The Manufacturing Edge on Path to Market

Pharmaceutical manufacturers employ sophisticated strategies to shorten the time to product launch, but how many consider adopting an advanced manufacturing technology as a strategy to do so? It turns out that manufacturers who have adopted continuous manufacturing have shortened their time to FDA approval and their time from approval to product launch. Might this strategy work for others?

When Stelios Tsinontides joined FDA as director of the Office of Pharmaceutical Manufacturing Assessment in October 2019, he saw the full landscape of global pharmaceutical manufacturing for the first time. He noted there were only six FDA-approved applications using continuous manufacturing for solid oral drug products. Despite his 29-year career in the pharmaceutical industry, he was puzzled as to why so few manufacturers had embraced continuous manufacturing. “I just assumed that many more pharma manufacturers would have embraced this technology given its widespread adoption in other industries,” he explains. Then he set out to understand why. “I heard through our engagements with manufacturers that they had concerns about FDA’s application review delaying their product launches as well as some concerns related to postapproval changes and inspections,” he says.

Now concerned himself, Tsinontides initiated an internal audit of applications to FDA’s Center for Drug Evaluation and Research (CDER), and the findings surprised even his most seasoned colleagues. Rather than delaying product launches, the audit found that FDA had approved applications employing continuous manufacturing three months faster than those employing traditional batch manufacturing. What’s more, these products also hit the market faster after approval. Based on the sales figures for these drugs, these continuous manufacturers enjoyed $100 million–$500 million of earlier revenue based on their shortened launches. “Once I saw these numbers, I knew based on my industry experience that this story needed to be shared broadly with pharma decision-makers,” he says.

Tsinontides wasn’t the only one curious about the slow adoption of continuous manufacturing for pharmaceuticals. In 2020, Clifford Rossi, a professor at the University of Maryland School of Business and a financial risk expert, began to explore the financial aspects of continuous pharmaceutical manufacturing. “For decades, it’s been significantly cheaper to manufacture overseas, especially in China,” he says. “I assumed that pharma manufacturers were not investing in continuous manufacturing due to the financial risks and economics, and perhaps even due to tax rates.”

To investigate further, Rossi developed a stochastic financial model that also showed him something different than expected. Continuous manufacturing in new facilities provided economic benefits and even an economic advantage for US manufacturers as compared to batch manufacturers abroad. He found the contribution of continuous manufacturing to the expected net present value over the life cycle of a drug to be nearly $500 million. “When comparing investments in continuous or batch strategies for a new US facility, the results clearly suggest that the lower costs associated with continuous manufacturing should lead to more investment in it—even for generic firms,” he says. “It seems that continuous manufacturing may not only be worth the investment, but its adoption could also help to reshape global pharmaceutical supply chains.”

As the data from CDER’s audit and the University of Maryland study began to trickle in, Tsinontides started to wonder how FDA had approved applications with advanced manufacturing technology so fast. He reached out to his colleague Sau “Larry” Lee, PhD, senior scientific advisor to CDER’s Emerging Technology Program, to understand. “For those wishing to adopt a new technology, CDER created an Emerging Technology Program to allow early engagements with the agency, even prior to filing a regulatory submission,” informs Lee.

Formed in 2014, the program allows an organization to meet with FDA experts from review and inspection programs to discuss and resolve potential regulatory issues prior to filing a submission. It turns out that all of the FDA-approved continuous manufacturing applicants had engaged with CDER’s Emerging Technology Program. “We’ll engage with those adopting new technologies, and our early interactions do not even need to be product-specific,” says Lee.

The application to participate in the Emerging Technology Program is a straightforward document with a five-page limit that includes basic items such as a description of the technology and an explanation as to why it is substantially novel. “It’s very important that applicants to the program describe how their proposed new technology could potentially improve product quality,” Lee notes. “We try to develop familiarity and internal expertise on their technology so we can carry that forward to the application assessment and facility inspection.”

