mAbs Present Twin Challenge
At 155 K or more Daltons, mAbs present a complicated challenge for biosimilar developers. Just correctly identifying the complete structure of the reference product can be daunting. Originators will not share information such as “the exact sequence and all of the post-translational modifications,” says Fiona Greer, Ph.D., global director, biopharma services development for SGS M-Scan, a provider of analytical services with biologics experience.
“We’re talking about a different scale of protein to conquer with the antibody,” explains Dr. Greer. “Smaller proteins like growth hormones and even erythropoietin—which is a bigger molecule but that’s because 30 percent of its mass is carbohydrate—are relatively straightforward in terms of physicochemical characterization.”
The second big challenge is proving that your product is sufficiently comparable to the reference product. To some extent the same analytical tools are used for each task (mass spec, peptide mapping, various chromatographic approaches, etc.) to analyze both primary and higher-order structure. De novo analysis approaches are used in determining the reference compound’s structure, keeping in mind there are always small variations among some critical attributes that regulators have deemed acceptable.
Demonstrating structural similarity is a bit different. “Actually we interrogate the two molecules (reference and biosimilar) to see if there are any differences, so we keep drilling down. On the first pass, the molecular weights might be the same. Then we might do the peptide map to spot any differences. If there aren’t any, we would we go to the next level, each time going deeper into the molecules,” said Dr. Greer.
“Physicochemical comparison is only the first step,” she stresses. “The second step would be to see if those differences impact the biological activity or safety profile. We have learned in Europe that EMA expects the primary amino acid structure to be the same to be a biosimilar—this is now clearly stated in the revised Quality Guideline. However, there can be slight differences, for example, in the carbohydrate structure or C-terminal lysine heterogeneity if this does not affect the efficacy or safety of the molecule—but this is always treated on a case-by-case basis.”
Cut Cost and Risk with SUT
Single-use technology’s (SUT) inherent flexibility and lower costs can mitigate the higher risk presented by biosimilar projects, says Bill Whitford, Ph.D., senior market manager for cell culture at Thermo Fisher Scientific.
“It can take a year or two to get a glass and steel facility going. You can obtain a disposable bioreactor, even a 2,000 liter one, within a matter of weeks and people have had them operating within hours and days of receiving them,” notes Dr. Whitford.
“The initial investment is also reduced. For example the cost of a single-use bioreactor can be 1/10 of a glass and steel welded one. It requires much less footprint and qualification of the facility. You save in square footage, in classification of the facility, and in the services required. A single-use bioreactor can operate without any purified water.”
It’s also easier to move or expand SUT operations. “Once you validate the tank and the liner for your purpose, you’ve validated the concept, and you can put a bag in another site in a different unit and all that validation transfers,” said Dr. Whitford.
Integration of Analytics Is Powerful
Echoing the importance of correctly characterizing CQAs of both reference product and biosimilar, Phil Ball, Ph.D., technical director, Eden Biodesign (part of The Watson Group), notes that the recent advances in combining the results of differing analytical methods is providing biosimilar developers with a powerful new tool.
“It’s not so much a single technology as a strategy,” he remarks. “This is a big step forward. We now use a range of highly sensitive and precise analytical methods and can combine that data to get a greater understanding of the product.”
Dr. Ball also says disposable technologies are likely to play an important role in containing costs. “We don’t believe biosimilars will completely erode the original markets, at least in the near term, and it’s likely that there will be more than one biosimilar manufacturer for any given reference product. This means that the bulk manufacturing demand and required process volumes for a single biosimilar manufacturer are likely to be less than those required by the originator company.
“This brings us in to the range where disposable manufacturing options become viable. We know that disposable technologies can provide us with improved cost of goods at these scales and also greater flexibility,” he points out. “You can install these systems in a small-scale facility with decreased capital costs, and the flexibility may allow you to produce multiple biosimilars in a single facility.”