Despite the Barr verdict from 1993 in which the US Food & Drug Administration
concentrated on OOS results the appropriate handling of deviant analysis
results is still an important issue in FDA inspections. A 483 form from an
inspection in spring 2006 shows many findings with regard to OOS.
Following are some examples from the inspection report:
Your firm failed to perform adequate investigations with
scientifically justifiable conclusions to incidents of out-of-specification
results or production deviations and/or failed to implement appropriate
corrective actions for the root cause determination.
The Quality Control Unit failed to ensure that Phase I
Laboratory Investigations were adequately investigated, documented, and
trended after they were removed from the
system in September 2005 and
transferred to a manual logbook.
The investigation report TWR #1540 for finished product
testing of Metformin HCl Extended-release (XT) Tablets, 1000 mg Lot No.
F575F0620 Sublot C was specifically for related compounds testing. The unknown
related compound in this sample was OOS. With-in specification results were
obtained upon retest of the sample and the firm concluded that the OOS result
was due to contaminated glassware.
This statement indicates that there is no
definitive assignable cause for the OOS result since they state that the
contamination could have come from glassware or sample handling. The
investigation does not explain how glassware contamination or sample handling
may have increased the unknown related compound for this sample. If in fact
the contamination was due to sample handling then the proposed corrective
action of additional glassware cleaning would not be appropriate. In this
case, the investigation indicated that the current glassware cleaning
procedure may not be adequate for this particular product but does not explain
why. The corrective action does not address training for all analysts on the
required glassware procedure nor does it state if this will be incorporated
into the analytical procedure for this product. Furthermore, the investigation
was inconclusive and the results were invalidated without extending the
investigation into the manufacturing area.
There is no scientific justification for invalidating the OOS
the laboratory practices shown in this investigation were
These examples show that FDA investigators set a great value on
the effort to find out what caused the OOS result. The determination of the real
cause for an OOS result is also a central request in the FDA Guidance for
Industry Investigating Out-of-Specification (OOS) Test Results for
Pharmaceutical Production from October 2006. It is pointed out there that The
objective of such an investigation should be to identify the root cause of the
OOS result and take appropriate corrective and preventative action.
The examples from the 483 form further show that many companies not only find it
difficult to identify the cause for an OOS result, but also to take appropriate
corrective and preventive actions. As the quote shows, though, the guideline
does request exactly these actions.