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Guideline for Handling of Out of Specification (OOS) results occurs during analysis of Raw Material and Pharmaceutical Drug Products (Different stages like – In-process, Bulk, Intermediate, Finished Product & Stability Study Samples)

Handling Out of Specification (OOS) Results

1.0   Objective :

• • To lay down the procedure for investigation of Out of Specification (OOS) result(s) that occurs during sample testing in the Quality Control Laboratory.

• • This SOP is not applicable to microbiological analysis.

2.0   Scope :

• • This SOP is applicable to Out of Specification (OOS) results obtained or all tests (Physical, Chemical) performed in the laboratory for –

• • • Raw Materials,

• • • Packing Materials,

• • • In-process,

• • • Semi-finished/Intermediates and

• • • Finished Products including stability studies,

• • • Process validation samples, and

• • • Sample tested as part of complaint investigation, in Quality Control Laboratory.

3.0   Responsibility – Handling of Out of Specification (OOS) Results

• • Analyst / Executive:

• • Be aware of potential problems that could occur during the testing.

• • Use calibrated equipments.

• • To inform and initiate the Out of Specification (OOS) procedure.

• • Information of Out of Specification (OOS) results to Section In-charge / Head of Department.

• • The retail the sample preparation and initiate superior in case of any suspected results.

• • To investigate in co-ordination with Section In-charge / Head of Department.

• • Section In-charge/ Head-Quality Control

• • To interrogate / interview the analyst to identify the root cause for the Out of Specification (OOS)

• • To conduct the laboratory investigation and timely completion.

• • Review Out of Specification (OOS) report

• • Plan hypothesis testing during laboratory investigation

• • Report the Out of Specification (OOS) to QA department

• • To trend the Out of Specification (OOS) (Quarterly as well as annually)

• • Head Quality Assurance / Designee

• • Evaluate the Out of Specification (OOS) results and instruct for investigation if required.

• • Review and approve the Out of Specification (OOS) trend analysis report.

• • Suggest necessary corrective and preventive action if required.

• • Dispose the batch.

• • Inform QP /MA holder through DRA.

• • Inform contract manufacturers on Out of Specification (OOS) results.

• • Cross Functional Departments:

• • To support on investigation with respect to manufacturing site.

4.0   Procedure – Handling of Out of Specification (OOS) Results

• • Definitions of Terms :

• • Out of Specification (OOS) Results

• • The result that does not meet the pre-established specification of test product shall be called as OOS (out of specification).

• • Assignable Cause / Conclusive Error:

• • A cause, which is identified as the reason to invalidate a test result.

• • The assignable cause as conclusion derived from direct or indirect evidence found during the investigation process. 

• • Non- Assignable Cause / Inconclusive Error:

• • A cause, which is other than assignable cause and cannot be assigned to any finding.

• • Retest :

• • Performing the test over again using material / product from original composite sample, if it has not been compromised and / or is still available. If not, a new sample to be used.

• • Re-dilution:

• • The act of repeating test method dilution(s) from the original stock sample and / or standard solution and measuring the final dilution.

• • Re-sample:

• • A new sample from the original container where possible, required in the event of insufficient material from the original composite sample or proven issue with original sample integrity.

• • Obvious error :

• • An event / apparent / clear reason for obtaining an Out of Specification (OOS) result (but not limited to).

• • • Calculation error,

• • • Spillage of sample solution,

• • • Incomplete transfer of sample,

• • • Incorrect instrument parameters and

• • • Sample preparation.

• • Hypothesis /  Investigative testing:

• • It is the testing performed to help confirm or discount a possible route cause i.e. what might have happened that can be tested?

• • For example, it shall include further testing regarding sample filtration / centrifugation, sonication / extraction, dilution and potential equipment failure etc. multiple hypothesis can be explored.

• • This is applicable to Phase-Ib investigation. 

• • General Procedure :

• • After completion of Out of Specification (OOS) investigation, the same shall be communicated to respective QP’s / Regulatory bodies and customer based on technical agreement.

• • The Out of Specification (OOS) process isn’t 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, LOD, residual solvent etc.)

• • The Out of Specification (OOS) procedure isn’t applicable to scale up / trail batches method validation / verification and method transfer.

• • While performing the analysis, analyst must not knowingly continue an analysis after occurring of some obvious errors like spilling of sample solution or incomplete transfer of a sample that can lead to unexpected results.

• • After completion of analysis, analyst must check the data for compliance with specifications.

• • If no obvious explanation exists for Out of Specification (OOS) result, then follow the given below procedure.

• • • Do not discard the Standard and Test Preparations

• • • Retain all Glassware and Sample,

• • • Check the whole analysis for compliance (Self-check)

• • • Report the Out of Specification (OOS) result immediately to Head QC / Designee.

