OR WAIT null SECS
Agnes Shanley is senior editor of Pharmaceutical Technology.
Lawrence Yu, Deputy Director, Office of Pharmaceutical Quality at FDA’s Center for Drug Evaluation and Research (CDER), shares insights with Pharmaceutical Technology.
For more than a decade, FDA’s leaders have realized that overly prescriptive regulations can inhibit innovation in the industry. Over the past few years, FDA has changed its organizational structure and processes to help encourage consistency of inspection and review, as well as a dialogue between industry and regulators. Lawrence Yu, Deputy Director, Office of Pharmaceutical Quality at FDA’s Center for Drug Evaluation and Research (CDER), shared insights with Pharmaceutical Technology.
PharmTech: FDA leadership has been encouraging industry to use more modern manufacturing and quality methods for years. However, some companies have sensed a disconnect between senior leadership’s position and the day-to-day actions of inspectors and reviewers. What is FDA doing to encourage trust and ensure that everyone within the agency understands and supports modern manufacturing?
Yu: One of the hallmarks from the time that the Office of Pharmaceutical Quality (OPQ) was established has been the use of team-based integrated quality assessment, which leverages members across disciplines, including assigned investigators from the Office of Regulatory Affairs, as part of the extended review team. This approach helps ensure that reviewers and inspectors are on the same page and that there is consistency in the evaluation of modern manufacturing methods in a regulatory submission as well as during on-site inspections.
The integrated quality assessment approach is supported by extensive training in science, technology, and communication, covering such modern manufacturing platforms as continuous manufacturing, process analytical technology (PAT) tools such as near-infrared based methods, process design tools, and process monitoring and control techniques. Guidance for industry documents, such as FDA’s PAT guidance, provide transparency regarding the agency’s current thinking and internal policies and procedures and also help ensure consistency amongst agency staff. FDA is also involved in research and development in advanced manufacturing, product analysis, data analysis, and modeling.
When OPQ established the Emerging Technology Program, we built on our prior experience with PAT and quality by design (QbD). The Emerging Technology Team (ETT) features members from both review and inspection programs, and is involved in FDA’s oversight of emerging technologies.
PharmTech: Many of the industry’s quality challenges are connected to legacy, rather than new, drugs. Is FDA taking any actions to help reduce the delays that can result when manufacturers submit requests for approval to improve processes for legacy products? What is your advice to managers who may have been putting off investing in more modern technologies due to fear of costs and delays?
Yu: Managers considering implementing newer technology should consider all aspects of the business case for implementation, which can include benefits such as increased reliability and lower costs due to better process efficiency and control. Companies concerned about implementation costs and delays are encouraged to contact the agency to have a discussion with the ETT.
PharmTech: Ever since the PAT initiative, we have heard about real-time release and real-time release testing (RTRT), yet there seem to have been relatively few cases where it has been approved. What issues need to be resolved?
Yu: There have been real-time release testing elements in approved applications. Continuous manufacturing platforms support implementation of RTRT, which can strengthen the business case for moving towards continuous manufacturing. Regarding dissolution modeling, there has been much recent work, including on FDA’s part, on physiologically-based pharmacokinetic absorption models, which could be useful to support RTRT.
PharmTech: What must be done first if the industry is to be able to move to advanced process control and, eventually, advanced manufacturing, and such concepts as predictive maintenance?
Yu: At this point, pharmaceutical manufacturing is still at the stage of automation, rather than advanced manufacturing. FDA has made an effort to establish staff know-how so the workforce is ready to handle applications involving multivariate data and statistics. Further, academic institutions have trained a growing number of specialists in this area, providing the necessary intelligence to support the adoption of advanced process control in the pharma industry.
Within CDER, we have state-of-the-art research facilities in both PAT and process/product analysis. This capability provides training opportunities for reviewers on topics including various spectroscopy techniques and statistical process control. Importantly, knowledge is exchanged between researchers and reviewers to support advanced manufacturing.
Regarding predictive maintenance, any models used for release are classified as high impact models. There is discussion of this in the International Council for Harmonization (ICH) Points to Consider Guide for ICH Q8/Q9/Q10 Implementation. Facilities need detailed plans for maintenance of such models throughout the life of a product. FDA is still learning, with industry, about this evolving concept.
PharmTech: What should manufacturers focus on, first and in the short term, if they are to begin to move toward Six Sigma quality? How about smaller companies making lower margin product?
Yu: The ultimate focus should always be on benefit to the patient, and as such, firms should establish specifications based on clinical relevance--that is, potential impact on clinical performance. As companies develop a culture of quality and a focus on continuous improvement, firms should evaluate parameters that may limit process capability and conduct data analysis to understand, control, and monitor those factors. The same core values apply to companies of all sizes making all products.
Vol. 41, No. 8
When referring to this article, please cite it as A. Shanley, “Encouraging Innovation at FDA: An Interview with CDER’s Lawrence Yu,” Pharmaceutical Technology 41 (8) 2017.