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My drug failed a light-obscuration test, but after I filtered the drug for microscopic particle counting, I couldn?t see any significant particulate on the filter. What might have caused the failure, and why is it not visible?
Q: My drug failed a light-obscuration test, but after I filtered the drug for microscopic particle counting, I couldn’t see any significant particulate on the filter. What might have caused the failure, and why is it not visible?
A: One possibility is that what caused the failure was not solid particulate. A light-obscuration test can respond to droplets of suspended liquid (e.g., silicone oil in an aqueous product or water in an oil-based product), or even to air bubbles, as if they were solid, discrete particles. Air bubbles, of course, vanish completely upon filtration, water evaporates, and residual oil typically is not visible on the standard mixed-cellulose ester (MCE) filters used for USP <788> microscopic particle counts. Even on a membrane filter made of a smooth material such as polycarbonate, oil residue from a filtered product may not be visible.
The other possibility is that solid particulate was present in the liquid, but that its morphology prevents it from being seen easily on the filter. Very fine precipitates, as opposed to randomly sourced environmental particles, may be difficult, if not impossible, to see on an MCE filter because of its surface texture. Even on a smooth membrane filter, very fine particulate may form a layer that is too thin to be seen readily with ordinary oblique top lighting, even at a low angle. The same difficulties can occur with the stringy or amorphous precipitates that form in proteinaceous drug products, or with thin flakes of glass delamination. Using a smooth-surfaced membrane filter and a microscope equipped with episcopic or coaxial illumination (i.e., light directed down through the objective at a 90° angle to the filter surface) will allow particulates of these types, not apparent under other conditions, to be adequately visualized.
—Scott Stoeffler, senior research microscopist at McCrone Associates
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.