• • • In case the original sample isn’t available then resample only after the approval of Head QA.

• • There is no need of formal laboratory investigation in situation like power failure, instrument failure, spilling of sample solution or incomplete transfer of sample, but the same shall be reported and recorded appropriately. (Refer SOP “Handling of Laboratory Incident”.

• • After confirmation of Out of Specification (OOS) results immediately OOS shall be logged.

• • Log all the OOS result in OOS log (refer Annexure – III) and assign OOS number as follows:

OOS/XX/YYY

OOS – Out of Specification

XX    – Denotes last two digits of year (21 for 2021)

YYY – Denotes serial number starting from 001 in calendar year

• • Head QC shall inform on OOS results to Head QA, once it is logged in Out of Specification (OOS) register.

• • Single Out of Specification (OOS) shall be logged and accordingly investigation shall be carried out for one set of sample analysed / prepared on the same day and same test.

• • Raise a separate form of theOut of Specification (OOS) investigation form for each test and every test that is not complying with the specification.

• • For example : If a sample isn’t complying with specification for “Moisture Content” and “Related Substances”, then raise two separate OOS forms.

• • Averaging shall be used only incase where, either the specification as per Guidelines or test procedure or the protocol specifies so (example S1, S2 & S3 criteria of dissolution).

• • In case the trend is abnormal then it shall be logged as OOT (Refer SOP for Out of Trend ) and shall be investigating accordingly before entering to next stage criteria.

• Cause response for occurrence of Out of Specification (OOS) shall be divided in two categories:

• • Assignable Cause

• • Non-assignable cause.

• Out of Specification (OOS) results with assignable cause can be due to but not limited to:

• • Laboratory error for e.g.:

• • Wrong dilution,

• • Usage of different volumetric glassware,

• • Instrumental error,

• • Calculation error,

• • Mistake in following the method of analysis,

• • Usage of incorrect standard and / or sample etc.

• • Error in sampling

• • Handling, storage or mix up of samples.

• • Non-process related or operator error.

• There are two type of categorized for the Out of Specification (OOS) investigation:

• • Phase-I Investigation (Laboratory Investigation)

• • Phase-II Investigation (Full Scale Investigation)

• Phase – IA: Out of Specification (OOS) – Investigation

• • As a toll for investigation, analyst and Head Quality control shall use relevant portion of checklist (Annexure II) and not necessarily in the sequential order in which the points are listed.

• • If required specific questionnaire shall also be prepared for a particular test.

• • If during investigation, obvious error(s) identified as calculation error,

• • Then the analyst shall recalculate the results and document shall be corrected.

• • Check whether it its Re-occurrence for the discrepancy notified and if its repeated then previous CAPA shall be verified.

• • If during investigation, obvious error(s) identified other than the calculation error.

• • Then the analysis shall be repeated for one more time in duplicate (i.e. single preparation and two injection) using original solution / sample portion by the same analyst or equally competent and qualified analyst in absence of first analyst taking care to omit all errors identified during the investigation.

• • If the original solution / sample portion are found to be not suitable,

• • Then freshly prepared solutions/fresh portion from the original sample shall be used.

• • A review of the reasons / investigation for any laboratory errors shall be assessed with respect to education / training need, procedural revision, impact on other batches, analysis done during the same run and impact on previous analysis done by the analyst and CAPA shall be in place.

• • Consider the sample to be “passing” if the above recalculated or repeat analysis results complies with the specification and forward the investigation report to QA.

• • Consider the sample to be “failing” if the above recalculated or repeat analysis results doesn’t comply with the specification and forward the investigation report to QA for further evaluation.

• • If the repeat analysis results meet the specification then the initial Out of Specification (OOS) results shall be invalidated due to obvious reason and repeated results (individual with average results) shall be reported for the disposition of the product / material under test.

• • Corrective / preventive actions determined shall be implemented in case of identified obvious reason, if applicable and forward the investigation report to QA.

• • In case the above recalculated results or repeated analysis results fails to meet the specification,

• • Then forward the investigation report to QA for further evaluation.

• • Head QA/ designee shall inform on the Out of Specification (OOS) to QP/MAH / contact giver the OOS.

• • Phase – IB: Out of Specification (OOS) – Investigation

• • When the laboratory error isn’t identified at phase IA,

• • Attempt shall be made to identify the probable cause by conducting hypothesis or investigation testing.

• • The hypothesis study shall be conducted consisting of several experiments designed to find out the cause as per Annexure II procedure (but not limited to).

