BioPharm

www.biopharminternational.com October 2018 BioPharm International eBook 11 must be tested to determine the degree of preclinical and clini- cal studies that may be needed to bridge the potential uncertainties (e.g., immunogenicity) that cannot be addressed by analytical tests alone. Under the 'totality of evi- dence' concept, the approvability of a biosimilar does not rely on additional analytical studies alone to ensure biosimilarity. Unlike a generic, it is impos- sible for a biosimilar to show that its quality attributes are identi- cal to the reference product due to t he i n herent comple x it y of protein molecules. In fact, all of the biosimilars approved in the United States are considered by current legislation to be new bio- logical products without official interchangeability with the refer- ence product. FDA has indicated that interchangeability likely will be handled in the post-approval setting. However, this is a topic u nder sig n i f ic a nt a nd leng t hy d i sc u ssion w it h i n t he age nc y. The EMA does not address inter- c ha ngeabi l it y nor subst it ut ion in its g uidance documents, but r at he r le ave s it to i nd iv idu a l European Union member states to further deliberate. ANALYTICAL ADVANCES B i o Ph a r m: W hat adva nces have there been to either analy tical equipment, technique, methodol- ogy, or approach to support bio- similar it y testing in biosimilar products in development? Tabler (PPD Laboratories' bioana- lytical lab): Due to potential minor structural differences between a biosimilar and innovator prod- uc t, t here has been debate on whether a single PK immunoassay could be used to assess biosimilar- ity. Our early approaches in 2010 used separately validated assays for each analyte. The alternative was to use a single assay, with the biosimilar as the reference stan- dard and the approved product(s) crossed into the assay. Advantages of the single assay approach were many. In addition to simplif y ing data inter preta- tion, it allowed for blinded study sample analysis without doubling the number of samples analyzed. The single assay approach became the standard in the industry after 2014 when the uniform approach for de te r m i n i ng bio a na ly t ic a l biosi m i la r it y recom mended by Marini et al. (3) became widely adopted. For i m mu noge n ic it y a s s ay s, the current industry practice is also to use a single assay, w ith t h e b i o s i m i l a r a s a c a p t u r e reage nt (a nd a s t he con f i r ma- tory drug) when assessing anti- d r ug a nt ib o dy (A DA) for b ot h the biosimilar and the approved products. Using this approach is considered reasonably risk-based, a s sa fet y a nd i m mu nogen ic it y have presu mably a l ready b een assessed for the innovator. Evolutions in signal amplifica- tion and dissociation techniques have led to significant improve- ments in sensitiv it y for immu- noassays suppor ting PK and in drug tolerance (ability to detect A DA s i n t he pr e s e nc e of bio - logic drug) for immunogenicit y assays. T his adds value to data generated, but can be challeng- ing when contemporar y results for the biosimilar are compared to historical data for the innova- tor. Advances in equipment and software have also led to improve- ments in automation, both in the laborator y and in data process- ing. Automation has been key in allowing ligand-binding assays to meet the intense throughput and turnaround requirements of bio- similar studies. REFERENCES 1. J. Yuan, W.W. Xu, and H.F. Poon, Int J Biopharm Sci. online, DOI: 10.31021/ ijbs.201811091, May 24, 2018. 2. S. Berger, "How Analytical Technologies Support the Development of Biosimilar Drugs," blog.waters.com/how-analytical- technology-supports-the-development-of- biosimilar-drugs, Jan. 12, 2017. 3. J.C. Marini et al., The AAPS Journal 16 (6) 1149–1158 (2014). BP Biopharma Laboratory Best Practices Biosimilar Analysis "All of the biosimilars approved in the United States are considered by current legislation to be new biological products without official interchangeability." —Wu, PPD Consulting "Advances in equipment and software have also led to improvements in automation, both in the laboratory and in data processing." —Tabler, PPD Laboratories

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