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March 2012

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The Pharmaceutical Microbiology Forum Email List <[log in to unmask]>
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Tue, 13 Mar 2012 08:07:26 -0700
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The Pharmaceutical Microbiology Forum Email List <[log in to unmask]>
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Kate Ambrus <[log in to unmask]>
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Fortunately, we never had to submit any product to the regulatory agencies where the spikes/neutralizationcontrols were negative. But it can take some time to arrive at the correct combination of inactivating the antibiortic and neutralizing the preservative.
 
Yes - the initial levels are obtained in a neutral medium - in saline+Tween 80 or peptone water. But I think the issue here is the lack of inactivation of the API's during the validation testing.
 
Also - having the challenge organism not grow during the testing, does not mean it is killed.The API may be just simply not completely inactivated and not allowing the test organism to grow (it is being inhibited). With the cyclosporine experience, we saw no recovery of A. brasilienses in the AET testing, but once we started using filtrarion to remove the cyclosporine, the A. brasiliensis level was shown to be at 10E5 CFU/mL.
 
We became aware of the problem during validation testing, and continued to work on it until we solved it. I suppose it is possible that some actives cannot be easily inactivated - but we have not come across this situation before submitting to the FDA or such. I am prettuy sure they would have not accepted the data otherwise.
 
Kate Ambrus


________________________________
From: Brian Matthews <[log in to unmask]>
To: [log in to unmask] 
Sent: Monday, March 12, 2012 8:38 AM
Subject: Re: [PMFLIST] Antimicrobial efficacy

Surely, for the control value the inoculum count in a neutral medium (such
as peptone broth) will be used to determine the number of organisms
introduced.  The inoculum recovery in the product will form the time 0
count - and might well be very low (or 0) if the product has a high level
of antimicrobial activity whether this is from AI or preservatives.

Regards,

Brian Matthews.

On 11 March 2012 07:12, Madupa papaiah <[log in to unmask]> wrote:

> Kate,
> I agree with you completely. But on a different prospective, when a
> formulation contianing API as an antibacterial component and the
> preservative is not being neutralized during the method suitability, this
> (as we have seen in some cases, due to the effect of antibacterial API in
> the formulation), how this is seen by the regulator? When the formulation
> is spiked with known concentration of USP strains and the spiked
> concentration is proved by the positive controls at the T0, then is it
> mandatory to obtain the recovery? If the recovery is not obtained due to
> the antibcaterial API, is it still not acceptable, based on the data, that
> the formualtion as a whole is capbale of kiling the total spike ? any
> experience where the recovery is not obtained and the data is submitted for
> the regulatory where the regulatory has accepted the filing? Rgds,
>
> On Fri, Mar 9, 2012 at 7:59 AM, Kate Ambrus <[log in to unmask]> wrote:
>
> > Yes - in my former positions we have tested preserved antibiotic
> products.
> > I don't think you need to worry about the concentration of the antibiotic
> > in the case of the AET test. An AET does not have anything to do with the
> > antibiotic - which can be tested in a chemical or microbial assay.
> >
> > What you could do is to assume what your lowest concentration of the
> > preservative would be at the end of shelf life, and test several lower
> > concentrations of the preservative in the AET test.
> >
> > The neutralization of the agents may get tricky - since the antibiotic
> can
> > inhibit the growth of the test organisms. If I recall we used to place
> all
> > of the test aliquots and dilutions to be plated into an 0.45 (I think or
> > may have been 0.22) filter, and washed it with a validated volume of a
> > validated diluent. Seems like Flid A or D worked well in most cases. The
> > filters were then placed onto the TSA or SDA media. Reading Aspergillus
> may
> > be tricky and should probably be done as early as possible. Also we found
> > that Porato Dextrose agar minimized the size of the colonies and often
> used
> > this media instead of SDA (after sidee by side validation).
> >
> > The preservative was inactivated with a validated diluent media - and
> > taken care of that way.
> >
> > So the validation may be a little tricky, but has been done many times -
> > we used to test antibiotics in ophthalmic solutions. Again - would not
> vary
> > the concentration of the antibiotic, but would test the AET at the lowest
> > assumed concentraiton of the preservative that would be expected to be in
> > the product at the end of shelf life.
> >
> > Kate Ambrus
> >
> >
> > ________________________________
> > From: Jelena Peric <[log in to unmask]>
> > To: [log in to unmask]
> > Sent: Thursday, March 8, 2012 2:49 AM
> > Subject: [PMFLIST] Antimicrobial efficacy
> >
> > Dear All,
> >
> >
> > have you ever tested the antimicrobial efficacy (i.e. efficacy of
> > antimicrobial preservation) according to EP 5.1.3., or USP, on an
> > antibiotic oral solution, or in any other antibiotic preparation that
> > contains preservatives in addition to the antibiotic?
> >
> > The test is usually used to demonstrate that the chosen preservative
> > concentration in a product is effective. During developmental stages of a
> > product, different probes with different preservative concentrations are
> > usually tested in order to demonstrate that the choice of a
> > preservative and its concentration is justified, and that the product
> still
> > complies even if the preservative content drops for what ever reason
> during
> > shelf life.
> >
> > In my case, the situation is more complicated because of the presence of
> > the antibiotic. What would be the right experimental design in my case?
> > The simplest way would be to do the test on the final formulation, and to
> > claim that the product is adequately preserved - but by doing so, I would
> > not find out which test microorganisms are inhibited by the preservative,
> > and which ones by the antibiotic, and what happens if the content of any
> of
> > the antimicrobial substances drops during shelf life.
> >
> > Maybe I should test the final product formulation with the targeted
> > preservative concentration, and than the same formulation but with the
> > preservative concentration lowered (for example, 80% of the targeted
> > concentration). Maybe I should see what happens if the content of the
> > antibiotic drops to 80%, or what happens in the placebo (without the
> > antibiotic) with the targeted preservative concentration or the lowered
> > preservative concentration...
> > What would you do in this case?
> >
> > Any thoughts will be appreciated,
> >
> >
> > Jelena
> >
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> >
> > Biolog - http://www.biolog.com
> >
> > Biomerieux - http://industry.biomerieux-usa.com
> >
> > Biotest - http://www.BiotestUSA.com/micro<
> http://www.biotestusa.com/micro>
> >
> > Lonza Rapid Testing Solutions - http://www.lonza.com/rts
> >
> > MicroBioLogics, Inc. - http://www.microbiologics.com
> >
> > Pall - http://www.pall.com
> >
> > NovaTek International - http://www.ntint.com
> >
> > Rapid Micro Biosystems - http://www.rapidmicrobio.com  (formerly GPS)
> >
> > Steris - http://www.sterislifesciences.com/
> >
> > Veltek Associates, Inc - http://www.sterile.com
> >
> > =================================
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> ------------------
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> The Microbiology Network (http://microbiol.org) and supported by
> our sponsors (http://microbiol.org/sponsor.htm) as a service to
> the scientific community.
>
> Please take a second to visit our sponsors' web sites and say thank you
> for their support of this service.
>
> Accugenix - http://www.accugenix.com
>
> American Type Culture Collection - http://www.atcc.org
>
> BD Diagnostic Systems - http://www.bd.com/ds/
>
> Biolog - http://www.biolog.com
>
> Biomerieux - http://industry.biomerieux-usa.com
>
> Biotest - http://www.BiotestUSA.com/micro
>
> Lonza Rapid Testing Solutions - http://www.lonza.com/rts
>
> MicroBioLogics, Inc. - http://www.microbiologics.com
>
> Pall - http://www.pall.com
>
> NovaTek International - http://www.ntint.com
>
> Rapid Micro Biosystems - http://www.rapidmicrobio.com  (formerly GPS)
>
> Steris - http://www.sterislifesciences.com/
>
> Veltek Associates, Inc - http://www.sterile.com
>
> =================================
> The nature of this service is to provide a medium for communication.  The
> specific statements and endorsements of individuals participating in the
> discussions are not necessarily those of The Microbiology Network, Inc.,
> the PMF, or the sponsors of the list.
>

