Water Treatment System

(Sistem Pengolahan Air)

2018
 Sarana Penunjang Kritis
Industri Farmasi
• Sistem Pengolahan Air
• Sistem Tata Udara (HVAC)
• Sistem Udara Bertekanan
 WATER SYSTEM
DESIGN PHILOSOPHIES
• Pharmaceutical water is the most widely used
ingredient in drug manufacturing and the
main component in equipment/system
cleaning.
• Control of microbiological quality is important
• It must be demonstrate that all
pharmaceutical water can be produced
consistently to specification
 DESIGN PHILOSOPHIES
• Specification of the pharmaceutical water
quality
• Critical process parameter
• cGMP compliance issues
• Design range vs operating range
 Why Purify Raw Water?
• Although reasonably pure, it is always variable
• Seasonal variations may occur in water
• Some regions have very poor quality of water
• Must remove impurities to prevent product
contamination
• Control microbes to avoid contaminating
products
 Major Water Impurities

•Non Ionic & Suspended REMOVAL

•Gases Purification
techniques
•Ionic & Dissolved
Most Common Dissolved Solids in Raw
Waters
•Calcium
Bicarbonate Ca(HCO3)2
Sulfate CaSO4
•Magnesium •Silica
Bicarbonate Mg(HCO3)2 Oxide SiO2
Sulfate MgSO4 •Iron
•Sodium Bicarbonate Fe(HCO3)2
Bicarbonate NaHCO3 Hydroxide Fe(OH)3
Sulfate Na2SO4 Sulfate FeSO4
Chloride NaCl Organic
 SOURCE OF RAW WATER
1. Rain water
2. Surface or ground water
3. Well or borehole
4. Municipal or civil – “tap water”
5. Purchased in bulk
 Treatment Guidance
• The following should be monitored :
– Sources of water
– Treatment Procedures
– Water Treatment Equipment
– Treated water tests
– Monitoring records required
 Water Treatment Diagram (example)

Raw Water Raw Water Water Tap water Tap Water

source storage tank pre-treatment storage tank

Soft water Reverse

Softener Filter (10µm) EDI
storage tank Osmosis

Filter WFI Storage

( 0,2 µm) PW tank Distiller
tank

Distribution Distribution
Pretreatment of Raw Water (example)

Sedimentation- Iron Carbon

Raw Water
Sand Filter removal filter

Treated
Water
Types of water used in pharmaceutical
processes

• Tap water
• Softened water
• Purified water
• High purified water
• Water for Injection
• Pure, or clean steam
 Purified Water
USP
• Is obtained from water complying with U.S.
- Environmental Protection Agency (EPA),
- National Primary Drinking Water Regulations (NPDWR),
- or comparable regulations of the European Union or Japan,
- and will be referred to subsequently as Drinking water.
• Contain no added substance
• Is obtained by a suitable process
• Meets the requirements for water Conductivity
• Meets the requirements for TOC
 Purified Water (PW)
(USP)
• It is used for as excipient in the production of :
a.Nonparenteral preparations, and
b.Other pharmaceutical applications
(cleaning/rinsing, tests and assays)
• Purification of water sources : by unit operations that
could include deionisation, distillation, ion excange,
RO, EDI, filtration, UV light
 USP Water For Injection
• Meets all of the requirements for “Purified water”
• Is obtained by a suitable process and purified by
distillation or RO (European union only accept
distillation)
• Meets the requirements of the Bacterial Endotoxin
test and contains not more than 0.25EU/mL
• Is prepared using suitable means to minimize
microbial growth.
 USP Specifications: PW vs. WFI
PW (Purified WFI (Water for
Water) Injection)
Water conductivity < 1,3 μS/cm at < 1,3 μS/cm at 25°C*
25°C*
Total Organic Carbon < 0.5 ppm < 0.5 ppm
(TOC)
Aerobic Microbial < 100 CFU/ mL < 10 CFU/100 mL
Contamination (<0.1 CFU/mL)
Endotoxin content Not Specified < 0.25 EU/mL
Production Obtained by Obtained by suitable
Methods suitable process process and purified by
distillation.

*In-line measurement, from equivalent values from USP table

CFU=Colony Forming Units
All Pharmaceutical water must also meet the EPA standard for microbiological quality of
potable water
Selection of Water for Pharmaceutical Purposes (USP)
WATER FOR PHARMACEUTICAL PURPOSES
DRINKING WATER MEETS
QUALITY ATTRIBUTES OF EPA NATIONAL
PRIMARY DRINKING WATER REGULATIONS

Typical Treatment steps

. Softening . Reverse Osmosis
. Dechlorination . Ultrafiltration
. Deionization . Distillation

FOR
OTHER
USES

WATER FOR SPECIAL

PHARMACEUTICAL WATER FOR
PURIFIED Distillation
PURPOSES INJECTION
WATER or Reverse Osmosis
(e.g. bulk pharmaceutical (WFI)
Chemicals, process water)

