OUT OF SPECIFICATION (OOS) OR NSQ RESULTS

1.0 Objective:
  The objective of OOS investigation should be to identify the root cause of the OOS result Or NSQ results and take appropriate corrective and preventative action. Investigation should include a review of Laboratory testing, review of production and sampling procedures, and will often include additional laboratory testing and Cross functional investigation along with the handling of associated samples and test data

 

   
2.0 SCOPE:
  2.1 This procedure is applicable to all OOS results generated from the following sample types at

Your Unit Name

    2.1.1 Raw Materials.
    2.1.2 Primary  packaging material.
    2.1.3 In process samples where there is no provision in Batch Manufacturing Record (BMR) for further processing.
    2.1.4 Process validation samples.
    2.1.5 Finished product samples.
    2.1.6 Stability samples.
  2.2 This SOP is not applicable to OOS results generated from the following analysis types, which are investigated per individual procedures as referenced below,
    2.2.1 Rinse water/swab sample for cleaning verification/validation samples.
    2.2.2 Evaluation samples, Pre-shipment samples (Note: It is to be handled through Laboratory Incident per SOP.)
    2.2.3 System suitability Unexpected event in chromatographic analysis (e.g. initial replicate RSD, tailing factor, theoretical plate, resolution solution or as applicable) (Note: It is to be handled through Laboratory Incident per SOP QC.)
    2.2.4 In-process testing is done solely for the purposes of triggering real time equipment or system adjustment to prevent process drift.
    2.2.5 Analysis covered under the scope of SOP on “Laboratory Incidents” and Out of Trend Investigation  are not included within the scope of this procedure
    2.2.6 Process optimization batch sample, characterization batch sample, developmental stages samples which are required to establish process parameters and assessed against specific protocol limits, shall not be consider under OOS investigation scope). (Note: It is to be handled through Laboratory Incident per SOP.)
    2.2.7 Production aid materials (i.e. Gas samples, cleaning agents, Materials used in the water plant, etc.), which are not participated in the Drug Product Manufacturing.
    2.2.8 This SOP is not applicable to incomplete analysis where results are not derived.
  2.3 The purpose of the investigation is to determine the root cause, Contributing clause Or probable cause of the laboratory Unexpected event. The investigation shall be thorough, timely, unbiased, well documented and scientifically sound and justifiable.
   
3.0 RESPONSIBILITY:    
  QC Analyst (Chemist / Officer) : ·      To participate in an investigation.

·      The analyst should ensure that only those instruments meeting established performance specifications are used for analysis and that all instruments are properly calibrated before initiating analysis.

·      The first responsibility for achieving accurate laboratory testing results lies with the analyst who is performing the test.

·      The analyst should be aware of potential problems that could occur during the testing process and should watch for problems that could create inaccurate results.

·      To immediately communicate the generation of OOS results to the Section Supervisor or appropriate member of QC management based on availability.

·      The cause of the malfunction should be identified and, if possible, corrected before a decision is made whether to use any data prior to the suspect period.

·      Analysts must check the data for compliance with test specifications before discarding test preparations or standard preparations

·      To preserve the test preparations, standard preparations (i.e. final dilution, stock solution), reagents, and glassware (flasks, pipettes, etc.) until the investigation is concluded or root cause confirmed.

·      To participate in the investigation and carry out further investigation analysis per written and approved instructions.

       
  QC Supervisor or designee : ·      To carry out investigation of OOS result as per the procedure defined in the SOP.

·      To review the unexpected event of analytical raw data.

·      An assessment of the accuracy of the results should be started immediately

·      Discuss the test method with the analyst, confirm analyst knowledge of and performance of the correct procedure.

·      Determine that appropriate reference standards, solvents, reagents, and other solutions were used and that they met quality control specifications.

·      Examine the raw data obtained in the analysis, including chromatograms and spectra, and identify abnormality or suspect information.

·      Verify that the calculations used to convert raw data values into a final test result are scientifically sound, appropriate, and correct; also determine if unauthorized or unvalidated changes have been made to automated calculation methods.

·      Review historical data of laboratory investigation during initial assessment to determine if similar unexpected events have occurred previously, what were the corrective and preventive actions and their effectiveness.

·      Confirm the performance of the instruments.

·      Evaluate the performance of the test method to ensure that it is performing according to the standard expected based on method validation data and historical data

·      To initiate the actions recommended in investigation form.

·      To take corrective and or preventive action based on the OOS investigation and impart training to the analyst.

       
  QC Head or designee : ·       To review & to provide guidance for investigation.

·       To interview laboratory analysts using the Guidance for Laboratory Investigation Phase-Ia (Preliminary investigation through check list) targeting identification of root cause, with visual confirmation of all pertinent parameters, for example: samples, equipment calibrations, chromatography, sample solutions, storage conditions, etc.

·       To review and discuss with subject matter experts, as needed, Analytical Test Procedures, analytical method validation reports, method transfer reports and forced degradation data to assist in identifying and confirming the root cause.

·       To decide study plan based on investigation and allot instruction note for any hypothetical study.

·       To take corrective and preventive action based on the OOS investigation and impart training to the analyst.

       
  Production Head or designee   ·       To participate in investigation.

·       To carry out  Phase II manufacturing investigation / cross functional investigation.

·       To carry out Phase-II.

·       To participate in Re sampling plan.

·       To participate in Phase III discussion and conclusion

  ADL Dept.   ·        To assist for OOS investigation, as required.

·        To carry out Phase III investigation

·        R&D user trail analysis shall be plan at ADL Lab

 

       
  R&D Dept.   ·        To assist for OOS investigation, as required.

·        To carry out Phase III investigation

·        To investigate the OOS result based on the user trial.

