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

GMP News No. 159

GMP News
8 January 2002
 

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

 
At the beginning of 2001, the draft of the "Note for Guidance on theQuality of Water for Pharmaceutical Use" was published and raised tobe discussed by the pharmaceutical industry (see GMP News of 2 July2001).The revised draft was accepted by CPMP/CVMP in November and is mandatoryfrom 1 June 2002.

In comparison with the first draft, some important changes have been made. In general, thechanges are given in bold print. This News will above all refer to thechanges. Items that have not been modified can be found in the News of2 July 2001.

Distillation is still the only methodaccepted for the manufacture of WFI. Compared with distillation, thereliability of other methods has still been considered as insufficientlyproven. The new water quality Highly-Purified Water has already beenreferred to in July's News.

We would like to emphasise that thedocument is applied to waters both in the pharmaceutical production and inAPI manufacture. It does not refer to cases in which drugs arereconstituted 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 waterqualities is potable water, the requirements on which are fixed by thecompetent authorities (the reference to the EU Directive 80/778/EC hasbeen deleted). However, the potable water's quality should be checkedon site by the pharmaceutical manufacturer. Potable water can also be usedin chemical synthesis or in early cleaning stages, if no higher qualitiesare demanded.

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

Water present as an excipient in thefinal formulation
In this field, some changes havebeen made. What is striking is the fact that Highly Purified Water ishardly required any more.

Table 1: Sterile medicinal products

Sterile medicinal products

MinimumAcceptable 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

Minimumacceptable 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. cysticfibrosis, medicinal products administrated by nebulisation are required tobe sterile and non-pyrogenic. In such cases WFI or sterilised HPW shouldbe used.

** For some products, such as veterinaryteat dips, it may be acceptable to use potable water where justified andauthorised, taking account of the variability in chemical compositionand microbiological quality.

 

Water used during manufacture of ActivePharmaceutical Ingredients (APIs) and medicinal products excluding waterpresent as an excipient in the final formulation

Table 3: Water used during themanufacture of APIs (revised)

Type of manufacture

Product requirements

Minimum acceptable quality of water

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

No requirements for sterility orapyrogenicity in API or the pharmaceutical product in which it willbe used

Potable Water*

Fermentation media

No requirements for sterility orapyrogenicity in API or the pharmaceutical product in which it willbe used

Potable Water*

Extraction of herbals

No requirements for sterility orapyrogenicity in API or the pharmaceutical product in which it willbe used

Potable Water**

Final isolation and purification

No requirements for sterility orapyrogenicity in API or the pharmaceutical product in which it willbe used

Potable Water*

Final isolation and purification

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

Purified Water

Final isolation and purification

API is sterile and not intended forparenteral use

Purified Water

Final isolation and purification

API is not sterile, but is intendedfor use in a sterile, parenteral product

Highly Purified Water

Final isolation and purification

API is sterile and apyrogenic

WFI

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

** The applicant would need todemonstrate that potential variations in the water quality, particularlywith respect to minimal composition, would not influence the compositionof the extract.

Table 4: Water used during manufacture ofmedicinal 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 tonon-sterile lyophilisation

Purified

Used in formulation prior tosterile lyophilisation

WFI

* For some veterinary premix products,e.g. granulated concentrates, it may be acceptable to use potable waterwhere justified and authorised, taking account of the variability inchemical composition and microbiological quality.

 

Table 5: Water used for cleaning and rinsingof 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 usedin the API manufacture

Initial rinse including CIP* ofequipment, containers and closures, if applicable

Pharmaceutical products – nonsterile

Potable Water

Final rinse including CIP* ofequipment, containers and closures, if applicable

Pharmaceutical products – nonsterile

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

Initial** rinse of containers /closures

Sterile products

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

Final rinse*** of containers /closures

Sterile non-parenteral products

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

Final rinse*** of containers /closures

Sterile parenteral products

WFI

* CIP = Cleaning in Place

** Some containers, e.g. plasticcontainers for eyedrops, may not need an initial rinse, indeed this may becounter-productive since particulates counts could be increased as aresult. In some cases, e.g. blow-fill-seal processes, rinsing cannot beapplied.

*** If equipment is dried after rinsingwith 70% alcohol, the alcohol should be diluted in water of the samequality as the water used for the final rinse.

 

Writer:
Dr Andreas Mangel, CONCEPT HEIDELBERG

 

 

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