By Bruce Blau
In June 2016, Alvotech opened their new biosimilar manufacturing facility in Reykjavik, Iceland, using best of breed solutions from leading Life Science vendors. The key directive for Alvotech was to create a flexible, agile process which could adapt and be used for any conceivable process. The result: A high yield disposable fermentation and downstream process, with a fill-and-finish line for vials and prefilled syringes, tied together with a complete, end-to-end upstream/downstream automation and Manufacturing Execution System.
Pros and cons of biopharmaceuticals
Biopharmaceuticals have proven themselves to be extremely effective for a wide array of ailments, ranging from infectious diseases, to neurological disorders, to diabetes and arthritis1. They not only provide remedies for patients, some of whom previously had few other effective options, but also come with far fewer side effects than conventional chemical-based medications. The side effects from typical, chemical-based medicines can not only add to the misery of an existing ailment, but also increase costs to a patient by way of additional medications and procedures.
The major downside of biopharmaceuticals is, of course, the cost to develop them. The Tufts Center for the Study of Drug Development reported2 in 2014 that it took $2.6 billion to develop and win approval for a new drug. These expenses are understandable, considering both the time and manpower required to design a new drug, and the clinical trials that are required to test them.
But when a manufacturer finally has a drug approved by the U.S. Food and Drug Administration (FDA) — 513 were approved in 2015 — the rewards are lucrative. A biopharmaceutical manufacturer can reap many billions Gilead Sciences, maker of the hepatitis C drug, Sovaldi, pulled in $24.5 billion in 20144 — and patents assure the companies of exclusivity to keep profits rolling in for years.
The massive profits go hand in hand with exorbitant prices that the manufacturers are able to charge for new biopharmaceutical drugs, which often puts the patients who desperately need these medications in an impossible situation. In many instances, health insurance companies will simply not pay for biopharmaceutical treatments. Without the help of insurance, many families have to either choose to let a loved one suffer or die, or go very deeply into debt in order to pay for the medication. Patients in developing countries are often completely shut out from the possibility of obtaining them at all.
Biosimilars arrived on the scene in recent years as an alternative that could offer some promise to patients in this predicament. Sometimes confused with “generic” chemical-based medicines, there is an important difference5 with biosimilars: generics are identical to their brand-named counterparts, while biosimilars are not. The U.S. Affordable Care Act states that biosimilars have “no clinically meaningful differences between the biological product and the reference product in terms of safety, purity, and potency.”
Biosimilars are developed in the same manner as the original and offer the very same benefits. However, since they are manufactured without the costs of research and development, biosimilar manufacturers can offer the drugs to patients at a fraction of the price of the original drugs.
Alvotech is born
Bringing down the cost of biopharmaceutical products and making them more available worldwide were major motivators for Alvotech’s founder, Robert Wessman, and business development executive Emmanuelle Lepine. They felt passionately about getting these medications to not only patients in the West who were priced out of these vital medicines, but also patients in third-world nations, who simply have no access.
Eef Schimmelpennink took the CEO reins in 2016. He noted in his remarks at the facility’s grand opening that one of the top-selling biopharmaceutical drugs on the market made $15 billion dollars the previous year, which was equal to Iceland’s entire gross domestic product for the year. He felt that this was not a sustainable economic model for a society and was determined to have Alvotech change that trend.
After considering various locations in the world, Wessman and his team settled upon Iceland for the plant’s location for a number of important reasons. Iceland happens to occupy a strategic location between the world‘s biggest markets — the United States and Europe. Alvotech also wanted to avail itself of the attractive pool of talent that Iceland has to offer. The company specifically chose to erect their facility at the University of Iceland, so they could be in place for future collaborations with the university.
The intellectual property (IP) environment was also a factor. Iceland has no IP covering the antibodies that Alvotech planned to develop. That meant that the company could get a valuable six-month head start over its competitors when releasing their products.
Yet another feature that appealed to the founders was the abundance of green energy in Iceland. The island touts the fact that almost 100% of the energy used there is obtained from geothermal energy and hydroelectric power.
Partnering with Finesse
Finesse Solutions entered the picture in 2013, before Alvotech broke ground on the Reykjavik facility. Finesse was making a name for itself in upstream automation and was chosen to design the manufacturing process for the new facility. Dr. Barbara Paldus, Finesse CEO, was brought into the discussion later that year, as was Dr. Fjalar Kristjansson, who would become Alvotech’s COO.
The Finesse team examined Alvotech’s original process concept design and, over the following months, came up with alternate ideas. Little by little, the small Silicon Valley company impressed the Alvotech executives to the point where an agreement — and then a contract — was signed in summer 2014.
