Out Of Specification (OOS) Handling and Investigation

Out Of Specification (OOS), Purpose : Out Of Specification (OOS), The purpose of this SOP is to define the procedure for handling of OOS results in the Quality Control Laboratory of XX Pharmaceuticals Ltd. Out Of Specification (OOS),Scope : [][]This SOP is applicable for all Out of Specification (OOS) results detected during testing of any […]

Out Of Specification (OOS), Purpose :

Out Of Specification (OOS), The purpose of this SOP is to define the procedure for handling of OOS results in the Quality Control Laboratory of XX Pharmaceuticals Ltd.

Out Of Specification (OOS),Scope :

[][]This SOP is applicable for all Out of Specification (OOS) results detected during testing of any product or materials in Quality Control Laboratory of general block of XX Pharmaceuticals Limited.
[][]If an out of specification results is generated for dissolution/ Drug release, uniformity of dosage units, weight variation, disintegration test, In process sample and any other test which is used to measure variability in a lot this SOP does not apply. In such cases respective Pharmacopoeial guidelines or criteria shall be apply.
[][]This SOP does not apply to samples of various stages like In process samples, Intermediate samples, scale up batches, method validation, method development, solvents, packaging material, wash water, decontamination samples, evaluation samples, raw material received from new vendor, description and solubility test, tests where tentative limits given.
[][]This SOP does not apply for OOS to tests like Bulk density, Sieve analysis, Particle size and other physical parameters.
[][]This SOP does not apply when system suitability failure, bracketing standard, transcriptional errors or processing method errors (In case of failure due to the integration parameters for the HPLC).
[][]This SOP does not apply to incomplete analysis where result is not derived.
[][]Out of Specification is not applicable for out laboratory testing.

Definitions / Abbreviation:

[][]Standard Operating Procedure (SOP): Standard Operating Procedure. A written authorized procedure, which gives instructions for performing operations.
[][]QC: Quality Control.
[][]CAPA: Corrective action and preventive action.
[][]OOS result: An OOS result is a result from a defined test procedure that fails to meet established specifications or criteria. An OOS result does not constitute a failure unless further investigation confirms this result.
[][]Atypical result: Results that are still within specification but are unexpected, questionable, irregular, deviant or abnormal.
[][]Obvious error : Obvious error can be occurred due to:
Calculation Error
Laboratory error
[][]Laboratory Error: A mistake that occurs within the test laboratory caused by an analyst or piece of equipment. Examples include use of incorrect standards, improper sample or standard preparation, improperly calibrated balances, equipment failure and miscalculations.
[][]Laboratory Investigation: The investigation that is conducted within the laboratory to determine the cause of the OOS results.
[][]Assignable Cause: An identified reason for obtaining an OOS or aberrant/anomalous result.
[][]No Assignable Cause: When no result could be identified.
[][]Review: To check all critical parameters involved in the test which may cause of the OOS results.
[][]Reanalysis: Further analysis with the same dilution of sample or of same aliquots which produced OOS results.
[][]Retest: Re-examining the material from the original sample that was used as the source of the aliquot that produced OOS result.
[][]Resample: 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.


The roles and responsibility is as follows:

Executive, QC

[][]Analysis of any product or materials and to notify the OOS results to supervisor.

Sr. Executive, QC

[][]To ensure the initial investigation of the test parameters and to organize the testing.

Manager, Quality Control

[][]To ensure that this procedure is kept up to date.
[][]To confirm that the SOP reflects the required working practices.
[][]To make decision for re-sampling.
[][]To arrange training on the SOP to all concerned personnel and to ensure implementation of the SOP after training.

Head of Quality Assurance

[][]Approval of the SOP.
[][]To take the final decision to release the batch.
[][]To ensure the overall implementation of the SOP.


[][]The procedure mentioned below shall be followed if a Laboratory result for raw materials sample, In-process Sample or Finished Product sample fails to meet the Specification.
[][]Analyst shall not destroy the sample preparation / solution and shall retain the prepared solutions, Standards and Sample solutions until the investigations have been concluded.
[][]Retain all Glassware, Blend & Finished Product Sample.
[][]Check the whole analysis for compliance (Self-check).
[][]Inform immediately to the Supervisor about the OOS result.
[][]Supervisor will discuss with the analyst about the test method and confirm analyst knowledge of and performance of the correct procedure.
[][]Check if a laboratory error could be the cause of OOS results and inform Manager, QC.
[][]Check and record the present conditions in Notification of out of specification (OOS) result as per Annexure-I.
[][]Follow the Flow Chart (Annexure-II) for OOS Investigation
[][]The QC Manager should assess the data promptly to ascertain if the results may be attributed to laboratory error, or whether the results could indicate problems in the manufacturing process.

