October 25, 2023
Host: Oliver Ball, Business Development Team, Dark Horse
Presenters:
Opening Remarks
Oliver Ball: Okay, so welcome, everybody. Welcome to the third in the unbridled Excellence webinar series by Dark Horse consulting group.
My name's Oliver Ball. I'm part of the business development team here at Dark Horse. This is now the third webinar in the series, and the purpose of which is really designed to give the wider cell and gene community some insight into some of the common challenges that we see in the cell and gene space.
Dark Horse has a pretty deep reputation and experience base in the field. We've now had, I think, over 350 clients, all in the cell and gene space across about 700 projects over the 8 or 9 years we've been running.
So we're pretty uniquely positioned within the sector, and I think this gives us a good platform, and a good opportunity to share some of the insights and experiences that we've generated across that client base for the benefit of the wider group.
So I just wanted to highlight very quickly before we start a couple more webinars that we've got coming up soon, because there's more to come, and I'm very excited about the next 2 that we have.
The next one coming up will be a regulatory roundup live event, where we actually will have 5 of our regulatory experts meeting for a panel discussion and the topics there will be fairly wide-ranging across current regulatory affairs issues in the cell and gene space.
So there'll be a discussion of recent trends with FDA. Some touching base on some of the advisory committee meetings that are happening at the moment, including the Brainstorm and Vertex meetings.
There'll also be discussion on the recent comparability guidance that was released in draft format which Tal actually was leading authorship of when she was at the agency earlier in the year.
And they'll benefit, not just from their ex-FDA experience, but obviously also the experience that we have interacting with the agency through our clients, which we do pretty regularly. So we're pretty tuned into how the agency is thinking about current topics.
If you have anything in that area that you're interested in us touching on during that discussion, then do put that information in when you register for the webinar, and we can make sure that it gets covered. Otherwise you can also actually submit questions in the event itself. And once you join up, so that's happening on Tuesday, November fourteenth. I think it's going to be a really good one, so do make sure to register for that.
The final one of the year is going to be with our managing partners, Katie Spink, Anthony Davies and Rob Allen, which will be a round up of the 2023 year trends from the calendar year, things that we've observed, and looking around the corner into 2024, what we can expect to come, how we can expect the economic situation to develop.
So again, the 3 here have some really fantastic perspectives across the industry, and that I think you'll all find very valuable, so do make sure to dial in on December thirteenth for that.
So now on for today's events. Unfortunately due to personal circumstances, Alicia is not able to join us today, but she actually generated a lot of the content for this, and Brent is going to be stepping in to fill her shoes on today's webinar.
Brent's one of our principal consultants at Dark Horse, he has very deep experience in analytical development. Previously VP of process and analytical development at BioPharma and director of analytical development at CRISPR Therapeutics. So a really important expert in the field.
Josh Beckett is a senior consultant at Dark Horse, who also has very deep experience in analytical method development, tech transfer and validation, particularly on the gene therapy side. Having previously been at ThermoFisher's Assay Development and Analytics group.
So just a quick reminder before I hand over to the main presentation that you can submit questions using the chat function of the Zoom interface which will be discussed in the Q&A session at the end of today's session. So if there's any topics that you're interested in us discussing, please submit those into the chat box and Brent and Josh will get to them later in the talk.
So finally, the recording, there is a recording of the webinar that will be available for you to view on demand, share with your colleagues. Details of which will be circulated after the webinar.
So without further ado, I will hand over to Josh, who will drive the first half of the presentation today. So over to you, Josh.
Part 1: Introduction to Phase-Appropriate Analytical Development
Introduction
Joshua Beckett: Thank you, Oli, for the introduction. Hi! And welcome everybody. My name is Joshua Beckett. I am a senior consultant here at Dark Horse, and I've been with the company for almost 4 years now.
Today, we are here to discuss phase appropriate analytical development. You know, we get a lot of questions from clients, not only about how to develop an analytical program, but also about the when.
And really the challenge with cell and gene therapy is, there's not very detailed guidance around a lot of this, and we thought it would be helpful to provide some insight and how we've helped clients in the past.
So in the first half of the webinar I will introduce phase-appropriate analytical development and how that approach can help make decisions around things like characterization versus release testing, qualification and validation. And then I will go through a high level, analytical development pathway that goes through different stages of a product's lifetime.
For the second half of the webinar, my colleague Brent, will discuss potency testing development and how that really fits into this phase appropriate approach. So I will note that you know, the topics we are discussing today are very complex, and many could be the subject of their own webinar. So today really is kind of this high level introduction to the concepts.
