September 26, 2023
Host: Oliver Ball, Team Manager of Business Development, Dark Horse
Main Presenter: David Jasek - Practice Expert, Dark Horse (10+ years pharmaceutical industry experience)
Panel Members:
Opening Remarks
Oliver Ball: Hello! To those who are just dropping in now, we're just going to wait a few minutes for everybody to join before we get going today.
Alright. So I think we will get going. And people can join in as when they're available.
So thank you all for joining today for the second of the Dark Horse's unbridled Excellence webinar series.
And this is the second of a series of presentations and webinar sessions that Dark Horse are hosting, really for the benefit of our audience, to benefit from the experience that Dark Horse has gathered over the years.
My name is Oliver Ball. I'm team manager of business development here at Dark Horse, I'll be hosting the webinar today, along with David Jasek, who will be providing the presentation today.
So, as many of you will know, Dark Horse has got a very deep level of experience in the cell and gene therapy space with over 300 clients and more than 650 projects now over the 8 or 9 years that we've been running.
And the intention of the webinar series that we're putting on is really to share some of the experiences and the best practices that we have developed over that vast experience.
This is all in cell and gene therapy space and really spans across all different development stages, therapeutic modalities, geographical regions. And what you're going to hear today is really a distillation of some of that experience into the topic at hand.
We also have coming up a third webinar, which will be on phase appropriate analytical developments which will be hosted by Josh Beckett and Alicja Fiedorowicz, in October, the end of October, which will be a very interesting presentation.
Following that one, we also have a panel of our regulatory subject matter experts, who will be speaking in November. This is a live version of our regulatory roundup, where we discuss current affairs in cell and gene therapy regulatory space, comments on AdComs and things like that. So that would be a really unique opportunity to benefit from specifically the expertise of some of our regulatory team.
Following that in December we have a final webinar of the year which will be actually featuring our 3 executive leadership team, Anthony Davies, Katie Spink, and Rob Allen, who will be providing commentary on the 2023 calendar year key takeaways and themes from the year, and also gazing into their crystal balls to predict on what 2024 will bring us.
So that again will be a pretty unique opportunity to hear the thoughts and comments of some folks who have a very unique and powerful perspective in the cell and gene therapy space.
So from here I will hand over to my colleague David, to start with today's content and as a quick reminder, we will be taking questions throughout and at the end of the presentation. So if you have any questions that come up during the course of today's presentation please submit them through the chat function in the Zoom webinar, and we will touch on those in Q&A at the end of the presentation.
So without further ado, I will hand over to David for today's proceedings.
Presenter and Panel Introductions
David Jasek: Thank you for the introduction, Oli. I'll just get my slides up.
So today's presentation is going to be on inspection management and response. So before we get into the presentation, I just wanted to talk very briefly about myself and introduce the other members of the team who will be on the panel.
So my name is David Jasek. I'm a practice expert with Dark Horse. I've got over 10 years of experience in the pharmaceutical industry. The majority of that is in various quality roles.
And those roles cover activities in Australia, the US, and the EU/UK. So had the blessing and the curse of dealing with a wide variety of different regulatory agencies and inspections.
And so this presentation will try and uncover the broadest range that we can.
I'll just throw over the microphone to some other members of the panel, just to very briefly introduce themselves.
Heath, if you don't mind going first.
Heath Coats: Sure thing, David. Hello, everyone. My name's Heath Coats. I'm a senior principal here with Dark Horse, and with the practice now a little over a year. I've been in post-FDA consulting land for about 4 years now. Prior to that I did serve as a reviewer and inspector in the division of manufacturing and product quality within CBER for close to 7 years, and prior to that I spent about 10 years running a validation program for a cell therapy contract manufacturing facility. So thank you all who attended today.
Liam Breen: Yeah, I'll jump in. Liam Breen, 8 years in the industry, just about, I think one and a half at Dark Horse. All of my time really has been in commercial quality roles, mainly with outsourced activity management.
That's me.
David Jasek: Thank you both. And Stephan Croft, who is an eligible QP and the Dark Horse head of quality will be joining the Q&A panel at the end of the presentation as well.
Presentation Overview
David Jasek: Alright, thank you, everyone. So getting into the meat of the presentation here. So unsurprisingly, we're going to cover this looking at inspection readiness and prep, the next section on managing an inspection itself, and finally moving on to the inspection response.
Inspection Readiness and Preparation
Understanding Regulatory Approaches
David Jasek: So starting with readiness and prep, one thing to think about, generally with inspections, is that different regulatory agencies really do have different approaches to how they go about reviewing submissions and setting up for inspections.
So there's quite a wide variety of different competent authorities out there, and just on the screen here some common larger ones, with the sort of inspections you might see, the sort of interactions you might have.
So it is critical to understand where your organization operates and what body they may be inspected by.
So, in addition to just the regulatory body itself, different types of inspections also have different approaches to readiness.
