DevelopingBiosimilars
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Characterizing the reference product
Characterization of the reference product defines the target biosimilar profile
The biosimilar manufacturer begins by identifying the critical quality attributes (CQAs) of the reference product and subsequently must develop manufacturing parameters that result in a highly similar product.1-3
Characterizing the reference product
Addressing the knowledge gap
For a biosimilar, the structural and functional targets are already known based on analyses and literature for the reference product.1,3 However, the reference product manufacturing information is proprietary; the cell line and manufacturing process development have to be created anew. Therefore, a biosimilar manufacturer must develop a new customized process to produce a product with defined characteristics.1,4
Characterizing the reference product
Identification of CQAs in eight categories

CQAs are characteristics that affect structure, purity, biological activity and stability of the biological drug.5 The development and manufacturing of biologics is a complex process, and a biosimilar has in-process quality tests during manufacturing that typically number in the hundreds.6 Each manufacturer determines the extent of testing and discusses their plan with health authorities.1

Characterizing the reference product
Establishing manufacturing parameters
Acceptance criteria are established for each CQA by testing multiple lots of the reference product. This determines the quality ranges and/or raw data/graphical comparisons, against which the candidate biosimilar will be evaluated.7
References
  1. US Food and Drug Administration. Scientific Considerations in Demonstrating Biosimilarity to a Reference Product. Silver Spring, MD: US Food and Drug Administration; 2015.
  2. McCamish M, Woollett G. The State of the Art in Development of Biosimilars. Clin Pharmacol Ther. 2012;91:405-417.
  3. US Food and Drug Administration. Development of Therapeutic Protein Biosimilars: Comparative Analytical Assessment and Other Quality-Related Considerations. Silver Spring, MD: US Food and Drug Administration; 2019.
  4. Lee JF, Litten JB, Grampp G. Comparability and biosimilarity: considerations for the healthcare provider. Curr Med Res Opin. 2012;28:1053-1058.
  5. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. ICH Harmonised Tripartite Guideline - Development and Manufacture of Drug Substances (Chemical Entities and Biotechnological/Biological Entities) Q11. ICH Expert Working Group; 2012.
  6. EuropaBio. Guide to Biological Medicines: A Focus on Biosimilar Medicines. Brussels: EuropaBio; 2011.
  7. Desanvicente-Celis Z, Gomez-Lopez A, Anaya JM. Similar biotherapeutic products: overview and reflections. Immunotherapy. 2012;4:1841-1857.
A unique cell line and targeted process
A targeted manufacturing process and unique cell line are developed for the biosimilar
A new manufacturing process is designed, involving many steps, from establishing a unique cell line through formulation, fill and finish of the final biosimilar.1,2
A unique cell line and targeted process
Cell line creation
Manufacturing begins with the creation of a unique cell line, engineered to express the gene that encodes for the biosimilar.2 Cells that produce biosimilar protein within the established quality ranges are selected and expanded to create a master cell bank.3
A unique cell line and targeted process
Cultivation and production
Cells from the master cell bank are cultured and expanded in large-scale bioreactors.2,3 The biosimilar protein is recovered and purified using techniques such as chromatography.2,5 CQAs are checked throughout the manufacturing process to ensure they remain within the established quality ranges.4,6
A unique cell line and targeted process
Formulation, fill and finish
The concentrated protein is formulated using ultrafiltration techniques and undergoes final sterile filtration. It is then packaged and stored under appropriate conditions to maintain shelf life.5,7
References
  1. Lee JF, Litten JB, Grampp G. Comparability and biosimilarity: considerations for the healthcare provider. Curr Med Res Opin. 2012;28:1053-1058.
  2. Dranitsaris G, Amir E, Dorward K. Biosimilars of Biological Drug Therapies: Regulatory, Clinical and Commercial Considerations. Drugs. 2011;71:1527-1536.
  3. Desanvicente-Celis Z, Gomez-Lopez A, Anaya JM. Similar biotherapeutic products: overview and reflections. Immunotherapy. 2012;4:1841-1857.
  4. US Food and Drug Administration. Development of Therapeutic Protein Biosimilars: Comparative Analytical Assessment and Other Quality-Related Considerations. Silver Spring, MD: US Food and Drug Administration; 2019.
  5. Hesse F, Wagner R. Developments and improvements in the manufacturing of human therapeutics with mammalian cell cultures. Trends Biotechnol. 2000;18:173-180.
  6. European Medicines Agency. Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues. London, UK: European Medicines Agency; 2014.
  7. Bee JS, Randolph TW, Carpenter JF, Bishop SM, Dimitrova MN. Effects of Surfaces and Leachables on the Stability of Biopharmaceuticals. J Pharm Sci. 2011;100:4158-4170.
Regulatory and development pathways
Biosimilarity is established based on the totality of evidence
Similarity between a biosimilar and reference product is established based on the totality of evidence. This includes comparative analytical (structural and functional) characterization, nonclinical evaluation, comparative clinical PK/PD data and comparative clinical studies.1,2 Highly similar analytical and PK/PD data infer a lower likelihood of clinical differences between a biosimilar and its reference product.3
PK = Pharmacokinetic
PD = Pharmacodynamic
Regulatory and development pathways
Structural and functional comparison
Structural and functional attributes of the biosimilar are evaluated against the predefined CQA quality ranges of the reference product.4 Key functions are matched with adequate consideration to assay variability, process variability and reference lot history.4,5
Important consideration:
Identified differences in attributes can be evaluated in clinical studies to confirm no clinically meaningful differences exist between the products.4
Regulatory and development pathways
Comparative clinical pharmacology studies
Comparative human PK/PD studies are fundamental to demonstrating similarity in safety and drug exposure over time. These profiles cannot be adequately predicted from in vitro characterization and functional assays alone.1

