Nurturing Manufacturing Agility

Human medicine arguably began when early healers created simple botanical preparations to treat a small number of people living near them. The large-scale electrical machines of the Industrial Revolution turned human medicine into the global pharmaceutical industry of today. This revolution exploded drug availability for patients; most adults in the United States now use at least one prescription drug every year. But some are now asking whether this large-scale, fixed-location manufacturing paradigm benefits patients as much as it could. Could a return to the roots of smaller-scale, localized manufacturing for some medicines offer benefits to patients?

The COVID-19 global pandemic revealed the limitations and rigidity of the traditional manufacturing paradigm. Because building a new brick and mortar facility takes time, manufacturers of drugs to treat patients with COVID-19 relied heavily on moving their processes among existing facilities to meet a rapidly changing and nonuniform global demand. It became a challenge for manufacturers to export and ship certain drug products due to human safety and other precautions. Technologies that enable more localized manufacturing would avoid these supply chain problems and allow for a rapid and focused response to patient demand.

Distributed and point-of-care manufacturing

Several pharmaceutical manufacturers are now developing smaller, more mobile drug manufacturing processes that can be deployed to multiple locations, including at the site of patient care. These distributed and point-of-care manufacturing technologies have the potential to improve the drug supply chain by providing enough flexibility and agility to address local patient needs. In the future, distributed manufacturing units might be deployed at a site during a public health emergency to meet local demand or at a healthcare facility to meet the specific needs of its patients.

Similar technologies may aide soldiers on a battlefield. The US Defense Advanced Research Projects Agency (DARPA) has long made investments in innovative pharmaceutical technologies to address the logistical obstacles of manufacturing and delivering drugs to soldiers on the front lines. The process of manufacturing, storing, and airlifting pharmaceuticals to soldiers on a battlefield can range from weeks to months. The military recognizes the potential value of a quicker and more agile approach to manufacturing near the point of care for frontline soldiers. The ultimate vision for their investments is effective small-batch pharmaceutical production without the need for stockpiling, cold storage, and complex logistics.

If a future with distributed and point-of-care manufacturing doesn’t look like traditional brick and mortar manufacturing, what might it look like? Prefabricated, mobile, modular manufacturing units might move frequently between different geographical locations. Manufacturing units at multiple locations, perhaps even 3D printers at patients’ bedsides, may operate under a single remote quality management system. This is no longer science fiction. FDA has seen some of these technologies from developers of distributed manufacturing processes.

Regulating distributed manufacturing

While FDA’s Center of Drug Evaluation and Research’s (CDER) does not have any approved drugs in its current purview made with distributed or point-of-care technology, experts know they are coming. A paper in the Journal of Pharmaceutical Sciences co-authored by representatives of four pharmaceutical companies tells of the “move toward adoption of point-of-care manufacturing to support on-demand patient access to medicine” (1). To glean more, CDER funded and participated in a series of workshops held by the National Academies of Sciences, Engineering, and Medicine (NASEM) to identify potential technologies FDA may see in the future. Distributed and point-of-care technologies featured prominently in NASEM’s resulting report, which predicts that mobile, end-to-end systems, “are becoming mature and robust enough to push the regulatory envelope within five to 10 years” (2).

CDER established an Emerging Technology Program (ETP) in 2014 to work collaboratively with companies wanting to implement innovative manufacturing technologies in advance of regulatory submissions. Companies developing distributed and point-of-care technologies are now actively working with CDER’s ETP and preparing regulatory submissions. Sau “Larry” Lee, senior scientific advisor to the ETP explains, “The ETP brings together FDA staff focused on application review, inspection, and policy to work with companies prior to submitting an application. Some of the needs of these companies relate to science and technology, but many relate to the policy framework.”

Of course, policymakers created the existing regulatory framework for pharmaceutical manufacturing while manufacturers were creating the modern brick-and-mortar manufacturing industry. As some manufacturers now evolve toward these smaller and more distributed manufacturing paradigms, the regulatory framework may need to similarly evolve to enable the timely adoption of these technologies while keeping patients safe.