I've got some examples on screen here, both in terms of the inspection activity itself. So a pre-approval inspection, but also whether that inspection is on site, whether it's remote or whether it's sort of hybrid approach of both.
So there's quite a lot of individual variation there for inspections. So this presentation really aims to take a bit of a general approach to looking at best practices, and cover as much as we can.
One thing I do want to keep in mind is generally this presentation is going to cover routine inspections, but obviously there are also for-cause or unannounced inspections, which you know can be a little bit more chaotic, depending on the specifics. But really, ideally, your organization should be inspection ready at all times. So the core elements that we talk through in this presentation would really still apply in the event of an unannounced inspection.
What Inspectors Look For
David Jasek: So okay, so we know our regulatory body, we know what sort of inspection we are expecting, but you know what is an inspector actually looking for on an individual level?
And from a sort of, you know, 30,000 feet level, looking down the broadest possible view, they want to see if there's any patient safety risk fundamentally, and whether you're meeting your legal obligations in terms of the license you have to operate.
That's very vague, I appreciate that. But that is really what inspectors are looking for from this higher level.
The individual details do vary here, depending on what sort of inspectorate you come under. So I just got up on the slide here some really good references for background reading on what inspectors are trained to look for and what procedures they follow during an inspection.
So if you Google any of these bold terms here, you'll pull up the appropriate documents. But again, this will vary, depending on you know whether you're under the FDA's jurisdiction, or the EMA, or you know some other regulatory body. So just make sure that you're looking in the correct area.
Core Elements of Inspection Preparation
David Jasek: So in any event, regardless of what a particular inspector is looking for, there's some really core elements to inspection prep that should be followed to make sure that you have the highest chance of a successful inspection. I'll take a little bit of time to go through these on the slide here.
Number one, I think probably the most critical one is really an organizational culture, that a successful inspection is everyone's responsibility. So this is something that really should be drilled into staff at a cultural level, and everyone has their own part to play in making sure that inspection can be carried out successfully.
One of the common threads I see in inspections that have gone badly is where an organization tends to think that you know inspection is something that QA will just kind of sort out, and they'll do it all. And you know, manufacturing, for example, don't need to get involved, really.
And that kind of cloistered approach really can lead to some significant issues during the inspection itself.
Another thing that sounds simple, but you do see, unfortunately, some organizations make errors here, is just understanding your license commitments, understanding what specific license you have or what application you put in, what's the legislation that affects that? Making sure that you're compliant to all of that before inspector is on site.
Also, another key element is just having a formal inspection prep procedure, or a policy in place that includes all of these elements here. These are all core things, and we'll dig into some of these further on in the presentation, but just having a company having a formal stance of approval, that sort of lays out their approach to all these areas will help guide your staff.
Having quality system that is functioning appropriately. The term we like to use is a system that's in place and under control. But really, what we mean is, you know, a QMS that can identify issues, it can appropriately investigate them, and then it can act on anything that's identified.
And the final element, and I'll cover this in a little more detail further on in the presentation as well, is a training plan for all staff on site to educate them on appropriate behavior during an inspection, you know how to talk to an inspector, but also, if they're involved in any inspection activity, what their role is and how they can best facilitate what's happening on the day.
So these are all really core elements that should be in place prior to any inspection.
And if you have, you know, an executive level role at an organization, I would say, these are the core takeaways to make sure that these are in place and understood by everyone at your site.
Key Preparation Questions
David Jasek: So, moving on a little bit to look at these areas in a bit more detail.
One of the key questions to ask yourself in terms of inspection prep is, you know, do you know what your highest risk elements are? Are you aware of any compliance gaps your organization has? Do you have any previous commitments to a regulator?
Have those been met? Do you have evidence of those having been completed? Really, just an awareness of your organization, and how they interface with the regulator or the relevant guidance is critical to setting yourself up in order to meet the challenges.
Do you know the true state of readiness of your organization with a real emphasis on the true state? Have you personally performed internal audits, or walk arounds of departments, you know, have you reviewed any QMS metrics? Do they actually demonstrate the state of control?
If this is something that isn't in your wheelhouse, you know, have you had maybe an external expert group come in to assess your readiness objectively and provide guidance based on that.
Have you been involved in any mock inspections? You know these are all things that really need to be run through personally in order to get an idea of the true state of readiness.
A lot of organizations, you know, think they're inspection ready. But in practice, you know, they're not always as advanced in some areas as they thought they might be.
So a real understanding of the organization's maturity and what's been, you know, completed is key here.
Another element again, this seems quite simple, really. But you know, are you appropriately staffed? Do you have SMEs with sufficient knowledge, you know, do you have backups for these SMEs? If you have, you know 1 guy, who is your analytical guy, and he knows everything, you know, if he can't come into work for whatever reason, on the day of the inspection, you know it doesn't present the best picture to an inspector.
