Pyrogens manufacture

Figure 5.6 shows that pyrogenic manufacturing gives excellent control over particle size distribution and median particle size. These grades of fumed silica differ in properties and require a different technological approaches to their dispersion since small particle size filler is more difficult to disperse. At the same time, smaller particle sizes give more transparent products and better reinforcement. 

Amorphous sihca exists also ia a variety of forms that are composed of small particles, possibly aggregated. Commonly encountered products iaclude sihca sols, sihca gels, precipitated sihca, and pyrogenic sihca (9,73). These products differ ia their modes of manufacture and the way ia which the primary particles aggregate (Fig. 8). Amorphous sihcas are characterhed by small ultimate particle si2e and high specific surface area. Their surfaces may be substantially anhydrous or may contain silanol, —SiOH, groups. These sihcas are frequentiy viewed as condensation polymers of sihcic acid, Si(OH)4. 

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. 

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. 

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. 

After weighing the dust filters, the amount of endotoxin was determined by shaking them In 10 ml of pyrogen free water and preparing serial dilutions. Llmulus lysate (Cape Cod Associates Inc.) was added to the dilutions according to the manufacturer s recommendations. The last dilution giving a stable clot was read as the Escherichia coll endotoxin equivalent concentration. Dilutions were also prepared with commercial E. coll endotoxin (. coll 026-B26, Dlfco) to assess the accuracy of the production reference standard. The values were always found to agree closely with the stated values. 

Finally, radiopharmaceuticals are often prepared on a daily basis within the framework of clinical studies which often last several months or years. They demand a viable and reproducible production chain, leading to a sterile- and pyrogen-free radiopharmaceutical of high radiochemical purity. Therefore, microprocessor-controlled automated synthesis devices [31] are developed in order to ensure routine pharmaceutical production. They are becoming mandatory in order to meet the demands related to Good Laboratory Practice (GLP) and Good Manufacturing Practice (GMP). 

Manufacturing or processing drug product would also include the preparation (e.g., sterilization, de-pyrogenation, irradiation, washing) by the applicant or applicant s contractor of container closure systems or packaging components. 

Several factors of design and manufacture are of great importance sterility, absence of pyrogens and foreign particulate matter, and tonicity. The last, when adjusted to the osmotic pressure of body fluids in the case of aqueous solutions, reduces the risk of tissue irritation and pain,... 

Sterile products have several unique dosage form properties, such as freedom from micro-organisms, freedom from pyrogens, freedom from particulates, and extremely high standards of purity and quality however, the ultimate goal in the manufacture of a sterile product is absolute absence of microbial contamination. The emphasis of this chapter will be the validation of the sterilization processes responsible for achieving this goal. 

For commercial processes, formed supports are more useful. Compared with other supports, fumed oxide supports showed new catalytic effects [41]. Some intensively investigated applications for these supports are abstracted in the following. SiC>2 pellets have been successfully introduced in a new generation of precious metal supports in vinylacetate monomer production [42]. This resulted in better selcctivities and an up to 50% higher space-time yield compared with supports based on natural alumo-silicates. In alkene hydration fumed silica pellets serve as a support for phosphoric acid. In this case, an increased catalyst lifetime and a higher space-time yield were observed [43]. Pyrogenic TiC>2 powder can be used as a starting material for the manufacture of monolithic catalysts [44] for the selective reduction of NOv with ammonia. 

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. 

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