If you haven’t heard of biosimilars, you’re not alone. The first biosimilar was approved in Europe in 2006, but they’ve only been available in the United States since 2015.3,4
So what are biosimilars? They are biologic medicines that are highly similar to existing licensed biologic products (often referred to as reference or innovator products) with no clinically meaningful differences in terms of safety and efficacy. Although sometimes compared to generic, small-molecule drugs, biosimilars are in fact fundamentally different from generics with respect to their size, complexity and manufacturing processes. For example, biologics can be up to 1,000 times the size of small-molecule drugs, and they are created from living organisms.5
Inroads to the U.S. marketplace became possible after the enactment of the Biologics Price Competition and Innovation Act (BPCIA) in 2010, which provided a legal pathway for FDA to approve biosimilars.6 Today, nearly a decade later, FDA has approved 26 biosimilars in the U.S. referencing nine different biologics, with 12 of those biosimilars currently available to physicians and patients.7,4,8,9,10,11,12,13,14,15,16,17
Most recently, 4 therapeutic oncology biosimilars (including the first oncology biosimilar approved by the FDA) launched in the U.S.—offering more affordable treatment options for both physicians and patients.13,16,17 The fact that 3 of these products have list prices that are at least 10 percent lower than their reference product certainly bodes well for the future cost savings that patients, providers and the healthcare system can anticipate from biosimilars.13,16
As companies increasingly invest in the development of biosimilars, physicians and patients may see even more treatment choices soon. Biotechnology company Amgen, for instance, has already invested more than $2 billion in the development of biosimilars across a pipeline of ten products, according to Gary Fanjiang, vice president of global development at Amgen. “We believe biosimilars may add tremendous value in terms of our mission of serving patients across the globe,” he says.18,19
Over the long term, strong competition on a level playing field can create a more sustainable marketplace with biosimilars, providing meaningful cost savings for the healthcare system.
“A robust and sustainable marketplace is rooted in a foundation of intellectual property, scientifically appropriate regulatory standards, scientifically accurate educational outreach, and head-to-head competition to create cost savings,” says Chad Pettit, executive director of global value, access, and policy at Amgen. “The savings that come through competition with biosimilars then allow healthcare dollars to be spent on innovative new technologies that address previously unmet medical needs.”20
Going forward, the hope is that more biosimilars will come to market. This will increase competition, which, in turn, will potentially provide more affordable treatment options for biologic medicines around the globe, including in the U.S.21 “We’ve already seen the average life expectancy of metastatic colon cancer patients improve as a result of biologics,” says Andrew Spiegel, who lost his mother to metastatic colon cancer in 1998 and now serves as executive director of the Global Colon Cancer Association. “Biosimilars have the potential to increase access to these treatment options.”2
Still unsure about what it takes to create biosimilars, or how they’re poised in the biologic medication landscape? Let’s go inside the lab to better understand the development process.
To develop a biosimilar, drug companies first identify a reference product.
The decision to bring a particular biosimilar to market involves many factors, including its potential impact on patient access and a company’s internal capabilities.
Scientists extensively test the reference product.
Once a reference product is selected for research and development, the biotechnology company purchases quantities of it to test and analyzes multiple batches. Through an understanding of the drugs’ mechanism of action (i.e., how it works in the body) and extensive testing, scientists seek to identify the critical quality attributes of the reference product, including its structure, biological activity, and function.22
Scientists and biotech experts start the production process.
When scientists have a clear understanding of the reference product, they start work in their manufacturing facility. They insert the DNA sequence into living cells. Once inside, the cell’s machinery transcribes and translates the DNA’s message into cells as they reproduce. As the cells reproduce and grow, they make the biologic product encoded by the DNA.23 This step of creating a cell line with the DNA sequence that will make the biologic product with the right critical quality attributes identified in the preceding step may take many years and potentially hundreds of attempts, to get a protein highly similar to the reference product.24
Scientists and biotech experts grow new cells.
Once the new DNA is inserted into cells, the new cell line needs to replicate. This phase, often known as “seeding,” typically takes several weeks or more to make just one batch of a biologic medicine. As the number of cells and their concentration increases in a controlled manner, they’re transferred from, for example, a 50-liter bioreactor to successively larger vessels. Cells will continue to grow and divide as long as their environment remains favorable, so it’s critical to continuously monitor temperature, pH, agitation speed, and dissolved oxygen concentrations in the cell cultures.25
New cells produce a protein that will become the biosimilar.
In this step, bioreactors are filled with a production medium that is equilibrated to the proper temperature, pH, and oxygen levels to stimulate protein production in a carefully controlled environment.26,27 Staff wear special uniforms and a HEPA filtration system replaces all of the air in the room every two minutes to ensure a clean environment.25
Scientists recover, purify, and test the new medicine.