So making sure you have some depth in these areas, and then also making sure that you have enough staff to support ongoing activities as well as the inspection.
For pre-announced inspections, have you reached out to the inspector to get an idea of any pre-requests they might have. So typically they'll have a list of documents they might want to see, or general information on your site. Just make sure you're reaching out to the inspector and getting that information ahead of time to help the inspection go smoothly.
And another one that is quite simple here, in terms of just logistical preparation, is making sure that you have an audit host who's appropriate. So typically, this is your site head of quality, but it's making sure you have someone who the organization deems, you know, responsible for management of the inspection.
It very much helps to have a single organized person for that role for clear reasons.
Logistical Preparation
David Jasek: So there's also some logistical items that can often be overlooked. So I do want to spend a little bit of time to go through these again. These may seem very simple and straightforward, but a lot of thought put into them to make sure that the inspection can be successfully implemented.
So getting in touch with the inspector, not only to deal with any pre-requests they may have, but just to talk around the logistics, you know, when will they arrive on site? What's the length of the audit going to be? You know, what's the timings they're thinking?
You know most inspectors are, you know, they'll sort of meet you halfway here if there's any constraints on the site's activity. But just to have that discussion, you know you don't want to plan for them to show at a particular time, but they can't make it, for whatever reason. It again, doesn't present well to a regulatory agency.
An inspector will definitely, if they're on site, want a tour of the facility, and this should be planned to a very high degree of detail.
So planning out the route that you'll walk, making sure that it covers the areas you do expect an inspector to want to view. So it's comprehensive, but it presents your organization in the best light, you know, making sure, it sounds simple, make sure it's clean, making sure all of the rubbish bins, the trash cans are empty, making sure that all the scuffs on the walls are painted over.
You know these sort of things that will just help present your organization, you know, in the most professional manner possible. These will be helpful.
Another one is having audit meeting rooms. So the audit room and then a separate back room really should be prepared as a minimum of spaces to run the inspection, and I'll go into a little bit more detail later on these individual rooms. But you know, making sure they have Wi-Fi, they have power, they have, you know, printers, they're not in the middle of your manufacturing area, in the middle of a warehouse. They're somewhat segregated.
Making sure the restrooms are nearby. These kind of things again, it sounds simple, but just making sure that everything is in place logistically, in order to support the operation of the audit.
Personnel logistics arranged. So will you need extra staff on site for the days of the audit in order to maintain normal operations as well as support the audit itself. Have you got parking for them, you know, is there a cafeteria? How will they get food? You know, it's not going to necessarily stop for lunch. But how is this going to work? Logistically again, it seems simple, but it does need a little bit of thought put into it to make sure that you're not stuck with an awkward situation at lunchtime.
This is a really key one around making sure records are available. A lot of sites have an off-site archive or document store. So inspectors are flexible if documents they'd like to view are told off site, they understand this would take time. Okay, so this isn't a critical element in and of itself, just making sure that anything the inspector is likely to want to view, get it on site ahead of the audit, just, you know, make sure it's stored appropriately. All of these sort of things, but just make sure you can, you know, reduce any potential downtime and again, make your organization look on top of things, look a bit more professional.
So anything that's pretty core that you think they're likely to want, get that on site before the audit day itself.
And one final thing here, and this is more for larger organizations that have multiple sites. Sometimes there's additional corporate requirements, you know they may need to have legal representation on site. They may need to have, you know, a member of the executive or the sort of general manager of the region on site as well. So just make sure that you're aware of any additional corporate requirements you have here, and you can manage those, you know, according to your organization's practices.
Staff Training
David Jasek: Okay, so that was all of the logistical elements. But I did mention staff training earlier in the core items, and I really want to reiterate how critical this is. So all staff that will be involved in the inspection should undergo a degree of training.
Ultimately a single inappropriate or unguarded comment really can make or break an inspection, and I have seen this happen where you know staff untrained properly, or show inappropriate documents. They'll have, you know, totally unguarded conversations with the inspector. They will say incorrect things to the inspector. And all of these can lead you in a poor state.
So the training regime should be put in place for all staff, and there's a number of things on the slide here that should be covered under that. But I would say the top 2 are the core ones. So making sure staff can stay calm under pressure when they're talking to the inspector and making sure that they are always truthful to the inspector, are really the 2 primary things.
It is worth mentioning that you will have a list of SMEs or other personnel at your site that are likely to deal with the inspector. However, you know during the site tour or other times, the inspector can really request to talk to anyone on site.
So just make sure that everyone has a degree of training on how to engage the inspector and how to sort of stay calm, not only your SMEs, and I would say advanced training for people that, you know, will be presenting data absolutely. But a general base level of training for everyone is important here.
