Preparing for and Communicating Manufacturing Changes During Late Stage Development Smoothes Biotech Clearance Process with FDA

Comparability studies for changes which inevitably occur during Phases II and III for biotech products must be planned for by the firms conducting them, FDA is stressing. The agency is also cautioning that communication with FDA during the end-of-Phase-II and pre-biologic license application (BLA) meetings and through the submission and preapproval inspection process is important to understand common expectations and make it easier to work through issues that will arise due to these changes.

Center for Drug Evaluation and Research (CDER) Biology Team Leader Chana Fuchs noted at the AAPS National Biotech Conference in San Francisco in mid-May that in the biotech context change is expected.  “I have not seen an IND where change did not happen.  So comparability is needed.”

The CDER official cited case studies in which changes made during Phases II and III resulted in various issues and delays.

In one case, Phase III manufacturing changes in a monoclonal antibody “resulted in a different product, literally.”  Although the resulting product had similar characterization profiles it did not meet the same specifications as the original molecule.  A clinical trial could not confirm that the materials were indistinguishable, and a human PK study showed that there were significant PK differences.  “So they needed to do another clinical trial,” Fuchs commented, “which is the only way to kind of resolve differences at that point.”

Another example cited involved a human IgG2 monoclonal antibody that was produced in Chinese hamster ovary (CHO) cells.  “Prior to Phase II, which is pretty early,” Fuchs explained, “there were multiple manufacturing changes made between cell lines, bioreactors, scale-up, manufacturing site, the process, and downstream.”  In the submission comparability plan no data were presented, and “the plan did not provide sufficient detail, did not provide acceptance criteria, and did not address viral safety risks.”

The CDER official commented that “the feedback that the company wanted and needed to have by a certain time so they could start their studies was not going to be there.  That is a time delay.”

[More FDA advice on facilitating Phase II/III and BLA submissions is provided for subscribers here. See the companion “In the News” story for insights into problem avoidance earlier in the development process.]