Investigation of out of specifications.pdf
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The document outlines the process for investigating out-of-specification (OOS), out-of-trend (OOT), or atypical test results. It involves a multi-phase investigation including: Phase I involves an initial laboratory investigation to identify any errors. Phase II is a full-scale investigation including manufacturing process review, additional laboratory testing through retesting or resampling, and identification of any assignable causes. Phase III ensures corrective and preventative actions are taken as needed and other potentially impacted batches are evaluated. The goal is to thoroughly investigate to determine if the batch should be rejected or can be released and prevent future occurrences.
Investigation of out of specifications.pdf
- 2. Laboratory Analysis OOS (OOT) Result Phase II Investigation Manufacturing Investigation Product Impact Assessment Additional Laboratory Test Batch Disposition Phase l Investigation Satisfactory Overview
- 3. Phase I Investigation Phase l Investigation No Further Investigation Required Obvious Error Document and Correct Invalid Result Manufacturing Process Investigation Additional Laboratory Investigation No Error found Laboratory Data Analysis, Hypothesis Test Full Scale / Phase II Investigation Overview
- 4. Follow Approved Protocol Execute Investigation (Retesting and/or Resampling) Phase II Additional Laboratory Test OOS Results Obtained Confirm OOS No Further Retest No Assignable Cause Report All Results Assignable Cause Report Retest Results Generate CAPA Impact Assessment/ Disposition Batch Invalidate Original Results Batch Disposition Phase III Investigation Overview
- 5. Identification of OOS Result • Out-of-Specification (OOS) Result – • Test result that does not comply with the pre-determined acceptance criteria. • Test results that fall outside of established acceptance criteria which have been established in official compendia and/or by company documentation. • Out of Trend (OOT) Result – • Is generally a stability result that does not follow the expected trend, either in comparison with other stability batches or with respect to previous results collected during a stability study. However the trends of starting materials and in-process samples may also yield out of trend data. • The result is not necessarily OOS but does not look like a typical data point. • Should be considered for environmental trend analysis such as for viable and non viable data (action limit or warning limit trends) • Atypical / Aberrant / Anomalous Result – • Results that are still within specification but are unexpected, questionable, irregular, deviant or abnormal. Examples would be chromatograms that show unexpected peaks, unexpected results for stability test point, etc. Investigation
- 6. Investigation of OOS Investigations of "Out of Specification (OOS) / Out of Trend (OOT)/ Atypical results" have to be done in cases of: Batch release testing and testing of starting materials. In-Process Control testing: if data is used for batch calculations/decisions and if in a dossier and on Certificates of Analysis. Stability studies on marketed batches of finished products and or active pharmaceutical ingredients, on-going / follow up stability (no stress tests) Previous released batch used as reference sample in an OOS investigation showing OOS or suspect results. Batches for clinical trials. All solutions and reagents should be retained until all data has been second person verified as being within the defined acceptance criteria. Pharmacopoeia have specific criteria for additional analyses of specific tests (i.e. dissolution level specification for S1, S2 & S3 testing; Uniformity of dosage units specification for testing of 20 additional units; Sterility Testing). However if the sample test criteria is usually the first level of testing and a sample has to be tested to the next level this should be investigated as it is not following the normal trend. The OOS process is not applicable for In-process testing while trying to achieve a manufacturing process end-point i.e. adjustment of the manufacturing process. (e.g. pH, viscosity), and for studies conducted at variable parameters to check the impact of drift (e.g. process validation at variable parameters). Investigation
- 7. Investigation of OOS Objective • To identify the route cause • To conclude by a decision either batch rejection or release • To take appropriate corrective and preventive action Should Be • Through • Timely • Unbiased • Well documented • Scientifically sound Investigation
- 8. Phase I laboratory investigation • Investigation should include an initial assessment of laboratory data • Investigation should be done before discarding test preparation • Hypothesis test can be conducted using the original test preparations • If obvious error found laboratory test result should be invalidated and retest should be done Investigation
- 10. Phase II / Full Scale Investigation • No obvious laboratory error found in initial laboratory investigation • For contract laboratory, laboratory should send the data obtained to manufacturers for full scale investigation • Should be conducted using predefined procedure (SOP) • Production procedure review • Sampling procedure review • Additional laboratory testing • Highest priority Investigation
- 11. Phase II / Full Scale Investigation Phase II Investigation Manufacturing investigation Additional Laboratory Test Investigation
- 12. Manufacturing/ Production Process Review • Should be conducted by QCU • Should involve all other relevant department i.e. production, development, engineering, if needed • If contract manufacturer then all site (contract manufacturing site) • timely, thorough, and well-documented Investigation
- 13. Written record of the review should include the following information A clear statement of the reason for the investigation. A summary of the aspects of the manufacturing process that may have caused the problem. The results of a documentation review, with the assignment of actual or probable cause. The results of a review made to determine if the problem has occurred previously. A description of corrective actions taken. Manufacturing/ Production Process Review Investigation
- 14. If error found, investigation terminated & product rejected However, a failure investigation that extends to other batches or products that may have been associated with the specific failure must be completed If reprocessed after additional testing, the investigation should include comments and the signatures of appropriate production and quality control personnel Appropriate CAPA should be taken Manufacturing/ Production Process Review Investigation