I've certainly been involved with issues at sites where, for example, the people at the front desk have no idea what the regulator is, you know they have no training at all, and you know they might refuse to let the FDA on site or things like that. They can really get things off to a very bad start just because no one had thought that they would need any kind of information or training.
So even just the basics really makes a big difference.
Mock Inspections
David Jasek: Another element that is strongly encouraged is around mock inspections. So these are a key tool for not only training staff for, you know, dealing with an inspection, or, you know, becoming experts in areas but also testing your background practices and assessing the readiness of your organization.
So these can be done in a whole variety of different ways. They can be very small scale to full, large scale. It really just depends on what your organization needs or what your strategy is.
A sort of general approach would be what I've got outlined on this slide here where you're kind of taking a cyclical approach. It's often similar to what you see sites do for internal inspections, internal audits, where you're feeding back. So you may run multiple mock inspections based on what you find, and each one sort of you know, improving your staff's abilities, you know, streamlining your processes, making sure that, you know, you have certain documents ready. These sort of things.
One thing worth mentioning is that mock inspections are typically run by the quality group on site. There's a real benefit to having an external expert come in and either perform the mock inspections or sort of act as inspectors, just to have an independent view on what works and what doesn't work, and to be able to provide feedback to the organization that's a bit more objective and perhaps a bit more expert.
There is significant value in your site for that.
Key Takeaway
David Jasek: So in terms of a high level view on inspection preparation, that covers most of the key elements there. One critical question, I think, is worth asking is, do you know the true state of readiness of your organization. And we did allude to this earlier, but just having a real understanding of where you are, you know, have you actually done walk arounds? Have you done mock inspections? Have you had an external group come in?
All of this stuff to really understand how ready your organization is. It's very common that sites are not as ready as they think they are for an inspection. And this can lead to issues during the inspection itself.
So I do want to really highlight, this is the key takeaway for the inspection prep section.
Managing an Inspection
Three-Pillar Approach
David Jasek: Moving on to the inspection management section here.
There's several different ways to manage an inspection. In my experience, the best way to look at your inspection operations to be effective is to really divide your organization into 3 separate pillars.
So I would call these, you know, the front room, the back room, and routine operations.
So, looking at these in turn. The front room is the group of people who are directly engaged with the inspectors. They're answering the inspector's questions, they provide any inspector with information, they have to give them summaries of what you've done on site or talking through records, that kind of activity.
The back room is a separate group of staff, and they're involved purely in supporting the front room. So they're doing no day-to-day operations. They're purely involved in getting documents to fulfill requests for the inspector, getting SMEs ready to talk to the inspector, you know, facilitating what's going on in the front.
And then the third group is really only indirectly involved in the inspection. So they're maintaining their routine operations.
So you know, you do want to keep, you know, if you have, if you have a manufacturing campaign during an inspection that manufacturing campaign should keep running during the inspection, so you will need people to do that activity to ensure that you're being compliant to your organization's policies.
And just to make it look like you have a functioning site, even if it is a slightly reduced, you know, workforce or working pattern. You know, if the inspector's on their tour and they just see a complete ghost town with empty benches, no one around, empty rooms, nothing happening in the warehouse that is a bit of a red flag, and that can cause them to push and investigate certain areas. So just keeping routine operations running is an important part of the inspection operation.
Opening Meeting
David Jasek: So I want to go through and look at some of the key elements that happen during an inspection, and one of them is the opening meeting. So this is essentially, really the first event of the inspection. This would happen in the front room, and you would have a set of attendees that are listed out here. Critically, please make sure you have all people that are named on the license, if possible. This is another common error that we see that regulators like to see people that are named on the license, that they're real people, they can judge their effectiveness.
So during the opening meeting there should be an opening presentation to sort of update the inspector on your site, type of activities done, types of, you know, products that you manufacture, anything that's changed since last inspection. Really just an overview of events that have happened.
Often I see what's happened, and no offense to my colleague Oli from the introduction, but try and keep sales and business development people off this presentation, because what can happen is it becomes a bit of a brag where they can talk through, you know, sales numbers, or, you know, customers, and these sort of things. That information, there's nothing wrong with that. But that's not really appropriate, and that's not something that the inspector is going to really care about.
Just make sure this is put together by, you know the appropriate people with the appropriate information there for the inspector.
Also, during this opening meeting, is a really good opportunity to confirm the agenda and the scope.
You know, as I mentioned earlier, there may be, you know, if you have a manufacturing campaign, maybe you know your head of manufacturing currently can't attend outside of his other duties. So he's only available in the afternoon, or something like that. That's generally fine, as long as you're upfront about communicating to an inspector and you can set up, you know, rough agreed times for these things. It tends to not be an issue. But you just want to make sure you can confirm all this with the inspector so you're being transparent.
There's usually some pre-requests that have already gone out to the inspector. But based on the opening meeting, or just based on their current thoughts, they may want some additional information straight away. This could be as simple as a list of procedures you have on site, or maybe some core procedures they hadn't seen, you know, information around your site master file, or your license, things like that. Just make sure these are ready to give to the inspector. They often come up.
