Stepchild in the spotlight: FDA’s deputy commissioner Gottlieb discusses manufacturing challenges

In a speech yesterday at the 13th International GMP conference in Georgia, FDA Deputy Commissioner Scott Gottlieb discussed the Critical Path initiative, and the manufacturing challenges facing the industry, and what the Agency is doing to help drug makers embrace a "quality by design" approach to development and manufacturing. Coming from a high-level FDA official, the speech clearly conveyed a message that 21st Century GMPs are not some "flavor of the month" and that the Agency is behind initiatives like process analytical technologies (PAT). Perhaps more drug companies now playing "wait and see" will take note? (Decades of adversarial interaction are, clearly, hard to shake off. A case in point: drug companies often complain about FDA inspectors and inspections, but, over the last 3-4 years, only two drug companies have opted for the "dispute resolution" that FDA offers. Companies may still put off addressing questions and issues proactively with FDA, and then suffer the consequences, e.g. delayed applications. If anyone needed additional proof that manufacturing is no longer the drug industry's stepchild, here are excerpts from his speech "...Like clinical development, manufacturing has also become a bottleneck in recent years to getting medicines to patients. Too often, drugs are delayed from the market because of manufacturing problems, or new tools that can improve the process while reducing the cost of manufacturing the drugs go underutilized. Like clinical development, manufacturing hasnt benefited in recent years from the same kind of scientific advances that have helped advance other industries, or even advances that have become part of the front end of drug discovery. That needs to change if were going to realize all of the potential from those new discoveries that are being made in laboratories, and if were going to help reduce the cost of getting these treatments to patients. As we begin to see more novel drug delivery systems and complex drugs, addressing key quality issues and establishing meaningful specifications become important. Theres a need to better understand the relationship between quality and safety and efficacy and to apply risk-based approaches for establishing relevant quality specifications. Conventional drug manufacturing is generally accomplished using batch processing with in-process and final product testing conducted on samples to assure quality. This approach has been successful in providing quality drugs, but there are still important opportunities for improvements in the efficiency and quality assurance by better and more innovative applications of modern process development and control technologies including modern process analytical methods. The problem has been that the drug industry seemed hesitant to introduce these new techniques and technologies. And from a public health perspective, this is undesirable. One reason often suggested for this hesitation is "regulatory uncertainty" -- in some instances, people didnt know what to expect from the FDA. The truth is there are important regulatory and technical questions that need to be addressed. But our GMP regulations for drugs havent been updated in 25 years. Meanwhile, best practices in manufacturing technologies and methods have undergone significant progress over that time, particularly in other high-tech industries. For example, the semiconductor industry like the drug industry also has a very low tolerance for impurities and inaccuracies in production. And when its production processes were lagging because of high costs and too many errors that industry helped invent the six sigma production methods. Through continuous quality improvement, those methods achieved enormous improvements in production cost and quality, and they have since been widely adopted in manufacturing industries. But manufacturing hasnt received its due attention in the pharmaceutical industry, even though many experts on manufacturing processes including many of you here today believe that large savings in production costs could be realized while achieving even higher quality standards. That needs to change. And we need to make sure that our regulations are encouraging and facilitating such progress, which is needed today more than ever. So our broad-based GMP program is aimed at developing new regulatory policies based on the latest science of risk management and quality assurance. The new standards are being designed to encourage cost-reducing and precision-enhancing innovation in manufacturing and technology, and to ensure that all three FDA medical centers use consistent and up-to-date methods, including inspectors specializing in particular types of production methods. Drug manufacturing is evolving from an art form to one that is now science and engineering based. Effectively using this knowledge in regulatory decisions and in establishing quality specifications we all use, and then finding better ways to evaluate manufacturing processes -- this can all significantly improve the efficiency of both your manufacturing programs and our regulatory processes. The initiative that weve been working on together is designed to do just that through an integrated systems approach to product quality regulation. And so in this regard, our model for a good manufacturing program can be characterized by one where: Product quality and performance would be achieved and assured by design of effective and efficient manufacturing processes; Where product specifications would be based on mechanistic understanding of how formulation and process factors impact product performance; Where there would be continuous "real time" assurance of quality, and continuous quality improvement; Where regulatory policies and procedures would be tailored to recognize the level of scientific knowledge supporting product applications, process validation, and process capability, and; Where risk based regulatory scrutiny would relate to the level of scientific understanding of how formulation and manufacturing process factors affect product quality and performance and the capability of various strategies to prevent or mitigate the risk of producing poor quality products. Our efforts to achieve these goals through our GMP initiative are founded on