I think many of us have been discussing the blatant obstruction demonstrated in the December 2024 Warning Letter to Brands International Corporation, a drug manufacturer located in Ontario, Canada, citing it for limiting and delaying FDA’s inspection. Which it is important to remember congress has said is a big no-no.
I just want to stress that the Quality Manager there had a really bad day, week, month, year.
Good writeup of what to do around building your procedure for interviewing of employees during an inspection over at FDA Law blog.
This draft guidance lays out a solid approach by using a risk-based credibility assessment framework to establish and evaluate the credibility of AI models. This involves:
Determining if the model is adequate for the intended use
Defining the question of interest the AI model will address
Defining the context of use for the AI model
Assessing the AI model risk based on model influence and decision consequence
Developing a plan to establish model credibility commensurate with the risk
Executing the plan and documenting results
I think may of us are in the midst of figuring out how to provide sufficient transparency around AI model development, evaluation, and outputs to support regulatory decision-making and what will be found to be acceptable. This sort of guidance is a good way for the agency to further that discussion and I definitely plan on commenting on this one.
Usually I expect the FDA to publish some basic primer material as a webinar, so I was a little surprised when “Considerations for Complying With 21 CFR 211.110” was recently published as a draft. I’ve been rereading it, looking for what is actually worthy of a guidance here, and quite frankly, struggling.
It literally is a refresher course on 21CFR211.110. Maybe I should read it as “No we were serious about ICH Q8 and critical quality attributes.” Or maybe it is just the result of one too many bad Type C meetings lately.
Anyway, good refresher on product quality, in-process controls and samples. Still I think this would be better as a webinar with some graphics. Maybe I’ll better understand why this was published based on what sort of crazy comments are made and I can scratch my head and wonder what shenanigans some of these companies are up to.
This draft guidance adopts the ICH E3(R1) definitions for protocol deviation and important protocol deviation, providing more standardized terminology, which is a great thing. Avoiding the term “protocol violation”, it primarily uses “protocol deviation” and “important protocol deviation.”
The FDA guidance provides detailed sections on the roles and responsibilities of investigators, sponsors, and IRBs in monitoring, mitigating, and reporting protocol deviations. It as specific recommendations for reporting protocol deviations to sponsors, IRBs, and FDA, including timelines and methods.
It mostly seems a good application of a quality-by-design approach, focusing on critical-to-quality factors and risk-based monitoring for clinical studies. Hopefully it will help clear up confusion in this area.
I hasn’t been difficult to notice that a whole lot of biological new drug applications have been rejected in the last few years, many for CMC reasons. Recently CDER Director Patrizia Cavazzoni spoke on the matter at a recent at a Duke University and FDA event at the National Press Club iin the video above.
“Our standards have not changed. We have exactly the same standards as we had in 2018 and 2019,” she said, before going on to talk about how the quality related issues the FDA is seeing: contamination, overall oversight, manufacturing controls or insufficient quality management systems.
Max Van Tassell, a senior pharmaceutical quality assessor in CDER’s Office of Pharmaceutical Quality, provided insights from analyzing 100 complete response letters (CRLs) for Biologics License Applications (BLAs) issued between 2014 and 2024. He noted that facility-related deficiencies in CRLs typically stem from inadequate demonstration that proposed corrective and preventive actions would effectively mitigate risks identified during on-site inspections.
It should be a key takeaway from this presentation that:
Investigations of a Dog 