Day-2, Session -7.

“Pharmacopoeial requirements for

Pharmaceutical water”
(35m)

Speaker - Sumant Baukhandi, PhD

Pharmacopoeial Requirements

†EP requirements
†USP requirements
†Key points
†Monitoring
†Control
 Pharmacopoeial Requirements
EP – 3 Types of Waters:
 Purified Water - monograph
 High Purified Water - monograph
 Water for Injections - monograph

 Potable Water – is not covered by a monograph,

but must comply with the standards laid down by
the competent authority
Pharmacopoeial Requirements
USP – 8 Types of Waters:
1. Non-potable
2. Potable (drinkable) water
3. USP purified water
4. USP water for injection (WFI)
5. USP sterile water for injection
FPs
6. USP sterile water for inhalation as
per
7. USP bacteriostatic water for injection USP
8. USP sterile water for irrigation
 Pharmacopoeial Requirements
EP - Purified Water:
 PUW is used for preparation of medicinal products
other than those that require water which is sterile
and / or apyrogenic
 PUW which satisfies the test for endotoxins may be
used in the manufacture of dialysis solutions
 Prepared by distillation, by ion exchange or by any
other suitable method
 Pharmacopoeial Requirements
USP – Purified Water:
PUW is used as an excipient in production
of non-parenteral preparations and in other
pharmaceutical applications,
such as cleaning of certain equipment and
non-parenteral product-contact components
PUW must meet the requirements for ionic
and organic chemical purity and must be
protected from microbial contamination
 Pharmacopoeial Requirements
USP – Purified Water:
PUW should be tested for Conductivity, TOC,
microbiological quality
For the sake of purity comparison, the
analogous Stage 1 and 2 conductivity
requirements for Purified Water at 25 0C are
1.3 µS/cm and 2.1 µS/cm, respectively
 Feed is Drinking Water - This water may be purified
using unit operations that include de-ionization,
distillation, ion exchange, reverse osmosis, filtration, or
other suitable purification procedures
Purified Water System Skid
 Pharmacopoeial Requirements
EP – Highly Purified Water:
 HPW is intended for use in the preparation of
medicinal products where water of high biological
quality is needed, except where WFI is used
 Current production methods include double pass
Reverse Osmosis coupled with other suitable
techniques, such as ultra-filtration and
(Electro)de-ionization
 It meets the same quality standards as WFI but its
production methods are considerably less reliable
than the multiple distillation for WFI, and
consequently not used as WFI
 Pharmacopoeial Requirements
USP – Highly Purified Water:
 HPW is intended for use in the preparation of
medicinal products where water of high biological
quality is needed, except where WFI is used
 It uses materials that are highly efficient de-ionizers
and that do not contribute copper ions or organics to
the water, assuring a very high quality water.
 It meets the same quality standards as WFI but its
production methods are considerably less reliable than
the multiple distillation for WFI, and consequently not
used as WFI
 Bioburden 10 CFU / 100 mL
 Pharmacopoeial Requirements
USP – Highly Purified Water:
 It is water that is prepared by deionizing previously
distilled water, and then filtering it through a 0.45-
µm rated membrane. This water must have an in-
line conductivity of not greater than 0.15 µS/cm
(6.67 Megohm-cm) at 25 0C
 If the water of this purity contacts the atmosphere
even briefly as it is being used or drawn from its
purification system, its conductivity will immediately
degrade, by as much as about 1.0 µS/cm, as
atmospheric carbon dioxide dissolves in the water
and equilibrates to bicarbonate ions
 Pharmacopoeial Requirements
EP –Water for Injection:
 WFI is the water for preparation of medicines
for parenteral administration when water is
used as a vehicle (WFI in bulk) and
 for dissolving or diluting substances or preparations for
parenteral administration before use (sterile WFI)
 It complies with monograph of PUW with
additional requirements for BET (0.25 IU of
En/mL), conductivity & TOC
 Multiple distillation is the only official method for
WFI generation
 Pharmacopoeial Requirements
USP –Water for Injection:
 WFI is used as an excipient in production of
parenteral and other preparations, where
product endotoxin content must be controlled,
and in other pharmaceutical applications, such as
cleaning of certain equipment and parenteral product-
contact components
 It complies with all chemical requirements of
the monograph of PUW as well as an
additional bacterial endotoxin specification
Reference: USP <1231>
 Pharmacopoeial Requirements
Validation
 The pharmacopoeias recommend validating the water
system, adequately
 Validation to include sampling from points identified as
critical
 Sampling methodology
 Testing methodology – Dilution plate or membrane
filtration – which is the method of choice
 Microbiological test media – nutrient / R2A agar
 Incubation conditions
 Evaluation
 Pharmacopoeial Requirements
Contamination Control
 The pharmacopoeias recommend adequate control of
microbial contamination
 Effective systems to minimize microbial pass &
propagation at different stages of treatment
 Effective storage, distribution, sanitization
 UV treatment – dose, exposure
 Ozone treatment
 Other technology requirements regarding – material of
construction, vent filters, welds quality, sanitary fittings,
slopes, surface finish, dead legs, re-circulation loop, etc..
 Periodic inspection of the system
 Change control management
 Water System – Biofilms

• Major Concern is Bio-films:

• Microbial settling & colonizing on pipe surfaces
• Mainly Pseudomonas species
• Surface pits provide cavities for initial settlers
• Biofilms are a collection of micro-organisms surrounded by a matrix
(slime layer that they secrete), which forms on surfaces in contact
with water
Biofilm formation and growth

O2

Biofilm

• Quorum sensing and chemical signaling

• Microcolonies with extracellular matrix
• Network of channels
• Cells experience different environmental conditions
• Multi-species
 Biofilm formation and growth
Given the heterogeneity of the environment, how is the
bio-film community structured?
There is a strong relationship between the cell’s
environment and its physiology and structure.

Biofilm Nutrient levels Variety of environmental

decrease towards niches form
formation the center Science
News
Biofilm in Automated water systems

The above figure shows that the surface

irregularities in such a finish are large enough to
harbor several layers of Pseudomonas aeruginosa
 Pharmacopoeial Requirements
Monitoring
 The pharmacopoeias recommend adequate monitoring
program for water system
 This includes established written SOPs for sampling,
monitoring of water samples, periodically
 Scientific rationale
 Sampling plan – based on risks of contamination and
criticality of use -
 Sampling methodology
 Testing methodology – Dilution plate or membrane
filtration – which is the method of choice
 Microbiological test media – nutrient / R2A agar
 Incubation conditions
Pharmacopoeial Requirements
۩ References:
2. EMEA Guidance – Water for Pharmaceutical
Purposes
3. EP
4. USP General Chapter <1231) - Water for
Pharmaceutical Use
5. USFDA Guidance – High Purity Water (1993)
 THANKS!
For inquiries please contact –
Sumant Baukhandi, PhD

Director – Pharma Institute of GMPs,

Director – pharmaACCESS

7, Phase-1, Vasant Vihar,

Dehradun-246 006
Uttaranchal State, INDIA

Landphone: 91-135 276 3092

Cellphone: 91- 99970 10901
Email ID: pigmpinstt@gmail.com ;
sumant091154@rediffmail.com

Website: www.pigmp.com