I wholeheartedly agree with your comments. The one good thing about all of
the proposed revisions is that they are sooooooo messed up that it should be
obvious that they need to be COMPLETELY redone. I am preparing a Stimuli to
the Revision Process article on MLT methodology in which I am outlining a
simple and scientifically sound approach to testing non-sterile products. I
would like to suggest that you do the same for Specifications for
Non-sterile products - I think this could would serve as a valuable starting
point for a re-write of <1111>. I would think that the specs for most
products could be essentially the same:
- Water activity of less than 0.75, no testing required on the finished
- Microbial count from TSA plates of no more than 100 cfu/g of mL.
- Microbial count from SDA plates of no more than 50 cfu/g or mL (actually
the compendial use of SDA is misguided, but it makes people happy. We don't
get too radical!)
- If gram negative bacteria are detected they must be identified. Clinical
significance should be assessed using Bergey's and/or Manual for Clinical
- If S. aureus is detected it's clinical significance should be based on the
numbers present and enterotoxin production (using above references).
Just some food for thought,
> -----Original Message-----
> From: Tony & Roz Cundell [SMTP:[log in to unmask]]
> Sent: Sunday, July 11, 1999 1:29 PM
> To: [log in to unmask]
> Subject: [PMFLIST] Burkholderia, Pseudomonas, Candida & Clostridium
> as Objectionable Microorganisms in Tabets?
> 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
> 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
> 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
> cutoff value of <0.6 when only highly specialized xerophilic fungi and
> osmophilic yeast grow at water activites below 0.75 and these organisms
> 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
> tract, gastrointestinal tract, genitourinary tract a patient is at a
> risk from their endogenous microflora than the consumption of a
> 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
> of monitoring food stuffs for canning, Clostridim is so ubiquitous that it
> cannot be used as a microbiological criteria. It is virtually improssible
> 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
> 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
> Virsus which dones not mention Burkholderia, Pseudomonas, & Clostridium as
> risk and claims Candida is too ubiquitous to be excluded from food.
> The control point for microbiological attributes of tablets and capsules
> 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
> Routine Microbial limit testing of tablets and capsules should not
> 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
> to urge that this section of the preview be greatly modified.
> Tony Cundell
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