Every group needs a contrarian, so here goes......
No time to do a literature search but I can tell you from 17 years of
industrial microbiology experience, pathogens do survive low water activity
products. I've seen Salmonella in sesame seeds, Staph in dried lactose
powder, coliforms in tablets (yes... dried, compressed tablets), etc. etc.
etc. (And yes, no laboratory contamination as evidenced by extensive OOS
As Bob points out, harvesting plump delicate ATCC strains from a TSA slant,
suspending them in physilogoical saline, dropping them on a dried powder,
and then assaying for plate count does not reflect real life contamination
situations. Obviously most GN and GP bacteria won't grow in low Aw
products, but they can survive for a long time.
Getting entangled in discussions of infectious dose may be heading down the
wrong path, too many variables. What about the question of cGMP
ompliance -- surviving pathogens isolated by the industrial microbiologist
are indicators of unclean manufacturing practices. Where there are
coliforms or Staph or Salmonella there could be a whole lot more.
Coliforms isolated from the tablets referenced above contaminated the
product because the water used in cleaning the equipment was contaminated.
And they survived quite a long time. Health risk, probably not; cGMP
violation, I think so.
[log in to unmask]
Celsis Laboratory Group
(These are my opinions and not necessarily those of my employer)
---- Original Message -----
From: rfriedel <[log in to unmask]>
To: <[log in to unmask]>
Sent: Friday, March 31, 2000 10:24 AM
Subject: Re: [PMFLIST] Dry dosage forms microbial testing.
> I agree with many of your comments. As I have stated in the USP articles
> water activity, the stresses of compression, shearing, heat and drying are
> inimical to the microorganisms which may be present. At what point do we
> stop and conclude that an immunocompromised patient should receive a
> dosage form. Much of the hoopla regarding contamination incidents has
> centered around foods. While coming to work a few days ago, there was
> another incident of Listeria contamination in hot dogs. Foods provide
> more nutritional capacity that a pharmaceutical product, particularly the
> materials used to make tablets.
> Now matter how much we try, laboratory contamination simulations do not in
> any way mimic reality. However, they do give us a warm, "fuzzy" feeling
> accomplishment; especially when they give the false illusion of actually
> simulating reality.
> It all started out with Salmonella contamination of thyroid medicine in
> Sweden during the 1960's. The article is:
> Kallings, L.O., Ringertz, O. & Silverstolpe. (1966) "Microbiological
> Contamination of Medical Preparations" Acta Pharm Suec, Jun;3(3):219-28.
> Bob Friedel
> Quality Assurance Manager
> Perritt Laboratories
> [log in to unmask]
> ----- Original Message -----
> From: George Spite <[log in to unmask]>
> To: <[log in to unmask]>
> Sent: Thursday, March 30, 2000 10:01 PM
> Subject: Re: [PMFLIST] Dry dosage forms microbial testing.
> > Frank,
> > 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
> > 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
> > consuming bean sprouts at a salad bar. The third investigator suffered
> > ill effects as he had no sprouts - he was smart - that's why he was the
> > investigator. The health dept. found B. cereus in the millions from
> > samples.
> > We don't test for sporeformers in raw materials....yet!!!!
> > There was USP talk about testing for the presence of Clostridia in
> > products. Don't know where that's at presently.
> > Where do we draw the line for what to test oral products for? Do we
> > 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
> > years.
> > Then there is the concern for the immunocompromised population. When
> > take tablets do they handle them with sterilized fingers and drink
> > water out of sterile glasses while breathing in sterile air? Is the
> > 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
> > of Shigella (flexneri?) caused ill effects orally. E. coli and
> > ranged in the millions for symptoms to occur. S. aureus has to number
> > the millions to produce the enterotoxins for oral pathogenicity
> > the FDA's bad bug website article and the ideal environment for
> > production is a cream puff not a dry tablet or capsule. Staph. aureus
> > 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
> > has the details on that incident please enlighten me. To my knowledge
> > hasn't been any other incidence of pathogen contamination of solid oral
> > pharmacuetical products nor dry raw materials going into them. If
> > 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
> > > 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
> > testing
> > > decisions based on water activity of raw materials. Also Anthony
> > > addressed water activity and the need or lack of need to routinely
> > > finished dry dosage drugs - water activity 0.3 or less.
> > >
> > > I am interested in responses from fellow forumeers as to
> > > they consider it necessary to test dry doses microbially. Such testing
> > > proposed by the USP -where is it now?
> > >
> > > I recently completed a study inoculating dry dose forms
> > > uncoated, capsules and granulations-for-capsules with up to 10,000
> > cfu/dose
> > > unit. As expected E. coli, S. aureus, Ps. aeruginosa, Salmonella, and
> > > 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
> > > studies?
> > >
> > > Wouldn't such results along with Friedel's and Cundell's
> > > put a near kabosh on testing of dry dose forms? Note: the microbes
> > > inoculated onto the tablets, etc. If they were in the granulation
> > > compression wouldn't kill off be even quicker - instantaneous? Can
> > > share any microbial study information or articles on microbe
> > > 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
> > > Considering these results what is the rationale for the tight limits I
> > have
> > > read about for manufacturing equipment surface sampling - 1 to 2 cfu
> > sq.
> > > cm - some limits are even tighter for non-sterile (he states as he
> > his
> > > coated tablet dosage form in his fingers and gulps it down with city
> > > water)?
> > >
> > >
> > >
> > > Thank you,
> > >
> > > George Spite
> > >
> > >
> > >
> > >
> > > ------------------
> > > The PMFList (http://microbiol.org/PMFList_info.htm) is operated from
> > > The Microbiology Network (http://microbiol.org) and supported by
> > > our sponsors (http://microbiol.org/sponsor.htm) as a service to
> > > the scientific community.
> > >
> > >
> > ------------------
> > The PMFList (http://microbiol.org/PMFList_info.htm) is operated from
> > The Microbiology Network (http://microbiol.org) and supported by
> > our sponsors (http://microbiol.org/sponsor.htm) as a service to
> > the scientific community.
> The PMFList (http://microbiol.org/PMFList_info.htm) is operated from
> The Microbiology Network (http://microbiol.org) and supported by
> our sponsors (http://microbiol.org/sponsor.htm) as a service to
> the scientific community.
The PMFList (http://microbiol.org/PMFList_info.htm) is operated from
The Microbiology Network (http://microbiol.org) and supported by
our sponsors (http://microbiol.org/sponsor.htm) as a service to
the scientific community.