October 2014 Spotlight

RX-360 CHOOSES AUDIT LEADER

Rx-360, a not-for-profit international consortium representing the world’s leading pharmaceutical and biotech organizations, announced in June a partnership wherein BSI Supply Chain Solutions would lead its international joint audit program. BSI will work with Rx-360 to streamline the audit process and ensure supplier compliance with quality and security standards through verification audits.

Recognizing that globalization complicates quality and security of the supply chain, Rx-360 developed this program to allow multiple companies working with the same business partner to participate in a standardized audit without sacrificing product or process confidentiality. This should reduce audit costs, standardize the audit scope, expand the number of audits conducted, and ultimately reduce supplier audit fatigue while maintaining high-quality standards.

BSI was selected for this engagement following a thorough RFP process involving several other qualified auditing firms. With more than 70,000 clients worldwide and over 150,000 audit days in 150 countries each year, BSI has the necessary resources and infrastructure and is positioned to serve as a partner with Rx-360 members’ supplier base. Its VerifEYE supplier verification services will provide on-the-ground local auditors familiar with regional language, customs, and traditions. They will be trained to Rx-360 standards, including current good manufacturing practice (CGMP) regulations and supply chain security.

BSI’s integration into Rx-360’s Joint Audit program is currently under way. To learn more, go to www .Rx-360.org.

GOT YOUR SBIR/STTR GRANT?  CONSIDER I-CORP

The National Science Foundation (NSF) and the National Institutes of Health (NIH) are collaborating to provide NIH- funded researchers with training to help them evaluate the commercial potential of their scientific discoveries. “I-Corps at NIH” is a pilot program of the NSF’s Innovation Corps External Web Site Policy (I-Corps) program specially tailored to biomedical projects. Recipients of Small Business Innovation Research and/or Small Business Technology Transfer (SBIR/STTR) awards from participating NIH institutes are eligible to apply to I-Corps at NIH.

The program is a nine-week “boot camp” in which business-savvy instructors with biomedical business experience work closely with teams of researchers to help them explore potential markets for their federally funded innovations. Participating NIH institutes include the National Cancer Institute; the National Heart, Lung, and Blood Institute; the National Institute of Neurological Disorders and Stroke; and the National Center for Advancing Translational Sciences. I-Corps will also provide real-time interactions with customers to validate a technology’s market potential. The first 24 selected teams will receive supplemental funding from NIH to support entrepreneurial training, mentorship, and collaboration opportunities.

NIH awards >US$700 million in SBIR/STTR research and development awards each year. All people and organizations involved in I-Corps become part of the NSF-established National Innovation Network, a nationwide “web” created to leverage the community that develops among grantees.

For more information about I-Corps at NIH, see http:// grants.nih .gov/grants/guide/pa-files/PAR-14-261.html.

COULD BIOSIMILARS ERODE THE BIOLOGICS MARKET?

In a June 2014 report, research and consulting firm GlobalData suggests that increasing prevalence of biosimilars could negatively affect the biologics market beyond 2019. Despite that and an initial projected compound annual growth rate (CAGR) of 8.3%, the report predicts an overall biologics market value to rise from US$162 billion in 2013 to more than $262 billion by 2019. Patent expirations of branded biologics and clearer regulatory frameworks for biosimilars afterward should allow the latter to capture market share.

“A number of factors are driving the initiative toward global adoption of biosimilars,” says Joshua Owide, GlobalData’s director of healthcare industry dynamics, “from austerity measures and slow economic growth in the United States to an aging population and increasing demand for healthcare in countries such as Japan.”

“Savings made from choosing biosimilars over biologics are not as substantial as first anticipated. The cost of biosimilars is expected to be around 20–30% lower than that of branded biologic therapies. This remains a significant reduction, nonetheless, with many biologics commanding hundreds of thousands of dollars for a year of treatment.”

Some biologic manufacturers seek to slow the entry of biosimilars into the market, but they are attracting attention from contract manufacturing organizations (CMOs; e.g., Lonza and Celltrion) and contract research organizations (CROs; e.g., Quintiles and Paraxel) as well as multiindustry conglomerates (e.g., Samsung and LG).

