Discovery

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.

Review the literature on both the disease and the reference product

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Biosimilars are biologics

BioEngage

Biosimilars are biologics

INNOVATOR BIOLOGICS

The cost of available innovator biologics is a major pain point for health care providers (HCPs), patients, and insurance companies.¹

BIOSIMILARS

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

Long-term studies and real-world experience with innovator biologics have helped 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.²

Because of this experience, HCPs are also confident in the efficacy of innovator 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.²

Critical quality attributes (CQAs)

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Biosimilars are not generics

BioEngage

Biosimilars are not generics

Differences between generics and biosimilars:

A generic drug, by definition, is an exact copy of its reference medicine.³
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 8-10 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.⁵
Biosimilars are “highly similar” to—but not identical copies of—their reference biologic.⁵

Next, we acquire the reference product and use sophisticated analytical tests to determine its CQAs, which:⁸

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 quality biosimilar.⁹ 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 innovator 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.^2,10

Then we identify the desired attribute profile of the reference product, subsequently requiring the development of manufacturing parameters that result in a highly similar product.

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:

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 the 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.

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.

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.

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 to the reference product. This requires:^10,11

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. Published April 2015. Accessed December 21, 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. 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. Published April 2015. Accessed December 21, 2018. 5. Mellstedt H, Niederwieser D, Ludwig H. The challenge of biosimilars. Ann Oncol. 2008;19:411-419. 6. 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. Published June 2009. Accessed December 21, 2018. 7. EuropaBio. Guide to Biological Medicines: A Focus on Biosimilar Medicines. 2011. 8. Vulto AG, 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, 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. 10. Desanvincente-Celis Z, Gomez-Lopez A, Anaya JM. Similar biotherapeutic products: overview and reflections. Immunotherapy. 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.