4.Quality of Water

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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.

44

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.

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

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

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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.

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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.

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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

Total organic carbon NMT 0.5 mg/L NMT 0.5 mg/L NMT 0.5 mg/L

Conductivity (20 o C / 25 o C) 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 --- ---

Heavy metals NMT 0.1 ppm NMT 0.1 ppm NMT 0.1 ppm

Nitrates --- 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.

Sterility Complies --- ---

Bacterial endotoxin < 0.25 IU/ml < 0.25 IU/ml < 0.25 IU/ml *

* 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 SolutionsHaemodiafiltration 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 requirementsMinimum

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 Potable water *

Extraction of herbal Potable water **

Final isolation and purification

Potable water *

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Water used during the manufacture of Active Pharmaceutical Ingredients (APIs) (2)

Type of manufacture Product requirementsMinimum

acceptable quality of water


API is not sterile, but is intended for use in a sterile, non-parenteral productAPI is sterile and not intended for parenteral use


API is not sterile, but is intended for use in a sterile, parenteral product

Purified Water with an endotoxin limit of 0.25EU/ml and control of specified organisms.

API is sterile and apyrogenic

Purified Water


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,

ClosuresProduct type Minimum Acceptable

quality of water

Initial rinse Intermidiates and API

API

Pharmaceutical products non-sterile

Pharmaceutical products non-sterile

Potable water

Final rinse Use same quality of water as used in the API manufacture

Initial rinse including CIP* of equipment, containers and closures, if applicable.

Potable water

Final rinse including CIP* of equipment, containers and closures, if applicable.

Purified Water or use same quality of water as used in manufacture of medicinal product, if highly quality than Purified Water

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Cleaning/Rinsing of Equipment, Containers,

ClosuresProduct type

Minimum Acceptable quality of water

Initial rinse** including CIP* of equipment, containers and closures, if applicable.

Sterile products

Sterile non-parenteral products

Final rinse*** including CIP* of equipment, containers and closures, if applicable.

Sterile parenteral products

WFI ****

Purified Water

Final rinse*** including CIP* of equipment, containers and closures, if applicable.

Purified Water or use same quality of water as used in manufacture of medicinal product, if highly quality than Purified Water

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* 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.

2424WHO Technical Report Series, No. 929, 2005

Annex 3WHO Good Manufacturing Practices : Water for pharmaceutical use

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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 un-plasticized 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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6.5.3 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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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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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 WFIEuropean 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 at 30 35 o C for 5 days.

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

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Total viable aerobic count test for Purified WaterEuropean 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 incubating at 30 35 o 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 BulkEuropean 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 o C

Water for Injection Membrane Filtration Method

Minimum sample 100 ml.

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

Note for Guidance on Quality of Water for Pharmaceutical useIntroductionBackground (1)Background (2)ScopeRequirements of The European PharmacopoeiaPotable WaterWater for InjectionHighly Purified WaterPurified WaterEuropean Pharmacopoeia (2005)Quality of Water for Pharmaceutical UseWater present as an excipient in the final formulationSterile Medicinal ProductsNon-sterile Medicinal ProductsWater used during manufacture of APIs and medicinal productsWater used during the manufacture of Active Pharmaceutical Ingredients (APIs) (1)Water used during the manufacture of Active Pharmaceutical Ingredients (APIs) (2)Water used during manufacture of medicinal products which is not present in the final formulationWater used for cleaning/rinsing of equipment, containers and closuresWater used for cleaning/rinsing (1)Water used for cleaning/rinsing (2)Water used for cleaning/rinsing (3)6. Water purification, storage and distribution systems6.5 Requirements for water distribution pipework (1)6.5 Requirements for water distribution pipework (2)6.5 Requirements for water distribution pipework (3)6.5 Requirements for water distribution pipework (4)Total viable aerobic count test for WFIEuropean Pharmacopoeia (2005)Total viable aerobic count test for Purified WaterEuropean Pharmacopoeia (2005)TOC test for Purified Water in BulkEuropean Pharmacopoeia (2005)Total viable count test, USP 28 (2005)

4.Quality of Water

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