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1. Objective:
This document describes the procedure for reporting, investigating, and documenting Out-of-Specification (OOS) laboratory test results. This document is also intended to help in determining the root cause and establishing appropriate corrective and preventive actions (CAPA) for laboratory investigations.
2. Scope:
This SOP applies to all laboratory OOS investigations identified in Quality Control (QC). This includes, but is not limited to:
• Finished product, raw materials, packaging materials and stability samples, which are tested by approved, analytical methods.
• Cleaning and process validation samples.
• Method validation, method transfer and compendial method equivalency studies.
• Uniformity of Dosage unit results that have failed level 2requirements.
• Dissolution results that have failed stage 3 requirements.
This process does not include the following:
• Uniformity of Dosage unit results that have not met levels 1 specification.
• Dissolution results that have not met stage 1 or 2 specifications.
• OOS in Microbiological results.
3.Responsibilities:
3.1 Analyst for informing the OOS situation to the QC manager/supervisor.
3.2 Head QC or designee to conduct investigation.
3.3 QC Manager/supervisor or his designee for recording and allocation of OOS number.
3.4 Head of QA or designee to take final decision and make closure of the OOS investigation.
3.5 If required, relevant department heads or designees and/or subject matter experts (QC, Production, R & D, Engineering, Warehouse and Packaging development) – for participating in the phase II investigation as needed and identified by QA.
4. Accountability:
4.1 Head of Quality.
5. Precautions
NA
6. Procedure:
6.1 Definitions and/or abbreviations
6.1.1 Additional Testing: Testing performed as part of the laboratory investigation, and may consist of re-measurements, re-dilutions, etc.
6.1.2 Assignable Cause: A scientifically sound explanation of a laboratory error that led to the OOS result.
6.1.3 CAPA (Corrective and Preventive Action): A corrective and preventive action plan designed to prevent errors in laboratory and/or manufacturing from recurrence. CAPAs require regular follow-up to verify that they adequately address concerns that resulted in the generation of OOS result.
6.1.4 Concurrent Sample: A sample that was analyzed during the same run as the sample with the suspect result.
6.1.5 Confirmation Testing: Testing performed following the experimental testing by either one or two different analysts to either confirm or invalidate the original OOS test result.
6.1.6 Control Sample: Sample with a known test value from a previously tested lot, or a sample, that was run concurrently with the sample yielding OOS result. This sample is to confirm system consistency when the suspect sample is re-injected.
6.1.7 Experimental Testing: Testing performed in Phase II of the investigation prior to conformation test, in which the analyst shall make every effort to identify either a root cause or most probable root cause. Results obtained during experimental testing shall not be used to justify the disposition of the suspect lot of product.
6.1.8 Effective Date: The day that this procedure shall be initiated for use based on approval and any required training.
6.1.9 Field Alert Report (FAR): A report that is submitted to the United States, Food and Drug Administration (US FDA) on batches, distributed in U.S.A. market, which failed to meet the approved or agreed-upon specification, i.e., an OOS result. Examples of these would be the product batches on stability. The investigation report has to be provided to the body within three (3) working days from the date of reporting of the OOS result, unless the OOS result is invalidated through investigation.
6.1.10 Hypothesis Testing: Reanalysis performed in an attempt to confirm the original results, and/or to confirm various hypothesis of potential causes of an OOS result.
6.1.11 Inconclusive Results: A result(s) that neither confirms, nor invalidates the original OOS result(s). For example, result(s) may contain conflicting data, but are reportable.
6.1.12 Initial Sample Preparation: Solution prepared during the initial analysis from the original sample, from which the suspect or OOS test results were obtained.
6.1.13 Laboratory Investigation Report (LIR): A formal, well documented investigation report made by laboratory management (QC Manager, Supervisor) to identify specific cause of an OOS result.
6.1.14 Manufacturing Investigation Report (MIR): An investigation conducted by the QA along with the SME of the manufacturing department to verify if any in-process deviations, etc., occurred during the production of the suspect lot(s), which could have potentially led to the OOS result.
6.1.15 Manufacturing or In-process error: An error or deviation that occurred during the manufacturing process that resulted in the sample having an OOS result, as determined by the QC Laboratory.