Back Room Operations
David Jasek: So that's the sort of opening meeting at a high level. I do want to look at the back room operations. So this is something that doesn't always get as much attention as it possibly should. So I do want to spend a little bit of time going through this here, because it is a really critical part to having a successful inspection.
So the back room as mentioned previously, is responsible for sort of gathering requests and submitting all that information to the front room to present to the auditor. So, having clear reporting lines is absolutely critical here. You want someone with authority, someone who is going to be appropriate in that role, a single person who can clearly communicate what's happening.
There should be scribes in the front room during an inspection. So just note taking what is happening, what the inspector is saying, what the request might be, that sort of thing. Ideally, if you have the capability, getting this transmitted live into the back room is a huge benefit. So you know, it can be someone typing in a, you know, a Google Doc or something in the front room and a TV in the back room that's displaying that just to keep them updated on what's happening in the room.
This is really important for making sure they're on top of things and they get some context around the requests.
Request tracking system. So this is absolutely critical. There's a lot of different ways to do this. Some e-commerce systems have this built in, but that's not needed necessarily. You know, you can use again like a Google sheet or something like that. It is totally fine. A shared spreadsheet works well. Paper based systems can work well. It depends what your organization is comfortable with and what the scale and scope of the inspection is. So a lot of different ways to do this. But the key thing is making sure that it works, you've tested it out, you can track things, you can reconcile requests.
So basically, whatever works, as long as you practice it, and everyone's comfortable with it, that's what we should use.
So apart from request tracking and issuance, reviewing requests is the other critical activity for the back room itself. So everything that goes into the front room really should be reviewed in the back room to make sure that it's complete and accurate. So this can be as simple as being sure all the pages, you know, if you printed something, all the pages are there, or they're in the right order. Or it may be correcting minor issues in documents. All of that is fine. Just make sure you're following your procedures at your company for corrected documents. If something's already been approved, you know, take care for correcting it, because the inspector will see what's happened.
Providing Data to Inspectors
David Jasek: So we've been through some of this already in terms of providing data directly to inspectors. If you're giving electronic documentation, I would say, try to use PDF or locked copies that can't be edited, if you're giving them to an inspector.
Some inspectors will want to see someone use the system. If you have a, you know a LIMS system or an eQMS, they may want to see how it functions in practice and pull up records. That's fine. Generally, the best way to do this is someone from the back room, you know, to go into the front room to sort of, you know, act as the hands of an inspector. You don't want an inspector to have direct access to these systems. It should go through an intermediary who's an expert at your site to just make sure that you again, you can practice this and also just make sure there's as little ambiguity around requests as possible.
Inspectors generally have no problems clarifying a request, and as long as you're transparent and making it clear that you are trying to fulfill it, you just want to make sure you're doing it in the right way. It's not a problem to ask a clarification question or 2 around a request.
Fixing Issues During Inspections
David Jasek: Another element that comes up often is, should we fix things during inspections? I would say generally, no. It does depend. If there's a small error that can be, you know, fixed quickly, that can be done. But care should be taken around this. If it's something that needs an investigation in order to address the root cause, or to resolve, then that shouldn't be rushed. Your process should be followed for that.
You know, ultimately, if something's identified, if a gap is identified by an inspector, and you rectify it, you know, somehow, during the inspection, that's almost certainly going to still be listed in the audit report itself. That's not going away. You may be mitigating the severity of the issue, but you're not resolving the issue. So the kind of utility of fixing things during inspections, it really does vary. It's something that should be done carefully.
Handling Difficult Inspectors
David Jasek: Okay, so handling difficult inspectors. So number one, I'm going to have to ask Heath Coats to close his ears for this section. As an ex-FDA inspector, unfortunately, some inspectors can be difficult to deal with.
So I have a couple of key points on here just to set some principles.
So number one, don't try and argue with an inspector. You probably won't win, and you'll only irritate them. So just leave that to one side. Don't argue with an inspector. There will be an opportunity for you to give a formal response to the inspector's findings, and that's not necessarily on the day to the inspector's face.
But don't argue with them. Try to not get defensive about their findings, even if they may be unreasonable or coming across, you know unprofessional.
I've brought this up several times, but be really careful who talks to the inspector, you know, make sure where you can. These are people who are composed and knowledgeable.
Ask the inspector what their specific concerns are, you know, if they're getting a little bit worked up about a particular issue, just ask them to clarify, you know what is the specific thing that they're worried about? Is it a patient safety issue? Is it a compliance issue? You know, what are they concerned about? And then you might find, if they have a little bit more clarity there, that you can address at least part of what they're worried about.
