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Dec 21, 2023

Strengthening the U.S. Biomanufacturing Sector Through Standardization

The advancement and commercialization of bioprocesses in the United States is

The advancement and commercialization of bioprocesses in the United States is hindered by a lack of suitable and available pilot-scale and manufacturing-scale facilities. This challenge stems in part from our inability to repurpose facilities that are no longer needed due to a lack of standardization and inadequate original design. Historically, most biomanufacturing facilities have been built with a single product in mind and with a focus on delivering a facility as cheaply and quickly as possible. While this might be the best approach for individual private companies, it is not the best approach for the bioeconomy as a whole. The Biden-Harris Administration should establish a program to standardize the construction of biomanufacturing facilities across the United States that also permits facilities to be repurposed for different products in the future.

Through government-incentivized standardization, better biomanufacturing facilities can be built that can be redeployed as needed to meet future market and governmental needs and ultimately solve our nation's lack of biomanufacturing capacity. This program will help protect U.S. investment in the bioeconomy and accelerate the commercialization of biotechnology. Enforcement of existing construction standards and the establishment of new standards that are strictly adhered to through a series of incentivization programs will establish a world-leading biomanufacturing footprint that increases supply resilience for key products (vaccines, vitamins, nutritional ingredients, enzymes, renewable plastics), reduces reliance on foreign countries, and increases the number of domestic biomanufacturing jobs. Furthermore, improved availability of pilot-scale and manufacturing-scale facilities will accelerate growth in biotechnology across the United States.

This memo details a framework for developing and deploying the necessary standards to enable repurposing of biomanufacturing facilities in the future. A team of 10–12 experts led by the National Institute for Standards and Technology (NIST) should develop these standards. A government-sponsored incentivization program with an estimated cost of $50 million per year would then subsidize the building of new facilities and recognition of participating companies.

Currently, the United States faces a shortage in both pilot-scale and manufacturing-scale biomanufacturing facilities that severely hinders product development and commercialization. This challenge is particularly large for the fermentation industry, where new facilities take years to build and require hundreds of millions of dollars in infrastructure investment. Many companies rely on costly foreign assets to advance their technology or delay their commercialization for years as they wait for access to one of the limited contract pilot or manufacturing facilities in the United States.

Why do we have such a shortage of these facilities? It is because numerous facilities have been shut down due to changing market conditions, failed product launches, or bankruptcy. When the facilities were ultimately abandoned and dismantled for scrap, the opportunity to repurpose expensive infrastructure was lost along with them.

Most U.S. biomanufacturing facilities are built to produce a specific product, making it difficult to repurpose them for alternative products. Due to strict financing and tight timelines for commercialization, companies often build the minimally viable facility, ultimately resulting in a facility with niche characteristics specific to their specific process and that has a low likelihood of being repurposed. When the facility is no longer needed for its original purpose—due to changes in market demand or financial challenges—it is very unlikely to be purchased by another organization.

This challenge is not unique to the biomanufacturing industry. In fact, even in the highly established automotive industry, less than half of its manufacturing facilities are repurposed. The rate of repurposing biomanufacturing facilities is much lower, given the lower level of standardization. Furthermore, nearly 30% of currently running biomanufacturing facilities have some idle capacity that could be repurposed. This is disappointing considering that many of these biomanufacturing facilities have similar upstream operations involving a seed bioreactor (a small bioreactor to be used as inoculum for a larger vessel) to initiate fermentation followed by a production reactor and then harvest tanks. Downstream processing operations are less similar across facilities and typically represent far less than half the capital required to build a new facility.

The United States has been a hot spot for biotech investment, with many startups and many commercial successes. We also have a robust supply of corn dextrose (a critical input for most industrial fermentation), reasonable energy costs, and the engineering infrastructure to build world-class biomanufacturing facilities providing advantages over many foreign locations. Our existing biomanufacturing footprint is already substantial, with hundreds of biomanufacturing facilities across the country at a variety of scales, but the design of these facilities lacks the standardization needed to meet the current and future needs of our biomanufacturing industry. There have been some success stories of facilities being repurposed, such as the one used by Gevo for the production of bio-butanol in Minnesota or the Freedom Pines facility in Georgia repurposed by LanzaTech.

