarat Farmakope dan CPOB.

Bahan baku air untuk farmasi harus memenuhi

standard air minum yg telah ditetapkan .
Dasar Pemikiran (2).

1. Potential untuk tumbuhnya bakteri.

2. Air untuk produk parenteral dapat
terkontaminasi oleh pyrogen ataupun
endotoksin.
3. Sehingga diperlukan adanya spesifikasi
tertentu dan test secara periodik.
4. System treatmentnya harus tervalidasi dengan
baik dan benar.
 Jenis - jenis (Types) air yg dipakai di Industri Farmasi.

1. Purified Water
2. Water for Injections WFI
3. Softened Water
4. Water for Final Rinse
5. Pure, or clean Steam
6. Water for cooling Autoclaves
 Mengapa harus purify raw water ?

1. Tingkat kemurnian air sangat bervariasi.

2. Perbedaan/perubahan iklim dapat
mempengaruhi kualitas air.
3. Di beberapa tempat / negara , mempunyai
kualitas air yg jelek.
4. Untuk mencegah terjadinya kontaminasi produk.
5. Kontrol mikroba diperlukan untuk menghindari
kontaminasi dari produk.
Kontaminasi Air (1).
Air murni (pure water) tidak tersedia di alam, air dari
alam biasanya mengandung kontaminan yang
dikelompokkan dalam :

1. Inorganic compounds
2. Organic compounds
3. Solids
4. Gases
5. Micro-organisms
Kontaminasi Air (2)
Problem mineral :.

1. Calcium and magnesium

2. Iron and manganese
3. Silicates
4. Carbon dioxide
5. Hydrogen sulfide
6. Phosphates
7. Copper
8. Alluminium
9. Heavy metals : Arsenic, lead, cadmium.
10. Nitrates
Kontaminasi Air (4)
Micro-organisms Biofilm

Algae

Protozoa
Cryptosporidium
Giardia

Bacteria
Pseudomonas
Gram negative, non-fermenting bacteria
Escherichia coli and coliforms
Formasi Biofilm :
1. Mengambang di permukaan air,
menggunakan/mengeluarkan
polymucosaccharides untuk membentuk koloni.
2. Membentuk komplek koloni yg terdiri micro-
colonies dan bakteri.
Turbidity (kekeruhan) dapat disebabkan oleh :

1. Lumpur dan tanah liat serta material yg tersuspensi

dapat menyebabkan kekeruhan.
2. Partikel partikel halus termasuk "colloids"
3. Penghilangan benda benda koloidal biasanya
merupakan langkah awal dalam water treatment
 Water hardness
Tingkat kekerasan air

Water hardness mg/L or ppm

classification as CaCO3
Soft
0-60
Moderate 61-120

Hard 121-180

Very Hard > 180

Source of raw water (sumber air baku)

1. Rain water ( air hujan )

2. Surface or ground water ( air permukaan / air
tanah)
3. Well or borehole ( air sumur / sumur bor )
4. Municipal or civil tap water
5. Purchased in bulk
Well water ( air sumur )
1. Inspect exposed parts of the well
2. Depth of well

Check:
1. Nearby septic systems
2. Hazardous materials usage (pesticides,
fertilizers, etc)
3. Potability
4. Well maintenance
Raw water storage
1. Persyaratan/ketentuan untuk air sebelum
dilakukan pre-treatment .
2. Check material dari konstruksi:
Concrete, steel are acceptable but check corrosion
Plastics or plastic linings may leach
3. Check cover
To keep out insects, birds and animals
4. Check disinfection practices
WHO water treatment guidance
The following should be monitored
Sources of water (sumber air)
Treatment procedures
Water treatment equipment
Treated water tests
Monitoring records required
Pre-treatment steps
1. Primary filtration and multi-media filter (Sand
filter)
2. Coagulation or flocculation
3. Desalination
4. Softening
 Chlorine removal
Activated-carbon (AC) filtration
or bisulphite
1. AC removes chlorine but bacteria can then grow
2. AC filtration can remove organic impurities
3. Bisulphite leaves sulphate residues but is
anti-microbial
Pretreatment
schematic drawing
float
operated excess water recycled activated
carbon
To water
valve from deioniser
air filter sand filter filter softener &
DI plant
spray ball

Water is kept raw water in break tank

circulating

cartridge
filter
centrifugal pump 5 micrometers
air break to drain

S trap to sewer
Water Softener schematic drawing
"soft" water to deioniser
by pass valve

brine and salt tank

zeolite water softener

-exchanges
brine
-Ca and Mg for Na

"hard" water
in

drain
 Water pre-treatment
complex
External raw water storage

Pretreatment room
Proses Pemurnian
dan
PenyulinganAir
 Tujuan

Mempelajari dasar-dasar teknologi dan persyaratan

untuk :
1. Water treatment systems
2. Storage requirements (persyaratan dan cara
penyimpanannya)
3. Sampling dan testing
4. Different types of water used in pharmaceuticals
5. Microbial limits, disinfection
Water system design
1. Pipes sloped so water does not pool and can
drain easily
2. Sanitary fittings & connections
3. Constructed of suitable materials such as
stainless steel
4. Circulate the water
Further water treatment purification stages
downstream of the pre-treatment system
1. Filtration
2. Disinfection
3. Reverse osmosis or de-ionization
4. Distillation or ultra-filtration
 Water system design (1)
There should be no dead legs

Flow direction arrows

on pipes are important

Deadleg section

X <2D
If D=25mm & distance X is
greater than 50mm, we have
a dead leg that is too long.

