Preformulation stage analytical development

The therapeutically active dmg can be extracted from plant or animal tissue, or be a product of fermentation (qv), as in the case of antibiotics. Frequentiy, it is synthesized and designed to correlate stmcture with therapeutic activity. Pharmacologic activity is first tested on laboratory animals. When the results ate encouraging, physical and chemical properties are determined in the so-called preformulation stage, and analytical procedures are developed for quahty control (see Qualityassurance/qualitycontrol). 

A pilot production is at about a lOOx level in general, the full scale-batch and the technology transfer at this stage should comprise preformulation information, product development report, and product stability and analytical methods reports. This is the time to finalize the batch production documentation for the lOOx level. The objectives of prevalidation trials at this stage are to qualify and optimize the process in full-scale production equipment and facilities. 

This level of preformulation should be initiated in the beginning of the development cycle. The data consist of physicochemical properties of the chemical substance and analytical properties useful in the development of analytical methods, the evaluation of material quality, and testing for the acceptance of the formulation developed. In the early stage of development, the synthetic scheme is developed and the material available for preformulation may be limited. Thus the lack of supply quantities may affect the quality of data obtained. As the development cycle is pushed forward and the drug availability improves, data should be updated or refined with the use of more complicated and accurate methods. Part 1 of the preformulation report may be published before the establishment of specifications. The portion of this report consisting of analytical data may be known as an analytical profile in some organizations. 

For the purposes of this discussion, we will assume that the project objectives are known, that priority has been established, that there are sufficient amounts of raw materials to carry out the investigations and that initial analytical procedures have been developed. A fundamental point that must be kept in mind throughout the early stages is that for New Chemical Entities (NCEs) the toxicological profile will not normally have been established at the preformulation stage. It is of paramount importance, therefore, to take all due precautions throughout the study. The preformulation study has several distinct phases (in approximate chronological order) ... 

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