However, there are numerous stories of facilities that were unable to be repurposed, such as the INEOS facility that was shuttered in India River, Florida. Repurposing these facilities is challenging for two primary reasons:

In order to increase the rate at which our biomanufacturing facilities are repurposed, we need to establish the policies and programs to make all new biomanufacturing facilities sustainable, more reliable, and capable of meeting the future needs of the industry. These policies and associated standards will establish a minimum set of guidelines for construction materials, sterilizability, cleanability, unit operation isolation, mixing, aeration, and process material handling that will enable a broad range of compatibility across many bioprocesses. As a specific example, all fermentors, bioreactors, and harvest tanks should be constructed out of 316L grade stainless steel minimum to ensure that the vast majority of fermentation and cell culture broths could be housed in these vessels without material compatibility concerns. Unfortunately, many of the U.S. biomanufacturing facilities in operation today were constructed with 304 grade stainless steel, which is incompatible with high-salt or high-chloride content broths. Furthermore, all process equipment containing living microorganisms should be designed to aseptic standards, even if the current product is not required to be axenic (absent of foreign microorganisms).

These standards should focus on upstream equipment (fermentors, media preparation tanks, sterilization systems), which are fairly universal across the food, pharma, and industrial biotech industries. While there are some opportunities to apply these standards to downstream process equipment, the downstream unit operations required to manufacture different biotech products vary significantly, making it more challenging to repurpose equipment.

Fortunately, guiding principles covering most factors that need to be addressed have already been developed by experts in the American Society of Mechanical Engineers (ASME), Bioprocess Equipment (BPE), and the International Society for Pharmaceutical Engineering (ISPE). These standards cover the gamut of biomanufacturing specifications: piping, mixing, valves, construction materials, and, in some cases, the design of specific unit operations. Companies are often forced to decide between following best practices in facility design and making tight timelines and budgets.

Following these standards increases capital costs of the associated equipment by 20% to 30%, and can extend construction timelines, preventing companies from adopting the standards even though it directly improves their top or bottom line by improving process reliability. Our biggest gap today is not ability to standardize but rather the incentivization to standardize. If the government provides incentives to adopt these standards, many companies will participate as it is widely recognized that these standards will result in facilities that are more reliable and more flexible for future products.

The National Institute for Standards and Technology (NIST) should initiate a program focused on biomanufacturing standards. The proposed program could be housed or coordinated out of a new office at the NIST—for example, as described in the previously proposed "Bio for America Program Office (BAPO)"—which should collaborate closely with the Office of the Secretary of Commerce and the Under Secretary of Commerce for Standards and Technology, as well as additional government and nongovernmental stakeholders as appropriate. NIST is the appropriate choice because it harbors cross-disciplinary expertise in engineering, and the physical, information, chemical, and biological sciences; is a nonregulatory agency of the U.S. Department of Commerce, whose mission it is "to drive U.S. economic competitiveness, strengthen domestic industry, and spur the growth of quality jobs in all communities across the country"; and is a neutral convener for industry consortia, standards development organizations, federal labs, universities, public workshops, and interlaboratory comparability testing.

The Biden-Harris Administration should sponsor an initiative to incentivize the standardization that will enables the repurposing of biomanufacturing facilities, resulting in a more integrated and seamless bioeconomy. To do so, Congress should appropriate funds for a program focused on biomanufacturing standards at NIST. This program should:

First, the program will need to be funded by Congress and stood up within NIST. The award amounts will vary based on the facility size, but it is estimated that each participating company will receive $6 million on average, leading to a total program cost in the range of $30 million to $50 million per year. While the costs might seem high, the investment is at reduced risk by design, since facilities that adopt the program are better equipped to be repurposed should the original company abandon the facility.

