Quality control preformulation studies

Process validation is intended to show and document that the process described, when operating within the designated parameters, will produce product of the appropriate quality and demonstrate that the manufacturing process is under full control. Process validation should extend from laboratory-scale and preformulation studies (say to of production scale) to formulation to pilot-scale manufacture (say production scale) to full industrial-scale manufacture, with a clear, logical, and continuous path between these stages. The magnitude of scale-up at each stage should not normally exceed a factor of 10. 

To establish quality assurance, control of dosage forms, starting from clinical trial to production for market introduction, must be imposed on in-process operations and product testing for compliance with the specifications and guidelines of quality operation to ensure product attributes. Occasionally, specifications may be revised because of new evidence discovered in the continuous preformulation study. 

Hydrates and solvates can be prepared by crystallization in water or an organic solvent or by conversion of the anhydrous material through moisture or solvent adsorption. In quality control testing, hydrates or solvates are identified by the assay of water of crystallization or solvent found in the crystal. Water determination is achieved by Karl Fischer titration or a coulometric method or loss-on-drying by the USP method. In the preformulation study, the hot stage microscope is a useful simple technique. TGA can also be an informative tool, as shown in Figure 15. 

Important to quality control are the comparison and confirmation of drug substance identity, excipients, and packaging components. Techniques such as Fourier transform IR (FTIR), attenuated total reflectance (ATR), NIR, Raman spectroscopy are used with increased regularity. The detection of foreign metal contaminants is essential with inductively coupled plasma spectroscopy (ICP), atomic absorption (AA), and X-ray fluorescence. Also notable is the increased attention to analysis of chiral compounds, as in the synthesis of drug substances. Optical rotation, ORD, and CD are currently the preferred instruments for this practice. The analytical techniques commonly used in the preformulation study are discussed in the following. 

FdPLC has contributed many successes in product development and in quality control for the pharmaceutical industry. The UV detector coupling with HPLC equipment is the most important analytical instrument for preformulation, QC/QA, and in-process control in pharmaceutical analysis. HPLC is a basic and reliable analytical tool for preformulation study because of the high-resolution capacity, accuracy, and reproducibility of the equipment. Its primary function includes search for and detection of impurities in drug substances, as well as stability evaluation of dosage forms in terms of detection and quantitation of degradation products. 

FDA initiatives and other government regulations influence pharmaceutical manufacturing operations, including preformulation studies and quality control systems. These regulatory issues include the topics outlined below. 

There is no doubt that isothermal microcalorimetry has the potential to be very useful in studies of chemical degradation. The success will be greatest for solution-state reactions for which the reacting concentration is known, but even these can be limited by physical artifacts by, for example, the slow diffusion of oxygen into the liquid from the head space. The use of this technique for solid-state reactions is certainly not impossible, but is an area where great care is needed. The technique may therefore be used readily in a preformulation environment for solution systems, but is perhaps better applied in a QC (quality control) role for well-characterized solid-state processes. 

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