• • Hypothesis testing shall be performed using the original aliquots by re-measurement to confirm / in-validate the original Out of Specification (OOS) results, regarding

• • • Sample filtration / centrifugation,

• • • sonication / extraction and dilution etc..,

• • If is has not been compromised and/or is still available.

• • Hypothesis / investigative testing shall be done as follows (but not limited to):

• • • Reinjection from same vial of standard and test solution.

• • • Re-filtration / re-centrifugation of the original test solution.

• • • Re-dilution from original stock solution.

• • • Additional sonication / shaking of the same solution where ever applicable.

• • • Interview the analyst to assess knowledge of the correct procedure.

• • Hypothesis testing results shall not be used to replace original suspected analytical results.

• • It can only be used to confirm or discount a probable cause.

• • From the above hypothesis testing, if assignable cause identified then invalidate the initial test data

• • Repeat the testing using original sample preferably by the first analyst or equal competent and qualified analyst in case of non-availability of first analyst under supervision by omitting the error.

• • If original sample not sufficient to complete the investigation testing or sample is compromised or sample integrity is suspected,

• • Re-sampling shall be performed with sound scientific justification and approved by Head QA.

• • Consider the sample to be “passing” only if results comply with the specification and forward the investigation report for QA comments.

• • A review of the reason/ investigation for laboratory errors shall be assessed with respect to education / training needs, protocol revision, impact on other batches analysis done during the same run, impact on other batches, impact on previous analysis done by the analyst and CAPA shall be put in place.                  

• • Once the final conclusion from laboratory arrived, the same shall be indicated in the report of Laboratory Investigation of Out of Specification (OOS) results and forward to QA with all relevant attachments for evaluation and disposition.

• • When a final conclusion is reached as “consider sample as passed” the same shall be considered as final result by replacing the originally obtained Out of Specification (OOS) results.

• • The photocopy of Out of Specification (OOS) report shall be attached along with the corresponding analytical report.

• • From the above hypothesis testing, if no assignable or root cause is identified or if the results doesn’t comply with the specification, then forward investigation report to QA for phase II investigation.

• • In case of repeat failures during stability studies, owing to the inherent nature of the molecule towards stress condition, then stability study shall be continued as per protocol for stability data generation and regulatory filing purpose. Out of Specification (OOS), if any, shall be logged and investigated appropriately till the time of study.

• Review of Phase IA and IB investigation at Quality Assurance:        

• • Head QA or designee shall review the laboratory investigation finding and completeness of investigation.

• • Where necessary, Head QA or designee shall recommend for additional investigation / data.

• • Based on review, where obvious error / assignable cause for obtaining an Out of Specification (OOS) is identified in the laboratory,

• • Head QA or designee shall ensure proper CAPA is in place and shall dispose the OOS result once proposed actions are completed.

• • Based on review, where obvious error / assignable cause for obtaining an Out of Specification (OOS) is not identified in the laboratory,

• • Head QA or designee shall review the data for completeness and propose for phase II investigation.   

• Phase II Full Scale Investigation of Out of Specification (OOS) Result:

  • Phase IIA: Review of manufacturing / Vendor and raw material and packaging material:  

• • QA shall intimate the failure details to relevant function like warehouse / manufacturing / vendor (where necessary) and initiate the investigation.

• • Relevant function shall review the following (but not limited to) to identify, if any assignable cause: 

• • • Summation of process sequences that shall have caused the problem.

• • • Review of production activity to confirm the operator is properly trained, the appropriate standard operating procedures are available and were followed and instructions given in the batch records were followed.

• • • Calculations review.

• • • Review of performance of machine(s) / personnel /associated with the batch.

• • • Review of critical process parameters in the batch.

• • • Evaluation of storage and transportation of raw materials and samples used in the batch.

• • • Evaluation of sampling procedure.

• • • Historical trends, where applicable, including problem that has occurred previously.

• • • The investigation shall be comprehensive to evaluate the impact on previous batches.

• • • Nature of materials used in the batch manufacturing (e.g. hygroscopic, light sensitive etc.)

• • • Evaluation of materials used in the other batches (has the problem been noticed before).

• • • History of vendor.

• • • Impact on earlier supplies.

• • • Any other specific material related behavior.

• • • Vendor investigation report (where necessary)

• • • Review of DMF for raw material as and when required.

• • • Review of packaging material process.

• • During investigation and conclusion, assistance of other department(s) shall be sought as appropriate.

  • QA shall review the sampling levels for the material / product.

• • In case of normal sampling, as per SOP is being carried out, 100% sampling shall be recommended based on criticality and nature of Out of Specification (OOS).

• • In case material is under reduced testing proposal shall be revoked as per criticality.

• • The sampling plan and nature of Out of Specification (OOS) and testing shall be reviewed to 100 % sampling and complete testing for next three consignments until revision to reduced testing as per the relevant SOP.

