FDA Budget Matters: Investing in Advanced Domestic Manufacturing

By: Scott Gottlieb, M.D.

There’s new technology that can improve drug quality, address shortages of medicines, lower drug costs, and bring pharmaceutical manufacturing back to the United States. At the FDA, we’re focused on propelling these innovations, collectively referred to as advanced manufacturing.

Dr. Scott GottliebAdvanced manufacturing, which includes various technologies, such as continuous manufacturing and 3D printing, holds great promise for improving the American market for drugs and biologicals.

Consider continuous manufacturing. These methods integrate traditional step-wise manufacturing processes into a single system that’s based on modern process monitoring and controls. This enables a steady output of finished drug products even as raw materials are continuously added to the closed system. The closed and continuous nature of these manufacturing systems means that the process is easier to control. These systems also require smaller footprints to operate.

And they’re far more efficient than standard manufacturing processes.

3D printing is another approach to advanced manufacturing. These methods are capable of manufacturing pre-determined 3D geometric structures of solid drug products in various shapes, strengths and distributions of active and inactive ingredients. This approach provides a unique opportunity to produce medicines that are tailored for individual needs of patients.

But harnessing the potential of these innovations requires deliberate private and public investments and new policy development. We need to define how these new technologies will be regulated for their reliability and safety. And provide clear guidance on how they can be adopted by sponsors.

The FDA is taking many steps to help realize the potential of advanced manufacturing. We’ve been issuing guidance on emerging technologies and approving continuous manufacturing for several New Drug Applications. However, to drive an earnest and more efficient conversion to these often-superior platforms, it’s going to take a broader effort on the part of the Agency.

The bottom line is this: Drug makers won’t switch to these systems until we create a clear path toward their adoption, and provide more regulatory certainty that changing over to a new manufacturing system won’t be an obstacle to either new or generic drug approvals. The FDA recognizes that it’ll require additional investment in policies and programs that’ll provide regulatory clarity to enable these new methods to be more quickly and widely adopted. To achieve these goals, the President’s fiscal year 2019 budget dedicates $58 million to accelerate the development of the regulatory and scientific architecture needed to progress this technology.

diagrams of continuous and batch manufacturingMany of the technologies currently used in traditional “batch” drug manufacturing – where the ultimate finished product is made after many stops and starts in a series of steps – are decades old. This shouldn’t come as a complete surprise. Drug development is a risky endeavor. After drug makers have navigated the years of risk involved in discovering and developing a new medicine, the last thing they want to do is inject a whole bunch of uncertainty at the last step toward approval – the adoption of the manufacturing process. So most drug makers have continued to use tried and true methods, even if these conventional processes have shortcomings.

However, this customary calculus is changing.

These continuous manufacturing systems are more ideally suited to new trends in drug development, such as personalized medicine and regenerative medicine products. Drugs that target small patient populations will require much greater manufacturing flexibility. The small scale of continuous manufacturing equipment works well for these endeavors. Close and continuous manufacturing systems can provide cost-effective drug product for early stage clinical development and yet can easily ramp up production for commercialization.

While development trends and market forces have made the commercial impetus for private capital investment in these technologies clear, meaningful adoption will not occur without supporting regulatory science and a collaborative regulatory environment. To drive adoption, the FDA will need to establish clear principles for how these new platforms will be evaluated and approved. We need to invest in the regulatory science to develop policies to support these innovations. That includes, for example, the development of analytical tools for monitoring these continuous systems. While much of this scientific work will be done outside the agency (typically through public and private partnerships) the basic regulatory principles need to be defined by the FDA.

The FDA has recognized and embraced the potential for this technology for years. We established an Emerging Technology Team in 2014 that works collaboratively with companies for both new and currently marketed drugs to support the use of advanced manufacturing.

The FDA’s Center for Biologics Evaluation and Research is building on that effort. We’re advancing the application of continuous manufacturing and other cutting-edge technologies. These manufacturing approaches may be ideally suited to new biological platforms like cell and gene therapies, as well as vaccines. In some cases, these manufacturing approaches may be the key enabling technology for the safe and effective development of these new biological platforms.

