Method Specificity Selectivity

The issue regarding the desired level of test method specificity/selectivity is one that requires some case-by-case evaluation. In most instances, the key potential contaminant is considered to be the last active drug agent(s) that was in contact with the equipment surfaces. Typically, if it can be demonstrated that the active agent(s) has been removed to an acceptable residual level, and if the equipment is visibly cleaned, then the assumption is made that drug product excipients and other non-therapeutic agents have been adequately removed. For this reason, most test methods used to support cleaning validation are based on existing analytical assays for the active drug agent. Modifications are usually required to account for the lower levels of drug being assayed and for the different sample matrix involved.

It is important to consider that, in many cases, the test method does not have to be stability indicating. If the compound being assayed is stable in the sample matrix then it will not be necessary to demonstrate the ability to determine the compound in the presence of potential degradation products. Thus, it may be adequate to substitute a non-selective test, such as a UV absorption measurement, for a more time-consuming and resource-intensive method. Nevertheless, consideration should be given to other potential sources of interference. These may include other components of the product residue, i.e., product excipients, agents used in the cleaning process, and compounds that may be introduced by the sampling procedure or analytical sample workup. Interferences arising from the cleaning process include the components of any detergent as well as any acids, bases or organic solvents that may be used to clean the equipment. Likewise, one needs to consider potential interferences from the swabs that may be used in sampling and from any solvents used for extraction of the analyte.

The FDA considers the removal of detergent residues an important aspect of the overall cleaning process [2]. If detergents are used to clean the manufacturing equipment, it is expected that they will be completely removed by rinsing, and that the removal be validated by testing for absence of residues. Unlike the situation with product residues it is not always as straightforward in selecting which component of the detergent to target for residue analysis. The pharmaceutical manufacturer may not have access to the specific composition of the detergent, although suppliers are usually willing to provide information on the chemical class of active agent(s). Moreover, there is commonly more than one component that is responsible for the cleaning action of the detergent product. It then becomes a question of whether to develop a test for a specific target component or for the whole detergent product. If choosing a single component, one should focus on testing for the particular component that is the most difficult to rinse from the equipment surface. A systematic procedure for identifying the selective adsorber in formulated detergents was described recently by Smith [4], He used FTIR spectroscopy to identify the component of a formulated cleaning agent that was the last to rinse from stainless steel and borosilicate glass surfaces.

One analytical technique that provides an excellent means of conducting whole detergent product analysis is that referred to as Total Organic Carbon (TOC) analysis. Using this technique, organic compounds are oxidized to CO2 which is then quantitated, typically by non-dispersive infrared absorption or by conductivity. TOC analysis is non-specific and offers low detection limits, potentially down to low parts-per-billion levels. Furthermore, TOC analysis is theoretically capable of quantitating any carbon-containing compound. These attributes make TOC ideal for measuring low levels of residual detergent in water rinses and on swabs with low carbon background, thus precluding the need to investigate the complexity of the detergent formulation components. Because of its broad applicability to all organic carbon-containing compounds TOC analysis has been proposed as the method of choice in validating cleaning procedures for biopharmaceutical products produced by recombinant DNA technology [5]. Cleaning validation for this class of pharmaceutical products presents a unique challenge because of the wide range of potential contaminants, including proteins, carbohydrates, nucleic acids, as well as the cleaning detergents. However, FDA site inspectors generally give strong preference to product specific cleaning validation assays. This is particularly true in multiple product facilities, which are becoming more common for proteins as more recombinant products are gaining market approvals.

It is not always clear when it would be appropriate to use a non-specific analytical technique, such as TOC analysis, and when a specific assay for residual drug product contaminant should be used. FDA guidelines strongly imply that a direct measurement of the residue or contaminant should be made [2], However, there needs to be further discussion between industry and the regulatory agencies to define how specific this measurement must be in order to ensure an acceptable level of cleaning. The efficiency advantages of TOC analysis, combined with the logical justification of using TOC results as a worst case assessment of residual levels, should make this technique more widely accepted from both industrial and regulatory perspectives than it currently is.

This discussion has focused on analysis for potential chemical residues. However, the potential for microbial contamination should also be considered in establishing a cleaning process for manufacturing equipment. Generally, pharmaceutical firms have established microbial standards for both sterile and non-sterile facilities, and these are routinely monitored to ensure conformance.

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