Erratic Recovery-Test Results

Q: We’re attempting to validate a clean-in-place process using total organic carbon (TOC) as the analytical method. Our swab-sample recovery tests are giving us inconsistent results. Recovery values range from 95% to 205%, and there seems to be no correlation with the amount of drug product deposited on the coupon. What could be the problem?

A: TOC, unlike high-performance liquid chromatography (HPLC), is a nonspecific analytical method. The advantage in cleaning validation is that TOC can detect excipients, partial reactants, and detergents, in addition to the drug product. When coupled with visual inspection and other indirect tests, TOC can help minimize the overall contamination of the final product. However, because TOC is a nonspecific method, you need to account for and minimize potential sources of error to achieve consistent results. The erratic recovery in your studies is likely associated with one of these errors.

First, the measurement device should be capable of achieving the desired level of accuracy, sensitivity, specificity, and reproducibility per CFR 211.165. Guidance in US Pharmacopeia <1225> and the International Conference on Harmonization’s Q2 (R1) can help validate the analytical method. Use spike samples (i.e., pure water samples spiked with a known quantity of the target organic compound) to challenge the instrument accuracy before performing the swab-recovery tests. The swabs, vials, and coupons also can influence the consistency of results. Organic contaminants on these materials can contribute to the overall TOC result. Be sure to use swabs that have been certified for low TOC background. Swabs used in conjunction with HPLC methods often have high and variable organic content because it is not a crucial parameter for HPLC. Similarly, the vials selected for the testing should be certified for low TOC content. If you are cleaning the glassware yourself, use a mild caustic cleaning agent followed by thorough rinsing with low-TOC water. Finally, the coupons should be cleaned properly. They could be baked in a furnace to burn off residual organics or cleaned using a mild caustic detergent, then rinsed thoroughly with low-TOC water.

—Kevin Aumiller, senior applications specialist at GE Analytical Instruments

If you have a problem with your equipment or process, an industry expert may have the solution. Please send your question to Erik Greb, editor of Equipment and Processing Report, and we may be able to provide an answer in a future issue. All questions will remain anonymous.