CBI’s BioMAN Program Hosts Summit on Science to Manage Risk in Biomanufacturing

Summary: Science to Manage Risk in Biomanufacturing

(November 17, 2010)

Event details (PDF)

The fastest growing segment of the pharmaceutical industry is biologics. Due to their complexity and increasing prevalence, manufacturing these products in a safe and cost-effective manner and managing risk over the product and process lifecycle is becoming even more important to biopharmaceutical firms, regulators and broader society. Recent, well-publicized viral contamination events have highlighted the need to reassess the risks in biomanufacturing. These events spurred scientists, regulators, and members of the pharmaceutical industry to reconsider existing methods used to evaluate the quality of biologics during the development and production process and to develop technologies that proactively identify, assess and mitigate risks, viral contamination being one example.

Yet, little progress has been made regarding the best way to implement new technologies into practice. Biotechnology firms face many of the same obstacles currently affecting the pharmaceutical industry: trimmed R&D budgets, globalization of manufacturing and narrowed pipelines. Regulatory barriers to process change are significant. Ensuring that changes in a manufacturing process meet regulatory guidelines requires a large investment of both time and money. All of which make the implementation of any changes difficult. For this reason, steps need to be taken by the managerial component of biotechnology firms as well as regulatory agencies to ensure adoption of advances that reduce the prevalence of risks in biomanufacturing.

To help address these issues, the MIT Center for Biomedical Innovation’s (CBI) Biomanufacturing Research Program held a summit bringing thought leaders from industry, government and academia together in MIT’s Wong Auditorium to discuss the inherent risks faced in biomanufacturing and new science and technologies that could help manage that risk. New research presented at the conference showcased some of these technologies which MIT CBI faculty director, Anthony Sinskey, described as, “almost revolutionary in its potential in biomanufacturing.” Over 100 participants attended the conference which culminated in a poster session that showcased new technologies developed in MIT labs, as well as others, with the potential to impact biomanufacturing.


An Industry-wide Problem

In response to any viral contamination, the goal of a firm is typically to decontaminate the plant, resume production of biologics, and take the appropriate actions to prevent a future occurrence. When faced with such an issue, the ownership of the problem is entirely on the firm. However, Scott Stern of the MIT Sloan School of Management and National Bureau of Economics Research argues that this is counterproductive. Individual firms have little incentive to share information regarding their procedures for handling adverse events. However, these low-probability, high-impact events, affect the industry as a whole, and collaboration should be present in how all firms deal with these events. His suggestions for risk reduction and better preparedness for future events include tighter regulatory incentives and competitive disincentives.

Stern’s suggestions to move towards more collaborative business practices were echoed by the president and founder of Quantum Consulting, Michael Wiebe. In the wake of a contamination event, a firm will compile a list of lessons learned. However, a single company will only have one, or possibly two, events to learn from. Instead, Wiebe said, “If you could learn from the industry experience as a whole it would be very valuable.” In the absence of collaboration, industry-wide learning is difficult: typically, firms do not publically disclose the occurrence of a viral contamination event unless there is a material financial impact. To address this issue, Wiebe is working with Dr. James Leung, a Visiting Scientist at MIT, to create an industry consortium, the Consortium on Adventitious Agents Contamination in Biomanufacturing (CAACB), under the auspices of MIT CBI’s Biomanufacturing Research Program. Through the CAACB, companies will share detailed information related to cases of viral contamination. The MIT team will analyze current knowledge of specific cases of viral contamination, approaches to root cause identification, barrier technologies and other risk mitigation strategies used before and after a contamination and the results will be shared back with industry.

Collaboration need not be limited to other firms, however, as pointed out by FDA staff fellow George Miesegaes. Based on his own experiences, he sees the need for increased communication between regulatory agencies like the FDA and firms. He believes meetings prior to phase I trials would prove immensely useful as they would allow sponsors the opportunity “to explain the technology completely to regulatory personnel early in development”. He cited past success stories that included directed studies and collaborations between the agency and either academia or industry.

Risk is not limited to viral contamination, but is present throughout all aspects of biomanufacturing. Robert Di Scipio, president and CEO of Aegis Analytical Corporation, indicated that firms face risk on a variety of scales, from organizational and geographical risks to regulatory and technological risks. The vice president of commercial process development at Genzyme, Konstantin Konstantinov, agreed saying that while it is often easier to talk about technological and scientific risk the “risk related to business processes, organizational structure and business decisions are very critical.” One clear example is the use of contract manufacturing organizations for product manufacture. Large sponsor companies can employ as many as 20 different manufacturers, Di Scipio said. Yet under federal regulations the sponsor is liable for the product quality, not the contract organization. In the event of a problem, the sponsor is disconnected from the manufacturing process, slowing the determination of the root cause. These issues have begun to lead to a more collaborative approach to manufacture through increased data sharing, capital co-investment and increased risk sharing.