Take gene therapy as one example. Many gene therapies are being developed for very small populations ranging from tens to hundreds of patients. It can be costly and slow to build traditional manufacturing platforms to support such small yields, or to switch from a small, research grade manufacturing platform to one capable of supporting bigger trials, or commercial launch. And when it comes to products like gene therapies, a lot of the uncertainty is in how these products are manufactured. So, switching between different manufacturing platforms can create risk.

Applying continuous manufacturing approaches to these products could allow for the development of a quality manufacturing process that could support the production of enough commercial grade product to conduct an initial clinical trial as small as 10 to 20 patients. This would represent one production “cassette.”  Using continuous manufacturing, the scaling of manufacturing for larger trials wouldn’t require the build out of a completely new manufacturing facility. It would just require the introduction of additional “cassettes” into the closed system. Subsequently, if the clinical trial produced definitive data on safety and efficacy, then marketing could commence with product produced by making use of additional manufacturing cassettes. This could have a transformational effect on the costs and feasibility of applying gene therapy to rare diseases.

These manufacturing technologies are not only suited to emerging technologies, but also help address old challenges, like issues with drug shortages and pharmaceutical quality.

Drug shortages are a serious public health issue. What’s not widely known is that quality issues cause the majority of drug shortages. These quality issues are often related to facility remediation efforts and product manufacturing issues. Drug shortages have consequences for patient access to critical and lifesaving drugs. They also can cause prices to rise, in some cases substantially.

Continuous manufacturing systems may be far less prone to the shortcomings that trigger many drug shortages. This technology also reduces the number of steps in the manufacturing process and centralizes all manufacturing steps in one location. Simplification and centralization, in turn, allows for issues to be identified – and remedied – more quickly. In this way, continuous manufacturing helps address the primary root causes of drug shortages. Advanced manufacturing techniques also allow for more flexible manufacturing capacity, which enables manufacturers to respond to drug shortages faster. With these systems, drug makers can more quickly adjust volumes based on product demand and therefore release product to the market more quickly.

This flexibility – and the capacity to increase production easily – could also be important for vaccines; both for seasonal flu and vaccines to combat new outbreaks.

For example, egg-based vaccine manufacturing requires about six months to meet demand, which requires the World Health Organization and public health agencies to predict the flu strand six months prior to the flu season. In contrast, advanced manufacturing has the potential to expedite the process, shortening the amount of time between when the flu strain is selected and distributed.

This can allow us to produce the vaccine closer to the flu season, when we might have more certainty about the circulating strain. It also allows us to switch the strain more easily in the event of an unforeseen change. Or to produce a new vaccine in the event of a pandemic. These approaches also enable easier scaling of manufacturing if vaccine supplies should run short.

This additional flexibility when it comes to manufacturing can also provide a critical boost for emergency preparedness products, enabling manufacturing that can be more easily scaled to quickly respond to new threats. Consider when access to a vaccine is a key strategic need; for example, a vaccine to guard against a bioterror threat. Instead of stockpiling massive volumes of the vaccine; we would instead be able to mothball a just-in-time continuous manufacturing platform. The system could then scale up production in the event of an infectious threat.

Advanced manufacturing also provides an opportunity for the U.S. to regain a leadership position in pharmaceutical manufacturing and bring more high-quality manufacturing jobs back to this country. Many of the products that would benefit from advanced manufacturing are breakthrough-designated drug products that are usually first approved and marketed in the U.S. But many are still manufactured overseas. The traditional approach to manufacturing drugs requires large facilities and a lot of manual labor. Drug makers have made a calculation that these manufacturing sites can be operated more cheaply in countries with lower labor costs.

Continuous manufacturing changes this calculus.

These advanced platforms are small footprint operations. They require a reduced complement of more highly skilled workers. It’s the sort of manufacturing where America excels.

The U.S. is the current pioneer for advanced manufacturing. Our investments in educating engineers and establishing a research base for the development of domestic facilities will ensure that we maintain our lead in the world. Many U.S. universities have already established advanced manufacturing academic programs that train on these approaches. Some are funded through grants from the FDA that were authorized in 21st Century Cures. These approaches have also been applied with success to other fields, such electronic devices and chemical industries.

Producing more drugs domestically doesn’t just mean more American jobs. It could also reduce import costs for manufacturers and increase security of our supply chain.

Continuous manufacturing technologies could save 30 percent in manufacturing costs. This estimate does not include the savings from potential future technologies. That totals $60 billion per year in savings in the United States. This can help reduce drug costs. PCAST estimates that “Continuous manufacturing may reduce manufacturing costs, which currently consume as much as 27 percent of the revenue for many pharmaceutical companies, by up to 40 to 50 percent.”

