FDA Highlights Value and Challenges of Advanced Drug Manufacturing

In its ongoing campaign to encourage industry adoption of more efficient and reliable pharmaceutical production methods, FDA is expanding its Emerging Technology Program (ETP) and providing more support for new drug applications (NDAs) that present advanced manufacturing technologies. While these initiatives aim to limit drug shortages and recalls due to quality issues, the program also seeks to expand investment in domestic production to enhance access to critical therapies and vaccines for U.S. patients. At the same time, the agency is collaborating with foreign regulatory authorities to support international harmonization of policies designed to advance continuous manufacturing operations for drugs and biotech therapies around the world.

The challenges of meeting urgent demands for more new medical products during the COVID-19 pandemic has highlighted the value of more responsive and flexible manufacturing methods, including manufacturing systems that can be scaled up more quickly and automated processes that can reduce in-plant staff and permit more flexible employee work schedules. These developments have increased collaboration and partnering among biopharma manufacturers over the past 18 months, as competitors have worked together to accelerate access to needed therapies by providing fill/finish services for vaccine makers and active ingredients (APIs) for finished dosage forms, among other joint efforts.

These issues and opportunities will be discussed at an FDA conference on innovations in pharmaceutical manufacturing, as outlined in a report on the topic issued in March 2021 by the National Academy of Sciences, Engineering and Medicine (NASEM).¹ This review requested by for the Center for Drug Evaluation and Research (CDER) of the importance and challenges for advancing innovative biopharmaceutical manufacturing aims to reduce quality-related shortages that can limit patient access to safe and effective drugs. The virtual meeting on Oct. 28 and 29, 2021 will discuss industry advances in manufacturing systems and policies and actions for moving forward.

CDER support for these initiatives appears to be having an impact, according to in a recent commentary by Center leaders.² CDER director Patrizia Cavazzoni and Michael Kopcha, director of CDER’s Office of Pharmaceutical Quality (OPQ), note that the agency approved its first application for a drug produced by continuous manufacturing in 2015 and ten more applications since then that utilize advanced approaches for finished dosage forms, APIs and biological molecules. Now more than 100 proposals utilizing a range of innovative technologies have been presented to agency officials, necessitating an expansion in the ETP program to handle the workload.

International impacts

FDA’s advanced manufacturing initiative also aims to enhance the competitiveness of U.S. firms in the global pharmaceutical market by lowering costs and promoting quality. Acting commissioner Janet Woodcock cites visible success in this area in a tweet posted Oct. 15, 2021, reporting that more than 80% of the drugs made using advanced manufacturing technologies are produced domestically. An FDA Center for Advancement of Manufacturing Pharmaceuticals and Biopharmaceuticals established in June 2021 is coordinating analysis related to such topics as end-to-end continuous manufacturing, portable and modular distributed manufacturing platforms, and use of artificial intelligence or advanced modeling approaches in manufacturing.

At the same time, FDA is promoting international coordination and agreement on the scientific issues and regulatory policies related to implementing and overseeing modern drug manufacturing, as seen in the new draft Q13 guidance developed through the International Council for Harmonization (ICH). FDA recently posted the initial version of this standard for Continuous Manufacturing of Drug Substances and Drug Products, which applies to new drugs, generics, therapeutic proteins and biosimilars. Manufacturers and other stakeholders should submit comments on the draft document to FDA by Dec. 13, 2021.³

This ICH initiative aims to advance biopharmaceutical quality through operations that reduce manual handling that leads to human error, utilize online monitoring and controls, increase manufacturing speed and efficiency, and install smaller equipment that cuts costs.Ultimately advanced manufacturing systems would enable firms to respond “more nimbly” in the event of drug shortages and to adopt tailored systems that fit the needs of precision medicine.

Yet, FDA and industry face key challenges in advancing these initiatives. The agency’s traditional focus on ensuring the safety and efficacy of novel therapies has discouraged manufacturers from adopting less traditional production processes, especially when the evaluation of advanced manufacturing systems in an NDA might complicate or delay market approval. To move forward in this area, the NASEM report points out that FDA needs a program for evaluating innovative manufacturing processes and mechanisms outside the traditional NDA process, along with flexible and efficient procedures for processing post-approval changes to advance modern manufacturing methods for approved products. CDER leaders note that Congress has provided important funding to support advanced manufacturing, but that the agency will require added expertise and resources to progress further in building its capacity for assessing multiple novel technologies.

Congress is supporting these efforts, as seen in the recent House passage of legislation (HR 4369) to create national centers for excellence in continuous manufacturers at universities around the country. The measure benefitted from strong bipartisan support for authorizing $100 million to fund programs at several academic centers designed to improve drug quality and mitigate shortages.

Notes

1. https://www.nap.edu/catalog/26009/innovations-in-pharmaceutical-manufacturing-on-the-horizon-technical-challenges-regulatory

2. https://www.fda.gov/news-events/fda-voices/fdas-advanced-manufacturing-initiatives-helping-provide-quality-human-drugs-patients?utm_medium=email&utm_source=govdelivery

3. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/q13-continuous-manufacturing-drug-substances-and-drug-products?utm_medium=email&utm_source=govdelivery