Need for Modernization of Pharmaceutical Manufacturing Science

The Need

Everyone’s talking about safety and cost of drugs these days, but the hidden crisis in healthcare is the state of pharmaceutical manufacturing. This is the root cause of the import of unsafe and sometimes even deadly drugs from overseas. Manufacturing is a very important component in getting safe drugs to patients. In fact, it is the last step in the chain of very complex events before a drug reaches the pharmacy shelves. When that critical link is broken, it opens the door for something like the heparin crisis. Pharmaceutical manufacturing lags far behind the manufacturing techniques of the 21st Century1 and the science required to transform a new discovery to a marketable new drug has definitely not kept pace with advances on the drug discovery side.

The issues with pharmaceutical manufacturing largely result from unsolved problems in pharmaceutical product development. Product development thus has a direct impact on manufacturing. However, pharmaceutical product development today is more of an art than science2. Once the new drug discovery is made, product development and manufacturing are left to traditional “tried and true” practices. This is one of the key factors leading also to high cost of developing new drugs and the long time required for new discoveries to reach the market. Marked advances in chemistry, chemical engineering, computer modeling, instrumentation, analytical science, and product formulations that could be used to increase efficiency are not applied in pharmaceutical product development and manufacturing. Empirical methods used today are labor intensive and time consuming and cannot predict product and manufacturing performance. Pharmaceutical development and manufacturing must be modernized.

Other industries have examined their manufacturing technologies and have modernized them. This has allowed these industries to become more competitive and to have products of superior value. Why has this not happened in the pharmaceutical industry? It is primarily because the science required to do so is lacking and the process of pharmaceutical manufacturing is highly regulated. The interplay of tight FDA regulation to ensure product safety, the high cost of re-approval of process innovations and inadequate science-based understanding of pharmaceutical science and manufacturing insures that once a manufacturing process is approved, it is left substantially unchanged for the duration of the product life.

Lack of science puts the FDA in a difficult position too. The reviewers have limited data and science to review and approve the documents submitted for approval of manufacturing processes. To ensure public safety, they have to check and verify every hypothesis and every experimental result, and exercise extreme caution before they approve the applications. The process is lengthy and resource intensive. It did not have to be this way if there was science readily available to back the submissions. For example, one does not need to verify how long it takes to heat water in a vessel because the science and engineering to determine that has been developed and is widely available. This is why the FDA is encouraging development of science-based regulations and quality by design.

Cost of Goods (COGS) for Brand-Name pharmaceuticals can be as high as 30% of the total sales revenues of these companies. In comparison, the percentage of sales revenues spent on R&D by these pharmaceutical companies is only 10-15%3. For Generics, COGS can be as high as 50% of their total sales revenues. However, little funding is devoted by industry or government to new science and engineering technology for reducing the costs associated with development and manufacturing. Indeed, according to the FDA, new science and technology in product/process development and manufacturing are lagging substantially behind the tremendous advances in the basic sciences for discovery.

One important impetus for increased focus on pharmaceutical development and manufacturing research has been provided by the US FDA which has recently signaled an increased willingness to change regulatory practice to make regulations science driven and to encourage innovation in product development and manufacture 4, 5. Concepts such as process analytical technology, quality by design, and design space have been widely discussed and initial attempts have been made to inject these concepts into practice. However, the barriers to progress in development and manufacture methodology lie in the limited fundamental understanding of the complex materials and processes with which the industry must work. To build that understanding and to develop the basic tools needed to substantially advance these domains, the need for a systematic program of research has to be established.

The good news is that the scientists in academia in this country have agreed to collaborate with the scientists in the FDA and in the industry to take a leading role in developing the basic science required to develop and manufacture high quality pharmaceutical products. Faculty and researchers from eleven major universities in the United States have agreed to collaborate to form the National Institute for Pharmaceutical Technology and Education (NIPTE). NIPTE’s mission is to conduct fundamental research in pharmaceutical development and manufacturing science. The NIPTE member universities have some of the strongest pharmaceutical sciences and engineering departments in the country, and they are obviously the best place for conducting non-product specific, relatively long-term basic research.

NIPTE mission implies two interconnected agendas:

• A research agenda leading to the development of the necessary fundamental knowledge.
• An education agenda for the development of a strong human resource pool to develop this knowledge and to implement it in the field.

Research Agenda

• Promote research interaction between industry, academia and government.
• Develop an understanding of factors affecting variability in drug development, scale-up, quality, and manufacturing.
• Improve the scientific basis for understanding the behavior of pharmaceutical materials and the requisite processing steps.
• Develop tools to predict product performance early in the development process
• Develop strategies to allow rapid design and scale-up of manufacturing processes
• Reduce risk and time-to-market for new drugs improve quality of drugs and pharmaceutical products.

The Education Agenda

• Create a “pipeline” of diverse talent that commences at the undergraduate level and continues throughout graduate, postgraduate, and continuing education, augmenting the available workforce in academia, industry, and government.
• Develop and implement an integrated Education and Training plan which incorporates NIPTE research findings, NIPTE will create and deliver educational and training programs that will prepare the technical cadre needed by the industry and the FDA to implement and regulate these new technologies.

1. “New prescriptions for drug makers: Update the plants,” The Wall Street Journal, September 12, 2003 by Aboud Leila and Scott Henry.
2. ”Challenges and Opportunity on the Critical Path to New Medical Products,” FDA, March, 2004.
3. ”Analysis of Manufacturing Costs in Pharmaceutical Companies,” Prabir Basu, et.al. J. Pharmaceutical Innovation, p30, March, 2008.
4. FDA, PAT-A Framework for Innovative Pharmaceutical Development, Manufacturing and Quality Assurance. Guidance for Industry (2004), http://www.fda.gov/cder/guidance/6419fnl.pdf
5. FDA, Pharmaceutical cGMPs for the 21st Century - A Risk-Based Approach Final Report - Fall 2004, www.fda.gov/cder/gmp/gmp2004/GMP_finalreport2004.html