The National Institute for Innovation in Manufacturing Biopharmaceuticals (NIIMBL) was launched in March 2017 as a cooperative agreement with the National Institute for Standards and Technology (NIST), part of the US Department of Commerce. NIIMBL is one of the newest members of Manufacturing USA, a network of manufacturing innovation institutes through which industry, academia, and government work together to accelerate implementation of advanced manufacturing and develop a trained workforce in several key sectors of ththe US economy.
NIIMBL’s mission is to accelerate innovation in biopharmaceutical manufacturing, support the development of standards to enable more efficient and rapid manufacturing capabilities, and educate and train a world-leading workforce to support an industry sector that is supplying medicines for patients around the globe. NIIMBL is a catalyst for innovation that leverages the resources of small, medium, and large companies as well as academic institutions, government laboratories, state governments, and nonprofits.
The institute is supported by an initial investment by NIST of US$70 million over five years to help establish the institute. The federal funding will catalyze more than US$130 million in additional support, both cash and in kind from industry, universities, state economic development funding, and nonprofits. At the end of the five-year federal investment, NIIMBL is expected to continue operations through the demonstrated return on investment to its partners.
Its portfolio includes innovations that support the efficient, high-quality production of existing products (such as antibodies, blood clotting factors and vaccines) as well as emerging products (such as cell therapies, gene therapies and exosomes). The US-based public−private partnership represented within NIIMBL is the most significant investment designed to address the current and future needs of the biopharmaceutical manufacturing community. The results of its efforts potentially will result in improved patient access to biopharmaceutical medicines that are increasingly effective, safe, and potent.
A Market and an Industry at the Crossroads
The United States is the largest market for biopharmaceuticals, accounting for approximately one-third of total global sales. According to the Pharmaceutical Research and Manufacturers Association (PhRMA), the US biopharmaceutical sector accounts for 17% of all domestic research and development (R&D) funded by businesses, making it the world leader in biopharmaceutical R&D. The US biopharmaceutical industry contributed an estimated $1.2 trillion to economic output in 2014, or roughly 3.8% of total US output. More than 803,000 people work in the biopharmaceutical industry in the United States, and it supports directly and indirectly over 4.7 million jobs across the country (1).
Industry–academic partnerships played a key role in the early development of this industry and have been responsible in part for the success of US biopharmaceutical manufacturing over the past 30 years. Such partnerships led to development of manufacturing methods that enabled recombinant insulin, monoclonal antibodies (MAbs), and recombinant vaccines to be introduced into the market for the benefit of millions of patients worldwide. Today’s biomanufacturing industry again finds itself at a crossroads, with at least three major avenues of future opportunity.
Increased Complexity and Variability of Industrial Manufacturing: Existing biopharmaceutical products, such as therapeutic proteins and MAbs, are in clinical studies for treatment of diseases with very large potential patient populations (e.g., Alzheimer’s, diabetes, and infectious diseases). Meeting future demand will require industrialization of large-scale manufacturing processes and operations to address diverse product portfolios, with the goal of shortening process development timelines and increasing productivity. At the same time, precision medicines that accommodate individual variability in genes, environments, and patient lifestyles will require efficient manufacturing at very small scales while maintaining product quality and efficacy at reasonable cost.
Emerging Product Needs: Emerging products (e.g., gene and cell therapies) show significant promise for treating serious diseases without effective therapies. Many such therapies must be manufactured at the scale of individual lots for each patient, creating challenges in manufacturing consistency and product characterization. To enable patient access to emerging therapies, a need exists for new small-scale, fully automated manufacturing platforms, integrated with robust product and process measurement capabilities.
Reference Standards and Measurement Technologies: Development of appropriate reference standards and measurement technologies for biological products is challenging because of their complexity. Although extremely efficacious, biological products rely on complex manufacturing processes that are currently expensive because of their capital investment, highly manual nature of the process, and raw material requirements. A paucity of adequate standards (e.g., for raw materials and contaminants) exist in support of efficient development and manufacturing for existing and emerging products. Measurement technologies, particularly for process monitoring and for product quality attributes, also are needed to enable advanced control strategies (such as for real-time feedback or feed-forward control) that will improve the efficiency of biomanufacturing processes.
