On 05 August 2016 the EMA published a Q&A paper on production of water for injections (WFI) by non-distillation methods, which the European pharmacopoeia recently approved in the revised WFI monograph. The document is intended to provide assistance in using reverse osmosis (Part I) and to give detailed information on controlling biofilms (Part II).
However, in many places the paper is kept rather general.
We have asked our author Fritz Röder for his opinion on the new document. Don’t miss his interesting replies, which reflect his in-depth experience with the installation and operation of water systems.
Actually, the EMA document is supposed to facilitate implementation of the rewritten WFI monograph of the European pharmacopoeia. But you have noticed a number of items that cannot readily be implemented in practice and that are in need of clarification. Would you tell us what they are?
Yes, the Q&A paper leaves me with the impression that one or the other detail could have been more clearly stated. There are numerous ambiguities or at least items in need of further discussion.
- For example, the distribution system should be sterilisable by steam “along with other sanitisation methods”. This probably means an additional ozonisation. However, that is not easy to implement in practice. Especially the heat resistance of many components such as ozone generators, relevant measuring instruments and UV systems should be checked. Where appropriate these parts must be excluded from sterilisation.
- There is also reference to steam-resistant reverse-osmosis membranes (capable of withstanding heat up to 120°C). This falls within the context of the potential bacterial contamination of the membrane surfaces. However, such membranes are not yet available. Currently available membranes can withstand up to 85°C.
- Sampling: Daily samples should be taken throughout the distribution system from sampling points, if used. This is very work intensive and costly, and it could amount to a knockout criterion for this method. Demands from industry for alternative manufacturing methods for WFI arose to no small degree from the potential savings offered by the membrane method. Demanding such intensive sampling would be enough to alienate many pharmaceutical manufacturers. But costs could be reduced by application of rapid microbiological methods. Particularly bacteria counting devices with multiple sample inputs would be decisive here for an economically feasible calculation.
- What’s more, the document explicitly recommends using “rapid microbiological methods”. The monograph of the European pharmacopoeia becomes interesting in relation to the rapid methods. The monograph specifically calls for conventional processes, namely incubation. Therefore, the Q&A document refers to the European pharmacopoeia 5.1.6 (Alternative Methods). U.S. regulatory works do not have this acceptance problem (see USP 1223 and 1231). Accordingly, at present the rapid methods can be approved solely for use in addition to sampling and not as a replacement for the classic methods.
- Statements on trending are inconsistent: At one and the same time it is indicated that the trending frequency is critical (line 388) and that it should take place on an annual basis at most (line 377). Trending is ordinarily performed with the PQR. How trending can reasonably take place more often than annually remains unclear. Seasonal changes in the water should be detected, and to do this it is necessary to have an overview of an entire year, including statistical evaluation. What can be done more often is the collection of data.
The second part of the document concentrates on controlling biofilms. Are there helpful hints on this?
The second part is kept general for the most part. No information is found in it that is not already included, for example, in the new version of USP 1231 “Water for Pharmaceutical Purposes”. More detailed information is available here: https://www.gmp-publishing.com/en/new-releases/the-new-usp-1231.html
In your opinion are there any important topics that are not addressed at all in the Question-and-Answer paper?
One important topic that is not mentioned is “operation and maintenance”. The effort involved would clearly be more intensive than in the case of conventional systems for producing purified water (not WFI). This topic should be discussed in detail, as it, too, entails a block of costs that should not be underestimated. After all, a pharmaceutical entrepreneur will only display innovative behaviour and use recently approved technologies if it is economically feasible to do so.
The deadline for comments is 4 November 2016. With a view to the numerous ambiguities all stakeholders should exercise this option.
EMA/INS/GMP/489331/2016: Questions and answers on production of water for injections by non-distillation methods – reverse osmosis and biofilms and control strategies
This interview was conducted by our editor Dr. Sabine Paris with
The Download The New USP <1231>: Water for Pharmaceutical Purposes highlights the following aspects of the new USP <1231>:
- Short Overview – What is USP<1231> and what is new?
- Detailed overview with explanations and important notes
- Source water considerations
- Monographs of water qualities
- Validation and qualification of water systems
- Design and operation of water systems
- Chemical Evaluations
- Microbial evaluations
- Alert and action levels and specifications