The US Food and Drug Adminstration released its Pharmaceutical Quality for the 21st Century: A Risk-Based Approach report in 2004. Since that time, the concepts around quality by design (QbD) have been discussed in multiple meetings and regulatory guidances, including in three finalized guidelines by the International Conference on Harmonization (ICH) (1–3). Christine Moore, acting deputy director of the Office for New Drug Quality Assessment, and Joseph Famulare, deputy director of the Office of Compliance, both within FDA's Center for Drug Evaluation and Research (CDER), address some common industry questions about how to implement the manufacturing practice.
PharmTech» Controlling variability duringthe manufacturing process seems to be the biggest challenge facing industry with regard to QbD implementation because this approach involves different instrumentation and additional testing. And yet, process analytical technology (PAT) can offer industry great advantages. Why do you think there is so much pushback from industry with this issue, and what might it take for industry to accept the changed approach that FDA is promoting?»Moore: I see a few major concerns of companies in shifting toward implementing PAT. First is the unavailability of the equipment in current pharmaceutical plants and the data-management systems needed for tracking, control, and knowledge management. Also, many manufacturers are unfamiliar with the equipment and its operation, which could lead to a steep initial learning curve and new needs for maintenance on the manufacturing floor. The second hurdle I perceive is cultural. The traditional mindset of the pharmaceutical industry often has been to put a validated process in place and not look at it again unless it breaks. PAT systems can allow for a continuous window on the operation which will give you much greater and richer information so that the manufacturer can more easily detect process drifts and correct them before they become problems. I think as more companies implement QbD and PAT approaches, the regulatory and business benefits will become more evident.
PharmTech» Pharmaceutical manufacturers also face QbD challenges with legacy products and scale-up. How does FDA intend to address these issues?
»Famulare: Firms have different motivations for applying new technologies to legacy products, including finding ways to gain better process control and efficiency. Commercial data, in conjunction with additional development work, can lead to anything from better process controls to seeing the need to update the application with new specifications for the product, and may or may not include the implementation of a design space. ICH Q10 Pharmaceutical Quality System (PQS) provides guidance in implementing these approaches during all phases of the product life cycle, including technology transfer and scale-up.
FDA continues to train compliance and investigative staff in advanced technologies, risk-management, and quality systems. CDER compliance technical experts lead and participate in preapproval and postapproval inspections on occasions where their expertise is needed and in the foreign arena, which has proven very helpful in looking at many of these opportunities. CDER's Office of Compliance (OC) has been instrumental in coordinating joint inspections with international colleagues [e.g., the European Medicines Agency] that have new technologies working and is open to preoperational visits where new technologies are put into place.
PharmTech» Some recent industry presentations have discussed the size of the design space and what's most effective. What's the regulatory perspective on the size of a design space and how close a company's process results come to the edges of the design space?
»Famulare: The value of design space is not its size—or where the process lies within the design space—but the process understanding it represents based upon good development and knowledge obtained during the commercial process over the product's life cycle when the design space is changed. This allow for a firm's self-management of change to foster innovation and continual improvement. In the past, many processes remained fixed based upon limited knowledge at the time of development and were limited to fixed processes prescribed in applications.
Design space will provide the opportunity to present a good understanding of the proposed process based on development and to innovate and improve the process. As described in ICH Q10, developing an effective control strategy based upon the most current product and process understanding should provide the opportunity for manufacturers to control variability and to produce a quality product minimizing deviations. In addition, FDA's draft process validation guidance addresses more clearly than ever before that validation is not a fixed activity but should be a life-cycle approach that can be adapted to work with or without design space and can be used with modern technologies that continually monitor or measure the process.