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10 BioPharm International eBook June 2018 www.biopharminternational.com s id e c h a i n s . A ny d i f f e r e nc e s between the biosimilar and the reference product need to be jus- tified," states Cecil Nick, vice-pres- ident, Biotechnology, at PAREXEL Consulting, the consulting divi- s io n o f PA R E X E L , a c ont r ac t research organization (CRO). To create an improved version of a reference product, a biobetter can be developed by using an improved delivery system, improved formu- lation, or other modification that enhances efficacy and safety. If the molecular structure of the active ingredient is altered in any way, how- ever, then it would be considered a related, but new, molecular entity. "Typical improvements would be longer half-life, higher potency, or reduced side effects," says Michiel E. Ultee, PhD, principal, Ulteemit BioConsulting. Biosimilars require less money and time to develop because they have an abbreviated approval path- way. "However, proving that a bio- similar meets the criteria set out in the Biologics Price Competition and Innovation Act (BPCI) is not a simple task, especially if develop- ers wish to take advantage of new and more efficient expression sys- tems and manufacturing processes," says Dr. Darrell Sleep, chief scientific officer, Albumedix, a biotherapeutics company specializing in albumin- based products and technologies for advanced drug and vaccine formula- tion and drug delivery. "For example, the establishment of the reference product cell bank is a unique event and cannot be replicated. The biosimilar will also require extensive product analysis to demonstrate its high degree of bio- equivalence. Information attained through an extensive structural and functional characterization of the ref- erence product including primary and higher-order structure, post- translational modifications, product- and process-related impurities, pro- tein formulation/aggregation and in vitro/in vivo activities will form the basis of the biosimilar development," Sleep adds. Biobetters are meant to improve the pharmacological profile of the original reference biological prod- uct. Biobetters offer drug developers the advantage of an entirely new biological entity interacting with an already therapeutically validated biological target. "Biobetters therefore build on the success of existing approved biolog- ics while addressing their suboptimal performance by providing enhanced safety, efficacy, tolerability, or a bet- ter dosing regimen resulting from known in vitro or in vivo chemical or structural instability, product het- erogeneity, immunogenicity, high drug doses, frequent administrations, suboptimal route of administration, off-target toxicity/adverse events, sub- optimal selectivity, suboptimal speci- ficity, a suboptimal formulation in terms of handling before or during administration to the patient, poor bioavailability, lack/suboptimal of targeting to disease site, and short half-life leading to either high-dosing frequency or large-volume dosing resulting in unwanted toxicity, which then has to be managed or accepted by the patient if there is not suitable alternative therapy," says Sleep. Improvement over the reference biologic can be done by, for example, structural changes to the original biologic by chemical modification, improving the post-translation modi- fication profile, introducing amino acid modification/substitutions, extending the circulatory half-life, or developing an improved formula- tion/presentation, Sleep adds. MANUFACTURING STRATEGY Biobetters have somewhat different manufacturing strategies than bio- similars because biobetters do not have to exactly match the reference biological entity. "In the case of bio- similars, the manufacturing strategy is to some degree straight-jacketed by the need to maximize similarity to the reference product," notes Nick. "Thus, the practice has been to use the same host-cell species as the orig- inator in order to maximize similar- ity and then to hone the process to further minimize differences even at the expense of a reduced yield." However, biobetters do not have to deal with such restrictions, and new expression systems with better pro- ductivity can be introduced, which would reduce costs. An example is glyco-engineering technology, which has allowed for bacteria, yeast, and fungi to be modified to glycosylate proteins in the desired way. "Since productivity can be higher and costs lower, these represent attractive manufacturing alterna- tives. Changes downstream from the fermentation process have far less impact on product structure, and therefore, downstream pro- cess improvements can be applied similarly to both biosimilars and biobetters, although, in the case of biosimilars, more caution is required to ensure no clinically meaningful changes are introduced," Nick says. A biobetter is based on the same fundamental mechanism of action of the therapeutic, Ultee points out, but the molecular structure can be dif- ferent, with the possibility of amino- acid sequence changes as well as changes in post-translational modifi- cations. The manufacturing strategies for biobetters have more flexibility than those for a biosimilar, because with a biobetter, one is not making a nearly identical copy of an existing protein drug. "Manufact ur ing a biosimilar requires constant comparison to the reference product through the manufacturing process to ensure that process variations do not cause Single-Use Systems Manufacturing