Pharmaceutical industry activity

Pharmacovigilance has resulted in two practical levels of regulatory and pharmaceutical industry activity and communication. One level is simply to... 

I have chosen to exclude fermentation and other biological processes from this hook although products from those processes continue to he an increasingly important source of pharmaceutical actives in todays world. This decision was made because the chemical routes remain the largest source of actives to the pharmaceutical industry. Actives supplied by biological processes are no less important than chemically generated actives but are sufficiently different to be worthy of their own volume. 

In order to parameterize a QSAR equation, a quantihed activity for a set of compounds must be known. These are called lead compounds, at least in the pharmaceutical industry. Typically, test results are available for only a small number of compounds. Because of this, it can be difficult to choose a number of descriptors that will give useful results without htting to anomalies in the test set. Three to hve lead compounds per descriptor in the QSAR equation are normally considered an adequate number. If two descriptors are nearly col-linear with one another, then one should be omitted even though it may have a large correlation coefficient. 

Memfield s concept of a solid phase method for peptide synthesis and his devel opment of methods for carrying it out set the stage for an entirely new way to do chem ical reactions Solid phase synthesis has been extended to include numerous other classes of compounds and has helped spawn a whole new field called combinatorial chemistry Combinatorial synthesis allows a chemist using solid phase techniques to prepare hun dreds of related compounds (called libraries) at a time It is one of the most active areas of organic synthesis especially m the pharmaceutical industry... 

Full details of this work were pubHshed (6) and the processes, or variants of them, were introduced in a number of other countries. In the United States, the pharmaceutical industry continued to provide manufacturing sites, treating plasma fractionation as a normal commercial activity. In many other countries processing was undertaken by the Red Cross or blood transfusion services that emerged following Wodd War II. In these organisations plasma fractionation was part of a larger operation to provide whole blood, blood components, and speciaUst medical services on a national basis. These different approaches resulted in the development of two distinct sectors in the plasma fractionation industry ie, a commercial or for-profit sector based on paid donors and a noncommercial or not-for-profit sector based on unpaid donors. 

The number of microencapsulated commercial oral formulations available and the volume of these formulations sold annuaUy is comparatively smaU. This may reflect the difficulty of developing new dmg formulations and bringing them successfully to market or the fact that existing microencapsulation techniques have had difficulty economically producing mictocapsules that meet the strict performance requirements of the pharmaceutical industry. One appHcation that is a particularly active area of development is mictocapsules or microspheres for oral deUvery of vaccines (45,46). 

Although the techniques described have resulted in the determination of many protein stmctures, the number is only a small fraction of the available protein sequences. Theoretical methods aimed at predicting the 3-D stmcture of a protein from its sequence therefore form a very active area of research. This is important both to understanding proteins and to the practical appHcations in biotechnology and the pharmaceutical industries. 

The recognition of differences in the pharmacological activity of enantiomeric molecules has created the need to administer them - and therefore to obtain them -as isolated enantiomers. However, nowadays this problem affects not only the pharmaceutical industry, but also the agrochemical industry and food additive producers, both of which are increasingly concerned by this subject. 

These and other FDA policy decisions launched the pharmaceutical industry and academia into a new era of developing stereoselective processes for the manufacture of enantiopure active pharmaceutical ingredients (APIs). 

The separation of enantiomers is a very important topic to the pharmaceutical industry. It is well recognized that the biological activities and bioavailabilities of enantiomers often differ [1]. To further complicate matters, the pharmacokinetic profile of the racemate is often not just the sum of the profiles of the individual enantiomers. In many cases, one enantiomer has the desired pharmacological activity, whereas the other enantiomer may be responsible for undesirable side-effects. What often gets lost however is the fact that, in some cases, one enantiomer may be inert and, in many cases, both enantiomers may have therapeutic value, though not for the same disease state. It is also possible for one enantiomer to mediate the harmful effects of the other enantiomer. For instance, in the case of indacrinone, one enantiomer is a diuretic but causes uric acid retention, whereas the other enantiomer causes uric acid elimination. Thus, administration of a mixture of enantiomers, although not necessarily racemic, may have therapeutic value. 

