Out-of-specification(OOS) , FDA Guidance – Lab Investigation Steps

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What is OOS ?

An explicit set of requirements is called specification and typically it needs to be satisfied by a material, product, or service. So when a material, product or service fail to meet one or more of the applicable specifications, it is referred to as being out of specification, abbreviated as OOS.

FDA Guidance on OOS

FDA Requires that

  • Finished Pharmaceuticals (DP) and Active Pharmaceutical Ingredients (APIs) to be manufactured in accordance with current good manufacturing practice under section 501(a)(2)(B) of the Act.
  • Current good manufacturing practice for APIs includes the performance of scientifically sound Raw material testing, In-process monitoring, Release and stability testing, Process validation, and adequate investigations of any OOS result obtained from such testing.
  • The responsibility of a contract testing laboratory in meeting these requirements is equivalent to that of a manufacturing firm.

FDA Guidance Applied on

  • Chemistry-based lab testing of drugs regulated by CDER/CBER
  • Tests are performed on API, excipients and other components, in-process materials, and finished drug products.
  • Products purchased outside but tested in house.
  • Contract firms performing testing on such products.
  • As long as CGMP regulations (21 CFR 210 and 211 and the FD&C Act Section 501(a)(2)(B) apply.

OOS and Out-of-Trend(OOT) results

OOS ResultOOT Results
– Test results that fall outside of established acceptance criteria which have been established in official compendia and/or by company documentation:
– Raw Material Specifications, In-Process/Final Product Testing, etc.		– Is generally a stability result that does not follow the expected trend, either in comparison with other stability batches or with respect to previous results collected during a stability study.
– The trends of starting materials and in-process samples may also yield out of trend data. The result is not necessarily OOS but does not look like a typical data point.

Atypical / Aberrant / Anomalous Result : These are results that are still within specification but are unexpected, questionable, irregular, deviant or abnormal. Examples would be chromatograms that show unexpected peaks, unexpected results for stability test point, etc.

Phase 1 Lab Investigations:

The first phase includes

  • Assessment of the accuracy of the laboratory’s data.
  • The investigation should be thorough, timely, unbiased, well-documented, and scientifically sound.
  • Test preparations (including the composite or the homogenous source of the aliquot tested) are not to be discarded as they are necessary for investigation
  • For contract laboratories, the laboratory should convey its data, findings, and supporting documentation to the manufacturing firm’s Quality Control Unit (QA), who should then initiate the full-scale OOS investigation.

Phase 2 – Lab Investigation for OOS – Full Scale

  • When clear evidence of laboratory error exists, laboratory testing results should be invalidated.
  • When evidence of laboratory error remains unclear, a full-scale OOS investigation should be conducted by the manufacturing firm to determine what caused the unexpected results.
  • Quality Control Unit (QA) conducts the investigation.
  • Other pertinent departments participate are Manufacturing, Process Development, Maintenance, Engineering, QC, Metrology, etc.

The key to unlock the OOS problem:

  • Complete review of all manufacturing and process development documents with a written record of the review.
  • “In cases where manufacturing occurs off-site (i.e., performed by a contract manufacturer or at multiple manufacturing sites), all sites potentially involved should be included in the investigation.”
  • Review all documents and records of the manufacturing process.
  • A written record of the review includes:
    • A clear statement of the reason
    • Summary of manufacturing process aspects that could cause the problem
    • Results of documentation review with probable cause.
    • Results of previous reviews
    • Description of corrective actions to be taken.

Manufacturing investigations should have a full root cause analysis.

  • Look deeper into the problem
  • Establish a sequence of events – create a timeline
  • Develop a cross-functional team to help put a new set of eyes on the issue
  • Don’t be in a hurry to establish a cause and close the investigation
  • Leave no stone unturned

Full-scale OOS investigation may include additional laboratory testing. A number of practices are used during the laboratory phase of an investigation. These include:

  • Retesting (a portion of the original sample)
  • Resampling.