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Advanced Mammalian Biomanufacturing Innovation Center (AMBIC)

Clemson University

Johns Hopkins University

University of Delaware

University of Massachusetts Lowell

Last Reviewed: 03/13/2017

Center Mission and Rationale

Over the past two decades, the biopharmaceutical industry has emerged as one of the major manufacturing industries and engines of growth in the US economy. Biomanufacturing represents nearly 2% of the total US GDP and its fraction is expanding. Much of biomanufacturing involves the use of cells to make medicines. Examples of these types of medicines include cancer medicines and vaccines. A key element in developing these medicines is the need to establish complex manufacturing processes. AMBIC will implement engineering innovations to enhance the capabilities of our nation to manufacture these important life-extending and life-saving medicines. Such improvements will improve the competitiveness of US biomanufacturing in coming decades leading to more economic investment by these companies and more jobs for American workers. 

The mission of AMBIC is to develop enabling technologies, knowledge, design tools and methods that apply and integrate high-throughput and genome-based technologies to fast-track advanced biomanufacturing processes. AMBIC is the first I/UCRC dedicated to mammalian cell culture upstream development focusing on Chinese hamster ovary (CHO) cells, the principal biopharmaceutical production host of industry. AMBIC will bring together leading academic and industrial biotechnologists focused on mammalian cell culture manufacturing at a pre-competitive research level to address the complex problems in biopharmaceutical manufacturing. This multi-university center will allow AMBIC to leverage the skills and the expertise of many faculty members across the Sites. AMBIC will be a critical catalyst towards maintaining national excellence in biopharmaceutical production by conducting research in:

1) Understanding Industrially-Relevant Biology (e.g., all -omics, bioinformatics, process and product quality, etc.);

2) Process Monitoring & Control (e.g., analytics, instrumentation, data mining and modeling);

3) Consensus and Standardization Issues (e.g., standards, simple fingerprints, raw material issues, regulatory issues, forensic bioprocessing, clonality).

Through systems-level biology analysis, novel cell line development, bioreactor optimization, and advanced analytics, AMBIC will provide transformative solutions that can lower biomanufacturing costs and improve bioprocessing efficiency. Most importantly, these advances may ultimately serve to make more biopharmaceuticals available to patients that need them and lower overall health care costs for consumers. In addition, AMBIC will establish and maintain a pipeline of educated and motivated students at multiple levels for careers in biopharmaceutical manufacturing and development. Collaborations with corporate partners will enable the students to work on the most pressing problems that the industry faces. Furthermore, this center will serve to engage and excite students from under-represented minority populations to pursue a career in life sciences, engineering, or related STEM fields. An important part of the AMBIC activities and a committed goal of the PI's is to increase the participation of women and under-represented minorities in STEM disciplines by energizing students from all backgrounds about the exciting opportunities to help others through STEM careers in biotechnology and biomedicine.

Research program

Understanding Industrially-Relevant Biology

(e.g. all -omics, bioinformatics, process and product quality, etc.). Research under this theme seeks to understand basic principles of relevant cell biology that address issues in the industry. Projects could include topics such as: developing and improving `omic and metabolic models, identifying early markers for stability, understanding effects of raw materials on cells, biomarkers for cell behavior, epigenetic and ncRNA studies, identifying cell characteristics amenable to continuous processing, and identifying hotspots for target integration. This list is not exhaustive, but rather representative.

Process Monitoring & Control

(e.g. analytics, instrumentation, data mining and modeling). Research under this theme seeks to develop new analytical tools, sensors, and equipment, as well as approaches to integrate data from these devices, into improved methods for process monitoring and control. Projects could include topics such as: in silico modeling for process integration, real-time omics profiling, statistical process control, sensors for at-line, in-line, on-line product assays, measuring and controlling variability in raw materials, systems biology models for product quality predictions, predictive feed forward control models for critical quality attributes, and data mining tools for pattern recognition. Again, this list is intended only to be representative.

Consensus and Standardization Issues

(e.g. standards, simple fingerprints, raw material issues, regulatory issues, forensic bioprocessing, clonality). Research under this theme addresses important questions that new biological insights offer in the context of industry-wide impact where each company has unique products, processes, and platforms; yet has seen common issues impact multiple organizations or where organizations seek to develop industry-wide standards to facilitate regulatory compliance and best practices. Such projects could include work on: leachables and extractables, impurities, sustainability issues, performance standards for disposables, omics and clone characterization, demonstration projects for new technologies, standardizing the CHO genome, and building a better CHO. 

Facilities and Laboratory

Johns Hopkins University Facilities and Infrastructure.

