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Note for Guidance on Quality of Water

for Pharmaceutical use

The European Agency for the Evaluation of


Medical Products
Praphon Angtrakool
Food and Drug Administration
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Introduction

Water may be present as

An excipient

Used for reconstitution of products

During systhesis

During production of the finished product

As a cleaning agent for rinsing vessels, equipment.


Primary packaging materials, etc.
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Background (1)

A new Ph Eur. monograph entiled Highly Purified Water


has been adopted and will be implemented in the Ph Eur.
from 1st January 2002

WFI should be prepared only by distillation as laid down


in Ph Eur.

The CPMP/CVMP Quality Working Party and Inspections


Party have recently reconsidered the use of RO water for
preparation of WFI.

Background (2)

They have concluded on the available evidence, that the


production of water by RO and associated technologies
is considered to lack the robustness of distillation and
concerns remain about the potential risks associated
with, for examples, fouling of membrane (chemical and
biological), failure of membrane integrity and lack of
effective validation.

Hence the current view is that Highly Purified Water is


not acceptable for WFI.

Scope

This document is intended to provide guidance to the


industry on the pharmaceutical use of difference grades
of water in the manufacture of active pharmaceutical
ingredients and medicinal products for human and
veterinary use.

This guidance is not intended to cover situations where,


for example

Medicinal products are prepared extemporaneously.

Where preparations are reconstituted/diluted with water prior to


use by a pharmacist. (eg. Oral antibiotic mixtures)

In the case of veterinary products, by the user. (eg. Sheep drips)

Requirements of The European Pharmacopoeia

The European Pharmacopoeia provides standards for


the following grades of water

Water for Injections

Highly Purified Water

Purified Water
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Potable Water

Potable Water is not covered by a pharmacopoeial


monograph but must comply with the regulations on water
laid down by the competent authority.

Potable water may be used in chemical synthesis and in


the early stages of cleaning pharmaceutical manufacturing
equipment unless there are specific technical or quality
requirements for higher grades of water.
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Water for Injection

Water for Injection is water for the preparation of medicines


for parenteral administration when water is used as a
vehicle (water for injections in bulk) and for dissolving or
diluting substances or preparations for parenteral
administration before use. (sterilised water for injections)

Water for Injection complies with the tests for Purified


Water with additional for bacterial endotoxins (not more
than 0.25 IU of endotoxin per ml.), conductivity and Total
Organic Carbon.

Highly Purified Water

Highly Purified Water intended for use in the preparation


of products where water of high biological quality is
needed, except where Water for Injections is required.

Current production methods include, for example,


double-pass reverse osmosis coupled with other suitable
techniques such as ultra-filtration and de-ionization.

Highly Purified Water meets the same quality standards


as WFI but the production methods are considered less
reliable than distillation and thus it is considered
unacceptable for use as WFI.

Purified Water

Purified water is water for preparation of medicinal


products other than those that require the use of water
which is sterile and/or apyrogenic.

Purified water which satisfies the test for endotoxins may


be used in the manufacture of dialysis solution.

Purified water is prepared by distillation, by reverse


osmosis, by Ion exchange, by any other suitable method
from water that complies with the regulation on water
intended for human consumption laid down by the
competent authority.

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European Pharmacopoeia (2005)


Test

WFI

Highly Purified

Purified

NMT 0.5 mg/L

NMT 0.5 mg/L

NMT 0.5 mg/L

1.1 / 1.3 S-cm-1

1.1 / 1.3 S-cm-1

4.3 / 5.1 S-cm-1

Ammonium

NMT 0.2 ppm

---

---

Aluminium

---

NMT 10 ppb *

NMT 10 ppb *

Ca and Mg

Complies

---

---

NMT 0.1 ppm

NMT 0.1 ppm

NMT 0.1 ppm

---

NMT 0.2 ppm

NMT 0.2 ppm

Residue on evaporation

Complies

---

---

Particulate contamination

Complies

---

---

Total viable aerobic count

10 micro./ 100 ml.

10 micro./ 100 ml.

100 micro./ ml.

Complies

---

---

< 0.25 IU/ml

< 0.25 IU/ml

< 0.25 IU/ml *

Total organic carbon


Conductivity (20 o C / 25 o C)

Heavy metals
Nitrates

Sterility
Bacterial endotoxin

* If intended for use in the manufacture of dialysis solution

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Quality of Water for Pharmaceutical Use

Validation and qualification of water purification, storage


and distribution systems are a fundamental part of GMP
and form an integral of the GMP inspection.

The grade of water used should take account of the


nature and intended used of the finished product and
the stage at which the water used.
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Water present as an excipient in the final formulation

WFI is required for those products intended for parenteral


administration and this includes for haemofiltration and
haemodiafiltration, and peritoneal dialysis.

For convenience the pharmaceutical industry often uses


WFI for the preparation of ophthalmic, sterile nasal/ear
and cutaneous preparation.

In such situation, Highly Purified Water represents a


useful alternative with the added advantage of satisfying
the industrys need for large volume.