6.1.16 Most Probable Cause: A scientifically justified determination of the most probable cause for a potential laboratory error.
6.1.17 Original Result: The original test result obtained from the initial analysis of the sample composite and solution.
6.1.18 Outlier: A markedly different result obtained in a series of results while using a validated method.
6.1.19 Out-of-Specification Test Result: A test result that is not in compliance to acceptance criteria established in drug applications, DMFs, official compendia, or in-house company specifications.
6.1.20 Obvious Error: An error, which is clearly and scientifically identified beyond doubt during the Phase I investigation to be causing the OOS result.
6.1.21 Phase I Investigation: The initial investigation performed by the analyst and laboratory management, i.e. section supervisor, when an OOS result is obtained in the laboratory. The investigational process initially involves interviewing the analyst/s and completion of a laboratory investigation checklist in an attempt to identify or to rule out potential laboratory errors.
6.1.22 Phase II Investigation: An investigation that follows a Phase I investigation, in which no obvious laboratory error was identified. Phase II Investigations may include additional experimental testing and is used to verify the validity of the initial OOS result by confirmation testing performed by either one or two additional analysts.
6.1.23 Reanalysis: Re-measurements or re-injection of the original sample solutions.
6.1.24 Resample: Refers to collection of additional or new sample portion(s) of the same lot(s) that was originally found to be yielding OOS result. The only suitable reasons for resampling are as follows: (1) There is insufficient amount of sample left to adequately reanalyze the sample, and (2) The investigation has scientifically/ conclusively proved that the original sample collected was not representative of the lot, or the sample was not collected properly.
6.1.25 Retest: Repeat testing performed on the original sample bottle or composite that yielded the original failing results. The retest will be performed in triplicate.
6.1.26 Root cause: The most basic reason for a defect or problem in a product or process.
6.1.27 SOP: Standard Operating Procedure
6.1.28 Suspect Results: A result that is under investigation simply because it has been identified as an OOS result.
6.2 General responsibilities
6.2.1 QC analysts shall understand and adhere to this procedure, while completely documenting all aspects of the OOS investigation.
6.2.2 In the event of an obvious laboratory error, i.e., spilling of sample solution or dry sample composite, inadvertent actions by analyst when taking observations on instruments, etc. analyst shall document the event in laboratory worksheets and inform QC manager/supervisor. This shall be addressed through incidents as per SOP No. QA062 (Handling of Incidence).Any analysis that could be invalidated later due to a potential OOS result should not be continued. Stop all testing if a laboratory error occurs, or is discovered before final results are obtained.
6.2.3 QC analysts shall use only calibrated instruments/equipments for the analysis and will also ensure successful initial system suitability test (SST) requirements before proceeding to use the instrument for analysis of the sample.
6.2.4 QC analysts shall isolate and retain all standard, and sample solutions, reagents, glassware including volumetric flasks, pipettes, chromatography vials used in the test etc. on obtaining an OOS result.
6.2.5 QC analysts shall inform QC Manager/supervisor about the occurrence of the OOS result.
6.3 Preliminary Investigation
6.3.1 QC Manager/supervisor shall initiate investigation (after informing the QC Manager/ and QA) and complete the preliminary investigation checklist (PIC) (Annexure – III) by interviewing the analyst(s), to ensure consistency with investigations.
6.3.2 QC Manager/supervisor shall allot a unique number to the OOS documentation as under:
For OSD : OOS/AAA/XX/YYY
Where:
OOS denotes Out Of Specification.
AAA denotes the facility where the OOS has occurred i.e. OSD, MDI, DPI, VIS,
INF, LYO, SLD, ION, PFS etc.
XX denotes the last two digits of the year. i.e. 15, 16…..etc.
YYY denotes a sequentially increasing number i.e. 001, 002, …….. for the year XX.
6.4 Phase I:Preliminary laboratory investigation (Initial)
6.4.1 QC Manager /supervisor using the PIC, shall verify that the analyst’s training was appropriate and current, the analytical method was followed completely, including sample and standard weights, dilutions, glassware, appropriate solvents and check the calculations.
