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OOS Investigations

This document discusses handling out-of-specification results and outlines requirements from the FDA and Barr court case. It provides guidance on conducting a proper investigation when an OOS result occurs, including identifying the reason, describing what happened, evaluating other potentially affected batches, determining the root cause, identifying corrective and preventive actions, and evaluating product impact. It emphasizes that investigations must be thorough, well-documented, and completed within 30 days to identify issues and prevent future recurrences.

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322 views20 pages

OOS Investigations

This document discusses handling out-of-specification results and outlines requirements from the FDA and Barr court case. It provides guidance on conducting a proper investigation when an OOS result occurs, including identifying the reason, describing what happened, evaluating other potentially affected batches, determining the root cause, identifying corrective and preventive actions, and evaluating product impact. It emphasizes that investigations must be thorough, well-documented, and completed within 30 days to identify issues and prevent future recurrences.

Uploaded by

ShanePoole
Copyright
© © All Rights Reserved
We take content rights seriously. If you suspect this is your content, claim it here.
Available Formats
Download as PPTX, PDF, TXT or read online on Scribd
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Handling Out-of-Specification

Results
1
QUALITY CONTROL FOR REGULATED
ENVIRONMENTS
UNIVERSITY OF HOUSTON

OOS
(Out of Specification)
2

The failure of a batch or any of its components to

meet any of its specifications


OOS indicates non-compliance with specifications
Handling an OOS has many of the same features as

handling a deviation or exception

Deviations/exceptions are events where something happened


that was unexpected or unplanned (i.e. event transpired
differently than detailed in the SOP or batch record)

CGMPs
3

21 CFR 211.192
Any unexplained discrepancy of the failure of a

batch or any of its contents to meet any of its


specifications shall be thoroughly investigated,
whether or not the batch has already been
distributed.

CGMPs
4

21 CFR 211.192
The investigation shall extend to other batches of

the same drug product and other drug products that


may have been associated with the specific failure or
discrepancy.
A written record of the investigation shall be made
and shall include the conclusions and follow-up.

Barr Court Case


5

Civil action by FDA, June 12, 1992.


Judge Alfred M. Wolin.
Can the FDA expand the cGMPs interpretation into

the statistical areas of outliers, retesting, resampling,


averaging and sample size and other areas of failure
investigations,

The Barr Decision


6
In 1993, Barr Laboratories was sued by the US government (i.e., the US

Food and Drug Administration) regarding a whole set of issues, including


the way the company dealt with OOS results

Barr lost and the judge who heard the case, Judge Wolin, issued a ruling commonly
referred to as the Barr Decision

The Barr Decision made the OOS problem into a major problem for the QC

laboratory by creating a regulatory requirement where, following an OOS


result, an investigation must be initiated before any retesting can be done
Consequently, OOS results arising from random variation must be
investigated before actions (i.e., retesting) can be taken to decide whether or
not it is a random event

This creates additional work for QC laboratories, and an intense desire to simplify
investigations by blaming OOS results on laboratory error

This can create situations in which retesting leads to testing a product into compliance with
repeated claims of laboratory error
An outside observer might conclude that the laboratory is not competent to be performing the test.

Barr (contd)
7

Most QC supervisors who have received basic statistical

training know that statistical formulas can be used to calculate


the proper number of replicates needed to overcome a single
failing result
The number of replicates is based on previous data concerning
the variability of the product and test method
In the Barr Decision, however, the judge offered the opinion
that seven passing results are needed to overcome one OOS
result

This caused a number of companies to adopt a "seven replicate rule" when


confronted with an OOS test result
This procedure and the testimony that originally led to the judge's
conclusion were completely without scientific foundation.

OOS Topics in the Barr Case


8

Out of specification results


Product failure
Informal and formal investigations
Testing and retesting
Sampling and resampling
Averaging
Outliers

Barr Decision
9

Failure investigation is central


Failure investigation

Immediate
Timely follow-up
Appropriate resolution
Documented

Avoid
Testing into Compliance
10

Retesting: Additional test should be for the same

sample, only after a failure investigation is underway

Testing into compliance is not acceptable

Retest only by predetermined written SOP

Linkage of Systems
11

EVENT
Identify All Lots
Consider All Possibilities

Investigation

Product Impact
Root Cause

Corrective Action
Preventive Action Lot Disposition

Scope and Definition


12

Purpose of Investigations

Identify
Correct
Evaluate Product Impact / Disposition
Prevent Similar Events from Happening in the Future;

The Deviation/OOS Event is the Initiating Feature of

the CAPA Program

Is the First Result Real?


13

Are the first results true and accurate?

Validated methods?
Changes in validated methods?
Qualified and calibrated laboratory equipment?
Correct instrumentation parameters?
Correct sample and standard weights?
Reference standards dried properly?

Content of Investigation Report


14

Reason for the Investigation

What Event or Finding Prompted Investigation


How and When Identified
Remember to Consider Tracking / Trending Evaluation
Consider Related Activities, Think Global

Describe What Happened

What
When
Where
What Immediate Actions Were Taken

Content of Investigation Report


15

Identify Other Batches Potentially Affected

Justify Selection
Remember Distributed Lots

Identify Root Cause, Where Possible

Why, Why, Why


Document Factors Considered
Ensure Data Support Conclusions
Avoid Conjecture
Often a Multi-Disciplinary Exercise

Content of Investigation Report


16

Identify Corrective Actions

Resist: Operator Error Corrected with Retraining


May Include Additional Monitoring / Assessment
Implementation Must be Timely

Identify Preventive Actions

Success Depends on Adequate Identification of Root Cause


Interim Solution May Include Additional Monitoring

Content of Investigation Report


17

Evaluate Product Impact / Disposition

Additional Testing / Results


Justify Accept / Reject Criteria
Justify if Differences in Lot Disposition
Remember to Consider Tox Evaluation

Provide Follow-up to Assure Effectiveness

Does Preventive Action Provide a Durable Fix


What are Criteria for Durable Fix

OOS Investigations:
FDA Focus
18

Pre-established protocol for investigating OOS

results
Summary of specific investigation steps:

Evaluation of other batches


Conclusion and follow-up
Action necessary to prevent similar recurrences

OOS Investigations:
FDA Focus (continued)
19

Timely investigation must be performed within 30

business days

Investigate before retest

Well documented
Scientifically sound

Where do companies run into trouble with their investigations?


20

Lack of Documented Investigation


Incomplete Investigation

Factors Not Considered / Documented


Associated Lots Not Identified / Evaluated
Root Cause Not Established or Justified
Conclusions Not Supported by Data

Timelines Not Followed, Not Extended


Corrective / Preventive Actions Not Implemented,

Tracked or Completed

Effectiveness Not Verified

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