Investigation of out of specifications.pdf

OOS

1. Investigation Of OOS

2. Laboratory Analysis
OOS (OOT) Result
Phase II Investigation
Manufacturing
Investigation
Product Impact
Assessment
Additional Laboratory Test
Batch Disposition
Phase l Investigation
Satisfactory
Overview

3. Phase I Investigation
Phase l Investigation
No Further Investigation
Required
Obvious Error
Document and Correct
Invalid Result
Manufacturing Process
Investigation
Additional Laboratory
Investigation
No Error found
Laboratory Data Analysis, Hypothesis Test
Full Scale / Phase II
Investigation
Overview

4. Follow Approved Protocol
Execute Investigation (Retesting and/or Resampling)
Phase II
Additional Laboratory Test
OOS Results Obtained
Confirm OOS
No Further Retest
No Assignable Cause
Report All Results
Assignable Cause
Report Retest
Results
Generate
CAPA
Impact Assessment/
Disposition Batch
Invalidate
Original
Results
Batch Disposition
Phase III Investigation
Overview

5. Identification of OOS Result
•Out-of-Specification (OOS) Result –
•Test result that does not comply with the pre-determined acceptance criteria.
•Test results that fall outside of established acceptance criteria which have been established in official compendia and/or by
company documentation.
•Out of Trend (OOT) Result –
•Is generally a stability result that does not follow the expected trend, either in comparison with other stability batches orwith
respect to previous results collected during a stability study. However the trends of starting materials and in-process samples may
also yield out of trend data.
•The result is not necessarily OOS but does not look like a typical data point.
•Should be considered for environmental trend analysis such as for viable and non viable data (action limit or warning limit trends)
•Atypical / Aberrant / Anomalous Result –
•Results that are still within specification but are unexpected, questionable, irregular, deviant or abnormal. Examples wouldbe
chromatograms that show unexpected peaks, unexpected results for stability test point, etc.
Investigation

6. Investigation of OOS
Investigations of "Out of Specification (OOS) / Out of Trend (OOT)/ Atypical results" have to be done in cases of:
Batch release testing and testing of starting materials.
In-Process Control testing: if data is used for batch calculations/decisions and if in a dossier and on Certificates of Analysis.
Stability studies on marketed batches of finished products and or active pharmaceutical ingredients, on-going / follow up stability
(no stress tests)
Previous released batch used as reference sample in an OOS investigation showing OOS or suspect results.
Batches for clinical trials.
All solutions and reagents should be retained until all data has been second person verified as being within the defined acceptance
criteria.
Pharmacopoeia have specific criteria for additional analyses of specific tests (i.e. dissolution level specification for S1, S2 & S3 testing;
Uniformity of dosage units specification for testing of 20 additional units; Sterility Testing).
However if the sample test criteria is usually the first level of testing and a sample has to be tested to the next level this should be
investigated as it is not following the normal trend.
The OOS process is not applicable for In-process testing while trying to achieve a manufacturing process end-point i.e. adjustment of the
manufacturing process. (e.g. pH, viscosity), and for studies conducted at variable parameters to check the impact of drift (e.g.process
validation at variable parameters).
Investigation

7. Investigation of OOS
Objective
•To identify the route cause
•To conclude by a decision either
batch rejection or release
•To take appropriate corrective and
preventive action
Should Be
•Through
•Timely
•Unbiased
•Well documented
•Scientifically sound
Investigation

8. Phase I laboratory investigation
•Investigation should include an initial assessment of laboratory
data
•Investigation should be done before discarding test preparation
•Hypothesis test can be conducted using the original test
preparations
•If obvious error found laboratory test result should be invalidated
and retest should be done
Investigation

9. Investigation

10. Phase II / Full Scale Investigation
•No obvious laboratory error found in initial laboratory
investigation
•For contract laboratory, laboratory should send the data
obtained to manufacturers for full scale investigation
•Should be conducted using predefined procedure (SOP)
•Production procedure review
•Sampling procedure review
•Additional laboratory testing
•Highest priority
Investigation

11. Phase II / Full Scale Investigation
Phase II
Investigation
Manufacturing
investigation
Additional
Laboratory Test
Investigation

