Analyzing The Business Case Drivers For Continuous Drug Product Manufacturing

By Lawrence De Belder, Johnson & Johnson

These are exciting times for us, the continuous manufacturing enthusiasts.

Many large pharmaceutical companies have realized the benefits that continuous manufacturing can bring and have invested in equipment lines (or are planning to do so). Health authorities and government organizations are seeking ways to stimulate the deployment of continuous manufacturing in the industry, because they too see advantages for public health, be it better process control or shorter time to market. Technology vendors and service providers realize this is not a niche market anymore, but the way of the future, and are preparing to play a role as well. Universities are conducting research on materials, equipment, and process analytical technology (PAT) and modeling. And all of these combined efforts  are generating knowledge and understanding that will help to the industry achieve the benefits that continuous manufacturing has long promised.

Batch Vs. Continuous

The drawbacks of current batch processes are many:

• Long cycle times
• Labor intensive — it takes a lot of people to make a batch
• Large facility footprint — multiple rooms are required to accommodate several stages, and material sits around taking up space while waiting to be released High levels of variability
• Inefficiency — quality is only measured after making large batches, which always carries a risk of having to be completely discarded
• Significant material and effort requirements — for development, and again to transfer the product toward commercial production (because processes in larger-scale equipment must be proven to be equivalent)

Continuous manufacturing promises to solve all these issues. Cycle times can be reduced from weeks to hours. A line can be run with only a few people, on a small footprint, and without work in process — which reduces cost, lowers inventory, and increases supply chain reliability. Quality can be monitored continuously, and overall variability is lower. Product can be developed and transferred with much less material and effort, and in some cases this can result in faster speed to market.

But is this always the case? And if so, why isn’t everyone deploying this technology on large scale in their commercial network?

In order to overcome the barriers to complete industry deployment of this technology, we need to gain a better understanding of the different types of benefits that are being used in business cases — and also of the pitfalls that prevent companies from reaping them or their leaders from approving the necessary budgets. The benefits of continuous manufacturing can be bucketed into three main categories: commercial, product development, and technology transfer. Each category of advantages will have a different focus, and each will have its own factors (benefit drivers) that carry more weight than others.

Commercial Benefits

Manufacturing of oral solid dosage drug products involves many process steps: chemical weighing, bin blending, milling, spraying liquid preparation, granulation, drying, blending, compression, and coating. In traditional batch operations, each of these processes (unit operations) takes place in separate rooms, involves operators, and yields half-finished material that needs to be transported and stored. These unit operations take up expensive GMP conditioned space,  require maintenance, and consume a significant amount of energy. In several of these steps, the quality department must first evaluate the process and release the half-finished product before it continues to the next step, resulting in very long cycle times. At the end of production, when the batch is finally finished, samples are taken and are sent to the lab for analysis. If the batch is within specifications, it is released to be sent to the market, but the risk having to destroy the complete batch due to out of specification results always exists.

Continuous manufacturing completely changes the old paradigm.

This new technology combines all processing operations into one machine, where excipients and API are continuously fed in, material continuously moves through all process steps, and a continuous stream of finished tablets comes out the back end of the line. Strategies must be implemented to ensure consistent quality, though this can be accomplished with process analytical technology (PAT) devices, models, and soft sensors, or a combination of the three.

With continuous manufacturing, there is no half-finished material between steps — no need to release, no risk of material expiring, and lower inventory of materials. One machine in one (multi-store) room means fewer operators and no transportation or cleaning of bins. Because there is only one batch record, batch record review is simplified. Smaller equipment also means less energy and water consumption, as well as smaller hold-up volume, resulting in better yields.

In continuous manufacturing operations, inventories and safety stocks are calculated based on cycle time, and shorter cycle times mean lower inventory. Aside from all these financial benefits that feeding into a lower cost of goods, consistent measuring of quality also gives you better process understanding. This means that if ever material is out of specification, it can be immediately diverted or the process can be stopped, limiting the amount of material to be rejected. Measuring quality (blend uniformity, humidity, dissolution, etc.) in-line instead reduces demand on the lab, which provides an additional benefit.

Needless to say, the commercial drivers of continuous manufacturing can be significant.

However, most of these benefits must be based on assumptions: real yields, cleaning and changeover times, and energy and water consumption will probably have to be estimated without having the actual equipment in house. Also, the reduction in lab effort occurs after a transition period: In the beginning, more effort is actually needed. Conventional analytical methods might need to be used in parallel to prove the in-line measurements are adequate. It might even be necessary to launch with parallel methods, only to switch off conventional lab tests after collecting enough data.

Workforce estimations should take into account the supporting functions that will be required to run and maintain a highly automated line in a more complex environment, where models and statistics rule. Operators will need higher skill sets — not only because of the complexity of PAT and model-based control strategies, but also because a flexible continuous manufacturing operations will likely require operators to be competent in running all unit operations(as opposed to batch operators, who typically become specialized in specific operations). People supporting the manufacturing process will also need more statistical knowledge and understanding of the science behind the process. Eventually, the goal will be to release finished product in real time, based on a combination of data from PAT and other sensors and models that show in a validated way that the material is within the design space — certain to be within release specifications. the qualified person who makes these decisions will need to understand the science behind the numbers.

From a capital investment perspective, the purchase of new production lines for this cheaper and more efficient way of manufacturing could compete with an existing network of mostly written-off batch equipment. This is true for new product introductions (NPIs), but even more so for transitioning already-marketed products from batch to continuous; in these cases, there is no additional volume to justifies the increase in manufacturing capacity. Underutilization of equipment is painful for production sites: The investment in a production line must be written off on a limited volume of products. To determine the right size for a continuous operation, try to balance loading the equipment as much as possible based on projected volume, while still leaving enough free capacity to absorb variations in forecast and enough experimental/validation time for additional products or to increase knowledge.

