SOP ON HANDLING OF OUT OF SPECIFICATION (OOS)
PURPOSE
To establish a procedure for evaluation and handling of ‘Out of specification (OOS)’ test results identified by Quality Control department.
SCOPE
This SOP covers procedure involved in investigation of out-of-specification (OOS) results pertaining to Starting materials, Packaging materials, finished products, in process samples and stability samples, applicable for this company. This SOP is not applicable to OOS results observed during the product development (Trial batches) and method validation.
EXCEPTION:
- In-process real testing performed for equipment, or process/ system adjustment to prevent process drift
- Market samples for which the storage conditions and transportation along with authenticity are not traceable.
- In process physical tests (e.g. average weight, hardness, thickness, etc.), conducted in production, these are handled through SOP on “Handling, Management and Investigation of Deviation”.
- Testing with environmental monitoring.
- Analytical data generated by Analyst / Chemist at the time of training and Analyst qualification.
- Product complaint samples sent by Complainant, but evaluated by quality assurance (QA) to be not fit for testing and/ or having an “unknown” on “unacceptable” handling/ storage.
REFERENCE(S)
- EU guidance: Good manufacturing practices
- MHRA guidance for out of specification investigation, 2013.
CROSS REFERENCE DOCUMENTS
- Document(s) and Data Control Procedure
- Training Program for Employees
- Change Control Management
- Good Document Practice (GDP)
ATTACHMENTS
Format of Log Book for Out of Specification
Format for Out of Specification (OOS) Report.
Extension for OOS Record No
Format of Periodic Trend of OOS
Format for Assessment of developing trends.
Format for Intimation of OOS to Purchase Department
Flow chart for Laboratory Investigation
Flow chart for Phase I a Investigation
Flow chart for Phase I b Investigation
Flow chart for Phase II Investigation
Flow chart for Phase II (Conducting Laboratory Failure Investigation)
Flow chart for Phase II (No Assignable Cause)
Flow chart for Phase III investigation
DEFINITIONS
Assignable cause: An identified reason for obtaining an OOS or aberrant/anomalous result.
No Assignable cause: When no reason could be identified.
Reportable results: is the final analytical result. This result is appropriately defined in the written approved test method and derived from one full execution of that method, starting from original sample.
Most probable cause: Scientifically justified determination that the result appears to be laboratory error.
Investigation: Review and experiments jointly conducted by an investigator and the analyst to find the root cause attributing to OOS results. This could be a Laboratory (Phase-I) and/ or Cross functional Investigation (Phase-II). This should be through, timely, unbiased well documented and scientifically sound.
Retesting: Testing of Portion of original sample. The sample used for the retesting should be taken from the same homogeneous material that was originally collected from the lot, tested and yielded the OOS results. For a liquid or single use formulation pack it may be from the original unit product or composite. For a solid it’s to be an additional weighing from the same sample composite prepared for the original test. This may include the preparation of fresh standards and/ or other test reagents as appropriate.
Re-sample: A new sample from the original container where possible, required in the event of insufficient material remaining from original sample composite or proven issue with original sample integrity.
CA (Corrective Action): Corrective action is an aspect of quality management that aims to rectify a task, process, product, or even a person’s behavior when any of these factors produce errors or have deviated from an intended plan. Corrective actions can be thought of as improvements to an organization to eliminate undesirable effects.
PA (Preventive Action): Action to eliminate the cause of a potential nonconformity or other undesirable potential situation.
Hypothesis / Simulation Study: Structured documented sequence of experiments which are designed to identify the root cause for the failure. This shall be based on series of discussions, thought processes and scientific rationales’ focused on what might have occurred to yield the OOS results. Each Experiment shall have pre-defined expectation that actually what outcome we want to observe through that particular experiment. Investigational tools can be used to design Hypothesis / Simulation protocol i.e. five whys? ; Cause and Effect Diagram; FMEA; Fish Bone diagram etc.
Cross Functional investigation: Cross functional investigation includes all the departments that could be implicated (e.g. Manufacturing process, Development, Maintenance, Engineering etc.) in the OOS results. This process to investigate the OOS failure through review of manufacturing process, conditions, input materials and it’s documentation as defined in SOP.