Before the medicine is ready, it must be purified, filtered, and tested.25 To start, the protein solution is mixed with buffer—a pH stable liquid—to begin the recovery purification process.28 It then goes through a special heating and cooling sanitization system, as well as multiple filtration and purification steps to remove any impurities or debris. Finally, to ensure product quality, the medicine goes through more than 250 tests. Robotics and human analysis are used at this stage.25,29
Trained technicians pack and store the medicine.
After the final product has been tested, it is formulated and put into vials or syringes. During formulation, which takes place in aseptic suites to ensure sterility, the therapeutic protein is put into a mixture of inert components to help ensure that it remains stable during distribution and storage. Technicians continuously monitor and inspect vials and syringes as they move through this step.25
Trained technicians and FDA regulators inspect the final product.
Every batch of product goes through thorough manual and automated inspection processes. Highly trained staff examine products at least twice, and there are additional state-of-the-art safeguards in place to help prevent human errors. For example, a warning prompt will sound if vials aren’t being held in the correct viewing position for proper inspection.25
Ultimately, that last step may be the most important one. As Leah Christl, executive director of global regulatory and R&D policy at Amgen, and who previously spent more than 15 years of her career at FDA, puts it, “When the FDA approves a biosimilar product, it means that the evaluation of that product has met the standards for biosimilarity and its safety and efficacy profile for its labeled conditions of use.”
And that’s a pretty big deal, according to Dr. Madelaine A. Feldman, president of the Coalition of State Rheumatology Organizations and chair of the Alliance for Safe Biologic Medicines. “With the advance of biosimilars, there’s the potential to significantly lower the prices of these medicines, offering physicians and patients more treatment options,” she says.2 “Lower prices and more options, I don’t think it gets any better than that.”
1 U.S. Food and Drug Administration. Biosimilars: More Treatment Choices and Innovation. October 23, 2017. URL: https://www.fda.gov/consumers/consumer-updates/biosimilars-more-treatment-choices-and-innovation. Accessed December 11, 2019.
2 Chapman MA, Charles D, Loaiza-Bonilla A. The role of biosimilars in patient access to therapeutic antibodies for immune mediated inflammatory diseases. Curr Pharm Des. URL: https://www.ncbi.nlm.nih.gov/pubmed/29189136. Accessed September 20, 2019.
3 GaBI Online - Generics and Biosimilars Initiative. Biosimilars use in Europe [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International. November 2011. URL: www.gabionline.net/Reports/Biosimilars-use-in-Europe. Accessed November 25, 2019.
4 Sandoz. Sandoz launches Zarxio™ (filgrastim-sndz), the first biosimilar in the United States. September 3, 2015. URL: https://www.sandoz.com/news/media-releases/sandoz-launches-zarxiotm-filgrastim-sndz-first-biosimilar-united-states. Accessed November 25, 2019.
5 Sekhon and Saluja. Biosimilars. 2011;1:1–11.
6 Biologics Price Competition and Innovation Act of 2009. 42 USC § 262.
7 U.S. Food and Drug Administration. FDA-Approved Biosimilar Products, Biosimilar Product Information. November 2019. URL: https://www.fda.gov/drugs/developmentapprovalprocess/howdrugsaredevelopedandapproved/approvalapplications/therapeuticbiologicapplications/biosimilars/ucm580432.htm. Accessed December 11, 2019.
8 Big Molecule Watch. Celltrion and Hospira Have Launched Inflectra® in U.S. December 8, 2016. URL: https://www.bigmoleculewatch.com/2016/12/08/inflectra-launched-in-us/. Accessed November 25, 2019.
9 Merck. Merck Announces U.S. Launch of RENFLEXIS™ (infliximab-abda), a Biosimilar of Remicade, for All Eligible Indications. July 24, 2017. URL: https://investors.merck.com/news/press-release-details/2017/Merck-Announces-US-Launch-of-RENFLEXIS-infliximab-abda-a-Biosimilar-of-Remicade-for-All-Eligible-Indications/default.aspx. Accessed November 25, 2019.
10 The Center for Biosimilars. Mylan Confirms That It Has Launched Fulphila in the United States. July 30, 2018. URL: https://www.centerforbiosimilars.com/news/mylan-confirms-that-it-has-launched-fulphila-in-the-united-states. Accessed November 25, 2019.
11 The Center for Biosimilars. Pfizer Launches Biosimilar Filgrastim, Nivestym, at a Substantial Discount. October 3, 2018. URL: https://www.centerforbiosimilars.com/news/pfizer-launches-biosimilar-filgrastim-nivestym-at-a-substantial-discount. Accessed November 25, 2019.
12 The Center for Biosimilars. Coherus Confirms That It Has Launched Its Pegfilgrastim Biosimilar, Udenyca. January 4, 2019. URL: https://www.centerforbiosimilars.com/news/coherus-confirms-that-it-has-launched-its-pegfilgrastim-biosimilar-udenyca. Accessed November 25, 2019.