Product Development Benefits

The faster a company can develop a product, the faster it can be on the market, providing a longer period of exclusivity and profit before the patent expires and generic competition kicks in. Continuous manufacturing can help speed drug development: Instead of having to produce a complete batch for every set of parameters in a design of experiments (DoE), a continuous line can be adjusted on the fly, and after a period of stabilization (until the process is in steady state), the results of the new parameters can already be captured. As a result, experiments that normally take weeks can be reduced to hours, and experiments can be conducted with a lot less API — which is very desirable in an environment where the amount of available API often is scarce. If API availability is a constraint, companies sometimes cannot develop a formulation as robust as they would like. Or, they have to stick with a wet granulation process, when further development might have made direct compression achievable. (Direct compression is by far the preferred manufacturing process, because it is leaner, does not include a liquid phase, and involves less complex equipment.)

Faster and cheaper development, with the potential of decreased time to market, are great benefit drivers, but they, too, require assumptions to be made. Will it be possible to design a robust manufacturing process, which can be challenging with poor-flowing material/API? A thorough feasibility phase to assess capabilities and boundaries of different equipment types on the market is recommended before committing to a specific direction. Some companies mitigate this risk by combining drug product development for continuous manufacturing with an effort to improve the morphologic characteristics of the API, to get the flowability and sticking properties below a critical value. The projected reduction in development time can be partially lost due to unexpected issues during equipment design — which is always more likely with a technology that is not yet mature and standardized.

During development, a continuous manufacturing line can be designed for one specific product, though several companies (including Johnson & Johnson) have transitioned to a platform approach, committing to develop a large part of their oral solid dosage product pipeline using this technology. In such situations, the line needs to balance flexibility and complexity/cost.  A business case for this strategy must consider further assumptions: What products will come out of the early development pipeline? How accurate is the API cost projection? Will we have enough API available? How much development work will be needed to get to the desired robustness level? Decision makers will have to trust projections that show that technical difficulties will be overcome and that the benefits will justify the investment.

Technology Transfer Benefits

In a typical batch environment, processes are developed on small-scale equipment, clinical batches on medium-scale equipment, and commercial production on large-scale equipment. For each transition from one scale to the next, a number of batches are necessary to demonstrate that the quality aspects of the final product are identical.

In the case of continuous manufacturing, the same size equipment is used from development up through commercial manufacturing — the only change in scale is the amount of time the line is run. This significantly reduces the amount of effort and API needed to transfer from R&D to the supply chain.

Of course, the realization of tech transfer benefits will depend on the actual commercialization of the products that were developed on a continuous manufacturing line. Cost will not be avoided completely, and the amount of residual effort will depend strongly implantation of strategies aligned with the regulatory and quality groups. One additional difficulty is the technology is at the beginning of the maturity curve, but designs are evolving quickly, and new vendors are entering the market at a fast pace. Between the time a development line is designed and installed and a commercial line needs to be built, the technology might already have evolved significantly, increasing the effort required to prove similarity between the two lines.

Future Outlook

Continuous manufacturing appears to be the way of the future for solid dosage drug product manufacturing. Although the ship has left the harbor, storms will need to be weathered by the pharmaceutical industry before the technology is widely adopted throughout the supply chains of large and small pharmaceutical companies.

Because we are talking about a new technology, a great deal of knowledge still needs to be generated: knowledge that helps health authorities find the right balance between risk mitigation and operational efficiency, but also knowledge that helps pharma company leaders make the best possible decisions. This requires trust in the assumptions on the table. Pre-competitive collaboration and knowledge sharing between all parties involved will help the industry obtain a critical mass of knowledge more quickly, which is needed to secure the benefits the technology currently promises. Many big pharma companies are already collaborating and sharing with one another to a great extent, discussing learnings in focus groups or writing guidance documents together — but more can still be done. Efforts to combine the clusters of consortia and collaboration groups that are scattered throughout the landscape, collective projects to generate knowledge, and many other opportunities will undoubtedly emerge.

Equipment for continuous manufacturing is rapidly evolving. With a good balance between flexibility, low investment cost, and short implementation times as objectives, it would make sense for equipment lines to evolve into interchangeable unit operations, for which a modular approach and standardized hardware and software interfaces would be enablers.

Because the technology is new, novel insights are frequently discovered. And if newly acquired knowledge makes a process more robust, reduces risk, and makes quality more consistent, it would be useful to have a fast and relatively easy process for updating the control strategy. Regulators could play an important role by providing a shorter and faster pathway for submitting data supporting changes for process improvement, for instance together with an annual product review.

Hopefully these hurdles will overcome soon, and continuous manufacturing quickly becomes mainstream in the industry. Although there are many considerations, and smart deployment decisions need to be made, the benefits are undisputable — and over time they will become even more significant, impactful, and game-changing. Faster development and more efficient supply chains also mean saving more lives, and that is what drives our actions and feeds our passion.

About The Author

Lawrence De Belder, senior principal engineer at Johnson & Johnson, began his work in continuous manufacturing in 2012, assessing business opportunities for continuous manufacturing in both the consumer and pharmaceutical sectors of J&J. Eventually, he became the overall program manager for all continuous manufacturing projects and academic initiatives at Janssen, ensuring that coordination, knowledge-sharing, and standardization take place. He is a strong advocate of pre-competitive collaboration and plays an important role as a catalyst for partnerships with vendors, academics, and other pharmaceutical companies.

De Belder is also co-chair of the Continuous Manufacturing Work Group in the IQ Consortium. He earned his master’s degree in industrial engineering at Groep T in Leuven, Belgium.