The current thinking about Rapid Microbiological Methods and PAT

GMP News No. 723

GMP News
10 May 2006

Thecurrent thinking about Rapid Microbiological Methods and PAT

ECA's Masterclass "PAT in MicrobialQC" inspired Dr Peter Ball, Pall Europe, to summarize the currentthinking on introducing rapid microbiological methods.

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

The European Compliance Academy held a training course on ProcessAnalytical Technology (PAT) and Rapid Microbiology in Berlin on January25-27. The very high level of interest in this topic is evident from thehigh attendance at this meeting (32 people from around Europe). Several ofthe presentations addressed practical aspects of using Rapid Microbiologyas a tool for implementing PAT. A few also addressed some of thephilosophical challenges that are evident when considering the adoption ofRapid Microbiology as part of a program to implement PAT. These challengesare important to consider and debate because - when reviewed at the mostbasic level - there are two main chains of thought about where RapidMicrobiology can fit into modern pharmaceutical manufacturing.

One chain of thought argues that Rapid Microbiology is fully consistentwith (and supportive of) the objectives of PAT. In this argument, RapidMicrobiology is currently a much more rapid to near real-time tool fordelivering microbiological data. According to this model, a process ofimplementing existing methods and (re)developing and validating newtechnologies for use in Pharmaceutical manufacturing will lead to thecurrent compendial methods (which are clearly far too slow and impreciseto be consistent with the aims and objectives of PAT) being replaced bynew rapid methods. Further, this model argues that as methods becomecloser to real-time and on-line, microbiological monitoring will move frombeing focused on final product testing to a proactive PAT-orientatedstrategy.

The second chain of thought, argued cogently in a recent article in thePharmaceutical Microbiology Forum Newsletter (see link below) is that aPAT strategy cannot replace testing of finished product from amicrobiological standpoint. This argument is based on the view that thereare no adequate process controls to demonstrate product sterility or othermicrobiological attributes of the finished product. Further, the articleargues that, because of the need to demonstrate microbiological quality ofthe finished product, real-time release (RTR) cannot be achieved under thecurrent regulatory climate except through parametric release ofterminally-sterilised products. Lastly, the article argues that RTR cannotbe achieved for aseptically produced products or for non-sterile productswithout a rapid test method that addresses the microbiologicalspecifications for the finished product.

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

'Data derived from manufacturing process validation studies and fromin-process controls may provide greater assurance that a batch meets aparticular monograph requirement than analytical data derived from anexamination of finished units drawn from that batch. On the basis of suchassurances, the analytical procedures in the monograph may be omitted bythe manufacturer in judging the compliance of the batch with thePharmacopeial standards'.

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

'Other suitable microbiological test methods can be considered forenvironmental monitoring, in process control testing, and finished productrelease testing after it is demonstrated that the methods are equivalentor better than traditional methods (e.g.USP)'.

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

Perhaps if the challenges of obtaining and analysing environmentalsamples can be better addressed and in a way that allows more accurate andmeaningful measurements of in-process microbiological data to be obtainedusing Rapid Microbiology, the emphasis will indeed shift from using rapidmethods as a tool focused on finished product release towards a tool fullyaligned with PAT ?


  • Newby, P.,G. Dalmaso, S. Lonardi, B. Riley, P. Cooney and K. Tyndall(2004). Qualitative Rapid MicrobiologicalMethods for Drug-Product Testing. Pharmaceutical Technology: 6-12


Dr Peter Ball
Pall Europe

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

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

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



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