Continuous Pharmaceutical Manufacturing
Why the Industry should Accelerate the Adoption of this Technology
The pharmaceutical industry has been slowly, but surely, embracing continuous manufacturing (CM) over the past decade. In fact, most large pharma companies have invested in continuous technologies, though the range has been broad, from single unit operations to end-to-end solutions. Some companies are just getting started, while others have successfully submitted drug applications with significant CM components.
There have been six such drugs approved in the US (Orkambi, Symdeko, and Trikafta by Vertex Pharmaceuticals; Prezista by Johnson & Johnson; Verzenio by Eli Lilly; and Daurismo by Pfizer), three in Europe (Orkambi and Symkevi by Vertex Pharmaceuticals; Prezista by J&J), and two in Japan (Tramacet by J&J and Verzenio by Eli Lilly).
This steadily growing adoption reflects the undeniable advantages CM provides, when compared to the current paradigm, batch manufacturing. First, as CM processes operate continuously, the process volumes are much smaller, requiring smaller unit operations. This reduces the CAPEX for both equipment and facilities. Second, CM processes are automated and require less personnel for operations. Integrated CM processes allow process material to flow directly from unit to unit, obviating storage and manual transport of process material across units.
Third, quality control (QC) testing and related personnel can be significantly reduced, as off-line testing of intermediate products/API/final product would be largely eliminated. Instead, real-time monitoring with process analytical technologies (PATs) and other sensors would allow for continuous monitoring, coupled with closed-loop control. In this way, the process material is constantly monitored, improving quality assurance. In addition, real-time release testing will be possible, reducing the time and cost to commercialization.
“The steadily growing adoption reflects the undeniable advantages continuous manufacturing provides.”
Fourth, in many instances, CM offers higher yield steps and/or ones that require less solvent. In some cases, we have observed that CM reactions can utilize cheaper and less pure raw materials, still yielding in-spec active pharmaceutical ingredient (API) and final drug product.
Fifth, utility costs are significantly reduced. For example, continuous reactors may be maintained at their target temperatures as material flows in and out of them. Conversely, with batch reactors, vessels need to be heated and cooled with each batch.
Sixth, as CM processes operate continuously, cleaning intervals may be performed only as required per validation protocol, and not after every single batch.
Finally, as lead times with CM processes are much shorter, manufacturers may require significantly less inventory and still maintain reliable service levels. Work-in-process inventory can be virtually eliminated, as process material will not be held up at any one point in the process.
These are some of the advantages of implementing CM, many of which will ultimately benefit patients through improved quality and better access; however, there may be others that can become noteworthy as this technology becomes more prevalent.
Integrated Continuous Manufacturing
At Continuus Pharmaceuticals, we are leveraging integrated continuous manufacturing (ICM), a platform that was initially developed at the Novartis-MIT Center for Continuous Manufacturing. ICM spans both drug substance and drug product manufacturing, coalescing these components, which normally reside in different facilities in the batch framework, into a single seamless process that produces final product from raw materials.
The API is not isolated; rather it remains in situ, with its quality ascertained by in-process methods (e.g., PATs). With ICM, an added benefit is that the entire manufacturing process can be engineered intelligently through a systems approach that prioritizes overall efficiency over local performance. Corrective steps can be eliminated as required characteristics are obtained initially, rather than modified downstream (e.g., particle size control through controlled crystallization instead of downstream milling). Finally, incorporating drug substance manufacturing removes the uncertainty of quality and uniformity of sourced API (e.g., if sourced from multiple vendors).
Challenges to Adoption
With all of these benefits, a logical question follows: why the slow adoption? There are several reasons. First, many companies have existing batch infrastructure in place, enabling them to minimize CAPEX for batch-made drugs. With continuous processes, an investment in new equipment/tools is required.
Second, companies have been batch manufacturing for decades, steadily ingraining this production philosophy within their corporate culture. For example, the idea of integrating drug substance and drug product manufacturing is not only revolutionary to many pharma veterans, but it can also be threatening, as it requires a new skill set.
“Integrated continuous manufacturing is a single seamless process that produces final product from raw materials.”
Third, as pharma has been a high-margin industry, R&D has focused mainly on the development of new products and treatment modalities, not improving manufacturing. Especially in the biotech space, companies hold steadfast to their original manufacturing processes, even if they are decades old. Part of the
reason for this position are the costs and regulatory implications of modifying an existing manufacturing process. However, it should be noted that J&J converted Prezista’s approved batch process to a continuous one and is looking to extend this strategy to other products due to the expected benefits.
Finally, there is uncertainty among companies on the regulatory risks of implementing novel manufacturing technologies. Fortunately, regulatory agencies are intelligently positioning themselves to better evaluate advanced manufacturing methods, such as continuous manufacturing. The Emerging Technologies Team (ETT) within the FDA’s Center for Drug Evaluation and Research (CDER) has been working with companies to advance the regulatory science for CM. The Innovative Manufacturing Technology Working Group (IMT-WG) within Japan’s regulatory agency (PMDA) has been tasked with similar responsibilities. Harmonization across
the agencies is further evidenced by the ongoing effort to align guidelines for the industry through ICH Q13, which is focused on continuous manufacturing.
A Robust Solution
Recent events have highlighted the fragile nature of pharmaceutical supply chains. An unfortunate consequence of the Coronavirus outbreak has been the disruption of multiple drugs manufactured in India, many of which contain starting materials and APIs originating from China. But health crises are not the only potential triggers — political disputes may also suspend the flow of critical drugs. These problems only add to existing woes that plague many generic manufacturers, as demonstrated by ongoing warning letters, plant shutdowns, and subsequent drug shortages. Janet Woodcock, director of CDER, emphasized some of these vulnerabilities in a 2019 Congressional Testimony.
“The Coronavirus outbreak has highlighted the fragile nature of pharmaceutical supply chains.”
Continuous manufacturing offers a solution to this problem. Its low-cost structure and environmentally acceptable footprint make it a viable enterprise in countries like the United States. Furthermore, in-country CM of critical drug substances (e.g., ICM) can provide companies a reliable source of these APIs. In fact, Sanofi recently started to build facilities across Europe to bolster its current suppliers. Governments should take note and consider similar strategies, as well as enabling economic and regulatory incentives (see “Why we need continuous manufacturing and how to make it happen” by Clive Badman, et al. for an in-depth analysis).
While slow adoption allows for conservative risk management, it also, in the case of health care, leaves people, often the most vulnerable, behind. Let us take this scourge that has terrorized the entire globe as an opportunity to modernize an outdated manufacturing system and better prepare ourselves for the uncertainty of the future.
CONTINUUS Pharmaceuticals, Inc.