[][]It is to be clarified together with the QC Manager whether there is an apparent analytical error. A formal check is to be carried out (Investigation stage 1) using Out of Specification (OOS) Results Investigation Checklist (Annexure – IV) which shall be issued by QC Manager making entry in the Out of specification investigation register (Annexure – III) and assigning sequential number as below:
e.g. OOS-001/xx
Where, OOS is the abbreviation of Out of Specification
001 is the sequential number of Out of Specification investigation
/ is separator
xx is last two digits of year 20xx

[][]At the first step, the QC Manager along with Analyst shall immediately try to find out any obvious Error (Example: Calculation error, Power outage, Equipment failure, Testing Error, Incorrect Instrument Parameters etc.)
[][]If any calculation error is found out, make correction the calculation and release the material/product; analyst shall be re-trained for the error parts.
[][]If the calculation / documentation are correct, proceed with the investigation of the stepwise analysis which may include re-examination of the actual solutions, test units, glassware used in the original measurements and preparations.
[][]The following steps should be taken as part of the investigation:
[][]Discuss the test method with the analyst; confirm analyst knowledge of and performance of the correct procedure.
[][]Examine the raw data obtained in the analysis, including chromatograms and spectra, and identify anomalous or suspect.
[][]Confirm the performance of the instruments.
[][]Determine that appropriate reference standards, solvents, reagents, and other solutions were used and that they meet quality control specifications.
[][]Evaluate the performance of the testing method to ensure that it is performing according to the standard expected based on method validation data.
[][]Document and preserve evidence of this investigation.
[][]Where a transient equipment malfunction or other problem in the dosage form (e.g. incomplete extraction) is suspected, re-inject the retained sample preparations to assign a cause for OOS results.
[][]When laboratory error is identified, determine the source of that error (root cause) generating CAPA as per the SOP for ‘Corrective and Preventive Action’  and take corrective action to ensure that it does not occur again. Recommend on Out of Specification (OOS) Results Investigation Checklist (Annexure – IV) for performing a repeat analysis on the same sample with the same analyst. If the repeat analysis result is passing, void the initial result and approve the batch based on the re-test result.
[][]If no apparent analytical error can be found, i.e. evidence of laboratory error remains unclear, investigation stage 2 should be conducted to determine what caused the unexpected results, which may include re-testing and/or re-sampling and further investigation.
[][]Before further investigations are carried out during the next step, the subsequent procedure has to be written down in the testing protocol (Annexure – IV).
Tasks in testing protocol:
“What” is to be done (retesting, re-sampling, etc.)?
“Who” will be carrying out the investigations (1st analyst, 2nd analyst, etc.)?
“How” will the investigations be carried out, which equipment, which reagents, additional analysis of reference samples (state batch and number of analysis)?
“How often” will the analysis be repeated (final criterion to prevent “analysis” into
[][]A justification for the procedure must be given by the QC manager prior to implementation of the testing protocol and the test plan must be approved.
The number of retests should be 3 times or more
[][]The investigation may involve re-testing a portion of the original sample. The sample used for the retesting should be taken from the same homogeneous material / product that was originally collected for the lot/batch, tested and yielded the OOS result. For a liquid, it may be from the original unit liquid product or composite of the liquid product; for a solid it may be an additional weighing from the same sample composite that had been prepared by the analyst.
[][]Decisions to retest should be based on the objectives of the testing and sound scientific judgment. Retesting should be performed by an analyst other than the one who performed the original test.
[][]If the result is within specification (passes), the material/product shall be re-analyzed by first analyst with the same sample and to investigate the first analyst.
[][]If investigation of first analyst found satisfactory then release the material/product
[][]If the material/product fails by the second analyst also, simultaneously analyze after re-sample with the previously approved material/product.
[][]Re-sampling should involve analyzing a specimen from the collection of a new sample from the batch. A re-sampling of the batch should be conducted if insufficient quantity of the original sample remains to perform all further testing or if the investigation shows that the original sample was not representative of the batch. This would be indicated, for example, by widely varied results obtained from several aliquots of the original composite (after determining there was no error in the performance of the analysis). Re-sampling should be performed by the same qualified, validated methods that were used for the initial sample. However, if the investigation reveals that the initial sampling method was in error, a new accurate sampling method must be developed, qualified and documented.
[][]If previously approved material/product passes within the specification and material/product under investigation meets the specification, release the material/product.
[][]In case of material if previously approved material passes within the specification and material under investigation fails to meet the specification, material shall be rejected.
[][]In case of product if previously approved product passes within the specification and product under investigation fails to meet the specification, the laboratory investigation may be extended to review the quality of the materials (raw & primary packaging) used in manufacturing of the finished product. If any problem in quality of the materials is identified which may have potential effect on the OOS scenario, the root cause will be attributed to that problem.
[][]The procedure is then to be implemented and the results be evaluated. The results are to be summarized in Annexure – VI (report level 2).
[][]Conclusion must be drawn and it must be stated which individual values will be entered in the result (on Certificate of Analysis).
[][]The error category of the initial OOS result must also be recorded.
[][]At measures, a statement must be made explaining how similar OOS results are to be avoided in future.
[][]During investigation of an OOS result, review the previous investigation reports to determine whether a similar occurrence has taken place.
[][]When the laboratory investigation does not determine that laboratory error caused the OOS result and testing result appears to be accurate, the laboratory investigation/report to be handed over to QA manager for a full-scale failure investigation as per the SOP for ‘Deviation Procedure’.
[][]In case the process error is identified during failure investigation, suitable corrective action shall be taken. Sample shall then be analyzed as per routine procedure and accordingly release, if the results are okay.
[][]Quality Assurance Manager will initiate the CAPA based on root cause found in the failure investigation. CAPA must be implemented within agreed time lime. All CAPAs must be implemented based on criticality.


Annexure-I: Notification of Out of Specification Result
Annexure-II: Flow Chart for OOS Investigation
Annexure-III: Out of Specification (OOS) Register
Annexure-IV: Out of Specification (OOS) Investigation Checklist
Annexure-V: Out of Specification (OOS) Testing Protocol
Annexure-VI: Out of Specification (OOS) Investigation Report

Leave a Comment

Your email address will not be published. Required fields are marked *

error: Content is protected by www.pharmaguideline.co.uk !!