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April 2000


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Anthony Cundell <[log in to unmask]>
Reply To:
The Pharmaceutical Microbiology Mail List <[log in to unmask]>
Mon, 3 Apr 2000 08:47:36 -0400
text/plain (150 lines)
I believe that the USP plans to add a test for Clostridium spp. to chapter <61> to harmonize with the EP.  It would be referenced in an individual USP/NF monograph.  I do not believe the USP will recommend routine Clostridium spp. testing.

Tony Cundell

>>> George Spite <[log in to unmask]> 03/30 10:01 PM >>>

Yes I would think sporeformers could survive in dry dose products.

I would think ingestion of sporeformers that have been stressed by
compression and dryness would not lead to significant growth in the harsh,
competitive gastrointestinal tract.

If I recall my food poisoning facts I think you need to ingest around
1,000,000 or more aerobic sporeformers, such as B.cereus, to experience
pathogenic effects.  I experienced this with a fellow FDA investigator after
consuming bean sprouts at a salad bar.  The third investigator suffered no
ill effects as he had no sprouts - he was smart - that's why he was the lead
investigator.  The health dept. found B. cereus in the millions from sprout

We don't test for sporeformers in raw materials....yet!!!!

There was USP talk about testing for the presence of Clostridia in finished
products.  Don't know where that's at presently.

Where do we draw the line for what to test oral products for?  Do we look
for parasite eggs, viruses, etc.?

Or do we look at reported incidences of known illness causing
contaminations -of sporeformers and others- and go from there?

These questions were posed before by fellow forumeers over the last several

Then there is the concern for the immunocompromised population.  When they
take tablets do they handle them with sterilized fingers and drink sterile
water out of sterile glasses while breathing in sterile air?  Is the food
sterile that they consume much more of than the tablets they take?

What numbers of specific microbes does one have to ingest to become ill?
The reference I read dealt with volunteers and the lowest number was 200 cfu
of Shigella (flexneri?) caused ill effects orally.  E. coli and Salmonella
ranged in the millions for symptoms to occur.  S. aureus has to number in
the millions to produce the enterotoxins for oral pathogenicity according to
the FDA's bad bug website article and the ideal environment for enterotoxin
production is a cream puff not a dry tablet or capsule.  Staph. aureus and
E. coli can be found in normal human GI tracts and the nasopharynx.

To my knowledge long ago and far away there was only one incidence of
Salmonella in a thyroid tablet for which I know no details about.  If anyone
has the details on that incident please enlighten me. To my knowledge there
hasn't been any other incidence of pathogen contamination of solid oral
pharmacuetical products nor dry raw materials going into them.  If anyone
has more info please share.

Thank you,

George Spite

----- Original Message -----
From: Settineri, Frank <[log in to unmask]>
To: <[log in to unmask]>
Sent: Thursday, March 30, 2000 7:17 AM
Subject: Re: [PMFLIST] Dry dosage forms microbial testing.

> What about spore formers?  Since they could be found in products with low
> water activities, would testing the products still be unwarranted?
> Frank Settineri
> 908-730-1222
>         ----------
>         From:  George Spite [SMTP:[log in to unmask]] 
>         Sent:  Tuesday, March 28, 2000 8:01 PM
>         To:  [log in to unmask] 
>         Subject:  [PMFLIST] Dry dosage forms microbial testing.
>         R. Friedel recently published in the PF regarding microbial
> decisions based on water activity of raw materials. Also Anthony Cundell
> addressed water activity and the need or lack of need to routinely test
> finished dry dosage drugs - water activity 0.3 or less.
>         I am interested in responses from fellow forumeers as to whether
> they consider it necessary to test dry doses microbially. Such testing was
> proposed by the USP -where is it now?
>         I recently completed a study inoculating dry dose forms coated,
> uncoated, capsules and granulations-for-capsules with up to 10,000
> unit. As expected E. coli, S. aureus, Ps. aeruginosa, Salmonella, and C.
> albicans died off in 3 to 7 days. A. niger was reduced in numbers. A
> colleague had performed a similar study at another company earlier and
> generated similar results. Has anyone reading this done or heard of such
> studies?
>         Wouldn't such results along with Friedel's and Cundell's opinions
> put a near kabosh on testing of dry dose forms? Note: the microbes were
> inoculated onto the tablets, etc. If they were in the granulation before
> compression wouldn't kill off be even quicker - instantaneous? Can anyone
> share any microbial study information or articles on microbe challenges
> using inoculated granulations then compressing or encapsulating them?
>         Wouldn't these findings and opinions also put the kabosh on
> environmental testing of non-sterile dry dose form manufacturing areas?
> Considering these results what is the rationale for the tight limits I
> read about for manufacturing equipment surface sampling - 1 to 2 cfu per
> cm - some limits are even tighter for non-sterile (he states as he takes
> coated tablet dosage form in his fingers and gulps it down with city
> water)?
>         Thank you,
>         George Spite
> ------------------
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The PMFList ( is operated from
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The PMFList ( is operated from
The Microbiology Network ( and supported by
our sponsors ( as a service to
the scientific community.