• • If there is possibility of a sampling error / bias / sample storage error identified additional samples shall be drawn (taking necessary precautions) and re-evaluated.

• • If assignable cause identified from manufacturing / vendor investigation, then record the observations made by the relevant functional team (warehouse / QC/ QA/ manufacturing / vendor).

• • Impact on previous supplies shall be assessed and concluded.

• • If the Out of Specification (OOS) is confirmed and assignable cause is found,

• • Head QA shall assess all finding of investigation and conclude whether the material is to be rejected or released along with the necessary corrective and preventive actions for preventing the same in future.

• • Further usage of material or process continuation shall be done through approved deviation only after reviewing the impact of deviation on the final quality of the product.

• • The same shall be handled as per SOP “Deviation Handling”

• • Where necessary, additional trials shall be taken, control shall be put or a detailed review of process shall be initiated along with involvement of PDL and R & D as applicable.

• • Where the Out of Specification (OOS) is confirmed, assignable cause is identified and further usage of material or process continuation is having impact on product quality,

• • Then reject the batch on the basis of findings and conclusion of the investigation and perform the impact analysis to identify any other batch of the same product or product manufactured in the same period if affected and close the OOS.

• • Evaluation of previous supplies made and its impact on finished product shall be assessed.

• • Where necessary depending on the criticality of the failure, the finished product recall procedure shall be initiated.

• • If no assignable cause is identified from manufacturing / vendor investigation,

• • Cross functional team (Manufacturing, QA & QC) shall evaluate the need of laboratory failure investigation i.e. phase IIB investigation, based on sound scientific justification.

• • Assignable cause is identified

• • After investigation, if production process reveals that Out of Specification (OOS) is due to process error then reject the batch based on the finding and conclusion of the investigation and perform the impact analysis to identify any other batch of the same product or product manufactured in the same period is affected and close the Out of Specification (OOS) through and scientific justification in terms of the proposed corrective and preventive action plan.

• • Assignable cause not identified

• • If the investigation doesn’t reveal any conclusive error for Out of Specification (OOS) results then continue additional laboratory testing procedure.

• • Phase IIB: Additional Laboratory Testing:

• • When investigation from manufacturing does not reveal any conclusive reason for the initial Out of Specification (OOS) result.

• • Then the repeat analysis shall be performed once by analyst B in triplicate except for uniformity of dosage unit test and dissolution test / drug release test, where the guideline of pharmacopoeia shall be followed.

• • Product behavior in the past will be considered before proceeding further.

  • Extended investigation if any shall be performed through an approved protocol as applicable.

• • The protocol shall describe the additional activities to be performed and shall specify the scientific and / or technical handling of the data.

• • Record the investigation details in Out of Specification (OOS) investigation form for the Phase-IIB investigation.

• • In case the test results of analysis performed by Analyst B are within the acceptance criteria as mentioned in Annexure-IV,

• • Then the analysis shall be performed once again by Analyst A or C under supervision as per STP, preferably by Analyst A.

• • If all six results were inconsistent and one or more results are out of specification (OOS) / acceptance criteria, then reject the batch.

• • Re-sampling shall be done only if investigation indicated so or if the sampled quantity is insufficient / exhausted.

• • As per the investigation flowchart-

    • When a final conclusion is reached as “Consider sample as passed” then individual results along with average of six results by analyst B & A/C shall be reported and original results shall be considered as invalid and the generated data shall be kept as supporting document.

• • • As per the investigation flowchart when a final conclusion is reached as “Consider sample as failed” the initially obtained Out of Specification (OOS) analytical value of first analyst shall be retained as final result.

• • A review of the reasons for laboratory errors shall be assessed with respect to

• • • Education / training needs,

• • • Procedural revisions,

• • • Impact on other batches analysis performed at the same time,

• • • Impact on previous analysis done by the same analyst and CAPA shall be in place.

• • Handling Procedure for Blend Uniformity OOS Result :

• • In case of out of specification results obtained for blend uniformity set-1,

• • • Based on the laboratory investigation if there is any assignable cause identified,

• • • Then invalidate the initial test results and repeat the testing for one more time using original sample by preferably the first analyst or

• • • Equal competent and qualified analyst in case of non-availability of first analyst under supervision by omitting the error.

• • In case the sample aliquots not sufficient for analysis, then the first analyst shall perform analysis on set-2 sample.

• • Based on the investigation if there is no assignable reason identified during the investigation

• • Then forward the Out of Specification (OOS) to Head-QA with all relevant documents for further investigation purpose.

• • If the investigation does not reveal any conclusive reason for Out of Specification (OOS) results then continue additional laboratory testing procedure.

