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October 2019

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Subject:
From:
Donald English <[log in to unmask]>
Reply To:
The Pharmaceutical Microbiology Forum Email List <[log in to unmask]>
Date:
Tue, 8 Oct 2019 18:50:40 -0400
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Dear Michael,

Never assume that microbial contamination in a finished product batch is homogeneous. In most cases, microbial contamination is never homogeneous in a batch.

For sterility test failures, it is somewhat difficult to justify a retest of the batch without determining whether the initial sterility result is due to laboratory error.  If there was no laboratory error during the initial sterility test result for an OSS, I do not feel that you have justification to conduct a retest on a larger amount of sterile test samples.  The sample size for sterility testing is too small to be statistically relevant in comparison to the total number of vials or ampules that are normally produced in a batch. I know that I just cause my sterile manufacturing friends a heart attack with this statement, but it is just my opinion.

For non-sterile products, I have seen companies perform a retest for OSS results.  For non-sterile products, I do recommend that you conduct a retest on all of the initial samples without compounding them together as part of your investigation to determine whether there was laboratory error during analysis and to determine whether the microbial contamination in a batch is homogeneous or not homogeneous. If the retest on the original test samples is OSS, there is no need to conduct a retest on a greater number of fresh test samples of the batch.  If the retest on the original test samples is found to be not OSS, I would conduct a retest on a greater number fresh samples without compounding them together to show that the batch is in compliance with the specification.  With this type of test result, it is possible to determine that there was laboratory error during the analysis.    If the product is labeled as a USP non-sterile product formulation, I would not conduct any type of retesting on the OSS samples because there is no statement in the USP to say that retesting is allowed.

If a sample fails an Antimicrobial Preservative Effectiveness test, I would not recommend that the sample be retested.  However, I would conduct an investigation as to why the sample failed challenge testing such as testing an uninoculated test sample for preservative levels.  With challenge test samples, you are on a slippery slope for retesting because no one will ever believe that an initial failing challenge test result is real.  Very difficult situation to be in.

When it comes to finished product batches that are not in compliance with the microbial test specification, management is never happy and manufacturing always blames the Quality Control Microbiology Laboratory for the test failure.  I have been in that foxhole many times when manufacturing or Product Development was attacking the integrity of the Microbiology Laboratory for OSS results.  In the end, the investigations always revealed that there was an error in manufacturing such as in cleaning and sanitization or ingredients used in the product formulations were incompatible with preservatives and packaging.  If you decide to retest or not retest an OSS test result, you need to have a written report documenting the  justification for your decision.

Don

Donald J. English Microbiological Quality Consulting LLC
Florham Park, New Jersey 07932

Sent from my iPhone

> On Oct 8, 2019, at 1:43 PM, Tony Cundell <[log in to unmask]> wrote:
> 
> The concept of an OOS result that would be investigated to determine the
> validity of the test was first introduced in the Federal Judge Wholin Barr
> Laboratories verses the U.S..
> 
> The FDA published the 2006 Guidance For Industry Investigating
> out-of-specification (OOS) test results for pharmaceutical products.
> 
> For cGMP compliance reasons it is ill-advised to retest a sample or
> resample from a batch without have a sound reason to invalidate the test.
> 
> In some circumstances it useful as part of a follow-up investigation to
> retest a product to determine the root cause of the failure but not to
> overcome the failing result.
> 
> Usually any container from a batch manufactured using a validate process
> should be representative of that batch. With microbial testing we must
> consider heterogeneity, variability of test results and microbial stability
> in the product.
> 
> On Tue, Oct 8, 2019 at 11:30 AM Michael Barton <[log in to unmask]>
> wrote:
> 
>> Hi all,
>> what are peoples thoughts on when you can or can not perform a re-test
>> following obtaining an Atypical or OOS result for a finished product?
>> 
>> Would you say that a re-analysis/re-test (from the same starting sample(s)
>> e.g bottles/sampled material in a container) is for additional information
>> only to support a decision or if the result is then within specification it
>> can be used as a final result and initial result was incorrect (i think
>> that that is not the expeceted, as you are not clearly justifying not using
>> teh original result).
>> 
>> I have previously heard that it is reasonable to assume that the filled
>> product with any contamination may not be homogenous and therefore you may
>> not be able to obtain repetitive results and confirm one way or another?
>> however if we do say that contamination within the batch is not
>> homogenous, how is it reasonably practical to allow us to take such small
>> samples for testing and release on the basis of a satisfactory result  if
>> it is understood that some of the batch we dont test could be contaminated
>> and possibly OOS?
>> 
>> Do we need to assume that our products are homogeneous?  Any references to
>> guidance documents/presentations would be appreciated.
>> 
>> Thanks Mike.
>> 
>> ------------------
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>> 
>> 
>> Science Advisory Board https://www.scienceboard.net/
>> 
>> Steris - http://www.sterislifesciences.com/
>> 
>> Charles River Laboratories - http://www.criver.com/
>> 
>> Veltek Associates, Inc - http://www.sterile.com
>> 
>> Microbiologics, Inc. - http://www.microbiologics.com
>> 
>> BD Industrial Media - http://www.bd.com/ds/
>> 
>> Boston Analytical http://www.bostonanalytical.com/
>> 
>> Associates of Cape Cod, Inc. - http://www.acciusa.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.
>> 
> 
> 
> -- 
> Tony Cundell, Ph. D.
> Consulting Microbiologist
> Email: [log in to unmask]
> Phone: 914 725-3947
> Cell: 914 841-0074
> 
> ------------------
> The PMFList (http://microbiologynetwork.com/pmflist.asp) is operated from
> The Microbiology Network (http://microbiologynetwork.com) and supported by
> our sponsors 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.
> If your company would be interested in sponsoring this community, please contact [log in to unmask]
> 
> 
> 
> Science Advisory Board https://www.scienceboard.net/
> 
> Steris - http://www.sterislifesciences.com/
> 
> Charles River Laboratories - http://www.criver.com/
> 
> Veltek Associates, Inc - http://www.sterile.com
> 
> Microbiologics, Inc. - http://www.microbiologics.com
> 
> BD Industrial Media - http://www.bd.com/ds/
> 
> Boston Analytical http://www.bostonanalytical.com/
> 
> Associates of Cape Cod, Inc. - http://www.acciusa.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://microbiologynetwork.com/pmflist.asp) is operated from
The Microbiology Network (http://microbiologynetwork.com) and supported by
our sponsors 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.
If your company would be interested in sponsoring this community, please contact [log in to unmask]



Science Advisory Board https://www.scienceboard.net/

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

Charles River Laboratories - http://www.criver.com/

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

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

BD Industrial Media - http://www.bd.com/ds/

Boston Analytical http://www.bostonanalytical.com/

Associates of Cape Cod, Inc. - http://www.acciusa.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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