“The biosimilars industry is already highly lucrative,” Owide observes. “More than 100 deals involving companies focused on biosimilar development have been completed over the past seven years, with a total value in excess of $10.7 billion. In addition, some national governments are targeting this market to sustain their domestic pharmaceutical industries. Most significantly, South Korea announced in 2011 that it aims to create ~120,000 new jobs in the sector with a bid to capture 22% of the global biosimilars market by 2020.”

INHALED INSULIN APPROVAL

MannKind Corporation announced this summer that the US Food and Drug Administration (FDA) has approved its Afrezza human insulin inhalation powder for glycemic control in adult patients with diabetes mellitus. It affects over 29 million people in the United States, according to the Centers for Disease Control and Prevention. Delivered at the start of a meal, Afrezza inhalation powder dissolves upon inhalation to the deep lung to deliver insulin quickly to the bloodstream. Peak insulin levels come within 12–15 minutes, and they decline to baseline by ~180 minutes.

“CONCENTRATED PERFUSION” CELL CULTURE

by John Bonham-Carter

Fed-batch and continuous culture are the two primary cell culture methods for large-scale production of cell-derived products such as monoclonal antibodies (MAbs). Although fed-batch operations are most prevalent today, process advances and a deeper understanding of continuous culture are prompting some bioprocess decision makers to adopt continuous culture as a production platform for both small- and large-scale production.

Gallus Biopharmaceuticals

Driven by market pressure for cost reductions and regulatory demands for consistent product quality, biopharmaceutical companies such as Genzyme (a Sanofi company) are implementing cell-retention processing solutions and technologies that significantly increase cell concentration and productivity while decreasing manufacturing facility size. The drive is on for more, better, and faster protein manufacturing.

Perfusion processing — continually harvesting a bioreactor using a cell-retention device — is a state-of- the-art platform that enables high cell concentrations and productivities in a smaller bioreactor than would be needed for fed-batch culture. Concentrated perfusion is a term specific to a process involving the Alternating Tangential Flow (ATF) System technology, which Repligen acquired form Refine Technology in June 2014.

Concentrated perfusion currently enables 90% cell viability at high cell densities (50–100 × 106/mL compared with cell densities of 10–40 × 106/mL with standard perfusion), so it can produce 2–3 g/L/day of protein. A 1,000-L bioreactor (at 1.5 vvd) can produce ≤4.5 kg/day. Constant, high-density harvesting in turn simplifies downstream purification, facilitating process robustness and reducing the size of or eliminating the need for large holding tanks.

Using an Alternating Tangential Flow System: The ATF technology was originally designed for perfusion mammalian cell culture in robust large-scale manufacturing. Janssen initially took the filtration system forward as a cell-retention device in a commercial setting. It is now used by other companies for large-scale commercial manufacturing of proteins. Current systems include a stainless steel device housing disposable hollow-fiber filters, but a complete single-use version is under design. That should improve accessibility and facilitate integration with other ready-to-use technologies such as prepacked chromatography columns.

More for Less: ATF System technology enables high cell densities and expression titers, rapid cell culture media exchange, reduced shear stress, and simultaneous harvest clarification (with no primary separation needed). Systems in use routinely produce 2–3 g/L/day of protein, but we expect 5 g/L/day to be achieved within five years. Even a high-dose blockbuster biologic could be manufactured using a 500-L vessel.

Technical advantages provide meaningful cost benefits. According to a Refine Technology model, a 500 kg/yr commercial process using disposable bioreactors has capital costs of US$107 million with fed-batch cell culture but ~$33 million with concentrated perfusion. By comparison, a facility with stainless steel bioreactors could spend ~$104 million for fed-batch manufacturing or $44 million using concentrated perfusion. Reductions in overall cost of goods (e.g., labor, material, consumables) are similarly dramatic, and space requirements are reduced by ~40% for perfusion systems. These figures suggest that perfusion technologies will see increasing consideration in coming years. Building multiple small manufacturing facilities using innovative, off-the-shelf technologies such as this could become the new norm.

John Bonham-Carter is director of ATF Systems for Repligen Corporation; [email protected]. Editor’s Note: See this month’s special report for more on new directions in downstream processing.