And this kind of really follows on if you can't directly address the issue, you know, maybe there is a gap that your organization just wasn't compliant in. That's fine. You can, you know, provide some background and context for what's going on which can help to defuse the situation a little bit. You may want to again be a bit careful here, but things like, you know, meeting minutes or things like, you know, drafted documents that may not be fully issued yet.
These can be useful. They can also open you up to potential other areas of investigation. So there is a balancing act here that you're going to have to sort through on an individual level.
But these can be tools to help mitigate the severity of a finding from an inspector.
Yeah, so just, I guess in summary kind of, you know, kill them with kindness. Just be nice to the inspectors. It's basically you won't win an argument is my fundamental advice here, so be as nice as possible. Try and fulfill all of their requests, you know, in a depth and composed manner, as you possibly can.
I do also want to mention the kind of flip side of this. Be aware of the silent treatment from inspectors. I've seen this happen where inspectors will just be very quiet, you know, they may review documents, they may look at you, they may not say anything, for, for you know prolonged periods of time, you know, wanting you to sort of fill the gap.
You know, that can be fine. Just be aware of what's happening here. You don't want to volunteer information, or you don't want to accidentally, you know, address things that are either incorrect or give the wrong context for something. So just be a bit careful here, you know, inspectors, they're very tricky, but they're very clever. So you want to be appropriately respectful.
Audit Closure
David Jasek: Okay, so moving on to some elements around the audit closure itself.
So the inspector will have their own wrap up meetings and their own sort of closure process for the audit. But if it's a, you know, if it's a multi day inspection, it is a good idea to have your own internal wrap up meetings to talk through what's happened, prepare for the next day, you know, do a bit of a temperature check, make sure everyone's on the same page with how they felt things went.
And for the final wrap up meeting, you know, with the inspector itself, attendance ideally should be the same as the opening meeting. And this meeting is led by the inspector. They'll say, you know roughly how long they need, you know, that would be the timing of it with you. Something that they will arrange.
I did mention this on the last set of slides, but you know the inspector will give you initial feedback during the wrap-up meeting. That's fine. Just make sure that you know you will be given an opportunity for a formal response, and it's not necessarily the best thing to have a gut response if there's any negative findings during this wrap up meeting.
That said, do make sure that you fully understand all of the inspector's findings before they leave site. So there's nothing wrong with, you know, asking for clarification, asking for additional information. That's good. The more information you have before the inspector leaves the better.
So just make sure that you know everyone is aware of the findings from the inspector, and you can then talk through how to begin to respond to them, which leads us into the final section of the presentation.
Inspection Response
Response Timelines
David Jasek: Okay, so you've prepared for your inspection, inspector's been on site, you went through the whole process, you had a nice closeout meeting, that was lovely. When should you expect a response? Now again, the answer is that it depends. Unfortunately, it really just depends on the different regulatory body and the different sort of format and type of the inspection.
So what I've got up on the slide here is just 2 examples, one from the MHRA and one from the FDA. So from the MHRA, they have, you know, fairly strict timelines on the issuance of the report, and when responses are expected.
For the FDA, for you know, pre-license inspection or pre-approval inspection, they will give you initial feedback in a Form 483 at the closing meeting itself, and responses should be, you know ASAP. So really for both, at the end of the closing meeting there should be an immediate turnaround from your organization in order to prepare the grounds for a response, and I'll go into how best to do that in the next set of slides.
Yeah, just one thing that if there's anything absolutely critical, all timelines go out the window. You'll hear back from the regulators as soon as possible if there's an identified patient safety risk that will obviously get escalated.
Possible Outcomes of Poor Inspections
David Jasek: Okay, so if you do have a poor inspection, what are the possible outcomes of this?
There's quite a wide variety. This can lead from anything to like sort of enhanced scrutiny, your organization seen as a little bit of a higher risk all the way through to, you know, loss or suspension of your license, or import or export bans.
And there's a lot of different steps on the way that, depending on the particular severity of the inspection findings. So getting an inspection finding isn't great, but it's not always the end of the world. It really does depend where you land on this scale, and one way to, you know, make sure you're near the higher end of the scale, you know the enhanced regulatory scrutiny end, is to make sure that you have a really robust audit response. This can put the regulators at ease and put your organization in the best stead to be, you know, compliant in the future and to remediate.
Inspection Response Strategy
David Jasek: In terms of the inspection response strategy, really, immediately after the inspection, immediately after the closeout meeting, if possible, or as soon as you can get to it, a formal cross disciplinary group should meet to discuss the outcome of the inspection and discuss the inspector's comments.
So any activity done by this group should be documented, you know, within your QMS. And evidence of any completed actions should be recorded, you know, appropriately. You should start that process immediately.
But the really critical first step for this group is what's on the slide here, you know, is the site under control, you know fundamentally, is there a patient safety risk? Is there a market action that needs to be done to address this.
And you know, obviously, hopefully, that should be no. And in almost all cases the answer is no. But it is a really critical first question for this group to address.
