In your opinion what is the current level of adoption of continuous pharmaceutical processing technologies in the industry?
Dr. Rapti Madurawe, Director, Division of Process Assessment I, Office of Process and Facilities, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, U.S. Food and Drug Administration: FDA is seeing an increased level of interest in continuous manufacturing of pharmaceuticals. Companies are developing continuous processes for the manufacture of drug substance and drug product. Continuous processes are being used for new products as well as for post-approval change of the approved batch process. Several drug products manufactured with continuous processes have been approved by the FDA. We also see companies building on their experience with the first approved continuous process to develop their next continuous process in the product pipeline.
Eric Langer, President & Managing Partner, BioPlan Associates, Inc.: For many reasons associated with efficiency, productivity, and smaller footprints, etc., continuous bioprocessing is clearly a direction most industries, including bio/pharma seek to take, theoretically. However, at present, to be fully continuous, the unit operations must generally all be continuous. Upstream continuous processes have been around for decades, but downstream processes continue to evolve into more efficient continuous operations.
Girish K. Malhotra, PE, EPCOT International: There is a misconception that continuous manufacturing is an off the shelf technology that can be applied in the API manufacturing and formulations of products. That is not true. Process technology selection decisions are made on the basis of “SINGLE” product demand and process economics. Generally, continuous process equipment due to chemistry is designed for a specific API product. Companies may not be able to use this equipment for other products. There are exceptions but they are rare. However, for continuous formulation the same equipment could be used but again, it has to operate and produce products (same API has to be formulated in different dosages using the same equipment) for more than 7,000 hours per year.
Merrilee Whitney, Head of Next Generation Bioprocessing, Merck: We see that this is an evolution beginning with process intensification and growing over the next five to ten years into a continuous manufacturing process, and is already taking place in the industry. Most of the major bio- and pharmaceutical customers as well as some CMOs clearly see the vast benefits of process intensification and have active programs and dedicated teams in place. According to our market research, it is estimated that roughly 35% of today’s commercial molecules will utilize process intensification methods in the near and mid-term. Our research suggests a larger adoption rate for new molecules in development, with cell line/media optimization and flow-through chromatography being well-established. However, lifecycle products may only adopt elements of intensification to optimize current processes. While many of the companies interviewed for our research have adopted elements of intensification, very few considered their processes fully intensified or continuous.
Peter Levison, Executive Director Business Development, Pall Biotech: Continuous processing is still in early adoption phases across the drug manufacturing industry, but there is already a great deal of progress for such early phases. Regulatory bodies, such as the US FDA, have been supportive, and even encouraging of, the advancement of continuous processes to enable further innovation in the drug treatments and therapies being developed for end users. In fact, small molecule drug manufacturers, such as Janssen (Prezista) have already successfully implemented commercial-scale continuous production processes.
As demand grows for safer, higher-quality and more efficacious drugs that are also more affordable, industry has been forced to find new ways to improve the production process. Even just ten to fifteen years ago, manufacturers were hesitant to accept/apply singleuse technologies. But market demand helped make single-use technologies an innovation enabler, and while they are not yet fully standardized, adoption is increasing. We expect a similar trajectory for continuous processes across the drug manufacturing market but predict that industry will adopt it more quickly.
Dave Sternasty, Vice President of Corporate Engineering and Global Health, Safety and Environment, Eli Lilly and Company: We believe that adoption of continuous manufacturing is trending positively and that different companies are at different points in their journey, experience or plans for adoption.
What are some barriers that need to be overcome in order to advance the uptake of this technology? On the part of pharmaceutical companies, is it a lack of confidence, a lack of successful examples, or just an unwillingness to change?
Madurawe: FDA generally gets favorable feedback on continuous processing. That said, implementing continuous manufacturing does require a capital investment up front. There is also a learning curve involved the first time a company implements a continuous manufacturing process. Constraints like these may pose a challenge for some companies, particularly when considering their existing investment in batch manufacturing. It is up to each company to decide whether continuous manufacturing is a practical approach for a specific product in their portfolio.
The monetary advantages of continuous manufacturing are more likely to be realized over a longer timeframe. Continuous manufacturing facilities and equipment are significantly smaller compared to batch manufacturing. These can reduce operational costs such as utility usage, waste, solvent use, and staffing, among other considerations. Continuous manufacturing also naturally lends itself to rapid process development, and a batch size increase is usually achieved by increasing run time without requiring a change to equipment size. This can help reduce the time from development to market. Since continuous manufacturing also allows for more nimble testing and control, it can help reduce the likelihood of manufacturing failures.
