May 30, 2019 PAO-M05-19-CL-002
iBio’s contract development and manufacturing services are built around the advantages provided by our plant-based recombinant protein production technology. We have been developing our plant expression system for many years, investing in continued research and development to improve the properties and performance of the host plant, the expression vectors and the expression system that we employ.
Though highly innovative, the concept of plant-based expression of therapeutic proteins is not necessarily new. The ability of these systems to produce various antibodies, vaccines, enzyme therapies and other therapeutic proteins has been explored for more than two decades, with several products evaluated in clinical trials and some achieving regulatory approval.
With a plant-based transient expression system, there is no need to develop optimized cell lines or invest in expensive bioreactor technologies for large-scale production, as is the case with mammalian cell culture. Transient transfection is applied at manufacturing scale; the plant is the bioreactor, and scale-up simply involves growing more plants. The result is consistent expression levels and protein quality, whether producing 1g or 1kg.
The use of plants rather than mammalian cells also eliminates potential contamination from adventitious agents, because human viruses do not replicate in plants, which simplifies downstream processing.
iBio’s protein-expression platform technology employs Nicotiana Benthamiana as a host, a model plant that has been used to express numerous recombinant proteins in the past and is very well adapted to hydroponic cultivation. After about five weeks of plant biomass amplification, genes of interest are delivered to plant cells using Agrobacterium tumefaciens as a DNA vehicle. Then, protein expression starts rapidly, resulting in the accumulation of up to gram quantities of target protein in leaves per kilogram of fresh plant tissue within one week.
All plants are grown in chemically defined media in climatically controlled vertical farming grow rooms. Plant health is confirmed at various checkpoints, and scale-up is achieved by simply growing more plants, with no concerns about changes in yield, protein structure or posttranslational modifications (PTMs). As a result, iBio’s plant-based system offers rapid evaluation of protein expression in an environment that greatly resembles manufacturing conditions.
With iBio’s technology, the time to IND filing can be reduced by six months or more compared with that required for CHO-based systems. A techno-economic analysis revealed that a plant-based protein manufacturing facility similar to iBio’s Bryan, Texas site would only cost a fraction of the amount required to build an equivalent modern CHO facility, and the cost of goods (COGS) for a mAb produced by iBio is less than published COGS values for mAbs produced using CHO systems.
Notably, vaccine antigens, including virus-like particles, antibodies, fusion proteins, interferons and cytokines, growth factors, protease inhibitors, clotting factors, enzymes for replacement therapy and other products that cannot be produced using more traditional expression systems have been expressed using the iBio platform.
The U.S. Food and Drug Administration encourages pharmaceutical manufacturers to design quality into their processes from the outset. At iBio, the use of a quality-by-design approach ensures the development of robust processes with high and reproducible product quality.
Our process development laboratory and pilot production facility were constructed using a quality-by-design (QbD) approach. Typically, labs and pilot-scale facilities are built by pharmaceutical companies before any manufacturing site is constructed. However, at iBio, we take the opposite approach to facilitate and speed up technology transfer and scale-up. Our manufacturing facility was constructed and operated first at full scale, allowing us the time to gain a robust understanding of its key features.
We built the process development lab and pilot plant after we had time to study data from the manufacturing facility — notably using the same design as the manufacturing plant and with scaled-down versions of the same equipment. As a result, these facilities are integral to our QbD approach. When we develop processes and scale them to the pilot plant, we do so knowing how they will translate to manufacturing scale.
iBio has invested in a state-of-the-art facility in Bryan, Texas with the capability to provide clients and collaborators with an integrated suite of services ranging from early product lead optimization, process development, production of preclinical and clinical batches of pharmaceutical active ingredient, analytical support and sterile filling. The technology and facility are capable of supporting the development and manufacture of both vaccine and therapeutic products. as well as recombinant proteins for use in medical devices and diagnostics and as clinical reagents.
We work with our clients to design and perform feasibility studies to enable them to determine whether the product generated using our plant-based technology is fit-for-purpose. Customers can have milligrams of protein for evaluation within six weeks after contract initiation. We can then take processes from the lab scale through process optimization for scale-up to cGMP protocols and move projects to clinical toxicology studies, human clinical trials and commercialization. Importantly, all of this work — from feasibility studies to process development, scale-up to non-cGMP and cGMP manufacturing — is performed in the same facility, eliminating the additional cost and delays typically associated with transferring technology from one site to another, even within the same company.