And then, as mentioned, start working on a response really immediately, you know, well in advance of any formal inspection report that you might get from the regulator.
That said working on a response doesn't necessarily mean completing actions. It may mean, you know, starting investigation to determine the root cause. And that's fine and appropriate, and that's what should be done. But just to get the ball rolling on that so you can have a robust response.
Response Structure
David Jasek: So in terms of the response itself, there's several different ways to write a response. I think this schema that's outlined on this slide is something that I've seen be very successful in the past.
So making sure the response addresses each individual deficiency that was identified, and you cover what actions the organization will take, the date that these actions will be completed, any intermediate controls, and then any retrospective review, if appropriate.
So I have an example that talks through these on the next slide.
But I do want to mention that you know there can be quite long-term actions. If significant investigation is needed, or, if you know, significant, you know, facility modifications are needed. This can be very long term things, and they can go through many different, you know, updates and iterations in order to satisfy the inspector.
So just to warn you in advance, this can be a lengthy process, both in terms of writing and in terms of completing the actions.
Response Example
David Jasek: But I do want to talk through a specific example. So I've just got a, you know, hypothetical example here. Let's say during the regulatory inspection, inspector viewed the deviation for a failed HEPA filter in a grade B area of the manufacturing suite, and determined that the deviation was insufficient, and it wasn't appropriate.
So as an example, way to respond to this inspection would be following the schema from the previous slide. It's to get a cross functional group to raise a new deviation, to investigate this, and to fully assess.
This deviation would identify the root cause, and then it would identify appropriate CAPA to be raised that would fully address the root cause of the deviation. That's the core action that you would take there as a remediation.
Your due date, your commitment to the inspector would be the estimated completion date of your CAPA. Again, this should be realistic. No inspector from any agency likes to hear you say, can we please extend this commitment? That's never going to be a conversation that is particularly well received.
So, in addition to your due date, this is a good example of where a review and implementation of intermediate controls should be performed.
So does the room that had the HEPA filter failure, does it currently meet grade B conditions? Do you have evidence to support that? Do you have trending data? Do you have your EM controls? How can you objectively verify?
And that should be included in your deviation and your response. If the room doesn't meet the specification, it should be placed out of use as a control.
And then also, this is really crying out for a retrospective review. So between the previous HEPA leak test and the HEPA failure, you know, how was the room used? Were any batches made, is there any risk to these batches? You know this should be assessed in your review, and this would be considered, you know, a robust response to what the inspector's finding. You weren't just addressing that he didn't like the deviation, you're addressing all the potential impacts that have come from that issue. And then you're having a more robust deviation investigation based on that. This is sort of the expectation of the gold standard that an inspector would want to see from the response.
Follow-up Communication
David Jasek: And then briefly, wanted to cover just communication or follow up with the inspector or with the regulatory agency. A lot of different ways to keep in touch. It does depend a little bit on the particular regulator. Some inspectors really want to see a lot of progress updates that may have a specific way they want them communicated. Other inspectors may not want them.
But fundamentally, it does depend a little bit, not only on the individual inspector or the regulatory agency, but also the severity of any findings or any remediation actions that you've committed to.
So the quick answer here is, you know it depends. But just make sure that you do have a way of communicating with the inspector, and you can update them on the status of the inspection and the remediation actions.
Summary
David Jasek: Okay? So that really covers the bulk of the presentation. I have a very quick summary slide here before I move on into the discussion and the Q&A section today.
Number one point to take away is that preparation before inspection is critical to building towards a successful outcome. Practice of audit roles, responsibilities, logistics, processes that you're going to follow for your back room, the more well-rounded and the more practiced these are, the less risk and error you will see during an inspection. And the final thing is that it may sound obvious, but a comprehensive and robust response to the inspection will leave your organization in the best possible position to move forward with the regulators.
And if all of these things are executed appropriately, then, you know ideally, your organization will be viewed as low risk by regulators, and you're likely to have either less frequent inspection schedules or, you know, less onerous regulatory oversight, because you're considered, you know, effectively a safe pair of hands, which is how your organization should want to be viewed from a regulatory perspective.
Okay, well, thank you everyone.
Q&A and Panel Discussion
David Jasek: I will now move on to the Q&A and discussion section. So if I could ask everyone, sorry everyone, all of our panelists to turn their cameras back on, please, and unmute themselves.
Thank you. So doesn't look like there's many questions in the chat. So I might just move ahead to the discussion section itself. So Stephan Croft, I did have a question I was hoping you could talk to.
I find that organizations often struggle with, you know resource or focus or sort of manager buy-in for inspection prep activities.
Is this something you can discuss on how you know if you're a quality professional or you know, regulatory professional at an organization, you can help your internal management with this and maybe get some resources towards the preparation side of things.
