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With so many new subscribers now coming to the newsletter each week, we’re resharing one of our favorite conversations from a few years back.
We’re bringing it back because it’s just as relevant today as it was when it was recorded, and Chris offers a wealth of knowledge on pre-approval inspections, 483 responses, and what FDA investigators are actually looking for. We’ve also been deploying quite a few auditors for PAI readiness recently, and the topic is always important.
Chris is a former FDA investigator who spent over a decade at the agency before moving into industry and consulting. The conversation covers what most companies misunderstand about pre-approval inspections, and the practical things that separate a smooth inspection from a painful one.
Chris began his career as an FDA investigator in the Detroit district, conducting GxP inspections across foods, drugs, biologics, and devices. He was one of seven people selected for the FDA’s Executive Development Program and advanced through headquarters roles in public affairs, congressional affairs, and the commissioner’s office, ultimately serving as Deputy Associate Commissioner for Public Affairs.
He was one of the key authors of the FDA’s major rewrite of the IND and NDA regulations in the 1980s, and he managed the tamper-resistant packaging regulations that followed the 1982 Tylenol cyanide poisonings. After the agency, he held senior regulatory and quality roles at Abbott Laboratories, AAIPharma, and Endeavor Pharmaceuticals before founding Coastal Pharmaceutical Consultants, which he ran for 12 years.
He’s now retired on his farm in North Carolina.
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Chris's key insights and practical takeaways
If you're short on time, here are the most important lessons from the discussion.
There are no secrets about pre-approval inspections, and the FDA wants you to know that. The agency publishes compliance program guides on its website that tell its own field and headquarters staff exactly what investigators should cover, what they write up, where reports go, and what recommendations compliance officers should make. There’s a specific guide for pre-approval inspections. Chris’s point: this material exists to educate the FDA’s own people, and industry can read the same thing to prepare. The information is public. Most companies just don’t go looking for it!
The PAI program exists because the field and headquarters used to operate in (sort of) isolation. Chris described an inspection of a new Parke-Davis sterile facility in Detroit early in his FDA career. The team found problems and issued a substantial 483. Two days after the report reached headquarters, the drug was approved and announced in the press. The field and the headquarters reviewers weren’t talking to each other. Around 1999, the FDA moved to fix that, partly by creating the pre-approval inspection program and sending headquarters reviewers into the field.
A PAI checks three specific things. First, whether what you said in your application matches what you actually have. Investigators look at the raw data behind your claims. If you said you have stability data supporting a two-year expiration date, they’ll want to see the raw stability data. Second, commercial readiness. If the FDA approves you tomorrow, is the plant truly ready to make a commercial product? Third, data integrity, which has only grown in importance since the program started.
A PAI is focused, but it can expand. Unlike a general inspection where the investigator can wander in and decide to look at the water system or the labs or manufacturing on a whim, a pre-approval inspection has a stated purpose tied to your pending application. You know what they’re there to look at. That said, if they find a problem, they can widen the scope.
FDA’s public dashboard is a genuinely useful preparation tool. The agency posts inspection data, recall data, top citations, and trends. Nick walked through it during the conversation. The broader theme connects back to the start: this isn’t secret information! The FDA has gotten much better at putting data on its website, even if the search function makes it hard to find. The top citations alone tell you where inspectors are finding problems.
ICH guidances aren’t law, and the FDA can’t write you up for ignoring one directly. An FDA investigator inspects you against your application, against good manufacturing practices, and against good clinical practices, not against ICH guidance documents or even the FDA’s own guidance documents, which don’t carry the force of regulation. The nuance is that when the FDA has adopted an ICH guidance as its own, it usually links it to an underlying regulatory requirement, and that requirement is what they cite. It’s worth watching what EMA, Health Canada, ANVISA, and PMDA are doing, along with technical reports from groups like PDA, to understand what inspectors broadly are focused on.
The biggest misconception: forgetting that the FDA’s job is to be the cop, not the consultant. When an investigator finds something they consider out of compliance, the natural question is “what should I do to fix it?” Investigators are trained not to answer that. It isn’t the agency’s job, the advice could backfire, and a different investigator might recommend something different and create a mess. Chris’s analogy runs throughout the conversation: the investigator is a cop on the beat, and the 483 is the ticket. You can argue your case before they write it, but once it’s written, your recourse is your day in court.
You’re allowed to disagree with the agency. A misconception Chris sees often is that companies feel they can’t push back. If you have good science and you’ve made a sound decision, an investigator disagreeing doesn’t automatically make them right. Before they write an observation into a 483, you have the chance to explain your reasoning and potentially avoid it entirely. The conversation matters.
New or out-of-area investigators can produce surprises, and that’s worth understanding. Companies sometimes call Chris saying they’ve operated for 25 years without an issue and suddenly received a 483 full of observations. His first question: was it a new investigator? Often the answer is yes. There’s pressure on younger investigators to demonstrate they can find problems, to earn their stripes. The FDA also moves people around more now, sending someone from California to inspect a plant in Connecticut where they know no one. None of that makes the observation wrong, but it explains the pattern. As Chris puts it, telling the cop you always drive 90 down this street doesn’t make it right. This time you got caught.