RESPONSIBILITY
Originating department shall be responsible:
Analyst is responsible for reporting the OOS results and inform to Executive and above.
To ensure that instrument used for analysis is calibrated.
QC reviewer is responsible for review of analytical data.
Executive and above is responsible for laboratory investigation of OOS results, preparation of hypothesis protocol, Preparation of retesting & resampling plan.
To immediately inform the OOS results to the Head QC or designee and shall not discard sample solution/stock solution/ instruments settings until evaluation of failure analytical results.
To participate in the investigation, participate in finding root cause and carry out the experimental analysis where applicable.
Head of Originating department/designee shall be responsible for:
Head/Designee Quality control is responsible for review of hypothesis protocol, retesting & resampling plan.
Head/Designee Quality control is responsible for preparation of trend and identification of human error during investigation of OOS on monthly basis and submitted to QA department.
Quality Assurance department shall be responsible for:
QA shall issue OOS form, CAPA (if required) and investigation form for identification or root cause of OOS.
QA reviewer is responsible for review of analytical data.
Quality assurance is responsible for review of hypothesis protocol and resampling or retesting plan.
Head – Quality Assurance/ Designee shall be responsible for:
Quality assurance is responsible for review & approval of hypothesis protocol and resampling or retesting plan.
To review, revised and approve of Out of Specification SOP.
To ensure implementation of the defined system.
Plant Head shall be responsible for:
To approve new or revised SOP.
To ensure the implementation of the defined system.
PROCEDURE:
Out of specification results:
Test results that does not comply with the pre-determined criteria (i.e. filed applications, drug master files, approved marketing submission, or official compendia or internal acceptance criteria)
Test results that fall outside of established acceptance criteria which have been established in official compendia and/ or by company documentation (i.e. Raw material specification, In-process / Final product testing, etc.)
The OOS shall be handled as follows; however, in case of contract manufacturing products if contract giver (MAH) has provided any procedure for handling of OOS, the same shall be adhered to. MAH procedure must cover all the aspects regarding the investigation of OOS results as mentioned in Company procedure.
However, if Company procedure in handling of OOS is found to be more elaborative and covering certain important aspects which are not addressed in MAH procedure then Company SOP shall be followed for investigation of OOS results. Such decision shall be conveyed to MAH holder.
The OOS process applies to in-process samples if data is used for batch calculation/decision and if in a dossier and on Certificate of Analysis. OOS shall not be applicable for in process testing while trying to achieve a manufacturing process end point i.e. adjustment of manufacturing process (e.g. pH, Viscosity, etc.), and studies conducted as variable parameters to check the impact of drift (e.g. process validation at variable parameters).
Note: During OOS investigation, in case of process validation samples from Various stages for variability evaluation like layer wise samples of in-process container, sample of filling Operation, samples of speed variability etc. retesting shall be done by single set of samples following the correct laboratory procedure preferably by original analyst from remaining set of samples collected during validation study.
The OOS process applies to previous released batch used as reference sample in an OOS investigation showing OOS or suspect results. However, a controlled sample prepared by using API and placebo in similar composition can be used for OOS investigation, if required.
OOS results noted for different tests for a particular batch shall be logged and reported as separate OOS. OOS for multiple samples in one sample set sequence can be addressed through single OOS only.
In case any OOS result is observed by an analyst, He / She shall report to immediate Executive QC or above.
After Identification of OOS, immediate executive QC or above then shall report this to QA within same day or next working day but not later than that, QA shall issue OOS form to QC on requisition with allocation of OOS numbers in the OOS log.
In case if OOS observed in samples analysis received from outside than QA will inform to contract giver/s within same day or next working day but later than that in reference to technical agreement. Also, if any operating staff fails to raise the OOS within same day or next working day but later than that, appropriate disciplinary action shall be taken.
The activity in OOS shall be initiated as follows:
The OOS details shall be recorded in the Log book as per Attachment-I.
Out Of Specification Numbering Allocation:
The OOS numbering system in Out of specification reports shall be generated from 1st January of the current year to the 31st December of the same year.
The number given to the Out of specification reports shall be unique and shall not be repeated.
The Out of specification report number consists of Eighteen characters.
As per define Plant code OOS numbering system shall allocated during issuance and maintained logbook by quality assurance department.
