Pharmaceutical Research Impact
Manufacturing is a very important component in getting safe drugs to patients. In fact, it is a critical step in the chain of very complex supply chain before a drug reaches the pharmacy shelves. When any critical link is broken, it opens the door for something like the heparin crisis where unsafe drugs led to the death of several patients. To ensure that patients receive the best medicines at a sustainable price there are a large number of initiatives being spearheaded by pharmaceutical companies and Regulatory Agencies in the U,S, and Europe to develop and adopt the manufacturing techniques of the 21st Century 1, 2, 3.
Though significant efforts are underway to change manufacturing technology, the team effort involving industry, FDA and academia needs to continue to transform pharmaceutical product development. Marked advances in chemistry, chemical engineering, computer modeling, instrumentation, analytical science, and product formulations that have been used to increase efficiency in other industries may be applied to pharmaceutical product development and manufacturing. This will make pharmaceutical manufacturing less labor intensive and time consuming and will improve the ability to predict product and manufacturing performance.
Other industries such as the auto industry and the petrochemical industry 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 uniformly across the pharmaceutical industry? In NIPTE's opinion, it is primarily because the science required to do so is lacking in the public domain 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 non-proprietary science-based understanding of pharmaceutical manufacturing ensures that once a manufacturing process is approved, it can be left substantially unchanged for the duration of the product life.
With more and more outsourcing and greater amounts of drug substance, pharmaceutical ingredients and products being imported from overseas it is important that there is a common technology foundation that all companies and manufacturing facilities around the world follow to ensure sustained product quality. Historically, the U.S. has always taken the lead in developing new technology. It is therefore a challenge for the scientists in industry, academia and regulatory agencies in the U.S. to join hands again and develop innovative, flexible and readily understandable technologies that can be followed all over the world.
Without a common understanding of pharmaceutical manufacturing processes the FDA is put in a difficult position. The FDA reviewers have limited knowledge with which 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 would not have to be this way if there was knowledge in the public domain 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.
One important impetus for increased focus on pharmaceutical development and manufacturing research has been provided by the US FDA which has signaled an increased willingness to change regulatory practice to make regulations science driven and to encourage innovation in product development and manufacture. 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 across the industry lie in the limited fundamental understanding of the complex materials and processes that is available in the public knowledge domain. To build that understanding and to develop the basic tools needed to substantially advance these domains, the need for a systematic program of publishable research has to be established. There needs to more text books, educational programs, research projects and published papers in many of the critical areas such that a body of knowledge can be built in the public domain.
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 will also partner with scientists from the industry on projects wherever there is interest and it is appropriate.
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.
In order to advance the NIPTE mission, strategic roadmaps have been developed for both education and research.
NIPTE's research agenda will be to conduct fundamental and basic research that will:
- 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
The main mission of the education and training components of NIPTE are:
- 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 expertise in areas that are going to be important in the execution of QbD, such as process control, multi-variate analysis, process modeling, material science, etc.
- 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.
- "Challenges and Opportunity on the Critical Path to New Medical Products," FDA, March, 2004.
- FDA, PAT-A Framework for Innovative Pharmaceutical Development, Manufacturing and Quality Assurance. Guidance for Industry (2004), http://www.fda.gov/cder/guidance/6419fnl.pdf
- FDA, Pharmaceutical cGMPs for the 21st Century - A Risk-Based Approach Final Report - Fall 2004, www.fda.gov/cder/gmp/gmp2004/GMP_finalreport2004.html