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Biologic and biosimilar manufacturing requires rigorous quality control.1

Exacting standards and tight specifications are followed at every stage. Continuous quality checks during manufacturing are essential.2

Biologics and biosimilars are produced using a sophisticated, highly technical, multistep process.2,3

  • Step 1 Small Scale

    A high-quality biologic or biosimilar is cultured and extracted from living cells by a robotics system

  • Step 2 Large Scale

    The biologic or biosimilar cells are grown to significant volume in bioreactors

  • Step 3 Purification

    The biologic or biosimilar goes through multiple purification steps, such as filtration and chromatography

  • Step 4 Packaging

    The biologic or biosimilar is securely packaged in sterile vials, syringes, or auto-injectors

Because biologics and biosimilars are cultured from living cells…

Minute variations are expected from batch to batch.4

In fact, differences between batches are natural and expected. Even in a reference biologic, no 2 batches are perfectly alike. That’s why it’s impossible to make an exact copy, and why the term “generic” cannot be applied to biosimilars.4-6

Quality control continues…

State-of-the-art technology is used to extensively analyze the structure, function, and chemical identity of both the biosimilar and the reference product to demonstrate that they are highly similar4:

Assays and other tests have evolved over the years, becoming far more sensitive.24 In fact, today’s assays are so sensitive, a biosimilar maker can often characterize the reference molecule more fully than when it was introduced.25

Close

Amino acid analysis

A biochemical technique to determine a protein’s primary structure.7

Peptide mapping

Protein is broken into discrete peptides for pattern analysis.8

Mass spectrometry

A test that separates isotopes, molecules, and molecular fragments according to mass.9

Nuclear magnetic resonance

Examines the structure of organic compounds based upon the characteristic spin states of the nuclei they contain and the magnetic fields they generate.10

X-ray crystallography

Determines 3-dimensional molecular structure by crystallizing a purified sample at high concentration, and the crystals are exposed to an x-ray beam.11

CD spectroscopy

Circular dichroism (CD) spectroscopy accurately estimates the secondary structure for a broad range of proteins.12

Neutralization assay

Aids in assessment of immunogenicity during biosimilar development.13

Surface plasmon resonance

A technique that measures molecular changes in close proximity to a specially prepared surface.14

Target binding

Assays used to assess and quantify the binding capacity of a biologic to its target(s).15

CDC assay

Characterizes antibodies through the presence and quantification of complement-dependent cytotoxicity (CDC) activity.16

ADCC assay

Characterizes antibodies through the presence and quantification of antibody-dependent cell-mediated cytotoxicity (ADCC) activity.16

Reverse signaling apoptosis bioassay

An assay used to assess apoptosis and activity as part of characterization of biosimilar molecules.17

Enzyme-linked immunosorbent assay (ELISA)

Assays that change color to identify a substance and measure concentration of antigens or antibodies.18

Analysis of post-translational modifications

Post-translational modifications influence the structure, stability, function, and interactivity of a protein.19

Fluorescence

Bound antibodies react with fluorescence-labeled anti-human immunoglobulin G (IgG) antibodies to show where antibodies from the patient are present.20

Isothermal titration calorimetry (ITC)

Measures the heat that is generated when molecules bind with one another.21

Ion-exchange chromatography

Separates molecules based on their net charge using resins.22

Ultraviolet absorption testing

Measures higher-order structure of proteins by monitoring signals from their amino acids.23

The result? Reliable, quality medicines with no clinically meaningful differences.

Compare profiles…

Similar N-glycans by oligosaccharide mapping (HILIC HPLC).26
In this test, the profile of the biosimilar (bottom) matches different batches of the reference biologic so closely they resemble duplicate house keys—and fit the same “lock,” the receptor site in the human body.

Small Scale Small Scale

Acceptable variation…

In vivo activity of 20 consecutive batches of a common biologic medicine.27

Biological activity (units/mg) Batch of drug substance 1234567891011121314151617181920150,000100,00050,0000AcceptableVariation

Same where it counts…

Same where it counts Same where it counts

Conclusion: A biosimilar medicine is proven to have no clinically meaningful differences from its reference biologic in safety, potency, and purity.5

“Minor differences in clinically inactive components are acceptable. Any differences between the proposed biosimilar product and the reference product are carefully evaluated by FDA to ensure the biosimilar meets FDA’s high approval standards.” 4

—US Food and Drug Administration

Boehringer Ingelheim:
Time-tested quality

While the field of biologic medicines has grown tremendously, Boehringer Ingelheim has over 35 years of biologic manufacturing experience,29 a number few can match. We continue to devote our time and resources to furthering the quality of our medicines—developing innovative new treatments, improving the highly technical manufacturing process, and expanding our global facilities to meet the demand.

