UH: QC

Quality Control for regulated EnvironmentsUniversity of Houston1Handling Out-of-Specification Results

OOS (Out of Specification)2The 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 exceptionDeviations/exceptions are events where something happened that was unexpected or unplanned (i.e. event transpired differently than detailed in the SOP or batch record)

CGMPs321 CFR 211.192Any 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.

CGMPs421 CFR 211.192The 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 Case5Civil 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 Decision6In 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 resultsBarr lost and the judge who heard the case, Judge Wolin, issued a ruling commonly referred to as the Barr DecisionThe 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 doneConsequently, 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 eventThis creates additional work for QC laboratories, and an intense desire to simplify investigations by blaming OOS results on laboratory errorThis can create situations in which retesting leads to testing a product into compliance with repeated claims of laboratory errorAn outside observer might conclude that the laboratory is not competent to be performing the test.

Barr (contd)7Most 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 resultThe number of replicates is based on previous data concerning the variability of the product and test methodIn the Barr Decision, however, the judge offered the opinion that seven passing results are needed to overcome one OOS resultThis caused a number of companies to adopt a "seven replicate rule" when confronted with an OOS test resultThis procedure and the testimony that originally led to the judge's conclusion were completely without scientific foundation.

OOS Topics in the Barr Case8Out of specification resultsProduct failureInformal and formal investigationsTesting and retestingSampling and resamplingAveragingOutliers

Barr Decision9Failure investigation is centralFailure investigationImmediateTimely follow-upAppropriate resolutionDocumented

Avoid Testing into Compliance10Retesting: Additional test should be for the same sample, only after a failure investigation is underwayTesting into compliance is not acceptableRetest only by predetermined written SOP

Linkage of Systems11

EVENTInvestigationCorrective ActionPreventive Action

Root CauseIdentify All LotsConsider All PossibilitiesProduct Impact

Lot Disposition

Scope and Definition12Purpose of Investigations Identify CorrectEvaluate 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?13Are 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 Report14Reason for the InvestigationWhat Event or Finding Prompted InvestigationHow and When IdentifiedRemember to Consider Tracking / Trending EvaluationConsider Related Activities, Think GlobalDescribe What HappenedWhatWhenWhereWhat Immediate Actions Were Taken

Content of Investigation Report15Identify Other Batches Potentially AffectedJustify SelectionRemember Distributed LotsIdentify Root Cause, Where PossibleWhy, Why, WhyDocument Factors Considered Ensure Data Support ConclusionsAvoid Conjecture Often a Multi-Disciplinary Exercise

Content of Investigation Report16Identify Corrective ActionsResist: Operator Error Corrected with RetrainingMay Include Additional Monitoring / AssessmentImplementation Must be TimelyIdentify Preventive ActionsSuccess Depends on Adequate Identification of Root CauseInterim Solution May Include Additional Monitoring

Content of Investigation Report17Evaluate Product Impact / Disposition Additional Testing / Results Justify Accept / Reject CriteriaJustify if Differences in Lot DispositionRemember to Consider Tox EvaluationProvide Follow-up to Assure EffectivenessDoes Preventive Action Provide a Durable FixWhat are Criteria for Durable Fix

OOS Investigations: FDA Focus18Pre-established protocol for investigating OOS resultsSummary of specific investigation steps:Evaluation of other batchesConclusion and follow-upAction necessary to prevent similar recurrences

OOS Investigations: FDA Focus (continued)19Timely investigation must be performed within 30 business daysInvestigate before retestWell documentedScientifically sound

Where do companies run into trouble with their investigations?20Lack of Documented InvestigationIncomplete InvestigationFactors Not Considered / DocumentedAssociated Lots Not Identified / EvaluatedRoot Cause Not Established or JustifiedConclusions Not Supported by DataTimelines Not Followed, Not ExtendedCorrective / Preventive Actions Not Implemented, Tracked or CompletedEffectiveness Not Verified