  Maintenance Dept.   ·        To assist for OOS investigation, as required.
       
  AQA designee : ·       To participate in investigation

·       To review analytical raw data

·       To review hypothesis study plan.

·       To prepare Annual summary report of OOS and trend.

       
  QA Head or designee : ·      To review and to ensure the implementation of this SOP.

·      Participate in investigation,

·      To plan suggest the hypothysis study

·      To review and authorize the hypothesis.

·      To approve the OOS investigation report (Phase-I, II and III).

·      To authorize re-sampling of material.

·      To provide conclusion of OOS investigation and approve the OOS investigation report.

·      To initiate brain storming with cross functional team to find out the root cause, suggestion of appropriate corrective and preventive actions.

·      To monitor and ensure compliance of actions recommended in the OOS investigation report.

·      To inform to regulatory department and R&D, wherever necessary.

4.0 PROCEDURE:
  4.1 Definition of Terms:
    4.1.1 Evaluation Samples
      Any sample which is for study and developmental purpose and analyzed against approved specific protocol.
    4.1.2 Out of specification test results (Not of Standard Quality)
      A result which is not conformed but out of limit at the first analysis considered as questionable and need to be investigated.  
    4.1.3 Investigation
      An investigation jointly conducted by cross-functional team that comprise the stake holder from QC, QA, Production etc. The purpose of the analytical investigation is to identify the root cause for the OOS result. The investigation should be timely, thorough, unbiased well documented and scientifically proven.
    4.1.4 Reanalysis
      Repeat the analysis by repeating one or more steps of the sample preparation from the original preparation of sample.
    4.1.5 Average value
      Mean value of the results.  In the event that valid, individual test results are generated which are both within and outside of acceptance criteria, averaging of these results so as to achieve a within specification result shall not be performed. All individual test results must be reported in the final documentation used for batch disposition.
    4.1.6 Re-sampling
      A new sample or a new specimen taken from the original container (s) that contained the originally submitted laboratory sample. Re-sampling is only to be done if the evidence indicates that the original sample was not representative, was improperly taken or was not stored appropriately.  In all cases any re-sampling must be decided by QA.
    4.1.7 Re-testing
      Testing of a portion of original sample.  The sample used for the retesting should be taken from the same homogeneous material that was originally collected from the lot, tested, and yielded the OOS results.  For a liquid or single-use, it may be from the original sample. For a solid, it is to be an additional weighing from the same sample composite prepared for the original test.  This may include the preparation of fresh standards and/or other test reagents, as appropriate (as per approved effective Analytical work report)
    4.1.8 Assignable cause
      A cause (i.e., root cause) that has been identified as the reason for the OOS result. The assignable cause is a conclusion derived from direct or indirect evidence found during the investigation process, from the interpretation of analytical data, or a combination of both.  OOS laboratory results can only be invalidated with the determination of an assigned root cause and must be approved by QC management and Quality Assurance as provided within this procedure.
    4.1.9 Analyst 1
      First qualified analyst by whom the unexpected result is generated.
    4.1.10 Analyst 2
      Any qualified analyst other than analyst-1 having skill more or equivalent to analyst-1.
    4.1.11 Analyst 3
      Any qualified analyst other than analyst-1 and 2 having skill more or equivalent to analyst-2.
    4.1.12 Corrective Action
      Action to be taken to eliminate the causes of an existing non-conformity, defect or other undesirable situation, in order to prevent recurrence.
    4.1.13 Preventive Action
      Action to be taken to eliminate the cause of a potential nonconformity, defect or other undesirable situation, in order to prevent occurrence in the future.
    4.1.14 Root Cause analysis
      A structured documented investigation that aims to identify the true cause(s) of Unexpected or deviation and corrective and preventive actions necessary to eliminate the deviation and prevent re-occurrence.
    4.1.15 Date of analysis
      The date of sample injection in case of HPLC/GC analysis. The date of sample preparation in case of other than HPLC /GC analysis.
    4.1.16 Hypothesis / Simulation Study
      Structured documented sequence of experiments which is designed to identify the root cause for the Unexpected event. This shall be based on series of discussions, thought processes and scientific rationales focused on what might have occurred to yield the OOS result (s). Each experiment shall have a discussion that states the potential outcomes expected through that particular experiment and how these potential outcomes will be interpreted.  Hypothesis studies must be written and approved in advance by QC & QA management.   Investigational tools can be used to design Hypothesis / Simulation protocol, e.g., “Five Whys? Cause and Effect Diagram; FMEA; Fish Bone diagram, etc.  Results from hypothesis testing are not to be used for release. Hypothesis planned shall be reviewed by AQA designee and approved by QA head/designee prior to proceeding.
    4.1.17 Cross Functional investigation
      Cross-functional investigation includes all departments that could be implicated (e.g., Manufacturing, Process Development, Maintenance, ADL, R&D Engineering, etc.) in the OOS result. This process investigates the Unexpected event through review of manufacturing process; conditions; input materials and documentation.
    4.1.18 Preliminary investigation closure
      Where investigation is completed but recommendation given in the investigation is not closed (i.e. corrective action, preventive action, training, impact analysis and other etc.).
    4.1.19 Permanent investigation closure
      Where investigation is completed and all recommendations given in the investigation are also closed (i.e. corrective action, preventive action, training, impact analysis and other etc.).
    4.1.20 Obvious Error
      Any error which occurs during execution of the method (Before arriving final results) and is identified during analysis.
       
