789 PARTICULATE MATTER IN OPHTHALMIC SOLUTIONS
Particulate matter consists of mobile, randomly sourced, extraneous substances, other than gas bubbles, that cannot be quantitated by chemical analysis because of the small amount of material they represent and because of their heterogeneous composition. Ophthalmic solutions should be essentially free from particles that can be observed on visual inspection. The tests described herein are physical tests performed for the purpose of enumerating extraneous particles within specific size ranges.
Every ophthalmic solution for which the monograph includes a test for Particulate matter is subject to the particulate matter limits set forth for the test being applied, unless otherwise specified in the individual monograph. When higher limits are appropriate, they will be specified in the individual monograph. Ophthalmic preparations that are suspensions, emulsions, or gels are exempt from these requirements, as are medical devices. Refer to the specific monograph when a question of test applicability occurs.
Light obscuration and microscopic procedures for the determination of particulate matter in ophthalmic solutions are identical to those for injections; therefore, where appropriate, Particulate Matter in Injections 788
is cross-referenced. This chapter provides a test approach in two stages. The ophthalmic solution is first tested by the light obscuration procedure (stage 1). If it fails to meet the prescribed limits, it must pass the microscopic procedure (stage 2) with its own set of test limits. Where for technical reasons the ophthalmic solution cannot be tested by light obscuration, microscopic testing may be used exclusively. Documentation is required, demonstrating that the light obscuration procedure is incapable of testing the ophthalmic solution or that it produces invalid results.
It is expected that most articles will meet the requirements on the basis of the light obscuration test alone; however, it may be necessary to test some articles by the light obscuration test followed by the microscopic test to reach a conclusion on conformance to requirements. Any product that is not a pure solution having a clarity and a viscosity approximating those of water may provide erroneous data when analyzed by the light obscuration counting method. Such materials may be analyzed by the microscopic counting method. In some instances, the viscosity of a material to be tested may be sufficiently high so as to preclude its analysis by either test method. In this event, a quantitative dilution with an appropriate diluent may be made to decrease viscosity, as necessary, to allow the analysis to be performed.
In the tests described below, the results obtained by examining a discrete unit or group of units for particulate matter cannot be extrapolated with certainty to other units that remain untested. Thus, sampling plans based on known operational factors must be developed if valid inferences are to be drawn from observed data to characterize the level of particulate matter in a large group of units. Sampling plans need to be based on consideration of product volume, particle numbers historically found to be present in comparison to limits, particle size distribution of particles present, and variability of particle counts between units.
LIGHT OBSCURATION PARTICLE COUNT TEST
This test applies to ophthalmic solutions, including solutions constituted from sterile solids, for which a test for Particulate matter is specified in the individual monograph. The test counts suspended particles that are solid or liquid.
Test Apparatus, Instrument Standardization, Test Environment, Test Procedure, and Calculations
Proceed as directed for Light Obscuration Particle Count Test
under Particulate Matter in Injections 788
The ophthalmic solution meets the requirements of the test if the average number of particles present in the units tested does not exceed the appropriate value listed in Table 1
. If the average number of particles exceeds the limit, test the article by the Microscopic Particle Count Test.
Table 1. Light Obscuration Test Particle Count
|| 10 µm
|| 25 µm
|Number of particles
||50 per mL
||5 per mL
MICROSCOPIC PARTICLE COUNT TEST
Some articles cannot be tested meaningfully by light obscuration. In such cases, individual monographs clearly specify that only a microscopic particle count is to be performed. The microscopic particle count test enumerates subvisible, essentially solid, particulate matter in ophthalmic solutions, after collection on a microporous membrane filter. Some ophthalmic solutions, such as solutions that do not filter readily because of their high viscosity, may be exempted from analysis using the microscopic test.
When performing the microscopic test, do not attempt to size or enumerate amorphous, semiliquid, or otherwise morphologically indistinct materials that have the appearance of a stain or discoloration on the membrane surface. These materials show little or no surface relief and present a gelatinous or film-like appearance. Because in solution this material consists of units on the order of 1 µm or less, which may be counted only after aggregation or deformation on an analytical membrane, interpretation of enumeration may be aided by testing a sample of the solution by the light obscuration particle count method.
The ophthalmic solution meets the requirements of the test if the average number of particles present in the units tested does not exceed the appropriate value listed in Table 2.
Table 2. Microscopic Method Particle Count
|| 10 µm
|| 25 µm
|| 50 µm
|50 per mL
||5 per mL
||2 per mL
: James W. Kelly, Ph.D., Scientist
Expert Committee : (PPI05) Parenteral Products-Industrial 05
USP29NF24 Page 2729
: Volume No. 28(5) Page 1496
Phone Number : 1-301-816-8167