| Sumario: | This case study describes a cleaning validation event in which failing results for API residue from a small molecule extended release tablet dosage form were observed. The initial two lots in the cleaning validation were successful. The third lot failed acceptable residue limits. Investigation of the failure comprised cleaning process development and performance; residue sampling, sample handling, sample analysis, and evaluation of the analytical method. Investigation of this event initially involved interviews of relevant personnel and reviews of associated documentation. Two areas were identified for further evaluation -- residue sampling and the cleaning process. Regarding sampling, a newly trained technician, working alone, sampled the first two acceptable lots, while an experienced technician working with a colleague sampled the third failing lot. Evaporation of sampling solvent occurred causing residue to be insufficiently recovered from the equipment surface resulting in erroneous false negative test results. Regarding the cleaning process, manufacturing operators commented that the new extended release formulation was more difficult to clean than the original immediate release formulation although the same cleaning procedure was utilized for both products. Evaluation of the cleaning process indicated that the process parameters were not optimal to clean the new extended release product. An improved cleaning process with increased cleaning agent concentration, increased cleaning time, and higher temperatures was developed, implemented, and ultimately validated. Cleaning validation sampling personnel must have good technical understanding of their work, and must know the technical reasons for the procedures they perform, and potential problems if procedures are not correctly performed. Sampling personnel training for cleaning validation should include a quantitative demonstration of acceptable cleaning by means of analytical testing. Training exercises must also include worst-case sampling such as with volatile solvents, multiple equipment, and other potential variations in sampling. SOPs must be carefully written to describe potential problems and include performance constraints to minimize variation and risks. There is an inherent danger when variation is not deliberately introduced into a validation project -- material variation, manufacturing operator variation, and in this case study, sampling personnel variation. Sampling by two different technicians enabled erroneous results to be discovered. Regarding the cleaning process, inactive ingredients in a formulation may have very significant effects on cleaning processes. Cleaning of residues does not depend solely on the properties of the API.
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