Biosimilars Discovery & Development | Amgen Biosimilars
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Biosimilar development: innovator biologics and biosimilars 101

Inside biosimilar drug development

Amgen employs a stringent development process that is customized for each biosimilar. To begin, it is imperative that we understand the structure and function of the reference product. To do so, we review the literature on both the disease and the reference product.

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Biosimilars are biologics

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Biosimilars are biologics

REFERENCE BIOLOGICS1

The cost of available reference biologics is a major pain point for healthcare providers (HCPs), patients, and insurance companies.

BIOSIMILARS1,2

Quality biosimilars create opportunities for potential savings in the healthcare system if there is successful adoption by physicians and acceptance by patients.
Long-term studies and real-world experience with reference biologics may help HCPs become more aware of the expected side effects. The history, clinical data, and real-world experience with these products means little about them is unknown.
A robust totality of evidence must be used to evaluate a biosimilar for market approval; it includes a rigorous assessment of structure, function, animal toxicity, human pharmacology, and clinical studies to assess safety, efficacy, and immunogenicity.
Because of this experience, HCPs are also confident in the efficacy of branded biologics, because they have seen results with their patients and in clinical data.
The totality of evidence includes a rigorous assessment of efficacy, safety, and immunogenicity.

Critical quality attributes (CQAs)

Then we acquire the reference product and use sophisticated analytical tests to determine its CQAs, which:7

  • Are critical to the safety, efficacy, and pharmacokinetics of the drug
  • Include, but are not limited to: primary structure, higher-order protein structure, receptor binding and immunochemical properties, stability, biological function, general properties and excipients, attached carbohydrates, and proper molecular folding2,8

Then we identify the desired attribute profile of the reference product, subsequently requiring the development of manufacturing parameters that result in a biosimilar product. Scientists typically evaluate over 100 attributes of the biosimilar in comparison to the reference product,, determining which are most important for producing a biosimilar that meets regulatory standards for high quality. Only the amino acid sequence of the reference product is known, so it is impossible to exactly replicate the manufacturing process. The attributes of the biosimilar medicine are highly unlikely to ever be identical to those of the reference product. The manufacturing of biologics is complex as the required production systems (eg, cell lines) are highly sensitive to the manufacturing process. Therefore, differences between the originator biologic and biosimilar are expected, and may be acceptable, as long as they can be demonstrated not to produce any clinically meaningful differences in the biosimilar compared with the reference product.2,8,9

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Comparative pharmacokinetic (PK)/pharmacodynamic (PD) studies

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Comparative pharmacokinetic (PK)/pharmacodynamic (PD) studies
Comparative PK/PD studies use healthy volunteers or patients to collect pharmacokinetic (PK) and pharmacodynamic (PD) data in order to demonstrate similarity in drug exposure and response in the body. They are conducted in one of two ways:6,7
  • Parallel group: healthy subjects or patients receive either the biosimilar medicine or the reference biologic
  • Crossover: two groups of subjects first receive either the biosimilar or the reference product, and then the groups are switched to receive the other treatment
Comparative clinical studies
Comparative clinical studies demonstrate the biosimilar medicine has similar efficacy, safety, and immunogenicity with no clinically meaningful differences to the reference product. These studies should be performed in a population that is sensitive enough to detect clinically meaningful differences between the biosimilar and the reference product, should any exist. A comparative clinical study will demonstrate:1
  • That efficacy is neither inferior nor superior to the reference product
  • That there are no clinically meaningful differences in safety and immunogenicity

Quality clone creation

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Screening process

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Screening process
An extensive screening process is used, consisting of the following steps:
Candidate clone evaluation9-11
  • Biosimilar design and development require an in-depth understanding of the structure and function of the reference product to establish a target quality profile.
  • Various host cell lines are evaluated based on their expected ability to produce desired protein with the target product quality profile.
  • The potential host cells selected from this preliminary assessment will be further evaluated based on their ability to grow the product in the next step.
Transfection and amplification9,10
  • This step encompasses producing the biologic.
  • Transfection refers to the insertion of the biologic's DNA into the host cell, creating a large number of clones. Each clone then reads the DNA and produces the protein biologic, the potential biosimilar, based on the DNA sequence.
Clone selection11,12
  • The scientists have now developed several versions of the biosimilar in clones.
  • The biosimilars are evaluated and compared for similarity to the reference product; a single best clone is then chosen to use for all future production of the biosimilar medicine.
  • This step requires extensive testing using scientific analytical tools.

Amgen has the deep scientific capabilities needed to create and select a promising clone from literally thousands of cells. The optimal clone produces the antibody that matches the biological function of the reference product as closely as possible, promoting the development of a biosimilar that has no clinically meaningful differences from the reference product.2,7

Customizing the biosimilar development process

Once the clone is chosen, we custom design a process to effectively produce the biosimilar with specific quality attributes so that the biosimilar is highly similar with no clinically meaningful differences to the reference product. This requires:8-10

  • In-depth analyses of the cell-growth conditions
  • Harvest of the biosimilar from the cell
  • Further refinement of the biosimilar

References: 1. Boccia R, Jacobs I, Popovian R, de Lima Lopes G Jr. Can biosimilars help achieve the goals of US health care reform? Cancer Manag Res. 2017;9:197-205. 2. US Food and Drug Administration. Guidance for industry: scientific considerations in demonstrating biosimilarity of a therapeutic protein product to a reference product. www.fda.gov/downloads/drugs/guidances/ucm291128.pdf. Accessed October 29, 2019. 3. Mellstedt H, Niederwieser D, Ludwig H. The challenge of biosimilars. Ann Oncol. 2008;19:411-419. 4. US Food and Drug Administration. Guidance for industry: quality considerations in demonstrating biosimilarity of a therapeutic protein product to a reference product. www.fda.gov/downloads/drugs/guidances/ucm291134.pdf. Accessed October 29, 2019. 5. US Federal Trade Commission. Emerging health care issues: follow-on biologic drug competition: a federal trade commission report. www.ftc.gov/reports/emerging-health-care-issues-follow-biologic-drug-competition-federal-trade-commission-report. Accessed October 29, 2019. 6. EuropaBio. Guide to Biological Medicines: A Focus on Biosimilar Medicines. 2011. 7. Vulto AG, Jaquez OA. The process defines the product: what really matters in biosimilar design and production? Rheumatology. 2017;56:iv14-iv29. 8. Blauvelt A, Cohen AD, Puig L, Vender R, van der Walt J, Wu JJ. Biosimilars for psoriasis: preclinical analytical assessment to determine similarity. Br J Dermatol. 2016;174:282-286. 9. Desanvincente-Celis Z, Gomez-Lopez A, Anaya JM. Similar biotherapeutic products: overview and reflections. Immunotherapy. 2012;4:1841-1857. 10. Conner J, Wuchterl D, Lopez M, et al. The biomanufacturing of biotechnology products. In: Shimasaki C, ed. Biotechnology Entrepreneurship: Starting, Managing, and Leading Biotech Companies. Waltham, MA: Academic Press; 2014:351-385. 11. Dranitsaris G, Amir E, Dorward K. Biosimilars of biological drug therapies. Drugs. 2011;71:1527-1536. 12. Ramanan S, Grampp G. Drift, evolution, and divergence in biologics and biosimilars manufacturing. BioDrugs. 2014;28:363-372.

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