• • The 2^nd analyst shall perform the analysis on Set-2/Set-3 (based on availability).

• • If the results of 2^nd analyst are acceptable,

• • Then 1^st analyst shall repeat the analysis on set-3 under supervision (in case sample set is not available re-sampling shall be allowed with approval of Head-QA by providing sound justification).

• • Follow the annexure –IV for acceptance criteria.

• • In case if results obtained from the two analyst show variation, then sampling technique will be reviewed.

• • Re-sampling shall be carried out only if investigation indicated so or if the sampled quantity is insufficient / exhausted.

Note: In case of exhibit batch appropriate decision shall be taken by QA in consultation with PDL / or R&D.

• • As per the investigation flowchart when a final conclusion is reached as “Consider sample as passed”

• • Then individual results along with average of result (set 1, 2 and 3 or as per sampling plan) by analyst B & A/C shall be reported and

• • Original results shall be considered as invalid and the generated data shall be kept as supporting data.

• • As per the investigation flowchart when a final conclusion is reached as “Consider sample as failed”

• • The initially Out of Specification (OOS) analytical value of first analyst shall be retained as final result.

• Procedure for raw materials and Packing materials

• • In case of out of specification results obtained for raw materials and packing materials,

• • Based on the laboratory investigation if there is any assignable cause identified,

• • Then invalidate the initial test results and repeat the testing for one more time in duplicate (i.e. two preparations and single injection of each preparation) using original solutions / sample portion using original sample by preferably the first analyst or equal competent and qualified analyst.

• • Re-sampling from the same container(s) for repeat analysis shall be performed only if investigation of Out of Specification (OOS) result indicates that the improper sampling or

• • Storage / handling of this sample is the reason for the Out of Specification (OOS) result or sample quantity is insufficient.

• • If results are within the specification then training is provided to analyst and material shall be released.

• • In case the above recalculated results or repeated analysis results fails to meet specification, or

• • In case laboratory error/investigation not identified then forward the investigation report to QA for further evaluation.

• • Based on the critically of the test only Head-QC shall decide whether repeat analysis is required or not.

• • Example#1: Material is rejected due to black particles, for this repeat test is not required,

• • Example #2: Incase one of the material assay by HPLC test is failing in borderline of the specification, then repeat analysis is required to confirm the same.

• • QA in coordination with Head-QC and Head-Store shall review the following (but not limited) to see if any assignable cause could be identified with respect to handling of materials in ware house.

• • Trend of materials, history of the supplier, evaluation of sampling procedure, evaluation of storage and transportation (materials and sample).

• • Any other specific material related behavior.

• • If no assignable cause is identified, Head QC/QA or his designee shall coordinated with Head-Purchase or designee and intimate the results to the material vendor and arrange for rejection of material through Head-QC or designee.

• • Once the material is rejected vendor has to provide the CAPA (Refer SOP – CAPA).

• Re-sampling procedure:

• • Re-sampling is not allowed unless it is proven that the original sample was non-representative and/or if found that sampling procedure adopted was wrong.

• • For any re-sampling Head-Quality Assurance shall authorize only upon satisfactory investigation proving that the original sample was not representative.

• • This incident shall be reported as deviation and shall be handled as per the SOP.

• • If re-sampling shall be recommended by Head-QA, same can be performed only upon corrective and preventive actions taken.

• • Re-sampling shall be performed under the authority of quality assurance with approved revised procedure or recommendations given in the investigation.

• Phase II Investigation-Out of Specification (OOS) results during Stability Studies:

• • During stability study any adverse change or Out of Specification (OOS) observed and confirmed in physical or chemical parameters shall be brought to the attention of Head-QA. Manufacturing, DRA and PDL / R&D.

• • Head-QA shall do investigation on the affected batch along with all other batches manufactured at the same time period and same shall be communicated to concern regulatory agencies through Head DRA.

• • Confirmed Out of Specification (OOS) test results during stability study must be reported as required by the applicable regulatory body and regulation.

• • The impact of the confirmed Out of Specification (OOS) shall be reviewed and where required necessary action shall be initiated action shall be initiated as detailed in the SOP on “Handling of Product Recall”.

• • QA In-charge shall assess all the finding of investigation and shall forward the. Out of Specification (OOS) investigation report to Production/R&D/Contract giver.

• • QA shall review the laboratory investigation into the suspect analytical results, process validation and / or method validation for possible causes in to the results obtained.

• • To conclude the investigation, all the results must be evaluated.

• • In case, exhibit batches/validation batches stability study fails with respect to the packs,

• • Then the same has to be informed to R & D & DRA for the discontinuation or continuation of the stability study program.