One example of promising investment in these technologies is recent efforts by General Electric to “launch prefabricated manufacturing units for producing virus-based gene and cell therapies, novel anti-cancer treatments and vaccines.” Innovations like these could make it more feasible for small, innovative biotech companies to enter the market and compete against larger pharmaceutical companies, especially for gene and cell-based cancers. This could provide a broader array of innovation, and infuse more competition into these promising therapeutic areas.

The agility of continuous manufacturing platforms should ultimately reduce costs of drug manufacturing and could provide savings to our health system. But the efficient adoption of these approaches will require a paradigm change in the regulation of manufacturing. And that will require an investment to write new principles for how the FDA oversees these tasks. This is the opportunity before the FDA, and the heart of the proposal in the President’s budget.

Scott Gottlieb, M.D., is Commissioner of the U.S. Food and Drug Administration

Follow Commissioner Gottlieb on Twitter @SGottliebFDA

Additional Resources:

“Continuous Manufacturing” -Common Guiding Principles Can Help Ensure Progress

Establishment of a Public Docket-Submission of Proposed Recommendations for Industry on Developing Continuous Manufacturing of Solid Dosage Drug Products in Pharmaceutical Manufacturing

Spotlight on CDER Science: Modernizing the Way Drugs Are Made: A Transition to Continuous Manufacturing

Emerging Technology Program

Continuous Manufacturing Has a Strong Impact on Drug Quality

By: Lawrence Yu, Ph.D.

If we used a time machine to transport a pharmaceutical scientist from the 1960s into a current pharmaceutical production plant of today, it might be surprising to learn that they would already be very familiar with most of the processes and production techniques being used. That’s because not much has changed in pharmaceutical production over the last 50 or so years.

Lawrence YuFor decades, most drugs have been manufactured using what is known as “batch” technology — a process whereby the ultimate finished product has been made after many stops and starts in a series of steps. Unfortunately each break in the process causes inefficiency and delay, as well as the increased possibility of defects and error.

Today, a new and exciting technology — continuous manufacturing — enables much faster production and more reliable products through an uninterrupted process. How much faster is continuous manufacturing?  In some cases, manufacturing that takes a month by batch technology might only take a day using continuous manufacturing techniques.

Of course, speed alone would not matter if continuous manufacturing compromised quality. But by eliminating breaks between steps and reducing opportunities for human errors during the stops and starts in the batch process, continuous manufacturing is more reliable — and safer. That’s a powerful combination.

There’s the added benefit that more efficient production of quality products can drive down manufacturing costs, possibly resulting in lower drug prices for consumers. Continuous manufacturing also allows manufacturers to respond much quicker to changes in demand, potentially contributing to prevention of drug shortages.

We are seeing a growing number of manufacturers working towards building continuous manufacturing into their processes. One manufacturer, Vertex, the maker of a cystic fibrosis drug called Orkambi (lumacaftor/ivacaftor) has been using the continuous manufacturing process for this drug since its approval date in July 2015.

Last Friday marked another significant step towards integrating continuous manufacturing into pharmaceutical production. FDA approved, for the first time, a manufacturer’s change in their production method from “batch” to continuous manufacturing. This new approval is for manufacturing Janssen Products, LP’s, medication for the treatment of HIV-1 infection, Prezista (darunavir). The company’s efforts in manufacturing advancement were facilitated by the use of FDA’s recently-released draft guidance to industry titled, Advancement of Emerging Technology Applications to Modernize the Pharmaceutical Manufacturing Base, a product of the agency’s Emerging Technology Team (ETT) designed to help manufacturers implement a variety of technological advancements.

Although it is not easy for drug manufacturers to transition from batch to continuous manufacturing, there are significant rewards. FDA encourages others in the pharmaceutical industry to consider similar efforts.

Progress comes at an opportune time. The medications we use are changing. We are entering an era of precision medicine, when drugs must be made with unique features and provided more quickly to patients in need. FDA will continue our efforts to encourage the advancement of continuous manufacturing as one of a variety of ways to enhance the quality of the medications used by the American public.

Lawrence Yu, Ph.D., is FDA’s Deputy Director, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research