Particulate Analysis

USP <788> Particulate Matter in Injections and USP <789> Particulate Matter in Ophthalmic Solutions  

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.  Injectable 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 fails to meet prescribed limits it may 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.

Study Outline

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  A minimum of three aliquots are withdrawn and particles ≥ 10µm and 25μm for injectables and ≥ 10µm, 25μm and 50µm for ophthalmic solutions are counted and sized.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 acceptance criteria are as stated in Table 1 through 3.

Table 1: Parenteral Infusion or Injectable Solutions with a nominal content of >100 mL

DiameterDiameter
≥ 10µm ≥ 25µm
Number of Particles 25/mL3/mL

Table 2: Parenteral Infusion or Injectable Solutions with a nominal content of <100 mL

DiameterDiameter
≥ 10µm ≥ 25µm
Number of Particles 6,000/mL600/mL

Table 3: Ophthalmic Solutions

DiameterDiameterDiameter
≥ 10µm ≥ 25µm≥ 50µm
Number of Particles 50/mL5/mL2/mL

If the average number of particles counted exceed these limits the test solution may 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 solution meets the requirements of the test if the average number of particles does not exceed the value listed in Tables 4 thru 6.

Table 4: Parenteral Infusion or Injectable Solutions with a nominal content of >100 mL

DiameterDiameter
≥ 10µm ≥ 25µm
Number of Particles 12/mL2/mL

Table 5: Parenteral Infusion or Injectable Solutions with a nominal content of <100 mL

DiameterDiameter
≥ 10µm ≥ 25µm
Number of Particles 3,000/mL300/mL

Table 6: Ophthalmic Solutions

DiameterDiameterDiameter
≥ 10µm ≥ 25µm≥ 50µm
Number of Particles 50/mL5/mL2/mL

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