References:
  1. 1. US Food and Drug Administration website. Biosimilar product regulatory review and approval. https://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/UCM581309.pdf. Accessed December 18, 2017.
  2. 2. Ryan AM. Frontiers in nonclinical drug development: biosimilars. Vet Pathol. 2015;52(2):419-426.
  3. 3. Boehringer Ingelheim. The biotechnology manufacturing process at a glance (e.g. manufacturing of antibodies). https://www.bioxcellence.com/about_us/about_biotechnology/manufacturing_process_glance.html. Accessed May 10, 2018.
  4. 4. US Food and Drug Administration website. Biosimilar and interchangeable products. https://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/ucm580419.htm#interchange. Accessed May 14, 2018.
  5. 5. Blackstone EA, Fuhr JP Jr. The economics of biosimilars. Am Health Drug Benefits. 2013;6(8):469-478.
  6. 6. Zezza D, Seamon K, Garnick R, et al. Biologics: can there be abbreviated applications, generics, or follow-on products? BioPharm Intl. 2003;16(7):1-6.
  7. 7. Biosynthesis website. Amino acid analysis/amino acid quantification. https://www.biosyn.com/amino-acid-analysis.aspx. Accessed July 6, 2018.
  8. 8. The Free Dictionary website. https://medical-dictionary.thefreedictionary.com/peptide+mapping. Accessed July 6, 2018.
  9. 9. Biosynthesis website. Mass spectrometry analysis. https://www.biosyn.com/mass-spectrometry-analysis.aspx. Accessed July 6, 2018.
  10. 10. Michigan State University website. Nuclear magnetic resonance spectroscopy. https://www2.chemistry.msu.edu/faculty/reusch/virttxtjml/spectrpy/nmr/nmr1.htm. Accessed July 6, 2018.
  11. 11. The Free Dictionary website. https://medical-dictionary.thefreedictionary.com/x-ray+crystallography. Accessed July 6, 2018.
  12. 12. Micsonai A, Wien F, Kernya L, et al. Accurate secondary structure prediction and fold recognition for circular dichroism spectroscopy. Proc Natl Acad Sci U S A. 2015;112(24):E3095-E3103.
  13. 13. Weislab website. Neutralization antibody assays. http://www.wieslab.com/bioanalytical-services/index.php?headId=191&pageId=200&subId=194&langId=1. Accessed July 6, 2018.
  14. 14. University of Leeds website. Biacore surface plasmon resonance (SPR) interaction analysis. http://www.fbs.leeds.ac.uk/facilities/biomolecular/spr.htm. Accessed July 6, 2018.
  15. 15. IBR website. Drug-target binding and ligand binding assays (LBA). https://www.ibr-inc.com/drug-target-binding/. Accessed July 6, 2018.
  16. 16. GenScript website. ADCC assay (SC1544) and CDC assay (SC1545) services. https://www.genscript.com/ADCC-and-CDC-assay-services.html. Accessed July 6, 2018.
  17. 17. Biocompare website. BioOutsource launches flagship reverse signaling apoptosis bioassay. https://www.biocompare.com/Life-Science-News/158357-BioOutsource-Launches-Flagship-Reverse-Signaling-Apoptosis-Bioassay/. Accessed July 6, 2018.
  18. 18. Weislab website. Enzyme-linked immunosorbent assay (ELISA). http://www.wieslab.com/bioanalytical-services/index.php?headId=191&subId=195&pageId=195&langId=1. Accessed July 6, 2018.
  19. 19. Intertek website. Post-translational modification analysis. http://www.intertek.com/pharmaceutical/biopharmaceuticals/post-translational-modifications/. Accessed July 6, 2018.
  20. 20. Weislab website. Indirect immunofluorescence. http://www.wieslab.com/bioanalytical-services/index.php?headId=74&pageId=103&subId=101&langId=1. Accessed July 6, 2018.
  21. 21. Nguyen T; Nicoya Lifesciences website. SPR, ITC, MST & BLI: what’s the optimal interaction technique for your research? https://nicoyalife.com/blog/spr-vs-itc-vs-mst-vs-bli/. Accessed July 6, 2018.
  22. 22. The Free Dictionary website. https://medical-dictionary.thefreedictionary.com/ion+exchange+chromatography. Accessed July 6, 2018.
  23. 23. Intertek website. Biophysical characterization of biologics. http://www.intertek.com/pharmaceutical/biopharmaceuticals/biophysical-characterisation/. Accessed July 6, 2018.
  24. 24. Fischer SK, Joyce A, Spengler M, et al. Emerging technologies to increase ligand binding assay sensitivity. AAPS J. 2015;17(1):93-101.
  25. 25. Dahodwala H, Sharfstein ST. Biosimilars: imitation games. ACS Med Chem Lett. 2017;8(7):690-693.
  26. 26. Data on file. Ridgefield, CT: Boehringer Ingelheim Biopharmaceuticals, Inc.
  27. 27. Brockmeyer C, Seidl A. Binocrit: assessment of quality, safety and efficacy of biopharmaceuticals. EJHP Practice. 2009;15:34-40.
  28. 28. Rugo HS, Linton KM, Cervi P, Rosenberg JA, Jacobs I. A clinician's guide to biosimilars in oncology. Cancer Treat Rev. 2016;46:73-79.
  29. 29. Boehringer Ingelheim BioXcellence™. Producing Value. Global Contract Manufacturing Excellence; November 2015.