Primary Aim and Challenges
Joshua Beckett: So really, the primary aim for any analytical development activities in a cell and gene therapy program is to really produce a robust program, and that robust program should yield reliable and consistent data, early phase suitable, scientifically sound methods as well as late phase validatable methods.
And now, for cell and gene therapy specifically, there really are 2 main challenges to this. Number one, you know, the sponsor may not have enough experience with the product or method in the beginning.
And because of this, you know, the analytical focus may need to shift throughout the development of the program and number 2, you know, phases of development may be condensed or even skipped, totally due to rapid clinical timelines.
So this is where clients tend to have a lot of questions for us. For example, you know how thoroughly do methods need to be developed early on? Do they need to qualify every method, and really at what level of qualification is actually suitable.
So overall, you know, sponsors need their clinical programs to advance. And for this to happen, sponsors need a robust analytical program.
But the beauty of all of this is not every method needs to proceed at the same pace, and not everything needs to happen at once. And this is really where that phase appropriate approach can be beneficial.
What is Phase-Appropriate Approach?
Joshua Beckett: So what is a phase appropriate approach? You know, in addition to the data and the methods I discussed in the last slide, there are a lot more factors that actually go into a robust analytical development program. These are things like cost. We all know, materials and reagents are very expensive in this field. You have timeline efficiency, resource optimization. It takes, you know, specialized, highly knowledgeable and trained personnel for this field as well as things like regulatory compliance.
So really, to optimally proceed in development, all these factors will need to be balanced because you can't do everything upfront, and if you wait too long you won't have enough time to develop that robust program.
So throughout development you may constantly be weighing these factors against each other. At a different stage of development, some of these factors may be more important than others. So in the next few slides I've discussed some areas where sponsors can consider taking a phase appropriate approach.
Characterization vs. Release Testing
Joshua Beckett: So one of the earliest possible, you know, phase-appropriate choices a sponsor can make is the choice of which methods will be considered characterization and which will become release testing.
Throughout development, several methods will be considered to assess the quality of a product, because ultimately, in the beginning you don't know which of these methods will have meaningful outcomes. So in early development, the sponsor's not having enough product knowledge, but they still want to be able to test all the relevant attributes with the best tools that they possibly can, really as a way to characterize their product as much as possible, really, in the end, looking for that meaningful release panel. So you want to do this, but you want to do it in a way that is also consistent with your resources and timeline.
So one way of doing that is a lot of sponsors will take a matrix approach to testing certain parameters. You know, this includes using several methods to test one parameter early and then really whittling down methods as development continues.
Along with not knowing, you know which methods will have a meaningful outcome, there will be the possibility of not having available method to actually assess every parameter of your product. You know this is where surrogate methods may be needed to be introduced early until a better method can be developed.
You know, example of this is, you know, using an infectious titer method, you know, as your potency readout while developing a functional potency method based on your product's mechanism of action.
And in reality you can't really qualify or validate every method that you've ever used which will lead us to another issue a sponsor may have to continue with.
Qualification vs. Validation
Joshua Beckett: And that will be when to qualify and validate your method. But first you know, what do really each of these mean? You know, I will acknowledge there's a lot of confusion in the industry around these terms. You know, the term qualification for methods doesn't really appear in any guidance, and the terms are often used interchangeably or inconsistently, which can lead sponsors to either not having the right amount of rigor in development, or really trying to overdo development.
So, starting with validation, this is more straightforward. You know there is a formal definition, along with several guidance to use when you're ready to validate your methods. These guidance include things like choosing which parameters to test for what type of methods as well as statistical analysis tools that you can use to evaluate your data.
And really, although there are guidance written, there still are some gaps in these guidances for the cell and gene therapy field.
On the other hand, we have qualification. You know, this is a little different. There is really no shared understanding of qualification. The definition of a qualified method may vary from sponsor to sponsor. But really, in the end, you know, methods are required to be validated, and it is going to be up to the sponsor's responsibility to really define and justify what they understand is qualified.
Really, in a perfect world, you know, a sponsor would probably just validate every method they could as soon as possible. But we don't live in this perfect world. So in various stages of development, you know, as a way to balance those factors, you know I spoke about earlier, things like cost, timeline efficiency or resource optimization, you know, a sponsor is going to choose to validate their methods first.
And really not all methods need to be qualified at the same time, or to the same level. You know, qualification should really be tailored to the method's intended use and used to confirm, and really qualification is going to be used to confirm method performance for key attributes, such as specificity, reproducibility, and in some cases sensitivity.
For example, you know, a method might be used as a qualitative test in early development, and you would only need to qualify a few parameters, say specificity and limited detection, you know, but as a sponsor gains further product and method experience, this qualitative test may need to evolve into a quantitative test, and then a larger set of parameters will need to be evaluated in a subsequent qualification.
