SOP FOR INVESTIGATION OF OUT OF SPECIFICATION (OOS) RESULT

I.                   Purpose  

The Purpose of the investigation is to determine the cause of the Out Of Specification results.

II.                SCOPE

            This procedure is applicable in Raw Material, Finished Product and Intermediates and Stability Study results. This procedure is not applicable for following:

-             Microbiological analysis results

-             Results of In-process samples for monitoring the manufacturing operation.

III.             Responsibility

            QC Assistant, QC Executive, QC Manager, QA Manager, Production Manager.

IV.             Accountability

Head QA

V.                Procedure

1.0               If any result, reading, measurement is obtained out of the established limit, it should be investigated as follows

2.0               Phase I Investigation

2.1               While carrying out the analysis, if any result is found out of specification, analyst should preserve the samples, standards, and dilutions.

2.2               Analyst should inform immediately to Head QC.

2.3               Investigation should be carried out as per the Format No.: F01/SOPQA023-00.

2.4               If any instrument or analyst error is identified, QC Head should take necessary corrective actions to rectify the error and take decision of retesting.

2.5               If the sample is not sufficient for analysis, analyst should resample in presence of QA person.

2.6               Retesting should be done by a different analyst using fresh solutions.

2.7               If the error is due to the following reasons

2.7.1         Improper sampling

2.7.2         Sample contamination

2.7.3         Calibration error

2.7.4         Having not followed SOP for sampling.

2.8               Incase the error is not identified in laboratory, then proceed for production and warehouse investigation.

2.9               The investigation should be carried out as per Phase II investigation.

2.10           After phase investigation by Head QA, corrective measures should be recommended

2.11           error found is identified  then the retest results should be substituted for the previous results.

2.12           RerAnalyst will resample as per SOP.

2.13           If the problem is due to the improper maintenance of instrument, or due to

2.14           Incase of error found in laboratory investigation, the sample should be retested.

2.15            

2.15.1     Retrain the QC Chemist, if the OOS is attributed to personal error. Document training procedures.

                              Responsibility:  Sr. QC Executive / QC Manager     

2.16           Retest / Resample

2.16.1     If an assignable cause related to Laboratory error (like sample preparation, analytical method, equipment or analyst etc.) is established using the initial aliquots of test solutions, the OOS result may be INVALIDATED, and cause will be documented.

2.16.2     Retest using same solutions of test preparations may be performed, and if the results meet specification, the subject batch may be RELEASED.

2.16.3     If the initial OOS results are not assigned to original solutions of test preparations, analyst error etc., Retest from the original portions of sample drawn may be performed after the same is authorized by QC Manager / Supervisor.  Retesting may be performed by the same analyst or a different Analyst other than the one performed original test.  The Retest is carried out to evaluate if OOS observation was due to,

2.16.3.1                       Error in weighment leading to error in Test Preparations.

2.16.3.2                       Analyst Error.

2.16.3.3                       Or any other parameter related to Test method used, Equipment Calibration etc.

2.16.4     Retesting from same portion of sample is performed in triplicate and if all individual results meet the intended specification and if none of the individual results are out of specification, results may be averaged.

2.16.5     If such retest results meet the specifications, cause of original OOS must be investigated. If the cause can be assigned to a definite Analytical Error with specificity to certain area of retesting, and the OOS is NOT related to manufacturing process, then original OOS may be INVALIDATED.

2.16.6     Depending upon the nature of Analytical error, a review should be performed, if such errors have past history.

2.16.7     Accordingly, review of Analytical Method, Equipment Calibration, or Retraining of Analyst may be performed.

2.16.8     Complete review of this investigation should be documented, to minimize re-occurrence of such incidents in future.

2.16.9     Re-sampling may be permitted ONLY IF, retest data from the original portion of the sample as carried out under section 3.2.3 and the subsequent investigation gives possible evidence in respect of errors in Sampling. However, in case of OOS of outsourced Raw Materials, intermediates and re-sampling may be performed even if there is no evidence suspected in        sampling errors primarily to support the original OOS data.

