Continuous Manufacturing: Addressing the Tough Questions

June 4, 2019

Although continuous approaches offer significant benefits for some products and processes, batch manufacturing is not going away any time soon.

On May 6 2019, at St. John’s University in New York City, the 11th annual Charles Jarowski Symposium in Industrial Pharmacy offered a realistic look at the opportunities and challenges posed by continuous pharmaceutical manufacturing. More than 20 products that are now awaiting FDA review involve continuous manufacturing, but there are few compelling economic reasons for generic pharmaceutical manufacturers to invest in the technology, noted Atul Dubey, director of pharmaceutical continuous manufacturing at the United States Pharmacopeia (USP).

Proponents of continuous manufacturing, and the agility and savings that it might enable, view this as a problem. Currently, 97% of the prescriptions filled in the US today involve generic pharmaceuticals, noted Ajaz Hussain, consultant and director of the National Institute for Pharmaceutical Technology and Education (NIPTE), a consortium of universities dedicated to advancing the concepts of modern pharmaceutical development and manufacturing. Within the past few years, long-standing NIPTE members such as Purdue and Rutgers Universities and the University of Puerto Rico (Mayaguez) have been joined by St. John’s and Long Island Universities, both based in New York City.

During his plenary lecture, Hussain, who headed FDA’s Office of Pharmaceutical Sciences (OPS) and the agency’s process analytical technology (PAT) team in the early 2000s, and later led Sandoz’s development of the first biosimilar to be submitted for approval by FDA, shared some of his experiences. As he said, continuous manufacturing could offer a solution to improving supply chain reliability, and help prevent shortages of medications. 

Taking note of the Big Pharma companies such as Novartis that have been working on continuous processes for years, Hussain said that the generic pharmaceuticals market is too fragmented for anyone to expect it to take this approach. “If the original product was not continuously manufactured, there is no incentive for generics companies to make the generic continuously. The initial investment for solids is significant,” he said, also acknowledging the need for expertise and technology for data manipulation and archiving as well as process analytical technology (PAT).

External manufacturing hubs, new prior knowledge

Hussain predicts that a new business model will develop, in which external manufacturing hubs based at universities, such as the Engineering Research Center for Structured Organic Particulate Systems (C-SOPS) at Rutgers University, and contract development and manufacturing organizations (CDMOs) will handle continuous manufacturing projects for industry, including generics firms.

He also emphasized the need for pharmaceutical “new prior knowledge (NPK),” or critical information on quality issues and potential failure modes to be made available to generic pharmaceutical manufacturers, a concept advanced in an article made openly accessible by NIPTE (1). 

Currently, generics manufacturers gain knowledge of the off-patent branded pharma molecule, but free access to NPK would allow them to connect the dots between drug substance characteristics and physico-chemical properties, product performance, therapeutic equivalence, and manufacturability. Advocates believe that access to NPK would drive faster development and regulatory review of generics and allow generics firms to sell more products. Currently, FDA data show that over half of approved generics are either never marketed, are sold intermittently, or reach the market only after significant delay, while abbreviated new drug applications (ANDAs) are not submitted for 10% of approved drugs (1).

From QbD to quality by control

Several speakers on the program emphasized the importance of feedforward and feedback control, which, Hussain noted, will be crucial in the commercialization of more advanced therapies.  In fact, pharmaceutical quality by design (QbD) is becoming much more dynamic than what had been outlined in the first FDA guidance on that topic, and is evolving into “quality by control.”

As pharmaceutical manufacturers become more comfortable with more advanced process control, the focus is shifting from the design space and locking in control strategy for the process during development, to greater use of feedback control so that any variation in input won’t result in a change in output.  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 final product quality. “Focus on final critical quality attributes and let anything else change if it has to change, to leave CQAs constant,” said Nagy, whose presentation focused on continuous crystallization and use of feedback and feedforward control.

“Unit operations must be considered as a system. In order to manipulate them, you need an array of continuous monitoring systems, but the real power is if we use this information for feedback control, and allow the system to change by manipulating critical process parameters to control critical quality attributes.”

As Nagy noted, PAT tools have been used for 15–20 years to improve process understanding but until fairly recently they had seldom been used in feedback controls. Software is now being developed, he said, to take these tools and use redundant information for data reconciliation to inferentially control CQAs that may not be directly measurable and maintain them at the desired value.