6.4.2 If a definite, clearly defined laboratory error is noted during this preliminary evaluation, QC Manager /supervisor shall assess the impact on other lot/s that have been simultaneously or concurrently analyzed along with the suspect sample.
6.4.3 QC Manager /supervisor shall invalidate the results and instruct the analyst to repeat the analysis in duplicate.
6.4.4 If a scientifically viable laboratory error is noted during the preliminary investigation, QC Manager /supervisor shall direct and sign off for hypothesis testing, if required, depending on the test that resulted in the OOS result. If a hypothesis testing is planned to be conducted, QC Manager/Supervisor shall document the rationale for choosing the hypothesis in the Laboratory investigation report (LIR) (Annexure – IV)
6.4.5 QC Manager /supervisor and analysts shall complete the PIC within 24hours of the initial reporting of the OOS test results (to avoid expiration of solutions prepared, etc.). If the PIC cannot be completed within this time frame, a justification for the delay is documented.
6.4.6 The analyst shall perform the appropriate testing from the following hypothesis for tests involving chromatography.
6.4.6.1 The analysts shall re-inject from the original HPLC standard and sample vials. This will assist in getting some important information like, confirmation of a suspect injection. If the vials do not have a sufficient volume for injection, then fresh solution may be filled from the original working solutions that were prepared. In the event of an impurity OOS result, this step also helps to indicate whether a glassware contamination is potentially the root cause for the OOS result.
6.4.6.2 QC analysts shall inject sample prepared by re-dilution of the working standard and sample solutions from their respective stock solutions. A change in area count(s) that differs from the original area counts (by more than the percentage mentioned in method validation report) indicates that the stock standard or sample(s) may not have been completely in solution, or that a dilution or pipetting error might have occurred.
6.4.6.3 QC analysts shall inject a control sample to demonstrate consistency within the system itself.
6.4.6.4 If the working standard and sample were originally filtered, then the analyst shall re-filter the working solution to determine if there was a filtering or filter retention error caused by insufficient rinsing of the filter.
6.4.7 QC manager /supervisor shall consider results from other applicable tests as well when evaluating potential root causes for the OOS. Ex: Tests for dissolution and disintegration.
6.4.8 For other analytical tests, which do not involve chromatography and for which scientifically sound root cause cannot be assigned, a retest protocol is written, which will best address all potential sources of laboratory error.
6.4.9 If an obvious, scientifically appropriate laboratory- based error is believed to be identified based on the hypothesis results, then document the conclusions, in the Laboratory Investigation Report (LIR) (Annexure – IV).
6.4.10 The first analyst shall conduct the analysis under supervisory oversight, or with another qualified analyst, at least in duplicate. i.e., if the analytical method requires the analysis of one sample portion to be analyzed for the test of Assay, then repeat the test with a minimum of duplicate (2) sample portions.
6.4.11 If all the repeated results are within specification, and differ from original results by greater than the margin of error for the test method, invalidate the original result(s) and report both the individual and average results of the repeat analysis in the worksheets.
6.4.12 If obvious and scientifically sound laboratory- based error is identified as a part of the hypothesis testing, and/or there is no valid reason to discard the original suspect result(s), proceed to Phase II Investigational testing (Annexure – IV).
6.5 Phase II: Full scale investigation
6.5.1 QC Manager/supervisor shall formally notify QA Manager/supervisor about the OOS result which entered Phase II investigation and also give them a synopsis of the Phase I investigation conducted in the laboratory.
6.5.2 QA Manager/ supervisor shall notify the Quality Assurance (QA) team, working in the Production / Manufacturing, provide details of suspect sample lot numbers, and request them to commence investigation in manufacturing documents.
6.5.3 QA Manager / supervisor shall conduct this review in accordance with SOP for Failure Investigation (QA010). SOP for Control of Non Conformities (QA059) shall be used by sterile facility for this review. If any event that has occurred in the manufacturing is a probable root causes for the OOS result, then it must be addressed either as an incident or a deviation as per respective SOPs, by the respective department.