- 15. Should be conducted by QCU Should involve all other relevant department i.e. production, development, engineering, if needed If contract manufacturer then all site (contract manufacturing site) Timely, thorough, and well-documented Manufacturing/ Production Process Review Investigation
- 17. Additional Laboratory Testing Decision should be taken based on the objective of the testing & should have sound scientific judgment Should have predefined retesting plan Should be done by analyst other than original analyst 2nd analyst should be qualified at least like original analyst should be from the same sample portion which has generated OOS result Investigation Retesting
- 18. Additional Laboratory Testing Should be done to identify instrument malfunction, sample handling error e.g. dilution error Testing to compliance is prohibited Maximum number of retest should be defined in SOP and should not be adjusted depending on the obtained result The firm's predetermined retesting procedures should contain a point at which the additional testing ends and the batch is evaluated If the results are unsatisfactory at this point, the batch is suspect and must be rejected or held pending further investigation Investigation Retesting
- 19. Additional Laboratory Testing Any deviation from SOP should be rare and any deviations from written specifications, sampling plans, test procedures, or other laboratory control mechanisms shall be recorded and justified. In such cases, before starting additional retesting, a protocol should be prepared (subject to approval by the QCU) that describes the additional testing to be performed and specifies the scientific and/or technical handling of the data. Investigation Retesting
- 20. Additional Laboratory Testing In the case of a clearly identified laboratory error, the retest results would substitute for the original test result. All original data should be retained, however, and an explanation recorded This record should be initialed and dated by the involved persons and include a discussion of the error and supervisory comments. If no laboratory or calculation errors are identified in the first test, there is no scientific basis for invalidating initial OOS results in favor of passing retest results. All test results, both passing and suspect, should be reported and considered in batch release decisions. (In other words, all data are reported in, for example, quality control reports, batch records, Certificates of Analysis) Investigation Retesting
- 21. Resampling Should rarely occur! If insufficient quantity of the original sample remains to perform all further testing then the procedure for obtaining a resample must be discussed and agreed by QA/Contract Giver/QA equivalent. The process of obtaining the resample should be recorded within the laboratory investigation. Re-sampling should be performed by the same qualified methods that were used for the initial sample. However, if the investigation determines that the initial sampling method was in error, a new accurate sampling method shall be developed, qualified and documented. It involves the collecting a new sample from the batch. Will occur when the original sample was not truly representative of the batch or there was a documented/traceable lab error in its preparation. Evidence indicates that the sample is compromised or invalid. Sound scientific justification must be employed if re-sampling is to occur. Investigation
- 22. 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 preventative action. Phase III Investigation Investigation
- 23. Phase III investigation 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. To conclude the investigation all of the results must be evaluated. The investigation report should contain a summary of the investigations performed; and a detailed conclusion. For 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. The batch quality must be determined and disposition decision taken. Investigation
- 25. Interpretation of investigation result The QCU is responsible for interpreting the results of the investigation Initial OOS result does not necessarily mean the subject batch fails and must be rejected. OOS result should be investigated, and the findings of the investigation, including retest results, should be interpreted to evaluate the batch and reach a decision regarding release or rejection. Where an investigation has revealed a cause, and the suspect result is invalidated, the result should not be used to evaluate the quality of the batch or lot Where the investigation indicates an OOS result is caused by a factor affecting the batch quality (i.e., an OOS result is confirmed), the result should be used in evaluating the quality of the batch or lot. Reporting
- 26. Interpretation of investigation result A confirmed OOS result indicates that the batch does not meet established standards or specifications and should result in the batch's rejection. For inconclusive investigations — in cases where an investigation (1) does not reveal a cause for the OOS test result (2) does not confirm the OOS result The OOS result should be given full consideration in the batch or lot disposition decision. In the first case (OOS confirmed), the investigation changes from an OOS investigation into a batch failure investigation, which must be extended to other batches or products that may have been associated with the specific failure. Reporting
- 27. Batch Disposition If no laboratory or calculation errors are identified in the Phase I and Phase II there is no scientific basis for invalidating initial OOS results in favour of passing retest results. All test results, both passing and suspect, should be reported (in all QC documents and any Certificates of Analysis) and all data has to be considered in batch release decisions. If the investigation determines that the initial sampling method was inherently inadequate, a new accurate sampling method must be developed, documented, and reviewed and approved by the Quality Assurance responsible for release. A consideration should be given to other lots sampled by the same method. An initial OOS result does not necessarily mean the subject batch fails and must be rejected. The OOS result should be investigated, and the findings of the investigation, including retest results, should be interpreted to evaluate the batch and reach a decision regarding release or rejection which should be fully documented.