AMBIC JHU infrastructure offers state of the art laboratory space and equipment housed in Maryland, Croft and Clark Halls on the Homewood Campuses and the Koch and Smith Buildings of the Medical Campus. Faculty laboratories and offices occupy approximately 10,000 square feet including the most advanced cell biology, bioprocessing equipment, analytics and computational resources used in mammalian cell culture biomanufacturing. Advanced cell culture bioreactors are presently equipped with sensors for dissolved oxygen, carbon dioxide, and continuous process data acquisition and control. AMBIC laboratories offer state-of-the art analytical instrumentation including seven mass spectrometers (LTQ-orbitrap velos, Q-Exactive orbitrap, TSQ-Vantage Triple Quadrupole, MALDI-TOT/TOF, MALDI-AXIMA Resonance, LCMS-8040 Triple Quadrupole Liquid Chromatograph Mass Spectrometer, and qTOF), next-generation and nanopore sequencers, confocal and fluorescence microscopes, analytical flow cytometers, HPLCs, GC-MS, Nanodrop UV-Vis spectrophotometers, ELISA plate readers, bioanalyzers, FPLC, fluorometer, cell culture incubators, biosafety hoods, ultracentrifuges, autoclaves, electroporator, PCR machines, advanced gel electrophoresis, western blot equipment and other molecular biology peripherals. In addition, a number of JHU core resources are available to all AMBIC participants. These core resources include the JHU Genetic Resources Core, Epigenetics and Deep Sequencing Center facilities with next generation high throughput sequencing capabilities including Illumina HiSeq and MiSeq and Ion Torrent devices, robotic scanners, and a PacBio machine for sequencing of the CHO genome. Other resources include flow cytometry and FACS sorting cores for isolating, characterizing, and distinguishing individual mammalian lines. Also available is the Mass Spectrometry-Proteomics Core with advanced mass spectrometric and bioinformatics facilities and the advanced metabolomics facility for characterizing intracellular metabolites. A Microscopy Center with confocal and electron microscopes for advanced cellular analysis is also present. A number of high performance computer systems are available on campus for data mining and bioinformatics analysis including the Maryland Advanced Research Computing Center (MARCC). Finally, AMBIC participating faculty collaborate on multiple research projects and serve as joint graduate thesis committee members that meet frequently to facilitate further intellectual and education exchanges that form the core of AMBIC.

University of Delaware Facilities and Infrastructure. Much of the proposed activities will occur in either the Delaware Biotechnology Institute (DBI) or Colburn Laboratory (CLB). DBI is a 72,000 sq. ft. state of the art life science building with emergency backup power, a dedicated data center, shared core facilities, and investigator laboratories. The core facilities include those related to genomics and genome sequencing, bioinformatics and computational biology (Cathy Wu, director), proteomics and mass spectrometry (Kelvin Lee, director), flow cytometry (in Terry Papoutsakis' laboratory), protein production and purification, and bioimaging. The bioimaging facility has several state of the art confocal microscopes, super resolution microscopes, TEM, SEM, AFM, and high-speed microscopes. CLB has shared use resources as well as investigator laboratories including shared cell culture spaces, laser scanning imagers, bioreactors, mass spectrometry for flux analysis and metabolites, and other relevant instrumentation. Both DBI and CLB are situated within a short walk. Moreover, other state of the art shared analytical instrumentation is available in the newly opened 150,000 sq. ft. Harker Laboratory. These unique and highly specialized facilities that exist at UD offer unprecedented opportunity to impact AMBIC in a positive way and provide UD a special role within the overall AMBIC framework. Other details regarding available equipment and facilities is provided in the relevant section of this NSF proposal.