Insights for immunogenicity are initially determined with an immunocompetent population. Sera from healthy subjects are used to detect anti-drug antibodies (ADAs).1
Regulatory and development pathways
Comparative clinical studies
A comparative clinical efficacy and safety assessment is the final stage to support a demonstration of biosimilarity.5 Biosimilar clinical studies are designed to detect clinically meaningful differences between a biosimilar and its reference product, should they exist, in a sensitive patient population using a sensitive endpoint.2,5,6

These studies use an equivalence design that is based on meta-analysis of historical data for the reference product and a balance of statistical and clinical considerations and feasibility.6
References
  1. US Food and Drug Administration. Scientific Considerations in Demonstrating Biosimilarity to a Reference Product. Silver Spring, MD: US Food and Drug Administration; 2015.
  2. European Medicines Agency. Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues. London, UK: European Medicines Agency; 2014.
  3. Kozlowski S. US FDA Perspectives on Biosimilar Biological Products. Presented at: 2014 Biotechnology Summit; June 13, 2014; Rockville, MD.
  4. US Food and Drug Administration. Development of Therapeutic Protein Biosimilars: Comparative Analytical Assessment and Other Quality-Related Considerations. Silver Spring, MD: US Food and Drug Administration; 2019.
  5. Markus R, Liu J, Ramchandani M, Landa D, Born T, Kaur P. Developing the Totality of Evidence for Biosimilars: Regulatory Considerations and Building Confidence for the Healthcare Community. BioDrugs. 2017;31:175-187.
  6. Isakov L, Jin B, Jacobs IA. Statistical Primer on Biosimilar Clinical Development. Am J Ther. 2016;23:e1903-e1910.
Demonstrating clinical similarity
The goal of comparative clinical studies is to demonstrate clinical similarity
The biosimilar licensure pathway has important distinctions from that of originator biologics.1 The goal of a biosimilar development program is not to independently establish clinical benefit, but rather to demonstrate that the proposed biologic product is biosimilar to the reference product with no clinically meaningful differences.2,3 Similarly, indication extrapolation is a regulatory concept that reduces or eliminates the requirement to study a proposed biosimilar with clinical trials in every indication of the reference product.2-4
Demonstrating clinical similarity
Considerations for clinical study design
The primary goal of a biosimilar clinical study is to demonstrate similarity between the biosimilar and reference product in terms of efficacy, safety and immunogenicity. Key clinical study design considerations include:2
Sensitive patient population
Study an immunocompetent population and consider comorbidities, concomitant medications, medication history and severity of disease2,4,5
Treatment regimen
Consider the route of administration and monotherapy vs. combination therapy with the standard of care4,6,7
Sensitive endpoints
Use prespecified, scientifically justified margins that are clinically relevant, readily assessable and able to detect differences. Continuous endpoints may be more sensitive than binary endpoints4,6
Study duration
