The document discusses handling out-of-specification (OOS) results in a quality control lab. It begins by summarizing a 1992 court case between Barr Laboratories and the FDA regarding OOS results. It then defines OOS results, unexpected results, and reportable values according to FDA guidelines. The document outlines when investigations of OOS results should be conducted and provides a flow chart depicting the investigation process. It also discusses retest sample size and the expectations of regulators regarding the handling and investigation of OOS results.

1. Handling
an OOS
in a
QC Lab
Sasha Nezlin
04 Sept 2012

2. Omrix at a glance
Handling an OOS in a QC Lab 2
04 Sept 2012

3. Barr Laboratories vs. FDA
 Barr were audited by FDA in 1989, 1991 and 1992
 Refused to accept a consent decree
 FDA was forced to go to court
 United States of America, Plaintiff V. Barr
Laboratories Inc., Defendants, Civil Suite 92-1744,
August 17 till October 12, 1992
 Judge Wolin decided on February 4, 1993 in favor
of the FDA
Handling an OOS in a QC Lab 3
04 Sept 2012

4. Judge Wolin’s decision
Handling an OOS in a QC Lab 4
04 Sept 2012

5. 13 years later …
Handling an OOS in a QC Lab 5

6. and another 5 years …
Handling an OOS in a QC Lab 6
04 Sept 2012

7. DEFINITION OF RESULTS
Batch failure,
used by FDA,
OOS Results - Test results laying
disliked by Judge
outside of the specifications
Wolin (Barr case)
Out of limits (OOL - alert / alarm)
Additional
unexpected peaks in
Questionable chromatogram
results (e.g. close
to spec / limit)
Out of trend
Unexpected Results
results that are aberrant, abnormal, anomalous, atypical, irregular or deviant
Handling an OOS in a QC Lab 7
04 Sept 2012

8. FDA DEFINITION OF REPORTABLE VALUE
REPORTABLE VALUE:
“This determination is considered one test and one result.”
 A reportable value is the end result of the complete
measurement method as documented.
 A reportable value is the value compared to the specifications.
 A reportable value is the value used for reporting.
 A reportable value is the value used for statistical analysis.
 Record in writing the operational definition of the reportable
value for each test method in the method documentation, any
protocols and any reports.
 Add “Only this reportable value can be compared to the
specification criteria.”
Handling an OOS in a QC Lab 8
04 Sept 2012

9. Investigations of OOS results should be performed for:
- Batch release testing and testing of starting materials.
- In-Process Control testing: if data is used for batch calculations /
decisions and if it is in a dossier and on Certificates of Analysis.
NOTE: OOS procedure is NOT applicable for in-process testing
used for process adjustment (eg - pH, viscosity, etc.), and for
validation studies (process - variable parameters, analytics -
robustness).
- Stability studies on marketed batches of finished products and or
active pharmaceutical ingredients, ongoing / follow up stability
(NOT applicable for stress / forced degradation tests).
- If the previous released GMP batch used as reference sample in
an OOS investigation produced OOS or questionable results the
investigation should be extended to include it.
- Batches for clinical trials – under cGMP, same rules for
investigation apply as for commercial batches.
Handling an OOS in a QC Lab 9
04 Sept 2012

10. Flow of investigation
In search of a root cause of OOS result
FDA officials say,
“If you didn’t document it, it didn’t happen.
In God we trust, for everyone else we require documentation.”
Handling an OOS in a QC Lab 10
04 Sept 2012

11. OOS Logic
Test by Lynn Torbeck
Document
No Report out
Out of Spec? results
Resample as
needed
Yes
Invalidate data, Yes Known Physical March 1999
Document,
Reason?
Start Over
No
No
Yes
2 nd Stage
Yes Original sample USP allows Yes (i.e. Content
Passes?
representative? resamples? Uniformity)
No No
Begin Lab Initial
Investigation USP <111> Outlier ID
Historical Data
Lab or Yes Yes Finish
Analyst Retest Passes?
Investigation
error?
No Copyright 1999 by
Yes No
L. Torbeck
Document
Other No and report
reason?
Document
Finish Review is Full
justification
investigation inconclusive Investigation
Yes
Yes Retest No
All pass? Retest n times
justified?
No
Handling an OOS in a QC Lab 11
04 Sept 2012

