Name: Inspection Readiness - Expected and Unexpected Regulatory Inspections
Uploaded: 2026-04-22T16:01:17.700Z
Duration: 45 min 8 s
Description: Inspection Readiness - Expected and Unexpected Regulatory Inspections

Transcript for "Inspection Readiness - Expected and Unexpected Regulatory Inspections": Unexpected and unexpected regulatory inspections. In a moment, I'll introduce you to our expert panel. And over the course of the next thirty minutes or so, we'll be looking at overall inspection readiness, the dangers of overconfidence. We're also going to take a look at the FDA's new draft guidance on four eighty three observations that was released in March 2026, and also what being inspection ready actually means. So I'm delighted to be joined today by two NSF pharma biotech experts, both also, former employees of the FDA. Let me introduce you to Tamika Kathe and to Julia Marais. Julia and Tamika, you're both very welcome. That's fine. Thank you. So, Tamika, I'm gonna start with you, if you don't mind. From an FDA perspective, where are companies most overconfident? Because the the the overconfidence issue can, you know, cloud people's judgment when they're preparing. That's actually an excellent question. And what we've seen from an FDA perspective is a trend, and that trend and overconfidence is around thinking your quality management system is stronger than what it is and that we can take for granted if we do have observations that we have time to respond to them, and we don't have to give the level of detail, and that can come later. So I see those three or four buckets of, one, we think we have a strong quality management system. Two, if we do get, 43 observations from FDA, We can respond, but we don't have to be thorough about it, and we should be okay. And I think those are the two major buckets that I see that there that companies really struggle with. Okay. So I just now pass over to you, Julia. In terms of that, where does the misinterpretation come from in terms of in misinterpreting the guidance, and how does that contribute? Yeah. I think a lot of firms are taking a look at all of the guidances that FDA publishes, you know, over the year and and kind of retrospectively. And they look at that as as a checklist type of system when in reality, the guidances are giving industry a window into how FDA is going to evaluate your systems. But more holistically, firms need to be thinking about their specific manufacturing operation and what the risk is to the specific products that they are manufacturing. So the guidances are helpful as a starting point, but that's definitely not the endpoint for firms. Okay. So if I gather this correctly, it's that you have to pay attention to the detail, particularly on your form four eighty three. Make sure you're comprehensive in your responses. But then don't treat the guidance as a checklist. You know, get into the weeds on it and make sure you're you're aligned with what what is expected of you. In terms of the the change, I know, Tamika, you and I have spoken about this, at length recently. There was a change to the draft guidance for form four eighty three in March. Just in terms of that, what problem is the agency actually trying to solve by issuing the guidance? Again, Brian, great question. The reason the draft guidance came out in March 2026 is because there are a couple of things that were being identified internally within FDA. One of them is the fact that when 40 threes were issued, companies would not respond comprehensively. So there was always a gap around the actual CAPA itself in responding and putting corrective actions in place. The other piece is if they did have a CAPA in place, even if it was pretty comprehensive, they never had a timeline of when they should expect the cap to be closed or the target date of closure. And then the third is having a thorough investigation comprehensively. So keep in mind, the 43 is just a snapshot. The expectation of FDA is for you to do a thorough evaluation of your entire quality management system. So if you have a observations around, let's say, investigations as a whole, they expect for you to comprehensively look at all investigations and look at your system and see where the gaps are. They may have only identified one or two, but there's a trend there, and it's your responsibility to do so. So I think the guidance right now is perfect because what it does is provide what we've always known internally as expectations of FDA, but it was always clear to firms. And now the expectation is clearly defined and is actually exciting to know that FDA is providing more guidance. In the past, they wouldn't provide any, and then you would respond. It would not be thorough, and they would easily write you a warning letter, either because there were repeat observations that you never addressed or you just thoroughly did not respond to the 43 within your actual, capa and identifying those 43 observations. So for them, it was low hanging fruit. Here's your warning letter. Now they're providing a little bit more, guidance around it and what the expectation is. Before, there was no expectation. Now they're providing that. Just on the issue of expectations, Julia, I know both yourself and and Tamika worked with the FDA. What has changed most in in the FDA's