Science Policy
day one project

通过标准化加强美国生物制造部门

06.01.23 | 9分钟阅读 | Text byChris Stowers

Summary

美国生物处理的进步和商业化受到了lack合适且可用的试点规模和制造规模的设施。这一挑战部分是由于我们无法重新使用的设施,而这些设施由于缺乏标准化和原始设计不足而不再需要。从历史上看,大多数生物制造设施都考虑到了单一产品,并专注于尽可能廉价,迅速地提供设施。尽管这可能是单个私营公司的最佳方法,但它并不是整个生物经济学的最佳方法。Biden-Harris管理局应建立一项计划,以标准化整个美国的生物制造设施的建设,该设施还允许将来对不同产品重新使用设施。

Through government-incentivized standardization, better biomanufacturing facilities can be built that can be redeployed as needed to meet future market and governmental needs and ultimatelysolveour 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.

挑战和机会

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.

为什么我们缺乏这些设施?这是因为由于市场状况不断变化,产品发布失败或破产,许多设施已关闭。当这些设施最终被废弃并拆除以进行废料时,与它们一起重新利用昂贵的基础设施的机会就会丢失。

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 arerepurposed. The rate of repurposing biomanufacturing facilities is much lower, given the lower level of standardization. Furthermore, nearly30%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 byGevofor the production of bio-butanol in Minnesota or theFreedom Pines facilityin Georgia repurposed by LanzaTech.

但是,有许多关于设施无法重新使用的故事,例如INEOSfacility that wasshutteredin India River, Florida. Repurposing these facilities is challenging for two primary reasons:

  1. A lack of forethought that the facility could be repurposed in the future (i.e., no space for additional equipment, equipment difficult to modify, materials of construction that do not have broad range of process compatibility).
  2. A lack of standardization in the detailed design (materials of construction, valve arrangements, pipe sloping, etc.) that prevents processes with higher aseptic requirements (lower contamination rates) from being implemented.

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).

这些标准应集中在上游设备(发酵罐,媒体准备罐,灭菌系统)上,这些设备在整个食品,制药和工业生物技术行业中相当普遍。虽然有一些机会将这些标准应用于下游过程设备,但生产不同生物技术产品所需的下游单元操作差异很大,因此重新利用设备的更具挑战性。

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.

遵循这些标准会增加资本成本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 “美国本计划办公室(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驾驶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.

Plan of Action

拜登 - 哈里斯管理局(Biden-Harris Administration)应赞助一项倡议,以激励标准化,以使生物制造设施重新利用,从而导致更加集成和无缝的生物经济性。为此,国会应为NIST的生物制造标准的计划提供适当的资金。该程序应:

首先,该计划将需要由国会资助,并在NIST内站起来。奖励金额将根据设施规模而有所不同,但据估计,每家参与的公司平均将获得600万美元,从而导致计划的总成本在每年3000万美元至5000万美元之间。虽然成本似乎很高,但该投资的风险降低了,因为如果原始公司放弃该设施,则采用该计划的设施可以更好地重新使用。

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.

标准发布后,NIST应该劳恩ch (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.

最后,为了衡量该计划的成功,NIST应该跟踪参与设施的重新部署的速度。未参与该计划的设施重新部署的成功率也应作为基准。10年后,预计重新部署率至少会提高两倍。如果不发生这种情况,则应对该程序进行重新评估,并应进行调查,以了解为什么没有重新部署参与设施。如果需要,应调整现有的生物制造标准。

Conclusion

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.

经常问的问题
What will it cost to run the incentivization program?

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.

How will we ensure that the program funding is provided equitably across companies and to areas that will generate the most return for the U.S. bioeconomy?

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.

How long will it take before the impact of this program is realized?

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.

标准是否需要足够一般才能适应所有行业,还是需要特定于行业的行业?

保持整个行业的标准将军可以重新利用不同行业的设施。在整个行业中存在不同的标准,并且存在于某些行业而不是其他行业,这是重新部署设施的当前挑战的一部分。

How would U.S. standards fit into the global biomanufacturing system? Do U.S. and global standards need to align?

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.

How often would the NIST team need to meet to reevaluate standards so they remain current?
最初,该团队每月至少需要一次开会一次,以监督新标准的发展和推出。该计划完全开发和启动后,该团队将每季度开会,以评估该计划的整体性能,并根据需要对标准进行次要修订。
Does making standards mean more jobs?
Yes, at least in the long term. Standardizing our biomanufacturing footprint will enable more biotechnology processes to be commercialized in the United States, leading to job growth. Furthermore, it will reduce the cost of U.S. biomanufacturing since fewer new facilities will need to be built, freeing up funds that can be invested in other biotech processes.
Could program funding be offered in terms of government-guaranteed loans rather than direct incentives to participating companies?
虽然可以提供政府担保的贷款ns would be less attractive to the large, established companies that build most of the large biomanufacturing facilities in the United States. Large companies are likely to be more attracted to participate if direct incentivization payments were made.