Excipient fermentation processes

Like APIs, pharmaceutical excipients are made by chemical synthesis, fermentation, recovery from natural materials, and so on. Often purification procedures may not be employed in the manufacture of such pharmaceutical excipients as clays, celluloses, starches, and natural gums. In addition, the physical and chemical change of certain excipients during processing is not uncommon. Unlike APIs, many excipients have complicated chemical and physical structures that do not yield easily to modern analytical and chromatographic methods. 

Independent use patents offer the weakest patent protection. They almost invite others to seek possibilities to circumvent them and they do not cover the products that result from the invented new use. Wherever the necessary requirements are fulfilled, product patents should be applied for. In the first example given above, it seems hardly justified to construct product claims for (all) products made by the modified fermentation process. The excipient with adjuvant effects could probably be patented as a product patent, claiming "vaccines containing substance X as a novel adjuvant" with the non-obvious advantage of a better tolerability or efficacy over existing adjuvants. As for the third example, any advantageous characteristic of the resulting product may be used to justify a product patent. 

Excipients manufactured by fermentation processes, such as dextrose, citric acid, mannitol, and trehalose, should be specially controlled for endotoxin levels. Mycotoxin (highly toxic metabolic products of certain fimgi species) contamination of an excipient derived from natural material has not been specifically addressed by regulatory authorities. The German health authority issued a draft guideline in 1997 where a limit was specified for Aflotoxins Mi, Bi, and the sum of Bi, B2, Gi, and G2 in the starting material for pharmaceutical products. 

Figure 8.7 Overview of the manufacture of Betaferon, a recombinant human IFN-(3 produced in E. coli. The product differs from native human IFN-(3 in that it is unglycosylated and cysteine residue 17 had been replaced by a serine residue. E. coli fermentation is achieved using minimal salts/glucose media and product accumulates intracellularly in inclusion body (IB) form. During downstream processing, the lbs are solubilized in butanol, with subseguent removal of this denaturant to facilitate product refolding. After two consecutive gel-filtration steps, excipients are added, the product is filled into glass vials and freeze-dried. It exhibits a shelf life of 18 months when stored at 2-8 °C...

In an attempt to follow these recommendations and to increase product safety, a new rFVlll product was developed by the introduction of modifications to the fermentation, the purification process and the drug product formulation. These eliminated the requirements for human- and animal-derived raw materials and excipients at all stages of the production process. In order to distinguish between dif-... 

Many excipients are produced using multipurpose equipment. Fermentation tanks, reactors, dryers, grinders, centrifuges and other pieces of equipment are readily used or adapted for a variety of products. With few exceptions such multiple usage is satisfactory provided the equipment can be adequately cleaned according to written procedures. Equipment that contains tarry or gummy residues that cannot be removed easily should be dedicated for use only with limited portions of a process. 

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