Launched in June 2018, the BioProcess Insider digital information portal delivers the latest financial and business news and expert insider views influencing the commercialization of biopharmaceuticals. Here are just a few recent stories edited for our space limitations in print. For more discussion and in-depth analysis, check out the website at www.bioprocessinsider.com. Every edition provides expert and insider perspectives on current financial movements and deal-making; the newest technology purchases and capacity investments; regulations affecting the bioprocessing sector; global market actions and reactions; and industry trends.

HyperStack Shortage Caused By Gene Therapy Surge

Adoption of viral-vector technology in cell and gene therapy has led to six-month waiting lists for multilayer culture vessels. HyperStack vendor Corning plans to more than double its manufacturing capacity in response. Multilayer, scalable, and single-use culture flasks are used to produce viral vectors and gene therapies. According to Reinout Hesselink, an expert on cell and gene therapies and consultant at eXmoor Pharma Concepts, such equipment is in huge demand.

He told BioProcess Insider that a surge in gene therapy development has led to shortages and long waiting lists furthered by a lack of capacity from the only two vendors offering such products: Corning and Nunc (part of Thermo Fisher Scientific). “There is an increase in the number of gene therapies getting to later-stage development, and vendors can’t keep up,” he said.

Spun out of academia, gene therapies traditionally have been made using 175-mL culture vessels, he continued, but HyperStack-type systems with doubledigit layers have offered the industry a faster way to scale up production. “[Gene therapy makers] would like to scale-up into bioreactors, but there is not always the time and money to do this. People want clinical results as soon as possible,” leading to a scale-out strategy instead. “But from phase 2 onward, they are locked into that manufacturing process.” The only way to scale up more is to increase the number of stacked trays even further.

50 Stacks Per Batch: Andy Topping, chief scientific officer at Fujifilm Diosynth Biotechnologies, confirmed the shortage during a BPI Theater interview at the Biotechnology Innovation Organization’s annual convention in Boston this past June. His company uses up to 50 stacks per batch of product, so it pays “a lot of attention to the supply chain,” he told us, “because we become very dependent on them.” About the shortage, he said, “I think it just speaks a little bit to this explosion of early phase manufacturing.”

Running Full Capacity Seven Days Per Week: Topping added that the sudden surge has taken vendors “as much by surprise as anyone else,” although Hesselink said he believes that a similar shortage a few years back was driven by increased interest in mesenchymal stem cells (MSCs).

Nunc owner Thermo Fisher declined to comment on the shortage. But Corning spokesperson Chris Ward said his company is alert to the “rapid adoption of viral vector technology in cell and gene therapy” that has caused the shortage. “Despite our longstanding active project to increase production capacity, the pace of orders has exceeded our current production rate.” Corning’s HyperStack products are made at its facility in Kennebunk, ME. Ward did not disclose information on production volumes, but he confirmed the plant is “running at full capacity seven days per week.”

Meanwhile, Corning also is working to alleviate the shortage through qualifying a second source for gamma sterilization, optimizing current operations, and adding a new production line that should be validated and operational during the first quarter of 2019. “These plans are intended to more than double the current manufacturing capacity,” said Ward. “We are committed to developing additional capacity within the next few years to meet future demand.”

CAR-T Manufacturing Glitches: An Industry Problem

Novartis has reported problems with the manufacture of Kymriah (tisagenlecleucel). But contract development and manufacturing organization (CDMO) Lonza says that growing pains are normal with a new field such as chimeric antigen receptor T (CAR-T) cell technology.

In August 2017, Novartis became the first company to receive US Food and Drug Administration (FDA) approval for such a cell therapy, which treats diffuse large B-cell lymphoma (DLBCL). But in its second-quarter results, the Swiss company admitted to some issues in Kymriah manufacturing.

“We have seen some variability in our product specifications,” CEO Vasant Narasimhan told stakeholders. “This is something we’re looking at now in DLBCL to make sure that we can continue to ramp up demand.”

Novartis Oncology CEO Liz Barrett added that the company is working directly with the FDA to resolve the issue “as well as looking at new ways to improve our output to meet more commercial specification on Kymriah.” Second quarter Kymriah sales stood at US$16 million (€13.7 million). And in March 2018, it was approved for a second indication.

New Field, New Technologies: Barret also said variability in commercial specifications isn’t unusual with a new therapy as it launches into a new target patient population.