- 28. Disposition of Batch In those cases where the investigation indicates an OOS result is caused by a factor affecting the batch quality (i.e., an OOS result is confirmed), the result should be used in evaluating the quality of the batch or lot. A confirmed OOS result indicates that the batch does not meet established standards or specifications and should result in the batch's rejection and proper disposition. Other lots should be reviewed to assess impact. For inconclusive investigations — in cases where an investigation:- (1) does not reveal a cause for the OOS test result and (2) does not confirm the OOS result the OOS result should be given full consideration (most probable cause determined) in the batch or lot disposition decision by the certifying QP and the potential for a batch specific variation also needs considering. Any decision to release a batch, in spite of an initial OOS result that has not been invalidated, should come only after a full investigation has shown that the OOS result does not reflect the quality of the batch. In making such a decision, Quality Assurance/QP should always err on the side of caution.
- 29. Concluding The Investigation • The results should be evaluated, the batch quality should be determined, and a release decision should be made by the QCU. • The SOPs should be followed in arriving at this point. • Once a batch has been rejected, there is no limit to further testing to determine the cause of the failure so that a corrective action can be taken. Reporting
- 30. Averaging The validity of averaging depends upon the sample and its purpose. Using averages can provide more accurate results. For example, in the case of microbiological assays, the use of averages because of the innate variability of the microbiological test system. The kinetic scan of individual wells, or endotoxin data from a number of consecutive measurements, or with HPLC consecutive replicate injections from the same preparation (the determination is considered one test and one result), however, unexpected variation in replicate determinations should trigger investigation and documentation requirements. Averaging cannot be used in cases when testing is intended to measure variability within the product, such as powder blend/mixture uniformity or dosage form content uniformity. Reliance on averaging has the disadvantage of hiding variability among individual test results. For this reason, all individual test results should normally be reported as separate values. Where averaging of separate tests is appropriately specified by the test method, a single averaged result can be reported as the final test result. In some cases, a statistical treatment of the variability of results is reported. For example, in a test for dosage form content uniformity, the standard deviation (or relative standard deviation) is reported with the individual unit dose test results. Reporting
- 31. Averaging In the context of additional testing performed during an OOS investigation, averaging the result (s) of the original test that prompted the investigation and additional retest or resample results obtained during the OOS investigation is not appropriate because it hides variability among the individual results. Relying on averages of such data can be particularly misleading when some of the results are OOS and others are within specifications. It is critical that the laboratory provide all individual results for evaluation and consideration by Quality Assurance (Contract Giver/QP). All test results should conform to specifications (Note: a batch must be formulated with the intent to provide not less than 100 percent of the labelled or established amount of the active ingredient. Averaging must be specified by the test method. Reporting
- 32. Outlier Test An outlier may result from a deviation from prescribed test methods, or it may be the result of variability in the sample. It should never be assumed that the reason for an outlier is error in the testing procedure, rather than inherent variability in the sample being tested. Statistical analysis for Outlier test results can be as part of the investigation and analysis. However for validated chemical tests with relatively small variance and that the sample was considered homogeneous it cannot be used to justify the rejection of data. While OOS guidance is not directly intended for bioassay analysis, it can be used as a starting point for the investigation. Compendia such as the BP; PhEur and USP, provide guidance on outliers for these types of analysis. Reporting
- 33. Stability OOS/OOT Stability OOS/OOT situations should be escalated as soon as the suspect result is found. Follow the investigation as above for Phase I and Phase II. For OOS Situations Regulatory agencies will require notification within a short time point of discovery due to recall potential. If abnormal results are found at any stability interval which predicts that the test results may be OOS before the next testing interval, schedule additional testing before the next scheduled testing interval. This will help better determine appropriate actions to be taken. The stability OOS should link to the Product Recall procedures.
- 34. Stability OOS/OOT To facilitate the prompt identification of potential issues, and to ensure data quality, it is advantageous to use objective (often statistical) methods that detect potential out-of-trend (OOT) stability data quickly. OOT alerts can be classified into three categories to help identify the appropriate depth for an investigation. OOT stability alerts can be referred to as: analytical, process control, and compliance alerts, As the alert level increases from analytical to process control to compliance alert, the depth of investigation should increase.
- 35. Stability OOS/OOT A compliance alert defines a case in which an OOT result suggests the potential or likelihood for OOS results to occur before the expiration date within the same stability study (or for other studies) on the same product. The stability OOS should link to the Product Recall procedures. Historical data are needed to identify OOT alerts. An analytical alert is observed when a single result is aberrant but within specification limits (i.e., outside normal analytical or sampling variation and normal change over time).