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Accelerating product development

With biopharmaceutical companies under extreme pressure to move new products as quickly as possible into human clinical trials, developing a manufacturing process and producing sufficient quantities of clinical trial material represents a major critical path item standing between new discoveries and the first clinical trials. While a full CMC development

program can entail at least 24 months of intense effort resulting in a robust, scalable manufacturing process, the time and expense of such a program prior to proof-of-concept (POC) in humans is hard to justify. Therefore, many companies choose to focus on the speed with which they can develop a “good enough” manufacturing process to support initial clinical development. But what is “good enough?” Proper CMC development must result in products that are safe for use in humans and meet current regulatory guidelines for early stage clinical products. Since an “IND-enabling” manufacturing process does not need to be “commercially-enabling” or even suitable for the larger scales can short-cuts be taken in development that won’t impact safety or increase the risk of failure later due to manufacturing issues? Are new technologies that promise to shorten the time to GMP manufacturing but that are relatively untested worth the risk? What about royalty-bearing technologies that help meet these aggressive timelines?

Short-cuts in early development can include the use of “good enough” cell lines, which won’t support the number of generations or productivity needed for commercial scale, or purification processes incorporating non-scalable unit operations or with relatively low overall yields. Sub-optimal cell culture and purification processes early in product development are not unreasonable if the initial “good enough” process can be developed much more quickly than a fully optimized process. The benefit of this approach is that product candidates can enter clinical trials sooner, thereby reaching critical POC milestones sooner. If the product fails to show efficacy, its development can be terminated to enable scarce resources to be used for more promising pipeline candidates. This approach is not without some risk, however, as the strict regulatory requirements for product comparability must be maintained throughout development and commercialization requiring potentially expensive and time-consuming comparability programs to support manufacturing changes during and after clinical development and introducing the risk that a post-change product will NOT be comparable to the original product, requiring more clinical development than the budget and timeline had envisioned.

From both a technical and regulatory standpoint, a change in cell line is a very significant, posing the highest risk of changes in the resulting product. This risk could be mitigated by imposing strict criteria during screening for a replacement cell line later in development, for example, to increase productivity but still produce product with the same mix of glycoforms. Imagine the effort required, though, to screen hundreds of candidate new production cell lines for the same glycosylation pattern. A much more cost effective approach which de-risks the entire development program while adding little to the cost or time of the initial development program is to spend the time upfront to develop a commercially-viable production cell line. Companies seeking to avoid the cost of accessing new, proprietary technologies that enables rapid development of commercially suitable cell lines must decide whether to use a “good enough” cell line and face the inherent risks to comparability later or delay the initiation of clinical trials to complete development with traditional, non-royalty bearing technology. While each approach has been used successfully, the issue is really one of risk-tolerance, balancing the cost, time, and technical and regulatory risk of each pathway. To us, minimizing the risk of comparability differences by making a commercially-enabling cell line right from the start seems worth the cost of accessing new technologies to enable speed to clinic.