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David Myatt, PhD and Charlotte Morgan, PhD, BTF, a bioMrieux company
What value are plant isolates in microbiological quality in the pharma industry?
Increasingly, pharmaceutical companies are including their own isolates in the battery of microorganisms that they
use for media growth promotion testing and validation studies. These plant isolates are wild-type strains isolated
during environmental monitoring, sterility and bioburden testing, and routine testing for contamination or spoilage. In so
doing, these companies seek best microbiology practice, but it remains somewhat controversial. Some commentators
argue that compendial methods do not mandate such an approach, others challenge its scientific merit, and some
query the practicality. Notwithstanding a level of public debate, many companies are implementing standard operating
procedures and grappling with the practicalities of strain selection, culture maintenance that sustains the cultural
characteristics of wild plant isolates, a degree of regulatory uncertainty and, certainly, a paucity of guidance on
how to achieve the desired outcome, whether that is simply compliance or genuine commitment to more challenging
tests in pharmaceutical quality management.
30 Letter July/August 2011
ommendations in this regard are made in
Wild-type Strains guidelines issued by several authorities:
By definition, strains found in nature. But in our context, we mean to discuss Concerning the microbiological evalu-
strains that are recently-isolated in a manufacturing context, either from a con- ation of controlled environments, USP
trolled manufacturing environment or, perhaps, a contaminant of raw materials <1116> says for the Growth Promotion
or finished pharmaceutical product. These are strains that are not conditioned test, representative microflora isolated
through serial subculture to growth on rich laboratory culture media and may ex- from the controlled environment
hibit unstable phenotypic characteristics associated with oligotrophy, desiccation may also be used to test media.
or biofilm formation, namely traits that have enabled survival in harsh conditions
USP <1117> concerning Microbiolog-
and may not persist in strains that are serially passaged in rich culture media un-
characteristic of the environment from where they were isolated. ical Best Laboratory Practice suggests
microorganisms used in growth-pro-
motion testingmay include repre-
Trends in Use of Wild Isolates compliance (i.e., what auditors want) or sentative environmental isolates (but
best laboratory practice, even if they do these latter are not to be construed as
Lets begin by agreeing that this really
not subscribe to the view that the use of compendial requirements).
isnt anything new! Authorities on qual-
ity in pharmaceutical microbiology have these strains is a valuable exercise in veri- FDA Guidance for Industry for Sterile
been suggesting the merit of including fying the performance of their culture Drug Products Produced by Aseptic Pro-
wild-type isolates in media QC testing media or test methods. It certainly seems cessing Current Good Manufacturing
for many years (1, 2, 3) and auditors that there is now a widely-perceived Practice (September 2004) says The
now issue FDA 483 observations in re- need for compliance here (in the absence QC laboratory should determine if
lation to this expectation.(4) Certainly, of an FDA audit citation) given that the USP indicator organisms sufficiently
its become a topical matter in recent use of environmental isolates is strongly represent production-related isolates.
years, with periodic debate in industry recommended in a number of compen- Environmental monitoring and steril-
discussion forums and blogging sites.(5, dial references and other authoritative ity test isolates can be substituted (as
6, 7) While perspectives on the scientific documents. appropriate) or added to the growth
merits vary, and whether its a function It is also commonplace to see manufac- promotion challenge.
of regulatory attention or best micro- turers of personal care products and nu- FDA Guidance for Industry concerning
biological practice, use of plant isolates traceuticals include extensive batteries of Validation of Growth-Based Rapid Mi-
(or whatever you choose to call them) contaminant organisms (isolated from crobiological Methods for Sterility Testing
is now commonplace in pharmaceutical their raw materials or spoilage of their of Cellular and Gene Therapy Products
microbiology. products) in studies to verify the efficacy (draft guidance, February 2008) sug-
One authors own insight, gleaned from of their preservative systems. Of course, gests, in relation to selecting a panel of
many conversations with practicing conceptually, this is akin to the testing appropriate challenge microorganisms
pharmaceutical microbiologists, clearly of non-sterile pharmaceuticals for ob- for validating an RMM, the inclusion
indicates that many big pharma com- jectionable organisms that often origi- of isolates detected in starting materi-
panies and smaller ones alike are imple- nate as contaminants in raw materials or als, isolates detected by in-process test-
menting (or already have) the use of a few from the manufacturing environment.
of their own isolates to complement the Whatever the case, these practices are
founded on the idea that these micro- Isolated Look at this Article
compendial reference strains in growth
promotion testing of environmental organisms are a better challenge to the Testing of plant isolates, or wild-type
monitoring and sterility testing media, microbiological method than the stan- strains, is a regulatory expectation
and sometimes in validation studies for dard compendial strains. Arguments against such test-
new methods such as rapid microbio- Applications, Regulations and ing include practicalities related
logical methods (RMM) for sterility as- Recommendations to repeatability, reproducibility in
surance testing. In most cases, these labs The compendial references for sterility validations and cost
intend to make an annual assessment of tests, enumeration tests, specified micro- The real value derives from sig-
the frequency of species amongst their organisms, and antimicrobial effective- nificantly greater confidence in
environmental isolates and select either ness tests (USP chapters <71>, <61>, media, methods and systems
the two or three with highest frequency <62> and <51> respectively) and the that are validated and tested us-
or the highest frequency isolate from corresponding sections of the European ing strains that are more typical of
each of the Gram positive, Gram nega- Pharmacopoeia do not prescribe the use target organisms than those refer-
tive and fungal isolate groups. Their in- of environmental or other wild isolates. enced in compendial methods
tention is usually articulated in terms of However, a number of compelling rec-
Coming Soon!
The July/August PDA Journal of Pharmaceutical Science and Technology will include an article by Tim
Sandle called, A Review of Cleanroom Microflora: Types, Trends and Patterns
Sign up for an E-TOC Alert, go to journal.pda.org/cgi/alerts