Handling of Out-of-Specification and Out-of Trend Test Results


1.0 Objective

To lay down a procedure for handling of Out-of-Specification and Out-of-Trend Test Results.

2.0 Scope

This SOP shall be applicable for chemistry based testing of drug substances, excipients, components and drug products at formulation plant. The SOP is not applicable for the microbiological results.

3.0 Responsibility

3.1 Executive / Officer, QC :     To inform the OOS test result to Manager-QC.

3.2 Manager- QC/ designee :     To initiate the laboratory investigation on OOS test results and forwarding laboratory investigation report to Quality Assurance for final disposition, in case of real OOS test.

3.3 Head-QC/ designee :     To review and approve all investigations of OOS results before forwarding to Quality Assurance.

3.4 Head-QA/ designee :     To review and decide for final disposition of material  / products.

4.0 Abbreviations and Definitions

OOS                            :           Out-of-Specification

OOS Test Results       :           OOS test results include all results that fall outside the
specifications/ acceptance criteria established in regulatory Submissions or official compendia or in house tests. The term also applies to all in-process laboratory tests that are outside of established specifications.

OOT Test Result         :           An OOT result is a routine product review/stability results that does not follow the expected release trend.

5.0 Procedure

5.1 Out-of-Specification:

5.1.1 Expected type of errors: Type 1: Laboratory Error e.g. analyst error, incorrect calculation, malfunctioning of equipment, use of incorrect standards or sample preparation, lack of precision and mismeasurement etc. Type 2: Non-process related or operator error in manufacturing i.e. human or mechanical error, which occur during manufacture. e.g. failure to add a component, malfunction of equipment or cross contamination. Type 3: Process or manufacturing error due to poor control over processes e.g. incorrect mixing, heterogeneity of blends etc. Confirmation that this was the cause of OOS error shall constitute a product failure. Type 4: If no process error / Laboratory error shall be observed during the investigations and results of the tests shall constitute a product failure.

5.2 Phase-I Laboratory investigation :-

5.2.1 As soon as analyst observes an OOS, he/ she shall report the result and inform the Manager/ designee-QC.

5.2.2 The Manager / designee – QC shall inform to QA and request for the issuance of the form titled Laboratory Investigation Checklist for OOS test results (annexure -I) and OOS Test Results – Laboratory Investigation Report (annexure – II)

5.2.3 Manager / designee – QC shall initiate investigation as per annexure -I and II.

5.2.4 A step-by-step review of the calculations, test method, lab notebooks, instruments, etc as per annexure -I shall be done. Review of the sampling and testing procedure methodology. Review of reference standard / working standard used. Review of the calculations. Review of all the preparations mentioned in the standard test procedure. Examination of instruments / equipments used. Confirmation that equipment utilized was within calibration specifications and reagents standardized. Review of laboratory entry / entries containing the OOS test results. Rework of any original sample preparation where appropriate (e.g. suspected incomplete extraction of material analysis preparation matrix etc.). Review of supplier’s certificate of analysis (if applicable). Evaluate assay trend and variability data in order to assess the source of the OOS results.

5.2.5 If by investigations, an OOS result is identified as a laboratory error (Type 1) then OOS shall be overcome by retesting. It shall not constitute a product failure.

5.2.6 The sample used for the retesting shall be taken from the same homogeneous material that was originally collected form the lot, tested and yielded the OOS results. Retesting shall be performed by an analyst other than the one who performed the original tests. In the case of a clearly identified laboratory error, the retest results shall substitute for the original test results. The original results shall be retained. Record and report the results in the form titled “OOS Test Results – Labotratory Investigation Report” (Annexure-II).

5.2.7 The full phase investigations shall be done if the phase-1 laboratory investigation is ruled out.

5.3 Full scale:– Phase – II investigation

5.3.1 When the initial assessment does not determine that laboratory error caused the OOS result.

5.3.2 A full scale OOS investigation using a predefined procedure shall be conducted.

5.3.3 This investigation shall consist a production process review and additional laboratory work if required.

5.3.4 If during investigation, process related error is observed in the manufacturing. Product shall be evaluated as per SOP titled “Handling of Non-Conformances”.