|Technical/Regulatory Science Needs in Biopharmaceutical Manufacturing|
|Product Types: Antibodies, proteins, antibody-drug conjugates (ADCs), bispecific antibodies, vaccines, cell therapies, gene therapies, and oligonucleotides.|
|Topic Areas of Interest Cell Line Development, Cell Line Engineering: Increased productivity; alternative cell lines or platforms; cell line robustness|
|Analytical Methods and Process Control: Real time or rapid methods and in-line measurement methods; small volume and nondestructive methods for drug substance or drug product; predictive models and control algorithms; novel in-line and on-line sensors; rapid adventitious agent/bioburden testing; automation for cell testing and cell banking; extended characterization for excipient and raw material control and standardization; in vitro assays for clearance and biodistribution; device and container closure functionality measurements; industry-wide automation and control platforms including mathematical methods, software and analytics|
|Process Development: Process integration and intensification, including continuous and “connected” processes; large-scale frozen bulk storage methods; novel and optimized unit operations; improved scale-up and scale-down approaches; high-throughput process design and development platforms; mathematical models for manufacturing-scale unit operations; mobile, autonomous clean rooms; novel single-use disposable systems; novel automation, data acquisition and data handling approaches; small volume drug product processes; personalized medicine production|
|Reference Standards and Regulatory Science: Acceptable limits for impurities and particles; science-based compliance standards and reference standards for testing process or product, including CHO-based MAb, excipients, and surfactants; cell-based standards; rapid surrogate assays; standardization of interfaces and connectors for single-use equipment; harmonization approaches for standards; reducing risk in regulatory evaluation of innovations for continuous and connected processes, combination products, and aspects of “clonality”; multiattribute methods; standardization of data handling/data exchange systems for automation and control; standardized extractables, leachables, and particle testing|
|Supply Chain Management and IT Solutions: Rapid raw materials testing and understanding; improved methods to determine shelf-life and stability of intermediates; tracking methods for cell and gene therapy products; rapid pandemic response; standardized software for “–omics” data; cross-company knowledge-pooling tools that support industry-wide interests and allow data analytical and support regulatory filings.|
Manufacturing Readiness Levels
The focus of NIIMBL programs, as for all Manufacturing USA institutes, is on technology areas considered to have manufacturing readiness levels (MRL) from 4 to 7. An MRL is a measure developed by the US Department of Defense to assess how far a particular innovation is from industrial implementation. A technology that has been demonstrated in a laboratory environment is considered to be in MRL 4, whereas a technology demonstrated in a “production-representative environment” is in manufacturing readiness level (MRL) 7. As a result, NIIMBL technology development projects will involve collaborations among small and large companies and academic groups to take technologies with already demonstrated proof-of-concept in the laboratory to the preproduction stage for deployment in a simulated GMP or actual GMP environment. This focus on MRL 4−7 is distinct from the types of research projects executed in more common academic−industry consortia with their discovery-based, fundamental focus. This will ensure that the results of NIIMBL projects will have a more direct impact on biopharmaceutical manufacturing and drug quality and accessibility for patients.
Developing Standards and Measurement Capabilities
Of course, the close collaboration of NIIMBL and NIST researchers will play a critical role in enabling the transfer of technology from laboratories to production sites. NIST works with both industry and universities to develop standards and measurement capabilities that play a crucial role in the acceptance of drugs into the marketplace. That work includes analytical methods for characterization of products, contaminants, and process variants as well as standards for calibration of such analytical tools. With input, support, and feedback from the US Food and Drug Administration (FDA) Center for Biologics Evaluation and Research (CBER) and the FDA Center for Drug Evaluation and Research (CDER), NIIMBL leadership has established a framework for engaging participation of US FDA personnel on some NIIMBL committees, in open workshops, and in other activities. This engagement of NIST and FDA staff in NIIMBL will be extremely valuable to stakeholders in the innovation ecosystem as they work on implementing technology and workforce development projects.
|Education and Workforce Needs in Biopharmaceutical Manufacturing|
|Training Methods of Interest
|Training Needs: Technicians, Operators, Professional Scientists and Engineers
Governance and Priorities
NIIMBL’s governing structure reflects the broad nature of its portfolio and focus on industry needs. The financial commitment made by NIIMBL members from industry, academic institutions, government, and nonprofit sectors determines the level of representation on these committees. However, to ensure that the institute meets the needs of industry, a majority of the votes involving major decisions are allocated to industry members. A governing committee (GC) will provide guidance on overall NIIMBL operations, including budgets and project funding. A technical activities committee (TAC) will help drive the technology development effort, and a workforce activities committee (WAC) will do the same in education and workforce development. An essential feature of NIIMBL is the inclusion of a regulatory considerations committee (RCC), reflecting the great importance that regulatory issues play in biopharmaceutical manufacturing. The committee will facilitate awareness and acceptance of technical innovation to help prepare regulators for deployment of these technologies in manufacturing processes or in testing of regulated biological products. This will facilitate awareness and acceptance of technical innovation to help prepare regulators for the deployment of these technologies in manufacturing processes or in testing of regulated biological products.
Prioritizing Training Projects: NIIMBL plans to develop a US-specific roadmap to prioritize technical and workforce development projects in existing and emerging biopharmaceutical products. To this end, the institute recently executed a partnership with the BioPhorum Operations Group (BPOG) to help facilitate this effort in the coming years. The US-specific roadmap will build on existing roadmaps developed in certain biopharmaceutical manufacturing sectors such as antibodies and cell therapies with support from BPOG and NIST Advanced Manufacturing Technology (NIST AMTech) Consortia. The NIIMBL US-specific roadmap will focus on economic, regulatory, workforce development, and manufacturing research challenges facing the US biopharmaceutical manufacturing industry in both existing and emerging products. A first draft of the NIIMBL US-specific roadmap is expected to be available in 2018.
