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MDD Sample

Uploaded by

sabrina
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© © All Rights Reserved
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Download as PDF, TXT or read online on Scribd
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INVESTIGATION OF

MICROBIOLOGICAL DATA DEVIATIONS

INTRODUCTION

It is difficult to discuss the current climate ofproceduralizcd investigations without


some mention of the 1993 Barr Decision (Madsen, 1994). Barr Laboratories had a
history of repeated current good manufacturing prdctice (cOMP) deficiencies,
including repealed retesting and resampling of product as well as reprocessing of
defective product without adequate justification in a practice that has come to be
known as "testing to compliance." This is nol good practice - the out-of-
specification (OOS) data is telling the manufacturer important information about
the product and must be resolved. Unfortunately for the microbiology community,
this initial situation, as well as most of the subsequent writing on this topic, has
focused on 005 from an analytical chemistry perspectivc, The Food and Drug
Administration (FDA) has provided guidance following the Barr decision, and
drafted thc "Guidance for Industry - Investigating Out of Specification (005)
Test Results for Pharmaceutical Production" (FDA, 1998) which was rewriuen and
re-releascd in 2006, Interestingly, this guidance document only brieny touches upon
microbiological data, stating that "the USP prefers the use of averages because of
the innate variability of the biological test system.'" In addition, this guidance
document specifically excludes microbiology from its scope in footnote 3.
2 Seal( Sutton

On the international front. the International Conference on Hannonization of


Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)
has provided some guidance on what is meant by a "specification." The guidance
directs that

"Specifications arc chosen to confirm the quality of the drug substance and drug
product ralher than to establish full characterization, and should focus on those
characteristics found to be useful in ensuring the safety and efficacy of the drug
substance and drug product."
(lCH,2001)

This is a source of some confusion, as the FDA OOS guidance Siaies that it

.. applies 10 chemistry-based laboratory testing of drugs regulated by CDER. It is


directed lOward traditional drug tesling and release methods. These laboratory tests
are performed on activc pharmaccutieal ingrcdicnts, exeipicnts and other
components, in-process materials, and finishcd drug products..."
(FDA,2006)

So, in one major guidance document we see that in-process controls are exeluded
from OOS procedures, while they are included in another.

These guidance documents, although written for analytical chemistry tests, are
useful for microbiology investigations. For example, the FDA's focus on investigat-
ing a potential laboratory component (with its respective responsibilities) prior to
the full scale investigation is especially helpful. Great care should be Iaken,
however, in over-applying these documents into areas for which they arc not
appropriate.

The regional compendia include four tests of particular interest to this


discussion:

the sterility tests

the microbial limits tests

the bacterial endotoxin test

the antimicrobial efficacy lest.

Most of these tests have some instruction on investigation of data deviations -


these will be examined in the discussion of that particular test.

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