  4.2 When out of specification results are obtained, the analyst shall immediately notify the section head or designee and shall not discard sample solution/stock solution/ instruments settings until evaluation of unexpected event in analytical results. “OOS shall be initiation within 24 hrs. from the OOS results Identification.” Section head or designee shall take actions under Phase I Investigation listed below.
    Note: Any observation pertaining to obvious unusual error shall be recorded in the analytical raw data sheet. Examples include but not limited to, such as, wrong glassware used, Sample solution spillage from the flask during sonication, shaking; unstable weight displayed during weighing, crack in the glassware during analysis, foaming and frothing in the solution, incomplete transfer of sample composite which is identified by analyst etc. Same shall be notified immediately to concern section head for further action.
  4.3 Preamble:
    ·            Identification and Assessment of OOS test result comprises of Phase-I, Phase-II and Phase-III investigation.
    ·            Phase-I investigation is Laboratory investigation
    –          Phase-Ia Investigation- checklist based on Preliminary investigation to identify Assignable Cause Or No Assignable cause.
    –          Phase-Ib Investigation- Initial investigation is conducted by the analyst and supervisor using the Laboratory investigation based on hypothesis study.
    ·            Phase-II is conducted when the Phase-I investigation did not reveal an assignable laboratory error.
    –          Phase-IIa Investigation- Manufacturing investigation cross functional investicator
    –          Phase-IIb Investigation-Extended laboratory investigation.
   
  4.4 In case of OOS result is observed during analysis, the analyst shall intimate the same to QC Head/supervisor/Designee.
  4.5 Analyst should check the data for compliance with test Specification before discarding test preparations. When unexpected results are obtained and no obvious explanation exists, all test preparations should be retained, if stable for investigation purpose and informed to supervisor or designee. If errors are obvious such as spilling or incomplete transfer analyte should immediately inform to QC Supervisor or designee.
  4.6 Investigator or QC/AQA designee shall review of OOS results in co-operation with QC Head / supervisor/Designee .
  4.7 QC Head / Supervisor shall intimate to QA department for issuance of OOS form to the Analyst as per format

OOS numbering:

OOS/YY/001

YY: Current year for e.g.22 for 2022

001: Numbering starts from 001

So,

OOS/22/001

  4.8 QA Officer/Executive/ designee shall make entry in the investigation form issuance register Format No.: QC008/F/01 and issue the investigation form Format No.: QC008/F/02.
  4.9 Once OOS has been identified, Supervisor or QC designee shall carry out the assessment, assessment should be objective and timely. There should be no preconceived assumptions to the cause of the OOS results. To execute the further activity as per SOP, document all the observations,  findings and preserve records of the laboratory assessment.
  4.10 QC Head or Designee shall review the laboratory assessments and to take the decision for additional laboratory testing for investigation purpose and ensure compliance as per SOP.
  4.11 QC Head and QA Head shall classify OOS test results as Assignable cause or Non-assignable cause and should be investigated as Phase-I investigation and Phase-II investigation.
  4.12 Final decision for batch disposition shall be done by Head QA or Designee.
  4.13 In the case where OOS results obtained at a Contract Laboratory, the Contract Laboratory can use their own SOP if found adequate as per current guidelines. This can be determined during the Contract Laboratory’s audit or later stage. If it is not adequate then this SOP can be utilized in such instances and if required contract laboratory shall ask for the help for investigation purpose and submit the investigation finding report within 30 days of intimation.
  4.14 An appropriate laboratory investigation shall be conducted for the occurrence of a situation which indicates that testing was performed or testing results were generated non-conformance of the laboratory policies and procedures, or where results do not comply with established specifications/guidelines.
  4.15 Where applicable, to support the investigation, copies of relevant data and results, chromatography and all pertinent information shall be referenced and attached to the investigation report.
  4.16 If the analyst has made an obvious error (prior to result generation), Laboratory supervisor shall be consulted. This situation shall be documented in the Analytical work report and no investigation is required. If sample data has been generated, an investigation shall be initiated and if required than handle through Laboratory Incident QC065.

 

  4.17 If an analysis is invalidated due to unexpected event to meet overall system suitability criteria, sample results shall be calculated for investigative purposes only, but shall not be considered as valid reportable values. If an OOS result is obtained in the invalidated data, the OOS result shall be presented in the investigation findings.
  4.18 The analyst shall immediately notify a QC supervisor when a system suitability not meeting against specification, power irruption, Instrument breakdown, OOS result is obtained or laboratory deviation is observed, but in the case of power interruption (Not forcedly shut down done of instrument by Analyst) handle with incident. (QC065)
  4.19 OOS observed during stability sample analysis immediately informed to QA Head/Designee and further investigation to be initiated as per OOS flow chart.

For the phase -II investigation, extra sample of same age stability study sample used for further investigation.

  4.20 All laboratory investigations shall have the appropriate management level review and approval.
  4.21 Any laboratory investigation in which the OOS have been confirmed in the laboratory and ensured for no laboratory error shall be forwarded to the QA for further manufacturing investigation (Phase II Investigation).
  4.22 It is preferable to use same instrument during investigation testing as used during the original analysis.
  4.23 Out of Specification report shall be closed within 30 working days.
  4.24 Procedure:
    4.24.1 Conduct the investigation as per format No. QC008/F/02 and record it in OOS log as per format. QC008/F/01.
    4.24.2 All standard and sample solutions (both stock and working solutions) and related reagents/ solutions (mobile phase, diluents, etc.) must not be discarded until the test results have been reviewed by a data checker or supervisor who verifies that the test results are normal (acceptable). Label the tray where all unexpected event glassware kept as “DON’T DISCARD UNTIL FURTHER INSTRUCTIONS”.