• Reporting of Test results:

• • Averaging is acceptable only if the results are from replicate injections of the single homogeneous individual sample preparation.

• • When a test consists of replicated measurements to arrive at a result (Assay by HPLC)

• • Then the use of replicated to arrive at a single reportable result and the specific number of replicates used should be clearly specified in the standard test procedure.

• • Acceptance limits for variability amongst the replicated should also be mentioned in the STP.

• • Averaging of test results shall not be performed for the tests intended to measure variability.

• • Laboratory shall report all individual results in the OOS test report for evaluation and consideration.

• • Further, in case of reanalysis due to non-assignable cause all individual test results of initial and retested shall be reported in COA.

• • In case of a clearly identified laboratory error, the retest results would substitute for the original test results.

• • All reanalysis if done in individual sample preparation (duplicated),

• • All individual results shall be reported along with the average in COA.

• • The original Out of Specification (OOS) result shall not be averaged along with repeat analysis results.

• • Relying on averages of such data can be particularly misleading when some of the results are Out of Specification (OOS) and others are within specifications.

• • For example, in an assay of a finished drug with a specification of 90 to 110 %, an initial Out of Specification (OOS) result of 89 % followed by additional retest results of 90 % and 91 % would produce an average of 90 %. While this average would meet specifications the additional test results also tend to confirm the original OOS result.

• • In other case with the same specifications, an initial Out of Specification (OOS) result of 80 % followed by additional test results of 85 % and 105 % would also produce an average of 90 %.

• • Such results do not confirm the original Out of Specification (OOS) result as they show high variability and may not be reliable.

• • So in both above cases, the individual results, not the average, should be used to evaluate the quality of the product.

• • QA shall be responsible for approval or rejection of Out of Specification (OOS) E.g.: Drug Products, In-process materials.

• Outlier Tests:

• • To find our outlier results a predetermined experimental plan shall be worked out involving QA and other concerned department (if any) on case to case basis.

• • Value may be obtained that is markedly different from the others in a series obtained using a validated method.

• • Such a value may qualify as a statistical outlier.

• • 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 investigation and analysis.

• • Outlier testing is a statistical procedure for identifying from an array those data that are extreme.

• • For validated chemical tests with relatively small variance, and if the sample being tested can be considered homogeneous (for example, an assay of a composite of a dosage form drug to determine strength) and it cannot be used to justify the rejection of data.

• • An outlier test is only a statistical analysis of the data obtained from testing and retesting.

• • Investigations for the outlier test results shall be carried out as per SOP “Handling of Out of Trend Results”

• General Guidelines for Handling Out of Specification (OOS) Result:

• • In case when any particular analysis is outsourced to any contract testing laboratory and Out of Specification (OOS) is observed

• • Then all test results shall be provided to GALPHA for further evaluation and assessment.

• • Investigation report shall outline the corrective actions necessary to release batch if possible and to prevent similar reoccurrence in future.

• • Investigation shall be extended to other batches and products possibly affected due to process related error if required.

• • Use of investigational tool as per SOP “Investigation Tools used in Pharma” shall be done as appropriate to facilitate the investigation to identify the root cause.

• • Phase I investigation shall be completed within 10 working days and

• • Phase II investigation shall be completed within 20 working days (preferably)

• • So that investigation shall be completed within stipulated time period.

• • The investigation shall be completed within 30 working days from the discovery of the Out of Specification (OOS) result.

• • If the investigation could not be completed within 30 working days, request for extension shall be raised with justification and submitted to QA head.

• • If the Out of Specification (OOS) is caused by analyst error,

• • Then the analytical results of previously analyzed ten batches by that analyst shall be reviewed to evaluate the correctness of the results.

• • Impact assessment shall be done and accordingly corrective action shall be taken in consultation with Head QA.

• • If needed refresher / re-certification of the analyst shall be done.

• • In case, content uniformity test does not confirm to the acceptance criteria as defined in respective pharmacopoeia.

• • Then investigation shall be done as a part of OOT.

• • If errors are obvious, such as spilling of a sample solution or the incomplete transfer of a sample composite, the analyst shall document what had happened.

• • Analysts shall not knowingly continue an analysis they expect to invalidate at a later time for an assignable cause

• • i.e. analysis shall not be completed for the sole purpose of seeing what results can be obtained when obvious errors are known.

• • If the Out of Specification (OOS) investigation is inconclusive and the batch is rejected,

• • Then monitoring of the next three batches shall be carried out as per approved pre-defined protocol.

• • The results shall be reviewed by the QA and conclusion shall be drawn.

• • QA head shall inform to MA Holder / QP, Regulatory agencies through regulatory affairs within seven working days after closure of the Out of Specification (OOS).