One way to mitigate risk is through the advent and adoption of new technologies. Wiebe stressed that firms need to be proactive in their investment of technical innovations to address risk. Di Scipio echoed these sentiments saying that he would like to see a larger portion of technology budgets go towards innovation rather than resource management. Partnering with academic institutions can prove useful in learning and acquiring the latest technologies. For example, to mitigate the low frequency, high-impact risk of a viral contamination, firms must design and implement effective virus barriers and develop rapid, sensitive, broad-spectrum virus detection systems.


New science and technologies aimed at adventitious viruses

RNAi technology as a possible therapy has seen an uptake in interest in recent years. Fortunately for biotechnology firms, scientists have taken this same knowledge of combinatorial chemistry useful for bringing siRNA into the body and applied it to bringing siRNA into a bioreactor. Alnylam’s biotherapeutics branch, led by Anthony Rossomando, demonstrated that it was ahead of the curve in terms of exploring the delivery of siRNA into the bioreactor and its application in manufacturing.

If siRNA is to be used effectively in bioreactors, then its presence and delivery must not cause a decrease in cell density. Therefore, research as of late has focused on novel delivery systems to bring siRNA into the cell. Rossomando has honed in on one advanced lipid delivery system that has demonstrated comparable interference patterns with commercially available delivery systems. However, this system is non-toxic, unlike the commercial reagents, and it does not decrease the efficiency of cell density in a bioreactor.

RNAi was originally intended and is still being developed for the purpose of knocking down genes whose expression leads to unwanted outcomes, such as apoptosis, glycosylation, etc. In doing so, manufacturers can effectively extend the longevity and increase the efficiency of their product-producing cells. Alnylam has already demonstrated the successful knockdown of ten such genes at once, and has done so at a scale that is comparable to production bioreactors. However, what has excited manufacturers most is the potential of siRNA to serve as a virus barrier. By designing siRNAs against RNA helicase and RNA polymerase for a given virus, it becomes possible to block many adventitious and endogenous viruses. If you add a cocktail of siRNAs to a bioreactor, you could potentially prevent viral contamination. Some questions still remain: the sustainability of the knockdown, the clearance of the siRNA/lipid delivery system in the product, and the regulatory control the FDA will take. Regardless, the potential use of RNAi in biomanufacturing has created a lot of excitement. However, barrier technologies will likely still be needed due to the difficulty of creating broad-spectrum viral siRNAs.

New technologies lead to improved measurements

MIT professor of Chemical Engineering, J. Christopher Love, stated at the conference that there are two risks that should be on the mind of every manufacturer of biologics: “what goes into your vial that holds the drug, and what happens to the person that receives the vial.” Recent advances in the field of epigenetics, he says, are leading to an increased understanding of the role that epigenetic changes play on biotherapies. As a result, epigenetic effects are influencing the manufacture of biologics. Love’s research has taken advantage of this recently acquired knowledge to develop analytical tools that allow a more descriptive look at what is happening to cells during manufacturing.

His integrated, dynamic, single-cell analysis can help improve selection of biologic producers at the clonal level. There is an epigenetic component to the secretory state of cells. Protein secretion and other post-translational modifications can be measured using his advanced analytical tools. It will become possible to determine which cells in a bioreactor are the “super-producers”, and it may even be possible in the future to engineer cells such that they have stable and high levels of protein secretion.

Michael Strano, also from the MIT Department of Chemical Engineering, approaches the problem of analytical detection from the perspective of a chemist rather than a biologist. His instrumentation takes advantage of the extraordinary properties of carbon nanotubes to develop sensors capable of single molecule detection. His platform allows rapid determination of protein-protein interaction networks, and he is currently extending its capabilities to include the characterization of protein glycosylation. According to Strano, his lab is currently “developing chemistries sensitive to any analyte imaginable.”

James Harper, from the Biosensor and Molecular Technologies Group at MIT Lincoln Labs, sees many similarities between developing new technologies for chem-bio defense and biopharmaceutical manufacturing. “This idea of the low frequency but high impact event, that is exactly what chem-bio defense does” said Harper. One area of interest in chem-bio defense is the development of broad-spectrum antiviral therapeutics. Such technologies could be implemented into biomanufacturing operations as a way to create resistant cell lines. However, before technologies and solutions developed in chem-bio defense could be implemented into the biopharmaceutical industry, more interdisciplinary community exchanges are needed. “I think this has been a great day and continued discussion on these issues would be productive,” Harper said.

G.K. Raju, executive director of the pharmaceutical manufacturing initiatives at the CBI, points out that these new and exciting technologies are “asking us as an audience how we can use them to manage risk.” Ultimately, it is up to the industry to help guide how new science and new technology can be used in biomanufacturing.