12. Handling an OOS in a QC Lab 04 Sept 2012 Sasha Nezlin 12

13. When to open a deviation
 If the investigation shows no assignable cause
for the laboratory based failure - i.e. OOS is
confirmed - then full scale manufacturing
investigation should be conducted
 this is a regulatory requirement!
 When to initiate a manufacturing investigation:
– after initial (phase 1) investigation reveals no
laboratory errors has occurred?
– or after full laboratory investigation (phase 2)
was completed without evidence of lab error?
Handling an OOS in a QC Lab 13
04 Sept 2012

14. RETEST SAMPLE SIZE
Handling an OOS in a QC Lab 14
04 Sept 2012

15. RETEST SAMPLE SIZE (cont.)
Original test Investigation / Retesting
One analyst Two analysts, of at least the same level of experience ?
One analyst, of higher level of experience ?
Same analyst? Same analyst after training?
1 replicate Two tests in duplicates ?
2 replicates Two tests in triplicates ? Three tests in duplicates?
3 replicates Two tests in 4 replicates?
Handling an OOS in a QC Lab 15
04 Sept 2012

16. RETEST SAMPLE SIZE (cont.)
Original 2nd
Analyst Analyst
Prep Prep Prep Prep
#1 #2 #1 #2
Inj 1 Inj 2 Inj 1 Inj 2 Inj 1 Inj 2 Inj 1 Inj 2
Original Instrument Second Instrument
Handling an OOS in a QC Lab 16
04 Sept 2012

17. RETEST SAMPLE SIZE (cont.)
 This is an unresolved issue and the statisticians are
still at it.
 Barr case: Judge Wolin indicated 7 retests were
enough to discard an invalid result.
 Could be too much or not enough.
 Currently n= 3 to n=9.
 PDA OOS committee promised to recommend...
 Industry has been doing 2 x 2 x 2 (which is 4
sample preparations with 8 measurements), but
your strategy should reflect your assay and its
criticality and use.
Handling an OOS in a QC Lab 17
04 Sept 2012

18. Tracking and Trending Investigations
All laboratory corrective/preventive actions,
investigations and deviations must be tracked
and trended:
 To track method / instrumentation problems
 To specifically evaluate analyst performance, and
to identify training needs
 To track product / process problems
 To trend significant shifts in laboratory data
 To identify systematic issues and ensure
appropriate actions taken
Handling an OOS in a QC Lab 18
04 Sept 2012

19. Expectations of the regulator / auditor
 OOS results will be generated by the lab
 Comprehensive, honest approach to
investigation of OOS results is demonstrated
 Evaluation of OOS results is performed using
scientifically valid principles  3G
 Lab demonstrably learns from the experience
 Permanent solution to the problem / root cause
 Prevention, not just correction
3G™ Good science, Good judgment, Good documentation
Handling an OOS in a QC Lab 19
04 Sept 2012

20. References and useful links
1. FDA: Guidance for Industry Investigating Out-of-Specification (OOS) Test Results for
Pharmaceutical Production, Guidance for Industry, October 2006
(http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm070287.pdf)
2. MHRA “Out Of Specification Investigations”
(http://www.mhra.gov.uk/home/groups/is-insp/documents/websiteresources/con100182.pdf)
3. MHRA Out of specification (OOS) FAQs
(http://www.mhra.gov.uk/Howweregulate/Medicines/Inspectionandstandards/GoodManufacturingPractice/FAQ/OOSFA
Qs/index.htm)
4. Jenny Hantzinikolas, GMP Inspector, Office of Manufacturing Quality Laboratory, TGA
“Investigations - A Regulatory Perspective” 2008
5. United States of America, Plaintiff V. Barr Laboratories Inc., Defendants, Civil Suite 92-1744
(http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/Manufacturing/UCM216425.pdf)
(http://www.navigategmp.com/pdf/BarrLabs.pdf)
6. Lynn Torbeck “Preventing the practice of testing into compliance. A practical solutions guide”,
Pharmaceutical Technology, October 2002
7. Jeffrey D. Hofer “Considerations When Determining a Routine Sample Size for a Retest
Procedure”, Pharmaceutical Technology, November 2003
Handling an OOS in a QC Lab 20
04 Sept 2012

21. Questions?
Handling an OOS in a QC Lab 21
04 Sept 2012