2.16.10 Re-sampling may be performed after due authorization of QC Manager      after he has established that, all previous data using original portion of sample has been evaluated, and concluded that, the original sample was NOT drawn as per standard sampling procedure and therefore this sample was NOT truly representative of the batch being tested.

e. g.  Non representativeness of original sample is indicated by wide variation in results from several aliquots of the original sample as

            indicated under 3.2.11.

2.16.11 Re-sampling if permitted, should be performed using the same sampling procedure either by the same Analyst or by a different Analyst.

2.16.12 Evaluation of data from re-sampled material should be performed to determine if original sample was NOT representative. If there is   adequate evidence to support errors in initial sampling like contamination or wrong identification etc., and if it is established unambiguously that original OOS results were due to Faulty Sampling or Errors in Sampling Procedure, then only the original OOS results can be INVALIDATED.

If the investigation determines that the initial sampling method had indeed errors, a new accurate and representative sampling method must be developed, qualified, and documented.

2.16.13 Testing of re-sampled aliquot should be performed by in triplicate to establish new basis for batch release.

2.16.14 If each of 3 such data as well as the Average of these results meets specifications, original OOS result is INVALIDATED, and batch may be considered for RELEASE.  While taking such a decision, it should be equately established that there are NO FAILURES in Manufacturing Process, by conducting a review of Batch Production Record.

2.16.15 Out of three individual analyses, if any single preparation analysis fails the sample shall be rejected.

2.16.16 All steps leading to OOS investigations should be documented and review

of each failure should be correlated to occurrence of similar failures in the past.  An action plan should be prepared depending upon the nature of failure found which caused OOS.

2.16.17 If no assignable cause is found till this stage, the original OOS results should be considered VALID and the subject batch should be REJECTED.

2.16.18 For further detailed investigation into OOS result, Phase II investigation should be initiated to determine the cause of failures in manufacturing process.

3.2.19  In case of out of specification in “Description” test, the retest analysis is not required in triplicate, the description test will be tested for single time and batch can be decided based on single time analysis in retest.

2.17           Interpretation of Data

2.17.1     Pass lot when all retest or re-samples pass.

Responsibility:  QC Executive

2.17.2     For results originally out of the specification ranges, reject the lot when any retest or resample fails (the OOS result has been confirmed).

Responsibility:  QC Executive      

In case of raw material after retesting the same material if it is rejected and material send back to party then no further investigation is required.

                                    Responsibility:  QC Chemist

3.0                           Phase II investigation

3.1               If an Assignable cause could not be established during the Phase I investigation, or retest results were found to be out of specification, a review of Manufacturing Process of the subject batch should be carried out to identify the cause of Failure.

3.2               Phase II investigation is carried out by a Group consisting of

·         Manager QC/QA

·         Manager Production

3.3               Such an investigation consists of complete review / evaluation in to potential manufacturing causes of the OOS results.

3.4               Evaluation of Batch Production Records related to the subject batch.

3.5               Trend analysis of previous batches if there is any evidence to indicate Failures prior to observation of OOS result and also to assess the impact of failure on previous lots.

Note: Phase II investigation may be performed parallel to Phase I Investigation.

4.0               Information included in the Phase II investigation report is reviewed by a Group   chaired by the Production Manager, QA Manager and QC Manager. Phase II        investigation report is approved by QA Head. It is responsibility of this Group to      establish and document the cause of Failure and also recommend corrective action       plan to prevent recurrence of such Failures in future.   This Group also is   responsible to evaluate if there is any impact on preceding or succeeding lots of this             product.

5.0               Documentation

All documents related to the lot or batch in question are compiled by Quality         Control / Quality Assurance / Production Department and reports of all such investigations are filed separately and maintained by Manager QA. QA will       maintain the OOS log as per Format No. F03/SOPQA023-00.

6.0               After completion of investigation, if it rejected, the “Discrepancy / Rejection Memo” note shall be sent to purchase department having the following details.

            - Material                     :

            - Challan No / Date     :

            - Invoice No / Date     :

            - Challan Quantity      :

- Quantity Received    :

            - Discrepancy              :

7.0                           Time frame

All OOS investigations should be completed within 30 days of finding an OOS result. An extension of this 30 days period can be authorized in writing if needed

YES

YES

NO

NO

Perform extensive analysis by 2 analysts in triplicate

 Phase II Investigation is recorded in the Format No.: F02/SOPQA023-00.