Discovery

Biosimilar development:
biologics and biosimilars 101

Inside drug development

Amgen employs a stringent development process that is customized for each biosimilar. To begin, it is imperative that we understand the reference product. To do so, we:

  • Review the literature on both the disease and the reference product
  • Use the same scientists and state-of-the-art facilities that manufacture our novel medicines to produce our biosimilar medicines, as their creation requires the same high level of precision
BioEngage
Biologics vs biosimilars

BIOLOGICS

The cost of available branded biologics is a major pain point for health care providers (HCPs), patients, and insurance companies. It limits access to treatment because payers require higher co-pays for these products.1

BIOSIMILARS

High-quality biosimilars create opportunities for potential savings in the health care system if there is successful adoption by physicians and acceptance by patients.

With long-term studies and use of branded biologics, HCPs are very confident in the products’ safety and known 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 and immunogenicity.2

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 safety and immunogenicity.2

Amgen employs a stringent development process that is customized for each biosimilar. To begin, it is imperative that we understand the reference product. To do so, we:

  • Review the literature on both the disease and the reference product
  • Use the same scientists and state-of-the-art facilities that manufacture our novel medicines to produce our biosimilar medicines, as their creation requires the same high level of precision

Critical quality attributes (CQAs)

Next, we acquire the product and use sophisticated analytical tests to determine its critical quality attributes (CQAs), which8:

  • 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

Scientists typically evaluate over 100 attributes of the biosimilar in comparison to the reference product, determining which are most important for producing a high-quality biosimilar.9 Only the gene 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. However, the biosimilar is close enough to the reference product to demonstrate that any identified differences have no impact on the clinical attributes of the final product.2,10

BioEngage
Biosimilars are not generics

Differences between generics and biosimilars:

  • A generic drug, by definition, is an exact copy of its reference medicine.1
  • A generic must have the same chemical structure as its reference product and takes an average of 3-5 years to develop. Each biosimilar requires additional evidence beyond that needed for a generic to prove similarity and takes an average of 7-8 years to develop.4-6
  • Whereas generics require approximately 50 quality-assurance tests as part of the manufacturing process, biologics, including biosimilars, are complex and can require approximately 250 tests to ensure potency, purity, and quality.7
  • Unlike a generic, a biosimilar will not be identical to its reference product.4
  • Like fingerprints, biosimilars are “similar” to but not identical copies of the reference biologic.

Next, we acquire the product and use sophisticated analytical tests to determine its critical quality attributes (CQAs), which8:

  • 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

Scientists typically evaluate over 100 attributes of the biosimilar in comparison to the reference product, determining which are most important for producing a high-quality biosimilar.9 Only the gene 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. However, the biosimilar is close enough to the reference product to demonstrate that any identified differences have no impact on the clinical attributes of the final product.2,10

Quality clone creation

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 to ensure there are no clinically meaningful differences between the reference product and its biosimilar.

BioEngage
Screening process

An extensive screening process is used, consisting of the following steps:

Candidate clone evaluation10-12
  • The reference drug's host cell, along with other host cells, are evaluated based on their expected ability to produce the target biologic (reference product).
  • Success in this step requires deep understanding of both the importance of the host cell in growing the reference product and the impact on biological growth of selecting a different host cell.
  • 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 amplification10,11
  • 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 selection12,13
  • 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 to ensure the clone producing the highest quality biosimilar is selected.

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 to ensure there are no clinically meaningful differences between the reference product and its biosimilar.

Perfecting the process

Once the clone is chosen, we custom-design a process to most effectively produce the biosimilar and ensure its similarity to the reference product. This requires2,10:

  • 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. Scientific Considerations in Demonstrating Biosimilarity of a Therapeutic Protein Product to a Reference Product: Guidance for Industry. www.fda.gov/downloads/drugs/guidances/ucm291128.pdf. Published April 2015. Accessed April 23, 2018. 3. Camacho LH, Frost CP, Abella E, Morrow PK, Whittaker S. Biosimilars 101: considerations for U.S. oncologists in clinical practice. Cancer Med. 2014;3:889-899. 4. US Food and Drug Administration. Quality Considerations in Demonstrating Biosimilarity of a Therapeutic Protein Product to a Reference Product: Guidance for Industry. www.fda.gov/downloads/drugs/guidances/ucm291134.pdf. Published April 2015. Accessed April 23, 2018. 5. Mellstedt H, Niederwieser D, Ludwig H. The challenge of biosimilars. Ann Oncol. 2008;19:411-419. 6. U.S 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. Published June 2009. Accessed April 23, 2018. 7. EuropaBio. Guide to biological medicines: a focus on biosimilar medicines. www.medicinesforeurope.com/wp-content/uploads/20l6/03/WC500020062.pdf. Published 2012. Accessed April 23, 2018. 8. Vulto AF, Jaquez OA. The process defines the product: what really matters in biosimilar design and production? Rheumatology. 2017;56:iv14-iv29. 9. Blauvelt A, Cohen AD, Luig 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. 10. Desanvicente-Celis Z, Gomez-Lopez A, Anaya J-M. Similar biotherapeutic products: overview and reflections. lmmunother. 2012;4:1841-1857. 11. 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. 12. Dranitsaris G, Amir E, Dorward K. Biosimilars of biological drug therapies. Drugs. 2011;71:1527-1536. 13. Ramanan S, Grampp G. Drift, evolution, and divergence in biologics and biosimilars manufacturing. BioDrugs. 2014;28:363-372.

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