In a catalytic asymmetric reaction, a small amount of an enantio-merically pure catalyst, either an enzyme or a synthetic, soluble transition metal complex, is used to produce large quantities of an optically active compound from a precursor that may be chiral or achiral. In recent years, synthetic chemists have developed numerous catalytic asymmetric reaction processes that transform prochiral substrates into chiral products with impressive margins of enantio-selectivity, feats that were once the exclusive domain of enzymes.56 These developments have had an enormous impact on academic and industrial organic synthesis. In the pharmaceutical industry, where there is a great emphasis on the production of enantiomeri-cally pure compounds, effective catalytic asymmetric reactions are particularly valuable because one molecule of an enantiomerically pure catalyst can, in principle, direct the stereoselective formation of millions of chiral product molecules. Such reactions are thus highly productive and economical, and, when applicable, they make the wasteful practice of racemate resolution obsolete. 

An example of a separation primarily based on polar interactions using silica gel as the stationary phase is shown in figure 10. The macro-cyclic tricothecane derivatives are secondary metabolites of the soil fungi Myrothecium Verrucaia. They exhibit antibiotic, antifungal and cytostatic activity and, consequently, their analysis is of interest to the pharmaceutical industry. The column used was 25 cm long, 4.6 mm in diameter and packed with silica gel particles 5 p in diameter which should give approximately 25,000 theoretical plates if operated at the optimum velocity. The flow rate was 1.5 ml/min, and as the retention time of the last peak was about 40 minutes, the retention volume of the last peak would be about 60 ml. 

Pharmacopoeia publications provide a final important source of information for the pharmaceutical industry, regulatory authorities, and the healthcare professions. These are concerned with establishing quality standards. These publications include monographs that define specifications for the purity and identity of established pharmaceutical ingredients, both active and non-active, together with recognised analytical methods that may be used to evaluate them. The most relevant are the United States Pharmacopoeia (USP) and the European Pharmacopoeia (Ph.Eur). 

Comprehensive physicochemical characterization of any raw material is a crucial and multi-phased requirement for the selection and validation of that matter as a constituent of a product or part of the product development process (Morris et al., 1998). Such demand is especially important in the pharmaceutical industry because of the presence of several compounds assembled in a formulation, such as active substances and excipients, which highlights the importance of compatibility among them. Besides, variations in raw materials due to different sources, periods of extraction and various environmental factors may lead to failures in production and/or in the dosage form performance (Morris et al., 1998). Additionally, economic issues are also related to the need for investigating the physicochemical characteristics of raw materials since those features may determine the most adequate and low-cost material for specific procedures and dosage forms. 

Catalytic incineration has been appHed in the abatement of chlorinated VOC emissions in the pharmaceutical industry. The major compounds in the emission mixture are dichloromethane, perchloroethylene, dimethylformamide, oxitol, and toluene. The incinerator operates normally at 400-500 °C, but when emissions contain perchloroethylene the temperature is increased up to 500-600 °C. The emission mixture also contains water, which pushes the selectivity further toward HCl formation instead of formation of CI2. After oxidation, the product gases are washed with NaOH scrubbers. The purification level of over 99% can be achieved with the incinerator, the activity of which has been shown to be very stable after one year of continuous operation [69-71]. 

Influencing the efficacy or potency of chemicals is a strategy used by the pharmaceutical industry as part of the drug discovery process that can be incorporated into designing safer industrial chemicals. Efficacy is the maximal effect, either therapeutic or toxic, that a chemical can achieve. Potency is a measure of the amount of a substance that is needed to attain a given response level. Opioid analgesics are examples of where structural modifications have been used to establish a relationship between structure and activity. ... 

Metabolic and enzyme engineering have received a lot of attention in academic institutions and are now being applied for the optimization of biocatalysts used in the production of a diverse range of products. Engineered microorganisms, even with non-native enzyme activities, are being used for novel products and process improvements for the production of precursors, intermediates and complete compounds, required in the pharmaceutical industry (Chartrain et ai, 2000). 

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