Solid-Dose Continuous Manufacturing Presses On

Published on: 
Pharmaceutical Technology, Pharmaceutical Technology-09-01-2020, Volume 2020 Supplement, Issue 4
Pages: 29-31

Early adopters and equipment manufacturers refine their equipment and processes, paving the way for broader use.

Continuous manufacturing for oral solid-dosage (OSD) drugs continues to grow in acceptance as early adopters and equipment manufacturers refine their equipment and processes. With six small-molecule OSD drugs approved using continuous manufacturing—including both new products and existing products made in a batch process and now made in a continuous process—the precedent has been set for other companies to follow. By manufacturing in a new way, processors hope to reap benefits, such as faster development, a smaller equipment footprint, greater flexibility in manufacturing scale, tighter process control, and the potential for real-time release. The advanced process control with continuous monitoring used in continuous processes allows more consistent quality, which reduces waste and lowers operating costs.

“CM practitioners will need to have a more advanced level of process understanding to apply advanced quality measurement and control strategies. However, if carried out successfully, the payoff will be a flexible and robust drug supply chain that can be ramped up quickly in time of health crisis,” notes Professor Johannes Khinast, head of the Institute for Process and Particle Engineering in the Research Center Pharmaceutical Engineering (RCPE) at the Graz University of Technology in Austria.

“CM is a tremendous opportunity to advance drugs to the market at a much faster pace than traditional batch manufacturing and [enable] enhanced product quality based on enhanced process understanding and a richer data environment,” agrees Jose Luis Santos, head of Drug Product Continuous Manufacturing at contract development and manufacturing organization (CDMO) Hovione.

Material handling

A challenge for continuous manufacturing is that the material handling and feeding into the process is critical, and there are two primary concerns: some of the APIs and excipients are poorly flowing powders and feeding very low levels of API can be difficult.

“We need to significantly increase the consideration of process interconnection and materials aspects when designing and operating a continuous processing facility,” says Khinast. “The unpredictability of in-process material behaviour is tough, since small changes in the formulation can have significant effects on the rheology, stickiness, segregation tendency, chargeability and other parameters.”

Accurate and consistent feeding is a challenge, along with low-rate feeding and containment designs for high potency ingredients, agrees Sharon Nowak, business development manager at Coperion K-Tron USA. “High accuracy loss-in-weight feeders are at the heart of most continuous processes. As the pharmaceutical industry implements these systems, more and more robust designs in weighing technologies, loss-in-weight feeder controls, modularity in design, and also overall cleanability are being demanded,” she explains. Nowak points out that the importance of the refill system to the loss-in-weight feeders is crucial, but sometimes overlooked, by process designers. “It is imperative that the feeder technology and refill system chosen are designed to include not only optimal performance, but also integrated to ensure the highest accuracy and consistency levels in feeder mass flow output,” she cautions.

“The primary challenge with poorly flowing powders is inconsistent filling of the screw pitch,” adds Sarang Oka, process development engineer at Hovione. “Vendors have experimented with various agitator and screw geometries to improve screw filling, and these have shown promising results. Some powders, such as certain grades of silica with very low bulk density and substantial electrostatic adhesion tendency, however, continue to pose a challenge. Another trick in the book is coprocessing the poorly flowing powder with a flow aid prior to introducing the powder to a feeder.

Pretreating the API can be a solution if changing the feeder design doesn’t work, says Doug Hausner, senior manager, Continuous Manufacturing Business Development, Pharma Services, Thermo Fisher Scientific. “Silication is the most prevalent and easiest pretreatment, but there are a number of options and companies are coming to market with solutions,” he notes.

Although feeders have been designed to feed low levels of APIs, there is a limit. “There is a physical lower limit below which signal-to-noise ratios even for the most sophisticated load cells becomes too low for effective gravimetric control, and this handicaps our ability to feed below a certain flowrate,” says Oka. “A management strategy has been to preblend (in batch) the ingredient with low weight fraction in the formulation with another ingredient, and then feed the preblend at the combined, higher feedrate.”

Development, tech transfer, and digital twins

In theory, CM processes should not require scale-up; instead of larger equipment, the line can be run for a longer time. CM thus offers the potential for faster development and easier tech transfer, but practitioners are still working on achieving these benefits. 

Because development is conducted in the same equipment and the same scale, there is potential for faster development cycles, agrees Santos. He suggests, however, that development in CM is currently slowed by a steep learning curve at most companies.