Sufficient exposure to allow detection of any clinically meaningful differences in efficacy, safety and immunogenicity7
Comparator study design
Should allow comparative assessment of efficacy, safety and immunogenicity and may address considerations for switching treatments2,6
Demonstrating clinical similarity
Extrapolation to other indications
Extrapolation is the approval of a proposed biosimilar product in one or more additional indications for which the reference product is licensed, but for which the biosimilar has not been studied in clinical trials. Extrapolation is based on the consideration of all available data in the biosimilar marketing application, knowledge of the reference product and consideration of various scientific factors for each indication sought.2,5
NRAs = National regulatory agencies
Demonstrating clinical similarity
Pharmacovigilance, traceability and naming
Rigorous pharmacovigilance is essential for all biologics to protect patients and ensure any adverse events are quickly detected, reported and attributed to the correct product and manufacturer.8,9 The ability to identify biologic medicines, including biosimilars through all of the systems linked to pharmacovigilance is critical to enhancing patient safety.9,10 Distinguishable, unique product identifiers for biological products should be used to facilitate accurate prescribing, dispensing and pharmacovigilance.9
References
  1. US Food and Drug Administration. Development of Therapeutic Protein Biosimilars: Comparative Analytical Assessment and Other Quality-Related Considerations. Silver Spring, MD: US Food and Drug Administration; 2019.
  2. Markus R, Liu J, Ramchandani M, Landa D, Born T, Kaur P. Developing the Totality of Evidence for Biosimilars: Regulatory Considerations and Building Confidence for the Healthcare Community. BioDrugs. 2017;31:175-187.
  3. European Medicines Agency. Biosimilars in the EU Information guide for healthcare professionals. London, UK: European Medicines Agency; 2017.
  4. US Food and Drug Administration. Scientific Considerations in Demonstrating Biosimilarity to a Reference Product. Silver Spring, MD: US Food and Drug Administration; 2015.
  5. European Medicines Agency. Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues. London, UK: European Medicines Agency; 2014.
  6. Lai Z, La Noce A. Key design considerations on comparative clinical efficacy studies for biosimilars: adalimumab as an example. RMD Open. 2016;2:e000154.
  7. Alten R, Cronstein BN. Clinical trial development for biosimilars. Semin Arthritis Rheum. 2015;44:s2-s8.
  8. Felix T, Johansson TT, Colliatie JA, Goldberg MR, Fox AR. Biologic product identification and US pharmacovigilance in the biosimilars era. Nature Biotech. 2014;32:128-129.
  9. US Food and Drug Administration. Nonproprietary Naming of Biological Products. Silver Spring, MD: US Food and Drug Administration; 2017.
  10. Mellstedt H, Niederwieser D, Ludwig H. The challenge of biosimilars. Annals of Oncology. 2008;19:411-419.
4. Demonstrating clinical similarity
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1Characterization of the reference product defines the target biosimilar profile

Addressing the
knowledge gap

Identification of CQAs
in eight categories

Establishing
manufacturing parameters

References

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