The Road to Commercialization: A CDMO Perspective

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Richard Richieri, chief operations officer, Avid Bioservices

Avid has manufactured biologics since the early 1990s. Its early phase and late-phase projects (including commercial biologics) are approved in 90 countries. The company uses 2,000-L single-use bioreactors (three units), two 1,000-L bioreactors, and a few smaller ones, all in single-use configurations. Avid is expanding and will add six 2,000-L single-use bioreactors to its facility.

Richieri spoke about the road to biologics commercialization from Avid’s perspective as a contract development and manufacturing organization (CDMO), beginning with process validation: the collection and evaluation of data from the design phase through commercial production. Through the early stages of building and capturing knowledge, a company determines the basic process-control strategy it plans to use. A company needs to know its cell culture expansion criteria, product quality profile (cell-growth information), and viability profile. Bioreactor controls also are important as a company gains early knowledge of temperature, dissolved oxygen, pH, set points and parameters, and harvestability criteria. In phase 1, basic viral clearance studies usually use model viruses in duplicate to develop good orthogonal methods of removing and inactivating viruses. Flow rates are monitored to ensure that product is going through the column at an acceptable flow rate and that residence times in process development are equivalent to those in manufacturing. Avid ensures that every reactor configuration is the same, using identical bioreactor controllers and bioreactor units and applying design of experiment (DoE) studies to confirm that conditions are equivalent. The more that is known at small scale about kinetics and some of the mixing characteristics of different size reactors, the easier it is to scale up the process. Range-finding studies are critical toward finding optimal conditions for growth and productivity. Through those studies, a manufacturer develops a data set, the parameters of which carry over into manufacturing to compare ranges determined by the small-scale design space.

As a process proceeds into clinical trials, a manufacturer takes a “deeper dive” into process qualification for work at scale, continuing its process validation. The company performs risk analysis of its facility, equipment, and design and qualifies its utilities. Preapproved protocols will set predefined specifications and acceptance criteria. The process is run at scale with extensive testing at different time points, challenging every critical item to find and address weak points. Support studies happen at this time, examining median mixing times, end-of-production cell stability, and inoculum expansion robustness. For downstream support, a company examines buffer mixing, extractables and leachables related to product-contact films, carry over, process hold times, membrane sanitization, resin lifetime, buffer hold times, and virus validation (removal and inactivation). Other supporting activities include final container–closure studies, shipping validations, and raw-material evaluations. All studies eventually are combined into one process validation program. Richieri offered case studies of performance qualification at scale to determine critical process parameters, critical quality attributes, and acceptance criteria.

He showed examples of activities occurring during process validation and spoke about challenging resins to determine how well they remove viruses over repeated cycles. He also spoke about the importance of showing that there is no carryover in large-scale purification columns from one batch to the next. Additional qualification tasks include simulating small-scale work to show that a resin can handle many cycles and testing for impurities, recoveries, and yields. Final steps include ensuring that in-process holds can last as long as possible.

Given the large numbers of samples in process validation programs, Richieri emphasized the project-management challenges of coordinating between different groups internally and externally. He ended by reviewing key process monitoring activities during commercial manufacturing. Examples of those activities include trending growth and product quality and ongoing monitoring of critical parameters. Numerous tasks in process qualification require close coordination with a client, a CDMO, and all external suppliers and testing facilities. Continuous process verification offers the chance to reduce the number of tests to those that monitor key critical parameters. All results must ensure that the final process is robust and reproducible.

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