HPE Viatris Handbook | Page 8

present at trace levels , it is still necessary for them to be both identified and quantified . 8 – 10

For hetero-proteins secreted by the host cell , such as antibodies , the extraction process will be easier because a simple filtration makes it possible to separate the culture medium containing the target protein from the producing cells . 11 – 13 This medium therefore contains fewer HCPs even if the lyses produced during the cell / cell medium separation operations can release HCPs . For IgG antibodies , purification is greatly facilitated by the technique of affinity chromatography on Sepharose A which specifically binds the antibodies and subsequent intensive washings of the column eliminates almost all of the HCPs . A final elution with an adequate buffer leads to excellent yields .

Affinity chromatography was not available for use on an industrial scale until around the millennium . 14 As many of the biosimilar originators were developed during the 1980s and 1990s it is likely that the originators were actually less purified and contained more HCPs than the biosimilars . For example , batches of the originator rituximab ( Mabthera™ ), manufactured before 2010 were shown to contain more basic ionic variants than those manufactured later , indicating that the manufacturer had dramatically modified its purification process during the product life . 15

Biosimilars have also benefited from the stringent requirements of the regulatory authorities compared to originators especially with respect to residual HCPs and the level of protein aggregation . 12 , 13 In fact , when monoclonal antibodies were first commercialised , the issue of protein aggregates was largely underestimated and considered to be corrected , if it occurred , by ion exchange chromatography at the production level and by simple online filtration during administration . 16 However , highlighting problems linked to submicron size aggregates , such as the need to eliminate viral contaminants , has led the regulatory authorities to require that , prior to issue of a marketing authorisation , all new therapeutic proteins , including biosimilars , undergo detailed analysis of aggregate profiles as well as the means of avoiding pollution by viruses , which can be resolved through nanofiltration . As with affinity chromatography , this method was not widely available industrially during the development of originators and rarely used , except for blood-derived products .

The production processes can also induce alterations of the final product . Aggregation can occur , especially when the proteins are exposed to a triple interface , i . e ., the walls of any tubes and containers , liquid and gas . The liquid / gas interface is particularly harmful for some antibodies sensitive to aggregation such as cetuximab . 17 Therefore , any change in the production process such as the use of new reactor , filtration unit or pumping device requires careful validation and needs to be declared to the regulatory authorities . These minor alterations to the production process probably explain why , for example , there were a reported 15 ( bevacizumab ) and 50 ( infliximab ) changes to the manufacturing of monoclonal antibodies during the product life . 18 These changes are categorised as high , medium and low risk and demonstrate that a biological product , regardless of whether an originator or biosimilar , can exhibit batch-to-batch variability .

A critical quality attribute is a physical , chemical or microbiological property that should be within an appropriate limit to ensure the desired

The manufacture of biosimilars is a complex process that requires significant expertise and a high level of quality control quality of the biosimilar . Each CQA must be considered within a pre-defined variable range . 19 By definition , for a biosimilar approved in Europe or the US , each CQA must fall into the corresponding reference product ’ s range ( comparability exercise ) and , thus , biosimilars are non-inferior to the corresponding reference . Furthermore , with advancements in analytical methodology and the variability of some CQAs seen with older reference products , it can be argued that biosimilars represent a much higher quality product . This view could be espoused by pharmacists to encourage uptake of biosimilars and more widely embrace their use as high quality and safe alternatives .

Conclusion The manufacture of biosimilars is a complex process that requires significant expertise and a high level of quality control to ensure that the product is ‘ highly similar ’ to the reference biologic and without any clinically meaningful differences in safety , efficacy , or immunogenicity . Advances in analytical technics have allowed for the selection of optimal culture cell lines as well as upscaling and purification processes for the target protein . Taken together , these changes will provide reassurance to both prescribers and patients that a biosimilar will provide an equivalent clinical effect to the RP and smooth the transition process , enabling the treatment of more patients and a reduced drug expenditure for healthcare providers .