The current thinking about Rapid Microbiological Methods and PAT

GMP News No. 723

GMP News
10 May 2006

The current thinking about Rapid Microbiological Methods and PAT

ECA's Masterclass "PAT in Microbial QC" inspired Dr Peter Ball, Pall Europe, to summarize the current thinking on introducing rapid microbiological methods.

Please read the following article to get a better understanding of the different philosophies that exist in the industry as well as at regulatory agencies:

The European Compliance Academy held a training course on Process Analytical Technology (PAT) and Rapid Microbiology in Berlin on January 25-27. The very high level of interest in this topic is evident from the high attendance at this meeting (32 people from around Europe). Several of the presentations addressed practical aspects of using Rapid Microbiology as a tool for implementing PAT. A few also addressed some of the philosophical challenges that are evident when considering the adoption of Rapid Microbiology as part of a program to implement PAT. These challenges are important to consider and debate because - when reviewed at the most basic level - there are two main chains of thought about where Rapid Microbiology can fit into modern pharmaceutical manufacturing.

One chain of thought argues that Rapid Microbiology is fully consistent with (and supportive of) the objectives of PAT. In this argument, Rapid Microbiology is currently a much more rapid to near real-time tool for delivering microbiological data. According to this model, a process of implementing existing methods and (re)developing and validating new technologies for use in Pharmaceutical manufacturing will lead to the current compendial methods (which are clearly far too slow and imprecise to be consistent with the aims and objectives of PAT) being replaced by new rapid methods. Further, this model argues that as methods become closer to real-time and on-line, microbiological monitoring will move from being focused on final product testing to a proactive PAT-orientated strategy.

The second chain of thought, argued cogently in a recent article in the Pharmaceutical Microbiology Forum Newsletter (see link below) is that a PAT strategy cannot replace testing of finished product from a microbiological standpoint. This argument is based on the view that there are no adequate process controls to demonstrate product sterility or other microbiological attributes of the finished product. Further, the article argues that, because of the need to demonstrate microbiological quality of the finished product, real-time release (RTR) cannot be achieved under the current regulatory climate except through parametric release of terminally-sterilised products. Lastly, the article argues that RTR cannot be achieved for aseptically produced products or for non-sterile products without a rapid test method that addresses the microbiological specifications for the finished product.

From references cited in the PMF Newsletter article (and elsewhere) compendial and regulatory support for an alternative strategy to finished product testing is evident. For example, the United States Pharmacopeia volume 28 (January 2005) General Notices and Requirements Page 7, Procedures states:

'Data derived from manufacturing process validation studies and from in-process controls may provide greater assurance that a batch meets a particular monograph requirement than analytical data derived from an examination of finished units drawn from that batch. On the basis of such assurances, the analytical procedures in the monograph may be omitted by the manufacturer in judging the compliance of the batch with the Pharmacopeial standards'.

Regulatory support for the use of Rapid Microbiology, including the use of rapid methods as an in-process monitoring tool, is also evident. To take one example, the FDA CDER guideline 'Sterile Drug Products Produced by Aseptic Processing' (September 2004) states:

'Other suitable microbiological 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)'.

As described the PMF Newsletter article, the first approvals for a rapid test method, which was granted under the FDA CDER PAT initiative, were for release tests1. Perhaps this is not surprising as there are challenges to implementing rapid methods for in-process monitoring that go beyond philosophy. These include the challenges of recovering microorganisms from the environment (surfaces and air) and processing these samples in a simple and robust way prior to using any of the existing rapid microbiological methods.

Perhaps if the challenges of obtaining and analysing environmental samples can be better addressed and in a way that allows more accurate and meaningful measurements of in-process microbiological data to be obtained using Rapid Microbiology, the emphasis will indeed shift from using rapid methods as a tool focused on finished product release towards a tool fully aligned with PAT ?


  • Newby, P.,G. Dalmaso, S. Lonardi, B. Riley, P. Cooney and K. Tyndall (2004). Qualitative Rapid Microbiological Methods for Drug-Product Testing. Pharmaceutical Technology: 6-12
  • Please click here to read the mentioned PMF Newsletter article.

    Dr Peter Ball
    Pall Europe

    ECA would like to thank Dr Peter Ball for his support of ECA's activities to encourage the use of rapid microbiological methods in the pharmaceutical industry.

    Mike Edgington
    Director of Regulatory Affairs
    European Compliance Academy (ECA)

    With regards to microbiology, the European Compliance Academy offers the following courses:
    Microbiology for Non-Microbiologists, 19.-20. October 2006 in Berlin, Germany,
    Microbial Contamination - Corrective Actions, Preventive Actions, 23.-24. November 2006 in Vienna, Austria. 


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