OOS
Guidance
September 6, 2013

Sept 6, 2013

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Overview
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cGMP’s 21 CFR 211.192
U.S.A. vs. Barr Laboratories, Inc.
Able Laboratories
Reportable Results
Specifications
OOS flowchart
Specific OOS topics
Sept 6, 2013

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Specific Topics
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OOS definition
Initial and full investigations
Testing and retesting
Sampling and resampling
Averaging and Outliers

Sept 6, 2013

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cGMP’s 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.”

Sept 6, 2013

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cGMP’s 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.” Sept 6, 2013

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Barr Court Case
• Civil action by FDA, June 12, 1992.
• Judge Alfred M. Wolin
• Can the FDA expand the cGMP’s interpretation into the statistical areas of outliers, retesting, resampling, averaging and sample size and other areas of failure investigations, …”
Sept 6, 2013

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Barr Background
• “The current conflict surrounding these rules is best characterized as a confrontation between a humorless warden and his uncooperative prisoner. … These witnesses revealed an industry mired in uncertainty and conflict, guided by vague regulations which produce tugs-of-war of varying intensity.” Sept 6, 2013

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Able Laboratories
• On May 23, 2005, Able labs issued a Class
II recall of all of its 46 drug products
• The company immediately suspended operations and laid off 200 employees.
• The stock price in the last two weeks of
May dropped by more than 90%.
• The company went out of business.
Sept 6, 2013

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OOS Philosophy
• “Testing lies at the heart of a drug manufacturer’s successful operation.
Through testing companies validate their processes and ensure the quality of batches for release.” Judge Wolin
• If we can’t trust our measurements, we don’t have anything.
Sept 6, 2013

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Draft Version
• 30 September 1998
• “Guidance for Industry – Investigating Out of Specification (OOS) Test Results for
Pharmaceutical Production”
• Submitted comments by 30 November 1998
• These comments can be inspected by going to the FDA offices.
Sept 6, 2013

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Final Guidance
• 12 October 2006 in the Federal Register
• FDA authors include:
– Richard Friedman – Director of the Division of
Manufacturing & Product Quality
– Paul Haynie is responsible for the Guidance
– (301) 827-9020
– Hayniep@cder.fda.gov
Sept 6, 2013

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Controversial Topics
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Definition of reportable values?
Use of averaging?
Number of retests?
Second analyst?
Use of outlier testing?
What specification limits?
Defining testing into compliance?
Sept 6, 2013

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OOS Definition
• “… the term OOS results includes all test results that fall outside the specification or acceptance criteria established in drug applications, drug master files, official compendia, or by the manufacturer.
• Two Major Issues:
– What test results?
– What specifications?
Sept 6, 2013

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Scope
• “These laboratory tests are performed on active pharmaceutical ingredients, excipients and other components, in-process materials and finished drug products.
• “Laboratory testing … is necessary to confirm that components, container and closures, in-process materials and finished products conform to specifications, including stability specifications.
Sept 6, 2013

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Scope
• This guidance applies to chemistry-based laboratory testing of drugs regulated by
CDER.
• “The term also applies to all in-process laboratory tests ….”
• “… applies to in-house testing of drug product components that are purchased …”
Sept 6, 2013

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Reportable Values for Out-of-Specification
Test results
Lynn Torbeck
Pharmaceutical Technology
Vol. 23, No. 2, February 1999
Special