6.5.4 The IPQA shall include information such as to whether there were deviations noted on the batch record, any changes in the composition of the product (changes in the source or the vendor’s manufacturing of the raw materials), storage conditions in which the raw materials or finished product was held, manufacturing of the product, i.e., changes in the manufacturing process steps, changes in the manufacturing equipment, etc., or changes in the packaging configuration while documenting the Manufacturing Investigating Report (MIR).
6.5.5 The phase II investigation in the laboratory shall be conducted by the QC Manager or designee/ Head of Quality or designee.
6.5.6 QC Manager/ supervisor shall plan any additional laboratory experiment analysis, referring to steps given under 6.6, to identify potential root or the most probable root cause(s) for the OOS result.
6.6 Additional laboratory investigation
6.6.1 QC Manager/ supervisor shall develop protocols, using analytical test method and reported OOS results, for additional experiments, which may be planned for identification of the root cause or most probable root cause, if a laboratory error has occurred.
6.6.2 QC Manager shall review the historical data for the product under question while considering the following points:
6.6.2.1 Preparation and analysis of a new sample composite, and analysis from the original sample composite.
6.6.2.2 Preparation and analysis of duplicate from new stock standard preparations.
6.6.2.3 Preparation of the standard and sample solutions from the suspect OOS lot, and from lots, which may have had passing (within specification) results, if applicable, that were run concurrently with the sample with suspect results.
6.6.3 If the amount of sample is insufficient for the additional testing, then plan for re-sampling of the same lot with QA’s concurrence.
6.6.4 Make fresh reagents and test solutions, as necessary, to exclude if reagents may have contributed to OOS results, i.e., impurity failure.
6.6.5 The original analyst under supervisory oversight or another qualified analyst shall conduct the analysis as described in the investigation protocol.
6.6.6 Based on the experimental results obtained, ensure that the investigation conducted, yields one of the following about the OOS result:
6.6.6.1 The OOS sample result is a confirmed laboratory error.
6.6.6.2 The “most probable root cause” for the laboratory error can be identified.
6.6.6.3 A laboratory cause could not be identified for the initial OOS result, though the experimental testing gave results that conformed to respective specifications during phase II testing.
6.6.6.4 No laboratory error found, indicating that the sample gave a confirmed OOS result during Phase II testing by either the second and/or third analyst.
6.7 Confirmation Testing
6.7.1 Analyst 1 or Analyst 2, who is thoroughly trained and familiar with the product and its testing procedures, shall use the following procedure for performing confirmation testing, regardless of whether an assignable cause was identified or not during the experimental testing.
6.7.1.1 A fresh sample or sample composites is prepared from the originally collected sample (if possible).
6.7.1.2 If the sample quantity is insufficient to perform the required number of tests by the second, and potentially a third analyst), then QC Manager shall share the requisition for additional samples, to be collected from the original lot, so as to test the product, completely in line with this SOP.
6.7.1.3 QC Manager shall document details about the requisition of additional samples in the LIR.
6.7.2 QC Manager shall ensure that the second analyst conducts the analysis in triplicate. If the sample procedure requires that the original sample be run in duplicate or more, then the second analyst will prepare four sample portions for analysis.
6.7.3 QC Manager shall consider the OOS as confirmed, if one or more the individual portions analyzed by the second analyst falls outside of the established test specification, and report the original result.
6.7.4 If all results reported by the second analyst, are within the established test specification, the RSD is within values reported in method validation, and do not confirm the original OOS results the analysis will be conducted by the third analyst.
6.7.5 The third analyst shall perform the analysis in triplicate (for samples with a single sample portion), and on four portions for sample procedures requiring samples be run in duplicate or more.
6.7.6 The QC Manager shall report the original OOS result of the first analyst, if one or more results of the third analyst are outside of the required test specification.
6.7.7 Under any circumstances, the QC manager shall not average the OOS result with the other reported results to achieve a passing result.
6.7.8 QC Manager shall report means of all results by the second and third analyst along with the overall average of the two means, if results reported by the third analyst are within required test specifications, and they meet the SST and RSD criteria, as applicable.
6.7.9 QC Manager shall provide all results obtained to QA, if a root cause has not been scientifically determined, to help them in their lot disposition.
