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

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What is Out of-Specification Investigation and How to Proceed for it

What is Out of-Specification Investigation and How to Proceed for it

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FDA issued warning letter to the most of the drug substance and drug product manufacturer. During the inspection, FDA find out the fault, the way investigation of OOS had been carried out by the manufacturer. There is no proper investigation of OOS outcome. FDA warning letters often found that the procedure for handling of OOS is lacking or poorly scripted. It is very much important to know that how to meet the current regulatory expectation for OOS investigation. However, a specific and well drafted adequate OOS SOP is important for through investigation procedure assure an ample investigation. 

What is Out‑of-Specification (OOS):

When analytical results that does not meets the pre-established acceptance criteria of in-house test specification or official pharmacopeial monograph specification range then it termed as Out‑of-Specification results. OOS results may be observed during the analysis of packing materials, raw materials, excipients, drug substance, in-process or final drug products testing and stability study analysis. All ambiguous results which observed out of set specification is named as OOS results.

Investigation of Out‑of-Specification Results:

The main aim of OOS investigation should be focus on the definite outcome of the root cause for the OOS result. OOS SOP is very much important to conclude appropriate investigation. The investigation must be on time and competent enough to conclude it’s root cause identification, impact evaluation and finding efficient corrective action and preventive action’s. Most of the organisation have OOS SOP but either it may not appropriate or not followed properly. There is no through investigation carried out and no root cause investigations had been carried out for these OOS results.

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

Following is the important steps for performing the OOS investigations:

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

  1. Error related to analytical laboratory:
  2. Analytical instruments or equipment’s used for analysis is not in 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. Test sample is not uniform or homogenous:
  8. Sampling error i.e. sample is not uniform or proper
  9. Pooling of sample 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. Validated procedure not followed correctly or Deviation from the standard procedure,
  15. At the time of manufacturing in-process check or control not done properly,
  16. Error due to the 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 analytical development lab to quality control lab plays an important role to minimise the errors and subsequently the OOS investigations.

All the performed activities of investigations must be performed within specific time, thorough, very well written, clear, logical, impartial, scientifically proven, recorded, properly documented and reviewed by quality assurance and regulatory affairs department.

There must be competent CAPA system, which should be clearly illustrated the root cause of OOS results so that relevant effective corrective and preventive actions can be executed. 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 right at first time. Implement the efficient CAPA system to prevent repetitive errors to avoid the number of OOS in future.


  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.

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