With all the hoopla surrounding the passage of the Patient Protection and Affordable Care Act on March 23, 2010, relatively little notice was given to a piece of the legislation called the Biologics Price Competition and Innovation (BPCI) Act.
The BPCI established an abbreviated licensing pathway for drug firms to manufacture generic versions of biological drugs. The hitch was that they first have to prove the generic versions are similar to, or interchangeable with, an FDA-licensed reference product.
The law stipulates that a biological product can be demonstrated to be “biosimilar” if the data show that the product is “highly similar” to, and differs in no clinically meaningful way from, an existing approved biological drug. Because biosimilars are not direct copies of the original biologic drug, they are not the same as generic drugs — hence the name “similar.”
Biologics typically are liquid drugs used to treat cancer, rheumatoid arthritis, Crohn’s disease, and any number of other serious, often life-threatening ailments. Instead of being chemically synthesized like most drugs, biologics are made from living cells. Not surprisingly, they are costly and time-consuming to develop, and tend to be some of the most expensive drugs on the market. In addition, many biologics are used long-term by patients to treat chronic conditions.
To manufacture safe and effective biologic and biosimilar medicines, more steps and more stringent processes for each step are required than for small molecule medicines.
By formally approving the notion of “biosimilars,” the law was, in effect, inviting drug manufacturers to take a stab at manufacturing generic versions of biologics as a way to reduce health care costs. However, as of May 2014, more than four years later, the Food and Drug Administration had yet to approve a single biosimilar.
So what’s the hangup? There’s certainly no lack of financial incentive. Patents on a host of leading biological medicines, with estimated global sales of $80 billion, are set to expire by 2020. Many big pharma firms, as well as some generic manufacturers, are preparing to jump into generic biologics manufacturing. Although the investment needed to get into this market is huge, the pot for the winners is well worth the ante, and maybe even a raise or two.
“You already see Big Pharma looking at jumping into this market,” says Dave Marks, a principal at DME Alliance, an engineering firm that designs manufacturing facilities and processes for the pharmaceutical and other industries. “And some, but not all, smaller generic manufacturers are looking at it, but the pathway to approval of biosimilars is still not clear.”
Drug manufacturers may be taking a wait-and-see attitude, holding back to get a better sense of the regulatory waters before taking the plunge. “A few companies are ahead of the curve and will cut their teeth on the market,” Marks asserts. “Once there have been a few successes, others will follow.” Adds Kim Wong, director of facilities and GMP support for bioprocess R&D at Sanofi Pasteur in Toronto, “After the first one or two products have been approved, it will provide greater comfort for the industry. The market will gain momentum with time and success.”
Perhaps the biggest single reason drug manufacturers have been slow on the uptake is the huge challenge involved in manufacturing a biosimilar. First, a biosimilar manufacturer must recreate a highly similar large molecule with similar makeup and characteristics as the innovator firm’s drug. Then they must prove their product is highly similar to the original in its effect on patients. And they have to develop a commercial-scale, high-quality process with controls tight enough to ensure that the drug won’t be altered in any way that could impact its efficacy or purity.
“There are some unique challenges associated with biologics products manufacturing,” Marks says. “Large molecule products are more difficult to characterize and reproduce. It requires that you reproduce a manufacturing process and demonstrate equivalency of the product.”
Others with experience in the business of creating and manufacturing biologics agree. “What I have learned working on biosimilars is that this is not easy — it’s scientifically difficult to manufacture biosimilars,” says Victor Fung, executive director for development of the biosimilars portfolio at Amgen in Thousand Oaks, Calif.
“Manufacturing biosimilars requires developing a process to match a reference product,” says Fung, who has more than three decades of experience in the industry, having started at Genentech in 1982, moving on to Immunex in Seattle, and later joining Amgen in 2002. “It requires making good decisions around the host cell and your process. You also need to keep your processes in control to maintain similarity. Developing biosimilars requires a high level of scientific rigor.”
