Academia Tackles QbD Science: NIPTE Carries out FDA Grant and Educational Initiatives

The National Institute for Pharmaceutical Technology and Education (NIPTE) was formed in June 2007 as an independent nonprofit organization by 11 major US universities. Approximately 30 faculty members from the member universities* are collaborating on various NIPTE projects, as are scientists from Pfizer (New York), Baxter (Bloomington, IN), Abbott Laboratories (Abbott Park, IL), and the US Food and Drug Administration. The institute s research agenda, aimed at improving the quality of drugs and pharmaceutical products, includes the following:

• Developing an understanding of factors affecting variability in drug development, scale-up, quality, and manufacturing

• Improving the scientific basis for understanding the behavior of pharmaceutical materials and the requisite processing steps

• Developing tools to predict product performance early in the development process as well as strategies to allow rapid design and scale-up of manufacturing processes

• Reducing risk and time-to-market for new drugs.

Fulfilling the FDA contract

The US Food and Drug Administration's Center for Drug Evaluation and Research granted NIPTE a $1.19-million contract in September 2008 to help carry out the institute s bold agenda. The funds are to be used to develop quality-by-design (QbD) science for pharmaceutical developers and manufacturers. "The agency plans to make available and use NIPTE s research to develop the science that is badly required for rapid, industrywide QbD implementation," says NIPTE Executive Director Prabir Basu.

NIPTE researchers are looking at, among other things, how to develop a complete manufacturing process using QbD. This process includes tools that can help develop design space and process analytical technology applications; methodologies for conducting risk analysis and scale-up; design space protocols for unit operations; bioreactor modeling; characterization of excipients (i.e., understanding and predicting their physical and functional properties); pediatric formulations; biotechnology product development; and prediction models for active pharmaceutical ingredient and formulation properties such as solubility, taste, and stability.

"We are making good progress in designing protocols for scaling up unit operations such as blending, granulation, and fluid-bed drying," says Basu. "We are also making good progress on developing a QbD case study for developing a parenteral freeze-dried dosage form for a small molecule."

Once the FDA grant period ends in September 2010, NIPTE plans to hold a public workshop about its findings. Although there's no guarantee that the institute's work will lead FDA to revise related guidances, the availability of better science could change some current thinking on the part of regulators, including at the International Conference on Harmonization, says Basu.

Educating for the future

A major component of the institute's work is educating the industry and scientific community. NIPTE is developing educational materials and training programs on QbD-based science and applications with the ultimate goal of creating an academic curriculum.

"Many scientists in the industry and at our regulatory agency do not have adequate training in the science required or have available all the tools required to implement QbD," explains Basu. "In addition, at our universities, the disciplines such as pharmacy, chemistry, and engineering work in silos. An industry senior vice-president once commented that they have to sometimes hire three people to do one person's job. NIPTE s intent is to take the best educational materials from the entire available curriculum from all the current bachelor and master of science programs in pharmacy and pharmaceutical engineering and develop an integrated curriculum for a pharmaceutical science and engineering program that all the NIPTE schools and beyond can use as a model program."

Currently, NIPTE operates out of Purdue University in Indiana, but the long-term goal is to have at least one Center of Excellence at each of the member institutions, says Basu. In addition to using a potential new curriculum, each center would specialize in at least one topic or area of research in pharmaceutical process development and manufacturing so that QbD science can continue to develop.

As for current industry professionals, some retraining in QbD science and processes will be a must, says Basu. NIPTE programs will be available to companies' internal educational programs and to other interested parties.

Giving industry what it wants

Industry has endless questions about QbD implementation, many of which boil down to convincing management to support and fund the new risk-based science with the promise of regulatory and operational flexibility as a reward. What some may not understand, however, says Basu, is that to achieve the full benefits of QbD, there must be a full implementation of QbD similar to what other industries do.

"QbD implementation has to start early in process development. The product and process must be designed using sound scientific principles." In addition, a company's manufacturing plant and systems must be capable of operating a QbD system.

"A well-designed process will not perform satisfactorily if the manufacturing plant does not have well-developed systems of quality, effectiveness, performance, management, and continuous improvement," says Basu. Only then might companies experience the estimated 25-30% savings in cost of goods sold for implementing QbD.

Industry also wants to know how its day-to-day work will change once QbD processes are in operation. "Today, if we want to heat water in a tank, we do not need to develop a design space or validate that system. If we decide to heat acetone instead of water, we do not need to revise our design space or submit lengthy change requests. This is because the science is available to calculate how long it takes to heat water or acetone," explains Basu. "Our hope is that pharmaceutical science will reach that level someday so that we can develop a manufacturing process in one step from laboratory data and then be able to predict its performance with a high degree of accuracy to be able to control the process in the plant using sound manufacturing science and ensure product quality without requiring FDA approval for every process change we make."

Basu says that petrochemicals is one industry that has successfully implemented science-and risk-based approaches into its manufacturing processes. "Irrespective of the source of the crude oil, or the season, or the location of the refinery or gas station, the quality of gasoline is always the same. We do not have to readjust our cars everyday or move our cars from one place to the other," he explains. "There is a real need to invest in science and technology for our pharmaceutical process development and manufacturing science. Pharmaceutical companies are trying to save manufacturing costs by outsourcing, but QbD implementation can achieve much greater savings ... and help save our manufacturing jobs," he adds.

Looking ahead

NIPTE is not conducting research simply to satisfy academic curiosity or to be published, says Basu. "Our research should be useful to the regulators and industry to improve pharmaceutical product development and manufacturing. To this end, current good manufacturing practices must be complemented by current good manufacturing technologies. However, this is a big challenge for not only our industry and FDA, but also for academia in terms of working collaboratively with FDA, industry, foreign manufacturers, and regulatory agencies to bring QbD wherever it maybe required to make overall improvement of the quality of our pharmaceutical products."

*Member universities include Duquesne University, the Illinois Institute of Technology, Rutgers University, Purdue University, and the Universities of Puerto Rico, Connecticut, Iowa, Kansas, Kentucky, Maryland, and Minnesota.