Stephan Croft: Yeah, absolutely so. Hopefully, everyone can hear me and apologies if there's any background sound there. My son's having a meltdown in the background. So you can start off with an organizational survey. And this could be driven from any level in the organization. And we have to understand that when we're talking about inspection readiness, we can be talking about a site level or multiple sites within a network. But with organizational surveys generally low cost, they tend to be quite quick, and you can get an immediate feedback on a temperature check on people's experience, the levels of engagement, the levels of where they believe at the different levels in the organization their maturity is in respect to the awareness of the risks of inspections and audits and also on their ability to successfully host and close out because there's a whole loop there, as you mentioned earlier, David. So organizational surveys can look at the experience of an inspection team in actually handling the logistics of the inspection, understanding the legislative responsibilities and requirements for an inspection, understanding, as I say, the logistics of hosting an inspection, and then the follow up and close out.
And the other area is you can go through, and you can look at educating management at the various levels to make sure that they understand what the purpose of inspections are, the risks of inspection should they go south, to look at how inspections should be managed really is a reiteration of a lot of the material that you've put out David, but obviously making sure that the feedback and the information that we provide to management is up to date and aligned with the competent authority that is potentially inspecting you.
And one way to sometimes help this is identify and negotiate a sponsor as part of the program, so that management know that somebody senior in the company has sponsored it, that they are a stakeholder on the executive hopefully level. And that is important because you need someone to open doors for you.
You can look at when you start to develop an inspection readiness team, you can look at those that are interested in becoming a part of the team, because if people volunteer or they include it as part of their individual development programs or continuing professional development, they're obviously giving it willingly and they're motivated and engaged. So looking for the right people who can benefit from this. And they're going to be interacting across the organization at all different levels, potentially different sites.
And the other part is brainstorming areas of risk, of failures where things, you know changes in legislation, changes in the company that may have exposed risk, technology failure, events that have occurred, previous inspections, and all the highlighted areas of risk.
So again, there are areas to brainstorm looking at if you've got multiple sites is to look at the deficiencies that have been seen across multiple sites to make sure that if an event happens at one site it's not repeated across the network.
And then obviously building procedures and monthly routines and follow up actions and make sure that you know you're considering the use of mock inspections to highlight areas of failure or risk or immaturity in the organizations. And actually, you can use that and build that in as part of your self inspection program.
Hopefully that helps you there, David.
David Jasek: Yeah, thank you, Stephan. That was really good. We just had a question coming that I'm going to throw open to the whole panel here.
If an inspector, you know, during a regulatory inspection, if an inspector finds you for something that you can't find in the regulations, what is the best way to handle this? And I might start with Heath on this one.
Heath Coats: Sure, I'll go ahead and take a step with that as well, you know. Again you alluded to early in your talk about the varied inspection techniques that inspectors choose to use based on their attitudes and how they conduct their inspection. We also need to remember that the CFRs were written very generally to allow for interpretation by sponsors and applicants.
Well, unfortunately, sometimes, that liberal or subjective interpretation is also performed by inspectors as well, and sometimes you do run into situations where an inspector can either misinterpret one of the regulations, or just attempt to cite a firm for something that isn't in the regs. I'll refer back to what David had talked about during the talk, and that at some point in time you have to make the decision, it's no longer beneficial to have this argument, or have this discussion with the inspector at that point in time. You will have the opportunity and the responsibility to respond to your 483 observations, and then my suggestion would be, is in your response to that finding you quote your interpretation of the regs, and why you feel that this is not a regulatory relevant finding.
David Jasek: Thank you, Heath. Did anyone else in the panel want to comment on this question.
Liam Breen: I guess it's good to point out that even if it's not in the regs, if the intent is patient safety, it's always okay to do a bit better, meet them half way and try and step up to them.
Stephan Croft: I probably just flag an area of risk, David. I think that we absolutely should go back to any inspector if we believe fundamentally they've misinterpreted, or they've got the wrong angle on a deficiency. Because one of the stakeholders we have to represent is ourselves and our companies.
The area, though, that we need to be very, very sure of, though, is that we understood the deficiency in the first place, and we fully understand the clause that the deficiency is being cited under.
If we misrepresent ourselves, there is a chance that the inspector loses trust that we understand how to run our operation and loses trust and confidence in our ability to remediate. So we just need to be careful there when we push back. But if we do need to push back, we do it very respectfully, and we can recite our position.
David Jasek: Yeah, that's another good point. Thanks again, Stephan.
Closing Remarks
Oliver Ball: So I think we are just about out of time for today. Thank you all very much for participating as a reminder. The content will be available on demand so details of how to access that will be circulated after the webinar otherwise you can find your way to the contents on the Dark Horse website.
Please do join us again for our next webinar, which will be on the 25th of October on phase appropriate analytical developments. Details of that and other upcoming webinars will be available online.
So thank you all for coming. And we look forward to seeing you for the next one.
Thank you panelists.