The process hurdles alone are daunting. “You have to develop the process, then confirm the process can work in manufacturing, and then you have to execute the process — and make sure it’s in control,” Fung adds. “My role is to develop those processes and transfer them to our manufacturing network.”
Amgen’s good manufacturing practices for biologics consist of 11 steps (see chart), including cell development, culture, harvest, purification, filling and packaging. By contrast, the company has just 7 steps in its GMP protocol for small molecule (chemical) drugs. Amgen also has about 250 in-process tests for a typical biologic medicine during the manufacturing process, versus just 50 tests for a typical small molecule drug.
At the heart of successful biosimilar manufacturing is the need to understand the important attributes of the original product that the biosimilar must match. “Understanding the important process parameters controlling consistency has been the basis of developing our entire portfolio,” Fung says. “The best practices we have for our innovative (original) products are the same for biosimilars — we treat them the same. My advice would be: Don’t look at biosimilars as any different from the original biologics.”
According to FDA Commissioner Margaret A. Hamburg, in a speech before the annual meeting of the Generic Pharmaceutical Manufacturers Association, one of the stated goals of the BPCI is “to drive down medical costs.” However, the price reduction for biosimilars is likely to be less dramatic than for generic versions of chemical drugs. That’s because the up-front investment is greater, it takes longer to obtain approval, and biosimilars are more complex and expensive to manufacture. “The manufacturing costs and the capital costs are much more significant for the generic manufacturer of biologics than for chemical drugs,” Marks says. “These constraints are much more accentuated for biosimilars.”
THE PROCESS IS THE CHALLENGE
A key challenge facing biosimilar manufacturers is developing a process for making large molecules. “Part of the challenge has more to do with process development, because these are living organisms,” Marks explains. “The generic manufacturer will not have the use of the process of the original manufacturer,” he adds. “They will have to develop an expression system and a manufacturing process.”
At best, biosimilars can only be similar to the original, not identical. Because these are cultures made of living cells, each one is different. In other words, no two are exactly the same. Biosimilar manufacturers will have, as Sanofi Pasteur’s Wong puts it, “a very good indication of the product from the literature of the product. But it will not tell you how to make it.”
Another hurdle is the inherent instability of the proteins and related molecules. These have a tendency to degrade, leading to variations in product uniformity and the potential for changes in toxicity. The upshot is that materials need to be stabilized throughout production. Compounds with large molecules tend to react more to environmental influences including light and heat than other drug forms.
“Most biologics are injected into the patient, and they have to be free of antitoxins and free of impurity,” Marks adds. “They have a higher standard of requirements than tablet operations.” Because biologics are made of living cells, they are more vulnerable to contamination than chemical drugs. “The original biologic drug substance is typically a living cell and as such is susceptible to microbial contamination,” Marks says. “That’s a unique challenge.”
Biosimilar manufacturers must be able to scale their processes to commercial volumes. “Scaling up to production of biologics does present challenges, as there are many factors that can influence the properties of the molecule,” says Perry Siatis, vice president for Biologics Strategic Development at Abbvie. These include the type of cell, the growth conditions, the pH of the culture, oxygen levels in the culture, and the nutritional medium in which the cells are grown. Adds Siatis, “When using large industrial-scale cultures of hundreds or thousands of liters, the control of these factors can be very challenging.”
But some in the industry believe the most difficult aspect of manufacturing a biosimilar will not be manufacturing, but rather creating the similar product and proving its similarity to the original.
“Manufacturing the biosimilar is not the major hurdle, it’s proving that it is similar, and how to get it through the approval process,” says Sanofi Pasteur’s Wong. Companies will have to demonstrate that their biosimilar has similar impurity profiles and potency. “You compare your product with the original product,” he says. “It doesn’t have to be identical, but highly similar.”
Impurities — especially those introduced during manufacturing — may pose a big threat to the product quality of biosimilars. “Sometimes the impurity difference may not affect the clinical properties of the product, but sometimes it does,” Wong says. Unfortunately, what appears to be a less than significant impurity in a biosimilar could possibly have a significant effect on a patient.
