Particulate Matter Testing

The USP specifies that injectable products be 100% inspected to ensure that the product is free from visible foreign particulate matter ( 788 ). This is crucial because particulate matter in injectable drug products is considered a clinical hazard. Particulate matter has been implicated in the formation of granulomas in various internal organs in rats, as well as embolisms and phlebitis in humans.4 Pulmonary capillaries (the smallest capillary vessels in the human body) are about 7 (tm in size. This is why determination of particles about 7 Lm and larger is deemed important. 

Acceptable quality level (AQL) inspection acceptance criteria are applied to the inspections. Visible foreign particulate matter is considered a critical defect. Thus, AQL levels (the greatest percentage of defective units still acceptable for release) are 0.25-1.0% of the lot size. Consult the American National Standards Institute/American Society for Quality Z1.4 guideline for more detailed information on AQL sampling. The drawbacks of manual inspection are that it is prone to human error and is subjective. 

In a comparison study of automatic versus manual inspection, Louer et al. reported a much better rejection rate for known bad ampules (93% vs 54%). However, they also showed that the rate of rejection of good ampules by the automatic inspection machine increased significantly. Generally, the automatic visual inspection machines do not detect particles much smaller than the human threshold, but they will help to increase the rate of rejection of truly bad units while eliminating human error. 

Because particles having average diameters as small as 7 pm are considered problematic and the normal human eye can discern only down to 40 pm, what is done about the subvisual particles in between  

The USP includes different tests for the detection, sizing, and enumeration of subvisual particles, e.g., 10 and 25 pm. There are two test approaches for particulate matter recognized by the USP. They are automated liquid particle counting either by the light obscuration method or the light (laser) scattering method used mainly for SVPs, and the microscopic method used predominantly for LVPs. 

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C. Interpretation of Results—Particulate Matter Testing XVIII. BIOBURDEN TESTING OF PARENTERAL PRODUCT... 

Results of particulate matter tests are interpreted as following ... 

Particulate matter testing. Particulate matter testing will normally include limits for visible particulates and/or clarity of solution, as well as for subvisible particles. 

Bacterial Endotoxias Test (85)," "Biological Reactivity Tests, in vivo (88)," "Particulate Matter ia Injections (788)," and "Purified Water," JJSP 23 The U.S. Pharmacopeia Convention, RockviUe, Md., 1994. 

U. S. EPA Regulations on Standards ofPeformanceforNeir Stationay Sources, 40 CER 60, Appendix A, Reference Methods, Washington, D.C., 1993. ASTM D3685-92, Standard Test Methodfor Sampling and Determination of Particulate Matter in Stack Gases, American Society for Testing Materials, Philadelphia, Pa., 1992. 

The instrumental analyzer procedure, EPA Method 3A, is commonly used for the determination of oxygen and carbon dioxide concentrations in emissions from stationary sources. An integrated continuous gas sample is extracted from the test location and a portion of the sample is conveyed to one or more instrumental analyzers for determination of O9 and CO9 gas concentrations (see Fig. 25-30). The sample gas is conditioned prior to introduction to the gas analyzer by removing particulate matter and moisture. Sampling is conducted at a constant rate for the entire test run. Performance specifications and test procedures are provided in the method to ensure reliable data. 

Wood-fired power boilers are generally found at the mills where wood products are manufactured. They are fired with waste materials from the process, such as "hogged wood," sander dust, sawdust, bark, or process trim. Little information is available on gaseous emissions from wood-fired boilers, but extensive tests of particulate matter emissions are reported (19). These emissions range from 0.057 to 1.626 gm per dry standard cubic meter, with an average of 0.343 reported for 135 tests. Collection devices for particulate matter from wood-fired boilers are shown in Table 30-21. 

Americium released to the atmosphere will be associated with particulate matter and will be deposited on land or surface water by dry deposition or wet deposition (Essien et al. 1985). Dry deposition results from gravitational settling and impaction on surfaces, and wet deposition returns americium to earth in precipitation. Radionuclides resulting from atmospheric weapons tests are often injected into the lower stratosphere, while other atmospheric releases are into the troposphere. The residence time of particles in the atmosphere will depend on the altitude, latitude, season, and hemisphere because of atmospheric... 

Particulate matter is defined in the USP as extraneous, mobile, undissolved substances, other than gas bubbles, unintentionally present in parenteral solutions. Test methods and limits for particulates are stated in the USP for large-volume injections and small-volume injections. 

The application should state the rationale for the design of the in-use stability tests performed. The procedures used should be fully validated. One key factor is that the test should simulate the use of the product as far as practicable. This should include any reconstitution or dilution prior to use. Aliquots should be removed in an appropriate manner following, as far as possible, the usage pattern that will be encountered in practice. Physical (color, clarity, closure integrity, particulate matter, and particulates/particle size), chemical (assays for active ingredient, antioxidants and... 

Emissions from hazardous waste combustors are regulated under two statutory authorities RCRA and the CAA. The MACT standards set emission limitations for dioxins, furans, metals, particulate matter, total chlorine, hydrocarbons/carbon monoxide, and destruction and removal efficiency (DRE) for organics. Once a facility has demonstrated compliance with the MACT standards by conducting its comprehensive performance test (CPT) and submitting its notification of compliance (NOC), it is no longer subject to the RCRA emission requirements with a few exceptions. RCRA-permitted facilities, however, must continue to comply with their permitted emissions requirements until they obtain modifications to remove any duplicative emissions conditions from their RCRA... 

Particulate matter. When tested according to the general procedure <788>, meets the requirements under small volume injection. 

During occupational exposure, respiratory absorption of soluble and insoluble nickel compounds is the major route of entry, with gastrointestinal absorption secondary (WHO 1991). Inhalation exposure studies of nickel in humans and test animals show that nickel localizes in the lungs, with much lower levels in liver and kidneys (USPHS 1993). About half the inhaled nickel is deposited on bronchial mucosa and swept upward in mucous to be swallowed about 25% of the inhaled nickel is deposited in the pulmonary parenchyma (NAS 1975). The relative amount of inhaled nickel absorbed from the pulmonary tract is dependent on the chemical and physical properties of the nickel compound (USEPA 1986). Pulmonary absorption into the blood is greatest for nickel carbonyl vapor about half the inhaled amount is absorbed (USEPA 1980). Nickel in particulate matter is absorbed from the pulmonary tract to a lesser degree than nickel carbonyl however, smaller particles are absorbed more readily than larger ones (USEPA 1980). Large nickel particles (>2 pm in diameter) are deposited in the upper respiratory tract smaller particles tend to enter the lower respiratory tract. In humans, 35% of the inhaled nickel is absorbed into the blood from the respiratory tract the remainder is either swallowed or expectorated. Soluble nickel compounds... 

Freshwater and marine alga were unaffected at water diazinon concentrations that were fatal (i.e., 1000 pg/L) to aquatic invertebrates (Stadnyk and Campbell 1971 Shacklock and Croft 1981). However, diazinon at 1.0 pg/L induced extensive clumping of a freshwater alga (Chlorella pyrenoi-dosa) onto the antennae of Daphnia magna within 24 h (Stratton and Corke 1981). The affected daphnids were immobilized and settled to the bottom of the test containers. The causes of particulate matter adhesion are open to speculation, and additional research is merited. 

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