Manufacturing biosimilars

Size matters: biologics are complex

Unlike small-molecule drugs, biologics are large, complex structures that are manufactured in living cells and have significant natural variability.


Adapted from Kozlowski S, Woodcock J, et al. New Engl J Med 2011;365:385–388

Abraham J, Semin Oncol 2013;40:S5–S24

Manufacturing changes occur frequently for biologics

Number of post-approval manufacturing changes to monoclonal antibody therapeutics (accurate as of October 2014)


Adapted from Vezer B, Buzáz S, et al. Curr Med Res Opin. 2016;32:829–834

Reference biologics undergo molecular changes due to process changes

  • Manufacturing process changes may result in changes to quality attributes2
  • Comparability exercises are required when major changes are made to the manufacturing process2
  • EMA and FDA have extensive experience in regulating comparability exercises3 
  • A changed process is typically approved without additional clinical trials, thereby extrapolating based on an analytical comparability exercise3

Changes detected by CEC in pre- and post-change batches of rituximab1

CEC=cation exchange chromatography


Adapted from Schiestl M, Stangler T, et al. Nat Biotechnol 2011;29:310–312; 

ICH Guideline Q5E, June 2005. Available from: Accessed 11th November 2019

Declerck P, and Rezk MF. Rheumatology (Oxford) 2017;56:iv4–iv13

Variability is commonplace for all biologics

Number of post-approval manufacturing changes to monoclonal antibody therapeutics (accurate as of October 2014)

Variability is inherent to biologic manufacturing:
no two lots are the same even when the process is “unchanged”1,2


Adapted from Ramanan S and Grampp G. BioDrugs 2014;28:363–372;

Schiestl M, Stangler T, et al. Nat Biotechnol 2011;29:310–312

Advanced technologies have led to improved characterisation of complex biologicals allowing development of high-quality biosimilars

For more information on manufacturing biosimilars, please see the following publications:

The process defines the product: What really matters in biosimilar design and production?

Rheumatology (Oxford) 2017 1;56

Critical quality attributes (CQA) of a biologic are subject to post-translational variations at the cellular and/or manufacturing level. One of the founding principles of the biosimilarity exercise is to closely match the biosimilar’s fingerprint with that of its reference product. Therefore, and in contrast to original biological agents, the emphasis in biosimilar development is on analytical and nonclinical attributes. The manufacturer's ability to provide consistent production and quality control will greatly influence the acceptance of its biosimilar products.

Authorized manufacturing changes of therapeutic monoclonal antibodies (mAbs) in European public assessment report (EPAR) documents

Curr Med Res Opin 2016;32:829–34]

This study investigated number and types of manufacturing changes for originator monoclonal antibodies based on European Public Assessment Report documentation and ascertained the level of risk these changes might impart. The study highlighted EMA's significant experience of process changes for originator monoclonal antibodies and the impact they may have on the efficacy and safety of biologicals. This experience is valuable for biosimilar product development.


The focus of biosimilars development is not to establish benefit:risk but to demonstrate similarity to reference product. 

Replicating highly complex biologics has been made possible due to enormous analytical advances

Various methods contribute to a quality attribute fingerprint of the reference drug


Adapted from: Berkowitz S, Engen JR, et al. Nat Rev Drug Discov 2012;11:527–540;

Adapted from: Lee C, Jeong M, et al. Mabs 2017;9:968–977;

Adapted from: Turner A and Schiel JE. Anal Bioanal Chem 2018;410:2079–2093;

Cho IH, Lee N, et al. MAbs 2016;8:1136–1155

During the manufacture of biologics

Reference product batches are continually analysed to define a product’s Quality Target Product Profile (QTPP)

Trend in HMW for batches of trastuzumab over time

The physicochemical and functional properties of a reference product should be characterised comprehensively and monitored periodically to establish the target quality profile used to demonstrate similarity in analytical attributes.1


Adapted from Kim S, Song J, et al. MAbs 2017;9:704–714.

Once a QTPP is confirmed confirmatory similarity studies are performed


Adapted from Vanderkerckhove K, Seidl A, et al. AAPS J 2018;20:68

Real-world evidence is necessary to address any outstanding questions that remain post‑authorisation

For more information on biosimilar manufacturing procedure, please see the following publication:

Acceptable changes in quality attributes of glycosylated biopharmaceuticals

Nat Biotechnol 2011;29:310–2

This study analyses the quality profiles of the glycosylated biologics darbepoetin alfa, rituximab and etanercept and debates acceptable variations in quality attributes. This data, sourced from the market between 2007 and 2010, provides examples of acceptable variations for products that have remained on the market with unchanged product labels.

Future optimisation of biologics treatment

Transfer of HCPs’ confidence could improve patient adherence

Results from a non-interventional, retrospective multicentre trial in Germany. 13 dermatologists participated in the study and completed physician questionnaires for 246 patients.

Dependency between HCPs’ agreement to given statements and their patients’ therapy adherence and vice versa.


Adapted from Zschocke I, Ortland C, et al. J Eur Acad Dermatol Venereol 2017;31:1014–20

For more information on challenges affecting biosimilar use, please see the following publications:

Treatment outcomes with biosimilars: Be aware of the nocebo effect

Rheumatol Ther 2017;4:209–218

The authors focus on the wide adoption of biosimilars, the re-emergence of the nocebo effect and the implications it may have on both patients and physicians’ perceptions as well as on treatment success. The authors also provide practical strategies and recommendations to raise awareness and to limit the nocebo effect.

Non-pharmacological effects in switching medication: The nocebo effect in switching from originator to biosimilar agent

BioDrugs 2018;32:397–404

This review investigates the nocebo effect, defining the term and considering it in the process of switching from originator products to biosimilars. Three strategies aimed at mitigating the nocebo effect are discussed: positive framing, increasing patients and HCPs understanding of biosimilars and managed switching programs.

Best practices:

For more information on totality of evidence, please see the following publication:

Evolution of the EU Biosimilar Framework: Past and Future.

BioDrugs 2019;33(6):621-634

The authors of this review focused on the nature and extent of clinical confirmation, in addition to analytical and functional data required by the European Medical Agency (EMA) for the approval of biosimilar products.

Biosimilars in the EU: Information Guide for Healthcare Professionals

Curr Med Res Opin 2016;32:829–34

Since the EU approved the first biosimilar medicine (‘biosimilar’) in 2006, the EU has pioneered the regulation of biosimilars. Over the past 10 years, the EU has approved the highest number of biosimilars worldwide, amassing considerable experience of their use and safety.
This guide has been jointly developed by the EMA and European commission with the objective of providing healthcare professionals with reference information on both the science and regulation underpinning the use of biosimilars.

Interchangeability of Biosimilars: A European Perspective

Eur J Clin Pharmacol. 2019;75(1):1-11

The introduction of biosimilars has shown that even complex proteins used for chronic disease treatment can be successfully copied. This in turn triggered discussions on aspects such as interchangeability between biosimilars and their reference products as well as immunogenicity profile of biosimilars.