• • Any Out of Specification (OOS) investigation shall be completed within 30 working days unless otherwise justified.

• • Any justification has to be documented by giving the reasons for delay in investigation and shall be approved by Head-QA.

• • Quarterly trending of OOS shall be performed by QC (Annexure VI) and submit to QA for review and approval.

• • All the Out of Specification (OOS)’s shall be trended (Annexure V) in line with all the categories (tests) and products in every month and annually by Head QC/designee.

Note: Out of Specification (OOS) trending shall be done as per requirement based on category, product, instrument, or test etc. The trend shall be graphically demonstrated.

• • All the Out of Specification (OOS) investigation reports shall be intimated to CQA for final comments and closure.

• • The conclusive Out of Specification (OOS) investigation report, trending shall be shared to QA as a part of product quality review as per SOP for APQR.

• • Final copy of all Out of Specification (OOS) shall be maintained in QA.

5.0   Reference (S)

• • USFDA guidance on “Investigating Out of Specification (OOS) Test Results for Pharmaceutical Production”

• • ICH Guidelines

• • MHRA Guidelines

6.0   Annexure (S)

Annexure – I : Flow Chart – Out of Specification (OOS)

 

 

 

Annexure – II : OOS Investigation Form.

Click here for – Laboratory Investigation Checklist/OOS Phase I Checklist

Annexure – III : Out of Specification (OOS) Log.

Date	OOS No.	Product	Batch No.	A.R. No.	Test	OOS details	Analyst Name	Root cause/Probable root cause identified	CAPA No.	OOS close by/On (Head- QA/Designee)	Remarks

Annexure – IV: Retesting plan for Physical / Chemical Tests Phase-II Investigation (Additional Laboratory Testing)

Test	Measurement Technique	Minimum number of samples to be tested by 2nd analyst	Number of Measurement as per sample preparation	Acceptance Criteria
Blend Uniformity	Liquid Chromatography / gas Chromatography / Spectrophotometry	1 set of 10 samples or as per Sampling plan / specification	1	Shall comply with limits as mentioned in specification / process validation protocol (PVP)
Uniformity of Dosage Units / Contents Uniformity	Liquid Chromatography / gas Chromatography / Spectrophotometry	Respective Pharmacopeia/ Regulatory Guidelines	1	Respective Pharmacopeia / Regulatory Guidelines (Example: AV=25, by performing the additional 20 tablets)
Assay	Liquid Chromatography / gas Chromatography / Spectrophotometry	3	1	Each measurement shall comply with limits as mentioned in specification / process validation protocol and RSD shall be not more than 2%.
Dissolution (USP /BP/ IP)	Liquid Chromatography / gas Chromatography / Spectrophotometry	Respective Pharmacopeia/ Regulatory Guidelines	1	Respective Pharmacopeia / Regulatory Guidelines (i.e. Dissolution specification for S1,S2,S3 testing)
Impurities / Related Compounds / Related Substances	Liquid Chromatography / gas Chromatography / Spectrophotometry	3	1	Each measurement shall comply with limits as mentioned in specification % RSD limit shall comply for obtained results (Known and total impurities). Result Obtained                      Acceptance Criteria (%RSD) Less than 0.10%                     NA More than 0.10%                     NMT 15%
Residual Solvents	Liquid Chromatography / gas Chromatography / Spectrophotometry	3	1	Each measurement shall comply with limits as mentioned in specification % RSD limit shall comply for obtained results (Known and total impurities). Result Obtained                          Acceptance Criteria (%RSD) Less than 100 ppm                     NA 100 to 500 ppm                           NMT30% More than 500 ppm                     NMT 25%
Preservative Content	Liquid Chromatography / gas Chromatography / Spectrophotometry	3	1	Each measurement shall comply with limits as mentioned in specification
All other physical / chemical tests	Liquid Chromatography / gas Chromatography / Spectrophotometry	3	1	Each measurement shall comply with limits as mentioned in specification / process validation protocol

Annexure – V : Trend Analysis

Trend Analysis of Out of Specification Results of Year ……..

CONTENTS 

Sr. No.	Description
1.0	Objective
2.0	Scope
3.0	Responsibility
4.0	Procedure
5.0	Review and Conclusion
6.0	Way Forward Recommendation
7.0	Training

• Objective

• • The purpose of this document is to analyze the trend of the OOS occurring at quality control laboratory of the site.

• • This Trend analysis shall help to evaluate the area of concerns and to implement the remedial actions accordingly.

• Scope

• • The scope of this document shall be applicable to the QC labs of all the sites.

• Responsibility

• • Quality Control:

• • Perform the trending of OOS based upon the assigned probable root cause and identify the area of

• • Perform the trending of OOS based upon the assigned probable root cause and identify the area of concerns. Review the trending and the data compilation.