Example of label as mention below,

OOS Glassware Label

 

DON’T DISCARD UNTIL FURTHER INSTRUCTIONS

Product Name: –                                     Test: –

Analyst Name: –                                     Sign/Date :-

 

  4.25 Phase Ia Investigation: Preliminary Laboratory Investigation based on checklist
    4.25.1 The investigator (QC Supervisor or designee) and the analyst follow the evaluation procedure as per the checklist, concurrently documenting the finding for the potential error, the search for probable  causes, corrective actions and conclusions in the Phase Ia  Laboratory Investigation Report.
    4.25.2 The initial  Preliminary laboratory  investigation assessment will include, but not limited to, the following actions:
    4.25.3 During preliminary laboratory investigation, in need of identifying an assignable cause and to ensure the correctness of data, examine the raw data of the analysis and identify anomalous or suspect information,  Review the following (but not limited to):
    4.25.4 Spectra/chromatograms for retention time, peak area response, response ratio, system suitability compliance, bracketing standard response, excessive fronting or tailing, splitting of peak, improper chromatographic pattern, shoulder or co-eluting peak, shape of curve in case of potentiometric analysis etc. and compare it with the specimen or spectra/ chromatograms of previous analysis.
    4.25.5 Review steps of the test method with the analyst; find out exactly how the analyst weighed and transferred standard, sample and how the analyst prepared the standard and sample, how long the column was equilibrated before injection, etc.
    4.25.6 Examine the raw data obtained in the analysis, including chromatograms and spectra, and identify abnormal or suspecting information.
    4.25.7 Verify the peak integration (for HPLC and GC) are optimized, appropriate, and consistent for all standard and sample injections.
    4.25.8 Verify that all the calculations are correct and accurate.
    4.25.9 Confirm the performance of the instruments by checking instrument history. (Instrument calibration records and break down history).
    4.25.10 Ensure that the appropriate reference or working standards were used and they meet quality standards. Ensure that the solvents, reagents and other solutions were used and that they are within expiration date (also check for physical appearance).
    4.25.11 Examine the glassware condition for correctness of use in terms of volume, use of clear/low actinic glassware etc. Check the availability of solutions (standard/ sample stock solution and standard/sample working solutions).
    4.25.12 Fully document and preserve all records of the laboratory assessment.
    4.25.13 The Supervisor notes the findings from the initial assessment and outcome of the interview with the analyst in the “Phase Ia laboratory Investigation Report” and enters comments and observations based on previous experience, raw data checking and discussion with the analyst.
    4.25.14 QC Head / Supervisor should investigate for obvious laboratory errors which can occur when analyst perform analysis.
    4.25.15 If the root cause for the OOS is conclusively identified through the analyst interview /checklist /sample from  desk or bench, audit and initial testing the below process is followed,
    4.25.16 Any other batches/lots implicated in the error contributing to the OOS will be identified to be in scope unless removal from scope is justified in writing and approved by AQA designee and Head QA.
    4.25.17 Any other batches/lots also associated with, or common to the assigned root cause are also considered in scope, unless adequate scientific rationale is provided to specifically address why these related batches / samples are or are not impacted. Examples include: other batches in the analytical sequence where an equipment error or methodology issue is identified, other batches tested by same analyst and prepared alongside the samples found to generate OOS results, instrument, etc.  All batches in scope must be subjected to re-testing unless justified and approved by AQA designee and Head QA.
    4.25.18 If assignable cause is identified during QC supervisor assessment, correct the cause and re-measure the same original solutions (expired solutions can be re-measured for information purposes) or reanalyze the same original ground sample powder or sample with same number of original duplicate by the same analyst.
    4.25.19 Calculation error:
      Analyst and QC supervisor shall review for data correction. In case, investigation reveals that OOS is due to calculation errors (assignable cause) then correct the calculation and will not be carry out for further investigation.
    4.25.21 Equipment Breakdown:
      Analyst and QC supervisor shall document the event, annotate “equipment breakdown; analysis to be repeated” cross reference the maintenance record.
    4.25.22 Testing errors:
      For example, spilling of the sample solution, incomplete transfer of a sample; the analyst must document it immediately.

For microbiology it could be growth on a negative control plate not in the test sample area, negative or positive controls unexpected results.

