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May 15, 2012 (Vol. 32, No. 10)

Reducing Uncertainty Surrounding Biosimilar Production

  • 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

    Click Image To Enlarge +
    Recent advances in combining the results of differing analytical methods is providing biosimilar developers with powerful new tools. [Eden Biodesign]

    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.”

  • NMR for Biosimilar Process Optimization

    Click Image To Enlarge +
    According to Spinnovation Biologics, its Spedia-NMR technology, which was developed to assist in the manufacture of biologicals and biosimilars, can support more effective and characterized production processes.

    The European Medicines Agency (EMA) approved its first biosimilar—Omnitrope, in 2006—and has now okayed 14 biosimilar products. In the U.S., the FDA recently (Feb. 9, 2012) published long-awaited draft guidelines to assist companies in the development and approval of biosimilars.

    Although biosimilar manufacturers face a number of process-related obstacles, NMR profiling technology can support more effective and characterized production processes, according to Frederic Girard, Ph.D., CEO and co-founder of Spinnovation Biologics and Spinnovation Analytical. Spinnovation has developed Spedia-NMR™ technology to assist in the manufacture of biologicals and biosimilars.

    The original cell line, the exact fermentation and purification process, the active drug substance, and any information relating to biosimilars are in principle not available to the follow-on manufacturer, explains Dr. Girard, adding that it is possible that copy versions of established biologics may perform differently than the original branded version. In addition differences in impurities arising from the cell culture medium or breakdown products could have serious health implications.

    “Minute differences in raw materials, process, or the manufacturing environment, can result in vast differences in potential side effects caused by the final product,” says Dr. Girard. “Even two apparently similar biologics can affect the immune system in very distinct ways. This makes biosimilars distinct from small molecule generic products, and they consequently have to follow different registration pathways.”

    As a result of these issues, and the FDA Pathway for Biosimilars Act (2009), the introduction of new biosimilars to the marketplace has yet to reach its full potential. Biosimilar products require a demonstration of bioequivalence between the new version and the originator product as well as a well-considered pharmacovigilance plan.

    Solution with NMR

    Dr. Girard maintains that NMR profiling can enhance the development of biosimilars in two ways.

    “First, it can be used as a development tool to qualify cell culture media and achieve optimal conditions for biosimilars,” he points out. “Second, it can be used to examine spent media, intracellular media, or solutions from downstream processing to determine the identity and concentration of metabolites and eventual contaminants as an exercise in product safety and also to gain additional information on the newly developed ‘similar’ process.’”

    Process development and optimization of cell culture media is essential to commercial viability in the production of biosimilars. Downstream factors such as scalability, performance consistency, and overall cost of manufacture can all be positively influenced by increased understanding and control of early cell growth conditions and quality of raw materials.

    By understanding which factors limit cell-growth or are risk factors to low performance, developers can manipulate and monitor conditions for optimum production.

    “Overall NMR profiling can provide a rapid and useful method of reverse engineering and optimizing an existing biologic process to provide a sound basis for the production of a biosimilar,” says Dr. Girard.

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