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Sterile Medicinal Products


Sterile medicinal products

Minimum acceptable quality of water

Parenteral

WFI

Ophthalmic

Purified

Haemofiltration Solutions
Haemodiafiltration Solutions

WFI

Peritoneal Dialysis Solutions

WFI

Irrigation Solutions

WFI

Nasal/Ear Preparations

Purified

Cutaneous Preparation

Purified
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Non-sterile Medicinal Products


Non-sterile medicinal products

Minimum acceptable quality of water

Oral Preparations

Purified

Nebuliser Solutions

Purified *

Cutaneous Preparations

Purified **

Nasal/Ear Preparations

Purified

Rectal / Vaginal Preparations

Purified

* In certain disease states eg. cystic fibrosis, medicinal products administered by


nebulisation are required to be sterile and non-pyrogenic. In such cases WFI or
sterilised Highly Purified Water should be used.
** For some products such as veterinary teat dips it may be acceptable to use potable
water where justified and authorised taking account of the variability in chemical
composition and microbiological quality.

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Water used during manufacture of APIs


and medicinal products

Excluding water present as an excipient in the final


formulation.

The acceptable grade of water will depend heavily on


the stage at which it is to be used during manufacture,
the subsequent processing steps and the nature of the
final product.

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Water used during the manufacture of


Active Pharmaceutical Ingredients (APIs) (1)
Type of
manufacture

Product requirements

Minimum
acceptable
quality of water

Synthesis of all
intermediates of APIs
prior to final isolation
and purification steps

No requirement for sterility or apyrogenicity


in API, or the pharmaceutical product in
which it will be use

Potable water *

Fermentation media

No requirement for sterility or apyrogenicity


in API, or the pharmaceutical product in
which it will be use

Potable water *

Extraction of herbal

No requirement for sterility or apyrogenicity


in API, or the pharmaceutical product in
which it will be use

Potable water **

Final isolation and


purification

No requirement for sterility or apyrogenicity


in API, or the pharmaceutical product in
which it will be use

Potable water *
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Water used during the manufacture of


Active Pharmaceutical Ingredients (APIs) (2)
Type of manufacture

Product requirements

Minimum
acceptable quality
of water

Final isolation and


purification

API is not sterile, but is intended for use in Purified Water


a sterile, non-parenteral product

Final isolation and


purification

API is sterile and not intended for


parenteral use

Final isolation and


purification

API is not sterile, but is intended for use in Purified Water with
a sterile, parenteral product
an endotoxin limit of
0.25EU/ml and
control of specified
organisms.

Final isolation and


purification

API is sterile and apyrogenic

Purified Water

Water For Injections

Purified Water should be used where there are technical requirement for greater chemical purity.

**

The Application would need to demonstrate that potential variations in the water quality, particularly with
respect to mineral composition, would not influence the composition of the extract.

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Water used during manufacture of medicinal products


which is not present in the final formulation
Manufacture

Minimum acceptable quality of water

Granulation

Purified *

Tablet coating

Purified

Used in formulation prior to


non-sterile lyophilisation

Purified

Used in formulation prior to


sterile lyophilisation

WFI

* For some veterinary premix products eg. granulated concentrates it may be acceptable
to use potable water where justified and authorised taking account of the API or used
as an excipient in a medicinal product.

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Water used for cleaning/rinsing of equipment,


containers and closures

In general, the final rinse used for equipment,


containers/closures should use the same quality of
water as used in the final stage of manufacture of the
API or used as an exipient in a medicinal product.
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Water used for cleaning/rinsing (1)


Cleaning/Rinsing of
Equipment, Containers,
Closures

Product type

Minimum Acceptable
quality of water

Initial rinse

Intermidiates and
API

Potable water

Final rinse

API

Use same quality of water as


used in the API manufacture

Potable water
Initial rinse including CIP* Pharmaceutical
of equipment, containers
products non-sterile
and closures, if applicable.
Purified Water or use same
Final rinse including CIP* Pharmaceutical
of equipment, containers
products non-sterile quality of water as used in
manufacture of medicinal
and closures, if applicable.
product, if highly quality than
Purified Water
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Water used for cleaning/rinsing (2)


Cleaning/Rinsing of
Equipment, Containers,
Closures
Initial rinse** including CIP*
of equipment, containers
and closures, if applicable.

Product type

Sterile products

Minimum Acceptable
quality of water
Purified Water

Final rinse*** including CIP* Sterile non-parenteral Purified Water or use same
quality of water as used in
of equipment, containers
products
manufacture of medicinal
and closures, if applicable.
product, if highly quality
than Purified Water
Final rinse*** including CIP* Sterile parenteral
products
of equipment, containers
and closures, if applicable.

WFI ****
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Water used for cleaning/rinsing (3)


*

CIP = Clean In Place

**

Some container, e.g. plastic containers for eyedrops may not


need an initial rinse, indeed this may be counter-productive since
particulates counts could be increased as a result. In some cases
e.g. blow-fill-seal processes rinsing cannot be applied.

