Thursday, 18 July 2019

OOT | Out of Trends


Purpose

To lay down a procedure for Handling of Out of Trend results in Active Raw Material, Finished Product, stability study, environmental Monitoring & Water Trend in pharmaceutical industries.

Procedure:

Trending: Graphical illustration of data on how a process or product parameters behaves over time. Samples are periodically taken, checked or measured and results are plotted on the control charts.
Preparation of out of trend results:
  • Quality Assurance personnel shall prepare the trend of finished product as per finished product specification.
  • OOT limits shall be established based upon the APQR review data of minimum 20 commercial batches (Annual Product Quality Review). In case the said data is unavailable or insufficient (i.e. less than 20) due to ‘Nil’ or insufficient number of batches produced, data of all batches of the APQR of second last year be considered for setting control limits along with available data of the previous year’s APQR. Batches to be considered for such a trending must have been manufactured by the same process, and those with confirmed OOS and/or OOT shall not be considered.
  • OOT limit of finished product assay test shall be calculated as per below mentioned formula:
  • Upper Control Limit (UCL)=Mean+3 times Standard Deviation
  • Lower Control Limit (LCL)=Mean-3 times Standard Deviation
  • For processes, where there is tendency of getting scattered results and ±3 sigma values are broader than specification limits, in those cases extreme values (Observed highest and lowest value within set of data) within specification for calculation of control limit shall be considered as OOT limit.
  • During the review of analytical data, if any OOT result is observed from the established trend limit, then the concern QC personnel shall inform to Head Quality Control or designee report to QA for OOT results.
  • In case of stability samples, if assay results obtained beyond ± 5% of the result of its initial value then it shall be considered as OOT result.
  • Stability sample test result for related substance test, shall be considered as out of trend if :
  • For impurities (Individual or Total I.e. X) between 0.10 % to 0.2 % at particular station, if impurities result is decreases 100% from the previous station’s reported value then the impurities result shall be considered as OOT.
  • For impurities (Individual or Total) between 0.20 % to 1.0% at a particular station, if impurities results is decrease 50 % from the previous station’s reported value then the impurities results shall be considered as OOT.

The following are not treated as OOT:
  • The value obtained from any individual impurity is less than 0.10% or below LOQ (Limit of Quantitation).
  • Physical Tests: e.g. Description, Spray Rate etc.
  • Analytical data generated by analyst at the time of training and analyst qualification.
  • Analytical data generated during routine release of intermediates.
  • Analysis of those test parameters which have no specification limit i.e. those which are for ‘Monitoring’ or ‘Reporting’ or ‘Reference’ etc. purpose only.
  • Analysis of finished good. If there is an increasing trend of impurities.

Investigation procedure for out of trend results:
  • Phase-I(Laboratory Investigation):The analyst, section-Head/designee, shall investigate the reasons for OOT.
  • If laboratory investigation reveals that the OOT result is due to following obvious error, then Head-QC/Designee shall co-ordinate with Head-QA/designee and authorized to analyst for further action:

