Preformulation objectives

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. 

An objective of preformulation scientist is to determine the equilibrium solubility of a drug substance under physiological pH to identify the BCS class of drug candidate for further development. For BCS classification the test conditions are strictly defined by the FDA. The pH solubility profile of the test drug substance should be determined at 37°C in aqueous media with a pH in the range of 1-7.5. Standard buffer solutions described in the USP are considered to be appropriate for use in these studies. A number of pH conditions are used bracketing the pKa value for the respective test substance. For example, for a drug with a Ka of 5, solubility should be determined at... 

Based on the analysis of the preformulation data, likely excipients are selected and small batches may be produced. The number and size of the batches depend on the availability of the drug substance. The batches are intended to assess the feasibility of the formulation, including the types and levels of excipients, as well as the process and its operational variables, such as order of addition, mixing times, compression force, granulation time, etc. The goal is to develop a formulation and process that meets the criteria set forth earlier under Objectives. 

Candidate drugs being evaluated for development are often one of a series of related compounds that may have similar chemical properties, that is, similar paths of degradation may be deduced. However, this rarely tells us the rate at which they decompose, which is of more importance to pharmaceutical development terms. To elucidate their stability with respect to temperature, pH, light, and oxygen, a number of experiments need to be performed. The major objectives of the preformulation team are, therefore, to identify conditions to which the compound is sensitive, and to identify degradation profiles under these conditions. 

In order to achieve the potential clinical benefits that can be provided by a formulation, as exemplified in Table 7.1, biopharmaceutical input is needed from the start of preformulation, through formulation development, to documentation for regulatory applications. The main objective is to obtain and verify desirable drug delivery properties for a pharmaceutical formulation. The key activities are as follows ... 

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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