Out-of-specification OOS test results

The Court rejected FDA s position that a batch failure occurs when an individual test result doesn t meet specification. OOS results can be due to laboratory errors, non-process-related (operator) errors or process-related (manufacturing) errors. Only non-process or process-related errors are properly identified as failures. 

The Court mled that OOS results can be identified only through an investigation. The type and extent of the investigation depend on what caused the OOS result. 

Failure investigations must be documented and performed within 30 business days. 

The Court determined that laboratory errors occur when analysts make mistakes. These types of errors must be reported to and reviewed by a supervisor according to a written procedure. The review should be documented and the cause of the error identified if possible. 

Retesting is permissible if the OOS result was due to laboratory error. Other types of error require further investigation. 

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Finally, in reorganizing that the CGMPs cannot set regulations for OOS investigations in sufficient detail, the FDA has issued a draft, Guidance for Industry Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production [10]. 

FDA CDER, Guidance for Industry Investigating Out of Specification (OOS) Test Results for Pharmaceutical Production, Sept. 1998. 

Federal Regulations This document provides a summary of (and links to) the relevant sections of the Federal Food, Drug, and Cosmetic Act, including 21 Code of Federal Regulations (CFR) part 210 (CMPs for Manufacturing 21 CFR Part 211 (GMS for Finished Pharmaceuticals) and Guidance Documents for NDAs, ANDAs, and Out of Specification (OOS) Test Result Reporting. 

FDA/CDER (October 2006) Guidance for industry Investigating out-of-specification (OOS) test results for pharmaceutical production. 

FDA-483 issued for drug product. The FIPLC assay of X, has not assured that the test results are consistent and reliable. Since the approval of the product on Y, there have been two major changes to the testing procedure following out of specification (OOS) results ... 

An important piece of information typically contained in an APR is the number of out-of-specification (OOS) results identified over the course of the year for (in-process and finished-product) testing related to any single product. While this is valuable information, it maybe of further use to more frequently evaluate the OOS trends relate to high-volume products. 

Laboratory controls commence with sampling and testing of incoming materials according to written procedures. Some aspects of the tests include identity, quantity, purity, activity, heterogeneity, stability, sterility and safety. Intermediates and finished products are tested in accordance with pre-set specifications. Out of specification (OOS) results are investigated. OOS may be due to analyst or operator error, inappropriate method, production problems or an inherent problem with the samples. 

The Quality Control (QC) department has to operate according to Go(xl Quality Control Laboratoiy Practice (GQCLP) standards [2]. All QC methods have to be validated and verified before application. The instruments used for QC are qualified and calibrated before QC testing is performed. There is a procedure in place for the investigation of Out Of Specification (OOS) and Out Of Trend (OOT) results. The reference standards used should be certified, qualified and verified. Documentation and traceability are important such as in production. All raw data should be retained. 

It defines anew term, OOS or out-of-specification result, which refers to a result obtained for the pharmaceutical material or drug product that does not comply with the regulatory specification for the particular test performed. Previously, FDA inspectors would prematurely term OOS laboratory results as product failures, which clearly was not established without proper laboratory and possibly more extensive investigational activities outside the laboratory environment. 

Since the 1993 court decision against Barr Laboratories, 5 tjjg elimination of outliers has taken on a decidedly legal aspect in the U.S. (any non-U.S. company that wishes to export pharmaceuticals or preciwsor products to the U.S. market must adhere to this decision concerning out-of-specifica-tion results, too) the relevant section states that ... An alternative means to invalidate an individual OOS result... is the (outlier test). The court placed specific restrictions on the use of this test. (1) Firms cannot frequently reject results on this basis, (2) The USP standards govern its use in specific areas, (3) The test cannot be used for chemical testing results. ... A footnote explicitly refers only to a content uniformity test, 5 but it appears that the rule must be similarly interpreted for all other forms of inherently precise physicochemical methods. For a possible interpretation, see Section 4.24. 

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