unusual that the scope for microheterogeneity in biosimilars is narrower than theoretically acceptable. Step 3 The next step is the production of the biosimilar using the relevant set of complex biotechnology methods. First, different production clones are tested to determine to what extent they deliver products that are as similar as possible to the reference drug. Complex cycles of process variation and bioanalyses of the resulting products gradually lead to conditions that ensure the biosimilar resembles the reference drug in all aspects. This process is then specified in every conceivable detail and forms the basis for the production of all batches of the biosimilar according to the ‘the product is the process’ principle. Step 4 In the fourth step, the biosimilar is comprehensively checked – the ‘comparability exercise’. A key feature of this step is that all tests are performed head-to- head between the biosimilar and the reference drug (which also applies to the required clinical study at the end of this comparison). This is also a sequential process. Biosimilar development Comparative quality In the first step, quality, structural agreement, physicochemical and biological comparabilities are assessed. Possible deviations from the data of the reference drug must be explained adequately. Furthermore, the purity of the biosimilar is checked. The product is only released if previously defined specification criteria are fulfilled (see Figure 1). Comparative non-clinical In the second step, biosimilar and reference drug are compared in a preclinical setting (usually in vitro testing) and the required tests are specified in product-specific guidelines issued by the EMA. The pharmacokinetic and pharmacodynamic parameters and their predefined degree of similarity with the reference drug must be justified and determined. Comparative clinical In the third step, clinical comparability is demonstrated. These studies have more of the character of safety studies than efficacy studies. If the initial comparability exercise proves that the biosimilars and reference drugs are sufficiently similar, then it can also be expected that they will be clinically equivalent. However, these clinical studies are mandatory in order to prove the tolerability of the biosimilars. The manufacturing processes of biosimilars and reference drugs are inevitably different, so that it cannot be ruled out that components that are difficult or impossible to identify analytically might provoke clinical abnormalities. Phase I clinical studies initially focus on toxicology, pharmacokinetics and pharmacodynamics (purity, safety, uptake, distribution and excretion) and a safety profile is established. This is followed by studies on efficacy and safety in terms of severity and frequency of various side effects. These are performed in one or more representative indications in order to demonstrate a comparable efficacy and safety, including a comparable immunogenicity profile for the biosimilar and reference drugs. The focus and requirements for these Phase III studies differ depending on the biosimilar class. However, in accordance with the diversity and complexity of biologic pharmaceuticals, the EMA defines the requirements individually and in accordance with the guidelines laid down for the manufacturers. Figure 2 summarises the processes for biosimilar and reference medicines. Conclusions Manufacturing a biosimilar requires significant expertise to ensure that it is ‘highly similar’ to the originator biologic with no clinically meaningful differences in safety, efficacy, or immunogenicity. This means extensively identifying and comparing the structural and functional properties of the biosimilar and selecting optimal cell lines for culture, scaling up, and purification of the protein. For a biosimilar, comparative structural and functional characterisation provide the greatest contribution to clinical predictability. FIGURE 3 Summary of processes for biosimilar and reference medicines 9 Risk management plan Risk management plan Clinical studies: • Safety and efficacy • PK/PD • Immunogenicity Comparative clinical studies: • Safety and efficacy • PK/PD • Immunogenicity Comparative non-clinical studies Non-clinical studies Pharmaceutical quality studies Comparative quality studies Reference medicine 6 | 2019 | hospitalpharmacyeurope.com Biosimilar medicine Pharmaceutical quality studies References 1 Staub A et al Intact protein analysis in the biopharmaceutical field. J Pharm Biomed Anal 2011;55:810–22 2 Kirchhoff CM. Biosimilars: Key regulatory considerations and similarity assessment tools. Biotechnol Bioeng 2017;114:2696–705. 3 Vezer B et al. Authorized manufacturing changes for therapeutic monoclonal antibodies (mAbs) in European Public Assessment Report (EPAR) documents. Curr Med Res Opin 2016;32:829–34. 4 European Medicines Agency. Guideline on comparability of biotechnology-derived medicinal products after a change in the manufacturing process. www. ema.europa.eu/docs/en_GB/ document_library/Scientific_ guideline/2009/09/WC500003935. pdf (accessed September 2018) 5 Weise M et al. Biosimilars: what clinicians should know. Blood 2012;120:5111–17. 6 Weise M et al. Biosimilars: the science of extrapolation. Blood 2014;124:3191–6. 7 European Medicines Agency. Committee for Medicinal Products for Human Use (CHMP): Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: quality issues (revision 1). www. ema.europa.eu/docs/en_GB/ document_library/Scientific_ guideline/2014/06/WC500167838. pdf (accessed September 2018). 8 Vulto AG, Jaquez OA. The process defines the product: what really matters in biosimilar design and production? Rheumatology (Oxford) 2017;56(Suppl 4):iv14–iv29. 9 European Medicines Agency. Biosimilars in the EU: Information guide for healthcare professionals. www.ema.europa. eu/docs/en_GB/document_ library/Leaflet/2017/05/ WC500226648.pdf (accessed September 2018).