Pyrogens parenteral products

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. 

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... 

In general, all parenteral products must be manufactured under strict, current good manufacturing processes (cGMP) to ensure the final product is sterile and pyrogen-free. Sterilization is defined as the complete destruction of all living organisms or their spores or the complete removal from the product. 

All manufactured products are vulnerable to contamination by a myriad of aerosolized contaminants, including microorganisms, pyrogenic dust, ash, pollen, smoke, hydrocarbons, and other chemicals that are omnipresent in the environment (Pig. 1). Because of the potential dangers to the patient resulting from a parenteral product containing even minute quantities of these contaminants, exceptional measures are required to exclude them fromthe finished product. 

Parenteral products are expected to be sterile because of the risk of infection. Another critical biological characteristic is that they should be free from pyrogens. Pyrogens are substances that, when injected in sufficient amounts into the human body, give rise to a variety of extremely unpleasant symptoms of which the most recognizable is a rise in body temperature. In extreme conditions, the rise in body temperature can be so rapid and to such an extent that the patient dies (endotoxic shock). In the pharmacopeias, pyrogenic products have traditionally been defined in terms of the temperature rise induced in injected rabbits. 

Excipients derived from bacterial transformation or enzymatic processes, such as sugars (e.g., mannitol or dextrose), pose special concerns due to potential contamination by endotoxins. Endotoxins, or pyrogens, are lipopolysaccharides from gram-negative bacteria that can induce severe fever upon parenteral administration. Parenteral products have different limits for allowable endotoxin levels.57... 

As described earlier, there are stringent regulations for the parenteral products and only few excipients are acceptable for parenteral delivery. The excipient selected for the parenteral delivery should be biocompatible, sterilisable, non-pyrogenic, non-irritant to nerves and non-haemolytic. Very few excipients fit into all these requirements. For example, the sugar surfactants are biocompatible and have fairly good solubilisation potential but they have been found to be haemolytic [111]. The excipients that are acceptable for parenteral delivery are as follows ... 

The pharmacopoeias deal with ingredient water of two types. Purified Water and Water for Injection. The principal difference in biological quality between the two types of water is that Water for Injection is specified to be pyrogen-free (less than 0.25 Eu of bacterial endotoxin per mL). Only water of Water for Injection quality may be used to dissolve, dilute, or compound parenteral products, because endotoxins may pass through 0.22 pm sterilizing filters. Control of bacterial endotoxins is achieved in the first instance through control of microbiological contamination. 

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)... 

Unless the nature of the product makes pyrogen testing impossible, pyrogen testing should be carried out on all batches of parenteral products and solutions for irrigation of body cavities, wounds, operation cavities or the urogenital system where ... 

Single- and multiple-dose vials and ampules are used in medical practice. The vehicle (solvent), which is of greatest importance for parenteral products, is specially distilled, pyrogen-frcc water. The container of choice is glass. 

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. 

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. 

Historically, the rabbit pyrogen test constituted the most widely used method. This entails parenteral administration of the product to a group of healthy rabbits, with subsequent monitoring of rabbit temperature using rectal probes. Increased rabbit temperature above a certain point suggests the presence of pyrogenic substances. The basic rabbit method, as outlined in the European Pharmacopoeia, entails initial administration of the product to three rabbits. The product is considered to have passed the test if the total (summed) increase of the temperature of all three animals is less than 1.15 °C. If the total increase recorded is greater than 2.65 °C then the product has failed. However, if the response observed falls between these two limits... 

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. 

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. 

All radiopharmaceuticals for human administration are required to be pyrogen free. Also the tests for apyrogenicity must be modified when applied for these products. The classical rabbit test for pyrogens was never a convenient test for parenteral radiopharmaceuticals. Practical problems due to radioactive rabbits and the need for larger test volumes made this a difficult task. Today, the Limulus amebocyte test (LAL) is the method of choice and has been accepted by the Ph. monographs for many years. This test is normally done within an hour, compared to several days for the rabbit test. 

---