    4.25.23 Incorrect Instrument Parameters:
      For example, setting the detector at the wrong wavelength. Analyst and QC supervisor shall document the event, annotate “incorrect instrument parameter; analysis to be repeated” on all associated analytical documentation.
    4.25.24 Suspected laboratory error must be investigated and if a genuine error is found then the OOS result must be immediately invalidated. Retest shall be performed by the same analyst using the same sample (duplicate analysis). The OOS result must be disregarded (after appropriate recording and filling).
    4.25.25 If assignable cause is identified, then correct the cause and reanalyze the sample in duplicate sample preparation and report mean value and close the phase Ia investigation as per flow chart (Annexure-I).
    4.25.26 If assignable cause is not identified then proceed with Hypothesis testing as per Annexure-I flow chart {Same solution same vial (SSSV), Same solution different vail (SSDV), Re dilution, Extra sonication etc.}
    4.25.27 If outcome of result is not complying the specification, then initiate Phase Ib investigation
    4.25.28 After hypothesis testing if assignable cause is identified then perform analysis in duplicate by Analyst-I for confirmation of cause , and if outcome of result is complying the specification, then, Plan reanalysis in triplicate by Analyst 2 and 1, and report mean value shall be used for reporting purpose. if outcome of result is not complying the specification, then initiate Phase Ib investigation.
    4.25.29 After that Initiate the CAPA and submit the report to QA dept., and QA will take decision for final batch release, Hence no further investigation required.
    4.25.30 In hypothesis testing if no assignable cause is identified then need to be initiate for  Phase Ib investigation
  4.26 Phase-Ib investigation (Laboratory Extended Hypothysis Investigation)
    4.26.1 Phase-Ib investigation shall be driven by hypothesis analysis having sound scientific rational for the identification of the root cause for the Unexpected event of the result. Plan and execute hypothesis based on the probability of occurrence and variables of method of analysis during analysis.
    4.26.2 For designing a Hypothesis, consider below mentioned Out of Box Approach to investigate cause of unexpected event/OOS.
    4.26.3 Prepare standard / Sample solution as per hypothesis to determine the root cause.
    4.26.4 In case of Unexpected event in UV analysis, perform simultaneous testing of same sample aliquot using UV.
    4.26.5 For unexpected impurity peak in drug substance analysis, perform testing of individual component, leachable, label glue etc. used which may reveal source of unexpected peak.
    4.26.6 Perform heating or sonication beyond specification procedure to check increase of content or to identify cause of undesired impurity peaks.
    4.26.7 Each potential root cause identified, must be scrutinized through scientific experimentation and challenge to determine if it is assignable for generating an erroneous, invalid result that does not represent the sample(s) under test.  Assignable causes must also be evaluated for potential impact to other test results generated, whether those analyses yielded results within or outside of established specification limits.
    4.26.8 Identification of variables can further be extended through review of analytical validation documents (e.g. force degradation data), analytical method transfer data and other relevant discussion and data review available with Developmental data or analytical method validation data.
    4.26.9 Check if samples were incorrectly prepared, diluted, injected or stored at in appropriate environmental temperature of that containers not properly closed or possibility not sampled in the correct designate sample container.
    4.26.10 QC Head / Supervisor shall review completeness of the entire test procedure, equipment, standards, validity date, calibration and calculation in obtaining the test results.
    4.26.11 QC Head / Supervisor shall review and discuss in depth with the analyst, about the execution of the entire analytical testing procedure, instrument operation and malfunction, sample preparation, sample weighing and dilution techniques, sample storage, clean and correct glassware and calculation is used.
    4.26.12 In case the investigation reveals that OOS is solely due to analytical errors (assignable cause), a hypothesis study shall be performed to confirm the root cause. The repeat analysis shall be performed on the same sample / same sample solution by same analyst, after correcting the error or rectifying the cause of error.
    4.26.13 The analytical or analyst error must be thoroughly documented and properly invalidate with written results together with the investigator and analyst signature and date of the invalidated process.
    4.26.14 After hypothesis analysis if  No assignable cause is identified then QA shall perform Phase –II Investigation (cross-functional investigation), through manufacturing investigation (process related, non-process related and operator related) shall be done involving Head of Production and Head of Quality Assurance and the same shall be documented in Phase-II.
    4.26.15 After hypothesis analysis if assignable cause is identified then Section Head or Designee shall plan the sample to analysts-1 in duplicate. And if outcome of result is complying against specification, then, Plan reanalysis in triplicate by Analyst 2 and 1, and mean value shall be used for reporting purpose.
    4.26.16 After that Initiate the CAPA and submit the report to QA dept., and QA will take decision for final batch release, hence no further investigation required.
    4.26.17 If the test result does not comply with the specification, then QA shall perform cross-functional investigation, through manufacturing investigation (process related, non-process related and operator related) shall be done involving Head of Production and Head of Quality Assurance and the same shall be documented in Phase-II.
    4.26.18 After hypothesis testing if no assignable cause is identified then need to be documented every occurrence and initiate Phase II investigation.
  4.27 Phase-II investigation: Phase-II investigations are driven When the initial assessment does not determine that laboratory error caused the OOS result and testing results appear to be accurate, a full-scale OOS investigation using a predefined procedure should be conducted. The objective of such an investigation should be to identify the root cause of the OOS result and take appropriate corrective action and preventive action. A full-scale investigation should include a review of production and sampling procedures and will often include additional laboratory testing. Such investigations should be given the highest priority.
    4.27.1 Based on the requirement QA Head or designee shall plan the manufacturing investigation Phase IIa.
    4.27.2 The investigation should be conducted by the Quality assurance and shall involve all other departments that could be implicated, including manufacturing, process development, maintenance, and engineering. In cases where manufacturing occurs another site (Outsource), Other potential problems should be identified and investigated
    4.27.3 A full-scale OOS investigation should consist of a timely, thorough, and well-documented review. A written record of the review should include the following information.

1.      A clear statement of the reason for the investigation

2.      A summary of the aspects of the manufacturing process that may have caused the problem.

3.      The results of a documentation review, with the assignment of actual or probable cause.

4.      The results of a review made to determine if the problem has occurred previously.

5.      A description of corrective actions taken

    4.27.4 Based on the requirement QA Head or designee shall plan for additional laboratory investigation study Phase II b along with phase Ia.
    4.27.5 A full-scale OOS investigation may include additional laboratory testing beyond the testing performed in Phase I. These include (1) retesting a portion of the original sample and (2) resampling.

1.      Retesting

As a part of the investigation may involve retesting of a portion of the original sample. The sample used for the retesting should be taken from the same homogeneous material that was originally collected from the lot, tested, and yielded the OOS results. For a liquid, it may be from the original unit liquid product or composite of the liquid product; for a solid, it may be an additional weighing from the same sample composite prepared for the original test.

2.      Resampling

While retesting refers to analysis of the original, homogenous sample material, resampling involves analyzing a specimen from any additional units collected as part of the original sampling procedure or from a new sample collected from the batch, should that be necessary.