INGREDIENT Packaging and Packaging and

WATER Sterilization Sterilization

PACKAGED WATER
NON
STERILE WATER FOR INJECTION
PARENTERAL STERILE PURIFIED
STERILE WATER FOR IRRIGATION
DOSAGE WATER
STERILE BACTERIOSTATIC WATER
FORMS
FOR INJECTION
STERILE WATER FOR INHALATION
Materials that come into contact with systems
for WPU
• Includes : Pipe work, valves and fittings, seals,
diaphragms and instruments, should be selected to
satisfy the following objectives.
► Compatibility : All materials used should be compatible
with the temperature and chemicals used by or in the system.
► Prevention of leaching: All materials should be non-
leaching at the range of working temperatures.
► Corrosion resistance : PW, HPW and WFI are highly
corrosive. All materials should be corrosion resistance.
Materials that come into contact with systems
for WPU

► Smooth internal finish :Smooth internal surfaces help to

avoid roughness and crevices within the WPU system.
Crevices are frequently sites where corrosion can commence.
► Jointing : The selected system materials should be able to
be easily by welding in a controlled manner.
► Design of flanges or unions : Where flanges or unions are
used, they should be of a hygienic or sanitary design
Materials that come into contact with systems
for WPU

► Documentation : All system components should be fully

documented and be supported by original or certified copies
of material certificates.
► Materials : Suitable materials that may be considered for
sanitary elements of the system include 316 L (low carbon)
stainless steel, polypropylene, polyvinylidenedifluoride and
perfluoroalkoxy
(WHO, Technical Report Series 929/2005)
 SYSTEM DESIGN
• Type of products to be manufactured
• Pipes sloped so water does not pool and can be drain
easily
• Sanitary fittings & Connections
• Constructed of suitable materials
• Temperature of the systems
• Circulating or one way system ( a one way systems is
basically “dead leg”)
• Level of Quality that is desired
 SYSTEM DESIGN
• Incorporate non return valves
• Purified water systems require frequent
sanitization and microbiological monitoring to
ensure water of appropriate microbiological
quality at the point of use.
 PIPE SYSTEM DESIGN

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

There should be no dead legs

 WATER FOR FINAL RINSE

Water for final rinse must be of the

same quality as the water required
for pharmaceutical preparation
 Water purification & distribution loop
Purification process
Distillation system

Reverse Electro-
Feed osmosis deionisation Tank
water

Tank

Distribution loop
 Hot Storage, Hot Distribution
Control Valve
(optional)

Steam
Hot
Storage
Tank

Cond.
Most Advantageous When:
•Hot water is required
•Hot water is generated
•Microbial control is critical
Least Advantageous When:
•Ambient temperature water
required
 Biofilm
A biofilm is defined as bacterial cells adherent to each other
and/or to surfaces or interfaces and are covered by a slimy
substance, which acts as a shield, protecting the biofilm
from physical and chemical attack.

Ref: Biofilms – Survival and growth of bacteria in compendial high purity water systems by Frank Riedewald and Aidan W. Sexton:
Pharmaceutical engineering Vol.27 No 1.
Bio-film formation
1. Free swimming aquatic bacteria use
polymucosaccharides to colonise surfaces
2. Complex communities evolve which shed
micro-colonies and bacteria
 How to validate a water treatment system (USP)
• Defines the critical process parameters and their operating
ranges.
• A validation programs the design, installation, operation and
performance of equipment.
• Stages :
1. Design Qualification (DQ)
2. Qualification of the installation (IQ),
3. Operational Qualification (OQ),
4. Performance Qualification (PQ)
• Validation
 Validation of Water System

• Consists of three phases :

• Phase 1 : 2-4 weeks
• Phase 2 : 2- 4 weeks
• Phase 3 : 1 year
Phase 1: Investational Phase (2 – 4 weeks)

• DQ, IQ and OQ
• Develop
– operational parameters
– cleaning and sanitization procedures and frequencies
• Sample daily at each point of use
• End of Phase I, develop SOPs for the water
system
 Phase 2 : verifying control (2-4 weeks)

• Demonstrate the system is in control

• Same sampling as in phase 1
• The water can be used for production
Phase 3 : verifying long-term control (1 year)

• PQ
• Demonstrate the system in control over a long
period of time
• Weekly sampling

PUSTAKA :
1.WHO,TRS 929
2 .ISPE,Pharmaceutical Engineering Guide,vol.4,
Water and Steam Systems,2nd.Ed. 2011
3. BPOM RI ,Sarana Penunjang Kritis Industri Farmasi (2013)
Sand Filter,Carbon Filter,Softener
RO dan EDI Unit
PW Storage Tank,UV
Control Panel
Distiller
WFI Storage Tank
 Studi Kasus
• Departemen QC melaporkan bahwa hasil
pemeriksaan cemaran mikrobiologi PW yang
diambil sampelnya di ruang granulasi pada
tanggal 29 Agustus 2018 adalah 120 cfu/mL.
Tindakan apakah yang harus dilakukan oleh
industri tersebut ?