Langer: According to the BioPlan annual reports, a great majority of the industry is more comfortable with batch operations, and sees the complexity, training, and logistical requirements associated with continuous processes, such as perfusion bioreactors to be daunting. Rightly or wrongly, the impression of the risks and complexity associated with these devices exists. The industry has moved toward unit operations focusing on ‘process intensification’ rather than fully continuous, end-to-end processing.
Malhotra: Barriers are a combination of confidence, unwillingness as well as regulatory bodies. Once the product is commercial no one wants to change as they have to spend money to convince regulators of bio-equivalency. Since significant monies are being made with batch process, why take on unnecessary aggravation of dealing with regulators.
Whitney: Next Generation processing, as we consider it, is an evolutionary manufacturing approach beginning with unit operation optimization and evolving to connected, intensified processes with the potential of a fully continuous process – hence the uptake of this methodology takes time. Despite the fact that enabling technologies already exist, some still need to be improved and current technological gaps filled. System complexity, in-line monitoring and online analytics (e.g. PAT), or holistic, integrated process development expertise, are only a few known hurdles to adoption. The same applies for regulatory guidance which requires further evolution. For example, how will regulators define a batch in the framework of next generation biomanufacturing? This industry paradigm shift towards next generation processing represents a new mind-set for both management and process developers – even a totally new company culture for some of our stakeholders. The fact that there is no templated approach yet for the successful implementation of next generation bioprocessing, versus well characterized and heavily regulated pharma industry, may outweigh the clear potential this new way of manufacturing drugs will bring.
Levison: It’s a risk adverse industry to some extent because of the regulated nature of drug production. However, due to market changes, the time frame for accepting new, enabling technologies has become shorter. The industry is facing demand to produce more complicated molecules more efficiently and at a lower cost, so acceptance of more efficient approaches is not just nice to have – in some cases it is critical.
Sternasty: While there are a number of advantages that drive the adoption of continuous processing, there can be some concerns, some of which are true challenges and others may be perceived barriers. Those include:
- Alignment around the business case for moving to continuous processing, especially when a significant amount of existing batch process capacity or existing products are made reliably by batch processes.
- Questions around regulatory agency support or other concerns outside of the large market regions, which may be less familiar with the technology.
- Unfamiliarity with the technology in general and working through development of appropriate control strategies and supporting systems that come with transition to any new technology. For example, the level of process automation, use of Process Analytical Technology (PAT) and use of models can all contribute to some of the key advantages of the technology, yet they may require a different level of understanding and expertise from what some are doing today.
- Ability to integrate the technology into business and quality systems appropriately. While there are some questions (e.g., definition of a batch, management of larger process data sets, control and release of material, etc.) that need to be answered, we believe these are all manageable.
Globally, do you see differences in the adoption of continuous processing techniques/technologies? What has your experience been with the various global regulatory agencies? Have they been supportive? Non-committal?
Madurawe: FDA has discussed continuous manufacturing with the European Medicines Agency and the Japanese Pharmaceuticals and Medical Devices Agency. All three agencies have given presentations at continuous manufacturing workshops. The three agencies recognize the potential benefits of continuous manufacturing and support its adoption.
Malhotra: I do not see anyone adopting continuous manufacturing for API and formulations. Everyone dances to the FDA tune.
Whitney: There is no “one size fits all” solution and no established industry standard for what next generation manufacturing looks like, resulting in substantial diversity. Every organization has their own approach and implementation strategy based on their most critical needs and process bottlenecks. As industry adoption evolves over time, there will likely be an industry accepted template. Regulatory bodies are advocating in favor of next generation processing as they see the high potential of reducing the manual handling of products, as well as for better process control. Finally, we see collaborations between pharma manufacturers, regulatory agencies, industry associations and suppliers as key. A concrete example is the collaboration realized with one of our customers and the FDA on “inline virus spiking for linked polishing steps”. To familiarize the FDA with this novel approach, we presented this next generation processing method to them, in order to prepare for their review when filing the drug. This collaborative model is what is needed to advance the industry.
Levison: Continuous bioprocessing is being discussed globally. To our knowledge there is no region in the world that is not including continuous bioprocessing as integral themes for conferences and webinars etc. Particularly in Asia, we see great interest in rapid adoption and workforce training to evolve towards continuous processes. Similarly, the regulatory agencies have been supportive of moving towards continuous processes for the future.
Sternasty: Different markets are at different points with regards to their experience and the number of approved drug applications using continuous manufacturing. Both the U.S. Food and Drug Administration and European Medicines Agency have been very supportive and collaborative in encouraging and expecting the use of the technology to realize the potential advantages of the technology, which is consistent with similar approaches in the food and chemical industries. For example, the U.S. now has multiple drug products on the market made by this technology. We believe that trend will continue, and that we will see increased adoption of this process over time through global marketing of already approved products as well as new drugs as more manufacturers and regulators become experienced with continuous manufacturing.
