By Paul Thomas, Senior Editor

One of the sticking points of the Quality by Design movement has been a lack of viable examples for manufacturers to refer to. There has been a wealth of materials to educate, but little to emulate.

A healthy mix of case studies for small-molecule QbD projects has begun to appear (see PharmaView: QbD: Let the Demystification Begin), but precious few for biologics manufacturing. Thus the release of the “A-Mab Case Study” in November (coinciding with the ISPE annual meeting in San Diego) was a watershed moment. (The case study can be accessed here.)

The A-Mab study was developed by a working group comprised of volunteers from seven manufacturers (Abbott, Amgen, Genentech, GSK, Lilly, MedImmune, and Pfizer) and other interested parties. FDA and other regulators were consulted but chose to stay at arm’s length to let the ideas and concepts presented play out on their own. The goal was to create a document that would not only benefit those applying QbD to their products, but also those regulators reviewing QbD-based submissions.

The case study takes a typical biologics molecule (if there is such a thing)—a humanized IgG1 monoclonal antibody in development to treat non-Hodgkin’s Lymphoma—and applies Quality by Design principles from target product profile and early formulation studies on through process development and even approval and post-approval control and optimization strategies. While A-Mab is not an actual product, the data and experimentation contained within the case study reflect work undertaken at the participating manufacturers.

At 278 pages, A-Mab is a beast—it will be too much for some manufacturers to handle, but is like nothing we’ve seen before. “It’s a significant achievement for the industry,” says Sam Venugopal, one of those on the study’s Facilitator Team and a principal with PRTM Management Consultants. Just getting cohesive input from seven different manufacturers around a single sample molecule is in itself an achievement, he jokes.

Venugopal says that A-Mab could be viewed as a biotech sequel to the ACE Case Study that came out previously for small-molecule QbD. However, A-Mab is much more extensive, and holds something for everyone, he notes. Monoclonal antibodies represent a significant number of products currently in development, he adds, and have already benefited from robust product and process development work at many manufacturers.

But Venugopal is quick to point out (as does the document in its introduction) that it is not to be viewed as prescriptive for other bio-QbD projects. “Our intent all along was to take the principles of Quality by Design and push the envelope,” he says. “There are going to be some places where we push the boundaries between what is acceptable and not acceptable.”

Are A-Mab’s authors open to criticism? “Absolutely,” Venugopal says. “If there are points that we make that don’t hold water, we want to know about it.” ISPE and CASSS (formerly the California Separation Science Society) will be developing workshops and other forums for debate and interpretation of the A-Mab, he notes. Some events will take a high level view of the document, while others will drill down to examine specific sections.

And hopefully A-Mab will spawn further case work, Venugopal says. “This study could be used to, for example, develop another on what the technological challenges would be for a company that is trying to implement QbD,” he says. In other words, A-Mab’s impact will be greatest if it leads to more questioning and exploration regarding QbD, rather than serving as a definitive text for bio QbD.