The biggest weakness Chris sees in industry: investigations that are written for insiders. Deviations happen. Machines break, people make mistakes, experiments go wrong. FDA expects that. What matters is that you document what happened, follow your procedures, investigate, and put a corrective action in place. The failure is in the writing. Companies write investigations using their own acronyms, referencing their own procedures, assuming familiarity with equipment the reader has never seen. But the investigator doesn’t work at your company. An investigator should be able to read your investigation, whether it’s one page or twenty-five, and reach the end thinking “I know exactly what happened and you handled it right,” rather than walking away with fifty questions. Write for a layperson who doesn’t know your systems.
Apply the same logic to your 483 response. Don’t write the response as if you’re still talking to the investigator who was in the room. That person already understands what they wrote up. Your response gets read by people at the district office who weren’t at your plant, and possibly by headquarters reviewers who know nothing about your firm or its reputation. That’s your opportunity to lay out your argument clearly, to explain where the inspector missed a point or where there’s more to the story, so that someone with no context gets a clear picture.
The 15-day warning letter response window is short, and Chris agrees it’s unfair. Both Chris and Nick see the irony. The FDA can take months to issue a warning letter and sometimes a year to provide an establishment inspection report, even for inspections with no findings, yet companies get 15 days to respond. You can file for an extension, and you can make commitments about when you’ll deliver a fuller response. But the asymmetry is real. Part of the reason nobody fights it: when you’ve received a warning letter, you want the spotlight off you as fast as possible, so the unreasonableness of the timeline becomes a secondary concern.
Warning letters now often recommend hiring an outside firm, and that benefits everyone. Chris, as a former FDA investigator, was struck that the agency now sometimes recommends bringing in a consultant to help remediate. Nick has reviewed many warning letters that include exactly that. The shared point: FDA isn’t trying to shut companies down or prove the company is bad. The agency wants businesses running, people employed, and safe products reaching patients. Getting expert help moves a company back toward a compliant state faster and ends the costly cycle of reinspections.
Some of the hardest cases are small, family-owned firms that never built a culture of quality. Chris and Nick both see a recurring pattern: a business started by a parent or grandparent, now run by the next generation, making a few products, with the FDA having visited a few times as a low priority. Then a new investigator or a team arrives, finds practices that wouldn’t pass scrutiny, and the owners are genuinely shocked. A related problem Nick raises: reviewing the CV of the person responsible for quality and finding they aren’t qualified for the role. Startups founded by academics or clinicians can fall into a version of this, too, focused on the cure they believe in while treating manufacturing as an afterthought, when the FDA considers manufacturing just as important. A drug that isn’t made correctly won’t help the patient even if the science is sound.
Don’t be afraid! If you are, that fear is telling you something. Chris’s closing advice: if you’re afraid of the FDA walking in the door, ask why. If you’re worried about what your people will say, train them. If you’re worried about what they’ll find in the lab or in manufacturing, fix it first. Educate yourself on what the FDA looks at. Understand the team approach, where a sterile manufacturer might see a microbiologist examining the micro lab, an engineer reviewing water and air systems, and a reviewing chemist from headquarters asking questions based on your application. Be honest, be cooperative, and be willing to manage the logistics, asking whether something can happen tomorrow morning or whether the right person can lead a particular tour. Most good investigators will work with you to make the inspection successful.
One thing to bring back to your team
Pull one of your recent deviation investigations and hand it to someone who doesn’t work in your department. Then ask:
Can they reach the end and explain what happened, why it happened, and what you did about it, without asking you a single question?
Did you spell out the acronyms, explain the equipment, and walk through the procedure references, or did you assume knowledge a stranger wouldn’t have?
If an FDA investigator pulled this document tomorrow, would it build their confidence in your systems or generate fifty questions?
Now do the same thing with your most recent 483 response, if you have one. Was it written for the inspector who was in the room, or for the headquarters reviewer who has never set foot in your facility and doesn’t know your reputation?
The companies that handle inspections well aren’t the ones with no deviations. They’re the ones whose documentation tells a clear story to someone who wasn’t there.
Christopher Smith spent his career across the FDA, large and small pharmaceutical companies, and contract research organizations, with 47 years of experience in the industry. He began as an FDA investigator in the Detroit district, conducting GXP inspections, and spent 12 years at the agency in roles of increasing responsibility, including Assistant Director of Congressional Operations, Associate Director of Program Management, and Deputy Associate Commissioner for Public Affairs. He was one of the key authors of the FDA's last major rewrite of the IND and NDA regulations in the 1980s and managed several other FDA initiatives, including the tamper-resistant packaging regulations that followed the 1982 Tylenol cyanide poisonings. After the FDA, he served as Associate Director of Regulatory Affairs at Abbott Laboratories, held senior regulatory and quality leadership roles at AAIPharma, and was Vice President of Regulatory Affairs and Quality Assurance at Endeavor Pharmaceuticals, a women's health startup later sold to Barr Laboratories. He founded Coastal Pharmaceutical Consultants in 2011 and ran it for 12 years, conducting GMP and GCP audits, supporting firms through FDA inspections worldwide, and helping clients respond to 483s and warning letters. He’s now retired.
Connect with Chris on LinkedIn here.
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