As he noted, these approaches can be used whether the process is continuous, batch, or mixed. “A lot of continuous manufacturing platforms are really running on batch processes,” he noted.  AstraZeneca demonstrated how active feedback control might improve crystallization, Nagy said, using measurements to change the temperature profiles within the crystallizers to adjust temperature cycles and optimize the process.

Exploring continuous encapsulation 

Representing Big Pharma, experts from two early adopters of continuous manufacturing approaches shared their plans and some of their experiences. Takeda Pharmaceuticals, which acquired Shire Pharma’s continuous manufacturing expertise when it bought the company, has continued continuous research and piloting efforts begun by Shire in 2016, according to Jim Bonner, Takeda’s director of small-molecule drug product, who spoke in the program (2).  The company, along with Thermo Fisher’s Patheon, is exploring the use of continuous manufacturing for encapsulation as well as tableting, focusing on the continuous direct encapsulation of Vyvanse (lisdexamfetamine dimesylate), a treatment for attention deficit/hyperactivity disorder that was approved in 2007. Configuring encapsulation equipment for continuous manufacturing has been challenging, he noted.

The company has completed trial runs using near-infrared (NIR) and Raman spectroscopy, which involved scanning 30 different blends three times, then using product of least squares (PLS)-based chemometric methods on reference gravimetric rather than high-performance liquid chromatography (HPLC) assay data. Extensive design of experiments work has also been done, and the company is anticipating approval of the continuous process by 2020.  As Bonner pointed out, these efforts have underscored the need for more robust and economic PAT options and simplified model maintenance. In addition, he believes that FDA should be shown that loss-in-weight feedback data are more accurate than data provided by NIR models. 

Andrew Farrington, principal scientist for oral formulation sciences at Merck in West Point, PA, discussed the company’s pilot project, designed to build upon existing expertise in real-time release testing, raw materials monitoring, and QbD.  The pilot applies continuous-to-direct compression and film coating using tablet transmission NIR and tablet weighing instead of content uniformity, and hardness and disintegration instead of dissolution. The goals are to produce nearly 1 billion tablets per year with less than 90-day lead times from formulation to patient in a two-floor installation that is roughly one-third the size of traditional tableting facilities. 

The company engaged early in discussions with regulators, and is now working on both a continuous product development line, capable of manufacturing 5–20 kg/h of product, and a commercial line, with capacity of 10–90 kg/h. The advantages of the small-scale unit, he said, included a single point of control, facilitating remote equipment operation and potentially allowing operators to be removed from the processing environment.  The company has developed a predictive model based on material attributes for continuous feeding and has also tested twin screw granulation.  Although the company is optimistic about the role that continuous processes will play in the future, Farrington asserted that a mix of batch and continuous will be better for the industry’s assets and supply chains.


Scale-up issues: it’s not all about equipment

Focusing on scale-up issues was Michael Rooney, director of process engineering at Genesis Engineers, who considered some of the challenges that facilities face when using a continuous manufacturing approach to scale up oral solid dosage forms.  As he explained, one cannot simply inject continuous manufacturing into a batch facility. He used two 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 the latter case, he said, reducing labor costs was the primary goal.

In both cases, he said, using the continuous manufacturing scenario presented a conflict between the flows of people and those of raw materials. “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 to employ highly skilled technicians who would 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 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. For a more extensive interview with Rooney, please see the June 2019 edition of Pharmaceutical Technology (4). 

Continuous at USP

USP’s Atul Dubey, a Rutgers graduate whose new job title is one year old, discussed broad acceptance issues. “We need to focus on practical challenges of adoption, especially in the generics world,” he said. Starting manufacturing six months ahead of schedule can save a company a billion dollars, but in the end, investment is relative. “The switchover costs for a generic manufacturer are considerable,” he said, and the challenges entail investment and workforce skills.

The increase in popularity of continuous processes poses challenges for generics companies. “Some may ask ‘If I can use my batch facility, can I meet my continuous product profile?’,” he said. They are concerned about being shut out of the market for these drugs because they will have difficulty making a product that has been approved for use with continuous manufacturing. USP is starting the spade work on standardizing methodologies to help the industry consider continuous processes, including new standard materials and PAT strategy standards, and is also developing a five-day course with Rutgers’ C-SOPs.