expectations with this around April threes? Yeah. Well, you you know, it's interesting. So when I was at FDA, I was one of the reviewers that actually read the responses, the fifteen day responses to four eighty threes. And it was really surprising to see how much those responses vary from company to company. Right? You would you would see something completely different from one firm to the next firm. And I think it's it's really interesting to think about, you know, four a threes have been issued to firms for a really long time, but now in 2026 is the first time FDA has communicated what they're expecting from firms. Right? So it it was a bit of firms kind of guessing, doing their their best effort to provide these fifteen day responses. Right? But I think what's what's really important that sometimes firms don't understand is that that response, that fifteen day response to the four eighty three has major implications to whether your inspection classification is going to be considered high risk if it's mitigated by the response, and sort of what the next regulatory actions are. So I think in FDA providing this more explicit guidance industry, they're hoping to get responses that are of better quality, more consistent structure. I mean, think about there's a lot of guidance around how to prepare and submit a full drug application. Exactly. But this is another significant regulatory response that you have to do when you have an inspection. And before now, it was it was a bit of, you know, do you have good people working in your firm that understand how this process works, you know. And now there's there's more direct guidance on how you can how you have a better shot of giving a good response to Exactly. And may I take it back a little bit, Brian, just a little bit? Is, I agree with Julia 100%. That's why I'm, like, nodding and shaking my head because when I was in the agency, I was a consumer safety officer, And part of even looking at, the responses at our level, we had a chance to take a look at that. So if we went out and did an audit and issue a 43, the first layer would be for the inspector or the investigator or consumer safety officer to take a look at the initial response and give a, as Julia mentioned, recommendation to senior leadership and the compliance branch based upon the response to the 43. So we would give our first initial review and say, yes. We think this should be going towards a warning letter, or no. It is an appropriate response that we can continue to work with the firm and request for more, you know, documents if we need to, even give a little bit of guidance because they're moving in the right direction. So Julia is 100% accurate. This came from the investigational branch and their approach and assigning if this is going to be something that's escalated based upon risk. And, also, our recommendations could go to compliance branch or the centers itself for further review investigation. So everything that, Julia has mentioned is spot on from all levels and branches of FDA. Just one one thing comes to mind here from what both of you are talking about. We're talking about expectations and then the response. And it's interesting that some companies are very light on their response and companies can be quite detailed. How much the company's culture I know we might be going off in a going off in a bit of a tangent here. How much of the company's culture feed into the quality of that response? Do either of you want to answer that? So I'll say from no worries. I'll say from the initial approach as an investigator, if I went out and did the audit, and then I came back and they gave a response to my observations. What I noticed is usually the ones that were very thorough in their response are sometimes and it doesn't always mean sophistication of how long the company's been here and and been in business. It really boils down to the quality culture. If management took it seriously seriously around quality and understanding that we have to respond thoroughly and appropriately and within the fifteen days and not be combative and do thorough investigations and truly try to respond not just to the initial 43 observations, but anything that could could be connective and what we call that continuous quality management approach, then this is where the culture could reflect we're serious. We understand that we're taking this 43 observation as an as a opportunity for improvement, and we want to improve. And you can tell it through the response of the 43. And and I'd also go ahead, Brian. Okay. Cool. Say I'd say, you know, you only have fifteen business days to respond. Right? So that's not a lot of time. So if you don't have a culture where you are used to responding to things that need changing and and, you know, investigating thoroughly and assessing product risk, it's very hard for firms to to pull together a good response within fifteen business days if they don't already have that quality culture set up and if executive management isn't supporting their quality team appropriately. And I'll add on. You even have quality management systems. So you have to have the people, the systems, and the culture aligned, and then you can respond with it appropriately in fifteen business days. I have to say, you're actually answering questions now. I