Analyst shall fill the section 1.0, sample /test details .
All solutions, reagents, glassware (Pipette, Volumetric flask, Measuring cylinder, etc.) and instruments must be retained until all data has been verified by second person.
The sequence of events followed for laboratory analysis are given in the flow chart.
Phase I a (Preliminary laboratory investigation):
Phase I a investigation is to determine whether a clear obvious errors due to external circumstances such as powder spillage or those that the analyst has detected prior to generating data such as spilling samples that will negate the requirement of a Phase 1b investigation.
Preliminary laboratory investigation shall be followed as per flow chart.
Preliminary laboratory investigation shall be carried out by Executive QC or Above to determine if there is clear obvious error due to any external circumstances such as:
Check the calculation part used in the analysis. If any calculation error is observed, it shall be corrected and documented.
Check any power failure in the instrument. If any power failure is identified, document the event and annotate power failure. In such case analysis shall be repeated and documented.
Check any equipment failure during analysis. If any equipment failure is identified; then document the event, annotate equipment failure. In such case analysis shall be repeated and documented.
Check any spilling or incomplete transfer of sample solutions, if any error is identified, correct the error and analysis shall be repeated and documented.
Check any incorrect instrument parameters. If any error is identified; then document the event and annotate incorrect instrument parameters. In such case analysis shall be repeated and documented.
All the above information shall be recorded by Executive QC or above respectively. In case any obvious cause observed from above investigation, invalidate the result and repeat analysis as per QSD shall be performed by the preferably same analyst who had performed the original test and record the observations.
This shall be further verified by Executive QC or above shall forward his/her comments to Head QC/ Designee. Head QC/ Designee shall review the findings and shall take the final decision to close the investigation.
In case no QC error is identified during the preliminary laboratory investigation (Phase 1 a), initiate Phase-I b investigation as per flow chart.
Phase I b investigation:
Phase-I b Investigation- Initial investigation conducted by Executive QC or above using the laboratory investigation checklist to find out any assignable root cause for OOS results.
Phase-I b investigation shall be performed by Executive QC or above as per check list mentioned.
Investigation by the Analyst along with Executive QC or above shall be carried out as follows:
To check the label details (correct sample taken / used) of the sample.
Check the sample preparation or dilution (unusual events or problem) used in the analysis.
Check the expiry date and appearance of the reagents used in the analysis.
To check the calibration status of balance and instruments used for analysis.
To check the correct and clean glassware has been used for analysis.
Whether the analysis is carried out as per STP.
The volumetric solutions and reagents used during analysis with respect to strength and grade.
To check for correct working standard / reference standard’s potency is used.
Check the approved shade card, approved artwork used during packaging material analysis as per specification.
Check for correct methodology has been used e.g. version number.
Check for correct sampling method with current version has been used.
Check for any potential interfering activity at the time of testing.
Check if any other OOS results obtained on the batch of material under test.
All the above observations shall be recorded.
Analyst shall give his/her findings to executive QC or above for further verification.
Further investigation shall be carried out by Executive QC or above, the executive QC or above assessment shall be objective and timely.
The Analyst investigation should be restricted to data/ equipment/ analysis review only.
The Executive QC or above shall investigate the OOS results as follows:
To check the label details of sample and correct sample container used in analysis by Analyst.
To check that sample integrity is maintained and the sample chain of custody is appropriate.
To check the possibility that sample contamination has occurred during testing / re-testing procedure (e.g. sample left open to air or unattended). All glassware should be clearly labelled and kept securely.
Verify the sample storage condition and prepared solutions used in the analysis.
Discuss the test method with the concerned Analyst, confirm Analyst’s knowledge and performance of the correct procedure.
To check that analyst is trained on the method used in the analysis.
To check that correct specification / acceptance criteria applied.
Review the equipment log book used at the time of analysis.
Examine the raw data obtained in the analysis, including chromatograms, spectra, and identify anomalous or suspect information.
Check the system suitability conditions met before analysis and during analysis.
Verify that the calculations used to convert raw data values into a final test result are scientifically sound, appropriate and correct; also determine if unauthorized or invalidated changes have been made to automated calculation methods.
Confirm the performance and calibration status of the instruments used in the analysis.
