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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
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