In fact, the FDA is acutely aware of the possibility that a biosimilar drug — if not manufactured to the highest standards — could negatively impact the health of a patient. “The FDA issued a draft guidance on an issue common to all biologic products — how to study whether patients are at risk of having an unintended immune response to a biological product, and if they do, how to evaluate the impact of that response,” Dr. Hamburg told the generic manufacturers. “The high standards for approval of biosimilar and interchangeable products means that patients and health care professionals can be assured that, when these products go to market, they will meet the standards of safety, efficacy and high quality that everyone expects and counts on,” Dr. Hamburg said.
Much has changed since the early days of biological manufacturing. New technologies promise to enable manufacturers of biosimilars, once approved to get to market faster by leveraging today’s more flexible processes. “There is a high level of interest in developing single-use technologies and making the factory more flexible, which would enable the manufacturing of biosimilars at lower cost,” Marks says.
Single-use, or disposable materials may include bioreactors, solution storage containers, filters and other items that can be used for one or even a few production runs before being replaced with a new set of materials. They are attractive for a variety of reasons — they scale up rapidly and offer flexibility when making a quick switch between products being manufactured.
“Many of the original biologics products “were developed 15 or 20 years ago using what were state-of-the-art processes back then,” Wong points out. “Today there are new technologies and new methods that have increased the productivity of making a biological product, which means you can drive down the cost of producing biosimilars.”
Flexibility in manufacturing also enables companies to react faster to shifts in the market. “We have been investing in fast, flexible and nimble technologies that offer a very good approach to manufacturing biosimilars,” Fung says. “It allows you to react to the market as it changes, so that if you have under-predicted the demand, these facilities are quicker to construct. Similarly, they help you to not over-invest in a particular product. It allows for a margin of error when predicting your capacity and demand.”
The use of more up-to-date technologies in the manufacturing process may mean that biosimilars will be produced through the use of slightly different processes or even different materials to yield a highly similar end result. “An expected difference is that our processes will be different than those used a decade ago,” Fung explains. “This means using more state-of-the-art technologies. Or we might use a different reagent in a process.”
Manufacturers today, by tweaking or refining their processes, may actually come up with an improved product when making a biosimilar. “The media in which you cultivate the cells can have an impact on the product,” Fung adds. “We use this knowledge to optimize the product — in other words, we deliberately use media to optimize the product to affect it in the way we desire.”
Wong believes the market for biosimilars will be largely taken over by drug firms that already are making biologics and have extensive experience with their development and production. That said, he recognizes that the party is wide open to others. Some companies are already experienced in the art of biologicals, some may develop those skills on their own, and others may form a collaboration with a company already skilled in this area, he adds.
“A lot of generic chemical drug manufacturers have already started developing their own programs for biosimilars,” Wong says. “The barrier to enter the U.S. market is high, but if the potential for earnings is there, it’s worth it.”
As might be expected, biosimilars present an additional challenge once the product is ready for packaging. As an example, biosimilars have the potential to react more strongly to the silicon film lining the inside of a glass syringe or to the chemical makeup of a container’s stopper. The result is that biosimilar manufacturers will have to take special care when designing the packaging to ensure product safety, purity and efficacy.
Amgen’s Fung says the company plans to package its biosimilars in a way that is familiar to the end user. “We would look to make the packaging transparent and seamless, so it would look and feel the same to the end user like any biologic,” he says.
Likewise, the supply chain for biosimilars also will come in for greater scrutiny than that for chemical drugs. In Europe, the European Commission requires all EU member countries to take special measures to identify all biological medicines that are prescribed, dispensed and sold. Ultimately, these requirements are imposed on physicians, pharmacies and other healthcare professionals.
As the pharmaceutical industry prepares to launch an initial wave of biosimilar drugs to tap the $80 billion worth of biologics set to go off patent in a few years, there is a heightened sense of both the opportunities and the challenges this new market portends.
Drug manufacturers are acutely aware of the various obstacles they must navigate to be successful biosimilar producers. While regulatory concerns may loom large today, the labyrinth of manufacturing issues posed by biosimilars may prove to be even more challenging down the road.