By Kevin Richards, Industry Vice President, Reed ExhibitionsIn August 2002, the FDA announced a two-part initiative “Pharmaceutical cGMPs for the 21st Century: A Risk-Based Approach,” to encourage innovation that will increase efficiencies in pharmaceutical manufacturing, quality control and regulation.
Approximately one year later, the agency has issued a draft guidance entitled “PAT-A Framework for Innovative Pharmaceutical Manufacturing and Quality Assurance” for industry comment. This 21-page document provides a preliminary framework for implementation of process analytical technologies (PAT) and agency oversight. The FDA’s goals are to encourage innovation, increase understanding and control of the manufacturing process, generate quality information in real time, and enable continuous process improvement.
A process in need of modernization:While manufacturing science has made great advances in the past three decades, the pharmaceutical industry’s manufacturing processes have tended to remained static, largely due to regulatory procedures that permanently “lock in” process parameters. Introduction of innovative manufacturing technologies, it was thought, would cause regulatory delays. This mindset has made pharmaceutical manufacturers reluctant to make even small modifications that could potentially improve their manufacturing processes.
As a result, the pharmaceutical industry’s costs for equipment, personnel, and out of spec product are far higher than other technology industries. The electronics industry, for example, has used sophisticated manufacturing technologies to achieve Six Sigma quality while dramatically lowering production costs. By contrast, the pharmaceutical industry has remained at One Sigma levels.
Many major drug manufacturers are actively investigating solutions that are widely deployed for quality control in other processing industries. Several, including Pfizer, GlaxoSmithKline and Novartis, have actually installed non-invasive monitoring and testing technologies such as NIR (near infrared), LIF (laser induced fluorescence), Raman, vision systems, acoustics and chemical imaging systems.
Potential productivity gains from reduced variability and batch failure:The delayed implementation of modern quality control technologies may have also slowed the delivery of new medications to the marketplace. According to the Center for Drug Evaluation and Research (CDER), chemistry, manufacturing and controls issues were the top cause for approval delays in priority new molecular entities (NMEs) last year. Problems at manufacturing facilities lengthened review times for both standard and priority NMEs. And the problem is not limited to pharmaceutical products. Major changes in product manufacturing were also cited as the most frequent reason for delayed approvals of biologic license applications in 2001.
Meanwhile, the potential advantages of reducing variability and batch failure rate are tremendous. It is estimated that the pharmaceutical industry currently spends $90 billion annually on manufacturing, and 20-30% of that cost is tied up in activities that do not add value but are needed to ensure product quality.
Designing quality into the process:The PAT initiative’s new approach is intended to encourage manufacturers to design quality and consistency into the manufacturing process, rather than attempting to test them into the product. The FDA is encouraging manufacturers to propose new manufacturing technologies and quality assurance tools, such as data acquisition and analysis, modern process analyzers or process analytical chemistry tools, process and endpoint monitoring and control, and knowledge management tools that they want to use in processes that involve FDA regulation.
Ultimately, the agency believes that PAT will enable manufacturers to reduce cycle times by using online or inline measurements and controls; eliminate rejects and reprocessing; improve operator safety; reduce human errors; utilize smaller scale equipment and dedicated manufacturing facilities; improve energy and material use; and increase capacity utilization.