Advancing continuous manufacturing with FDA support

Continuous manufacturing

Krull explained that CM offers a distinct alternative to traditional batch manufacturing. Unlike batch processes, which require frequent pauses for testing, storage, and manual intervention, CM operates as an integrated system where materials flow seamlessly through connected unit operations. This continuous movement reduces manual handling, enables real-time monitoring and control and enhances efficiency.

"Continuous manufacturing consists of a series of two or more steps in which materials are continuously charged into the system and products are continuously discharged," Krull said. By eliminating the need for manual loading, unloading and intermediate testing, CM streamlines production and minimizes delays.

Krull also highlighted CM's flexibility, noting that batch sizes can be adjusted by modifying process runtime or material flow rates. Additionally, CM's continuous nature allows for better process control, leading to improved product quality. This makes it particularly appealing for pharmaceuticals, where high reliability and consistency are critical.

"Continuous manufacturing is especially well-suited for processes with high repeatability requirements, such as pharmaceutical products," he added.

Realizing operational and cost efficiencies

CM not only improves product quality but also delivers significant operational and cost efficiencies. By leveraging continuous processes, pharmaceutical companies can achieve comparable production rates with smaller, more efficient equipment, which reduces the manufacturing footprint and associated expenses.

Krull shared compelling data from companies already adopting CM, reporting a "50% reduction in operating costs, a 33% reduction in waste and an 80% reduction in manufacturing and testing cycle time," with some companies experiencing "up to a 66% reduction in time from testing to release."

"CM processes offer enhanced efficiency by reducing waste, minimizing personnel requirements and enabling the use of smaller equipment to achieve production goals," Krull explained. This combination of factors translates into significant cost savings and operational streamlining for manufacturers.

In addition to cost and efficiency gains, CM has demonstrated improved safety in certain applications, particularly for processes involving heat generation or volatile materials. Krull highlighted one example where a pharmaceutical company implemented CM for a Grignard reaction, a process known for spontaneously releasing heat.

"By applying CM, the company developed a safe and well-controlled process that required minimal operator involvement and reduced manual material handling," he noted.

Enhancing product quality and addressing drug shortages

The FDA sees CM as a transformative approach to enhancing product quality across the pharmaceutical industry and, in turn, improving patient access to essential medicines.

"Continuous manufacturing can produce higher quality medicine, facilitating six-sigma operation where no more than 3.4 defects occur per million opportunities," Krull explained.

This means CM enables an exceptionally precise and consistent manufacturing process, drastically reducing the likelihood of errors or defects in the final product. This level of quality control can reduce the types of quality-related issues that currently account for approximately 60% of all drug shortages. By bolstering drug supply chain reliability, CM positions the industry to meet demands during health crises better.

"Adoption of CM can also reduce or prevent drug shortages by reducing quality-related manufacturing issues," Krull said, emphasizing that CM can help pharmaceutical companies respond more flexibly and quickly to supply needs during public health emergencies. "CM can improve the industry's preparedness for public health emergencies by providing greater agility and flexibility in manufacturing capabilities."

Regulatory support and the path to adoption

Acknowledging the challenges and potential of CM, the FDA has actively promoted industry collaboration to support its adoption, addressing regulatory concerns over the past decade. Krull detailed the FDA's efforts, highlighting the role of the Center for Drug Evaluation and Research (CDER) in driving CM innovation. One pivotal initiative is the Emerging Technology Program (ETP), launched in 2014, which has facilitated early-stage discussions on CM technologies and guided companies through the regulatory process.

"The Emerging Technology Program was established in the FDA's Office of Pharmaceutical Quality to promote and facilitate the adoption of innovative approaches to pharmaceutical product design and manufacturing," Krull explained. He noted that the Emerging Technology Team, a cross-functional group of approximately 30 members, includes representatives from critical FDA divisions such as the Office of Pharmaceutical Quality, Office of Compliance, and Office of Regulatory Affairs, ensuring comprehensive support for novel technologies.

Since its inception, the ETP has reviewed over 160 proposals, 22 of which have led to successful regulatory submissions and approvals. Krull emphasized the program's flexibility, stating, "The submitted technologies don't necessarily need to fall into predefined categories, as long as they are novel and advance product quality."

Science-based policy and research collaboration

CDER is advancing CM not only through regulatory frameworks but also by driving research initiatives that push the boundaries of CM technology. Efforts in advanced process monitoring, process modeling, and industry 4.0 technologies are shaping regulatory compliance policies that align with cutting-edge manufacturing science.

"CDER Science and Research directly support regulatory efforts in a variety of ways," Krull explained, "by enhancing FDA's capacity for evaluating and monitoring drug quality, safety, and efficacy, and by modernizing existing regulatory pathways or creating new ones where none currently exist." These research-driven efforts ensure that CDER remains adaptable to the evolving pharmaceutical manufacturing needs.

Krull emphasized that CDER's research activities also foster collaboration with industry stakeholders, promoting shared learning to accelerate the adoption of innovative technologies.

"Shared learning and open communication between the Emerging Technology Program and industry stakeholders, along with the research efforts of the Office of Pharmaceutical Quality labs, have helped advance the adoption of emerging technologies to improve product quality," he noted.

Practical considerations for CM facilities

For companies transitioning to CM, the FDA recommends adapting facility procedures and integrating real-time testing capabilities to maintain product quality and reliability. Adjustments must accommodate the increased automation and dynamic conditions unique to CM, including features like real-time release testing and electronic batch records.

"Quality and production procedures will need to be updated compared to traditional batch processes, focusing on oversight of automated controls, process data, real-time release and electronic batch records," Krull emphasized.

Process robustness is another key consideration due to CM's continuous and dynamic nature.

"Demonstrating robustness, implementing effective process monitoring and developing a comprehensive control strategy are critical for CM," Krull explained.

He also advised including oversight of automation systems and material diversion strategies as part of facility planning to ensure seamless operations and product quality.

Continuous manufacturing and broader industry impact

In his closing remarks, Krull emphasized that the FDA's support for CM aligns with its broader mission to promote safe, high-quality, and efficient drug production. While the agency encourages CM adoption, it does not mandate it, and batch manufacturing remains an acceptable approach.

"FDA approvals are based on compliance with standards, regulations and laws, and the FDA recognizes that not all processes benefit from utilizing advanced manufacturing technologies," he explained.

Krull highlighted the potential benefits of CM for both innovative and generic drug manufacturers, including lower production costs and expedited regulatory approvals.

"Continuous manufacturing can deliver significant benefits for both manufacturers and patients," he stated, adding that early collaboration between industry stakeholders and regulators, along with international harmonization efforts, has addressed many concerns related to adopting advanced manufacturing technologies. Science, he emphasized, "needs to lead the way" in driving both the development and regulation of these innovations.

Through regulatory initiatives, collaboration and guidance, such as the FDA's ETP, the agency helps the pharmaceutical industry unlock CM's potential. By improving quality, reducing costs and enhancing flexibility, CM is set to transform drug production while maintaining regulatory rigor and prioritizing patient safety.

Alivia Kaylor is a scientist and the senior site editor of Pharma Life Sciences.