13 Amgen Biosimilars. Amgen And Allergan’s MVASI™ (bevacizumab-awwb) And KANJINTI™ (trastuzumab-anns) Now Available In The United States. July 18, 2019. URL: https://www.amgen.com/media/news-releases/2019/07/amgen-and-allergans-mvasi-bevacizumabawwb-and-kanjinti-trastuzumabanns-now-available-in-the-united-states/. Accessed November 25, 2019.
14 The Center for Biosimilars. Pfizer Launches Epoetin Alfa Biosimilar, Retacrit, at 33.5% Discount to Reference Epogen. URL: https://www.centerforbiosimilars.com/news/pfizer-launches-epoetin-alfa-biosimilar-retacrit-at-335-discount-to-reference-epogen. Accessed November 25, 2019.
15 The Center for Biosimilars. Novartis Confirms It Has Launched Biosimilar Pegfilgrastim, Ziextenzo, in the United States. November 15, 2019. URL: https://www.centerforbiosimilars.com/news/novartis-confirms-it-has-launched-biosimilar-pegfilgrastim-ziextenzo-in-the-united-states. Accessed November 25, 2019.
16 Teva. Teva and Celltrion Announce the Availability of TRUXIMA® (rituximab-abbs) Injection, the First Biosimilar to Rituxan® (rituximab) in the United States. November 7, 2019. URL: https://ir.tevapharm.com/investors/press-releases/press-release-details/2019/Teva-and-Celltrion-Announce-the-Availability-of-TRUXIMA-rituximab-abbs-Injection-the-First-Biosimilar-to-Rituxan-rituximab-in-the-United-States/default.aspx. Accessed November 25, 2019.
17 Mylan. Mylan and Biocon Launch Trastuzumab Biosimilar, Ogivri™ (trastuzumab-dkst), in the U.S. December 2, 2019. URL: http://newsroom.mylan.com/2019-12-02-Mylan-and-Biocon-Launch-Trastuzumab-Biosimilar-Ogivri-TM-trastuzumab-dkst-in-the-U-S. Accessed December 2, 2019.
18 Data on File, Amgen; 2019.
19 Amgen. Our Pipeline. URL: https://www.amgenbiosimilars.com/products/our-pipeline/. Accessed November 25, 2019.
20 IQVIA Institute for Human Data Science. The Global Use of Medicine in 2019 and Outlook to 2023. January 29, 2019. URL: https://www.iqvia.com/insights/the-iqvia-institute/reports/the-global-use-of-medicine-in-2019-and-outlook-to-2023. Accessed November 25, 2019.
21 Bernstein Research. Global Specialty Pharma & US Biotech: Biosimilars in EU & US - Apr-May data; EU Humira market growth, EU oncology tracking stronger, material price impact in US. Published July 10, 2019.
22 U.S. Food and Drug Administration. Guidance for Industry: Scientific Considerations in Demonstrating Biosimilarity to a Reference Product. April 2015. URL: https://www.fda.gov/media/82647/download. Accessed November 25, 2019.
23 Zhang J. Mammalian cell culture for biopharmaceutical production. In: Baltz RH, Davies JE, Demain AL, eds. Manual of Industrial Microbiology and Biotechnology. 3rd ed. Washington, DC: American Society of Microbiology; 2010:157-178.
24 Vulto et al. “The process defines the product: what really matters in biosimilar design and production?” Rheumatology (Oxford); August 2017. URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5850795/. Accessed November 25, 2019.
25 Amgen. “Biotechnology by Amgen.” Virtual Tour. URL: https://www.amgenbiotech.com/quality-processes.html#. Accessed November 25, 2019.
26 Walsh G. The drug manufacturing process. Biopharmaceuticals: Biochemistry and Biotechnology. 2nd ed. Hoboken, NJ: John Wiley & Sons; 2003:93-187.
27 Palomares LA, Estrada-Mondaca S, Ramirez OT. Production of recombinant proteins: challenges and solutions. In: Balbas P, Lorence A, eds. Methods in Molecular Biology, Vol 267: Recombinant Gene Expression: Reviews and Protocol. 2nd ed. Totowa, NJ: Humana Press Inc.; 2004:15-51.
28 Liu HF, Ma J, Winter C, Bayer R. Recovery and purification process development for monoclonal antibody production. mAbs. 2010;2(5):480-499.
29 Webster C, Copmann T, Garnick R, Green J, Hayes M, Woollett G.R., Lubiniecki A, Murano G, Seamon K, Zezza D, Landis J. Biologics: Can There Be Abbreviated Applications, Generics, or Follow-On Products? Biopharm Intl. 2003 (July):28-37.