Pyrogens parenteral preparations

Distilled water is often used in the formulahon of oral and topical pharmaceutical preparations and a low bacterial count is desirable. It is also used after distillation with a specially designed still, often made of glass, for the manufacture of parenteral preparations and a post-distillation heat sterilization stage is commonly included in the process. Water for such preparahons is often stored at 80°C in order to prevent bacterial growth and the production of pyrogenic substances which accompany such growth. 

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. 

Pyrogens may be detected in parenteral preparations (or other substances) by a number of methods. Two such methods are widely employed in the pharmaceutical industry. 

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. 

Injection, Emulsion An emulsion consisting of a sterile, pyrogen-free preparation intended to be administered parenterally. 

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). 

In Parenteral and Enteral Nutrition. Amino acid transfusion has been widely used since early times to maintain basic nitrogen metaboHsm when proteinaceous food caimot be eaten. It was very difficult to prepare a pyrogen-free transfusion from protein hydrolysates. Since the advances in L-amino acid production, the crystalline L-amino acids have been used and the problem of pyrogen in transfusion has been solved. The formulation of amino acid transfusion has been extensively investigated, and a solution or mixture in which the ratio between essential and nonessential amino acid is 1 1, has been widespread clinically. Special amino acid mixtures (eg, branched chain amino acids-enriched solution) have been developed for the treatment of several diseases (93). 

For parenteral use, the antibiotic is packed in sterile vials as a powder (reconstituted before use) or suspension. For oral use it is prepared in any of the standard presentations, such as film-coated tablets. Searching tests are carried out on an appreciable number of random samples of the finished product to ensure that it satisfies the stringent quahty control requirements for potency, purity, freedom horn pyrogens and sterility. 

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. 

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... 

If intended for use in large-volume preparations for parenteral use, compliance with a test for pyrogens may be required. 

Sterile aqueous solutions prepared with high purity ascorbic acid and pyrogen-free distilled water in glass-lined equipment under absolute sanitary operations and filled into ampules are necessary for injectable solutions for parenteral use in humans and animals. For all injectable products, it is important to select container, stopper, preservative, and other ingredients that are compatible. 

Nevertheless, pyrogenic reactions continued to be associated with parenteral therapy. Florence Siebert demonstrated in 1923 that the pyrogenic inducing bodies came from the water used to prepare the solutions, and care in using a pyrogen-free... 

Identity and purity, stability, and sterility and apyrogenicity. The identity and purity of radiopharmaceuticals is verified by determining the radionuclidic and radiochemical purity. Stability concerns the radioactive label, which is related to radiochemical purity at a certain time after preparation. Since Tc pharmaceuticals are formulated as sterile, pyrogen-free solutions, the safety requirements of drugs for parenteral use do apply. Safe handling of the radionuclide is equally important and must comply with Euratom Directives, regulated by national law for radiation protection, which also concerns the application of radionuclides in adults and in children for diagnostic procedures. 

As with sterile pharmaceuticals, pyrogens are of significant importance to medical devices. Any device intended for administration of a sterile parenteral pharmaceutical must (like the pharmaceutical preparation) be pyrogen free. So must all invasive and implantable devices. 

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 for Use in Preparing Parenteral Products (Pyrogen-free Water PFW)... 

Solutions intended for use as large or small volume parenterals, eye-drops, contact lens solutions, peritoneal dialysis solutions, and for irrigation (including non-intravenous water for irrigation use) should be prepared in a room complying with the conditions specified for Grade 2 in Appendix 1. The object should be to prepare a pyrogen-free solution with low microbial and particulate counts, suitable for later sterilization. 

Microbiological testing should be conducted on each lot of API required to be free of objectionable microorganisms. Appropriate testing should also be conducted on each lot of API required to be pyrogen free or with a specified endotoxin limit (e.g., APIs intended for use in the preparation of parenteral drug products). 

The European Pharmacopoeia requires the rabbit pyrogen test for a number of vaccines, some antibiotics, and specific excipients including glucose, if intended for the preparation of large volume parenterals (see Sect. 32.8). These products may be contaminated with pyrogens other than LPS, or are known to inhibit the LAL test. 

---