Follow
1.0 OBJECTIVE
To lay down a procedure for handling of Out of Trend (OOT) results during testing of
routine and stability samples in Laboratory and during review of Annual product quality,
water trends and environmental monitoring trends in Quality Assurance.
2.0 SCOPE
This procedure is applicable to tests like Assay, Dissolution, Loss on Drying, Water content, Related substances, Residual solvents, etc., and trends like Annual product quality review, water, environmental monitoring performed in Quality Assurance / Quality Control Laboratory.
3.0 RESPONSIBILITIES
3.1 Analyst / Observer / Reviewer is responsible for informing and initiating the OOT results for routine / Stability samples.
3.2 QC − Supervisor to conduct the laboratory investigation and QA personnel to conduct the manufacturing investigation.
3.3 QC – Head or Designee for review and Conclusion and QA – Head or Designee for review and closure of the OOT investigation.
3.4 QC – Head and QA – Head are responsible for ensuring compliance to this SOP.
4.0 ACCOUNTABILITY
4.1 Head of Quality.
5.0 PRECAUTIONS
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6.0 PROCEDURE
6.1 Definition
6.1.1 Out of Trend result: Any result that do not follow the expected trend in comparison with previous batches or results of previous analytical intervals for a material/product is defined as Out of Trend’ result.
6.1.2 Obvious error: An error that has a direct evidence, either through data or physical Observation
6.1.3 Original sample: The sample portion from the composite that was taken for initial analysis.
6.1.4 Assignable cause: An identified reason for obtaining Out of trend or aberrant results.
6.2 OOT Logging and preliminary action:
6.2.1 Analyst shall assess the obtained results of the critical quantitative attributes / parameters against continuous process verification following SOP QA101 and check whether the results are out of trend/control. For the identification of OOT results in the stability study samples Annexure-IV will be followed.
6.2.2 Analyst shall inform about the “Out of Trend” (OOT) result, as soon as possible to the supervisor or Head of the department.
6.2.3 To the extent possible, analyst shall retain aliquots of solutions, and / or portions of samples used for analysis under suitable storage conditions to facilitate the investigation.
6.2.4 Analyst/observer shall initiate the OOT using the format of “Report of Laboratory Investigation of OOT results” provided in Annexure-I, by indicating the summary of obtained results in the space provided.
6.2.5 The same shall be reported and numbered in an OOT register as given in Annexure-II.
6.2.6 Separate number shall be generated for each test belonging to one AR No.
6.2.7 For Dissolution test, irrespective of the number of units in the set found to be out of trend, only one OOT form shall be raised per each set of the sample of the AR No.
6.2.8 The number shall be given as below:
OOT/YY/XXX. Where, YY stands for year (13 for year 2013) and XXX stands for a three digit running sequence number generated through the register.
6.2.9 Investigation shall be carried out promptly by the Supervisor along with the analyst and findings shall be elaborated in the “Report of Laboratory Investigation of OOT results” form.
6.2.10 The Laboratory phase OOT investigation by QC shall be completed within 15 business days from the day of initiating OOT investigation.
6.2.11 QA – Reviewer shall assess the data available in the trends like product quality review, Water trends and Environmental trends etc., to evaluate any result to be considered as OOT and shall discuss with QA − Head / Designee to confirm the same.
6.2.12 QA – Reviewer shall initiate OOT investigation by following the steps 6.2.4 to 6.2.8.
6.2.13 Any OOT raised based on trends, shall be investigated by QA based on the available data only. QA shall recommend QC to perform analysis with the available sample (Retention sample, etc.,) if required.
6.3 Investigation by QC in the Laboratory
6.3.1 The QC supervisor or designee shall assess the data to ascertain if the result could be attributed to any obvious laboratory error by following the steps bellow:
6.3.2 QC supervisor or designee shall examine the actual sample, glassware and test solutions of sample and standard used in the original measurement.
6.3.3 QC supervisor or designee shall examine the raw data obtained in the analysis for any anomalous or suspect data.
6.3.4 QC supervisor or designee shall verify the calculations used for converting raw data into test results for correctness and also determine if any unauthorized changes have been made.
6.3.5 QC supervisor or designee shall confirm the performance of analytical equipment used by reviewing the calibration status and if need be the calibration data.
6.3.6 QC supervisor or designee shall determine whether correct reference standards or working standards, solvents and reagents of appropriate grade and validity were used.
6.3.7 QC supervisor or designee shall also evaluate from the initial obtained data whether the method is performing according to the standard based on method validation and historical data.
6.3.8 QC supervisor or designee shall also discuss the test procedure with the analyst to ascertain the knowledge / competency to perform the test as per standard procedure and controls.
6.3.9 As a tool for investigation QC supervisor or designee shall use relevant portion of the checklist as given in Annexure-III, but not necessarily in the sequential order in which the check points are listed. If need be, specific checklist may also be prepared for a particular test.
6.3.10 Each step of the investigation shall be documented in the same form as provided in Annexure-I as the investigation progresses. Additional sheets of paper shall be used, if necessary.
6.3.11 During the investigation, if any obvious error (s) is identified, then the analysis shall be repeated using original solutions / sample portion by the same analyst taking care to omit all errors identified during the investigation. If original solutions / sample portions are found to be suitable/not available, then freshly prepared solutions/fresh portion from the original sample shall be used.
6.3.12 If the above repeat analysis result (s) is within the trend, then QC shall summarize the findings in the investigation and shall forward the investigation report to QA for review the closure.
