Validation

It is worth reflecting that most of the general microbiological methods currently in use for total viable counts or recovery of named organism have not been "validated" as we understand the term today. Certainly they have a long period of use, but as debates on viable nonculturables, whether to use minimal media for recovery of water borne organisms, etc., have shown, this does not necessarily mean that the counts achieved have been accurate. Similarly, extensive work in clinical microbiology has repeatedly demonstrated that recovery of microorganisms from clinical specimens using standard isolation techniques is a far from robust procedure. Although the regulatory bodies insist on formalized validation, this must be set in the context of the widespread use of current methods, which can prove unreliable even in the most experienced hands.

For both qualitative and quantitative methods it will be assumed that the equipment used follows the traditional qualification process. Due to its very specific nature, apart from at a minimal level, it is probably unnecessary to develop a user requirement specification (URS). However, installation qualification (IQ), operational qualification (OQ) and performance qualification (PQ) are all required. As most of the equipment concerned is "driven" by computer software or hardware, the provisions of the GAMP guidelines published by ISPE should also be considered. This should certainly include:

• An audit of the software provider

• Access to the algorithms (or at least an agreement to how these might be accessed in the event of the company being dissolved for example)

• Life-cycle development; control of change, etc.

During the actual functionality checks it will be demonstrated that any security functions are operational; any additions, deletions or amendments to the data are recorded and ascribed to the individual performing the action, and the programme functions in a reliable and predictable manner as the menu is stepped through. Specific aspects relating to the equipment or method interface are now covered.

For the method itself, there has been growing support to treat microbiological methods where appropriate in the same manner as for chemical analysis. This approach was adopted to

• Meet the regulatory demands and

• Utilize an existing framework of tests by which the success or otherwise of the validation can be judged

Within this chapter, the definitions provided in the ICH/USP proposals have been used thus:

• Accuracy — the closeness of test results obtained to the true value of the article under test.

• Precision — the degree of agreement among individual test results when the analytical method is repeatedly applied to multiple samples. This may be measured either as reproducibility, i.e., when samples are analyzed at different times in different laboratories using different analysts or equipment or as repeatability, i.e., the analysis over a short time period of a test article by the same analyst using the same instrument (sometimes also called ruggedness).

• Linearity — the test method's ability to provide test results that are directly (or by an accepted mathematical transformation) proportional to the concentration of the analyte in a sample of a given range (normally 50 to 200% of the expected value). The range is the interval between the upper and lower limits.

• Limit of quantitation — the lowest level that can be determined with acceptable precision and accuracy.

• Specificity — the ability to measure accurately and specifically the analyte in the presence of other components that may be expected in the sample matrix.

• Robustness — the ability of an analytical procedure to remain unaffected by small but deliberate variations in the test methodology.

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