Next, design and building standards would be defined that ensure the highest chance of redeployment along with reliable operation. While relevant standards exist (i.e., ASME BPE Standards), they should be refined and elaborated by an expert panel established by NIST with the purpose of promoting repurposing. The adoption rate of the existing nonmandatory standards is low, particularly outside of the pharma industry. This new NIST program should establish a panel of experts, including industry and government representatives, to fully develop and publish these standards. A panel of 10–12 members could develop these standards in one year's time. Thereafter, the panel could be assembled regularly to review and update these standards as needed.

Once the standards are published, NIST should launch (and manage) a corresponding incentivization program to attract participation. The program should be designed such that an estimated 50% incremental cost savings would be achieved by adhering to these standards. In other words, the improved infrastructure established by following the standards would not be fully subsidized, but it would be subsidized at the rate of 50%. The NIST program could oversee applicants’ adherence to the new standards and provide awards as appropriate. NIST should also work with other federal government agencies that support development of biomanufacturing capacity (e.g., Department of Energy [DOE], Department of Defense [DoD], and Department of Agriculture [USDA]) to explore financial incentives and funding requirements to support adherence with the standards.

In addition, the government should recognize facilities built to the new standards with a certification that could be used to strengthen business through customer confidence in supply reliability and overall performance. NIST will publish a list of certified facilities annually and will seek opportunities to recognize companies that broadly participate as a way to recognize their adoption of this program. Furthermore, this type of certification could become a prerequisite for receiving funding from other government organizations (i.e., DoE, DoD, USDA) for biomanufacturing-related funding programs.

Last, to measure the program's success, NIST should track the rate of redeployment of participating facilities. The success rate of redeployment of facilities not participating in the program should also be tracked as a baseline. After 10 years, at least a twofold improvement in redeployment rate would be expected. If this does not occur, the program should be reevaluated and an investigation should be conducted to understand why the participating facilities were not redeployed. If needed, the existing biomanufacturing standards should be adjusted.

Given the large gap in biomanufacturing assets needed to meet our future needs across the United States, it is of paramount importance for the federal government to act soon to standardize our biomanufacturing facilities. This standardization will enable repurposing and will build a stronger bioeconomy. By establishing a program that standardizes the design and construction of biomanufacturing facilities across the country, we can ensure that facilities are built to meet the industry's long-term needs—securing the supply of critical products and reducing our reliance on foreign countries for biomanufacturing needs. In the long run, it will also spur biotech innovation, since startup companies will need to invest less in biomanufacturing due to the improved availability of manufacturing assets.

A committee will need to be established to create a detailed budget plan; however, rough estimates are as follows: A typical biomanufacturing facility costs between $100 million and $400 million to build, depending on scale and complexity. If the program is designed to support five biomanufacturing facilities per year, and we further assume an average construction cost of $200 million with $40 million of that being equipment that applies to the new standard, a 15% subsidy would result in ~$6 million being awarded to each participating facility. If we assume that following these standards increases the costs of the associated equipment by 30%, the net increase in costs would be from $40 million to $52 million. This 15% subsidy is designed to offset the cost of applying these new standards at roughly a 50 cents on the dollar rate. In addition, there will be some overhead costs to run the program at NIST, but these are expected to be small. Thus, the new program would cost in the range of $30 million to $50 million per year to run, depending on how many companies participate and are awarded on an annual basis.

When they apply for funding, companies will describe the facility to be built and how the funds will be used to make it more flexible for future use. A NIST panel of subject matter experts will evaluate and prioritize nominations, with an emphasis on selecting facilities across different manufacturing sectors: food, pharma, and industrial biotech.

Given that the life of biomanufacturing facilities is on the order of years, it is expected that this program will take several years before a true impact is observed. For this reason, the program evaluation is placed 10 years after launch, by which time it is expected that more than 20 facilities will have participated in the program, and at least a few will have been repurposed during that time.

Keeping the standards general across industries enables repurposing of facilities across different industries. The fact that different standards exist across industries, and are present in some industries but not others, is part of the current challenge in redeploying facilities.

The initial focus is on standardization within the United States. Eventually, standardization on a more global scale can be pursued, which will make it easier for the United States to leverage facilities internationally. However, international standardization presents a whole new set of challenges due to differences in equipment availability and materials of construction.

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