10/11 March 2020
The revision of the European Pharmacopoeia (monograph 0169) will introduce in Europe as of April 2017 the possibility to produce WFI using other techniques than distillation - like in the USA and Japan. For example, it will be allowed to produce WFI by reverse osmosis or ultrafiltration. However, many questions are still unanswered like for example how the robustness of the new procedure compared to distillation should be demonstrated; that is to say how the procedural lower microbiological safety of the membrane process should be compensated via further parameters. The now published Paper "Questions and answers on production of water for injections by non-distillation methods - reverse osmosis and biofilms and control strategies" has been therefore highly anticipated.
The document is composed of two parts. The first one provides explanations for the use of reverse osmosis for the production of WFI and the second one, instructions to control and avoid biofilms.
For the EMA, it is problematic that reverse osmosis is usually operated at ambient temperature which is favourable for the formation of a biofilm. The water system should thus be designed in such a way as to minimise the risk of microbiological contamination. Here, the EMA quotes:
The paragraph describing the qualification of such a water system contains - by contrast - few concrete instructions. In the following paragraph, the document addresses sampling during qualification and operation. A sentence of the next paragraph is particularly interesting: It mentions the use of rapid microbiological methods as a prerequisite to the control strategy. The methods should include: rapid endotoxin testing and alternative methods in line with Ph.Eur 5.1.6. For the EMA, preventative maintenance - including of course regular inspections and replacing the membranes of the reverse osmosis module - is utmost important.
The second part of the paper which is more comparable to an article than a guidance document provides basic information on biofilms, e.g. what is a biofilm and which strategies can help avoid or minimise the spreading of a biofilm. Here, the document lists general elements like design of the water system, monitoring, qualification and CAPA system, without any further explanation. Indications to remove a biofilm are provided: chemical and physical. Furthermore, the document explains that it may be difficult to remove an already existing biofilm from the system. That's why here again the use of rapid microbiological methods is mentioned as it allows to react more rapidly to first microbiological impurities before a biofilm can be formed.
The paper can be commented on until 4 November. The Q&A document on the production of WFI by membrane procedure can be found on the EMA website.