"Known Unknowns" Affect Critical Process Parameters & Critical Quality Attributes In The Bioproduction Cycle

By Jonathan Carson

Cell and Gene therapies (CGTs) are among the most complex medicines in terms of both their desired mechanism and especially their ontology. They are thus more challenging to produce, test, and bring to market than small molecules or even protein biologics. While the safety record of most of these has been very good, we’ve observed confounding and costly failures in mid-to-late Phase trials, due to evaporation of initial positive signs of efficacy. Could it be that variations in process (e.g., during manufacturing scale-up or scale-out) account for some of these higher p-values and elusive trial endpoints?

In an article titled “Why Controlling CQAs Isn’t Good Enough For Gene & Cell Therapies” by Dr. Mark F. Witcher, he states that the CGT development space needs to adopt more rigorous working definitions beneath the two over-arching regulatory terms provided for guidance in the design and control of drug quality: the Critical Process Parameter (CPP) and the Critical Quality Attribute (CQA). Simplistically stated, the CPP is like the lever or “cause” – and the CQA is the readout or “effect.”

He continues with while it’s well and good to track the known CQAs, it’s also necessary to deconvolute their meaning with more sophistication than in the past. Perhaps this Industry needs to do a better job to diminish the impact of “unknown” outputs i.e., through stringent process control over “knowns” via the process. Through this control, certain downstream attributes that Witcher coins as “u-CQAs” would be less inclined to wreak havoc.