Article Text

A8.31 Authorised manufacturing changes of therapeutic monoclonal antibodies in EPAR documents
  1. Z Zrubka,
  2. B Vezer,
  3. M Sebeszta
  1. Egis Pharmaceuticals Plc, Budapest, Hungary


Background and objectives The European Medicines Agency (EMA) has authorised biosimilar infliximab in September 2013 for use in the same indications as of the originator reference product. The approval of the first biosimilar monoclonal antibody (mAb) has brought the variability of biological medicines into the attention of practicing clinicians.

The quality attributes of biotechnology products are subject to change as a result of manufacturing process changes following the initial authorisation. According to the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) Q5E guideline,1 a comparability exercise should provide analytical evidence that such product changes have no adverse impact on product safety or efficacy, including immunogenicity.

Biosimilar development is based on the comparability exercise. The authorisation process has been detailed in the European Public Assessment Report (EPAR) of biosimilar infliximab. Schneider2 has published the number of manufacturing changes since the initial approval of 11 originator monoclonal antibodies and fusion proteins used in rheumatology indications.

However, the manufacturing changes of all monoclonal antibodies authorised by EMA have not been systematically analysed. The aim of our research is to collect and thoroughly investigate the number and types of manufacturing changes of originator mAbs according to their EPAR documents.3

Materials and methods Biotechnology products, authorised by EMA have their own publicly available EPARs with chronologic reports named “Procedural steps taken and scientific information after the authorisation”. 29 publicly available EPAR reports covering the period between 1998 and September 2014 were collected and evaluated.

Manufacturing changes were categorised in low/medium/high risk according to Lee et al.4

Results Until September 2014, 404 manufacturing changes were documented in therapeutic mAbs’ EPAR documents. 22 high risk, 286 medium risk and 96 low risk manufacturing changes were authorised by EMA.

Conclusions Variability is a common feature of biological medicines. The scientific principles of assessing manufacturing process changes of mAbs are well established and based on comprehensive state of the art physicochemical, analytical and functional comparative assessments. Prior the authorisation of the first biosimilar mAb, EMA evaluated extensively the manufacturing process changes of originator mAbs, and gained significant experience.


  1. ICH Q5E: Comparability of Biotechnological/Biological Products Subject to Changes in Their Manufacturing Process.

  2. Schneider CK. Ann Rheum Dis 2013; 72 :315–318.

  3. EPAR – Procedural steps taken and scientific information after authorisation.

  4. Lee JF, Litten JB, Grampp G. Comparability and biosimilarity: considerations for the healthcare provider. Curr Med Res Opin 2012; 28 (6):1053–1058.

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