Addressing Concerns with Biologics: Biosimilars May Cut Costs, but What Are the Risks?
In modern clinical medicine, small molecule drugs dominate our therapeutic landscape.1 These chemical drugs are often composed of a single molecule with simple structures. Now consider the very different world of biologics. Unlike the chemical reactions used to synthesize small molecule drugs, biologics are often large and complicated proteins, produced through a great diversity of processes that can individually and collectively affect protein composition.2 The very structure of biologics is highly dependent on exact manufacturing processes. Further complicating the development of biologics is the fact that they can be difficult to completely characterize, thus making a near identical copy of a drug, without a clear understanding of the specifications that produced it, can be extremely difficult.
Are Biosimilars Dangerous?
Recently, biosimilars have emerged as the equivalent of small molecule drug generics. The Food and Drug Administration approved the first biosimilar drug in March 2015.3 But biosimilar drugs are not generics. Whereas generics rely on the same active ingredient as a brand name drug, biologics and biosimilars have numerous points at which variation can be introduced. This variation can have profound effects on the clinical efficacy of drug therapies. For example, two companies can try to manufacture a protein via DNA cloning; however, the vector used to clone the target DNA sequence is likely different between companies, which could potentially affect the expression of the protein and even post-translational elements, such as glycosylation or phosphorylation patterns.
Once a biologic or biosimilar drug has been cloned into a cell, there are a number of steps that must be completed before the drug can be characterized and stabilized. At each step, even minor changes in conditions can result in significant changes to the end product, which is directly injected into patients. A company that creates an original biologic drug is not obligated to share manufacturing information with a company interested in creating a biosimilar. Any other company must then reverse-engineer a series of complicated steps with no guarantee that their end product is as effective or even non-toxic for humans. Ultimately, these issues have led some researchers to “sound the alarm” on the use of biosimilars in clinical care, or at least the comparison of these drugs to generics.4
Addressing the Challenges of Biologics and Biosimilars
Ultimately, whether a company is focused on the use of biologics or biosimilars, company researchers should realize the inherent complexity of creating biologics and, in particular, creating the same drug during each reiteration of the manufacturing process. However, there are a number of safeguards that can improve the development of these complex molecules:
- Control cell culture environment: Cell lines are popularly used by molecular biologists to produce biologics and biosimilars. However, the environment of the cells must be carefully recorded and monitored to ensure the manufacturing process has been faithfully followed. Thus, nutritional supplements in media must be carefully maintained, as well as flow rates in the hood, exposure to outside elements, temperature, etc. Additionally, cell lines are often cancer cells that are prone to rapid expansion and as such can accumulate mutations over time. Researchers must maintain sequencing information about their cell lines to ensure de novo mutations have not been generated.
- Characterization: The process of characterizing a protein drug is essential in the manufacturing process especially for companies interested in developing biosimilars. For example, part of the complexity of developing and using biologics is the potential for the drug to activate a patient’s immune system. Developing assays to assess the immunogenicity of a biosimilar (especially when compared to a biologic) can provide important clues about the manufacturing process and the potential “developability” of the protein drug.
There are many challenges in creating biologics and the biosimilar drugs meant to act like them. Given that these drugs are created in living organisms, it is essential to record and assess the growth conditions, the organisms themselves, how the protein is isolated and many other factors. Appropriate software options can facilitate this process by ensuring that complicated and large data sets are maintained within a single database. This can improve automation, efficiency and the likelihood of success. To learn how the BIOVIA Biologics Solution could support your organization in the production of large protein drugs, please contact us today.
- “Understanding Key Differences Between Biosimilars and Small Molecule Generics,” May 2013, http://www.pharmacypracticenews.com/download/sr1229_wm.pdf ↩
- “Biologics and Biosimilars,” March 2014, http://www.amgen.com/pdfs/misc/Biologics_and_Biosimilars_Overview.pdf ↩
- “FDA Approves Zarxio, Its First Biosimilar Drug,” March 6, 2015, http://www.nytimes.com/2015/03/07/health/fda-approves-zarxio-first-biosimilar-drug.html?_r=0 ↩
- “Biosimilars,” September 2012, https://www.washingtonpolicy.org/publications/brief/biosimilars-precarious-struggle-between-cost-driven-health-care-policy-and-patien ↩