Water for Injection (WFI) by non-distillation technologies from April 2017 – Ph. Eur.

RO Water for Injection? Allowed by the European Pharmacopoeia from April 2017?

The European Pharmacopoeia Commission recently announced the revision of monograph 0169 to allow for generation of EP Water for Injection (WFI) “by a purification process equivalent to distillation such as reverse osmosis, coupled with appropriate techniques”. These changes will align the EP with the USP and JP. Before making changes to existing WFI processes, a manufacturer must inform the appropriate regulatory agency(ies). Slides from an April 2015 EDQM webinar on Reverse Osmosis in the monograph.

So are we really going to see RO Water for Injection?

The recent press release from the EDQM states that non-distillation technology for producing WFI should be “equivalent in quality to that produced by distillation, where equivalence in quality does not simply mean compliance with a specification but also takes into account the robustness of the production method”. The press release also indicates that the next revision of Annex 1 ‘Manufacture of sterile medicinal products will include new guidance on production methods for Water for Injection (WFI).

One the main delays in the publication of the revised Annex 1 draft relates to the issue of WFI production. The lack of specific GMP guidance on appropriate technologies in the PhEur monograph has driven Annex 1 contributors to provide additional guidance on the GMP requirements for WFI production. It is expected that Annex 1 will permit multi-effect and vapour-compression distillation, as well as certain (but definitely not all) membrane technologies.

This could be great news for the Sterile Pharmaceutical Industry

If combined with other cost-saving measures, such as cold storage/distribution and chemical sanitation, could the energy savings be used to implement additional innovative solutions such as Rapid Microbiological Methods (RMM) or continuous PAT like monitoring? Such approaches may result in reducing risk management requirements and help meet important environmental targets.

It should also be noted that several new techniques for pre-treatment of WFI feed water are emerging. As risks associated with deteriorating raw water quality are growing, some existing WFI systems have failed because pre-treatment is end-of-life, or inadequate for the changing water quality. New pre-treatment methods designed for longer life and harsher feed water conditions are coming to market.

Rapid Microbiological Methods and Water for Injection

The traditional sterility test, with its 14-day incubation, is impractical and expensive. In addition, sterility sampling is so infrequent that failure detection is often improbable. Consequently, it seems sensible to examine options for a Rapid Online Sterility Testing in a Water for Injection production, storage and distribution system.

The use of RMMs (rapid microbiological methods) is well supported by regulatory guidance documents (e.g. PAT and other regulatory guidance) and there are many systems and methods on the market, based on ATP Bioluminescence of micro-colonies. Examples of RMM systems currently on the market include the Milliflex® Rapid Microbiology Detection and Enumeration system for Water or the BIOTRAK® REAL-TIME VIABLE PARTICLE COUNTER (read previous PharmOut blog on our work with viable airborne monitoring and the turndown of clean rooms.)

Using such systems, it’s conceivable that a reduction from 14 days to 7 days until release could be achieved. Why 7 days? Well, the 7 days consists of 5 days incubation time of the Rapid Sterility Test and additional days to wait for the results of environmental monitoring, bioburden and other testing.

Regulatory Guidance on RMMs   

In regulatory guidance documents and in pharmacopoeia, more and more views on rapid methods are shared. For example, the 2-year FDA initiative “Pharmaceutical cGMPs for the 21st Century: A risk-based approach”, which was started in 2002 integrated RMMs into the PAT initiative.

Additionally, to that in 2004, the FDA Guidance for Industry “Sterile Drug Products Produced by Aseptic Processing- current Good Manufacturing Practice” stated the following sentence: “Other suitable microbiological test methods (e.g., rapid test methods) can be considered for environmental monitoring, in-process control testing, and finished product release testing after it is demonstrated that the methods are equivalent or better than traditional methods (e.g. USP).”  The validation for alternative microbiological methods should follow the guidance in [11, 13] and in [9].

FDA endorsement as an appropriate alternative to the compendial Sterility Test

Commercially available rapid microbiological methods were evaluated by FDA researchers on their ability to serve as basis for the development of a Rapid Sterility Test. Close proximity to the traditional test led to the endorsement of a growth-based method with ATP-(Adenosine triphosphate) Bioluminescence as the principle of detection.

The revised monograph for Water for Injections (0169) will be published in Supplement 9.1.

See the following YouTube video on how RO systems work.