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By Anayo M. Ukeje, PhD/DIC and Kay Schmidt, MS
Dosage Form Design and Confirmation
Prior to starting feasibility formulation development, the baseline information/data generated on the new chemical entities (NCEs) — particularly the chemical structure, spectral data melt and transition properties — are compared to a library of compounds for any closely related compound(s). This, coupled with past development experience, helps in designing physicochemical experiments to determine the type (acid, salt, crystal, polymorph amorphic) and the most appropriate dosage form for drug product development. The dosage form stability and performance are confirmed as the product development is progressed through the various stages up to commercialization.
Feasibility Formulation and Feasibility Process Development
Formulation is the process in which different chemical substances, including the active drug, are combined to produce a final medicinal product [6.5]. Feasibility formulation studies involve developing small or bench-top formulations for physicochemical and drug-excipient compatibility screening to aid the dosage form stability evaluation, phase I clinical and eventual patient acceptability assessments.
After bench-top feasibility is confirmed, feasibility process development can be initiated. Process Development is a series of predefined experiments to identify critical variables in a process and determine how these variables may influence scale-up [6.6]. It is an essential step leading up to formal process validation and post-validation activities. Feasibility Process Development defines and tests desired operating parameters, which include the formulation composition, addition sequence, mixing speed, time, evaluation and the design of processing equipment.
Feasibility Sterilization Process Development for Sterile Products
Sterilization can be achieved by applying the proper combinations of heat, chemicals, irradiation, pressure and filtration. Feasibility sterilization studies are aimed at development and assessment of the sterilization method that achieves the primary objective of eliminating all microbial life from a product without effecting dosage form and formulation components or overall product quality.
Terminal sterilization is the process in which the finished pharmaceutical product is sterilized in-situ in the final container meant for delivery to the end user [6.7]. Two basic approaches are employed: Overkill and Probability of Survival. The Overkill method is used when the product can withstand excessive exposure to the sterilization processes without adverse effects. The Probability of Survival approach is used when there are limitations to exposure to the sterilization parameters that the product can withstand. In the probability approach, the process for the terminal sterilization is validated to achieve the destruction of the pre-sterilization bioburden with a minimum safety factor of an additional six-log reduction (1x10-6). The probability that no more than one unit per million is contaminated is considered to be an acceptable level of sterility assurance.
Due to API/excipent sensitivity to heat, some products cannot be terminally sterilized and must be aseptically prepared [6.8]. For heat-sensitive formulations, the product may be sterile filtered, however, sterile filtration cannot be applied to certain formulations, including suspensions or emulsions because sterilizing grade filter membranes with sub-micron pore sizes that remove microbial contaminants may also screen out API particles or micelles.
When sterile filtration is appropriate for liquid formulations [6.9], the affinity of the formulation components to the filter membrane, as well the degree of adsorption and/or absorption of the components to the membrane, become critical to the process and quality of the sterile product. For bulk sterilized products, the sensitivity or stability of the API/product to the applied heat or radiation is again critical to the overall process and product quality.
Feasibility Filling and Packaging Process Development
Primary and secondary packaging process development planning depends on the dosage form, appropriate filling and packaging equipment required, container and closure system and overall finished product presentation desired. The nature, complexity, costs and duration will differ among the various dosage forms. It is critical that the container and closure system be developed to fit the dosage form, delivery routes and planned presentation. It is equally important that the filling and packaging process equipment train be developed to ensure not only compatibility with the product, container and closure system, but also consistency in fill weight or volume to yield the desired delivered dose of the product. Container integrity needs to be assured as well. With the proper application of filling and packaging equipment suitable for the desired container/closure system and by controlling the filling and sealing of the containers and closure systems, the reproducible production of a product can be assured.
Predevelopment activities impact to SSQUIPP
Safety — The physicochemical properties of a drug substance influence its subsequent development and dosage form selection. Even when a drug substance passes early toxicological tests, there remain considerable safety issues to be considered and addressed all the way to the market.
Drug toxicity may be influenced by many factors. Sound scientific predevelopment and feasibility development activities can help reduce or eliminate these potential toxicological hazards and enhance product safety through extensive characterization and the correlation of the drug product in vitro data to in vivo performance.
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