As a supplier of techniques, technologies and expertise – what do you see as your role in promoting continuous processing technologies?
Madurawe: FDA created the Emerging Technology Team (ETT) to help facilitate implementation of novel pharmaceutical technologies, including continuous manufacturing. The ETT responds to presubmission questions and proposals about advanced pharmaceutical manufacturing technologies. The ETT also identifies potential gaps and policy issues and facilitates their resolution. More details on the ETT are given in the Guidance for Industry “Advancement of Emerging Technology Applications to Modernize the Pharmaceutical Manufacturing Base.”
The ETT helped support FDA’s approval of four continuous manufacturing products so far, including the first new drug product made using continuous manufacturing and the first switch from a batch process to a continuous process for a previously approved product.
The FDA has also used external grants, internal research activities and process modeling to better understand continuous manufacturing processes. Process modeling can help scientists determine how changes in process parameters affect drug quality.
Malhotra: Equipment and methods for continuous manufacturing have existed for more than 60+ years. However, with the product being under limited patent life and due to marketing pressures to get the product to the market no significant effort is made to commercialize the most optimum and economic process. Companies know that the patient will pay the price to get well and extend their life. When the product goes generic, many file for ANDAs and economies of scale are lost and commercialized processes are generally batch processes.
Whitney: Next generation processing is innovation through collaboration. It is a powerful triangle encompassing customers, suppliers, regulators, academics, government agencies and industry associations working collaboratively. The approach must be holistic from upstream down to final fill in order to be successful. Suppliers also need to develop truly integrated and automated solutions for our customers, enabling them to achieve their targeted goals for speed to market, cost savings, and quality improvement. Awareness and education through real case studies and practical hands-on training courses can demonstrate the value and promote next generation processing technologies, while installing confidence that this is the right path forward.
Levison: It sounds cliché, but Pall Corporation was built on innovation. Our team takes pride in advancing the markets in which we serve with mission-critical equipment, systems and consumables, complemented by exceptional customer service and support.
From the beginning, Pall Biotech was a leader in stainless steel equipment. As the industry evolved, we became an early pioneer in the development of integrated single-use technologies. Now, our team is focused on leading the industry in bringing full-cycle, scalable continuous bioprocessing solutions to fruition. We are also fully committed to working with industry associations, educators, partners and clients to get there.
Sternasty: Our efforts to implement continuous manufacturing required significant internal efforts to develop, optimize and implement the technology in Lilly’s Development and Manufacturing organizations. During that time, our internal efforts were augmented with shared learning with other companies and vendors, especially with companies that had made significant progress or already had approved products using the technology. This occurred through participation in various technical conferences and events, collaboration on published scientific literature, and one-on-one benchmarking. We also have been part of Industry consortia to develop positions that can inform regulatory guidance or positions on specific topics related to continuous manufacturing. Lilly maintains an active agenda across these areas, and we plan to continue to encourage and support further advancement and adoption of this technology, while shaping the environment.
In your opinion, will continuous processing become the preferred method for manufacturing pharmaceuticals? Or, will it become one of several available technologies available in a manufacturer’s toolkit?
Madurawe: There is plenty of room for batch processing and other technologies in pharmaceutical manufacturing. Many factors impact the selection of the manufacturing process for a given pharmaceutical. For example, the dosage form, formulation, unique attributes of the drug molecule, operational ease and safety, number of units needed, quality attributes necessary for clinical performance, etc. It seems unlikely that any one approach would be suitable for the wide variety of the current and future pharmaceuticals. As previously mentioned, it is up to each company to determine whether continuous manufacturing is a practical approach for them and for the specific drug under consideration.
Langer: The BioPlan annual report evaluates the trends associated with adoption of various bioreactor types at clinical scale for new production. This is an indication of the trends associated with broad adoption at commercial scale. We find relative stability in terms of adoption rates over time, except with single-use perfusion bioreactors. These devices have shown a rather consistent increase over each of the past 5 years. In comparison, for batch-fed stainless steel bioreactors, the trends are flat or slightly declining for adoption at clinical scale.
We can project that, similarly, we will see continuous devices increasing in adoption, as long as their use meets the demands of the facility, especially in terms of cost, operations, and productivity.
