Workshop summary: Technology solutions for improving the resilience of generic prescription drug manufacturing

On March 2, 2023, the authors convened a group of experts from academia, industry, government, and nonprofits to explore technology options for increasing the resilience in the supply of generic prescription drugs. The workshop was convened at the Massachusetts Institute of Technology with the help of the National Network for Critical Technology Assessment and financial support from the Alfred P. Sloan Foundation. This report, authored by the organizers, summarizes the discussion. Because the workshop was not open to the public, this summary maintains the anonymity of the speakers and does not attribute comments to individuals.

Motivation for the workshop

Assured high quality and consistent availability of medicines is a cornerstone of patient care, yet U.S. prescription drug supply chains are highly vulnerable to disruptions.  If drug shortages result, they may place patients’ health and even their lives at risk through treatment delays, rationing, increased likelihood of medication errors, and the substitution of possibly inferior alternatives.

Drug shortages result when supply chains cannot withstand demand or supply shocks.  Recent demand shocks included a post-COVID increase respiratory illnesses driving up demand for amoxicillin or an increase in the off-label use for certain diabetes drugs like Ozempic.  But shortages occur more frequently when supply disruptions – whether caused by manufacturing problems, natural disasters, or delays in obtaining ingredients – are significant enough that available inventories or scaling available manufacturing sites does not suffice.  Historically, manufacturing quality problems with older generic (off patent) medicines have been the most common cause of shortages drug shortages.

To ensure that medicines are available when and where they are needed, numerous reports from government, industry, and academia have called for greater supply chain resilience where supply chains can either absorb or recover readily from demand shocks and supply shocks, both unexpected (like natural disasters) and preventable (like manufacturing quality).

Advanced manufacturing technologies (AMTs) such as continuous manufacturing, are among oft-cited solutions to resolve or mitigate challenges in pharmaceutical manufacturing supply resilience.  Proponents of these technologies posit that AMTs enhance pharmaceutical manufacturing quality, speed, flexibility, and cost-effectiveness.  The Food and Drug Administration (FDA) has specifically called out continuous manufacturing as a technology that can help prevent drug shortages caused by product quality and manufacturing problems.

Despite the promise of AMTs to address drug manufacturing quality and shortages, AMTs have been slow to emerge, especially among generic drugs.  To date, there are a handful of branded drugs approved with continuous manufacturing but no generic drugs.  Even conferences and workshops are missing engagement from generic manufacturers.

To explore the application of AMTs in the generics manufacturing context, this workshop convened experts in the fields of material chemistry, manufacturing, economics, and regulatory science.  Participants explored the following questions:

• What are the key failure modes for pharmaceutical manufacturing and how do they differ for brands and generics?
• What are the AMT options to overcome those failure modes?
• What are the barriers for generic drug manufacturers to adopt those technologies?
• What are practical next steps that government, industry, or academia could take?

Main takeaways

The main takeaways from the workshop can be summarized as follows:

• The cost of AMTs outweighs the return on investment that generic manufacturers might expect relative to other options. Throughout the workshop, current and former generic business leaders spoke about the economics of the generic drug industry and the constraints they present in adoption of new technologies.  Demonstrations using continuous manufacturing for generics suggest that currently any production cost-efficiencies do not suffice when those products compete with low-cost foreign producers.

• AMTs, continuous manufacturing in particular, do not align with the fast turnover, large portfolio nature of generic drug manufacturing. The existing evidence on the value of AMT technologies applies to single, continually produced product.  This, however, does not translate well to generic drug manufacturing where the unstable nature of demand can lead to 20-30 products run on a single line over a course of a year, leading to frequent switchovers.  Developing a platform approach and better documenting the return on investment would be important for driving adoption of AMT technologies among mainstream generic manufacturers.
• Current direction for reducing regulatory barriers is insufficient. Business and government leaders acknowledged regulatory constraints and uncertainty that make it costly to change manufacturing technology and processes.  On the one hand is the work-in-progress nature of FDA’s regulations regarding the use of AMTs, with guidances and pilots in the works.  On the other hand is the nature of the generics business, with a large installed base of products and questions about how to address technology adoption for product portfolios, not just individual products.  While FDA is making process on the former, the latter remains unaddressed.
• A full range of technologies, not just AMTs, should be considered when addressing generic prescription drug supply chain resilience.  Although the workshop did not cover the full spectrum of technologies that could help address supply chain resilience for generics, participants argued that basic technologies such as record digitization might provide a better return on investment from a social perspective.

• The role of technology and its type (AMT vs low-tech) should match the specific vulnerabilities in supply chains. Workshop participants identified medical countermeasures, antibacterials, and pharmaceuticals with narrow therapeutic index (NTI) as most likely, preliminary use cases for continuous manufacturing.  These preliminary use cases should be assessed by the U.S. government as part of a broader effort to evaluate the return on investment on a broad range of interventions, whether technological or not.

• Given the lack of private incentives, U.S. government must spur AMT innovation and subsidize adoption of AMTs to generic drug supply. The government can alter the current business case for adopting AMT. To account for the variability in demand that makes continuous manufacturing unattractive for multi-product lines, participants recommended investments in developing a platform approach in such technologies. To address the large upfront costs, participants pointed to semiconductor manufacturing incentives in the CHIPS & Science Act as an example.
• Government drug supply chain resilience efforts should include prioritization of supply chains. Given the lack of private incentives, the role of U.S. government is critical.  But the size of the generic industry and the chemical industry that supports it is immense.  To best identify where and how to engage in support of drug supply chain resilience, U.S. government must take a systematic look on which supply chains are essential and which of these are vulnerable.¹

The full document provides a summary of each core session from the workshop and can be found here.