Injections pyrogens

Inflammation/abscess formation at the site of injection Pyrogenic effect (fever)... 

Water for injection, pyrogen-free Microbes and proteins are usually removed by filtration through filters of < 2 fxm. Used to reconstitute drugs prepared as lyophiles. Packed in sterile containers, expensive. 

Bacteriostatic water for injection is sterile and pyrogen-free and contains bacteriostatic agents. The dmg involved must be compatible with the antimicrobial agents present. 

Pyrogens the endotoxins responsible forfebrile reaction on injection, determined either by the rabbit test or the LAL test. Units are Endotoxin unit/ml (EU/ml). 

The ability to remove particulates has made RO indispensable in the production of ultra-pure water for microchip washing. Its ability to remove large molecules enables it to produce pyrogen-free water for the pharmaceuticals industry. In the USA and elsewhere RO is permitted for producing the water used in making up injectable preparations. The European Pharmacopoeia still insists on distillation for this, but the larger amounts of water needed for ampoule washing, etc. are often purified by RO. 

In the case of injectables and ophthalmic preparations which are manufactured aseptically but do not receive a sterilization treatment in their final container the packaging has to be sterilized. Dry heat at 170°C is often used for vials and ampoules. Containers and closures may also be sterilized by moist heat, chemicals and irradiation, but consideration for the destruction or removal of bacterial pyrogens may be necessary. 

Water for injection (WFI) is the most widely used solvent for parenteral preparations. The USP requirements for WFI and purified water have been recently updated to replace the traditional wet and colorimetric analytical methods with the more modern and cost-effective methods of conductivity and total organic carbon. Water for injection must be prepared and stored in a manner to ensure purity and freedom from pyrogens. The most common means of obtaining WFI is by the distillation of deionized water. This is the only method of preparation permitted by the European Pharmacopoeia (EP). In contrast, the USP and the Japanese Pharmacopeias also permit reverse osmosis to be used. The USP has also recently broadened its definition of source water to include not only the U.S. Environmental Protection Agency National Primary Drinking Water Standards, but also comparable regulations of the European Union or Japan. 

Sterility, freedom from pyrogens, and acceptably low level of extraneous particulate matter are critical quality attributes of all injectable products. Additional critical quality attributes depend on the clinical use of the product. For example, for IV, IM, and SC routes, isotonicity and physiological pH (7.4) are always desirable in order to minimize potential irritation upon injection. Other factors may preclude this, however. If the required dose of drug must be administered in a small volume, it may not be feasible to formulate an isotonic solution. Likewise, solubility or stability considerations may preclude formulation at physiological pH. This explains why formulation pH for injectable drugs varies from about pH 2 to about pH 11. 

Process controls include daily testing of water for injection (USP), conformation of fill doses and yields, checking and approving intermediate production tickets, and checking label identity and count. Finished product control includes all the tests necessary to ensure the potency, purity, and identity of the product. Parenteral products require additional tests, which include those for sterility, pyrogens, clarity, and particulate analysis, and for glass-sealed ampoules, leaker testing. 

One pyrogen test is a qualitative biological test based on the fever response of rabbits. If a pyrogenic substance is injected into the vein of a rabbit, a temperature elevation will occur within 3 hours. Many imitative medical agents will also cause a fever. 

The United States Pharmacopeia describes a pyrogen test using rabbits as a model (USP, 1995b). This test, which is the standard for limiting risks of a febrile reaction to an acceptable level, involves measuring the rise in body temperature in a group of three rabbits for 3 h after injection of 10 ml of test solution. 

Unless otherwise specified in the individual protocol, inject 10 ml of the test solution per kilogram of body weight into an ear vein of each of three rabbits, completing each injection within 10 min after the start of administration. The test solution is either the product, constituted if necessary as directed in the labeling, or the material under test. For pyrogen testing of devices or injection assemblies, use... 

The preparation of parenteral dosage forms of approved and potential drugs for animals is the same as for humans. Turco and King (1974) provide a comprehensive review of the subject, which, though written with human therapeutics in mind, contains very little that is not applicable to animals. Sterility, lack of pyrogenicity, blood compatibility, and low to no irritation at the point of injection are biological requirements there are also a corresponding set of physicochemical requirements. 

Sterile producfs for injection represent a particular challenge for the pharmaceutics development group. To prepare injectables, the pharmacists need not only sterile rooms in which to work at the laboratory, pilot plant, and production scales of operation, but they also require pyrogen-free wafer. Pyrogens are impurities, generally originating with... 

Manufacturing is performed in cleanroom conditions. Sterilization processes in the form of heat, steam, gas, or radiation are applied to ensure microorganisms are destroyed in the drug product. For protein-based drugs that can be damaged by the normal sterilization processes, the product is manufactured under aseptic conditions. Both sterility and pyrogen tests are performed to ensure parenteral drug products are safe to be injected. 

In 1 ml of aqueous extract of cotton dust, there may be as much as 30 ug of endotoxin-like material moreover, most dust extracts contain endotoxin. Cotton extracts are pyrogenic in rabbits, but daily injections produce tolerance, an effect similar to that of purified endotoxins. Further, rabbits made tolerant to injections of cotton extracts are also tolerant to I.V. injections of purified abortus equi endotoxin. Conversely, rabbits made tolerant to endotoxins are also tolerant to cotton extracts (62). 

USP XXIV specifies the limits and method of testing for chemical and pyrogenic contaminants for various compendial classifications of water, such as purified water and water for injection. 

The British Pharmacopia states, Water for injections is sterilized, distilled water, free from pyrogens. It is obtained by distilling potable water, purified water or distilled water. ... 

Water for injection used for other purposes (e.g., washing and rinsing product components and equipment) should be tested for pyrogens and aerobic viable count at least weekly. 

Using a sterile, nonpyrogenic disposable syringe and needle, inject 5.0 ml of pyrogen-free water to reconstitute the reagent. Reconstitution is more rapid if reagents are at room temperature. 

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. 

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