Out of Specification (OOS)

Out of specification pharmaceutical | Out of specification Guidelines | Out of specification – OOS Investigation | Out of specification reasons |

Out of Specification (OOS): The test result that does not comply with the pre determined acceptance criteria.

There can be several reasons for an Out of Specification (OOS) results. Some common factors include variations in manufacturing processes, equipment malfunction, human error during testing, contamination, inadequate quality control procedures, incorrect sampling techniques, or issues with the raw materials used in production.

Out of Specification (OOS) investigation will be performed as per Investigating and Handling Of Out Of Specification (OOS) Test Results SOP

Investigation of OOS will be carried out in two categories;

  1. Preliminary OOS investigation
  2. Full scale OOS investigation
  • Preliminary OOS investigation is carried out in different phases;
    • Preliminary laboratory investigation
    • Phase-I investigation
  • On obtaining OOS results, retain the test, standard any other solutions prepared and investigate by the analyst as preliminary laboratory investigation.
  • Preliminary laboratory investigation:
    • Analyst should investigate himself as part of the preliminary investigation as per checklist for Preliminary Laboratory Investigation.
    • Analyst should check the test data generated, solution prepared, instrument working and calibration status, specification and MOA, working standard status, any occurrence during the solution preparation.
    • In case if any assignable cause identified like documentation error, the same shall be corrected and the investigation shall be closed by taking prior approval by Head-QC after evaluation of QA
    • Investigation does not identify any assignable cause then phase-I investigation shall be initiated.

Phase –I investigation

    • As part of phase-I investigation, section head should investigate as per the checklist of phase-I investigation.
    • Section head should verify;
      • Solution prepared for analysis, calibration certificate of glassware used
      • Correctness and validity of specification and method of analysis
      • The correctness of calculation and raw data.
      • Instrument status / calibration status and performance of the instrument.
      • Validity of reagents used during the analysis of the material
      • Balance working/calibration status
      • Analyst competency level on the said analytical technique.
      • Working standard/ reference standard validity, storage condition and usage records.
    • If any assignable cause found during the investigation, invalid the initial result and hypothesis plan shall be defined by Head-QC.
    • During hypothesis testing, if assignable cause found, then the repeat analysis shall be performed by the same analyst.
    • If the repeated results are within the specification limit, then record and report the same and invalid the initial results. Generate CAPA and close the OOS by releasing the material/product.
    • If any assignable cause not identified, review the following data’s.
      • The trend data of previous batches and trend data of analysis of analyst who has performed the analysis in OOS execution.
    • The same shall be informed to QA in phase-I investigation.
    • Label the product as “ON HOLD” and inform the same to contract giver / Marketing Authority Holder / Quality Person.
    • The investigation will be extended to full scale OOS investigation of phase-II to find out the root cause of the failure.

Full scale OOS investigation is carried out in different phases;

  1. Phase-II investigation
  2. Phase-III investigation

Phase-II investigation

  • Manufacturing Investigation as Phase-II Investigation shall be carried out by Head QA or his/her designee and Head-Production or his/her designee as per checklist for Phase-II Investigation.
  • Phase-II investigation is nothing but manufacturing & extended laboratory investigation
  • Manufacturing investigation: (Material, Method, Machine, Man)
    • As part of manufacturing investigation, review BMR for quality of raw material added
    • Verify the approved status and analytical report No. of the RM
    • Physical stock of added materials
    • The record of temperature and humidity of the raw material storage area
    • Whether the proper sequence has been followed during addition of RM
    • Whether the required process parameters are maintained.
    • The equipment usage log books for calibration/validation and usage of equipment’s and cleaning record.
    • The persons involved in process are trained or not.
    • Temperature and humidity record of processing area.
  • If any assignable cause found during the investigation, CAPA shall be trigger and the decision for the disposition of batch shall be taken by Head-QA.
  • If all process parameter are found satisfactory and there is no assignable cause found during investigation, then conduct hypothesis testing to find out the possibility of laboratory error as extended investigation.

Extended laboratory investigation

  • Retesting and re-sampling shall be decided jointly by Head QC and Head- QA.
  • The sample used for retesting should be taken from the same homogeneous material that was originally collected from the lot
  • Re-sampling shall be performed
    • If the quantity of sample is not sufficient to perform further investigation.
    • If the investigation determines that the initial sampling method was in error, a new accurate sampling method must be developed, qualified and documented.
    • When the original sample was not truly representative of the batch.
  • In case of assignable cause found in hypothesis analysis, analysis shall be performed by the same analyst in triplicate.
  • If all the results failing, no further retest is required and all the results will be submitted to QA for OOS closure.
  • If the results obtained from analyst-II is also OOS and the results are nearer to the initial results then there is no further retesting is required and the results can be declared as confirmed OOS.
  • In case if the value reported by Analyst-II is within the specification limit then the analysis shall be repeated with analyst-III in triplicate to reconfirm the pass results.
  • If the repeated results of the analyst –III passes to confirm the specification results then based on the analyst-II and the analyst-III results, the batch shall be released and the analyst-I results shall be invalidated and CAPA to be generated and close OOS.
  • If the repeated results of the analyst-III is still OOS limit then based on Analyst-I and analyst-III results, the analyst-II results shall be invalidated and CAPA to be generated.
  • The decision of disposition of batch shall be taken by Head-quality and based on the recommendation of Head-QA, Phase-III investigation shall be performed.

Phase-III investigation

  • It involves in the manufacturing investigation for the other batches or products affected for the said non conformity.
  • Investigation of method validation, stability data and testing procedure shall be evaluated.

A confirmed OOS results indicated that the batch does not meet established standards or specifications and should result in batch rejection and proper disposition.

In case of raw material, move them to designated rejected area and inform to purchase department regarding the rejection. The next supply shall be accepted based on the acceptance of CAPA report provided by the vendor within 15 working days.

In case of stability samples, it needs to give the information to F & D and Regulatory affairs department for necessary corrective actions.

The OOS should be closed out with all supportive documentations within 30 days from the OOS occurred.

All Investigations regarding Out of Specification results should be documented and preserved.

In case of any Out of Specification results found during contract analysis, then the laboratory should follow their in-house OOS investigation procedure. The contract laboratory should convey its data, finding and supporting documentation to contract giver. If in case excess of samples require for Investigation then contract giver should provide the quantity as required by the external laboratory for further investigation.