The two companies visited major vendors around Europe to determine which equipment from each vendor would be, as Paldus put it, “Best of Breed.” Components were chosen from Thermo, GE and Danaher/Pall to complement Finesse’s own products. The resulting plan is a mixture of 1000L and 2000L high-yield disposable fermentation and downstream processes, with a fill- and-finish line for vials and prefilled syringes.
While very knowledgeable in all aspects of the technology, the Finesse team was nevertheless in uncharted waters. At that time, Alvotech’s plant was to be the largest single-use facility project of its day — a complete, end-to-end upstream/downstream automation and Manufacturing Execution System (MES), which even some of the industry’s largest manufacturers did not produce at the time. Finesse had even developed two completely new software platforms for the downstream portion — TruPur and TruChrom.
Fortunately for Finesse, they had earned the trust of the Alvotech team, who preferred smaller, more agile companies with whom they could work closely. Finesse already had engineers and support personnel who could supplement Alvotech’s small, but growing team, obviating the need for them to hire staff more quickly than they had intended.
Major challenge for both companies
The road to the ribbon-cutting was not a smooth one, however, for either company.
For Finesse, one of the biggest challenges was creating a manufacturing process for products that were just taking shape at the time. Because Alvotech’s production plans were still being finalized, Finesse assembled an aggregate of experts together to try to develop generic processes for generic cell lines.
While it seemed a monumental task, the directive to devise a flexible, agile process allowed the Finesse team to devise a rather impressive product. They created a biomanufacturing system that would be so adaptable that it could be used for any process that Alvotech could conceive.
On the Alvotech side, construction of the very modern and high-tech facility was on an ambitious schedule and the progress, at times, did not appear to be fast enough to meet it. Schimmelpennink visited the building site in October 2015, recalling that it seemed to be just a set of walls and floors, with nothing else built in. Kristjansson, however, was confidently predicting opening the facility a mere eight months later.
Combining the traditional Icelandic “Þetta reddast!” attitude (the saying translates to “it will all work out okay!”), along with dedicated work by his construction team and some good fortune, Kristjansson followed through and the facility did open as scheduled. Alvotech now has six drug products in its pipeline, with production expected to start at the end of 2016.
Alvotech’s design for success
The design of the Reykjavik plant was made to be completely streamlined. Components are received on the basement floor and then proceed upwards in the building to be processed. Quality control tests are completed in the basement and are sent up to the first floor lab for production. On the first floor, upstream processing scales the cell material from 400 ml up to 2000L, and then sends it directly to downstream processes, such as protein affinity purification and diafiltration. On the third — fill-and-finish — floor, the product is mixed with buffer material, sterilized, and then placed in vials and syringes. The third floor activities also include inspection, cold storage, packaging and final quality control.
Schimmelpennink cites the integrated structure of his company for his optimism for success. Alvotech has built this new state-of-the-art headquarters and manufacturing facility in Iceland, and has established five other locations around the world. Two Alvotech sites in Germany — in Jülich and another site currently being acquired in Hanover — are focused on R&D and, among other functions, perform cell line development, analytics, and protein characterization. Clinical and regulatory project management development is done in the Zürich facility.
Beauty as well as function
Walking into the Reykjavik facility is not the experience one would expect when entering a manufacturing plant. When he planned the building, Wessman devoted significant attention to aesthetics. Part of this came from having the structure on the campus of the University of Iceland; it was expected to be an attractive building, especially sitting next door to a well-known landmark, The Nordic House.
Wessman is, himself, an art aficionado and it is said that he has a significant collection in his own home. So, Wessman and his architect, Pálmar Kristmundsson, commissioned the Paris-based painter, Erro, to create large colorful paintings that cover 40 square meters of walls throughout the offices and common areas in the building.
Additionally, world-renowned Icelandic sculptor Sigurður Guðmundsson was brought in to create works of his own that are featured prominently inside and outside the facility. One of the structures adorning the atrium is made of polished steel and stands six meters high. The other artwork, which stands in the water feature in front of the building, is called “Data Pool.” It consists of two stone monoliths, which appear to be modernized versions of the Easter Island “Moai.”
Future for Alvotech and the biosimilars industry
As commercial production takes off, Alvotech plans to fit its second active pharmaceutical ingredient (API) suite, already constructed, with another production line that would accommodate commercial needs. This line would be built in the other half of the Reykjavik facility.
In the long term, Paldus sees Alvotech as having a significant effect on the industry, potentially changing the biosimilars landscape. More importantly, she feels that Alvotech will play a large role in expanding the availability of biopharmaceuticals in emerging markets.
Alvotech’s sister company, Alvogen, covers over 35 markets, worldwide, including the U.S., Central and Eastern Europe, and Asia-Pacific. With such a distribution network, they stand a chance to change the paradigm of how drugs are manufactured and sold in emerging countries. By getting the products to an affordable price point, Alvotech might well prove that Iceland can, in fact, provide affordable drug products to the rest of the world.