6.7.10 Head of Quality or designee will use all the available information from MIR and LIR, to decide the disposition of the suspect lot/s.
6.8 OOS Results Pertaining to Stability Samples
6.8.1 QC Manager and Head of Quality or designee shall handle OOS in stability samples in the same manner as regular OOS investigations. All decisions about continuing or discontinuing a stability study shall be documented with appropriate reasons.
6.8.2 QC Manager and Head of Quality or designee shall take decisions to continue or to end stability studies (with regard to OOS stability test failures) based on the following criteria.
6.8.2.1 Stability history and trending analyses available for the product in its respective packaging.
6.8.2.2 Results from previous time points for the current study.
6.8.2.3 Conditions in which the stability sample was stored during the current study.
6.8.2.4 Conditions in which the stability sample was stored following its removal from the respective chamber(s).
6.8.3 QC Manager and Head of Quality or designee shall submit a Field Alert Report (FAR) within three days of the OOS result identification, to the FDA (through Regulatory Affairs or QA), if the OOS is reported in a lot that has been distributed in the United States. They shall ensure that the FAR is initiated when an obvious error is not identified during the preliminary laboratory investigation using PIC.
6.8.4 QC Manager and Head of Quality or designee shall ensure to rescind the FAR, if the sample is found to be within the test specification during the Phase I or Phase II investigation.
6.9 OOS Results Pertaining to Raw materials/Packaging material
6.9.1 QC Manager/ Supervisor shall conduct a regular investigation if an incoming raw material or packaging material is found to be OOS, as compared to the vendor’s COA.
6.9.2 QC Manager/ Supervisor shall contact the respective vendor after the preliminary investigation, where no obvious assignable cause could be ascertained, but no later than the beginning of the Phase II testing.
6.9.3 QC Manager/ Supervisor shall instruct the warehouse personnel to quarantine the raw / packaging material if it is confirmed to be OOS.
6.9.4 Head of Quality or designee shall use the information available in the LIR, to take the disposition decision of the suspect raw/packaging material.
6.10 Corrective and Preventive Actions (CAPAs)
6.10.1 Managers/Supervisors at QC and QA shall design and use CAPA(s) to correct assignable root causes, if identified and to prevent their future recurrences.
6.10.2 Managers/Supervisors at QC and QA shall ensure timely logging of CAPAs in the CAPA logbook.
6.10.3 Managers/Supervisors at QC and QA shall prepare the CAPA so as to address the most likely root cause(s), as determined by the investigation.
6.10.4 Managers/Supervisors at QC and QA shall reference an ongoing or earlier investigation if the root cause is similar to the ongoing one for tracking purposes.
6.10.5 Managers/Supervisors at QC and QA shall document CAPAs completely in the LIR and ensure its proper implementation.
6.10.6 Managers/Supervisors at QC and QA shall review CAPAs on a half yearly basis to evaluate and trend them. They shall also ensure that a thorough impact assessment is performed to verify the effectiveness.
6.11 Investigational Time Frames
6.11.1 QC analysts shall report the OOS result to laboratory manager/ supervisor immediately or at the earliest available opportunity.
6.11.2 QC Manager/supervisor shall complete the preliminary investigation within 24 hours of the reporting.
6.11.3 QC Manager/supervisor shall complete the Phase I investigation within 3 working days of the preliminary investigation.
6.11.4 Managers/Supervisors at QC and QA shall complete the OOS investigation within 30 days on initial reporting.
6.11.5 QC Manager/supervisor shall seek an extension and approval using (Annexure-V) from Quality head or designee, if the investigation cannot be completed within the stipulated time frame.
6.11.6 Managers/Supervisors at QC and QA shall document the reason for the extension request indicating as to why the investigation was not completed within the initial time frame.
6.11.7 Head of Quality or designee shall grant only a maximum of two extensions (30 days each), before which the OOS investigation must be completed.
6.11.8 QA Managers/Supervisor shall trend all investigations half yearly (those completed on time and the ones not completed on time) statistically and specifically by type of error, cause of the extension to be requested, etc.
6.11.9 A deviation shall be raised if the investigation cannot be completed within the stipulated and the extension time frame (90 days).