    4.27.6 After hypothesis analysis if  No assignable cause is identified in the manufacturing investigation Phase IIa and additional laboratory investigation study Phase IIb then proceed for Phase-III investigation.
    4.27.7 After hypothesis analysis if assignable cause is identified in the manufacturing investigation Phase IIa or Phase II b additional laboratory investigation study then Section Head or Designee shall plan the sample to analysts-1 in duplicate for confirmatory cause. And if outcome of result is complying the specification, then Plan for reanalysis in triplicate by Analyst 2 and 1, and mean value shall be used for reporting purpose.
    4.27.8 After that Initiate the CAPA and submit the report to QA dept., and QA will take decision for final batch release, hence no further investigation required.
    4.27.9 If duplicate analysis result of analyst-1 for assignable cause is not complying the specification then, Plan Phase-III investigation.
    4.27.10 Along with all the result, impact assessment, risk assessment and suitable corrective and preventive actions shall be submitted to QA for final decision.
    4.27.11 Review previous history for similar occurrences.
    4.27.12 Forward the completed investigation to QA for final review and approval.
  4.28 Phase III Investigation:
    4.28.1 The investigation shall be extended to other batches to verify / evaluate possibility of product affected due to process related error.
    4.28.2 The investigation shall also be extended to other batches and products possibly affected due to operator error or malfunctioning of equipment.
    4.28.3 The phase III investigation should review the completed manufacturing investigation and combined laboratory investigation into the suspect analytical results, and/or method validation for possible causes into the results obtained from ADL Department, R&D Department.
    4.28.3 All investigation data of Phase I and Phase II shall be forwarded to R&D and ADL for the review purpose.
    4.28.4 After review of the all-related data of phase I and Phase II investigation, R&D take user trial with issuance of material from Warehouse /store Dept.
    4.28.5 R&D user trail analysis shall be done at ADL Lab.
    4.28.6 R&D shall investigate the OOS result based on the user trial.
    4.28.7 R&D shall take various type of user trial to find out the root cause.
    4.28.8 R&D make summary report for defining Corrective & preventive action along with  the reprocess criteria if required .
    4.28.9 Final conclusion shall prepared by all team member QA, QC, Production, ADL and R&D for outcome of Phase III investigation.
    4.28.10 Phase III final investigation report shall submit to QA head for final conclusion.
 

 

  4.28.11 Based on the final investigation report of Phase-III QA head take final decision for batch quality must be determined and disposition decision taken
    4.28.12 While performing impact assessment on other product batches, if impact found on marketed product batches then follow the procedure for product recall as per SOP No.: QA020.
  4.29 Test results shall be assessed as follows:
    4.29.1 If any retest result from Analyst 1 and Analyst 2, confirms to the initial results and no assignable cause is identified, the initial result shall be considered as confirmed.
    4.29.2 If the retest results from Analyst 1 and Analyst 2 both did not confirm to the initial results and no assignable cause identified, the original result is not confirmed and the re-test results shall be accepted. All the results including initial results will be forwarded to QA for further evaluation or decision for batch disposition. Average result of all the analysis shall be considered for final reporting.
    4.29.3 In the event of clearly identified laboratory issue (assignable cause), the retest results shall substituted for the original test results. The original results shall be invalidated for cause.
    4.29.4 If any material was reprocessed after additional testing, the investigation should include comments and signatures of appropriate production, quality assurance and  Quality Control personnel.
    4.29.5 QA shall review / investigate of production but not limited to followings in consultation with concern department in-charge/supervisor:
      4.29.5.1 Batch Manufacturing record review
      4.29.5.2 Equipment review
      4.29.5.3 Manpower attendance review
      4.29.5.4 Material review / discussion
      4.29.5.5 Process trends
      4.29.5.6 Any abnormal observation
    4.29.6 In case, investigation reveals that OOS is due to manufacturing error, further decision shall be taken by QA head/designee.
    4.29.7 Investigation report shall outline the necessary corrective actions to be taken to prevent reoccurrence.
    4.29.8 When manufacturing investigation does not reveal any abnormalities due to assignable cause, then final conclusion shall be derived through QA.
    4.29.9 Re-sampling shall be allowed only after proper justification and authorization by QA Head to eliminate the scope of sampling error.
    4.29.10 Then re-sampling of the target material shall be done and a new analysis shall be performed (five times or as recommended by QA Head). Reanalysis can be performed to support the manufacturing investigation subjected to QA approval.
    4.29.11 QC Head or designee shall fill the result in OOS investigation form after reviewing and checking the raw data and put his remark.
    4.29.12 OOS form shall be given to QA Head along with all the attachment / raw data for the review.
    4.29.13 After review, QA Head shall make conclusion in final conclusion column for the final disposition of product.
    4.29.14 Based on the OOS findings corrective action shall be taken as suggested by QC Head or by QA Head in OOS investigation form.

 

