"Note for Guidance on Quality of Water for Pharmaceutical Use"

GMP News No. 159

GMP News
8 January 2002
 

"Note for Guidance on Quality of Water for Pharmaceutical Use" 
- Final Version by the EMEA Committees for Proprietary Medicinal Products (CPMP) / Veterinary Medicinal Products (CVMP)

 
At the beginning of 2001, the draft of the "Note for Guidance on the Quality of Water for Pharmaceutical Use" was published and raised to be discussed by the pharmaceutical industry (see GMP News of 2 July 2001). The revised draft was accepted by CPMP/CVMP in November and is mandatory from 1 June 2002.

In comparison with the first draft, some important changes have been made. In general, the changes are given in bold print. This News will above all refer to the changes. Items that have not been modified can be found in the News of 2 July 2001.

Distillation is still the only method accepted for the manufacture of WFI. Compared with distillation, the reliability of other methods has still been considered as insufficiently proven. The new water quality Highly-Purified Water has already been referred to in July's News.

We would like to emphasise that the document is applied to waters both in the pharmaceutical production and in API manufacture. It does not refer to cases in which drugs are reconstituted on the spot by a pharmacist or a veterinary surgeon (e.g. antibiotic mixtures).

Water Quality: Potable Water
According to the Note for Guidance the basis for all pharmaceutical water qualities is potable water, the requirements on which are fixed by the competent authorities (the reference to the EU Directive 80/778/EC has been deleted). However, the potable water's quality should be checked on site by the pharmaceutical manufacturer. Potable water can also be used in chemical synthesis or in early cleaning stages, if no higher qualities are demanded.

Water Quality: WFI, Purified Water, Highly Purified Water
Here, the Note refers to the European Pharmacopoeia; as before, WFI may only be produced by means of distillation.

Water present as an excipient in the final formulation
In this field, some changes have been made. What is striking is the fact that Highly Purified Water is hardly required any more.

Table 1: Sterile medicinal products

Sterile medicinal products

Minimum Acceptable quality of Water

Parenteral

WFI

Ophthalmic

Purified

Haemofiltration Solution
Haemodiafiltration Solution

WFI

Peritoneal Dialysis Solutions

WFI

Irrigation Solutions

WFI

Nasal / Ear Preparations

Purified

Cutaneous Preparations

Purified

Table 2: Non-sterile medicinal products

Non-sterile medicinal product

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, e.g. cystic fibrosis, medicinal products administrated by nebulisation are required to be sterile and non-pyrogenic. In such cases WFI or sterilised HPW 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.

 

Water used during manufacture of Active Pharmaceutical Ingredients (APIs) and medicinal products excluding water present as an excipient in the final formulation

Table 3: Water used during the manufacture of APIs (revised)

Type of manufacture

Product requirements

Minimum acceptable quality of water

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

No requirements for sterility or apyrogenicity in API or the pharmaceutical product in which it will be used

Potable Water*

Fermentation media

No requirements for sterility or apyrogenicity in API or the pharmaceutical product in which it will be used

Potable Water*

Extraction of herbals

No requirements for sterility or apyrogenicity in API or the pharmaceutical product in which it will be used

Potable Water**

Final isolation and purification

No requirements for sterility or apyrogenicity in API or the pharmaceutical product in which it will be used

Potable Water*

Final isolation and purification

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

Purified Water

Final isolation and purification

API is sterile and not intended for parenteral use

Purified Water

Final isolation and purification

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

Highly Purified Water

Final isolation and purification

API is sterile and apyrogenic

WFI

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

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

Table 4: Water used during manufacture of medicinal products which is not present in the final formulation (revised)

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, e.g. granulated concentrates, it may be acceptable to use potable water where justified and authorised, taking account of the variability in chemical composition and microbiological quality.

 

Table 5: Water used for cleaning and rinsing of equipment, containers and closures (revised)

Cleaning / Rinsing of Equipment, Containers, Closures

Product type

Minimum acceptable quality of water

Initial rinse

Intermediates and API

Potable Water

Final Rinse

API

Use same quality of water as used in the API manufacture

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

Pharmaceutical products – non sterile

Potable Water

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

Pharmaceutical products – non sterile

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

Initial** rinse of containers / closures

Sterile products

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

Final rinse*** of containers / closures

Sterile non-parenteral products

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

Final rinse*** of containers / closures

Sterile parenteral products

WFI

* CIP = Cleaning in Place

** Some containers, 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.

 

Writer:
Dr Andreas Mangel, CONCEPT HEIDELBERG

 

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