Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production

Laboratory testing, which is required by the CGMP regulations (§§ 211.160 and 211.165), is necessary to confirm that components, containers and closures, in-process materials, and finished products conform to specifications, including stability specifications.


Testing also supports analytical and process validation efforts. General CGMP regulations covering laboratory operations provide for the establishment of scientifically sound and appropriate specifications, standards, and test procedures that are designed to ensure that components, containers and closures, in-process materials, and finished drug products conform to the established standards. 


Section 211.165(f) of the CGMP regulations specifies that finished drug products that fail to meet established standards, specifications, or other relevant quality control criteria must be rejected.


Both finished pharmaceuticals and active pharmaceutical ingredients (APIs) are 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.


This guidance for industry provides the Agency’s current thinking on how to evaluate out-of- specification (OOS) test results. 


For purposes of this document, the term OOS results includes all test results that fall outside the specifications or acceptance criteria established in drug applications, drug master files (DMFs), official compendia, or by the manufacturer. The term also applies to all in-process laboratory tests that are outside of established specifications.


This guidance applies to chemistry-based laboratory testing of drugs regulated by CDER. 


It is directed toward traditional drug testing and release methods. These laboratory tests are performed on active pharmaceutical ingredients, excipients and other components, in-process materials, and finished drug products to the extent that current good manufacturing practice ( CGMP) regulations (21 CFR parts 210 and 211) and the Federal Food, Drug, and Cosmetic Act (the Act) (section 501(a)(2)(B)) apply. 


The principles in this guidance also apply to in-house testing of drug product components that are purchased by a firm. This guidance can also be used by contract firms performing production and/or laboratory testing responsibilities. 


IDENTIFYING AND ASSESSING OOS TEST RESULTS 

FDA regulations require that an investigation be conducted whenever an OOS test result is obtained (§ 211.192).

The purpose of the investigation is to determine the cause of the OOS result. The source of the OOS result should be identified either as an aberration of the measurement process or an aberration of the manufacturing process. Even if a batch is rejected based on an OOS result, the investigation is necessary to determine if the result is associated with other batches of the same drug product or other products. Batch rejection does not negate the need to perform the investigation. 

The regulations require that a written record of the investigation be made, including the conclusions and follow-up (§ 211.192). 

To be meaningful, the investigation should be thorough, timely, unbiased, well-documented, and scientifically sound. The first phase of such an investigation should include an initial assessment of the accuracy of the laboratory's data. 

Whenever possible, this should be done before test preparations (including the composite or the homogenous source of the aliquot tested) are discarded. This way, hypotheses regarding laboratory error or instrument malfunctions can be tested using the same test preparations. If this initial assessment indicates that no causative errors were made in the analytical method used to arrive at the data, a full-scale OOS investigation should be conducted. For contract laboratories, the laboratory should convey its data, findings, and supporting documentation to the manufacturing firm’s quality unit (QU). The manufacturing firm’s QU should then initiate the Phase 2 (full-scale) OOS investigation, whenever no clearly causative laboratory error was identified.


INVESTIGATING OOS TEST RESULTS 

When the initial assessment does not determine that laboratory error caused the OOS result and testing results appear to be accurate, a full-scale OOS investigation using a predefined procedure should be conducted. The objective of such an investigation should be to identify the root cause of the OOS result and take appropriate corrective action and preventive action.

A full-scale investigation should include a review of production and sampling procedures and will often include additional laboratory testing. Such investigations should be given the highest priority.

Among the elements of this phase is evaluation of the impact of OOS result(s) on already distributed batche