Batch or Continuous? Ask the Right Questions During Scale Up

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On May 6, 2019, at St. John’s University in New York City, the 11th annual Charles Jarowski Symposium in Industrial Pharmacy examined the challenges and opportunities posed by continuous pharmaceutical manufacturing. A number of commercial products are already being made continuously, and more than 20 products that are now awaiting FDA approval use continuous manufacturing, said Atul Dubey, director of pharmaceutical continuous manufacturing at the United States Pharmacopeia (USP), who spoke on the program.

A crucial question is what the incentives will be for generic pharmaceutical manufacturers, which supply most of the prescriptions written in the United States, to invest in the technology and knowhow that continuous manufacturing requires. “How can we make continuous manufacturing easier for late adopters? In the end, we need to promote the quality of medicines, however they are made,” said Dubey. “We will also need to be able to produce drugs that were approved as continuously manufactured products so that they can be made via batch manufacturing,” he said, “since the reality is that not all manufacturers will embrace continuous manufacturing.”

At the program, experts from Merck and Takeda discussed continuous manufacturing pilot development programs underway at their companies, university professors summarized research findings, and Bayan Takizawa, cofounder and chief business officer at Continuus Pharmaceuticals highlighted pilots and projects underway to help advance end-to-end continuous manufacturing, from API to finished product.

QbD becomes more dynamic

A number of speakers suggested that the concept of pharmaceutical quality by design (QbD) is becoming much more dynamic than what was outlined in the first FDA guidance on that topic.  As pharmaceutical manufacturers have become more comfortable with more advanced process control, the emphasis is moving from the design space to greater use of feedback control. The idea, according to Zoltan Nagy, a professor at Purdue University’s School of Engineering, is “to make critical quality attributes tunable so that the system can find the conditions at which it needs to operate in order to ensure product quality.” Ajaz Hussain, director of the National Institute for Pharmaceutical Technology and Education (NIPTE), spoke of the need for reproducibility and repeatability, and to move from “one size fits all” attributes to multivariate personalization. “Twenty-first century quality and cures demand continual improvement and confidence, and that will require dynamic feedforward and feedback control,” he said. Click here for a full report on the symposium.

Scale-up considerations

Focusing on scale-up issues was Michael Rooney, director of process engineering at Genesis Engineers, who considered some of the challenges that existing manufacturing operations face when considering the implementation of a continuous manufacturing approach to scale up oral solid dosage (OSD) forms or replace a batch process with continuous. As he explained, one cannot simply inject continuous manufacturing into a batch facility, especially because legacy facilities tend to be single or two stories, and floor-to-floor distances do not help vertically integrate continuous. Rooney used two different case studies to illustrate the challenges of justifying the cost to convert to continuous. One involved the expansion of a commercial drug using a dry granulation process in an established facility, the other, expansion of a high volume over-the-counter (OTC) product that did not involve API. In this case, he said, reducing labor costs was the primary goal.

Conflicting material flows

In both cases, he said, using the continuous manufacturing scenario, the flows of people and raw material conflicted. “What began as a capacity question ended up as a question of return on investment,” he said. For one thing, with the branded drug company, it was found that the building, which was only 25 feet high, would need to be 60 feet high to accommodate continuous manufacturing. In addition, the shift from batch manufacturing would involve higher operating costs due to highly skilled technicians to attend to the PAT technology. The company, which had been trying to justify moving to continuous manufacturing on the back of one major product, is now working on building a continuous platform. “If you develop a platform for groups of product types, rather than try to replace existing batch capacity with continuous, it doesn’t have to run 100%. You can build a platform and a portfolio over time,” Rooney said.

In the second case, with the OTC product, second-level infrastructure costs hurt financials and there was no subject matter expert on site to develop the process analytical technology (PAT) required for continuous, Rooney said. In this facility’s case, moving to continuous had no real impact on product cost and the company wound up investing more in its batch process to avoid undue risk. “Continuous manufacturing may be great for flexibility but it should not be used as a capacity solution,” Rooney said. “People tend to emphasize the potential for continuous manufacturing to reduce the cost of goods sold (COGS), but it may require increased investment in PAT, process development, data handling, and storage and recall strategies,” he said.

In the end, companies must determine what will be more cost effective: reducing operator labor and facility costs or reducing time to market and starting to recoup product revenue sooner. For most companies, the transition to continuous manufacturing will be driven by product development scientists and engineers sooner than it will by the operations group, Rooney said. In addition, savings may often be more pronounced in Phase II and Phase III projects, rather than commercial production. In an interview after the conference, Rooney shared some insights into continuous pharmaceutical scale up with Pharmaceutical Technology.

Labor or time-to-market?

