Particulate Matter consists of randomly sourced extraneous substances coming from a manufacturing environment that cannot be quantitated by a chemical analysis because of their heterogeneous composition. Injectables Solutions should be essentially free from visually observed particulates. USP Chapters <788> and <789> describe a two stage test approach for enumerating particles within specific size ranges stated for parenteral and ophthalmic solutions. Method 1 – Light Obscuration is the preferred method unless the product is not appropriate due to viscosity or clarity then Method 2 – Microscopic Analysis is applied. For all other solutions they are first tested by Method 1, if a solution fais to meet prescribed limits it must then be tested by Method 2.
The results obtained from testing a group of test articles cannot be extrapolated to other test units with certainty therefore it is important to develop a sound sampling plan. The plan should be based on operational factors, product volume, historical particulate numbers, particulate size distribution and variability of counts between units.
Phase 1- Light Obscuration Method
For large-volume parenterals single units are tested, for small-volume parenterals, less than 25 mL, the contents of 10 or more are pooled for testing. The test solutions are analyzed using a HIAC liquid particle counting system. A minimum of three aliquots are withdrawn and particles ≥ 10µm and 25μm for injectables and ≥ 10µm, 25μm and are counted and sized. The counter calculates the average cumulative counts, average differential counts, average cumulative counts per ml and average differential counts per ml. The ophthalmic solution meets the requirements of the test if the average number of particles does not exceed 50 per mL for ≥ 10 µm size particles or 5 per mL for ≥ 25 µm. If the average number of particles counted exceed these limits the test solution must be tested by the Microscopic Method.
Phase 2- Microscopic Method
The total pooled solution volume or a single unit volume are vacuum filtered through a 1.0 µm or finer pore size membrane filter. After filtration, the membrane filters are placed into petri slide dishes and dried. Dried filters are analyzed under a microscope, using a calibrated graticule, at 100X magnification. Using oblique illumination at an angle of 10˚ – 20˚, the particulates on the surface of the membrane are sized and counted using the graticule micrometer. The ophthalmic solution meets the requirements of the test if the average number of particles does not exceed 50 per mL for ≥ 10 µm size particles, 5 per mL for ≥ 25 µm or 2 per mL for ≥ 50 µm size particles.
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