5.3.5 Re-sampling: If the initial aliquot from the original sample is not sufficient for retest or it is established during the course of investigation that the original sample was not stored properly, was not representative in nature, a second aliquot from the original sample is used. In case the original sample has been consumed during analysis, a second sample (new sampling) can be used. Re sampling shall be performed by the same 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. In case the original sample has been consumed during analysis then re sampling of new sample(s) shall be done only after QA approval as per form titled “Approval Form for Re-sampling” (Annexure-IV).

5.3.6 Additional Re-testing: If the process error is not identified, resampling shall be done as per sampling procedure and analysis shall be done in triplicate by two different analysts. If the sample fails by analyst A or analyst B the results shall constitute a product failure.

5.3.7 Retesting shall be allowed maximum 6 times during the investigation. Additional retesting shall not be considered simply to test the product into compliance.

5.3.8 Averaging: Retesting results such as those generating OOS and passing individual results within specification by two independent Analysts A & B shall be subjected to averaging of test data, e.g. an HPLC assay results may be determined by averaging the peak responses from a number of consecutive, replicate injections from the same preparation (usually 2 or 3). No value should be averaged which is out of specification limit. The complete scientific justifications shall be record before the decision of passing or rejecting the batch. All the results shall be recorded in the form titled “OOS Test Results – Laboratory Investigation Report” (Annexure-II).

5.3.9 The corrective and preventive action shall be done with all the investigations report.

5.3.10 No OOS shall be generated for Content uniformity and dissolutions. However the Pharmacopeia limits shall be applicable for the investigation.

5.3.11 The reporting of final results shall include all individual results and average results.

5.3.12 Investigation period: The OOS investigation shall be completed within 30 working days of initiation of analysis of the sample in question. If the investigation goes beyond the stipulated time which needs to be documentary justified.

5.3.13 The OOS investigation shall also be informed to the collaborator who are directly involved in the quality of the product.

5.3.14 Separate logs for raw material, stability and finished product shall be maintained and the numbering procedure is defined as below. Numbering procedure for raw material is as RMXXX/YY, where RM stands for Raw material and XXX stands for serial number as 001, 002, 003 and so on and last two digits stands for the calender year. Numbering procedure for stability is STXXX/YY where ST stands for Stability and XXX stands for serial number as 001, 002, 003 and so on and last two digits stands for the calender year. Numbering procedure for finished product is FGXXX/YY, where FG stands for Finished Goods XXX stands for serial number as 001, 002, 003 and so on and last two digits stands for the calendar year.

5.4 Out-of-Trend:

5.4.1 OOT identification and investigation shall be annual, routine production and stability study batches shall be evaluated.

5.4.2 All the abnormal results which are out of inhouse specification shall constitute the OOT result.

5.4.3 OOT shall be identified and investigated for critical test parameters like assay, degradation, impurities, microbiological etc.for following alert limits: Any abnormal results are outside the trends. The result is outside ± 5% of the initial result. The result is outside ± 3% of the previous results. The result is outside ± 5% of the mean of all previous results.

5.4.4 OOT alerts shall be classified as Analytical alert: observed when a single result is abnormal but within specification limits (i.e. outside normal analytical or sampling variation and normal change over time) Process control alert: observed when a succession of data points shows an atypical pattern possibly caused by changes in the laboratory or manufacturing process. Compliance alert: is the potential or likelihood for OOS results to occur before the expiration date within the stability study on the same product.

5.4.5 OOT identified shall be presented during annual product review for the respective product.

6.0 Forms and Records

6.1 Laboratory Investigation Check-list for OOS test results       :           Annexure-I

6.2 OOS Test Results- Laboratory Investigation Report             :           Annexure-II

6.3 Flow Chart OOS Investigation                                               :           Annexure-III

6.4 Approval Form for Resampling                                              :           Annexure-IV

7.0 Distribution

7.1 Master Copy :     Documentation Cell (QA)

7.2 Controlled Copies :     Quality Control, Production, Quality             Assurance

8.0 History

     Date    Revision Number                       Reason for Revision
                       New SOP