To ensure the safety of medicinal products, legislators have transferred tasks and responsibilities to certain function owners. The individual prerequisites and areas of responsibility are described in the drug law.
The function owners include
External consultants also play an increasingly important role and their qualifications must therefore also be checked.
Michael Hiob, PhD
The European Pharmacopoeia (Ph. Eur.) and the American Pharmacopoeia (USP) describe requirements for purified water and water for injections (WFI). In addition, both pharmacopoeias describe further water qualities for special purposes.
Since 2017 the European Pharmacopoeia also permits the use of membrane systems for the production of WFI. Therefore, the water quality "highly purified water" was eliminated in supplement 9.7. Due to the fact that "HPW" can still be found in various marketing authorisation dossiers, this water quality is likely to be used in practice for even longer. In addition, there is still a need for discussion in industry as to how WFI can be produced exactly using cold processes. The regulatory situation is not clear.
Purified water is intended by the pharmacopoeia for the manufacture of preparations that do not have to be sterile or pyrogen-free. In addition, purified water is often used as a starting material for the production of water for injections.
Highly purified water was intended for the manufacture of preparations for which a high biological quality of the treated water is required, but water for injections was not required.
Water for injections is used for the preparation of medicinal products for parenteral use, the solvent of which is water (water for injections in bulk). It can also be used to dissolve or dilute substances or preparations for parenteral use (sterilised water for injections).
The quality of each type of water must be proven by a number of tests described in the monographs. Physical-chemical tests include the determination of conductivity, tests for certain ions and the determination of TOC. Microbiological monitoring is required for all water qualities.
There is no monograph for pharmaceutical steam in the European Pharmacopoeia. In contrast, the USP contains a monograph on pure steam.
Herbert Bendlin, PhD, Fritz Röder
When generating pharmaceutical water, drinking water is pre-treated to remove substances that are not desired during further processing. The pre-treatment processes include filtration, chemical stabilisation, UV irradiation and softening of the water using ion exchange. The processes that are used depend on the initial quality of the feed water. This is determined by water analysis.
To produce Purified Water, different processes are combined in so-called treatment plants. Reverse osmosis is widely used to produce Purified Water and is often combined with electro-deionisation.
Furthermore, the generation of water for injections (WFI) is explained in this chapter. For WFI, distillation was for a long time the sole method of production.
Since April 2017, the new Ph. Eur. monograph has applied to water for injection, which also permits the production of WFI using membrane technology. As a result of this change, the monograph for Highly Purified Water (HPW) was removed from the Ph. Eur. in April 2019. The advantages and possible risks of cold WFI production using membrane technology are discussed in detail.
The functionality and potential application of different technologies such as ion exchange, reverse osmosis, electro-deionisation, ultrafiltration and the various technologies used during distillation are described in detail and evaluated based on their advantages and disadvantages.
Herbert Bendlin, PhD, Fritz Röder
The qualification of a water treatment system is extremely comprehensive. Not only the design qualification, installation qualification and operational qualification are controlled, but data is also collected over a 1-year period as part of the performance qualification. The water can be released for pharmaceutical production 4–8 weeks after starting the performance qualification, provided that the values meet the predefined requirements. Nevertheless, with view to commercial and patient risks, it is suggested to complete the second phase of the performance qualification prior to release of any product.
A comprehensive and meaningful risk analysis which also describes the acceptance criteria for testing is the basis for all qualification testing. As is customary during the qualification process, a qualification plan is created and released for each phase before testing is carried out. The tests are documented in test records. After the tests are carried out, a report is created for each phase and the test records are attached to it. The report is evaluated and approved. After successful completion of one qualification phase, the next phase can begin. Deviations that occur must be checked.
Warning and action limits are defined for the performance qualification (PQ). They can be determined in a number of different ways. The type and frequency of sampling is also important for the PQ. If possible, the withdrawal method used during sampling should be used (e. g. withdrawal using a hose).
On 22 April 2022, a corrected version of Revision 18 was published, considering that Directive 2003/94/EC was repealed in exchange for Directive (EU) 2017/1572 (for human medicinal products) and Commission Delegated Regulation (EU) 2017/1569 (for investigational medicinal products for human use).
On 26 May 2022, the European IVDR (EU) 2017/746 (In vitro Device Regulation) entered into force. This is accompanied by various transitional periods and requirements.
With this date the following Directives ceased to apply:
The dates for the granted transition periods have been partially adjusted:
With the current update of the GMP Compliance Adviser we have reviewed and updated section G.2 on Canadian Regulations.
With the current update of the GMP Compliance Adviser we have reviewed and updated section G.6 on Australian Regulations.
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