EMEA Guideline on Water for Pharmaceutical Use Revised

GMP News No. 217

GMP News
3 August 2002
 

EMEA Guideline on Water for Pharmaceutical Use Revised

 
At the beginning of 2001, the draft of the "Note for guidance on quality of water for pharmaceutical use" was published so that the industry could comment on it (see GMP News of 2 July 2001). The revised draft was adopted by CPMP/CVMP in November (GMP News of 8 January 2002) and came into operation on 1 June 2002.

Upon requests on the part of the industry, some changes were made to the tables 3 and 5 (marked in orange) even after the adoption by CPMP/CVMP.

In table 3, regarding the manufacture of non-sterile APIs that are intended for use in a sterile parenteral product, the requirement of 'highly purified water' was replaced by 'purified water with an endotoxin limit of 0,25 EU/ml and control of specified organisms'.

In table 5 titled 'Water Used for Cleaning/Rinsing', some modifications were made in connection with sterile products. Now the CIP (Cleaning in Place) procedure is also listed. For the initial rinse, only the water quality 'purified water' is now required; higher qualities are not mandatory any more.

For the final rinse of sterile parenteral products, the water quality WFI is still required. However, the water quality 'highly purified water' can be used in case a subsequent depyrogenisation step is applied and the use of 'highly purified water' is justified through validation data.

Water Present as an Excipient in the Final Formulation

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 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

Purified Water with an endotoxin limit of 0,25 EU/ml and control of specified organisms

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/Rinsing of Equipment, Containers and Closures (Revised)

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 excipient in a medicinal product.

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

Sterile products

Purified

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

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

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
 

**** Where a subsequent depyrogenisation step is employed the use of Highly Purified Water may be acceptable subject to suitable justification and validation data

 
Author:
Dr Andreas Mangel
CONCEPT HEIDELBERG

 

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