“We all need to be aware that this is an extremely new field,” said Lonza CEO Richard Ridinger. “[The] challenge in the industry: It’s not a Novartis issue, I think, it’s an industry issue.” He compared the problems in CAR-T manufacture with stability issues in production of biologics 15–20 years ago, saying “it was not so much different.” And he continued, “Lonza wants to be a part of the solution going forward,” so it is developing “maybe quite unique manufacturing technologies” to make CAR-T processes stable and affordable in the future. But when contacted by BioProcess Insider, Lonza declined to add further details at this time.

In recent years, the CDMO has invested heavily in cell and gene manufacturing. It expanded its capabilities and footprint through acquisition of European CDMO PharmaCell in May 2017. And in April this year, the company opened a 300,000-ft2 facility dedicated to cell and gene therapy manufacturing in Houston, TX. For the first six months of 2018, Lonza reported sales of 1.6 billion CHF ($1.6 billion).

Bioproduction: “A Tale of Two Facilities”

The advent of single-use bioreactors has revolutionized facility design, says an engineering firm that has worked in the manufacturing sector for almost 30 years. As the biotechnology industry matured through the 1990s, Jacobs Engineering acquired Triad Technologies and Sigel Group to expand its expertise in designing and constructing biotechnology facilities. The firm has since been involved with many prominent biomanufacturing facilities over the past few decades: e.g., ScheringPlough’s (now Merck & Co.) facility in Tuas, Singapore; Bristol-Myers Squibb’s large-scale biologics facility in Cruiserath, Ireland; and Novartis’ Biotechnology Center in Huningue, France.

Speaking to BioProcess Insider at the BPI Theater at BIO2018 in June, the firm’s vice president Sean Sommer spoke about the dichotomy between single-use and stainless steel being demanded from industry.

He called this situation “a tale of two facilities. . . . We’re seeing the need for capacity with traditional stainless steel manufacturing facilities to pump out as much product as possible, but also the need for disposable facilities with quick product turnover and high flexibility.”

According to Sommer, titers increasing as much as 30-fold have driven down bioreactor size and pushed disposables as a realistic solution for biomanufacturers. “That has enabled innovation around manufacturing: high production and throughput. In early years, a 500-cm chromatography column would have been large; now we’re seeing 2-m columns. You can see the innovation in manufacturing.”

Becoming the Data Stewards: The life science space represents ~12% of Jacobs’ total sales, pulling in about US$1.7 billion (€1.5 billion). So we asked Sommer what experience from other industries the firm can bring to bioproduction plants. “It really centers on what I would call ‘data disruption’ right now,” he said. “What’s going on with Uber in transportation, Amazon in retail, and so on — really the amount of data out there is not only from those industries. If you look at our industry, we need to be able to harness that. We need to be the data steward and make sure that we can collect and use data to help our clients make their plans smarter.”

To make the most of bioproduction data, Jacobs has created what it calls “Jacobs connected enterprise” to instill some of the best practices from other industries that it works with into its biomanufacturing designs. “To use a direct correlation within biomanufacturing would be leveraging the data that we create during the engineering cycle of a project through the construction cycle as well as through the commissioning and validation cycle of the project. We’re starting to implement those types of practices.”

Artist’s rendering of the RI facility WWW.AMGEN.COM

Amgen Breaks Ground on $160m RI Plant

Amgen has broken ground on a modular biomanufacturing facility based on single-use technology at a site in West Greenwich, RI. The groundbreaking ceremony was attended by Rhode Island governor Gina Raimondo and congressman Jim Langevin. Plant construction will begin in September.

First announced in April 2018, this site will make biologics for global markets once it goes into operation. It has been described as a “next-generation biomanufacturing plant” — a modular design based on enabling technologies such as disposables and process intensification — that the company says will be constructed in half the time at approximately quarter the capital cost of a traditional plant.

The plant replicates Amgen’s $200 million (€171 million) biologics production facility in Singapore, which opened its doors in 2014. The $160 million investment is expected to create more than 150 new jobs and is supported by Rhode Island state economic development programs, including a tax credit program that could be worth as much as $4.45 million for Amgen.

“Rhode Island competed to be the location for the company’s ‘next-generation’ biomanufacturing facility, and we were successful because of our skilled talent, ideal location, and potent incentives,” Rhode Island commerce secretary Stefan Pryor said in April.