PharmTech: Are there some basic misunderstandings in the industry today about continuous manufacturing and how easy it is to scale up?

Rooney: I’m a real proponent of continuous manufacturing, but it’s not perfect for everything.

PharmTech: What would make a process an ideal candidate for continuous manufacturing?

Rooney: Generally, continuous will be most practical for processes that involve direct compression or dry granulation. With direct compression, one is mixing components with minimal manipulating. In dry granulation, material is densified with a roller compactor, milled, blended, and compressed with a tablet press. Tablet press equipment has long been based on a continuous process anyway. In addition, the percentage of active shouldn’t be too low if a continuous approach is to work well, or at least be easy to implement. In some new oncology drugs, the API is so potent that drugs may only contain about 1–5% active ingredient. Using continuous manufacturing for these products can be very challenging, even though it is possible, because of the need to guarantee plus or minus 10% of label claims.

In addition, these formulas typically use a large number of other functional components (e.g., pH neutralizers and disintegrants). Sometimes up to 14 different components may be required, all in differing quantities. The best candidates for scale up using continuous manufacturing are products that involve dry granulation and direct compression, products where API percentages aren’t too low, and where there aren’t too many diverse excipients in the formulation.

Making the case to management

PharmTech: Are there considerations that people may forget when they propose continuous manufacturing projects to corporate managers?

Rooney: On the manufacturing side, the idea to use continuous often comes from managers who see continuous as a way to reduce labor and equipment footprint. Continuous will save both, but there are other factors to consider. In batch OSD plants, when you move material around you promote segregation or unblending. Continuous minimizes this movement, so managers may think it will help reduce segregation and even reduce the need to wash bins as frequently. But this is only part of the challenge. Based on data gathered during continuous manufacturing, facilities can use real-time release, eliminate testing and product quarantine and release to distribution. There is no worry about batch size, because batches are defined by time, with process validation documents establishing the maximum operating window. The challenge comes with using PAT. One has to characterize that product that is going through the process. Current PAT technology is capable of generating data in a matter of seconds and accumulating data very quickly, that has to be controlled, stored, and potentially retrieved at a later date. The equipment cannot run without the PAT working, but then how does the PAT system know how to work? 

PAT learns the comparator or monographs, which reflects thousands of hours of development. PAT takes a snapshot of what is moving past the analyzers, and compares the value to that from a monograph. But what if some peaks have shifted? There can be different sources of variability, which require multivariate analysis. This is not strictly an equipment decision.

Consider facility layout

PharmTech: Do people underestimate the challenges posed by facility layout?

Rooney: With continuous, one attempts to solve a lot of problems about particulate separation by coupling everything (e.g., placing feeders near blenders, and blenders near mills). Another challenge is the conversion of a formulation from batch to continuous considering the number of raw materials to be included in the process. You may only be able to blend three raw material ingredients in one blender, so if you are working with many ingredients, you may have to do a pre-blend that will then go into another blender, then add more material and send it to yet another blender.

You also have to select where you want to place your PAT system. In short, you are stacking operations vertically with many systems capable of failure or inaccuracies. Also consider that all these feeders must be fed via bulk containers. One of the big advantages of continuous is that it allows a facility to bring raw material containers straight into your plant and not stop to dispense individual batch materials. However, this is the opposite of what people in batch plants have been doing for the past 20 years.

In most batch facilities today, the dispensary is the dividing line between current good manufacturing practices (cGMP) and non-cGMP operations. Bulk corrugated containers can introduce contaminants into a facility. In general, the flows that are required for continuous manufacturing are counterintuitive to what people generally have, and there is a very different space classification for each. 

More CDMOs working in continuous

PharmTech: What might convince more generic pharmaceutical manufacturers to invest in continuous technology?

Rooney: I expect to see faster integration of continuous manufacturing in the OTC market, particularly for supplements. These lines run at much higher speeds and labor is a big component of their cost of goods. Continuous manufacturing allows OTC manufacturers to reduce operating costs.

For generic pharmaceuticals, the issues are different. Branded companies are not all going to share their development databases, monographs, and approaches to PAT, so generics manufacturers would have to invest in the same development that branded companies have to do. I expect to see more contract development and manufacturing organizations (CDMOs) investing in continuous manufacturing. Generic pharmaceutical manufacturers would be more likely to work with these CDMOs, to avoid having to invest in continuous manufacturing technology and expertise themselves.

Article Details

Pharmaceutical Technology
Vol. 43, No. 6
June 2019
Pages: 29–31

Citation

When referring to this article, please cite it as A. Shanley, “Batch or Continuous? Ask the Right Questions During Scale Up,” Pharmaceutical Technology 43 (6) 2019.