Determine that appropriate reference standards, working standards, solvents, reagents and other solutions were used and they met quality control specifications.
Evaluate and assess the performance of the test method to ensure that it is performing according to the standard expected based on method validation data and historical data.
To check any issues with environmental temperature / humidity within the area while the test was conducted.
To check the previous issues with the same test.
Review of other data for other batches performed within the same analysis set.
On completion of Analyst and executive QC or above investigation, re-analysis can be started only after initial hypothesis is documented and approved.
Re-Analysis shall be carried out on the original prepared sample solution (s) which was tested and yielded the OOS results.
A fresh sample solution may be prepared only if the original sample is unstable or if the STP requires the use of a freshly prepared solution; however this shall be properly documented.
Examples of Re-analysis may include further testing regarding sample re-injection, re-filtration, re-dilution and re-sonication/extraction. Multiple hypothesis can be explored.
Re-Injection: Re-injection of original sample preparation may be done where any equipment malfunction is suspected during the Preliminary Laboratory Investigation. Re-Injections can provide strong evidence that the problem should be attributed to the instrument, rather than the sample or its preparation. Re-Injection from the same vial may be conducted in a chromatographic analysis to investigate if the ‘OOS’ result is due to an injection error or programming error. The same vial (if necessary, after replacing the septum) shall be injected along with fresh system suitability.
Re-Filtration: Re-Filtration of the sample may be done to investigate if the ‘OOS’ result is due to filtration error such as improper filtration, inappropriate filter paper used, insufficiently saturated filter or contaminated vials / filters. The same dilution of the sample shall be re-filtered (taking all necessary precautions) and analyzed.
Re-Dilution: Re-Dilution may be done in case of any deviation identified in sample preparation / sample handling during the Preliminary Laboratory Investigation. The same stock solutions shall be re-diluted, wherever applicable and analyzed.
Re-Sonication: Re-Sonication/Re-Shaking or Re-stirring may be done if it appears that the ‘OOS’ result is due to incomplete solubilization of the analyte in the test preparation due to inadequate shaking and/or sonication or improper grinding of the test sample, wherever applicable. Further extraction of the sample shall be performed (the same stock solution may be sonicated and/or shaken for a longer period of time) and tested.
All the above observations from shall be recorded.
This investigation shall be fully documented and preserve the records of this laboratory assessment.
Whenever laboratory error is identified, the executive QC or above shall determine source of that error, perform impact assessment of the error on previous analysis and take corrective action to prevent its reoccurrence.
If no assignable cause is identified, hypothesis testing (i.e. an extension to initial hypothesis testing) can be explored. All the possible root causes shall be listed in the hypothesis.
Repeat testing shall not be performed if no laboratory error is identified.
If an assignable cause is attributed to OOS, repeat testing on the same sample shall be carried out as follows:
Repeat testing shall be done as per STP by the Analyst other than one who had performed the original test.
If the repeat tested sample results are as per the specification, Analyst shall report the results.
If the investigation determines Laboratory error then original test results shall be substituted with the Final repeat test results.
The original test results and all repeat test results must be retained along with the explanation recorded. It will not be included for data evaluation. Analyst shall submit his investigation to executive QC or above.
QC executive QC or above shall forward his comments to Head QC/ Designee. Head QC/ Designee shall review the findings and give his comments to Head- Quality Assurance, who shall take the final decision to close the investigation.
If the repeat testing on original sample does not yield result as per specifications, Head QC/ Designee shall submit the findings to QA reviewer. QA reviewer shall forward recommendation for extended investigation which shall be further approved by Head Quality Assurance.
If no assignable cause or evidence of error remains unclear then inform to QA and QA shall further inform to Production / Contract Giver / MAH / QP as the case may be.
No data shall be invalidated unless laboratory error is confirmed.
After phase I b investigation, if OOS is confirmed from quality control department. Phase II investigation shall be carried out as per flow chart given in the Attachment-X. Further testing not to be done in Quality control Laboratory.
Phase Ia & Ib investigation shall be completed by next working day unless justified.
Note – Phase II and phase III investigation are not applicable in case of Packaging materials and Raw materials as these are directly procured from approved vendors, so manufacturing investigation are not possible at our end. Whenever required OOS shall be informed to vendor for further investigation.