• • Initiate suitable Corrective and Preventive actions (If required) as per the evaluation of the trend.

• • Quality Assurance Head:

• • Review and approve the trend report, proposed CAPA as per identified area of concerns.

• • Ensure the CAPA effectiveness

• • Responsible for CAPA implementation and effectiveness.

• • Evaluation of gaps and the identified remediation

• • Procedure:

  • All then subjected OOS shall be listed down and the trend analysis shall be performed based upon all,  but not limited to, the following categories:

• • Total No. of OOS with respect to current & previous Month / Year:

• •  Inference:

• • OOS BREAK UP-Confirmed/Invalidated OOS:

• • Inference:

• • Section wise (RM/Stability/Finished Product/Micro/PM):

• • Inference:

• • Product wise:

• • Inference:

• • Instrument error wise (Instrument type/Instrument ID wise)

• •  Classification of instrument error:

• • Inference:

• • Human error sub-categorization:

• • (Lack of attention/ Lack of skill/Procedural Non-Clarity/Behavioural issue/Overload or Burdened/Intentional/Wrong STP or  reference document used)

• • Inference:

• • Review and conclusion:

• • Way Forward Recommendation: 

• • Training: Training to be provided as per recommendation

• • Test wise:

• • Inference:

• • Root cause, category wise (personnel error/Instrument error/Analytical Method error /Sampling error Materials/Document/Storage error/Non-Assignable/Manufacturing/Process/Other etc.)

• • Analytical error wise (Dilution error/Pipette error/Weigh error/Procedural error etc.)

• • Inference:

Annexure – VI : Quarterly trending of Out of Specification (OOS)

Sr. No.	Description	Page Number
1.0	Objective
2.0	Scope
3.0	Responsibility
4.0	Procedure
5.0	Review and Conclusion
6.0	Way Forward Recommendation
7.0	Re-Training/Re-Qualification

• Objective

• • The purpose of this document is to analyze the Quarterly trend of the OOS occurring at quality control laboratory of the site.

• • This Trend analysis shall help to evaluate the area of concerns and to implement the remedial actions accordingly.

• Scope

• • The scope of this document shall be applicable to the QC laboratory.

• Responsibility

• • Quality Control:

• • Perform the Quarterly trending of OOS based upon the assigned probable root cause and identify the area.

• • Perform the Quarterly trending of OOS based upon the assigned probable root cause and identify the area of concerns. Review the trending and the data compilation.

• • Initiate suitable Corrective and Preventive actions (If required) as per the evaluation of the trend.

• Head Quality Assurance/Designee :

• • Review and approve the Quarterly trend report, proposed CAPA as per identified area of concerns.

• • Ensure the CAPA effectiveness

• • Responsible for CAPA implementation and effectiveness.

• • Evaluation of gaps and the identified remediation.

• Procedure:

• • All then subjected OOS shall be listed down and the Quarterly trend analysis shall be performed based upon all,  but not limited to,  the following categories.

Sr.No	OOS No.	Details of OOS	Status (Open/Close)	Area	Root cause	Description of root cause	CAPA	Remarks (If any)

Section wise

Area of OOS

Jan.

Feb.

Mar.

Apr.

May

Jun.

Jul.

Aug.

Sep.

Oct.

Nov.

Dec.

RM

Stability

Finished Product

Microbiology

PM

Others

Total

Checked by Sig. & Date

Root cause

Area of OOS

Jan.

Feb.

Mar.

Apr.

May

Jun.

Jul.

Aug.

Sep.

Oct.

Nov.

Dec.

Human error

Instrument error

Analytical Method error

Sampling error

Document/Storage error

Non-Assignable

Manufacturing

Other

Total

Checked by Sig. & Date

Analytical error wise

Area of OOS

Jan.

Feb.

Mar.

Apr.

May

Jun.

Jul.

Aug.

Sep.

Oct.

Nov.

Dec.

Dilution error

Pipette error

Weigh error

Procedural error

Other

Total

Checked by Sig. & Date

Human error sub-categorization

Area of OOS

Jan.

Feb.

Mar.

Apr.

May

Jun.

Jul.

Aug.

Sep.

Oct.

Nov.

Dec.

Lack of attention

Lack of skill

Procedural Non-Clarity

Behavioural issue

Overload or Burdened

Intentional/Wrong STP or  reference document used

Total

Checked by Sig. & Date

• • Graphical Presentation

• • Review and conclusion

• • Way Forward Recommendation

• • Re-Training/Re-Qualification : Re-Training/Re-Qualification shall be provided as per recommendation given in section 6

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