Parenterals particulate matter

Injections and infusion fluids must be manufactured in a manner that will minimize or eliminate extraneous particulate matter. Parenteral solutions are generally filtered through 0.22 pm membrane filters to achieve sterility and remove particulate matter. Prefiltration through a coarser filter is often necessary to maintain adequate flow rates, or to prevent clogging of the filters during large-scale manufacturing. A talc or carbon filtration aid (or other filter aids) may also be necessary. If talc is used, it should be pretreated with a dilute acid solution to remove surface alkali and metals. 

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. 

Small-volume parenterals Appearance, color, particulate matter, dispersibility (suspensions), pH, sterility, pyrogenicity, and closure integrity... 

Inspect parenteral drug products visually for particulate matter and discoloration... 

Area clearance procedure for parenterals QA inspector responsibilities in injectable area Particulate matter in injectables, DSP criteria Visual inspection of lyophilized products parenterals... 

The purpose is to provide the USP criteria for the monitoring of liquid-borne particulate matter in injections (large- and small-volume parenterals). 

Small-Volume Parenterals Color, clarity of solutions, particulate matter, pH, sterility, endotoxins. Powders for injection solutions include clarity, color, reconstitution time and water content, pH, sterility, endotoxins/pyrogens, and particulate matter. Suspensions for injection should include additional particle size distribution, redispersability, and rheological properties. Emulsion for injection should include phase separation, viscosity, mean size, and distribution of dispersed globules. 

Large-Volume Parenterals Color, clarity, particulate matter, pH, sterility, endo-toxin/pyrogen, and volume. 

Finally, additional quality test being applied to many but not all pharmacopoeial parenteral solutions are the instrumental tests for particulate matter. Although almost impossible to remove in its entirety, particulate matter, however it is defined, are another direct measure of quality, the lower the number per unit volume the higher the quality. Fortunately instruments are now available that will accurately count the numbers of suspended particles in a solution down to 2.0 pm diameter. The interested... 

Akers, M. J. In Parenteral Quality Control Sterility, Pyrogen, Particulate Matter and Package Integrity Testing, 2d edition. New York Marcel Dekker, pp. 1-4 (1994). 

Parenteral products can be divided into two general classes according to the volume of the product. All parenteral products are sterilized and must meet all the requirements for sterility and particulate matter and must be pyrogen-free. They must be prepared using strict sanitation standards in environmentally controlled areas by individuals trained to meet these standards. The injections are overfilled with a small excess over the labeled volume to ensure that the... 

Particulate matter is viewed as unacceptable contamination in parenteral solutions. It is recognized that subvisible particulate matter will exist in certain amounts, but the USP now has limits for acceptable levels of particulate matter for SVIs (no more than 6000 particles per container >0.5 pm no more than 600 particles per container >25 pm). The USP is the only compendium in the world that contains limits for subvisible particulates in SVIs. All worldwide compendia have subvisible particle limits (particles per milliliter) for large-volume injections. SVI solutions with visible particulate matter should not used. Particulate matter creates problems in product quality and clinical safety. The primary sources of particulate matter are the container-closure systems and personnel. 

Mirtallo has added to the FDA guidelines, stressing the need to ensure that an appropriate dose of calcium is prescribed, to follow appropriate procedures when mixing parenteral nutrition solutions and to use automatic mixing devices strictly in accordance with the manufacturer s instructions (150). He has stressed the fact that more information is needed to substantiate the usefulness of filters in preventing adverse effects caused by the infusion of particulate matter present in parenteral nutrition admixtures. 

All parenterally injected solutions should be checked for particulate contamination but the above procedure is clearly impractical as a bulk screening exercise. Those products contaminated with particulate matter should be rejected. In practice, all products may be tested individually by humans against split white/black screens and/or under polarized light for obvious particulate contamination and again there is a method described in pharmacopoeias based on the split screen technique. Nowadays optical control equipment can take over this arduous and boring employment. 

Homogeneous solutions are the preferred formulation systems for parenteral administration because they can be easily visually inspected for the absence of particulate matter. For this reason, cosolvent solubilization is the first choice for parenteral products once purely aqueous systems provide insufficient solvency. The compositions of three commercial, injectable products are given in Table 39.5. The first product (1) has a low percentage of cosolvent in the separate solvent ampoule. The drug substance is provided as a dry powder because of its limited stability in solution. The second one (2) is solubiUzed with two cosolvents amounting to 50% of the total volume, whereas in the third product the drug dose is dissolved in a water-free mixture of cosolvents. This draws the attention to a further point to consider when cosolvents are employed in formulations. The formulation has to be devised such that the effect of dilution of... 

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

Therefore, admixture studies are performed on parenteral drugs with commonly used intravenous diluents. Studies are performed by preparing admixtures of the drug product with various diluents in an appropriate type of flexible intravenous bag. Initial samples are taken for analysis before the bags are stored in temperature-controlled stability chambers. Subsequent samples may be pulled at 6-, 12-, 24-, 48-, and 72-h time points. The analytical tests commonly performed include visual appearance, pH, and HPLC assay. Degradation products are not commonly tested unless the method has been previously evaluated for specificity and stability-indicating ability with a particular intravenous diluent. This is necessary because there may be differences in the stability profile of the product in its original formulation compared to the admixture solution. Formation of any particulate matter is detected by visual... 

Louer, R. C., Russoman, J. A., and Rasanen, P. R. Detection of particulate matter in parenteral solutions by image projection A concept and its feasibility. Bull. Parenter. Drug Assoc. 25 54, 1971. 

There is substantial evidence (much from the literature on drug abuse) indicating that particulate matter (undissolved substances) is a health hazard in parenteral products [21], The precise hazards depend very much on the physical and biological properties of the particles, and their site of lodgement in the vascular system. Phlebitis and pulmonary infarctions are the most significani problems associated with particulate matter. Particulate matter is an unwanted and unnecessary addition to parenteral therapy. 

Particulate matter in parenterals and IV solutions is described as undissolved particles, other than gas bubbles, unintentionally present in the solutions. Such particles can have unwanted effects if present at elevated levels. The purpose of the test for particulate matter is to ensure that these particles are below established safety limits. USP General Chapter <788> provides the directive for determining particulate count and size. This test is often conducted at release as well as monitored on stability. 

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