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By: Michael Kopcha, PhD, RPh, Director of the Office of Pharmaceutical Quality (OPQ), Center for Drug Evaluation and Research (CDER) and Patrizia Cavazzoni, MD, Director of CDER  

Patients with diseases including cystic fibrosis, HIV, breast cancer, leukemia, and asthma are benefitting from medications manufactured in newer, more expedient, and more flexible ways. This is because certain drug manufacturers have adopted advanced manufacturing: innovative and emerging approaches to produce medicines. 

Through a broad public health lens, advanced manufacturing is a key component of the overall U.S. strategy to strengthen domestic drug manufacturing and increase the domestic supply of quality medical products for consumers. Advanced manufacturing requires a skilled workforce and can help domestic companies operate with lower costs and fewer quality defects in smaller facilities, improving the global competitiveness of U.S. manufacturing. 

The U.S. Food and Drug Administration has long recognized the importance of advanced manufacturing. The FDA has received significant funding from Congress for advanced manufacturing-related projects, and we continue to work with manufacturers looking to implement these new technologies to benefit even more patients. To do so, the Center for Drug Evaluation and Research (CDER) has established numerous initiatives, including the development of a research program to better understand the science of advanced manufacturing. To date, this program has fueled nearly 60 research projects, including many collaborations with experts in the field. The knowledge gained from our research has helped us provide guidance for applicants seeking to use new technologies, such as continuous manufacturing, a technology that produces medicines in an integrated flowing process, as opposed to the traditional “batch” process that employs stops and starts between steps. 

These days advanced manufacturing is a global trend, with many foreign regulators also recognizing its benefits. The FDA is collaborating with our international regulatory counterparts in developing requirements to assist manufacturers who are exploring advanced manufacturing. For example, the FDA is spearheading the International Conference on Harmonization Q13 guideline on continuous manufacturing of drug substances and drug products, which is now available for public comment.

Unquestionably, an important outcome for patients is the FDA’s ability to approve quality, safe and effective drugs made by manufacturing technologies that ensure a seamless supply of these medicines. To this end, CDER created the Emerging Technology Program (ETP) and our colleagues in the Center for Biologics Evaluation and Research established the Advanced Technologies Team (CATT) to offer pre-submission support for applicants looking to adopt advanced manufacturing technologies for the development of human drugs. Our colleagues in the Office of Regulatory Affairs plan to strengthen their advanced manufacturing training for field investigators through strategic personnel additions.

Recent data suggests the program is working. In 2015, the FDA approved the first regulatory submission for a human drug produced by continuous manufacturing and the first produced by 3D printing. The FDA has now approved finished dosage forms, an active pharmaceutical ingredient, and biological molecules produced using advanced manufacturing technologies, with congressional funding helping to accelerate our efforts. The majority (more than 80%) of the drugs made using advanced manufacturing technologies are produced in the U.S.
 
We believe this trend will continue. The FDA has now accepted more than 100 proposals spanning a wide range of innovative technologies and has sponsored more than 100 meetings. In fact, the workload of the ETP has increased to the point that we are creating ETP 2.0 to meet workload challenges and enhance communication with companies that would like to adopt advanced manufacturing technologies in the future. Under the enhanced ETP, more FDA staff will be trained on new technologies to improve our ability to evaluate them. 

Funded by the FDA, an ad hoc committee of the National Academies of Sciences, Engineering, and Medicine recently published a consensus report identifying technologies the agency can expect to see in regulatory submissions in the future. We are now addressing any knowledge and experience gaps to form the regulatory framework required for these technologies, which include:

• End-to-end continuous manufacturing, a process that integrates active pharmaceutical ingredient and drug product manufacturing in one process. 
• Portable and modular distributed manufacturing platforms, so-called pharmacy-on-demand.
• Artificial intelligence or advanced modeling approaches in manufacturing.

To maintain the momentum of advanced manufacturing in the human drug and biologics programs, the FDA formally established an internal Center for Advancement of Manufacturing Pharmaceuticals and Biopharmaceuticals in June 2021 to enhance coordination and collaboration of science, regulatory, and policy activities. We hope this center and our ongoing efforts in collaboration with industry and other stakeholders will continue fueling American manufacturing innovation and, most importantly, assuring that U.S. patients and consumers have a consistent supply of quality medicines.