One of the most pronounced recent signals from the US government highlighting biosecurity as a national security priority, was Executive Order (EO) 14081, also called the “Biomanufacturing bill”, published in September 2022. The executive order calls for advancing biotechnology and biomanufacturing research and development. Its introduction by the administration was an exciting moment for synthetic biologists, climate enthusiasts and solar punk visionaries. The bill signified the recognition of the potential of synthetic biology to shift the prevailing dominance of a petroleum-based materials industry to a bio-based materials industry (EO focus area #1: to further climate change solutions). (EO focus area #2: to further food and agriculture innovation). Additionally, the bill advocated for the further advancement of biomanufacturing infrastructure, notably by nationalizing the manufacturing of medical countermeasures (EO focus area #3: to further human health). It acknowledged the US vulnerabilities in drug development, validate by the COVID-19 pandemic. Furthermore, the bill focused on protecting and expanding domestic biomanufacturing supply chain and infrastructure (EO focus area #4: supply chain resilience). Substantial funding was allocated to expand raw ingredients manufacturing nationally and reducing the vaccine supply chain dependency on international suppliers. Given concerns about repeating mistakes observed in the semiconductor industry and ongoing global competition in scientific advancement, this came to no surprise. Following this, a National Biotechnology and Biomanufacturing Initiative was promptly launched, concentrating on strengthening national infrastructure. By March 2023, the White House published an initial report outlining the research and development goals of relevant departments as a response ot the Bill.

However, a lot remains misunderstood or underappreciated about biomanufacturing. For instance, there is an absence of a comprehensive database detailing what raw materials are most critical to vaccine manufacturing and how they are typically sourced. While manufacturing drugs is indeed a complex process, the inherent complexity lies not in the drugs themselves but rather in establishing an infrastructure that can generate these drugs in large quantities, with every batch generated having predictable and similar properties. The industry has developed an extensive level of control over manufacturing processes over the years, becoming increasingly specialized and distributed. The challenge we face now is an inflexible biomanufacturing industry struggling to adapt to innovative technologies.

There are three issues I wish to highlight that significantly limit innovation in the drug development space. First, the highly intricate operations that come with manufacturing a drug. Next, the difficulty of transitioning a drug from molecule to clinic - often called the ‘valley of death’ in biopharma. And finally, the biomanufacturing industry’s risk aversion.

It’s essential to understand that making a drug product usually involves several Contract Development and Manufacturing Organizations (CDMOs), each specializing in a particular part of the manufacturing process. Starting with the critical raw materials, each is typically manufactured and ‘released’ with certain quality control by a separate manufacturer. For an mRNA vaccine, this involves plasmid DNA, and individual lipids. Following this, there is the active pharmaceutical ingredient (API). This is the molecule that has the medicinal properties in the human body. For an mRNA vaccine, this is the mRNA. The starting material is supplied to the API CDMO, again thoroughly tested, then used to manufacture the mRNA followed by another release procedure. Another CDMO then formulates the API into the final formulation, and, if you’re lucky, they also handle the fill and finish process of your product. Another CDMO could be responsible for the packaging of the product and supplying the product to your clinical trial sites is yet another procedure. Due to dependencies, it is very difficult to compress timelines of the entire process, and it necessitates drug innovators to persuade CDMOs to adopt novel processes suitable for their product. Furthermore, it demands a high level of excellence in supply chain coordination and quality management, often lacking for early stage companies. The notion of a ‘key turn’ or end-to-end CDMO offering a one-stop-shop solution is nothing more than a fanciful idea.

Early-stage drug development companies often lack the financial and operational capacity to bring their drugs to the clinic. If there is innovation in biomanufacturing during the preclinical stage, it is often lost in the ‘valley of death’, where larger pharma companies acquire assets for low prices, and biomanufacturing is put on the back burner.

Manufacturing excellence was touted as a value center in the 80s and 90s. Since then, it has rather transitioned to being seen as a major project cost and overhead by pharmaceutical companies. Smaller budgets don’t incentivize CDMO’s to innovate. Manufacturing in biopharma is inherently risk averse. Consequently, not much has changed in the way we manufacture drugs since the 90s, with egg-based manufacturing dominating over recombinant protein manufacturing.

It might come as a surprise to learn that the regulatory landscape, particularly FDA agencies, are aware of this issue and have attempted to incentivize companies to innovate more in their manufacturing processes. For example, the Center for Drug Evaluation and (CDER) Office of Pharmaceutical Quality (OPQ) emerging technologies program (ETP) or the Center for Biologics Evaluation and Research (CBER) Advanced Technology Team (CATT). More recent initiatives such as ARMI BioFabUSA, NIMBL, and BioMADE are also striing to promote a new narrative where biomanufacturing is once again appreciates as a major area of innovation by biopharma.

The Bill appears to incentivize the development of innovative products and the expansion of national infrastructure such as increasing CDMO capacity. But the Bill seems to fall short in truly incentivizing those researching and developing solutions in the Bill’s focus areas through pursuing innovative biomanufacturing strategies. Manufacturers adapt to what clients are willing to pay for, and the bill fails to recognize this demand-driven innovation.