BioPharm June eBook: Single-Use Systems

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12 BioPharm International eBook June 2018 with biosimilar manufacturing, adds Ultee. "For example, cell lines and processes that may be high yielding may need to be set aside in favor of others that produce a more closely similar protein to the original. These challenges can be addressed by a combination of upfront high- throughput screening to allow bet- ter clone and process selection and strong analytics for tight process con- trol in manufacturing." Once biosimilar developers have completed extensive characterization of the reference product, based on the knowledge of the reference prod- uct's manufacturing process, they can attempt to reverse-engineer the manufacturing process. However, the challenge then becomes the inevita- bility that they will be constrained by old bioprocessing systems as they attempt to follow it meticulously, according to Sleep. "Moreover, as biosimilars are inherently targeting smaller markets because they com- pete against the established reference product and other biosimilars, the temptation is to incorporate advances in manufacturing to increase expres- sion yields and streamline processes to reduce costs and maximize operat- ing profit. However, it is well known that even relatively minor changes to processes can alter substantially the molecule produced, particularly regarding product- and process- related impurities," Sleep says. "The challenge is therefore to balance the risk of developing a lower- cost manufacturing process while being able to demonstrate that the biosimilar developed is highly similar to the reference product and shows no clinically meaningful differences to the reference product in terms of safety, purity, and potency," he adds. Biobetters, however, generally have no need to demonstrate adequate similarity to the reference product at the structural and in-vitro function levels. "Instead there is a reliance on providing clinical evidence to sup- port every claim. Unlike biosimilars, there is no possibility to extrapo- late from the trial indication to all indications for which the compara- tor is approved and clinical studies will need to be performed in each indication for which licensure is requested," says Nick. "Unlike the original product, it will likely be no longer ethical to undertake placebo-controlled trials, meaning multiple non-inferiority studies will be required leading to the need for a much larger clinical study program than was required for the original product," he continues. For a biobetter, the technical chal- lenge revolves around the need to make the end product sufficiently better than the original such that medical professionals will switch from the original product with a proven history to the new biobet- ter, comments Ultee. "This challenge can be addressed by strong research, including lab and animal data as well as convincing clinical results." Unlike biosimilar developers, biobetter developers can take full advantage of the latest innovations in manufacturing technologies that are designed to optimize biopro- cessing because a biobetter will be classed as a new biological entity, Sleep points out. "In addition, there is an opportu- nity to address multiple deficiencies in the existing approved biologic. For example, it may be advantageous to remove known proteolytic cleav- age sites or known sites of immu- nogenicity by protein engineering or mask them by conjugation to polyethylene glycol (PEG). If the approved biologic has a propensity to aggregate which then limits the drug presentation, the formulation, or increases the risk of an immuno- genic reaction, protein engineering can be used to screen for variants with a reduced aggregation profile, reducing the immunological risk and creating the opportunity for new more stable formulations and pre- sentations, such as liquid prefilled syringes," Sleep adds. Depending on the intended indi- cation, the biobetter developer may also decide that the therapeutic index of the approved biologic could be improved by extending its circula- tory half-life. "This can be achieved by various techniques, including the chemical attachment of PEG to increase the hydrodynamic radius (size) to reduce elimination via kid- ney filtration. An alternative and more elegant approach is to apply protein fusion technology to a pro- tein with an intrinsically long cir- culatory half-life such as albumin, transferrin, or the Fc portion of IgG [immunoglobulin]," Sleep says. He goes on to explain that, while these three proteins fall above the kidney filtration limit, albumin and IgG have an additional advantage in that they have the longest circu- latory half-life of any plasma pro- teins, approximately three weeks, due to their additional interaction with the FcRn receptor, which sig- nificantly extends their half-life. "The introduction of platform half- life extension fusion technologies such as Fc or albumin fusions lends itself to platform purification pro- cesses whereby albumin or the Fc portion of IgG act as a purification tag, thus simplifying the purification processes and reducing development time and production costs." REFERENCES 1. FDA, "Biosimilar Development, Review, and Approval," Drugs/DevelopmentApprovalProcess/ HowDrugsareDevelopedandApproved/ ApprovalApplications/ TherapeuticBiologicApplications/ Biosimilars/ucm580429.htm, accessed Mar. 14, 2018. 2. Biosimilars Resource Center, "What is a Biobetter?", www. what-is-a-biobetter/, accessed Mar. 14, 2018. BP Single-Use Systems Manufacturing

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