Issue link: https://www.e-digitaleditions.com/i/1267517
Tablets & Capsules July 2020 32C gations due to the strategic differences required during the investigations. Analytes are generally expected to be uniformly distributed throughout the material or product, while bacteria, fungi, and mold begin to grow in a partic- ular region of the material or product and then spread. Phase I: Documentary Accuracy assessment. The accuracy assessment is an immediate non-experimental re-examination of the actual solutions, test units, glassware, methodology, and instru- mentation used in the original measurements and prepa- rations. It is conducted by the analyst and supervisor to determine if a laboratory error is the cause of the OOS, OOT, or unusual result. Any errors found invalidate the original result, and subsequent non-conforming material or product investigation or dietary supplement material review are not needed. Historical review. A historical review is performed when a definitive laboratory error is not found during the accuracy assessment. Although not discussed in the FDA guidance document, a historical review of previous testing of the material or product is highly beneficial. A historical review not only includes trending of previous test results and investigations but also an examination of applicable material or product certificates of analysis (COAs) and specifications. Phase I: Experimental examination Re-analysis. An experimental examination by re-anal- ysis is performed to assess whether there has been a tran- sient equipment malfunction resulting in an equipment error. This is done by re-injecting or re-introducing the final sample preparation or diluent through the input system. The re-injections should always be performed in replicates of ≥ 3 to obtain a mean and standard deviation and have a meaningful data set to compare to the original result. Any equipment errors found invalidate the original result and, as such, the need for subsequent non-con- forming material or product investigation or dietary sup- plement material review. Only re-analyze samples using the same standards, reagents, and other chemical preparations that were used in the original chemical analysis. Do not re-analyze sam- ple preparations that are known to be unstable or that have expired, and do not use expired standards, reagents, or other preparations for re-analysis. Insufficient sample ture. The investigation is usually, and most practically, conducted as two separate yet linked investigations. First, a laboratory OOS investigation determines if the OOS result is valid. If the result is valid, the next step is to perform a non-conforming material or product inves- tigation. For dietary supplement materials or products, this non-conforming investigation is referred to as a material review [1]. Even when the particular OOS mate- rial or product lot is rejected for use or distribution, the investigations are necessary to determine the cause and whether the issue may impact other lots of materials and/ or products. The FDA Center for Drug Evaluation and Research (CDER) issued a "Guidance for Industry: Out of Specification (OOS) Test Results for Pharmaceutical Pro- duction" that describes the agency's current thinking on the matter. Although this guidance focused on pharma- ceutical production, it applies to all FDA-regulated indus- tries that must conduct an OOS investigation, including dietary supplements. It is noted that the "responsibility of a contract testing laboratory in meeting these require- ments is equivalent to that of a manufacturing firm" as dictated in the FDA guidance. Laboratory OOS investigations In addition to determining if the original OOS result is valid, the laboratory OOS investigation should look for "out of trend" (OOT) and unusual test results. OOT test results are those not within the general tendency, pattern, or direction of a series of events, conditions, or previous results. It's important to note that an OOT test result may or may not be OOS. The most common OOT event is a stability test result that is not consistent with the stability profile generated from previous time intervals or other historical stability studies. An unusual test result is not necessarily OOS but is aberrant, atypical, or otherwise unexpected. Examples of unusual test results that should be investigated using the laboratory OOS investigation process include results that exceed set action or alert lev- els or do not meet a target level. Sudden occurrences of contaminants not previously observed and the presence of unexpected or extraneous chromatographic peaks should also be considered unusual and investigated. Upon the occurrence or discovery of an OOS, OOT, or unusual result, the analyst performing the test must notify their supervisor to initiate the laboratory OOS investigation. The laboratory OOS investigation itself is organized into two phases as depicted in Figure 1. As the figure shows, Phase I includes both a documentary review and experimental examination, while Phase II includes only an expanded experimental examination [5]. This type of thorough OOS process is especially important for contract labs to employ because much of the dietary sup- plement industry outsources product testing. Whenever possible, Phase I of the investigation should be done before test preparations are discarded to test hypotheses regarding potential laboratory error. It is highly recommended, and common practice, to segregate analytical and microbiological laboratory OOS investi- Figure 1 Laboratory OOS investigation organization • Phase I: • Accuracy assessment • Historical data review • Re-analysis • Re-test • Confirmatory testing • Phase II: • Expanded experimental examination Documentary Experimental examination