  4.30 Impact Assessment:
    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 preventive action.

    4.30.1 The investigation shall be extended to other batches to verify / evaluate possibility of product affected due to process related error.
    4.30.2 The investigation shall also be extended to other batches and products possibly affected due to operator error or malfunctioning of equipment.
    4.30.3 During impact assessment a designee of QA and respective department should review the completed manufacturing investigation and combined laboratory investigation in to suspect analytical result, and/or method validation for possible causes in to the result obtained.
    4.30.4 The conclude the investigation all the results must be evaluated.
    4.30.5 The investigation report should contain a summary of the investigations performed; and a detailed conclusion.
    4.30.6 The impact of OOS result on other batches, ongoing stability studies, validated process and testing procedures should be determined by quality control and quality assurance and be documented in the conclusion, along with appropriate corrective and preventive action.
  4.31 Trending and Evaluation of OOS:
    4.31.1 Trending and Evaluation of OOS shall be carried out quarterly by QA and shall be completed within 60 working days of due date established with below mentioned criteria:
    4.31.1.1 OOS with respect to test.
    4.31.1.2 OOS with respect to confirmed or unconfirmed OOS result.
    4.31.1.3 OOS with respect to analyst
    4.31.1.4 OOS with respect to product
    4.31.1.5 OOS with respect to production stage
    4.31.1.6 OOS with respect to instrument
    4.31.1.7 OOS with respect to method
    4.31.1.8 OOS with respect to analytical technique.
    4.31.2 QA shall prepare the graph (Bar type) for causes of Unexpected(X-axis) against number of OOS result generated (Y- axis).
    4.31.3 QA shall analyze the repetitive failure(s) from data of quarterly trending, and identify training / Corrective and/or Preventive action required. Effectiveness checks for training or other CAPAs will take place following implementation of the CAPA to determine if the numbers of errors have been reduced.  Further action will be taken as required based on evaluation of effectiveness check
    4.31.4 Where the repetitive Unexpected event is identified for any test of Product / material, high level of investigation shall be planned by initiating the incident to identify the underlying root cause. Investigation shall be done for such high level of investigation in support of the justification of repetitive Unexpected event and decide corrective and/or preventive action
    4.31.5 While preparation of quarterly trend, AQA personnel shall consider the open actionable (i.e. CAPA) of previously closed OOS investigation of about six months and verify that whether the open actionable has contributed for occurrence of OOS result e.g. For making a trend report for the quarter of January to March of the year, AQA shall verify all open actionable of previous OOS investigation that would have closed from the month June to December of previous year
    4.31.6 In case if open actionable is identified as the cause for the generation of OOS investigation, then AQA personnel shall notify about it to Head QA and Head Quality with the summary report
    4.31.7            Likewise, while making the trend report of next quarter (i.e. April to June), QA personnel shall consider the open actionable (i.e. CAPA) of previously closed OOS investigation of about six months and verify that whether any preconceived open actionable mentioned in the summary report of last quarter for Trend Report shall contributed for the occurrence of OOS result.
    4.31.8 Along with the Trend report the summary report for the open actionable shall be made by the QA personnel and same shall be approved by Head Quality Control followed by Head Quality.
    4.31.9 Repetitive incidences should have corrective and preventive actions, followed by Quality Plan.
    4.31.10 The AQA personnel shall prepare the annual summary report of Out of specification for every calendar year. The activity shall be completed within 90 days
  4.32 Closure of OOS Investigation:
    4.32.1 After completion of OOS investigation and cross-functional investigation, QA shall ensure for the necessary attachments are filed with the OOS investigation report.
    4.32.2 Impacted department Head shall monitor the each recommendation mentioned in OOS form.
    4.32.3 OOS investigation (i.e. Laboratory investigation and Manufacturing Investigation) shall be completed preferably and to the extent possible within 30 working days from the date that the OOS result is identified [Note:  In the case of commercially distributed batches, the preliminary laboratory investigation (i.e. hypothetical testing of original solutions) is to be concluded within 10 working days from the date of identification of Unexpected event result]
    4.32.4 OOS investigation shall not be closed until the Laboratory and Cross functional investigation is not completed if applicable.
    4.32.5 Based on the outcome of confirmed OOS investigation, Health Hazard evaluation shall be performed in case of commercial batches.
    4.32.6 In case of confirmed Out of Specification, impact evaluation on live batches of marketed product shall be initiated as applicable.
    4.32.7 Based on the outcome of confirmed Out of Specification investigation, reassessment of shelf life of product shall be performed.
    4.32.8 If an OOS investigation requires more time for closing than the defined period (i.e., 30 working days), then an extension must be requested by the Section Head or investigator and approved by Head Quality prior to the due date.
    4.32.9 An interim report shall be prepared for extension of closure. The interim report shall have proper justification, reason for extension and an impact assessment for the OOS investigation. The interim report should include a re-assessment of the batches in scope and a description of the investigation results to date. Interim report shall be approved by Head QA/Head Quality.
    4.32.10 Extension can be given for one month from the date of request for the extension. In any case extension time period shall not be exceeded more than 90 working days from the date of occurrence of out of specification results. If OOS investigation requires more time for closing than the defined period i.e. 90 working days, then the extension needs to be sanctioned from Quality Head with proper justification
    4.32.11 Disposition of batch/material shall be decided by QA concern with Head Quality after completion of cross functional investigation. Head Quality shall make a remark for disposition of batch/material.
    4.32.12 During preliminary investigation, any human errors is identified then it should be addressed as per the guidance provided in the Annexure – III.
      Time line mentioned in the above steps for the completion of OOS investigation is not applicable to process validation batches (new product) where R & D input is required
    4.32.13 Human errors shall be trended, corrective action and preventive action shall be derived to avoid the repetitive human errors.
  4.33 General consideration for OOS
    4.33.1 Outlier Tests
    4.33.1.1 The specific outlier test to be applied with relevant parameters specified in advance, also specify the minimum number of results required to obtain a statistically significant assessment from the specified outlier test.
    4.33.1.2 On rare occasions, a 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.
    4.33.1.3 If the OOS Unexpected results obtained in stability sample during testing, it should be informed to external party.
    4.33.1.4 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.
    4.33.2

Field Alert Reports

    4.33.2.1  
  4.33 Procedure for microbiological OOS investigation
    4.33.1 The procedure for microbiological OOS investigation shall be kept as similar as possible to the procedure for physiochemical OOS investigation. However, in view of the dynamic nature of microbiological sample, the value of retesting the original sample is limited. (Reference Micro SOP MB045).
    4.33.1 The following points to be considered and checked.
    4.33.3.1 Sample consideration
      1.    Was the correct sample tested?
      2.    Is there any evidence of sample contamination?
      3.    Is there any evidence of improper sample appearance, storage, handling or damage?
    4.33.3.2 Media preparation
      1.      Was the correct media used?
      2.      Were the settings for sterilization, correct?
      3.      Is there any indication of autoclave malfunction
      4.      Were there any expired media used
      5.      Were the negative control/positive control results, correct?