6.3.13 QA shall review the investigation to evaluate the scientific evidence for the existence of the obvious error. Based upon the confirmation of the obvious error and the repeat analysis results, QA shall close the OOT investigation. QA shall also recommend to QC to invalidate the initial results and to report the repeat analysis results.
6.3.14 In case the above repeated analysis results found to be comparable with initial results (i.e. Out of trend result) QC shall summarize the findings in the investigation and shall forward the investigation report to QA to initiate further investigation.
6.3.15 Based on the above investigation, QC shall consider the initial results are valid and shall retain the initial results.
6.3.16 In the case of no obvious error (s) being identified during the initial investigation, then additional investigation shall be conducted by QC based on the available data to ascertain any assignable cause which resulted in OOT.
6.3.17 If this additional investigation doesn’t reveal any probabilities of an assignable cause, then QC shall summarize the findings in the investigation and shall forward the investigation report to QA for review and to initiate further investigation.
6.3.18 In case, there are no probabilities of an assignable cause, QC shall consider the initial results are valid and shall report the initial results as final results.
6.3.19 If this additional investigation reveals probabilities of an assignable cause, then the original sample shall be analysed by making duplicate preparations by second analyst of at least equal competency and knowledge by avoiding the assignable cause.
6.3.20 If the result obtained during the above analysis in duplicate by the second analyst found to be comparable with the initial results (i.e. Out of trend) individually, then QC shall summarize the findings and forward the investigation report to QA for review and to initiate further investigation. QC shall consider the initial results are valid and shall report the initial results as final results.
6.3.21 If the results of the repeat analysis by the second analyst found to be within the trend individually, then the original sample shall be analysed by the first analyst again by making duplicate preparations omitting the assignable cause.
6.3.22 If the results of repeat analysis by the first analyst within the trend individually, then QC shall summarize the findings in the investigation and shall forward the investigation report to QA for review.
6.3.23 QA shall review the investigation to evaluate the scientific evidence for the existence of an assignable cause. Based on the confirmation of the assignable cause, QA shall close the OOT investigation. QA shall also recommend to QC to invalidate the initial results and to report the repeat analysis results of first analyst.
6.3.24 In case the above repeated analysis results by the first analyst comparable with the initial results (i.e. Out of trend results), then QC shall summarize the findings in the investigation and shall forward the investigation report to QA for review and initiating further investigation.
6.3.25 In any of the cases, if the first analyst is not available for repeating the analysis as per the flow chart, then, another equivalent and competent analyst can be utilized.
6.3.26 In any case, if QA recommends, to replace the original results with the repeat analysis results, shall be justified with scientific evidence.
6.3.27 In case of Related Substances i Impurities / Degradants / Residual Solvents /Dissolution, report the first measurement and for other tests, report the average of replicate measurements.
6.3.28 QA shall assess the reasons for laboratory errors with respect to training needs, SOP /testing procedures revisions, impact on previous analysis done, impact of batches previous analysis done by the analyst and corrective and preventive actions shall be put in p1ace.
6.3.29 A risk assessment shall be carried out wherever necessary.
6.3.30 Once the end of laboratory investigation is reached, the recommendation of reporting the results and corrective/preventive action wherever applicable shall be indicated in the relevant column of the investigation form.
6.3.31 At any point of time during the investigation, the results obtained found to be ‘Out of Specification’ then the same shall be investigated through ‘Out of specification’ investigation as per the relevant operating procedure.
6.4 Investigation by QA
6.4.1 The QA investigation shall be completed within 15 business days from the day of QC investigation conclusion.
6.4.2 QA shall initiate further investigation for Raw materials (API only) as following (but not limited to):
6.4.2.1 QA in coordination with Warehouse personnel shall review the storage of the materials in the warehouse, any violation in the temperature and humidity conditions, any abnormality in the physical nature of the material.
6.4.2.2 QA shall discuss with vendor on any specific inputs from them on a probable cause based on their experience.
6.4.2.3 QA shall initiate further investigation on the manufacturing side for In-process and
Finished products:
6.4.3 QA head or designee in coordination with production head or designee shall conduct a detailed investigation to identify, whether the OOT is due to ‘Process or Non-process related error.
6.4.3.1 During investigation, the following shall be verified (but not limited to):
6.4.3.2 Review of the production activity to confirm the operator is properly trained.
6.4.3.4 Review of calculation and various processes generated data.
6.4.3.5 Review of performance of the machine(s) associated with the data.
6.4.3.6 Review of critical process parameters of the batch
6.4.3.7 Review of historical trends where appropriate, and product development report, including similar problem in the past (wherever applicable)
6.4.3.8 Review of the effectiveness of Corrective action and Preventive action of incidents, Deviations related to the process (If any, reported)
6.4.4 For stability samples, QA shall initiate further investigation in the development side:
6.4.4.1 QA head or designee shall conduct and initiate investigation to ascertain if the problem is isolated for a batch or it is a general phenomenon that could affect other batches.
6.4.4.2 Where necessary, the other batches of the product shall be investigated.
6.4.4.3 Customer related product, customer suggestions and or directions will be consider for the part of the investigation.
6.4.5 QA shall summarize the findings during the investigation in the relevant portion of the investigation report as per the Annexure-I.
6.4.6 Based on the above investigations, QA shall conclude the investigation and shallrecommend necessary corrective and preventive actions.
6.4.7 OOT investigation by QC in the laboratory and further investigation by QA shall becompleted within 30 business days from the date of OOT initiation.