We also propose proprietary approaches to improved gene expression through codon optimization and expression vector selection. iBio is positioned to help clients screen and select optimal lead candidates and refine processes to ensure the best product yields and stability.
In addition to cloning the necessary vectors, biomass production, protein extraction and purification, iBio supports clients with automated and manual sterile fill and finish activities (ranging from hundreds to thousands of vials for early stage clinical trials and stability testing).
Finally, experienced analytical staff provide method development and validation support as part of projects and on an ad hoc basis, with special capabilities in protein characterization using mass spectrometry. A partnership with regulatory consultant CBR International, which has 20 years of experience in plant-based protein manufacturing, further ensures successful regulatory filing.
iBio is interested in supporting both early stage biotech and large pharma companies, as well as universities, spinouts and government agencies. In particular, we seek collaboration with companies in the early stages of development that have not yet committed to a specific manufacturing route or that have already decided to use plant-based expression technology.
The simplicity of our plant-based bioprocessing technology makes it well suited for implementation in areas of the world where there is limited access to capital or highly skilled biopharmaceutical workers. The short project timelines also make it attractive for the rapid development of drugs and vaccines in response to pandemics.
Despite the well-established underlying technology, plant-based therapeutic protein bioprocessing remains a relatively nascent field. When companies or government agencies wish to establish autonomous manufacturing capability using this technology, they often require assistance.
iBio has established the capacity to support such projects, enabling customers to license our platform technology. We also provide assistance with facility design and process implementation, certifying that their facility is operated in compliance with cGMP standards for pharmaceutical manufacturing. While we do not serve as architects or contractors, we participate in the early design stages, working in cooperation with our client’s engineers and architects.
This approach is particularly relevant in developing economies where large capital investments in biologics manufacturing infrastructure have not yet taken place. By supporting these types of projects, iBio is helping governments, NGOs, corporations and academic institutions install advanced manufacturing capabilities in developing markets.
It is unusual for a biopharmaceutical manufacturer to seek out opportunities for technology transfer. Most information-based sciences are advancing so rapidly, however, that the notion of holding on to advanced technologies is becoming outdated. iBio believes that, by sharing our technology platform through licensing partnerships, we are empowering others to meet the crucial needs of patients through the production of life-changing biologic drugs at reasonable costs — while establishing a successful business.
Examples of this approach are represented by partnerships with Bio-Manguinhos/Fiocruz, the technical scientific unit of the Oswaldo Cruz Foundation (Fiocruz) in Brazil, AzarGen Biotechnologies in South Africa and CC-Pharming Ltd. in China.
Bio-Manguinhos/Fiocruz will use iBio’s technology in a new plant-based multipurpose manufacturing facility in Brazil for the low-cost production of a novel yellow fever vaccine. The project has reached the technical design stage but is temporarily on hold at the behest of the government.
AzarGen Biotechnologies is an early stage pharma company developing a biosimilar rituximab product for the treatment of non-Hodgkin’s lymphoma using a plant-based process initially developed by iBio. The company is ready to produce material for preclinical studies and is preparing a pre-IND package for the FDA. The plant-based expression technology provides the only economically viable platform for the production of this biosimilar in South Africa.
CC-Pharming Ltd. and iBio recently formed a strategic partnership to develop products and manufacturing facilities for the Chinese biopharmaceutical market that leverage plant-based expression technology. The first product expected is a biobetter for rituximab. iBio will provide development and manufacturing services, and the two firms will work together to design and construct a manufacturing facility in China. Additional products will eventually be selected for development and sale in both China and the United States. As a result, iBio is both empowering CC-Pharming to perform autonomous manufacturing and collaborating with the company on additional products and sharing in its commercial success.
We are confident in the direct advantages that plant-based manufacturing and development offer and look forward to bringing drugs to market using this opportune process.
Dr. Marcel is a Senior Scientist in Molecular Biology and the Director of Early Stage Project Development at iBio CDMO. He received his Ph.D in plant cell and molecular biology at the RWTH University – Fraunhofer Institute, Aachen, Germany in 2006. Dr. Marcel joined the team of Dr. Barry Holtz in 2010 to develop and implement the midstream manufacturing protocols during the construction and operation of the biotherapeutics manufacturing facility in Bryan, Texas. As a senior scientist, Dr. Marcel optimized upstream and midstream manufacturing protocols and co-designed and operated the pilot-scale facility.