Sanitary Valve
Water scours deadleg
 Water system design (2)
1. Ball valves are unacceptable
2. Bacteria can grow when
the valve is closed

3. The water is contaminated

as it passes through the valve Stagnant water
inside valve
Water system design (3)

1. Sanitary pumps
2. Clamps and O rings
versus threaded fittings
3. Heat exchangers
4. Side arm level measuring devices are
unacceptable
 Typical de-ionizer schematic
from water softener
HCl NaOH

6 6
5 5
4 4
3 3
2 2
1 1

Water
must be Cationic column Anionic column Cartridge Cartridge
kept UV light filter 5 m filter 1 m

circulating Eluates to Ozone generator

neutralization
plant
Hygienic pump
Return to de-ioniser

Outlets or storage.
Drain line

Air break to sewer

Reverse osmosis (RO) theory
High pressure Low pressure

Semi-permeable
membrane
Feed
water

under Purified water

pressure raw water
Reject

Permeate
water

water

drain or recycle
 Typical 2-stage RO schematic
Water from softener or de-ioniser

Second stage reject water goes back to first stage buffer tank
1st stage buffer tank
Branch First stage RO cartridge
1st stage reject concentrate

Branch

First stage filtrate feeds second stage RO

. excess back to 1st stage buffer tank
with
Air break
to sewer 2nd stage buffer tank
Second stage RO cartridge

High pressure
pump
Cartridge
filter 1 m Hygienic pump
Second stage RO water
meets Pharmacopoeia Water returns to 1st stage buffer tank
standards Outlets or storage
Use of reverse osmosis
Advantages
Disadvantages
Many uses
purified water
feeding of distillation units or ultra-filtration units
Water for Final Rinse
Water for Injections (if permissible)
Ultra-filtration
Can be used for WFI or for Water For Final
Rinsing for parenteral manufacturing (if
permitted)
Removes organic contaminants, such as
endotoxins
Operation at 80C, and sterilization at 121 C
1. Single-effect distillation
simple distillation, single effect
vapour compression, thermo compression
2. Multi effect distillation
multiple effect stills
3. Clean steam generators
used where steam can come into contact with product contact
surfaces, e.g. sterilization-in-place (SIP)
 Typical water storage and distribution schematic
Hydrophobic air filter
Feed Water & burst disc
from
DI or RO Cartridge
filter 1 m Spray ball

Optional
Water must in-line filter
be kept 0,2 m

circulating
UV light
Outlets

Heat Exchanger
Ozone Generator Hygienic pump Air break
to drain
Disinfection (1)
Heat
One of the most reliable methods of disinfection
of water systems
Ozone
Produced easily
Leaves no residue
Disinfection (2)
UV
1. UV does not sterilize
2. Flow rate critical
3. Post-irradiation recontamination may be an issue
4. Lamps have finite life

Other chemicals
1. XO2
2. Halogen
3. Formaldehyde
Sampling (1)
1. There must be a sampling procedure
2. Sample integrity must be assured
3. Sampler training
4. Sample point
5. Sample size
Sampling (2)
1. Sample container
2. Sample label
3. Sample storage and transport
4. Arrival at the laboratory
5. Start of test
 Testing - setting specifications for purified water
or WFI - (1)
Ph. Eur. JP USP Int. Ph.
pH 5.0-7.0 5.0-7.0 5.0-7.0 pass test
Cl < 0.5 pass test - pass test
SO4 pass test pass test - pass test
NH4 < 0.2 < 0.05 - pass test
Ca/Mg pass test - - pass test
Nitrates < 0,2 pass test - pass test
Nitrites - pass test - -
 Testing - setting specifications for purified water
or WFI (2)
Ph. Eur. JP USP Int. Ph
Conductivity (S/cm) - - < 1.3 -
Oxidizable subs. pass test pass test - pass test
Solids (ppm) < 10 < 10 - nmt(*) 10
TOC (ppm) - < 0.5 < 0.5 -
Heavy metals - - - pass test
CO2 - - - pass test
Testing
1. Method verification
2. Chemical testing
3. Microbiological testing
test method
types of media used
incubation time and temperature
objectionable and indicator organisms
manufacturer must set specifications
Water for Injections

1. International pharmacopoeia requirements for

WFI are those for purified water plus it must be
free from pyrogens
2. Usually prepared by distillation
3. Storage time should be less than 24 hours
4. Microbial limits must be specified
Water for Final Rinse
Water for final rinse must be of the
same quality as the water required
for pharmaceutical preparation
Pyrogens and endotoxins
1. Any compound injected into mammals which gives
rise to fever is a Pyrogen
2. Endotoxins are pyrogenic, come from Gram negative
bacterial cell wall fragments
3. Detect endotoxins using a test for lipopolysaccharides
(LPS)
rabbit test detects pyrogens
LAL ( Limulus Amebocyte Lysate ) test detects endotoxins
4. Ultrafiltration, distillation, & RO may remove
pyrogens
 Suggested bacterial limits (CFU /mL)

Sampling location Target Alert Action

Raw water 200 300 500

Post multimedia filter 100 300 500
Post softener 100 300 500
Post activated carbon filter 50 300 500
Feed to RO 20 200 500
RO permeate 10 50 100
Points of Use 1 10 100