To meet this need, CDER developed the Framework for Advanced Manufacturing Evaluation (FRAME) initiative to establish such a regulatory framework that considers new possibilities for how drugs are made and provides clarity for manufacturers developing advanced technologies. A regulatory framework is complex because it encompasses many different elements including guidance, regulations, statutory authorities, application requirements, and standards. Many of these elements impact stakeholders beyond CDER. A key regulatory challenge is addressing both current and future technologies by considering how any framework change would affect existing technologies regulated across FDA. Ashley Boam, director of CDER’s Office of Policy for Pharmaceutical Quality, shares, “As CDER has navigated through the various components of the regulatory framework, it has by necessity turned into a highly collaborative FDA-wide effort.” The first, and arguably most difficult, step is identifying the existing areas of policy that FDA may consider addressing.

CDER is now increasing outreach to public stakeholders and asking for their input to better identify these areas of policy consideration for distributed and point-of-care technologies. CDER released a discussion paper to solicit public input on distributed and point-of-care manufacturing by Dec. 13, 2022 (3). This discussion paper presents areas of consideration for policy development based on CDER’s evaluation of the existing regulatory framework. Interested stakeholders were also invited to a public workshop held by the Product Quality Research Institute to share input on key questions related to these technologies, such as:

• How can manufacturers ensure location changes do not impact product quality?
• How could a new paradigm consisting of a “centralized quality system” at one location and multiple manufacturing units at others comply with current good manufacturing practice (CGMP) regulations?
• What type of business relationships are envisioned between health care facilities and companies developing point-of-care manufacturing platforms?

Answers to questions like these will help guide the development and implementation of an appropriate regulatory framework. In the future, CDER plans similar efforts to capture public input on the use of artificial intelligence in drug manufacturing.

FDA is not alone in preparing for advanced manufacturing technologies. The United Kingdom’s Medicines and Healthcare products Regulatory Agency (MHRA) is considering a new regulatory framework to enable the safe development of point-of-care products. Similar to CDER’s FRAME initiative, the MHRA’s new point-of-care regulatory framework aims to adapt regulations that do not create barriers for the implementation of advanced technologies yet ensure that drug products adhere to good manufacturing practices. Like FDA, MHRA has also sought public input to clarify if and how the point-of-care framework will impact other types of manufacturing and provide a level of flexibility that is absent from the current state.

The future of manufacturing

While the advancement of these innovative technologies on a large scale might increase the robustness of pharmaceutical manufacturing and reduce local drug shortages, a distributed and point-of-care manufacturing paradigm is not a panacea. For example, the ability to meet localized demand will require raw or starting materials that are distributed efficiently to the sites of manufacture. Still, if realized, Boam believes the future could be bright, “I could envision a scenario in which patient care and access to medicines are vastly improved because of these innovative approaches to manufacturing.” For his part, Lee posits, “I think pharmaceutical manufacturing is on the verge of reconstruction; we have reached the point where change is necessary to improve quality and access.” Patients are ready for the benefits of a more reliable and robust drug supply chain, and FDA is ready to make sure that the US regulatory framework doesn’t keep patients from realizing these benefits.

References

1. M. Algorri et al., J Pharm Sci. 111 (3) 593–607 (2022).

2. National Academies of Sciences, Innovations in Pharmaceutical Manufacturing on the Horizon: Technical Challenges, Regulatory Issues, and Recommendations (National Academies Press, Washington, DC, Feb 24, 2021).

3. CDER, Distributed Manufacturing and Point-of-Care Manufacturing of Drugs, Discussion Paper, FDA.gov (Oct. 18, 2022).

About the author

Adam C. Fisher, Phd, is Director of Science Staff, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, FDA.

Article details

Pharmaceutical Technology
Volume 46, Number 12
December 2022
Pages: 28-29

Citation

When referring to this article, please cite it as A. Fisher, “Nurturing Manufacturing Agility," Pharmaceutical Technology 46 (12) 28-29 (2022).