haven't even got a chance to ask yet. Because that was gonna be my next question about quality culture and in terms of how do technically complex companies struggle with this fifteen days and, you know, you you you've covered it there. So essentially here, we're looking at a variety of responses in terms of their comprehensiveness and and ability to answer the questions. And then this new guidance being a way to to give companies better guidance on what to expect of them. And then, of course, on my my tangent there in terms of where culture plays a part. So let's let's look at where things actually break down. Tamika, for you as a former inspector, how do inspectors identify weaknesses quickly? Because you're in there on the site for a limited amount of time. So are there things that always crop up everywhere, or what's the methodology the inspector takes? Great. Great question. Even as consulting, I always with our clients, I always mention the fact that when an investigator or consumer safety officer shows up, they always ask for the same thing over and over again. They're gonna ask for a list of, complaints, investigations, OOSs, change control. And I'll tell you why they're asking for this list of things with descriptors of what's the number, give me the identifying event and the summary, and also when things were opened and closed. They're looking for a quick trend to see, are we continuing to see product risk? Are we seeing the same product families that are getting complaints or investigations? Are we getting the same people or systems that keep popping up? They they don't have much time. So they're looking for a very quick trend by pulling some of these lists and see if they're, looking at trends. And then they're looking for what has been common within quality quality management and GMP violations as a whole historically. And they're trying to see, is your firm falling in that same arena and and identifying some of those gaps. There's always common ones. That's what they're looking for, and they just wanna tie it specifically to your company, your firm. In terms of the new guidance and I I I suppose in terms of the FDA, historically, root cause analysis has always been a common failure. Julia or Tamika, which what separates the good companies from the bad here? And, Julia, I'll actually let you start and I'll pick you back up. Yeah. Yeah. Of course. Of course. Yeah. I think root cause analysis is is always hard for firms because I think it's often hard for firms to sort of step outside of their usual systems and and really ask rigorous questions of, personnel and and their operating procedures. And I and I think sometimes firms are hesitant to be as critical on themselves as they need to be. So so that's so that's when you oftentimes get those root cause analysis that kind of always the same root cause for every single deviation and investigation. So so I think really having I I think it comes down to trading, and I think also having an outside set of eyes to help you look through, hey. What is your process for establishing root cause, and can this be improved? And are you having themes of the same root cause being listed for every different quality event? Tamika, I'd love to hear your thoughts too. Thank you, Julia. And I was thinking the same thing. That's why I'm over here smiling. And I will even say not understanding and recognizing, they're actually root cause analysis tools that are out there. And it's beyond just the five whys or beyond, you know, the fishbone diagram that most people know. There are a lot of root cause analysis tools that companies can use to, as you mentioned, to break the trend. Let's go deeper. Let's identify where we could be missing or have blind spots within some of our root cause analysis. I I think that the agency did a great job in developing a guidance document for OOS investigations. So it go it has a phased approach, which has helped identify and going deeper and not just saying, oh, it's just an analyst error or a human error. It does force you to go outside and think outside of the box and dive in deeper. And once you ruled out quite a bit of different, you know, opportunities where it could truly be a laboratory area era, then it forces you to think about from a manufacturing phase. So, I mean, I'll say FDA has done a great job with OOS guidance document that has been out there since 2006, but the principles are still the same. And thinking about root cause analysis, going deeper, doing and I will add in having a great SME or group of SMEs that will challenge the process and not always intimately related to the process. If you have a great investigational team and they've been doing this for years and they'll know where the bodies are buried and, you know, from different departments, it does help out a lot. And use your risk tools that are out there. Another great guidance that's out there is actually ICH q nine for risk quality risk management. That is a great tool to help identify a lot of the, challenges that people struggle with when even identifying risk and doing proper risk assessments and doing true risk analysis and identifying root causes. So if I was to sum up that from where things go wrong, the points are taken from from both of you is, you know, challenge the process as you just