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July 1999


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Tony & Roz Cundell <[log in to unmask]>
Reply To:
The Pharmaceutical Microbiology Mail List <[log in to unmask]>
Sun, 11 Jul 1999 13:29:09 -0400
text/plain (70 lines)
The Preview of USP chapter <1111> has Burkholderia, Pseudomonas, Candida &
Clostridium as Objectionable Microorganisms in tablets and capsules for
immuno-compromised individuals, individuals with CF and ulcers. The Decision
Tree suggests that a water activity of 0.6 be a cutoff for Microbial Limit
testing of Tablets and capsules for other patient populations.

This would appear to be misguided for the following reasons:

Burkholderia and Pseudomonas are well recognised pathogens of the lower
respiratory tract in immuno-compromised individuals and the source of the
organisms is the upper respiratory tract not the gastrointestinal tract
entering by inhalation not ingression.  Exposure to these organisms in water
and food is common and they are transient in the gastrointestinal tract.
These organisms would not survive in tablets and capsules that typically
have water activities of 0.3 to 0.4.  The decision tree has a water activity
cutoff value of <0.6 when only highly specialized xerophilic fungi and
osmophilic yeast grow at water activites below 0.75 and these organisms can
found in unique environments and are not associated with infection.
Furthermore thay require specialized microbiological media with a reduced
water activity to be cultivated so they would not be isolated in compenial
microbiological media.

Candida again is associated with immuno-compromised patients especially
those on ventilators, cathetized, etc. Since all indivduals are colonized
with Candida and they are readily isolated from the skin, upper respiratory
tract, gastrointestinal tract, genitourinary tract a patient is at a greater
risk from their endogenous microflora than the consumption of a contaminated
oral medication.  These points made about water activity equally apply to

Clostridium is ubiquitous present in soil, water and food.
C. perfrigens colonizes the gastrointestinal tract.  In fact with exception
of monitoring food stuffs for canning, Clostridim is so ubiquitous that it
cannot be used as a microbiological criteria. It is virtually improssible to
ensure that immuno-compromised individuals will not be exposed to
Clostridium.  With the exception of C. difficle where their presences is
selected by antibiotic treatment there is no evidence that immunocompromised
individuals have an increased risk of infection from Clostridium.

An authoritative source of information that may be applied to oral dosage
forms is the 1997 CDC publication USPHA/IDSA Guidelines for the Prevention
of opportunistic Infections in Persons Infected with Human Immunodefieciency
Virsus which dones not mention Burkholderia, Pseudomonas, & Clostridium as a
risk and claims Candida is too ubiquitous to be excluded from food.

The control point for microbiological attributes of tablets and capsules is
pharmaceutical ingredients and the manufacturing process.  We need to
formulate, select suppliers to exclude raw materials with a bioburden that
may contaminated our products.  Also we need a knowledge of how our
manufacturin process may contribute or reduce the bioburden of our products.
Routine Microbial limit testing of tablets and capsules should not conducted.

Furthermore why should there be different guidelines for one class of oral
doage forms based on recipients when a immunocompromised patient may be
receiving multiple medications.

I suggest that microbiologists encourage their companies to write to the USP
to urge that this section of the preview be greatly modified.

Tony Cundell

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