Clemson University Facilities and infrastructure. The proposed activities will occur in the Biosystem Research Complex (BRC), Life Sciences Building (LSB), Rhodes Hall, Earle Hall, or the Clemson University International Center for Automotive Research (CU-ICAR). The BRC (108,000 sq. ft.) at CU is a state-of-the-art biotechnology facility with emergency backup power, a dedicated data center, shared core facilities, and investigator laboratories. Faculty from multiple departments and colleges are housed together, share equipment, communicate daily, and cross-train graduate students. Dr. Harcum has 1450 sq. ft. of high quality laboratory space dedicated to bioreactor controls and cell culture optimization. The core facilities in BRC include genomics and genome sequencing, bioinformatics and computational biology (Dr. Saski is the Director), a Proteomics Facility, and the Multi-User Analytical Laboratory (MUAL) with Dr. Tharayil as the director. MUAL is a state of the art mass spectrometry facilty with a Orbitrap Fusion Tribrid mass spectrometer. Drs. Groff and Wang have general-use laboratory in Riggs Hall and wet-laboratory space in Rhodes Hall, which also houses the majority of Bioengineering. The LSB is a 100,000-square-foot facility that has LEED gold status. Researchers housed in the facility represent the disciplines of microbiology, biochemistry, food safety and genetics. The LSB facility encourages collaboration, offers state-of-the-art technology with it open suite laboratory design. The Clemson Light Imaging Facility (CLIF) is located in LSB. CLIF has numerous state of the art light microscopes, including spectral imaging confocal laser scanning systems, super resolution microscopes, TIRF laser systems, transmission and episcopic DIC, epifluorescence and brightfield microscopes, and high speed microscopes. TEM and SEM capabilities are located nearby in Pendleton, SC. A “palmetto cluster” with 38.2 TF peak performance using 512 nodes; 8 cores per node; 12 GB/node; and 80 GB disk/node is available for bioinformatics and modeling work. This system also contains 120 TB of large-scale, high performance disk storage and is housed at Clemson’s Information Technology Center in a 24/7 monitored environment with proper power, cooling and physical security. Additionally CUGL maintains a 32‐node 1GHz dual processor 1GM RAM Linux cluster and a 32‐node 2.3GHz dual processor 2GB RAM Apple cluster in BRC. The CU-ICAR Manufacturing Systems Research Laboratory is a 90,000-sq. ft. research center-housing faculty dedicated to manufacturing and systems integration research. The laboratory is constructed with high-speed wireless networking and has available to the project real-time flexible control hardware and software for controller prototyping, web-based control testing, and sensor monitoring research. Dr. Mears has 1000 sq. ft. of high quality laboratory space within CU-ICAR. These unique and highly specialized facilities that exist at CU offer unprecedented opportunity to impact AMBIC in a positive way and provide CU a special role within the overall AMBIC framework. 

University of Massachusetts Lowell Facilities and infrastructure. ABMIC’s proposed activities at UML site will be conducted in either the Massachusetts BioManufacturing Center (MBMC) or Core Research facility.  The MBMC offers 3 dedicated labs and one pilot plant. The analytical lab has state of the art instruments  such as HPLC, LC-MS, LC-MS-MS, UV-Vis, Fluorescence spectroscopy, and so on. The cell-culture lab is a BSL-1 level clean room, and has most equipment for cell culture activities such as incubators, biosafety cabinets, refrigerators, NOVA-400 and Cedex Bio metabolic analyzers, and Cedex Hires cell-counter. For cell culture, there are 4 ft biosafety cabinets (2), CO2 incubators with multi-position stir plates (3), Nexcelom Cellometer Auto T4 (total and viable cell counts) (1), CEDEX HiRes Cell counter (1), CEDEX BIO metabolic analyzer (1), Nova Biomedical BP 400 with autosampler (1), Sartorius A+ 5 L cell culture reactors with data logging (2), New Brunswick Scientific Celligen Plus 5 L cell culture reactor (1), New Brunswick BioFlo 100 1.3 L cell culture reactors (2), Inverted microscope (1), Phase contrast microscope (1). Near Infrared spectroscopy (Bruker Optics) (1), Tube-welder (Turumo) (1). For Microbial Culture, there are New Brunswick Scientific SF-116 16 L fermenters (3),  Sartorious 1 L microbial fermentors with data logging (1), floor model microbial shaker/incubators (3), tabletop water bath shaker/incubators (2), 6 ft biosaftey cabinet (1). The Materials Characterization Laboratory (MCL) offer SEM (JEOL 7401F FE-SEM and AMRAY SEM), two TEM (PHILIPS 120kV TEM and TOPCON 200kV TEM), AFM (PSIA XE-150 AFM), a Matrix Assisted Laser Desorption-Ionization Time of Flight Mass spectrometer (Waters MALDI-TOF MS), a Laser Scanning Confocal Microscope (FV300, Olympus), assorted instruments for sample preparation (e.g., microtomes, sputter coaters, evaporator) for further analytical needs. The Emerging Technologies and Innovation Center (ETIC) approved by the Commonwealth of Massachusetts provides 97,000 ft2 space for the core research facility and 6000 ft2 clean room facility for ABMIC. As part of the UMass system, researchers at UML have access the services of core facilities at the University of Massachusetts Medical School campus in Worcester. These include UMass Medical’s Molecular Biology Core Facility and associated Deep Sequencing Core Laboratory with ABI3730xl 96 capillary DNA sequencers, two Illumina Solexa GA IIx Genome Analyzers, one ABI SOLiD 4 Genome Analyzer.

Locations

Johns Hopkins University

3400 N. Charles Street

Baltimore, Maryland, 21218

United States

Clemson University

208 Biosystems Research Complex
105 Collings Street

Clemson, South Carolina, 29634

United States

University of Delaware

281 Delaware Biotechnology Institute

Newark, Delaware, 19716

United States

University of Massachusetts Lowell

Engineering Building 108

Lowell, Massachusetts, 01854

United States