said, Tamika. Be as you said, Julia, then be critical, of your own work, and not be so keen to pat yourself on the back, essentially. But then watch out for weak root cause analysis. And then the other point is a fresh set of eyes. Mhmm. And you have to come in, look at things from an external perspective without any understanding of what's going on in the company and the politics and to and to look at that with with a fresh set of eyes. So we've looked at, I suppose, you could say, where things go wrong. Now let's look at, the real readiness and what good looks like. Tamika, from your FDA experience, I'm gonna ask you the direct polar opposite of, the last the the question I asked you last time. When the FDA goes in, what signals to a company to the FDA that this company is genuinely prepared? Great. Great question. I always say, your first impression is a lasting impression. Most of the time, we just don't have enough time to cover everything. So very quickly, what we're trying to assess is how quickly can you provide requested, documents. How if I do a facility tour, I can randomly speak to anyone on the floor as an investigator. And if they are consistent, along with management as well as the documentation that I've requested, then I'm not gonna dig any deeper. There has to be some consistency across the board, and that kinda tells the story. If you were well prepared, the documents being requested come fairly quickly. And being honest, sometimes if you do you recognize that you have a gap within a particular system, a process, etcetera, yes, State statement. We we recognize that, you know, we have a risk. We recognize we have a gap. But part of our continuous improvement would be we're we're we're open to hiring consultancy, or we have a cap of that we put into place well before maybe you even showed up. We just haven't had a chance to implement it. So that level of transparency gives the optics that you care, that you take quality serious, that product is important, and you're not gonna take risk when it comes to product quality. Tamika, I love hold on, Brian. I love that word transparency because because I I also expect when I'm having conversations around the facility, it's not that I expect responses to always be perfect and the person knows, but acknowledge, you know, that's that's a great question. I'm not completely sure. I'll need to look at the SOP. Right? And and that goes into the transparency. If I can tell that the culture at the site is one that it's okay to say I'm not sure or I don't know instead of trying to come up with an answer that's then going to contradict what your SOP says. Mhmm. That's one of the biggest mistakes. Right? Be honest and transparent when you do and when you don't know. So, Julia, because of that, I might give you two questions back to back now. So Tamika talked about the ability for people to put their hands on documents very quickly, and the good data room is essential. With that, where does the documentation piece come in in terms of how readily available it is? And this is kind of the the tangent on the question. Over over time, we've all heard of companies that have coached their staff for these Yes. From a from a, how would you say, preventative or defensive, standpoint. What's your view on that? And then let's come back to the to the documentation piece. Mhmm. Well, I well, by coaching right. I I mean, you should definitely plan and practice for an inspection. Right? You absolutely do not want to have a defensive stature and way of responding. I think if you have prepared your team by practicing, doing mock inspections, having frequent external audits, then your personnel are not going to do a deer in headlights and and freak out when they're asked questions. Right? So they will be able to very calmly say, yep. You know, we have we have a two slide storyboard where I can explain to you the environmental monitoring program. Let me show you. And then if you wanna look at SOPs, here are the exact SOPs. You know the main bucket areas they are gonna ask about, so prepare for that. Have a person that you've already assigned that's going to introduce those sections and be able to answer questions. Right? And and as we said before, be transparent. If you don't have a document or if you haven't thought of the question that the investigator is asking you, say, that's a great question. You know, I'm gonna note that down and we're gonna get an answer for you. Mhmm. You know. Yeah. So, Tamika, then, how does the FDA distinguish between point corrections and systemic remediation? That is a great question. So when we're talking about point corrections, I'll tell you what I hear. I hear we identify a problem, and we're gonna do, like, a quick fix. And it isn't really a long term remediation strategy. And, again, I I will point back to thinking about not the whole entire quality management system or GMP operations or even product risk. You're just thinking about a checkbox activity. I wanna fix this one thing that's already been identified to me by an outside person, I. E. A regulatory body. It's not being comprehensive. It's not thinking about quality culture, product quality, or just in in general, the GMPs as a whole. And what is and how is that gonna be applicable for your business? It's gonna look different from, you