FDA compliance official highlights priorities, return to onsite inspections, and warning letter trends

Editor’s note: This article was updated on 10 October to reflect transcription errors in two paragraphs. 

Preventing diethylene glycol (DEG) or ethylene glycol (EG) contaminants from slipping into drugs and ensuring that ophthalmic drug manufacturers adequately test their sterile products are two priorities for the US Food and Drugs Administration (FDA) manufacturing quality teams.
 
Francis Godwin, director of the Office of Manufacturing Quality at the Office of Compliance FDA’s Center for Drug Evaluation and Research (CDER), discussed compliance trends in an interview with Focus. He stressed the importance of firms building a culture of quality and what keeps him up at night. The interview has been edited for length and clarity.
 
Focus: What are some of the Office of Compliance’s top priorities this year? According to your 2023 annual report, preventing diethylene glycol (DEG) or ethylene glycol (EG) contamination, curbing distribution of potentially dangerous ophthalmic products, and working towards implementation of the Drug Supply Chain Security Act were among its top priorities. Are these still high priorities?
 
Godwin: When it comes to compliance priorities for drug manufacturing, diethylene glycol and ophthalmic products remain priorities for us. The annual report talks about how there were outbreaks overseas and our heightened supply chain controls. In 2024, a lot of the warning letters are, for lack of a better term, preemptive strikes to make sure that firms have the right controls in place to prevent diethylene glycol from drugs entering the US supply chain.
 
Ophthalmic products is also an area where we have a heightened focus and priority mainly because they are required to be sterile and if they are of poor quality, they can be dangerous to consumers. Many of these products are over the counter and not subject to premarket review by the agency, so if a new entrant pops up, we must look at them. Ophthalmics is a priority and will remain a priority because of the nature of these drugs and the regulatory framework around them.
 
Focus: Can you discuss FDA's shift to onsite inspections? What is the breakdown of warning letters resulting from remote inspections versus onsite inspections and why FDA may inspect remotely?
 
Godwin: During the pandemic, there were travel restrictions. Even though [onsite] inspections did not stop, they were curtailed. FDA at large is returning to more onsite inspections as it ramps things up. As our colleagues in [the Office of Regulatory Affairs, now called the Office of Inspections and Investigations] have ramped up to onsite inspections, the pendulum has swung back. In FY 2024, and these numbers are subject to change, at the end of August, almost 80% of the warning letters that we issued for drug adulteration were based on an onsite inspection.
 
Focus: Will FDA continue to use alternative tools, such as electronic record review and remote inspections, to supplement onsite inspections?
 
Godwin: Prior to the pandemic, if you go back to FY 2019, all the warning letters were based on inspections. During the pandemic, they were based on using alternative tools such as record requests. We find ourselves with a mix and we are finding a sweet spot between the two. Most of our actions are based on onsite inspections and a quarter are based on electronic records or sampling. Use of these tools allows us to augment our inspectional resources.
 
Focus: Are data integrity lapses a major finding in inspections?
Godwin: Data integrity is a big issue, but it does not represent most of our cases. For FY 2024, about 17% of the warning letters [had data integrity issues], so it represents a small proportion. Why it matters so much is that if you find a serious data integrity issue at the facility, this calls into question the quality of the data coming from that facility.
 
Focus: Are most of the drug GMP warning letters issued so far in 2024 for OTC drugs? 
Godwin: Yes, if you look it though the end of August, 86% of the warning letters were issued to manufacturers of over-the-counter (OTC) drugs. I would categorize them as non-application drugs. This really ties into the globalization of drug manufacturing and the non-application products, there is no premarket review. Many warning letters stem from situations where an industrial manufacturers making industrial goods see a market need for an OTC drug. They say, ‘Let’s start manufacturing that,’ and they ship it to the US but they do not realize there are certain requirement for manufacturing drugs to the US.
 
Focus: What are some of the top GMP violations found in warning letters? The top GMP violations in FY 2023 warning letters were for deficient quality control units under 21 CFR 211.22, a problem found in 48 letters. The next highest area was inadequate control and testing of components, containers, and closures under 21 CFR 211.84, which were cited in 47 letters. Is this a recurring trend? These trends were reported in the Office of Compliance’s annual enforcement report for FY 2023. (RELATED: CDER’s Office of Compliance highlights enforcement actions in 2023, Regulatory Focus 17 January 2024).
 
Godwin: They are mostly the same. When you look at drug manufacturing under 21 CFR 22, the quality unit oversees making sure [the manufacturer] is meeting the requirements across the board. If you are doing inadequate raw material testing, your quality unit was inadequate because they were not ensuring appropriate testing. Also, 211.84 was a big-ticket item last year and it remains so this year. Part of the reasons it was so prolific last year was that it is associated with testing controls associated with diethylene glycol in situations where an ingredient of risk requires the correct identity test to confirm the ingredient is not a deadly poison.
 
Focus: How would you advise drug manufacturers to stay on top of their compliance efforts?
 
Godwin: Sure, I want to let them know there is another office in CDER and that is the Office of Pharmaceutical Quality, which strongly encourage companies to build a strong internal culture of quality. A strong culture of quality will help create a comprehensive approach where issues are detected and addressed. Even if FDA is not at the facility, the idea is that they function independently and when FDA shows up, they are verifying that the quality unit is doing the appropriate thing. The biggest issue with quality is that this comes from the top down as well as the bottom up.
 
Focus: Is there anything that keeps you up at night?
 
Godwin: For me one of the things that keep me up at night is that I know there are new manufacturers coming in that are making a high-risk drug and FDA may not have the opportunity to screen or do a premarket review and the firm themselves may not know the requirements to ensure safety and quality of the drug. This is a combination that keeps me up at night. Is there a new sterile ophthalmic manufacturer that doesn’t know they need a preservative in their drug or is not testing for sterility upon release? This is a pattern that we have had for quite a while and it does keep me up at night and it frustrates me.