12. Manufacturing/ Production Process Review
•Should be conducted by QCU
•Should involve all other relevant department i.e.
production, development, engineering, if needed
•If contract manufacturer then all site (contract
manufacturing site)
•timely, thorough, and well-documented
Investigation

13. Written record of the review should include the following
information
Aclearstatementofthereasonfortheinvestigation.
Asummaryoftheaspectsofthemanufacturingprocessthatmay
havecausedtheproblem.
Theresultsofadocumentationreview,withtheassignmentof
actualorprobablecause.
Theresultsofareviewmadetodetermineiftheproblemhas
occurredpreviously.
Adescriptionofcorrectiveactionstaken.
Manufacturing/ Production Process Review
Investigation

14. If error found, investigation terminated & product rejected
However, a failure investigation that extends to other batches or
products that may have been associated with the specific failure
must be completed
If reprocessed after additional testing, the investigation should
include comments and the signatures of appropriate production and
quality control personnel
Appropriate CAPA should be taken
Manufacturing/ Production Process Review
Investigation

15. Should be conducted by QCU
Should involve all other relevant department i.e.
production, development, engineering, if needed
If contract manufacturer then all site (contract
manufacturing site)
Timely, thorough, and well-documented
Manufacturing/ Production Process Review
Investigation

16. Additional Laboratory Testing
Retesting
Resampling
Investigation

17. Additional Laboratory Testing
Decision should be taken based on the objective of the testing &
should have sound scientific judgment
Should have predefined retesting plan
Should be done by analyst other than original analyst
2
nd
analyst should be qualified at least like original analyst
should be from the same sample portion which has generated
OOS result
Investigation
Retesting

18. Additional Laboratory Testing
Should be done to identify instrument malfunction, sample handling
error e.g. dilution error
Testing to compliance is prohibited
Maximum number of retest should be defined in SOP and should not be
adjusted depending on the obtained result
The firm's predetermined retesting procedures should contain a point
at which the additional testing ends and the batch is evaluated
If the results are unsatisfactory at this point, the batch is suspect and
must be rejected or held pending further investigation
Investigation
Retesting

19. Additional Laboratory Testing
Any deviation from SOP should be rare and any deviations from
written specifications, sampling plans, test procedures, or other
laboratory control mechanisms shall be recorded and justified.
In such cases, before starting additional retesting, a protocol
should be prepared (subject to approval by the QCU) that
describes the additional testing to be performed and specifies the
scientific and/or technical handling of the data.
Investigation
Retesting

20. Additional Laboratory Testing
In the case of a clearly identified laboratory error, the retest results
would substitute for the original test result. All original data should be
retained, however, and an explanation recorded This record should be
initialed and dated by the involved persons and include a discussion of
the error and supervisory comments.
If no laboratory or calculation errors are identified in the first test,
there is no scientific basis for invalidating initial OOS results in favor of
passing retest results. All test results, both passing and suspect, should
be reported and considered in batch release decisions. (In other words,
all data are reported in, for example, quality control reports, batch
records, Certificates of Analysis)
Investigation
Retesting

21. Resampling
Should rarely occur!
If insufficient quantity of the original sample remains to perform all further testing then the procedure for
obtaining a resample must be discussed and agreed by QA/Contract Giver/QA equivalent. The process of
obtaining the resample should be recorded within the laboratory investigation.
Re-sampling should be performed by the same qualified methods that were used for the initial sample.
However, if the investigation determines that the initial sampling method was in error, a new accurate sampling
method shall be developed, qualified and documented.
It involves the collecting a new sample from the batch.
Will occur when the original sample was not truly representative of the batch or there was a
documented/traceable lab error in its preparation.
Evidence indicates that the sample is compromised or invalid.
Sound scientific justification must be employed if re-sampling is to occur.
Investigation

22. If the batch is rejected there still needs to be an investigation.
To determine:
if other batches or products are affected.
identification and implementation of corrective and preventative action.
Phase III Investigation
Investigation

23. Phase III investigation
ThePhaseIIIinvestigationshouldreviewthecompletedmanufacturing
investigationandcombinedlaboratoryinvestigationintothesuspectanalytical
results,and/ormethodvalidationforpossiblecausesintotheresultsobtained.
Toconcludetheinvestigationalloftheresultsmustbeevaluated.
Theinvestigationreportshouldcontainasummaryoftheinvestigations
performed;andadetailedconclusion.
Formicrobiologicalinvestigations,whereappropriate,useriskanalysistoolsto
supportthedecisionstakenandconclusionsdrawn.Itmaynothavebeenpossible
todeterminetheactualrootcausethereforearobustmostprobablerootcause
mayhavetobegiven.
Thebatchqualitymustbedeterminedanddispositiondecisiontaken.
Investigation