know, one business to the next. So you have to define that and you have to adhere to it. And what a a good quality and not a corrective or reactive, as I like to call it, approach will put you in the right direction. So essentially then, if just to to wrap up this piece, it's about having systems in place that can withstand scrutiny. And again, to come back to my earlier point, a lot of this is dictated by the culture of the organization. Would that be true? I would agree. Okay. So the conclusion of the the form four eighty three where, you know, inspections really, are won or lost essentially. What what separates a strong versus a weak four eighty three response? Tamika, you can go first. I wanna actually go back to the new draft guidance. They did an excellent job in identifying key pieces from a that giving you guidance and recommendation around what would be in the past considered a weak response. An example would be, when you are writing the response, you do not identify who's the most responsible person. Now there's a section about management responsibility within the quality guidance. The other piece is not doing thorough investigations as I mentioned mentioned earlier. Now the draft guidance has a section around that as well as CAPA remediation and CAPA effectiveness, and it not being clearly defined within your response. I do wanna highlight something that's a little different. The guidance actually clearly mentions that now they expect for within the fifteen business days to have a comprehensive, I call it one stop shop response, where most of it should all be together and comprehensive and not piecemeal of, okay, we'll let you know next month. It should be rare. And if it's rare, then this we call it a interim review or interim report. They allow for that, but what they don't want is piecemeal out. They want everything to be more comprehensive. And I think that's kind of a great approach if you follow the guidance. So just go ahead, Julia. Because I was gonna ask you a question about that comprehensive piece and the speed versus accuracy in fifteen days. Yeah. So I yeah. I I first wanna, you know, piggyback off of what Tamika is saying in that, I think maybe what industry didn't understand prior to the guidance coming out is that it is the fifteen day response that the agency is using to decide your inspection classification. So it's it's a combination of the establishment inspection report that the investigator is writing Yeah. And then it's the fifteen day response from the firm and not responses after that because the, you know, the reviewer at headquarters does not have time to look at multiple responses. Right? So they are that's how they are assessing your inspection classification. So I I love that the guidance now clearly writes that to industry because I think previously, that was a common theme was, okay, we'll provide a thirty day, you know, update, a sixty day update, a ninety day update. And FDA is like, well, we're already done looking at your responses from the fifteen day response. Right? So I think that was a really important point that Tamika made there. So it's it's going back, Brian, the first impression is the best impression. It's no different than if I showed up physically into the firm. Now you're looking at it from a documentation standpoint. That fifteen days is your first window or the agency's first window to see exactly who you are and how comprehensive you're gonna respond and address the 43. That that sets the stage in classification. So comprehensiveness is a one stop shop, make the fifteen days count. Am I right? Yes. Okay. So we're coming up on time. So just before we wrap up, question to you both. What would you recommend the people do next if they have the four eighty three? Some people are saying we'll get an initial response in in fifteen days, and others are arguing for more comprehensive response. Who wants to go first? I'll I'll go back to the the draft guidance for March 2026. Now it it it implicitly speaks on the fact that they expect for you to have a comprehensive response within the fifteen days. You know? You have a small window for the interim, but, overall, I should be able to read in fifteen you know, within fifteen business days and you and provide that initial response. How is your company addressing directly the 483 observations and comprehensively addressing the issue as a whole. K. Julia? And and and you you asked, you know, what should you do when you are issued a four eighty three? I would say, you know, start collecting your ideas of how you're gonna respond to those four eighty threes, but then you really do need an outside set of eyes that knows how FDA is going to interpret your response. You wanna have those eyes read your responses and and really take it seriously that what you are gonna submit, take it seriously as what you would for any kind of supplement or NDA submission, any kind of regulatory submission. This conversation with FDA in your fifteen day response is really important, and so you wanna make sure that you you have good support around developing that narrative. So, basically, a great remediation strategy. Okay. I'm gonna throw a curveball question before we end. Do it. What happens if you disagree with the FDA? Yes. This actually, I've seen this happen. I've