Analytical Method Validation

Some essential considerations must be made in choosing a suitable analytical test method for testing completeness of cleaning. As a start, the quantitation limit of the test method must be lower than the predefined acceptance limit for residue levels. As will be discussed later in this chapter, the acceptance limit for a cleaning process is the maximum allowed level of contamination that has been judged not to jeopardize the safety, quality and integrity of a pharmaceutical product. Most state-of-the-art analytical techniques are capable of detecting and quantifying compounds at levels well below those which would be considered a safety concern. More often than not, a quantitation limit in the low parts-per-million range is adequate for the testing of rinse fluids and swab samples. With all of the advances in analytical technology, the task of detecting residual contaminants is often less formidable than the task of reproducibly cleaning the equipment to a defined tolerable limit of contamination.

Other considerations to make in choosing a suitable test method include the accuracy and precision achievable, as well as the specificity/selectivity that the method allows. The combined sampling and test method should be challenged for accuracy by testing the recovery of potential contaminants that have been added to the equipment surfaces or some small scale panel comprised of the same surface components. For example, a known amount of drug product or cleaning agent can be applied to a known surface area of equipment material and then rinsed or swabbed according to the sampling protocol. This should be done over a range of potential contamination levels, i.e., at the acceptance limit, as well as above and below the acceptance limit. The samples are then tested according to the proposed analysis method to ensure that the combined sampling and test method provides adequate recoveries. In the case of swab samples, it is usually necessary to test recovery of the potential contaminant from the swab by adding various amounts of contaminant to representative swabs and carrying them through the extraction procedure. These same experiments can be further refined to provide additional information regarding method precision, e.g., by having the experiments repeated on multiple days by more than one analyst.

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