What's Next In: Solid-Dosage Formulation

Dec 02, 2007

Individual Dosing, Process Simulation, and Continuous Processing

Individualized dosing for specific patient needs has been the goal of medical and pharmacotherapy specialists since they first envisioned pharmacogenetic evaluation. With the measurement of individual levels of metabolism, the optimum dose can be calculated for each individual patient. Dosage forms, however, are currently mass produced in defined dosages that may or may not be appropriate for each and every patient. To achieve the goal of individualized dosing, we will need to rethink pharmaceutical processing to produce individualized doses with the same controls that are in place for mass-produced dosage forms. The methods for producing individualized dosage forms are still being explored. Manufacturing of individualized dosages was considered by the National Institute of Pharmaceutical Technology and Education (NIPTE) to be a long-term goal in its Pharmaceutical Technology Roadmap, which was developed in the course of a year by meeting with scientists from industry, the US Food and Drug Administration, and academia.

Other advances that NIPTE envisions in the area of solid-dosage forms include the development of predictive mathematical models of current manufacturing processes including milling, granulation, drying, compaction, and coating. Once mathematical models are developed that can predict the performance of the product or intermediate-product from known material properties, the development process can be significantly shortened. In addition, variation in inputs can be used to predict the impact on product quality, and model predictive feedback control strategies can be implemented to ensure that product-quality specifications are met. The approach of predicting product quality using simulations based on known fundamental physics and engineering as well as knowledge of process and materials is distinctly different from the use of empirical, statistical modeling that one obtains from a factorial or other systematic design of experiments. Process simulation requires a fundamental understanding of the process and materials that, in many cases, is currently beyond our reach. The progress in the area of process simulation is rapid, although we have a long way to go before this becomes reality. Materials characterization of powders, however, is very complex and will require significant concerted effort using a variety of approaches.

Most current pharmaceutical processes are batch processes. The NIPTE Roadmap also includes an exploration of moving from batch to continuous processing. Unlike batch processing, continuous processing is more amenable to process monitoring and control algorithms that allow the process to run without human supervision. Of course, the size of the equipment for continuous processing will be reduced compared to the current batch-sized equipment to allow continuation of the processes for a sufficient time to take advantages of continuous processing. Continuous processing will also allow intermediate materials to be introduced in subsequent processes "just in time." For example, continuous wet-granulation feeds into continuous drying, which feeds directly onto a tablet press without inspection of the intermediate materials.

Robin Bogner, PhD, associate professor of pharmaceutics, Department of Pharmaceutical Sciences, School of Pharmacy at the University of Connecticut


A leading British pharmaceutical journal once stated, "Tablets have had their day, and will pass away to make room for something else." This prediction was made in 1895. It's fair to say the prediction was wrong, and tablets, along with capsules, remain the prevailing solid dosage forms. The situation doesn't seem likely to change in the future, even as such innovations as soft gels and oral disintegrating tablets (ODTs) retain niche sectors of the market.

What could have a significant impact on the future of solid dosage forms and formulations is growing attention by the US Food and Drug Administration on the quality and consistency of pharmaceutical manufacturing processes. In line with that, key FDA-driven initiatives will continue to gain prevalence among pharmaceutical manufacturers-and, by necessity, their suppliers-in the years to come. Of these, key is Quality by Design (QbD), which reflects the FDA's belief that quality needs to be built-in or by design. An important aspect of QbD is process analytical technology (PAT), an approach for providing on-line assessment of product quality throughout the manufacturing process. This approach enables the consistent generation of products of predetermined quality, supported by the ability to identify an appropriate design and control space for each manufacturing process.