Phase II investigation:
Note: Manufacturing investigation shall be conducted only during first instance of OOS observed for a Stability batch, Ex. if OOS observed for the first time at 2nd month data station and also observed at subsequent test stations for same test parameter then shall be conducted only at 2nd month and the investigation done earlier shall be referred wherever required. If observed in different parameters at subsequent test station, then manufacturing investigation shall be conducted.
Phase II investigation shall be conducted when phase I b investigation did not reveal any assignable cause of laboratory error. Phase II investigation includes the initial manufacturing investigation to determine whether the root cause OOS pertain to some deviation in manufacturing activity.
During phase II investigation, manufacturing of batch shall be investigated as per the “SOP on Investigations” and report shall be compiled.
In case any assignable cause of OOS is attributed in manufacturing process, the same shall be forwarded to QA reviewer along with CAPA and impact assessment. QA reviewer shall give its comments and forward the same to Head Quality Assurance for taking action on disposition of batch.
In case no assignable cause is identified during the manufacturing investigation, conduct laboratory failure investigation as per flow chart given in the Attachment XII.
Hypothesis / Investigative testing – is testing performed to help confirm or discount a possible root cause i.e. what might happened that can be tested. Investigational testing shall not be used to replace the suspected analytical results.
Hypothesis testing shall be performed during laboratory failure investigation. A written protocol shall be prepared for investigational testing which shall include the following points:
The description must fully document the hypothesis to test the theoretical root cause being investigated.
The description must fully document that what samples shall be tested.
The description must fully document the exact execution of the testing.
The description must fully document that how the data shall be evaluated.
Protocol for hypothesis/investigational testing shall be prepared and reviewed by Quality Control and same shall be approved by Quality Assurance.
The re-sampling must be discussed and agreed by QA/Contract Giver and can occur which shall include the following point:
If upon investigation, sufficient doubt is generated that the original sample is not adequate or representative of batch quality, insufficient quantity of the original sample or proven issue with original sample integrity, under such circumstances; Analyst/ Executive QC or above shall propose the re-sampling and QA evaluate the reason for re-sampling and shall put forth the proposal for re-sampling along with the justification thereof. Respective details for the same shall be filled as per Attachment-II. QA reviewer shall evaluate the justification of re-sampling. If sufficient reasons are found for re-sampling, QA reviewer shall document and give his/her recommendations for re-sampling to Head Quality Assurance. Head Quality Assurance shall finally approve of re-sampling, if any.
Re-sampling shall be performed by the same qualified, validated 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. Impact assessment on the previous batches shall be performed which were sampled using the same technique.
The re-sampling of material is not applicable for the packaging material; hence OOS shall be confirmed on repeat testing.
Re-Test shall be performed using the material from the original sample composite, if it has not been compromised or still available, a new sample shall be used from the original container where possible. Re-testing can also be performed on 2nd aliquot from the same sample that was source of original failure.
The retests shall be performed by a different analyst on different instrument. Retest protocol must be approved by Head Quality Assurance and /or MA Holder (if applicable) before re-testing and number of retests shall be done in five replicate preparation (in case of Assay, Related Substances and Residual Solvent). In case of Content Uniformity /Blend Uniformity/ Dissolution testing, multiple units are tested, hence retesting shall be performed by different analyst as per STP on different instrument. Analyst involved in retesting shall be at least as experienced and qualified in the method as the original analyst.
Note: In test parameters like Dissolution, Uniformity of Dosage units where Pharmacopoeia itself says for multistage testing, OOS shall be triggered if the test results at any stage of testing indicates that the sample will not comply with Pharmacopoeia requirement.
Different Analyst shall report the retest results which shall be further verified by executive QC or above.
In case investigation determines analyst error, all analysis using the same technique performed by the concerned analyst shall be reviewed.
If all re-tested sample results are as per specification and meets the acceptance criteria of RSD. Initial analysis data shall be invalidated and all re-testing results shall be used for reporting. Head Quality Assurance will take decision for disposition of such batch along with impact assessment.
If any or all re-tested samples results are not as per specification and / or not meets the acceptance criteria of RSD. All results shall be used for reporting and no data shall be invalidated.
