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Continuous manufacturing is a trend in the pharmaceutical market that seems to always be at the forefront of the news. With the FDA giving the thumbs up to companies transitioning from batch to continuous manufacturing, such as Johnson & Johnson, one thing has become apparent: this is one trend that isn’t going away any time soon.
In addition, continuous processing/manufacturing continues to be a commonly-discussed topic at industry trade shows, such as INTERPHEX.
Bayan Takizawa, MD, MBA, Co-Founder & Chief Business Officer of CONTINUUS Pharmaceuticals—a spin-out of the Novartis-MIT Center for Continuous Manufacturing—participated in a Q&A with Pharmaceutical Processing on continuous manufacturing operational best practices as well as trends for 2017. His edited responses are below.
To start, could you tell us a little bit about your company and what it is that you do?
CONTINUUS Pharmaceuticals is a spin-out of the Novartis-MIT Center for Continuous Manufacturing, a $65-million collaborative effort between a leading pharmaceutical company and a major research university. CONTINUUS is leveraging the novel continuous manufacturing platform that was developed at the Novartis-MIT Center: Integrated Continuous Manufacturing, or ICM. With ICM, drug manufacturing processes can be improved significantly, providing substantial benefits to companies and, more importantly, to patients.
CONTINUUS is working with pharmaceutical companies to improve their manufacturing processes. More specifically, we develop ICM processes for our clients’ compounds, which are currently produced via the outdated batch manufacturing methodology. As they transition their manufacturing processes to ICM, they will realize considerable benefits. We are also working with the National Science Foundation through a Phase II Small Business Innovation Research (SBIR) grant, and the U.S. FDA and Biomedical Advanced Research and Development Authority (BARDA) on a $4.4 million/three-year project to develop a science- and risk-based approach on how drug quality can be monitored and improved through ICM.
What are some of the benefits of continuous manufacturing? The downsides?
With ICM, the manufacturing lead time and plant footprint are significantly reduced. This is because processing times are decreased, unnecessary steps are eliminated, and the entire process is streamlined from start to finish (no more stops and starts). In fact, at the Novartis-MIT Center, they were able to optimize a process that normally takes 200 days to just two days. These major differences result in lower manufacturing costs, which will increase patient access through price reductions, as well as enable manufacturing to be done in the United States instead of outsourced abroad. Finally, drug quality will be improved through a plant-wide Quality-by-Design approach. In this way, the production process is constantly maintained in a state of control, ensuring high-quality drug products are always produced. Conversely, with batch manufacturing, batch-to-batch variability often results in inconsistent quality.
There are no downsides to continuous manufacturing—it is more advanced and better than the current standard, batch manufacturing. One major challenge for adoption of this novel manufacturing paradigm is that there already exists excess batch manufacturing infrastructure. In addition, pharmaceutical companies are cautious when implementing novel manufacturing practices because they are not sure how the regulatory agencies will respond to them. We believe, however, that agencies like the FDA understand the benefits of continuous manufacturing and are encouraging industry adoption. In fact, our recent contract with the FDA and BARDA indicates their interest in developing expertise on the subject matter.
Are there any instances that batch operations might be preferable to continuous manufacturing?
There may be some drug compounds that are better manufactured through a batch process, but we have not seen many. For example, some drugs may be formed through reactions that are not suitable for a continuous process. Fortunately, in many of these cases, we can modify the chemistry and offer a continuous synthetic route that is advantageous. Also, as previously mentioned, if a company has excess batch manufacturing capacity, it may not want to invest in novel manufacturing infrastructure.
Is continuous manufacturing more beneficial for certain types of companies or operations, as compared to others?
The operational benefits, which ultimately translate into lower cost of goods sold (COGS), are more critical for generic companies that have lower profit margins. However, the level of these COGS reductions (30-50 percent) is also significant for brand name pharmaceutical companies that are trying to reduce their cost structures.
What challenges do companies looking to implement continuous manufacturing at their facilities often experience?