Pharmaceutical manufacturers that move toward adopting advanced manufacturing benefit from increased support from FDA in the short term and can reap the rewards of using an advanced technology in the long term. The Emerging Technology Program has not only been effective in helping manufacturers expedite their product launches, but it is also well-received by participants who rate their satisfaction with the program an 8.9 out of 10 in exit interviews. Of course, a technology cannot remain emerging forever. This high level of regulatory engagement on continuous manufacturing will not continue indefinitely as technologies mature and adoption becomes more widespread.

Engagements with the program may explain how continuous manufacturing applications were approved quickly, but Tsinontides still wondered how these products had hit the market faster after approval. Most pharma manufacturers employ batch manufacturing, a process in which material is manually moved from one unit operation to the next, and product is made one batch at a time. Drug manufacturing has largely been conducted this way since the middle of last century. “After approval, batch manufacturers typically need to complete scale-up transfer, which can involve qualifying larger equipment, updating processes, and completing performance qualification for the commercial-scale process,” explains Tsinontides. “All of this takes time and effort.”

Many industries such as commodity chemicals and food processing have embraced continuous manufacturing as their default means of production, due to advantages including shorter processing times, reduced waste, and a smaller footprint. Continuous manufacturing uses an unbroken flow of material from one unit operation to the next with no stops in between, bringing opportunities for improved efficiency and fewer errors. “Continuous manufacturing also allows for agility related to production timing and rate, and is not necessarily a 24/7 production,” says Tsinontides.

While multiple factors can determine the time between drug approval and marketing, manufacturing scale-up by increasing equipment size is often the bottleneck. Continuous operations, by design, require fewer process and equipment changes to reach commercial-scale operations. Changes to accommodate the commercial scale in continuous processing typically involve simply increasing the run time on the same equipment and with the same controls. The decrease in time to market after approval, alone, accounted for $50 million–$125 million of the early revenue for continuous manufacturers.

FDA’s audit also looked at the regulatory burden for those adopting continuous manufacturing, related to making postapproval changes and being subject to pre-approval inspections. The FDA audit found that there was not a substantial difference in the number of process changes reported by batch and continuous applicants. However, continuous applicants reported no changes related to equipment, processing conditions, or batch-size range. Tsinontides says, “This observation aligns with the fact that continuous processes are often designed to have inherent flexibility to tailor production to demand.”

An FDA pre-approval inspection was conducted for the majority of batch products and all of the continuous products. “While continuous applications had more process-related issues observed during inspections than batch applications, it stands to reason that as FDA’s confidence in continuous manufacturing increases, the need for pre-approval inspections and the number of process-related issues should lessen,” contends Lee. The most important finding for continuous manufacturers was that pre-approval inspections did not adversely impact application approval timelines, as all were approved in the first FDA review cycle ahead of the goal date.

Owing to his engagements with technology developers in the Emerging Technology Program, Lee found another issue faced by manufacturers wanting to adopt continuous strategies. Many had faith in FDA’s willingness and ability to approve continuous manufacturing applications but had doubts about that of other global regulators. Often manufacturers deal with dozens of global regulators for a single international product launch.

To address this problem, Lee initiated an international effort to describe harmonized scientific and regulatory considerations for continuous manufacturing. The result was an international guideline on continuous manufacturing dubbed ICH Q13. “The goal of ICH Q13 is to commit regulators to consistent adoption of consensus-based guidelines to realize the benefits of continuous manufacturing for patients as well as industry,” says Lee. The ICH Q13 guideline has undergone global public consultation and is expected to be finalized before the end of the year. FDA’s hope is that manufacturers will have more confidence in the global regulatory support for continuous manufacturing adoption.

As continuous manufacturing transitions from the innovators to the early adopters in pharma, it seems the question is when, not if, pharma will broadly embrace continuous manufacturing. The rapidly changing demand caused by COVID-19 displayed the value of manufacturing agility and the problems caused by long, tangled supply chains and time-consuming manufacturing technology transfers. Many saw continuous manufacturing as a potential solution to these problems.

As continuous manufacturing hit the spotlight in 2020, so did its funding. The federal government alone awarded nearly $500 million to companies developing domestic continuous manufacturing technologies. Some of these technologies now approach maturity and regulatory filings, leaving FDA in a challenging but promising position.

Adam C. Fisher, PhD, Director of Science Staff, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, FDA