 

 

    4.33.3.3 Test performance
      1.      Was the test method used?
      2.      Was the raw data properly documented?
      3.      Was the analyst trained on the technique?
    4.33.3.4 Instruments checks
      1.      Were the settings for autoclave/sterilization cycle, correct?
      2.      Is the equipment calibration/maintenance being current
      3.      Is there any indication of autoclave malfunction
      4.      Was the incubator set at the current temperature
      5.      Was the laminar flow functioning correctly/media control, correct?
    4.33.4 The supervisor may initiate additional laboratory environmental testing (especially near work areas) and review historical laboratory environmental test data to assess whether environmental factors may have contributed to the OOS results.
    4.33.5 Early on the investigation, there should be review of purified water, raw material, test results, results from bracketing batches, production/cleaning records and environmental monitoring results to provide background to the investigation and assist the microbiologist to establish a root cause investigation decision taken.
    4.33.6 The procedure of the initial investigation is coordinated by the microbiologist and the analyst and if the work is invalidated (especially with reference to work area environmental monitoring) then at the point. The test should be repeated by the same analyst.
    4.33.7 If the investigation does not support invalidation, retesting should be                             performed in the triplicate either on the same sample or on a fresh sample (if possible).
    4.33.8 If the investigation is related to water or environmental monitoring, then the test should be repeated for that time point on 3 consecutive days in order to clarify whether the result is a one-off or part of a trend.
    4.33.9 The result should be submitted to the microbiologist for the review and assessment. This assessment may include the need for further microbiological work including identification or testing
    4.33.10 Microbiological investigations, where appropriate, use risk analysis tools to support the decisions taken and conclusions drawn. It may not have been possible to determine the actual root cause therefore a robust most probable root cause may have to be given
5.0 ANNEXURE:

 

Sr. No. Title of Formats Format No.
01 Flow Chart For Out Of Specification Result Investigation Annexure – I
02 Acceptance Criteria for replicate result Annexure – II
03 Guidance for Human Error Handling Annexure – III
6.0 FORMATS:

 

Sr. No. Title of Formats Format No.
01 Out of Specification Investigation Form Issuance Entry Register QC008/F/01-04
02 Out of Specification Investigation Form for Physio-Chemical analysis QC008/F/02-08
 

03

Out of Specification investigation form for Microbiology QC008/F/03-02
04 Extension form for OOS investigation. QC008/F/04-01
7.0 REFERENCES:

Sr. No. Particulars Reference document No.
01 International Conference on Harmonization ICH-Q7
02 SOP on change control QA010
03 FDA guideline for Industries: Investigation Out of Specification test for Pharmaceutical production, October 2006 Not Applicable
04 SOP on Laboratory Incident QC065
05 SOP on Out of Trend results QA040
06 EU guidance: Good Manufacturing practices. Not Applicable
07 MHRA guidance for out of specification investigation, 2013 Not Applicable
08 Root cause Analysis QA073
8.0 ABBREVIATIONS:

Sr. No. Long form Short form
01 Standard Operating procedure SOP
02 Quality Assurance QA
03 Quality Control QC
04 Active pharmaceutical Ingredient API
05 Certificate of Analysis COA
06 Not of Standard Quality NSQ
9.0 HISTORY OF CHANGE:

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 
Revision No. Date of effective Summary of change
04 01/06/2013 i. Periodic Review
ii. Editorial changes.
05 10/05/2019 i. Responsibilities are described in details.
ii. Investigation phases are defined and described in details.
iii. Number of tests to be performed in case of retest is revised from duplicate/triplicate to six times.
iv. Editorial changes.
06 09/05/2017 i. Format QC008/F/03 for microbiological OOS investigation incorporated.
ii. Title of format No.: QC008/F/02 revised.
07 13/09/2019 i. Editorial Changes.
ii. Scope of this SOP is elaborated to better understanding and comply of this SOP.
iii. Format QC008/F/02 is revised and updated for better understanding
iv. Phase I & II investigation procedure is elaborated
v. Annexure – I included for Out of Specification Flow chart for investigation
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Revision No. Date of effective Summary of change
07 13/09/2019 vi. Definition of terms updated for better understanding and ease of SOP
vii. Annexure – I, II.III incorporated
viii. Trending of OOS incorporated
ix. Phase – I & II investigation flow chart revised
x. References has been incorporated streamline the SOP
08 01/01/2019 i. OOS numbering system is revised as per change control no. CCP/18-19/183.
ii. Editorial changes.
09 31 OCT 2019 i. Title of the SOP revised.
ii. Point 4.3 is revised and updated as per the flow of the OOS investigation.
iii. Annexure I have been updated for flow chart understanding and revised according to flow of investigation
iv. Format QC008/F/01 revised and updated for the better understanding about OOS entry.
v. Format QC008/F/02 revised and update as per the flow of the investigation and CQA role incorporated.
vi. Refer change control CCP/19/269
10 13 MAY 2021 i 4.15.7 stability sample OOS initiation and investigation procedure incorporate.
ii Point No 3.0 ‘Responsibility’ has been elaborate for better clarity with respect to reviewed by QA department.
iii Point No 6 Format No. QC008/F/01 , QC008/F/02 and QC008/F/03 has been updated.
iv SOP aligned in accordance to SOP QA001 to add review by sign.
v Reference Change Control No. CCP/21/004.