Anfang des Jahres 2001 wurde der Draft der "Note for guidance on
quality of water for pharmaceutical use" veröffentlicht und der
Industrie zur Diskussion gestellt (siehe GMP-News
vom 25. Juni 2001). Der
überarbeitete Entwurf wurde vom CPMP/CVMP im November angenommen (GMP-News vom
21. Dezember 2001) und tritt zum 1. Juni 2002 in Kraft.
Auf Drängen der Industrie wurden nun nachträglich noch in den
Tabellen 3 und 5 einige Änderungen vorgenommen (orange hinterlegt).
In Tabelle 3 wurde bei nichtsterilen Wirkstoffen, die aber für die
Zubereitung von Parenteralia verwendet werden, bei der Schlussisolierung
und –reinigung die Wasserqualität "Highly Purified Water"
durch "Purified Water with an endotoxin limit of 0,25 EU/ml and
control of specified organisms" ersetzt.
Bei Tabelle 5 "Wasser für Reinigung und zum Spülen" haben
sich bei den sterilen Produkten einige Änderungen ergeben. Aufgeführt
wurde hier jetzt auch das CIP (Cleaning in Place) Procedere. Für die
anfängliche Spülung wird jetzt nur noch die Wasserqualität
"Purified Water" verlangt, höhere Wasserqualitäten müssen
nicht mehr verwendet werden.
Beim "Final Rinse" von "Sterilen parenteralen
Produkten" wird nach wie vor die Wasserqualität WFI gefordert, es
kann aber auch die Wasserqualität "Highly Purified Water"
verwendet werden, wenn ein späterer Depyrogenisierungsschritt angewendet
wird und der Gebrauch von "Highly Purified Water" durch
Validierungsdaten gesichert ist.
Tabelle 1: Sterile Produkte
|
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 |
Tabelle 2: Nichtsterile Produkte
|
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
Produktionswasser (Wirkstoffe und Pharmafertigung); nicht aber als
Bestandteil des Produkts
Tabelle 3: Wasser bei der Herstellung von APIs (neu gefasst)
|
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 potenial variations in
the water quality, particulary with respect to minimal composition, would
not influence the composition of the extract
Tabelle 4: Wasser, das bei der Pharmaherstellung verwendet wird, aber nicht im Endprodukt
enthalten ist (neu gefasst)
|
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
Tabelle 5: Wasser für die Reinigung und das Spülen von Ausrüstung,
Behältern und Verschlüssen (neu gefasst)
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