One major challenge is the existing batch infrastructure that many companies already have in place. When this occurs, companies are reluctant to invest in novel machinery. Another challenge is the pervasive mindset of the industry that pharmaceuticals should be produced via this outdated methodology simply because that is the way it has always been done. This is reinforced by the notion that regulators will balk at approving novel processes. We consider this belief erroneous, based on actions taken by the U.S. FDA and other regulatory agencies (e.g. the FDA has approved drugs produced in a continuous fashion). Also, there is a lack of experience in continuous manufacturing at most pharmaceutical companies, which is a result of decades of batch manufacturing.
What are some of the operational best practices for continuous manufacturing and how can companies implement these into their process/facility?
We believe that an end-to-end approach should be the best practice for the pharmaceutical industry. In this way, the entire manufacturing chain, from start to finish, can be optimized to eliminate unnecessary corrective steps that just add cost and time to the process. The mantra should be: get it right the first time.
Another best practice should be plant-wide integration, whereby the individual unit operations are intelligently integrated and critical process parameters are monitored in real-time. As these parameters drift, immediate corrective actions need to be executed in an automated fashion to maintain the entire process in a state of control. This will allow manufacturers to predict and maintain the final drug product within the desired specifications. Consequently, we can eliminate batch-to-batch variability and improve pharmaceutical drug quality.
The use of novel unit operations that allow and/or enhance continuous processing of drugs would be another best practice. This can have many benefits, including reduced residence times and overall lead times, which should lead to reductions in inventory levels.
Currently, most companies that engage in continuous manufacturing do so in a piece-meal or fragmented manner. They are already seeing benefits from this transition; however, we believe there is much more to be gained once an end-to-end strategy is implemented.
The FDA has become a strong advocate for continuous manufacturing. Why do you think that is?
We believe that the FDA’s rationale for advocating for continuous manufacturing stems from the improved drug product quality that can be obtained from these novel processes. We have all heard of the plant shut downs and drug shortages that have resulted from substandard manufacturing practices. Ultimately this impacts patient care. In addition, as companies streamline their processes and significantly reduce manufacturing lead time, their supply chains will become more flexible and responsive. In this way, companies will be able to respond quickly to changes in demand and ensure that life-saving drugs are accessible. Finally, with continuous manufacturing, costs are substantially reduced, which should also improve patient accessibility.
A number of industry professionals are hesitant to take the plunge and change to continuous manufacturing operations. Why do you think that is? How much does cost play into this?
Many industry professionals would rather maintain their current manufacturing practices because of their deep-rooted comfort level with this methodology. Traditionally, the drivers for cost reduction in pharmaceutical manufacturing have not been compelling, as the industry has enjoyed large profit margins. However, with current cost pressures and the emphasis on improved drug quality, many companies are taking initial steps toward modernizing their manufacturing processes. That is why so many companies have started to implement continuous manufacturing in some form—they have realized that the long-term benefits greatly outweigh initial investment costs.
Other companies have expressed concern about whether a continuously manufactured drug product will be approved. Do you foresee more drugs manufactured using continuous manufacturing will be approved in the future?
There is nothing in the regulatory guidelines that require manufacturing processes to be batch. In fact, the FDA has already approved continuously manufactured drugs (e.g. Vertex’s Orkambi). Thus, we believe that this regulatory concern is exaggerated. The FDA and other regulatory agencies have been proactive in learning more about this novel manufacturing platform and consistent in their actions.
What trends are you seeing in continuous manufacturing right now?
We are seeing an increase in interest in continuous manufacturing—not only from innovative pharmaceutical companies but also generic companies. The reasons are diverse, as the benefits of continuous manufacturing are broad. Also, there are more and more companies interested in explore end-to-end solutions.
What do you foresee for the future of continuous manufacturing in 2017?
This trend will continue, and more companies will invest in continuous manufacturing technologies. These investments will provide a significant competitive advantage to early adopters. As the pharmaceutical manufacturing industry evolves, higher-quality drugs will be produced faster and more cost effectively, ultimately benefiting patients around the world.