Evaluate the company’s system to investigate laboratory test failures (OOS). These investigations represent a key issue in deciding whether a product may be released or rejected and form the basis for retesting, and resampling.

In a recent court decision the judge used the term “out-of-specification” (OOS) laboratory result rather than the term “product failure” which is more common to FDA investigators and analysts. He ruled that an OOS result identified as a laboratory error by a failure investigation or an outlier test. The court provided explicit limitations on the use of outlier tests and these are discussed in a later segment of this document., or overcome by retesting. The court ruled on the use of retesting which is covered in a later segment of this document. is not a product failure. OOS results fall into three categories:

  • laboratory error
  • non-process related or operator error

  • process related or manufacturing process error


Laboratory errors occur when analysts make mistakes in following the method of analysis, use incorrect standards, and/or simply miscalculate the data. Laboratory errors must be determined through a failure investigation to identify the cause of the OOS. Once the nature of the OOS result has been identified it can be classified into one of the three categories above. The inquiry may vary with the object under investigation.


The exact cause of analyst error or mistake can be difficult to determine specifically and it is unrealistic to expect that analyst error will always be determined and documented. Nevertheless, a laboratory investigation consists of more than a retest. The inability to identify an error’s cause with confidence affects retesting procedures, not the investigation inquiry required for the initial OOS result.

The firm’s analyst should follow a written procedure, checking off each step as it is completed during the analytical procedure. We expect laboratory test data to be recorded directly in notebooks; use of scrap paper and loose paper must be avoided. These common sense measures enhance the accuracy and integrity of data.

Review and evaluate the laboratory SOP for product failure investigations. Specific procedures must be followed when single and multiple OOS results are investigated. For the single OOS result the investigation should include the following steps and these inquiries must be conducted before there is a retest of the sample:

– the analyst conducting the test should report the OOS result to the supervisor

– the analyst and the supervisor should conduct an informal laboratory investigation which addresses the following areas:

  1. discuss the testing procedure
  2. discuss the calculation

  3. examine the instruments

  4. review the notebooks containing the OOS result

An alternative means to invalidate an initial OOS result, provided the failure investigation proves inconclusive, is the “outlier” test. However, specific restrictions must be placed on the use of this test.

  1. Firms cannot frequently reject results on this basis.
  2. The USP standards govern its use in specific cases only.

  3. The test cannot be used for chemical testing results. An initial content uniformity test was OOS followed by a passing retest. The initial OOS result was claimed the result of analyst error based on a statistical evaluation of the data. The court ruled that the use of an outlier test is inappropriate in this case..

  4. It is never appropriate to utilize outlier tests for a statistically based test, i.e., content uniformity and dissolution.

Determine if the firm uses an outlier test and evaluate the SOP.

Determine that a full scale inquiry has been made for multiple OOS results. This inquiry involves quality control and quality assurance personnel in addition to laboratory workers to identify exact process or non process related errors.

When the laboratory investigation is inconclusive (reason for the error is not identified) the firm:

  1. Cannot conduct 2 retests and base release on average of three tests
  2. Cannot use outlier test in chemical tests

  3. Cannot use a re-sample to assume a sampling or preparation error

  4. Can conduct a retest of different tablets from the same sample when a retest is considered appropriate (see criteria elsewhere)


Formal investigations extending beyond the laboratory must follow an outline with particular attention to corrective action. The company must:

  1. State the reason for the investigation
  2. Provide summation of the process sequences that may have caused the problem

  3. Outline corrective actions necessary to save the batch and prevent similar recurrence

  4. List other batches and products possibly affected, the results of investigation of these batches and products, and any corrective action. Specifically:

– examine other batches of product made by the errant employee or machine

– examine other products produced by the errant process or operation

  1. Preserve the comments and signatures of all production and quality control personnel who conducted the investigation and approved any reprocessed material after additional testing


Analyst’s mistakes, such as undetected calculation errors, should be specified with particularity and supported by evidence. Investigations along with conclusions reached must be preserved with written documentation that enumerates each step of the investigation. The evaluation, conclusion and corrective action, if any, should be preserved in an investigation or failure report and placed into a central file.


All failure investigations should be performed within 20 business days of the problem’s occurrence and recorded and written into a failure or investigation report.


An OOS laboratory result can be overcome (invalidated) when laboratory error has been documented. However, non-process and process related errors resulting from operators making mistakes, equipment (other than laboratory equipment) malfunctions, or a manufacturing process that is fundamentally deficient, such as an improper mixing time, represent product failures.

Examine the results of investigations using the guidance in section 5 above and evaluate the decision to release, retest, or rework products.

Reference :-

Pharmaceutical Quality Control Labs (7/93)(USFDA)


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