seen those responses where I have issued a 43 observation. The the particular firm did not agree with the observation. You still can respectfully respond within fifteen business days, but you have to provide proof or evidence where that particular observation was incorrect. And you have to prove that, you know what, you have the investigator was given enough time to respond. You provided all the documentation at the time, and the information was still incorrect. What you cannot do is after the closing of the inspection, say, well, see, they just didn't understand. They didn't ask the right questions, or they didn't allow for me to provide the documentation. While the investigator is there, it is your responsibility to tell the story, prove through documentation exactly what you performed, and acknowledge the gaps when there are gaps, and that's the piece of the transparency. It is fine if you've done all of that and there's still an incorrect information that was within the 43 that you want to respond to and disagree with. You can respectfully do it in fifteen business days, but you have to have what they call objective evidence to support why you're disagreeing. And I would also say that that is why when you respond with your fifteen day response, right, there is a separate reviewer at headquarters that has seen your entire regulatory dossier, so your full NDA, AND, BLA, whatever it whatever it is, right, that can assess the risk of that four eighty three observation, the response to the fifteen day response to the observation in light of your larger drug product application and assess whether, okay, you know, the investigator saw this on-site. The firm is responding in this way. I'm gonna think around the risk to the actual product because I know the specifics of the entire manufacturing process, and then it's that reviewer at headquarters that is deciding what the final classification is. So you can speak to that reviewer and say, hey. The investigator saw this, but here's how I'm mitigating this risk, and I'm gonna explain it in the fifteen day response. And then that can help in your case as well. Mhmm. Okay. Before we finish up, quick fire question. One question for both of you. I'm gonna start with you, Tamika. Remind us, what's the one thing that the FDA looks for first? It's gonna sound silly, but one of the things they ask for is, can I have a copy of your organizational chart? And I know people are like, well, why is that? Why the organizational chart? Why is that important out of everything that you're asking for? It's because they're looking for responsibility. Who is the most responsible legal person in that facility when it comes to management review, oversight, providing resources, final decisions for product release that is connected to quality. They are looking for the most responsible person. So I always say the organizational chart kick starts the conversation around, are you serious about quality? Who are what is the reporting structure? Okay. Julia, my question for you. One mistake one regulatory mistake that companies must avoid or should avoid. Yeah. That should avoid. Well, I would say make sure you know what you have submitted to FDA previously. You you'd be surprised. From not knowing to the full extent everything they've submitted in a full application because that is going to come into play when investigators come on-site. So understanding what you've submitted previously, what the current conversation is with FDA, and what I mean by that is what's your inspectional history. Right? What what was your classification on the last couple of inspections? Have you had any product recalls? Right? So understanding what FDA is coming on-site with in their head about what your firm has done in the past. And I like to piggyback just slightly. It's the same mindset of what Julia has mentioned from a regulatory perspective, also from an investigational perspective. The investigator before they show up, they've already reviewed previous 40 threes, previous EIR. They wanna know your regulatory history in the past and any corrective actions that they've seen, you know, if you've been audited before, any corrective actions that you have because they're gonna go in and they're gonna verify if they've been performed. So it really is the same mindset of what Julia is mentioning even from an inspectional, standpoint of that regulatory history. Sometimes we were even work closely with the centers, and they'll provide us, depending on the type of investigation it is or what kind of inspection it is, guidance on this is what they've submitted. Please go in and verify, like, you know, for a PAI inspection. Can you verify what they have in their application? So Julia is 100% accurate. It's important to know what you submitted. Okay. Thank you to you both. That was fascinating. Absolutely fantastic. And I think if we can sum it up, it's really thoroughness in the response. Fifteen days means fifteen days. One stop shop as as you said, Tamika. And it is pay particular attention to the new March 2026 guidance. Again, to you both, thanks very much. If you want more information and you wanna get in touch with us about how NSF can help you, prepare for an inspection, you can contact us at lifesciences@nsf.org, and we'll talk to you again soon.