Currently, tech transfer is often conducted between units that are similar or identical in size and other characteristics, notes Oka. “One can be very confident that experiments performed, and results obtained on a standalone loss-in-weight feeder will translate well when an identical feeder is used to feed the same material in the integrated process train,” says Oka. “The challenge arises when development is performed on equipment that is different from commercial equipment. We still do not have correlations that help us transfer processes between dissimilar pieces of equipment or process trains. Recommended practice for organizations who wish to build multiple lines is to develop identical lines, if there is desire to transfer products between lines.”

Digital twins are proving to be a valuable tool for development of continuous processes. These computer models of a process allow process developers to run experiments in silico, allowing a greater number of experiments to be run more quickly and a better process understanding to be developed before evaluating process conditions on the actual equipment.

“People are pushing in the direction of digital twins to limit development time, because the software/control is often the rate limiting step in getting a system up and running, not the process development in a chemistry, manufacturing, and controls sense,” says Hausner. Digital twins also allow users to demonstrate the process on different production lines, such as when transferring to a different facility, he notes.

Running experiments off-line is particularly important for CM, because the process of cleaning between products is time-consuming. “Tools that help us minimize the use of the rig are incredibly important to us [because of the time for cleaning.]These tools could be very sophisticated models or simple tools based on engineering correlations that predict the performance of the product in the rig,” says Oka.

Digital twins have been commonly used to run in-silico residence time distribution (RTD) experiments, says Oka. “These experiments can be done either at the unit operation level or at the full process train level. Thorough characterization of the RTD enables one to track evolution of disturbance through the rig, a crucial element of today’s control schemes. The underlying models, if well calibrated, also enable the practitioner to ‘dial-in’ and test a desirable RTD.” Other uses of digital twins include understanding the impact of material properties and process parameters on process performance and eventually product quality.

RCPE’s particle-simulation based approach is a digital twin of CM processes, developed in collaboration with pharmaceutical companies and equipment suppliers. “We believe that such digital twins are crucial for the future of continuous manufacturing, as this technology allows us to better process and visualize real-time data to enhance our ability to predict and control the process dynamics,” says Khinast. “Specifically, we can use digital twins to monitor and predict critical quality attributes and key performance indicators throughout the process line, while simultaneously feeding data back to optimize the process output in terms of quality and yield. … Digital twins have the potential to make continuous manufacturing faster, cheaper, and less error-prone.”

Khinast says that RCPE’s digital twin allows development of key processes, such as continuous powder blending, based on material properties that can be measured with small amounts of material. “Because this in silico approach is based on the fundamental physics, it is far more efficient, compared to the traditional trial-and-error approach, when you need to transfer the product and process to a different set of equipment,” he explains.

Facility design

Simulations and modeling are also commonly used to identify bottlenecks and eliminate inefficiency in processes, explains Dave DiProspero, director of Pharmaceutical Process Technology at CRB. “A continuous manufacturer’s success, survival, and profitability depends heavily on process efficiency. During the times when equipment is being maintained, cleaned, turned over or idle work in progress awaiting upstream processes, efficiency is being reduced and profits are being lost,” says DiProspero. Modeling can be used to find efficiencies in areas such as personnel movement, travel distances from operation to warehouse, process loading and unloading times, and quality control holds. “Wherever and whenever a step in the process can provide for a time reduction, operational improvements are achieved,” he says.

Another aspect of facility design is the need for maximizing flexibility and capability to handle different products on the CM line. “One of the best practices for modern OSD facility design to address flow is to incorporate uniflow operations, with minimal path crossing or back tracking,” says DiProspero. “Ideally, process flow should run in a linear motion from raw materials in, to final drug product out. Placing the weigh/dispense unit operation close to the warehouse, with direct access, and combining unit operations (e.g., granulation/drying and blending/milling) are common today.”

Training and standards

In addition to optimizing the equipment and facilities, manufacturers need to develop the workforce for operating CM processes. Such teams are different from those that typically support batch solid dose manufacturing, says Santos. “Now the skill set should comprise a strong background as well on process modeling, automation, and control. PAT [process analytical technology] is now a mandatory role in the teams. The quality teams should either adjust themselves to embrace a new paradigm, or new focused teams should be put together,” he explains.

Training is becoming more available, compared to in the past when most had to figure things out for themselves, says Hausner. The United States Pharmacopeia, for example, is offering training and is also considering developing standards for CM. The International Society for Pharmaceutical Engineering (ISPE) is also discussing standards as related to standard capabilities and connectivity technology to allow systems integration, reports Hausner.

About the Author

Jennifer Markarian is manufacturing editor, Pharmaceutical Technology.

Article Details

Pharmaceutical Technology 
Supplement: APIs, Excipients, and Manufacturing
September 2020
Pages: 29–31


When referring to this article, please cite it as J. Markarian, “Solid-Dose Continuous Manufacturing Presses On,” APIs, Excipients, and Manufacturing Supplement (September 2020).