What's More Important, the Process or the Product?

Johnson & Johnson’s interest in acquiring vaccine maker Crucell and Novartis’s completion of a vaccine-manufacturing plant in North Carolina are two recent indications of the ongoing growth in biopharmaceuticals. Lower-cost follow-on biologics are an attractive option for many patients, especially in light of the country’s persistent economic problems. But manufacturers of follow-on biologics face challenges that their small-molecule counterparts do not face. For example, the biopharmaceutical industry saying has been that “the process is the product.” But the fact that an innovator’s process is protected by patents and kept secret would seem to pose problems for a company that intends to produce a follow-on biologic.

The past 15 years have witnessed great improvements in analytical techniques, and the makers of follow-on biologics have applied these techniques to learn all they could about therapeutic products. Existing technologies, such as chromatography and electrophoresis, have become more selective and sensitive. New technologies, including mass spectrometry and surface-plasma resonance, now provide important insights into proteins’ structures and functions. “We now can much better characterize proteins than [we could] 30 years ago,” says Terry Gerrard, president of TLG Consulting. These days, a follow-on biologics company “may know more about the reference product than the innovator did.”

Manufacturers use the detailed knowledge they gain from improved analytical techniques to develop processes that produce biopharmaceuticals with the same attributes as those of the reference products. As a company examines various batches of the reference product extensively over the course of three or four years, new and existing characterization methods can reveal differences in product attributes more clearly than before, thus indicating changes in the innovator’s manufacturing process. This extended analysis shows follow-on manufacturers the full range of the reference product’s attributes, which the manufacturer can use as “goalposts” with regulatory authorities, says Mark McCamish, global head of biopharmaceutical development at Sandoz, the generics unit of Novartis.

Analytical techniques, such as glycan analysis and various bioanalytical assays, help a follow-on manufacturer select the right cell line and develop the appropriate bioprocess and purification process for its product. During process development, in-line and real-time analysis can enhance personnel’s understanding of the process steps. Together, analytical data and information regarding process parameters help manufacturers identify the process steps and parameters that must be controlled to achieve the desired quality attributes. The recent availability of test methods with enhanced sensitivity help to improve companies’ understanding of innovator products and facilitate process development. And the recent establishment of an approval pathway for follow-on biologics allows manufacturers to begin process development sooner than before.

Studying the reference product with enhanced analytical techniques thus can help follow-on manufacturers establish a process that matches the innovator’s process results or product attributes as closely as possible. But the processes do not have to match exactly. “We’re not bound to accept the process that the originator developed 10 or 15 years ago. We tend to use state-of-the-art process technologies that may have come on board since the originator created their own product. That means we can create a new process from scratch. It’s often streamlined and more efficient than the originator’s process,” says McCamish. The maker of a follow-on biologic has to engineer its process in any way possible to achieve the necessary product attributes. “That’s a difference between us and an innovator,” says McCamish.

Advances in analytical techniques, processing technologies, and purification methods may mean that the traditional industry saying is no longer true. “The biosimilar manufacturer’s burden isn’t to understand the original manufacturing process. It is the responsibility of the biosimilar manufacturer to understand its process,” says Gerrard. If a follow-on manufacturer uses a certain column or method of fermentation, it must understand what variables can affect that manufacturing process and whether these variables will affect the product.

“We’re always going to come up with better manufacturing processes,” says Gerrard. As a follow-on manufacturer, “I don’t need to know a thing about the innovator’s process,” she adds. Follow-on manufacturers have a certain amount of flexibility in process development because different processes can yield the same product, as demonstrated by innovators that have won regulatory acceptance for their process changes. But this flexibility does not mean that the process itself isn’t important. “We need a rigorous manufacturing process that can yield a consistent product, one that you understand and control,” says Gerrard.

Analytical methods have made great strides in the past decade, and the industry now understands more about proteins’ structure and function than ever before. Scientific and technical advances will likely continue, potentially making follow-on manufacturers’ work easier and enabling innovators to develop new therapies that improve patients’ lives.