------------------
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.

Please take a second to visit our sponsors' web sites and say thank you for their support of this service.

Accugenix - http://www.accugenix.com

American Type Culture Collection - http://www.atcc.org

BD Diagnostic Systems - http://www.bd.com/ds/

Biolog - http://www.biolog.com

Biomerieux - http://industry.biomerieux-usa.com

Biotest - http://www.BiotestUSA.com/micro

Lonza Rapid Testing Solutions - http://www.lonza.com/rts

MicroBioLogics, Inc. - http://www.microbiologics.com

Pall - http://www.pall.com

NovaTek International - http://www.ntint.com

Rapid Micro Biosystems - http://www.rapidmicrobio.com  (formerly GPS)

Steris - http://www.sterislifesciences.com/

Veltek Associates, Inc - http://www.sterile.com

=================================
The nature of this service is to provide a medium for communication.  The specific statements and endorsements of individuals participating in the discussions are not necessarily those of The Microbiology Network, Inc., the PMF, or the sponsors of the list.

------------------
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.

Please take a second to visit our sponsors' web sites and say thank you for their support of this service.

Accugenix - http://www.accugenix.com

American Type Culture Collection - http://www.atcc.org

BD Diagnostic Systems - http://www.bd.com/ds/

Biolog - http://www.biolog.com

Biomerieux - http://industry.biomerieux-usa.com

Biotest - http://www.BiotestUSA.com/micro

Lonza Rapid Testing Solutions - http://www.lonza.com/rts

MicroBioLogics, Inc. - http://www.microbiologics.com

Pall - http://www.pall.com

NovaTek International - http://www.ntint.com

Rapid Micro Biosystems - http://www.rapidmicrobio.com  (formerly GPS)

Steris - http://www.sterislifesciences.com/

Veltek Associates, Inc - http://www.sterile.com

=================================
The nature of this service is to provide a medium for communication.  The specific statements and endorsements of individuals participating in the discussions are not necessarily those of The Microbiology Network, Inc., the PMF, or the sponsors of the list.

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