24. Reporting Test Result
Result
Averaging
Appropriate
In-
appropriate
Outlier
Reporting

25. Interpretation of investigation result
TheQCUisresponsibleforinterpretingtheresultsoftheinvestigation
InitialOOSresultdoesnotnecessarilymeanthesubjectbatchfailsandmustbe
rejected.
OOSresultshouldbeinvestigated,andthefindingsoftheinvestigation,
includingretestresults,shouldbeinterpretedtoevaluatethebatchandreacha
decisionregardingreleaseorrejection.
Whereaninvestigationhasrevealedacause,andthesuspectresultis
invalidated,theresultshouldnotbeusedtoevaluatethequalityofthebatchor
lot
WheretheinvestigationindicatesanOOSresultiscausedbyafactoraffecting
thebatchquality(i.e.,anOOSresultisconfirmed),theresultshouldbeusedin
evaluatingthequalityofthebatchorlot.
Reporting

26. Interpretation of investigation result
A confirmed OOS result indicates that the batch does not meet
established standards or specifications and should result in the batch's
rejection.
For inconclusive investigations —in cases where an investigation
(1) does not reveal a cause for the OOS test result
(2) does not confirm the OOS result
The OOS result should be given full consideration in the batch or lot
disposition decision.
In the first case (OOS confirmed), the investigation changes from an
OOS investigation into a batch failure investigation, which must be
extended to other batches or products that may have been associated
with the specific failure.
Reporting

27. Batch Disposition
IfnolaboratoryorcalculationerrorsareidentifiedinthePhaseIandPhaseIIthereisno
scientificbasisforinvalidatinginitialOOSresultsinfavourofpassingretestresults.Alltest
results,bothpassingandsuspect,shouldbereported(inallQCdocumentsandanyCertificates
ofAnalysis)andalldatahastobeconsideredinbatchreleasedecisions.
Iftheinvestigationdeterminesthattheinitialsamplingmethodwasinherentlyinadequate,a
newaccuratesamplingmethodmustbedeveloped,documented,andreviewedandapprovedby
theQualityAssuranceresponsibleforrelease.Aconsiderationshouldbegiventootherlots
sampledbythesamemethod.
AninitialOOSresultdoesnotnecessarilymeanthesubjectbatchfailsandmustberejected.The
OOSresultshouldbeinvestigated,andthefindingsoftheinvestigation,includingretestresults,
shouldbeinterpretedtoevaluatethebatchandreachadecisionregardingreleaseorrejection
whichshouldbefullydocumented.

28. Disposition of Batch
In those cases where the investigation indicates an OOS result is caused by a factor affecting the batch
quality (i.e., an OOS result is confirmed), the result should be used in evaluating the quality of the
batch or lot. A confirmed OOS result indicates that the batch does not meet established standards or
specifications and should result in the batch's rejection and proper disposition. Other lots should be
reviewed to assess impact.
For inconclusive investigations —in cases where an investigation:-
(1) does not reveal a cause for the OOS test result and
(2) does not confirm the OOS result
the OOS result should be given full consideration (most probable cause determined) in the batch or
lot disposition decision by the certifying QP and the potential for a batch specific variation also
needs considering.
Any decision to release a batch, in spite of an initial OOS result that has not been invalidated, should
come only after a full investigation has shown that the OOS result does not reflect the quality of the
batch. In making such a decision, Quality Assurance/QP should always err on the side of caution.