During Phase II investigation, if any anomalous results are observed, it’s investigation will be done starting from Phase–I using additional copy of controlled formats of the SOP.
Acceptance criteria of analysis by different analyst is tabulated below:
Acceptance Criteria: % RSD of results from five replicate preparations by different analyst should be:
1. Assay: NMT 2%
2. Residual Solvents:
| Observed results | % RSD |
| Less than LOQ | Not Applicable |
| LOQ to 200 ppm | NMT 20 % |
| 201 to 1000 ppm | NMT 15% |
| Above 1000 ppm | NMT 10% |
| Related Substances / Impurities / Degradation substances (individually specified/unspecified and total): | |
| Observed results | % RSD |
| Less than 0.05% | Not Applicable |
| 0.05 % to 0.10 % | NMT 50 % |
| 0.11 % to 0.20 % | NMT 25 % |
| Above 0.20 % | NMT 15 % |
| Note: Individual results of different analyst shall complies the specification for all test parameters | |
After the completion of Phase II investigation, initiate Phase III (if required) investigation as per flow chart given in the Attachment-XIII.
Phase III Investigation:
The phase III investigation includes the review of completed manufacturing investigation and combined laboratory investigation in to suspect analytical results and/or method validation for possible causes in to results obtained.
Phase III investigation shall perform as per Flow chart.
During Phase III investigation, other batches history shall be investigated and all the results shall be evaluated.
In charge production shall review the completed manufacturing investigation along with CAPA and impact assessment. Incharge production give his comments to QA reviewer.
In charge QC shall review the combined laboratory investigation along with CAPA and impact assessment. Head QC/ Designee give his comments to QA reviewer.
The impact of OOS result on other batches, ongoing stability studies, Batches in market (if OOS observed in stability samples in commercial product) validated processes and testing procedures shall be determined by Quality Control and Quality Assurance. This shall be documented in the conclusion along with appropriate corrective and preventive actions.
QA reviewer shall give his findings to Head Quality Assurance and he will take decision for disposition of such batch and close the OOS.
An OOS investigation shall be completed within 30 working days.
If the investigation exceeds more than 30 working days, a prior approval from Head Quality Assurance shall be taken for further investigation.
CA and PA shall be recorded in CAPA log for tracking as per SOP No. of corrective and preventive action. Record of implementation and effectiveness shall be maintained with source document i.e. OOS.
If any OOS is confirmed, justification to not perform any other remaining testing shall be written by QC Head of Impacted area. For e.g. In process, FG, RM etc. Approval of Head Quality will essentially be required for not doing so.
Whenever any OOS is observed in RM and PM section, it shall be immediately inform to respective section of purchase.
conclusion:
An initial OOS result does not necessarily mean the subject batch fails and must be rejected.
If no laboratory or calculation errors are identified in the Phase I and Phase II there is no scientific basis for invalidating the initial OOS results in favor of passing the retest results. All the results, both passing and suspected, should be reported (in all QC documents and any COA) and all data has to be considered in batch release decision.
The OOS result shall be investigated and the findings of the investigation including retest results shall be interpreted to establish the root cause & to evaluate the batch and reach decision regarding release or rejection.
A confirmed OOS result shall indicate that the batch does not meet established standard or specification and shall result in the batch rejection.
Records shall be kept of complete data derived from all tests performed to ensure compliance with established specification and standards.
Trending
OOS record shall be trended on half yearly basis and accordingly appropriate corrective and preventive action shall be taken wherever required.
Assessment of developing trends (i.e. errors which have gone up from previous trends, any new type of error) shall be done on half yearly basis and appropriate corrective and preventive action shall be taken wherever required.
Handling of OOS at contract testing laboratory:
In case of OOS result generated at contract laboratory, contract laboratory shall communicate its analytical data, findings and supporting documentation to the quality control manager on immediate basis for further assessment.
Manager shall take immediate corrective action based on instructions available in approved effective SOP and discussion with plant Quality head or designee.
Material Disposition:
A summary of the concerns not resolved and how the concern(s) influence the disposition of the lot(s), product(s), and process(s) associated with the OOS shall be provided. The recommended disposition shall be documented.
The rationale for the disposition decision shall be summarized, documented and approved by Plant Quality Head, Plant Head and Head QA as applicable.