“Continuous may not be USP’s traditional space, but we have to move forward,” Dubey noted.  In the end, he says, there is a need to make it easier and faster for late adopters to shift to continuous. “USP is interested in promoting quality of meds, however they are made…but generics manufacturers need to be able to produce drugs that were approved as continuously manufactured products via batch manufacturing, because the reality is that not all manufacturers will embrace continuous manufacturing,” he said.

End-to-end continuous: a holy grail or achievable goal?

Bayan Takizawa, cofounder and chief business officeratContinuus Pharmaceuticals, highlighted pilots and projects underway to help advance end-to-end continuous manufacturing, from API to finished product. There will be a need for deep process understanding, i.e., understanding CPPs, how to identify and monitor them reliably and consistently, and connect them to feedforward and feedback control loops. “A lot of upfront work is required,” he said.

He also discussed the company’s pilot plant, which is currently operating with a throughput of 25,000 kg/year, using a five-stage continuous reactor with PAT (an infra-red system to monitor cake height), and recovering and reusing solvents in a closed loop.

As he noted, industry inertia is a barrier to adoption.  He also suggested that equipment vendors need to embrace novel technologies. “Companies balk out of fear that the regulators won’t get new technologies, but FDA has been very supportive of continuous manufacturing,” he said, noting the fact that the agency’s Emerging Technologies Team (ETT) has advocated greater use of continuous.  In addition, he says, the Japanese Pharmaceuticals and Medical Devices Agency (PDMA) has recently set up an organization analogous to the ETT in Japan.

Continuous filtration work has shown good results so far, said Takizawa. He also pointed to work underway for a large-volume generic drug company in India, which found that using continuous could reduce overall costs by 30–35%; cut the number of unit operations by 80–85%; reduce solvent requirements by more than 60% and footprint by about 90%; and contract product lead time from months to less than 48 hours.

However, he noted, continuous is not a “slam dunk.”  “Staff expertise is an important issue.  Without strong technical support to handle development, data manipulation, and failure modes and effects analysis, you won’t have database to drive PAT. In addition, continuous would have an impact on existing facilities and traditional work and product flows,” he noted.

Parenterals and crystallization

On the academic side, University of Connecticut Professor Diane Burgess described work underway at the University of Connecticut evaluating continuous manufacturing for complex parenterals, in this case, liposomal formulations. The project began in 2013, but the miniaturized equipment was completed around 2018, going from the size of a standard lab bench to that a small refrigerator. Testing involved 11 liposome products, including generic formulations.

Zoltan Nagy summarized work at Purdue using plug flow crystallizers and oscillatory flow using stirred tanks. “A large amount of fine crystals can create filtration problems, but if we allow spatial cycles, nucleation occurs in the middle of the reactor, and no fines result in the product.” Purdue’s team implemented a particle flow code (PFC) model with encrust formation that constantly de-fouls the system, yielding product with desired quality attributes. “Instead of having a steady state you have periodic steady state and periodically transfer several sections following periodic cycles in a phase diagram. It’s not steady state but it is a controlled state in which amplitude of oscillation is within allowable levels given CQAs.  A crystal size distribution (CSD) feedback controller detects the upper and lower bounds and triggers the point of crystal collection,” he said. Using a traditional control approach in this situation would lead to fouling, he added.

In short, the program provided a look at the work underway to make continuous manufacturing a reality in more pharmaceutical operations, and how dynamic control will contribute to better batch and continuous processes in the future. 


1. A. Hussain, K. Morris, V. Gurvich, “Pharmaceutical NPK: Twenty-First Century Assurance of Therapeutic Equivalence,” AAPS PharmSciTech, April 2019.
2. J. Bonner, “Continuous Manufacturing Challenges to Commercialization” a presentation made at the 11thannual Charles I. Jarowski Symposium in Industrial Pharmacy,” May 6, 2019.
3. A. Farrington, “Challenges with Continuous Manufacturing: Integrated Development Strategy for Continuous Manufacturing of Oral Drug Products,” a presentation made at the 11th annual Charles I. Jarowski Symposium in Industrial Pharmacy,” May 6, 2019.
4. A. Shanley, PharmTech, 43 (6) 29–31 (2019).