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 ?
Reference
- 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.
Author:
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)
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