Issue link: https://www.e-digitaleditions.com/i/1267517
32D July 2020 Tablets & Capsules hypotheses about the cause of the OOS result regarding potential cross-contamination or a transient equipment malfunction for automated microbiological systems. Phase II: Expanded experimental examination An expanded experimental examination of the material or product laboratory OOS investigation may be under- taken if Phase I finds no meaningful errors and does not determine a cause for the OOS, OOT, or unusual result. This may include collecting additional samples for test- ing; sample testing not dictated on the specification, such as different test methodology; testing that encompasses method variations; or the inclusion of additional quality control samples. A resampling of the material using the same proce- dure as the initial sampling process (same location and technique) can also help rule out a possible error or contamination concern during the original sampling. Alternatively, an enhanced representative and statistical sampling of the material or product lot such as random sampling of (√n + 1) containers may be beneficial. Spa- tial sampling of large containers (such as super sacks or bulk bags) to incorporate samples from the top, middle, and bottom or sides and middle using a thief sample device may be needed. As with the Phase I re-test, all actions or testing to be undertaken for the expanded experimental examination must be defined, reviewed, and approved by quality unit management prior to execution. Documentation In a cGMP environment, "if it's not documented, it didn't happen," so each laboratory OOS investigation must be assigned a unique alphanumeric identification and every aspect of the investigation must be docu- mented on an applicable form. OOS investigations must also be reviewed and approved by the quality unit man- agement who will compile and track all OOS investiga- tions for tracking, monitoring, and trending purposes. Tara Lin Couch, PhD, is the senior director of dietary supple- ments and tobacco services at EAS Consulting Group, Alex- andria, VA (571 447 5500, www.easconsulting.com). References 1. https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/ cfcfr/cfrsearch.cfm?cfrpart=111 2. https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/ cfcfr/CFRSearch.cfm?CFRPart=210 3. https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/ cfcfr/CFRSearch.cfm?CFRPart=211 4. https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/ cfcfr/CFRSearch.cfm?fr=111.113 5. https://www.fda.gov/media/71001/download 6. https://law.justia.com/cases/federal/district-courts/ FSupp/812/458/1762275/ preparation amounts must not be diluted and re-analyzed with standard or method modifications because doing so introduces additional variables, making a true assessment of just the equipment impossible. Re-test. Re-testing of the original analyte sample may be required if no meaningful errors have been found during the documentary reviews or equipment assess- ment. An experimental examination by re-test is con- ducted by re-testing the original sample. Ideally, this is accomplished with the same first analyst and a second analyst to provide sufficient data to do an abbreviated accuracy, precision, and ruggedness assessment of the test method performance. No change in the testing methodology is made. Replicates of ≥ 3 are needed from each analyst to obtain a mean and standard deviation for both data sets. The second analyst must be appropriately trained to conduct the test and is preferably more experi- enced than the original analyst. All of the data obtained is compared to the original OOS result and to each other to determine if the origi- nal result is valid. Consideration must always be given to the expected method variability. Pre-assigned criteria for relative percent standard deviation and percent difference assessment requirements can also be included based on test method validation or verification experiments. According to the U.S. v Barr Laboratories court decision, retesting "cannot continue ad infinitum" and materials and products cannot be "tested into compliance" [6]. This means that OOS results cannot be averaged with passing results to obtain a "reported" average value that meets the material or product specification. Furthermore, test- ing cannot be repeated until a desired result is obtained. It's critical that the number of tests to be performed is defined and then reviewed and approved by quality unit management prior to the performance of any testing. Best practice is to include these instructions in a laboratory OOS investigation procedure. Confirmatory testing. Confirmatory testing is con- ducted when an assignable cause has not been found during the accuracy assessment or historical review of a microbiological OOS investigation. Confirmatory testing only applies to quantitative testing of bacteria, mold, or fungi. No confirmatory tests are performed for absence/ presence microbiological methods of pathogens such as E. Coli, Salmonella, or S. Aureus due to the confirmatory nature of the test methods themselves, potential ramifi- cations of the presence of the bacteria, and the non-ho- mogeneous nature of the microbiological contaminants. A non-conforming material or product investigation, or material review for dietary supplements, is always required in this case. Confirmatory testing is typically performed by re-test- ing the sample using a larger 25-gram sample size, rather than a 10-gram sample, to either validate or invalidate the original result. Preferably, quantitative confirmation testing should be performed by a different microbiolo- gist. Replicate retests of ≥ 3 additional sub-samples from the original sample should be conducted to examine