Engaging the Industry
NIIMBL held its first national meeting at the National Academies of Science Building in Washington, DC, on 4 May of this year. In attendance were many industry, academic, and government participants who discussed industry needs, shared ideas for novel technology, evaluated regulatory and workforce development initiatives, and developed future plans for collaboration.
Steve Doares (vice president for manufacturing sciences at Biogen) delivered a keynote lecture on the technical needs for the future of large-scale manufacturing of biologics. Greg Russotti (vice president for technical operations at Celgene) offered an excellent overview of the issues facing manufacturers of novel therapeutics that are just entering the marketplace. FDA CDER director Janet Woodcock, CBER director Peter Marks, and Biotechnology Industry Organization (BIO) CEO Jim Greenwood also presented their perspectives on the importance of the innovation to be catalyzed by NIIMBL for the future of US biopharmaceutical manufacturing, public health, and economic development.
A “Small and Medium Enterprise (SME) Innovation Showcase” provided a forum for companies to describe their technologies and capabilities. Discussions during this meeting, together with the results of industry surveys performed by NIIMBL, helped provide some insights into potential topic areas for NIIMBL programs, as listed in the “Technical/Regulatory Topics” and “Education and Workforce Development Topics” boxes. Many themes apply to both existing and emerging products, whereas others address particular needs associated with products in clinical-trial stages. A second NIIMBL national meeting is already being planned.
In ongoing operations, NIIMBL will launch project calls twice a year specific to technology development, regulatory standards, and workforce development. To facilitate interactions among industry members and overcome barriers to communication and innovation, NIIMBL established a community portal through which member organizations and individuals within them can provide detailed information on their research infrastructure, equipment, interests, expertise, and publication records. In addition, teaming meetings are ongoing to encourage communications and ideation between industry and academic members.
NIIMBL is seeking to enhance its membership base at all levels and welcomes requests for information about its mission, programs, and long-term goals. We envision a future in which NIIMBL will be viewed by industry as an essential partner in the continued innovation cycle needed the meet the challenges of this evolving industry, including the development of the best-trained personnel for biomanufacturing. We also strive to position NIIMBL as the preferred site for exchange of ideas, perspectives, and guidance on regulatory issues and as a central repository of information on potential partners that can provide much-needed expertise, infrastructure, equipment, and personnel for technology and regulatory advances.
This work was performed under financial assistance award 70NANB17H002 from the U.S. Department of Commerce, National Institute of Standards and Technology.
1 Biopharmaceutical Spotlight: The Biopharmaceutical Industry in the United States. SelectUSA; www.selectusa.gov/pharmaceutical-and-biotech-industries-united-states.
Kelvin H. Lee, KHL@udel.edu, is the director of NIIMBL and Gore Professor of chemical and biomolecular engineering at the University of Delaware; Stacy Springs, email@example.com, is the associate director of NIIMBL and executive director of the Biomanufacturing (BioMAN) program at the Massachusetts Institute of Technology; Ruben G. Carbonell, firstname.lastname@example.org, is the CTO for NIIMBL, a professor of chemical and biomolecular engineering at NC State University, and director (on leave) of the Biomanufacturing Training and Education Center (BTEC).
|Training for Competence, Not Just Compliance by Ben Locwin|
|In an interview with his colleague and industry member, Scott Endicott (vice president, Med Tech division, at Ancillare LP, a global clinical trial supply chain logistics company), Ben Locwin asked for insights on current approaches to training in the biopharmaceutical industry. Endicott was formerly part of New Jersey’s Bio Manufacturing Extension Partnership (NJMEP). He suggested that applications of learning/ training management in the bioindustry are lagging for the following main reasons:
|Locwin explains that the first point is resource- and spend-directed, and this is where the determination is made whether to fund training programs in an upcoming year (or quarter, and so on.). The three subsequent bullet points all are closely related to salient strategic planning: If training programs are created as reactionary responses, that necessarily means they were planned without forethought and therefore as knee-jerk reactions to a primary motive force (often a significant process deviation, CAPA, and/or regulatory agency observation or threat of action).|
|Assuming that an entire training function hasn’t been assembled simply to address adverse events and that there is indeed a modicum of planning behind it, ensuring proper training in gap analyses and needs assessments allows proactive training to offset potential future business risks. The greater the potential risks there are within your company’s risk registry, the more emphasis you should place on ensuring that your business is protecting itself from them.|
|Being accountable from the perspective of training, developing relevant metrics to demonstrate performance of the available programs is the way to ensure that a training function is “doing what it’s intending to do.” Too often, business metrics are just “wallpaper” that many people don’t read or react to. And this is often the case with training metrics: Measures such as saturation rate (number of employees “trained” at something) and training dollars spent per employee are commonly seen training-level metrics that allow training departments to purvey a set of bar charts and time series plots to paste next to top-level business operations performance. But such measures are spurious, and often are tenuously (if at all) connected to a measure of the actual competence of the employees who have been trained for particular tasks. Time would be spent much better in improving how training is being conducted and also on conducting root-cause analyses to determine why a particular failure actually occurred.|
|Ben Locwin, PhD, MBA, is president of Healthcare Science Advisors and an executive director for Hoffmann-La Roche; email@example.com.|