In respect of testing particulate matter, Dr Mike Groves (University of Illinois, United States) examined definitions of "insoluble "and "particulate”. The US Pharmacopeia (USP) referred to "mobile, randomly sourced extraneous matter not quantified by chemical analysis and of homogeneous composition”. If the particulate matter was not randomly sourced, and was present in significant amounts, then the product was treated as "contaminated”. He stressed that some random particulate matter was always present — but it could be minimised, as a direct measure of product quality — although it was not necessarily harmful. In practice, the distribution of particle sizes might not be Gaussian, but a family of curves approximated to a log-Gaussian distribution. As filter pore size was reduced, the log curve moved to a smaller log size.
He referred to chapter 788 of the USP for two methods, replete with enormous experimental detail, to measure particulate matter in parenteral solutions. A consensus of numerical levels of particulate matter was achievable in quality control but there was no scientific or clinical rationale. Particles found varied enormously in size and shape, many being aggregates of smaller ones, and thus a pharmacopoeia had to measure the range of large and small particles. If using a filter method, particles could be retained for optional identification.
Dr Groves distinguished between "intrinsic "and "extrinsic "particulate matter: the former might be left after cleaning, or might not have been removed before filling vials, whereas the latter arose from the filling environment or during subsequent administration and use. Typical particulate matter found in injections included clays, pigments, oil, glass, iron oxide, asbestos, barium salts, organic compounds (such as starch, silicones, phthalates, cellulose and rubber), and skin cells and micro-organisms.
Of the three distinct procedures for measuring particles, he regarded the Coulter counting system (which measured a variable voltage across the flow system) as semi-obsolete, but he accepted that it was sensitive to contaminants. The two current USP procedures were the Hyac (light obscuration on passing two light sources) or, more classically, filtration and examination by light microscopy. Both methods related to a purely arbitrary limit of 2 or 3 particles per ml greater than 25 µm for small volume parenteral products. He thought it not too cynical to recognise that many random extraneous particles might be administered to the patient without harm — but one still looked to the redesign of administration equipment to reduce this end-use risk. He referred to the increasing size of protein and similar biomolecules: might these, in time, become classed as particulates? The USP had proposed (in USP Forum, March, 2000) to test prefilled hypodermic syringes containing parenteral products for particulate matter as an indicator of quality. Dr Groves looked to realistic, production-achievable, numerical limits for particulate matter — as a distinct issue from possible embolism or other clinical hazard. The total particulate matter mass, and the small size, were — or should be — minimal. It was "simply a matter of good housekeeping "— a general quality issue, he concluded.