When it comes to investigating OOS results, a clear line should be drawn between the responsibilities of a contract testing laboratory (CTL) and that of the manufacturer/sponsor. Before we come to the testing part, here are some questions (not all inclusive) to be asked by your firm before selecting a CTL for outsourced testing: (1) Is the CTL registered and regulated by the regulatory agencies (e.g., FDA for products destined for the US market)? (2) Does the CTL have an established Quality System including procedure(s) for investigating Out of Specification/Out of Tolerance/Unexpected results (UR)? (3) Does the OOS procedure at the CTL meet the requirements of the current FDA OOS Guidance document? (4) Is the CTL accredited by a recognized organization (e.g., per ISO/IEC 17025:2017)?

Once these are answered to your satisfaction, it is required to establish a mutually agreed Quality Agreement between the sponsor and CTL that clearly defines the responsibility of each party in case of a laboratory failure. In the May 2022 revision of the guidance document “Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production,” FDA states that “This guidance can also be used by contract firms performing production and/or laboratory testing responsibilities. Specifically, the guidance discusses how to investigate OOS test results, including the responsibilities of laboratory personnel, the laboratory phase of the investigation, additional testing that may be necessary, when to expand the investigation outside the laboratory, and the final evaluation of all test results,” and “The responsibility of a contract testing laboratory in meeting these requirements is equivalent to that of a manufacturing firm.

The Quality Agreement between CTL and sponsor should dictate prompt notification (typically within 24 hours) of any OOS/OOT/UR results detected from the CTL to the sponsor. The CTL is responsible for conducting Phase I investigation to find a root cause related to laboratory error. There is a misconception that, if an OOS happens at a CTL, they have the full responsibility for investigation. The sponsor should be keenly aware of the CTL’s investigation strategy and weigh in on hypothesis testing. Ideally, sponsors should open an OOS investigation within their quality system in parallel with the CTL OOS investigation. As part of Phase I investigation, a CTL may reinject/reanalyze part of the already prepared sample that produced the discrepant result to investigate instrument malfunction. If a clear laboratory error is identified during Phase I investigation, the CTL should implement appropriate corrective/preventive actions. However, a CTL should never perform a Phase II retest with a newly prepared sample without a written approval from the sponsor. Per FDA guidance, where the CTL cannot find laboratory related error for the discrepant result upon completion of Phase I investigation, their next step would be to contact the sponsor. “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.” It is critical for the sponsor (manufacturing firm) to complete Phase II investigation per their own OOS procedure before authorizing a retest. “Decisions to retest should be based on the objectives of the testing and sound scientific judgment.” The CTL and the sponsor should collaborate to design a predefined retest plan demonstrating detailed descriptions of samples (original sample vs. resample or both), number of retests, analysts (original vs. new analyst or both), instrument (original vs. new) and decisions based on outcomes.

It is important to remember that a CTL cannot make a batch disposition decision. This responsibility lies solely with the QU of the sponsor (manufacturing site). All results produced during the original test, investigations/hypothesis, and retests must be considered by the QU before making a batch disposition decision. Some CTLs provide Certificate of Analysis (CoA) to their sponsors as part of their service agreement. In such cases, per FDA guidance, “…when investigation by a contract laboratory does not determine an assignable cause, all test results should be reported to the customer on the certificate of analysis.” FDA also recommends in addition to the CoA, “…OOS investigation reports be provided to the customer.

Timely and collaborative communication between a CTL and its sponsor is particularly important for investigating OOS/OOT/UR results. Both parties play important roles in the investigation process. However, it is critical that certain responsibilities and decision making that are restricted to the sponsor should not be undertaken by the CTL.

If you have any questions relating to your site’s OOS investigation program and enhancing OOS investigation procedures, please contact Mrinmoy Nag at m.nag@lachmanconsultants.com for an assessment.