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26 BioPharm International ® Emerging Therapies eBook September 2024 www.biopharminternational.com Development The regulatory approval step The biology of a therapy, especially gene therapies, is different, which causes challenges in manufacturing, according to Macedone, and some of these challenges are created in early stages of pre-clinical process de- velopment and scale up. "It's important to mitigate those variables to the [highest] extent possible," says Macedone. "Having choices across a variety of pa- rameters—adherent versus suspension cell culture, transfection reagents, downstream purification in columns versus centrif ugation, and others—is an effective way to model optimal yields in process de- velopment that will carry through scale up." Compared to traditional dr ug products, emerg- i ng t her apies h ave shor ter de ve lopment t i mes, accord i n g to P i n aud . T he y a l s o re qu i re h ig he r quantities and doses. "This is especially true when electable for condit iona l or accelerated approva l upon unequivocal [Phase II] data, eliminating the need for [Phase III] development to get approval," says P i naud. "But t h is ca n mea n t hat ea rly CMC work and process readiness (f ull spectr um of val- idated analytical methods; validated process; suf- f icient stabi l it y a nd process robust ness suppor t- ing data, etc.) may not be complete, which creates a gap. In other modalities, this investment is done in parallel to [Phase III] development. So even if an emerging t herapy has positive [Phase II] clin ica l outcome, they cannot be so easily approved due to lack of CMC readiness." T he cont i nuou s e volut ion of r eg u l a t ion s f or e me r g i n g t he r apie s c r e a t e s u nce r t a i nt y a b out reg u l ator y e x p e c t at ion s, s t ates P i n aud . "O p e n communication with regulators is therefore essen- tia l, and t his is anot her time when work ing wit h a CDMO that has established relationships can be advantageous." The road to the patient "Emerging therapies generally have smaller patient pools that cannot 'justify' high development costs," Pinaud cautions. "These advanced modalities are still in early maturity, and we have not solved the prob- lems of complex and high-priced manufacturing. Be- cause many of these therapies need high doses, this results in high drug price tags, which rolls downhill into healthcare reimbursement issues." Problems that may arise that would impede a new emerging therapy getting to the patients that need them could be lessened by during the work early to ensure regulatory compliance and to mitigating risk, according to Macedone. "Investing time and resources in process and analytical development helps to ensure consistent execution in GMP clinical and commercial manufacturing down the road. It can prevent errors and deviations that can delay or reject manufacturing runs and product releases," says Macedone. "There can also be supply chain challenges," says Pinaud. "For instance, with gene therapies, formula- tions for viral vectors typically require deep/ultra-low temperature freezing and these are often not avail- able in smaller clinical centers. Access then becomes an issue for larger indications with less centralized treatment options." "[E]stablishing a robust supply chain with rigor- ous qualification and audit standards, secondar y suppliers to establish redundancy wherever possi- ble, and a rational planning and inventory manage- ment procedure are all ways to help avoid disruption in vendor performance and raw material delivery," says Macedone. "Finally, building a culture of quality that permeates the organization is an important way to ensure that disruptions in production are avoided at the outset," he concludes. Q Complying with GMP [good manufacturing practices] requirements is not negotiable ... — Wade Macedone, Andelyn Biosciences DRUG DIGEST: Delving into Biopharmaceutical Development and Manufacturing In this exclusive Drug Digest video interview, Felicity Thomas, Associate Editorial Director, Pharmaceutical Technology® Group, interviews experts from Biosynth and the University of Maryland about biopharmaceutical drug development and manufacturing. During the discussion, Hans de Backer and Peter Timmerman from Biosynth and Anupreet Kaur from the University of Maryland go into detail about the evolution of biopharmaceutical development, highlighting challenges and potential future trends. Additionally, the intricacies of monoclonal antibodies and the complexity of the supply chain are explored.