Wrong interpretation of chromatogram: Head-QA/designee and Head- QA/designee shall review the chromatogram then supervisor shall re-integrate the chromatogram.
Calculation/Transcription Error: Analyst shall make the corrections in the analytical raw data sheet by following the current version of SOP on Good Documentation Practices. All such correction shall be counter signed by reviewer after talking suitable corrective and preventive action (s).
Equipment / Instrument Failure or incorrect Instrument Parameters: Analyst and section head / designee shall document the event and annotate “Instrument / Equipment failure or incorrect instrument parameters “Then repeat analysis shall be carried out after talking suitable corrective action (s). Original analyst shall perform the repeat analysis by using the same sample (Analysis shall be done on a second dilution from some portion of sample that was source of the first dilution or analysis shall be done on a portion of the same sample).        
Note: To prove the instrument, QC analyst may re-inject the original sample after intimating to section –Head QC as part of investigation testing to verify the instrument malfunctioning during analysis.
Testing Error: If error is due to spilling of sample solution or incomplete transfer of sample, analyst should document what had happened. 
  • Analyst should not knowingly continue an analysis they expect to invalidate at a letter time for an assignable case (e.g. analysis should not be completed for the sole purpose of seeing what result can be obtained when obvious error are known).
  • If The case of OOT is found to be an ‘Obvious error’ then the concerned analysis / initiator` shall take necessary, step as specified above and based on corrected result sample shall be released after appropriate corrective and preventive action and investigation shall be closed.
  • If laboratory investigation reveals that the OOT result is due to the assignable case e.g. analytical error then repeat analysis shall be carried out in triplicate, after talking suitable corrective action (s). Original analyst shall have performed the repeat analysis by using the same sample (analysis shall be done on a second dilution from the same portion of sample that was source of the first dilution or analysis shall be done on a portion of the same sample).
  • Batch shall be approved if all result meets the following criteria as applicable (But Not limited to):
  • All individual result are within trend limit.
  • In case of assay determination by HPLC, the overall % RSD shall not be more than 2.0%.
  • In case of assay determination by GC, the overall % RSD shall not be more than 10.0 %.
  • In case of assay determination by UV, the overall % RSD shall not be more than 5.0 %.
  • In the case of impurities, the RSD shall not be more than 25.0 % if the impurity content is between 0.05 to 0.10 % and RSD shall not be more than 15.0 %, if the impurity content is between 0.10 to 0.5 % and the RSD shall not be more than 10.0 %, if the impurity content is above 0.5%.
  • Note: If laboratory error identified in phase I investigation than to prove the analytical error hypothesis testing may be planned.
  • Phase-II Investigation: When the initial assessment does not determine that laboratory error caused the OOT result, a full-scale OOT investigation should be conducted through a cross functional team.
  • This investigation may consist of an additional laboratory work and/or production process review. The objective of full scale OOT investigation is to identify the root cause of the OOT result and take appropriate CAPA.
  • A full-scale OOT investigation may include (But not limited to) the additional laboratory testing (Re-analysis). Re-analysis shall be performed by second analyst (Analyst B) in triplicate other than the original analyst, on original sample (i.e. analysis shall be done on a second dilution from the same portion of sample that was source of the first dilution or analysis shall be done on a portion of the same sample previously collected for analysis).
  • In case one or more result (s) of analysis B is / are out of trend than the analysis shall be discontinued. And investigation shall be extended to manufacturing process and sampling activities. 
  • In case all the three result triplicate analysis performed by analyst B are within the trend than the analysis shall be performed once again triplicate by third analyst (Analyst C).
  • Batch shall be approved if all six result (B & C) meet the acceptance criteria as below:
  • All individual result are within trend limit.
  • In case of assay determination by HPLC, the overall % RSD shall not be  more than 2.0 %.
  • In case of assay determination by GC, the overall % RSD shall not be  more than 10.0 %.
  • In case of assay determination by UV, the overall % of RSD shall be not more than 5 %.
  • In the case of impurities, the RSD shall not be more than 25.0 % if the impurities content is between 0.05 to 0.10 % and the RSD shall not be more than 15.0 % if the impurities content is between 0.10 to 0.50 % and the RSD shall not be more than 10.0 % if the impurities content is above 0.50 %.
  • If all six result of analysis ‘B’ and ‘C’ meet the acceptance criteria, then hypothesis testing shall be planned to find out the root cause of initial failure (Result of analyst ‘A”) as per approved hypothesis protocol.
  • In case of unsuccessful attempt to identify the laboratory error, investigation shall be extended to manufacturing process (Review of production process and procedure etc.) And sampling activity (Review of any error in sampling procedure / handling of sample / storage of sample etc.)
  • If sampling error is identified, then after re-sampling, original analysis (A) shall performed the analysis in triplicate and batch shall be approved, if result meets the acceptance criteria as mentioned in point no.: 4.9.1.3
  • Re-sampling may also be done if:
  • The sample quantity is insufficient / exhausted (For stability sample, sample from stock shall be used).     
  • Original sample was not representative sample of the batch.    
  • Original sample was improperly sampled / prepared.   
  • Original sample was not stored appropriately and may have been adversely affected by exposure to humidity, light or heat.
  • Re-sampling should be performed same qualified methods that were used for the initial sampling by qualified personnel. However, if investigation determine that the initial sampling method was inherently inadequate, a new accurate sampling method shall be developed, documented, reviewed and approved by QA. In such a case, the re-sampling shall be done with the new approved sampling method. A consideration should be given to other lots sample by the same method.  
  • If investigation reveals that error is related to manufacturing process, then appropriate CAPA shall be initiated.   
  • If the manufacturing investigation remains inconclusive, then the final action shall be taken by Head-Quality / Designee.

General Guidelines:
  • The original OOT result shall not be averaged along with repeat analysis results.
  • After re-analysis, average of values, shall be reported on certificate of analysis.
  • Investigation report shall outline the corrective and preventive action necessary to release the batch.
  • If OOT is due to process related error, operator error or malfunctioning of equipment /instrument etc. then investigation shall be extended and risk /impact assessment shall
  • be done for possibly affected other batches and products.
  • The investigation should be completed within 30 working days from the occurrence of the OOT result. Action shall be reported to Head-Quality/Designee for further advice and CAPA shall be initiated.
  • If the OOT is caused by analyst error the analyst shall be re-trained. This re-training shall be documented and copy is to be kept along with the OOT result.

Interpretation of Investigation Results:
  • Head-QC/Head-QA is responsible for interpreting the results of the investigation. The OOT result should be investigated and the findings of the investigation including retest results should be interpreted to evaluate the batch and to take a decision regarding OOT cause.
  • In those instances, where an investigation has revealed a case and the suspect result is invalidated the result should not be used to evaluate the quality of the batch or lot. A confirmed OOT result indicates that the batch does not meet established trend limits.
  • Invalidation of a discrete test result may be done only upon the observation and documentation of a test event that can reasonably be determine to have caused the OOT result. In case of investigation, ‘INVALID’ stamp needs to put in red color in record of analysis and all relevant chromatogram, spectra, etc.


Rahul Kashyap is the executive in a Leading Pharma Company, he author in-depth guide that teach pharma industry owner and workers way to follow, manage and grow the quality work in this Field.

2 comments:


EmoticonEmoticon