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  • What is Out-of-Specification Investigation and How to Proceed with it?

    Out-of-specification (OOS) implies that analytical results do not meet the pre-established acceptance criteria of in-house test specifications, or the official pharmacopeial monograph specification range; or product registered specifications and the results for finished product testing are in process are falling out of specification limits as mentioned in the drug master file or drug application and compendia. OOS results may be observed during the analysis of packing materials, raw materials, excipients, drug substances, in-process or final drug product testing, and stability study analysis. All ambiguous results observed out of set specification are named OOS results.

    The Food and Drug Administration (FDA) recently gave revised guidance for the industry on investigating Out-of-Specification test results for pharmaceutical production. The guidance provides industry on how to evaluate out-of-specification (OOS) test results and the term OOS. The results include all test results that fall outside the specifications or acceptance criteria established in drug applications, drug master files (DMFs), official compendia, or by the manufacturer and also apply to all the in-process laboratory tests that are outside of established specifications, it also discusses on how to investigate OOS test results including the responsibilities of laboratory personnel, the laboratory phase, additional testing that may be necessary and when to expand the investigation outside the laboratory and the final evaluation of all test results.

    In the pharmaceutical industry, it is highly important to control quality and to ensure consistent product quality during the FDA inspection. During the inspection, if the FDA finds out the faults in the way the investigation of OOS had been carried out by the manufacturer, FDA issues a warning letter to most drug substances and drug product manufacturers if there is no proper investigation of the OOS outcome. FDA warning letters are for the procedure in handling OOS if it is lacking or poorly scripted, further it is very important to know how to meet the current regulatory expectation for OOS investigation. However, a specific and well-drafted adequate OOS SOP is important for a thorough investigation procedure to assure an ample investigation. 

    Investigation of Out‑of-Specification Results

    The main aim of the OOS investigation is to focus on the definite outcome of the root cause of the OOS result. OOS Standard Operating Procedure (SOP) is essential for concluding the investigation. The investigation must be performed on time and competent enough to conclude its root cause identification, impact evaluation, and find efficient corrective action and preventive action. Most organizations have OOS SOP but either it may not be appropriate or not followed properly also there is no thorough investigation carried out and no root cause investigations had been carried out for these OOS results.

    When OOS is observed then systematic investigation needs to be done to check if there is an appropriate root cause. Prior to proceeding with proper OOS investigation, we need to cross-check analytical error methodically and confirm the initial test results by repeating the analysis with the original sample and solutions.

    The following are the important steps for performing the OOS investigations:

    OOS may be observed due to the following errors but is not restricted to these factors.

    1. Error related to the analytical laboratory
    2. Analytical instruments or equipment used for analysis are not in a valid calibration state.
    3. Analytical test procedure not followed properly
    4. Analyst Error
    5. Error while doing calculations
    6. Error due to the instrument failure
    7. The test sample is not uniform or homogenous
    8. Sampling error i.e. sample is not uniform or proper
    9. Pooling of samples is not appropriate
    10. Error at the time of sample handling
    11. Manufacturing process-related error
    12. Quality of used excipients, raw materials or intermediates
    13. Operator error
    14. The validated procedure was not followed correctly or Deviation from the standard procedure
    15. At the time of manufacturing in-process checks or control is not done properly
    16. Error due to equipment failure

    Action plan for the OOS Investigations

    1. Phase I: Investigation includes primary investigations and extended laboratory investigations.
    2. Phase II: Investigation includes comprehensive manufacturing investigations.
    3. Phase III: Investigation includes extended manufacturing evaluation, resampling, and reanalysis of the samples.

    Systematic and careful analytical method transfer from the analytical development lab to the quality control lab plays an important role to minimize errors and subsequently OOS investigations. All the performed activities of investigations must be performed within a specific time, thorough, very well written, clear, logical, impartial, scientifically proven, recorded, properly documented, and reviewed by the quality assurance and regulatory affairs department.

    There must be a competent CAPA system, which should clearly illustrate the root cause of OOS results so that relevant effective corrective and preventive actions can be executed. The most common CAPA is related to analyst error hence to prevent this, adequate training must be provided to the analyst and need to ensure that the performed activity is right the first time. Implement the efficient CAPA system to prevent repetitive errors to avoid the number of OOS in the future.

    For further information on OOS Investigations, feel free to contact us here.


    What is the purpose of an OOS investigation?

    The purpose of an OOS investigation is to identify the root cause of the OOS results and to take appropriate corrective and preventive action (CAPA). The investigation should include a review of production & sampling procedures and also include additional laboratory testing.

    What is an Out of specification (OOS) in the FDA?

    The term OOS includes all the test results that fall outside the specifications or the acceptance criteria established in drug applications, official compendia, drug master files (DMFs), or by the manufacturer.

    What is CAPA in Out-of-specification?

    CAPA (corrective and preventive action) is a systematic approach that includes the action needed to correct, avoid repetition (corrective action), and eliminate the cause of non-compliant products and other quality problems (preventive action).  

    What is the difference between OOS and OOT in pharma?

    Out-of-Specification (OOS) is the result of established acceptance criteria where comparison is done with the results versus predefined specification criteria while Out-of-Trend (OOT) is the time-dependent results compared, but may show variation or fall outside from the historical results values.


    1. Guidance for Industry Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production, U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Rockville, MD,
    2. ICH Q6(A), Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances. Published by European Medicines Agency, London,
    3. Ravi, G, Gupta, N.V., Raghunandan, H.V., Shashikanth, D. FDA guidelines for Out-of-Specifications (OOS) in industries, Int J PharmTech Res,  
    4. Kumar, K. A, and Gupta, N. V. (2015) Handling of Out-of-Specification Results, International Journal of Pharmaceutical Quality Assurance,
    5. Barr (1993) the United States of America, Plaintiff, v. BARR Laboratories, INC., et al., Defendants.