*** If equipment is dried after rinsing with 70% alcohol, the alcohol
should be diluted in water of the same quality as the water used
for the final rinse.
**** Where a subsequent depyrogenisation step is employed the use
of Highly Purified Water may be acceptable subject to suitable
justification and validation data.

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Annex 3
WHO Good Manufacturing Practices :
Water for pharmaceutical use

WHO Technical Report Series, No. 929, 2005


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6. Water purification, storage and distribution systems


6.2 Materials that come into contact with systems for water
for pharmaceutical use

Suitable materials that may be considered for


sanitary elements of the system include :

316 L (low carbon) stainless steel

Polypropylene (PP)

Polyvinylidenedifluoride (PVDF)

Perfluoroalkoxy (PFA)

Other materials such as materials such as unplasticized polyvinylchloride (uPVC) may be used
for non-hygienic designed water treatment
equipment such as ion exchangers and softeners.

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6.5 Requirements for water distribution pipework (1)


6.5.3 Bio-contamination control techniques
The following control techniques may be used alone or
more commonly in combination.

Maintenance of continuous turbulent flow circulation within


water distribution systems reduces the propensity for the
formation of biofilms.

The maintenance of the design velocity for a specific system


should be proven during the system qualification and the
maintenance of satisfactory performance should be monitored.

During the operation of a distribution system, short-term


fluctuations in the flow velocity are unlikely to cause
contamination problems provided that cessation of flow, flow
reversal or pressure loss does not occur.

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6.5 Requirements for water distribution pipework (2)


6.5.3 Bio-contamination control techniques

(cont.)

The system design should ensure the shortest possible


length of pipework.

For ambient temperature systems, pipework should be


isolated from adjacent hot pipes.

Deadlegs in the pipework installation greater than 1.5


times the branch diameter should be avoided.

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6.5 Requirements for water distribution pipework (3)


6.5.3 Bio-contamination control techniques

(cont.)

Pressure gauges should be separated from the system


by membranes.

Hygienic pattern diaphragm valves should be used.

Pipework should be laid to falls to allow drainage.

The growth of microorganisms can be inhibited by :

ultraviolet radiation sources in pipework;

maintaining the system heated (guidance


temperature 7080 C);
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6.5 Requirements for water distribution pipework (4)


6.5.3 Bio-contamination control techniques

(cont.)

The growth of microorganisms can be inhibited by : (cont.)

sterilizing or sanitizing the system periodically using


superheated hot water or clean steam; and

routine chemical sanitization using ozone or other


suitable chemical agents. When chemical
sanitization is used, it is essential to prove that the
agent has been removed prior to using the water.
Ozone can be effectively removed by using
ultraviolet radiation.

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Total viable aerobic count test for WFI


European Pharmacopoeia (2005)

During production and subsequent storage, appropriate measures


are taken to ensure that the total viable aerobic count is
adequately controlled and monitored.

Appropriate alert and action limits are set so as to detect adverse


trends.

Under normal conditions, an appropriate action limit is a total


viable aerobic count (2.6.12) of 10 micro-organisms per 100 ml.
when determined by membrane filtration, using agar medium S,
using at least 200 ml. of water for injections in bulk and incubating
o

at 30 35 C for 5 days.

For aseptic processing, stricter alert limits may need to be applied.30

Total viable aerobic count test for Purified Water


European Pharmacopoeia (2005)

During production and subsequent storage, appropriate measures


are taken to ensure that the total viable aerobic count is
adequately controlled and monitored.

Appropriate alert and action limits are set so as to detect adverse


trends.

Under normal conditions, an appropriate action limit is a total


viable aerobic count (2.6.12) of 100 micro-organisms per milliliter,
determined by membrane filtration, using agar medium S and
o

incubating at 30 35 C for 5 days.

The size of the sample is to be chosen in relation to the expected


result.

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TOC test for Purified Water in Bulk


European Pharmacopoeia (2005)

In addition, the test for total organic carbon (2.2.44)


with a limit of 0.5 mg./L or alternatively the following
test for oxidisable substances is carried out : to 100 ml.
add 10 ml. of dilute sulphuric acid R and 0.1 ml. of
0.02 M potassium permanganate and boil for 5 min;
the solution remains faintly pink.
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Total viable count test, USP 28 (2005)


Methodologies that can be recommended as generally
satisfactory for monitoring pharmaceutical water system
are as follows :

Purified Water

Pour Plate Method

Minimum sample 1.0 ml.

Plate count agar 48 to 72 hours incubation at 30 - 35 C

Water for Injection

Membrane Filtration Method

Minimum sample 100 ml.

Plate count agar 48 to 72 hours incubation at 30 - 35 C

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Reference
1.

European Pharmacopoeia 5.0, 2005

2.

Note for Guidance on Quality of Water for Pharmaceutical use.


The European Agency for the Evaluation of Medical Products, 2002

3.

The United State Pharmacopoeia 28, 2005

4.

WHO Good Manufacturing Practices : water for pharmaceutical


use. In : WHO Expert Committee on Specification for
Pharmaceutical Preparations. Thirty-ninth report. Geneva, World
Health Organization, 2005, Annex 3 (WHO Technical Report
Series, No. 929)
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