Assessment of USFDA Warning Letters & 483’s Related to Improper Handling of OOS Results

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The US Food and Drug Administration (FDA) inspection trend of recent warning letters is typically related to deficient investigation of failure results, unacceptable examination of Out of Specification (OOS) outcome and ineffective corrective action and preventive action (CAPAs).

Regulatory agency USFDA is controlling the drug substances or drug products manufactured and marketed in or outside the countries. There are serious cGMP deviations and violations observed in manufacturing facilities of drug substances and drug products. Hence there must be strict compliance required as per 21 CFR (Code of federal regulations). There’s no proper control in computerised system which can restrict the illegal access or data manipulation.

Warning letters and 483’s related to OOS results:

As per USFDA, most of the investigations of failure results observed in batches not conforming to the specification in response to out-of-specification (OOS) report is either inadequate or not properly documented. The origin of OOS result is due to following 4 main reasons:

  1. Deficient quality system
  2. Infringement of data integrity
  3. Inadequate laboratory controls
  4. Imperfect production controls

 The errors observed in laboratory due to inadequate controls for computerized system, non-compliant instruments to CFR part 11 condition, deficient laboratory control and poorly written standard operating procedures (SOP) or analytical test methods.

Root cause investigation of OOS results should be allotted by planned, detailed procedure for analytical test results, product deficiencies and failing of batch results. As per regulatory expectation extensive, separate and self-sufficient evaluation of the system for the investigation of OOS results, non-compliance, inconsistency, and complaints with comprehensive plan of action to correct the system.

A recent review of warning letters issued by USFDA up to August 2020 confirms that the warning letters given to the organizations due to OOS results aren’t evaluated properly. Following are the reasons related to OOS results:

  1. Analytical data of OOS investigation isn’t incorporated entirely from existing data, only selected data is included.
  2. Inadequate investigation of failure because of the analytical reasons such as weight of standard or sample, dilution factor, correction factor wrong data was recorded hence product not meets the specification.
  3. Non-compliance of results of finished product batch due to deficient investigation of significant deviations during manufacturing.    
  4. Unsuccessful to adequately investigate an out-of-specification (OOS) microbial test result obtained during release testing.
  5. Stability program is deficient, firm didn’t to follow a written testing program designed to assess the stability characteristics of drug products and to use results of stability testing to test the suitable storage conditions and expiration dates.
  6. Failing to establish laboratory controls that include scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure that components, drug product containers, closures, in-process materials, labelling, and drug products to follow proper standards of purity, identity, strength, and quality.
  7. Failure to adequately investigate OOS results and implement appropriate corrective actions.
  8. Failure of quality unit to make sure that drugs are appropriately tested and so the results are reported. Failing to regulate and obey written procedures for examining serious nonconformities or the failure of API batches to meets the specifications. Failure to verify the suitability of analytical methods.
  9. Firm didn’t thoroughly investigate any unexplained discrepancy or failure of a batch or any of its components to comply any of its specifications, whether or not the batch has already been distributed, Firm unsuccessful to establish an adequate quality unit and thus the responsibilities, and procedures applicable to the quality control (QC) unit weren’t in writing and fully followed.
  10. Firm failed make sure that laboratory records included complete data derived from all tests necessary to make sure compliance with established specifications and standards.
  11. Firm’s QC failed to approve or reject all procedures or specifications impacting on the identity, strength, quality, and purity of the drug product.


Main worry of USFDA in pharmaceutical industry is associated to the data integrity complications and infringement of 21 CFR, Part 211 and 212. Hence firm requires more stringent control on the instruments and its computerised systems to avoid any manipulation and infringement of data integrity.

All standard operating procedures (SOP’s) must be more specific, effectively drafted and adequate. Hence to avoid any regulatory observation’s it’s obligatory to follow the SOP’s with no cutting corners.


  1. Warning letters by USFDA,, Inspections-compliance-enforcement-and-criminal-investigations/compliance-actions-and-activities/warning-letters,
  2. Guidance for Industry, “Q10 Pharmaceutical Quality System”, U.S. Department of Health and Human Services Food and Drug Administration,
  3. Guidance for Industry, Data Integrity and Compliance With CGM Draft Guidance, U.S. Department of Health and Human Services Food and Drug Administration, April 2016, Pharmaceutical Quality/Manufacturing Standards (CGMP),
  4. US CFR Title 21, Part 211.192 (Government Printing Office, Washington, DC) 162.

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