sound science and engineering principles for how we can better assess and mitigate the risks of poor product and process quality. I know that many of you have been instrumental in helping us understand and begin to meet these challenges. At FDA, we appreciate these scientific collaborations, but we also know that much work still remains. Through our policies known as current Good Manufacturing Practices or cGMP initiative, under the leadership of Janet Woodcock and David Horowitz and Joe Famulare and many others, FDA has set out to overhaul our regulatory and quality control systems for pharmaceutical products, to encourage manufacturers to modernize their methods, equipment and facilities, to lower costs as well as improve the quality and reduce manufacturing glitches that sometimes keep drugs from the market. As you recall, in August 2002, we announced the Pharmaceutical Current Good Manufacturing Practices (cGMPs) for the 21st Century initiative, to enhance and modernize the regulation of pharmaceutical manufacturing and product quality ” to bring a 21st century focus to this critical FDA responsibility. This initiative intends to modernize FDAs regulation of pharmaceutical quality for veterinary and human drugs and select human biological products such as vaccines. As part of this initiative, the inspection, as well as the chemistry, manufacturing, and controls (CMC) regulatory programs were evaluated to develop a modern and integrated pharmaceutical quality regulatory system A key element of the cGMP initiative is our effort to encourage adoption of state-of-the-art quality control systems in manufacturing. This work is based on a premise that has guided improvements in manufacturing processes in other industries. That quality cannot be tested into products; it should be built into products by design.This includes the use of process analytic technology, for design, analysis, and control of manufacturing, with the goal of ensuring final product quality by allowing timely measures, during manufacturing, of critical quality and performance attributes of raw and in-process materials.We are also identifying key applied science questions that are part of the submissions that companies make to FDA that need to be addressed, and working to address them. This includes changes in how we approach the CMC portion of drug submissions, to make sure that the focus is on critical understanding of the manufacturing process itself and less on format and data. Under the leadership of Moheb Nasr, the head of FDAs Office of New Drug Quality Assessment (ONDQA), the agency is developing a new pharmaceutical quality assessment system based on scientific knowledge and understanding of product and process that applies quality-by-design principles (QbD). The objective of QbD is to facilitate innovation in product and process development and continuous manufacturing improvement throughout product lifecycles. We want to provide regulatory flexibility to set appropriate specifications and incorporate post-approval changes that can lead to better outcomes, and we want to streamline the submission and the review process to help make the adoption of better technologies and approaches to manufacturing more efficient and less costly. A manufacturing plan developed under a quality-by-design approach enables the product design to meet patient requirements right from the start. The attributes of the raw materials and process parameters are linked to product attributes. Quality by design allows the impact of product attributes and patient safety and efficacy are well understood, so as changes are introduced to improve efficiency, it can be quickly and clearly determined whether or not the goal of improving quality without negatively impacting safety and efficacy can be achieved. To accelerate these developments and the QbD approach for CMC submissions, we recently restructured the CMC office, and also added additional engineers and pharmaceutical scientists to its staff. Last fall (October 5-7, 2005), we co-sponsored a workshop to try and develop an internationally harmonized approach to quality by design. Were also working to develop an ICH guideline on comprehensive overall quality summary and eventually will articulate our approach to encouraging adoption of QbD in a guidance document. We also plan to issue our Quality Systems final Guidance by the summer of 2006. The CMC staff is working in close collaboration with the pharmaceutical inspectorate staff in the field, who are also adapting their scientific approaches and their tools to better target their critical inspectional work on areas of manufacturing where the greatest risks are found as well as the best opportunities for measuring quality approaches. Its important that we are taking an efficient, risk-based approach to how we inspect facilities, to make sure were getting the most regulatory bang for our buck and identifying the areas where problems are likely to lurk. To help achieve these ends, we also plan to complete soon a report that summarizes the work of our risk management work group, which was charged with identifying continuous improvements in the risk model for prioritizing sites for manufacturing inspections. Developing and manufacturing new medical innovations is a difficult and complex process, but one that can bring great value to patients. Im confident that the same collaboration and innovative thinking that your bringing to the FDA to help us tackle some of our challenges on the manufacturing front can also be brought to bear on other pressing challenges in our regulatory mission. We also need to remember that the long and difficult process of improving the process for developing and manufacturing new drugs is a delicate one that requires the right mix of incentives, safeguards, and effective regulation to make sure people can derive the maximum benefit from safe and effective new medical technologies. Only by adopting policies that improve the process for developing new medical technologies while protecting the incentives to develop new innovations and reward cost-effective medical practice and the most high value use of new technology, will we continue to realize the full public health benefits of these innovations. We look forward to working with all of you on these shared goals and appreciate your participation here today. -AMS