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.