EMEA Guideline on Water for Pharmaceutical Use Revised

GMP News No. 217

GMP News
3 August 2002
 

EMEAGuideline on Water for Pharmaceutical Use Revised

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

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

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

In table 5 titled 'Water Used for Cleaning/Rinsing', some modificationswere made in connection with sterile products. Now the CIP (Cleaning inPlace) procedure is also listed. For the initial rinse, only the waterquality 'purified water' is now required; higher qualities are notmandatory any more.

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

Water Present as an Excipient in the FinalFormulation

Table 1: Sterile Medicinal Products

Sterile medicinal products

Minimum Acceptablequality 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 acceptablequality 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 productsadministrated by nebulisation are required to be sterile andnon-pyrogenic. In such cases WFI or sterilised HPW should be used.

** For some products such as veterinary teat dips it may be acceptableto use potable water where justified and authorised taking accountof the variability in chemical composition and microbiological quality

Water Used During Manufacture of APIs andMedicinal 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 isolationand purification steps

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

Potable Water*

Fermentation media

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

Potable Water*

Extraction of herbals

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

Potable Water**

Final isolation and purification

No requirements for sterility or apyrogenicity in API or thepharmaceutical 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 controlof specified organisms

Final isolation and purification

API is sterile and apyrogenic

WFI

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

** The Applicant would need to demonstrate that potential variations inthe water quality, particularly with respect to minimal composition, wouldnot influence the composition of the extract

Table 4: Water Used During Manufacture of Medicinal Products Which IsNot 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 itmay be acceptable to use potable water where justified and authorisedtaking account of the variability in chemical composition andmicrobiological quality

Table 5: Water Used for Cleaning/Rinsing of Equipment, Containers andClosures (Revised)

In general, the final rinse used for equipment, containers/closuresshould use the same quality of water as used in the final stage ofmanufacture 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 andclosures, 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 inmanufacture of medicinal product, if higher quality than PurifiedWater

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 inmanufacture of medicinal product, if higher quality than PurifiedWater

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 needan initial rinse, indeed this may be counter-productive since particulatescounts could be increased as a result. In some cases e.g. Blow-fill-sealprocesses rinsing cannot be applied

*** If equipment is dried after rinsing with 70% alcohol, the alcoholshould be diluted in water of the same quality as the water used for thefinal rinse
 

**** Where a subsequent depyrogenisation step is employed the use ofHighly Purified Water may be acceptable subject to suitable justificationand validation data

 
Author:
Dr Andreas Mangel
CONCEPT HEIDELBERG

 

 

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