Whitney: The industry needs to be much more efficient in how it manufactures and supplies products. Pharmaceutical manufacturing platforms need to be agile, able to adapt to specific requirements, extend capacity rapidly, and able to react to market demand quickly. However, it is critical to remember that continuous processing is not always the goal. Continuous processing is only one potential solution in an effort to increase process flexibility, speed, and quality while lowering cost. We must offer a set of solutions from which the proper technology can be selected to meet the end-user’s goals. The final choice of which process technology or manufacturing approach to take, whether it be hybrid, semi continuous, fully continuous, fedbatch, batch, depends heavily on the desired outcomes and specific situation of each customer. Within our next generation processing program, we truly consider what makes the most sense for our customer’s set of circumstances.
Levison: We see it as an evolution of technologies. A lot of the fundamental building blocks of the process and theories of application remain the same. Generally, a continuous process will use the same buffers, chromatography media, membranes etc., that are used in a current batch process only they are used in a slightly different way.
It is a misperception that the transition from batch to continuous processing is challenging - that is not actually the case.
As an industry, we must look to innovate across the board, and introduce technologies that can help change the direction of processes for the better. There is no point in seeking to implement continuous processes for drug production if they can only be used in the lab - scalability is critical.
Sternasty: There are a number of advantages for this technology, which provide compelling reasons for adoption. For example, we have found that our continuous direct compression platform provides additional robustness that shows continuous processes may be advantageous for an even wider range of products than batch process platforms. However, there may be certain situations where continuous is not possible or less preferred due to specific technical limitations or other non-technical (e.g., business) reasons. Additionally, adoption and broadening the use of this technology will take time. That means continuous process should remain part of set of available technology platforms. However, as experience, familiarity and expertise grow in continuous technologies, we expect it to be used across an increasing number of products and portfolios.
Finally, can you tell us what you see as the future for continuous processing?
Madurawe: As noted in FDA’s 2018 Strategic Policy Roadmap, continuous manufacturing remains a priority for the agency. We’re encouraged by the progress we have seen in the development and implementation of continuous manufacturing processes. Some of the continuous processes that were first approved by FDA are now approved by several other global health authorities. We see some contract manufacturing organizations (CMO) getting involved in continuous manufacturing. We hope these types of positive movements will facilitate the adoption of continuous manufacturing by a broader array of pharmaceutical companies.
Langer: The pharma/bio industry is aware of the benefits of continuous bioprocessing, and process intensification. But there is likely a long learning and adoption curve for new devices being introduced into a GMP environment, and many regulatory questions are still unanswered, or are evolving slowly. As with single-use devices, which have taken decades to become mainstream, continuous process evolution, and the benefits they will offer, are likely to come slowly.
Malhotra: For API the answer is NO.
For formulations there is a distinct possibility but the business model will have to change. “Creative destruction” could do that but possibilities are minimal at this point
Industry has not realized the ramifications of “continuous manufacturing” and its impact on the total pharma landscape when it comes to contract manufacturing. Companies practicing “continuous manufacturing” will keep the technology in-house and that means the number of overall contract batch manufacturing companies will be significantly reduced. Impact of this is going to be a changed landscape and reduced pharma employment. No one is thinking the short-term ramifications/impact of the technology. All will find its level but unless the industry opens it thinking to other ideas, the downside impact might not be pleasant.
Whitney: We see this as an evolution that will happen over the next five to ten years, starting with process intensification technologies. As we have an extensive knowledge of our customers’ processes, we can strategically evolve their manufacturing process to fit their growth plans. Flexible, modular and automated facility design, integrated plug-and-play end-to-end solutions, digital tools, and singleuse will continue to play a critical role in the future of continuous processing. Broadening up the holistic view of bioprocessing beyond integrated upstream and downstream solutions to include the supply management aspect will also be indispensable in the future to alleviate demand uncertainty.
Levison: This is a data-driven industry, and right now, a lot of exploration and resulting data is being published about continuous processes, with a promising outlook. Just as single-use technologies transitioned from undesirable to completely acceptable, continuous processes will continue to gain traction - the efficiencies in time, footprint, operations, and process resources are just too hard to ignore.
We expect that just as we have seen with single-use technologies, the industry will realize the need for continuous process automation and standardization as these approaches become more feasible and scalable. And just as Pall has been active in the continued adoption and maturation of the single-use sector, we are working hard to align as a key contributor to the continuous standardization process.
Unlike single-use technologies, however, we expect continuous adoption to happen much quicker - perhaps even within the next decade!
Sternasty: We think the future of continuous manufacturing is bright based on the progress made to date, especially in small molecule/drug product and applicability of the concepts to other types of processing.
Each company is at different phases and may have its own challenges to work out, but we believe these can be addressed by not only sharing within given technology platforms and therapeutic areas but across those boundaries as well. Ultimately, we think this will result in a win not only for Industry, but, even more importantly, for the patients we serve.