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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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