29. Concluding The Investigation
•Theresultsshouldbeevaluated,thebatchqualityshouldbe
determined,andareleasedecisionshouldbemadebytheQCU.
•TheSOPsshouldbefollowedinarrivingatthispoint.
•Onceabatchhasbeenrejected,thereisnolimittofurther
testingtodeterminethecauseofthefailuresothatacorrective
actioncanbetaken.
Reporting

30. Averaging
Thevalidityofaveragingdependsuponthesampleanditspurpose.Usingaveragescanprovidemore
accurateresults.Forexample,inthecaseofmicrobiologicalassays,theuseofaveragesbecauseofthe
innatevariabilityofthemicrobiologicaltestsystem.Thekineticscanofindividualwells,orendotoxin
datafromanumberofconsecutivemeasurements,orwithHPLCconsecutivereplicateinjectionsfromthe
samepreparation(thedeterminationisconsideredonetestandoneresult),however,unexpected
variationinreplicatedeterminationsshouldtriggerinvestigationanddocumentationrequirements.
Averagingcannotbeusedincaseswhentestingisintendedtomeasurevariabilitywithintheproduct,
suchaspowderblend/mixtureuniformityordosageformcontentuniformity.
Relianceonaveraginghasthedisadvantageofhidingvariabilityamongindividualtestresults.Forthis
reason,allindividualtestresultsshouldnormallybereportedasseparatevalues.Whereaveragingof
separatetestsisappropriatelyspecifiedbythetestmethod,asingleaveragedresultcanbereportedas
thefinaltestresult.Insomecases,astatisticaltreatmentofthevariabilityofresultsisreported.For
example,inatestfordosageformcontentuniformity,thestandarddeviation(orrelativestandard
deviation)isreportedwiththeindividualunitdosetestresults.
Reporting

31. Averaging
InthecontextofadditionaltestingperformedduringanOOSinvestigation,
averagingtheresult(s)oftheoriginaltestthatpromptedtheinvestigation
andadditionalretestorresampleresultsobtainedduringtheOOS
investigationisnotappropriatebecauseithidesvariabilityamongthe
individualresults.Relyingonaveragesofsuchdatacanbeparticularly
misleadingwhensomeoftheresultsareOOSandothersarewithin
specifications.Itiscriticalthatthelaboratoryprovideallindividualresultsfor
evaluationandconsiderationbyQualityAssurance(ContractGiver/QP).
Alltestresultsshouldconformtospecifications(Note:abatchmustbe
formulatedwiththeintenttoprovidenotlessthan100percentofthe
labelledorestablishedamountoftheactiveingredient.
Averagingmustbespecifiedbythetestmethod.
Reporting

32. Outlier Test
An outlier may result from a deviation from prescribed test methods, or it may be the
result of variability in the sample. It should never be assumed that the reason for an
outlier is error in the testing procedure, rather than inherent variability in the sample
being tested.
Statistical analysis for Outlier test results can be as part of the investigationand
analysis. However for validated chemical tests with relatively small variance and that
the sample was considered homogeneous it cannot be used to justify the rejection of
data.
While OOS guidance is not directly intended for bioassay analysis, it can be used as a
starting point for the investigation. Compendia such as the BP; PhEurand USP, provide
guidance on outliers for these types of analysis.
Reporting

33. Stability OOS/OOT
Stability OOS/OOT situations should be escalated as soon as the suspect result is
found. Follow the investigation as above for Phase I and Phase II. For OOS
Situations Regulatory agencies will require notification within a short time point
of discovery due to recall potential.
If abnormal results are found at any stability interval which predicts that the test
results may be OOS before the next testing interval, schedule additional testing
before the next scheduled testing interval. This will help better determine
appropriate actions to be taken.
The stability OOS should link to the Product Recall procedures.

34. Stability OOS/OOT
To facilitate the prompt identification of potential issues, and to ensure data
quality, it is advantageous to use objective (often statistical) methods that
detect potential out-of-trend (OOT) stability data quickly.
OOT alerts can be classified into three categories to help identify the
appropriate depth for an investigation. OOT stability alerts can be referred to
as:
analytical,
process control, and
compliance alerts,
As the alert level increases from analytical to process control to compliance
alert, the depth of investigation should increase.

35. Stability OOS/OOT
AcompliancealertdefinesacaseinwhichanOOTresultsuggeststhe
potentialorlikelihoodforOOSresultstooccurbeforetheexpirationdate
withinthesamestabilitystudy(orforotherstudies)onthesameproduct.
ThestabilityOOSshouldlinktotheProductRecallprocedures.
HistoricaldataareneededtoidentifyOOTalerts.
Ananalyticalalertisobservedwhenasingleresultisaberrantbutwithin
specificationlimits(i.e.,outsidenormalanalyticalorsamplingvariationand
normalchangeovertime).