Endotoxins parenteral preparations

Its major disadvantage is its selectivity it only detects endotoxin-based pyrogens. In practice, however, endotoxin represents the pyrogen that is by far the most likely to be present in pharmaceutical products. The LAL method is used extensively within the industry. It is used not only to detect endotoxin in finished parenteral preparations, but also in WFI and in biological fluids, such as serum or cerebrospinal fluid. 

According to the Ph. Eur. parenteral preparations should be sterile, free from visible and non-visible particles and free from endotoxins/pyrogens (see Sect. 12.8). 

Radiopharmaceuticals for parenteral use must comply with the Ph. Eur. mmiograph for parenteral preparations, so they have to be sterile and with a very low or absent endotoxin COTicentration. For parenteral administration a sterile injectirm in a disposable injection syringe is often filled from a multiple dose solution in a glass vial. 

For enzymes intended for parenteral use, the manufacturer must assure that the enzyme preparation is essentially pure and free of endotoxins. Electrophoretic and immunologic tests provide the requisite evidence of purity and homogeneity. Most importandy, the manufacturer must remove toxic impurities, eg, bacterial hpopolysacchati.de (endotoxins) which might cause severe toxic reactions such as anaphylactic shock, fever, and vascular coUapse. 

Fur enzymes intended lor parenteral use. the manufacturer must assure that the enzyme preparation is essentially pure and free of endotoxins. All... 

Most purified and WFI systems, including RO and UF systems, have the potential for the development of endotoxins. If the final excipient is purported to be pyrogen free or sterile, or will be used in preparing parenteral products, validation of the system to control endotoxins should be conducted and routine testing of the process water for endotoxins should be performed (preferably by the LAL method). 

Water used in the preparation of parenteral drugs is tested for endotoxins. 

Water used in the final isolation and purification steps of nonsterile APIs intended for use in the preparation of parenteral products should be tested and controlled for bioburden and endotoxins. 

The water used for preparing parenteral solutions needs to meet USP requirements for water for injection. These requirements include bacterial endotoxins no greater than 0.25 eu/mL, total organic content less than 500 ppb, and a conductivity of 1.3 iS/cm. Water for injection is prepared by distillation or a two-stage RO process. A typical process to produce water for injection consists of multimedia filtration, softener, activated carbon, 1-5 qm preflltration, UV treatment, two-stage RO, mixed DI, UV, and sterile filtration. 

An example of calculating the limits for endotoxins A morphine containing injection solution with the strength of 100 mg/5 mL has been prepared. Because the product will be administered parenterally a bacterial endotoxins test has to be performed. Therefore the administration route has to be known is this intravenous or intrathecal or epidural. For endotoxins in intravenous administration the requirement is maximally 5 EU/kg body weight during 1 h. Based on a body weight of 70 kg this means 350 EU/h. Secondly the maximal dose (in volume of the product per hour) will determine the actual limit. This depends on the need of the patient as well. If he needs the full 5 mL, this makes the requirement for the product to be 350 EU/5 mL = 70 EU/mL. 

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