So in general, you know, the term qualification is used to mean that the method is suitable and fit for purpose. But this really means that each sponsor, what this really means is that you know, each sponsor is going to have to decide what that definition is, and eventually justify that.
Analytical Development Pathway Through Product Stages
Joshua Beckett: So in the next few slides, I will illustrate a very high analytical development pathway through different stages of a product's lifetime.
Early Development
Joshua Beckett: So in the beginning, a sponsor's main analytical focus is on method selection and early optimization of those methods. You know, at this stage of development a sponsor will not have enough experience with the product or methods really to be able to start qualification.
That said, you know these methods still should be scientifically sound. Now you ask, you know what is scientifically sound? Again, like qualification, there's no shared meaning you know, of this term, and this will need to be justified as well by the sponsor. But really, you know, you can justify this by taking into account your experience with the product as well as what's going on in the industry today.
You know, at this stage we see a lot of clients with a wide range of development of methods. A lot of them are still in the research level, and a lot of clients will come to us to help transition those methods into a GMP setting.
I do want to caution you, though, that for important methods that you use, things that define dose, safety assays, say, you know, off target editing for gene editing projects, you know, these methods, if not really developed carefully in the beginning, can cause major problems in later phases.
Phase 1
Joshua Beckett: Moving on to phase one, you know, a sponsor's main analytical focus here is on implementing their testing panel. You know at this point, it is at this point where we recommend a sponsor should really start to think about qualification. Again as noted before, qualification involves confirming the method's performance for key attributes consistent with the method's intended use.
You know, methods can be partially qualified at this stage, you know, it's not an absolute requirement. But there will be scrutiny given to those important methods I mentioned in the last slide. Things like dose defining and safety assays.
And really what methods you choose to qualify and when is really dependent on your program. We have a lot of clients in the rare disease space that want to use earlier data for later phases. So you know, they will have methods that will need to be qualified earlier than other clients.
It's understood that as a sponsor progresses through phase one, and even into Phase 2, they still might not have enough information, enough experience with their product or methods to really be able to fully qualify them.
And also from aside of not having enough experience to qualify method, material roadblocks or material limitations can be a real roadblock at the earlier stages, as there might not be suitable material manufactured to start the qualification process.
Phase 3
Joshua Beckett: Moving into phase 3, you know, here the sponsors should have enough experience with the product, and the method needed to, you know, start fully qualifying. Again, remember, qualified methods are required going into pivotal studies. But again, there's no formal definition or criteria to deem a method qualified. And this is really something that the sponsor's going to have to define and justify. In general, you know we recommend qualification to be a protocol driven activity. A lot of clients we see will use the ICH guidelines without robustness to structure their qualifications. You may or may not have predefined acceptance criteria depending on the method, but we do recommend that clients use qualification as a dry run for validation. We also recommend that clients get buy-in from agencies on your qualification plans or protocols, as this will make sure that you and the agency's expectations align.
And as the sponsor proceeds through those pivotal studies, they will continue to gain experience with the product and methods really needed for those commercial activities.
Commercial/BLA Stage
Joshua Beckett: So finally, we're at a point where the sponsor will have enough knowledge of the product and methods to fully validate them. You know, again, like qualification, validation is a protocol driven activity. You may repeat some qualification studies you did in the past, or you may totally reevaluate all parameters needed. Again, you will follow the ICH validation guidelines this time, including robustness.
But really unlike qualification, validation is going to require predefined acceptance criteria, and using qualification as a dry run for validation, you can get this acceptance criteria tested during the qualification and then tighten or redefine for validation.
You know, method SOPs and validation protocols will also need to be pre-approved before use.
Post-Approval
Joshua Beckett: So once the sponsor has all their methods validated, you know their primary focus will then shift to data trending as well as continued verification of method performance.
There is always going to be a possibility of a revalidation of a method, you know, and this can be due to things like changes in instruments or discontinued instruments, discontinued reagents as well as things like post-market commitments to update or replace existing methods.
So really overall, you know, this cycle of continued verification of method performance and possible revalidation really never stops.
So now I will pass the webinar on to my colleague Brent, to go through the second half. Thank you.
Part 2: Potency Testing Development
Introduction to Potency Testing
Brent Morse: Yeah, so as Josh mentioned, I'm going to take us through the second portion of the talk. And so, just to briefly recap what we've discussed so far, so Josh introduced the concept of phase appropriate analytical development, and we discussed some of the early decisions that you might need to contend with in the context of this phase appropriate development. And we went through some of these stages of product development, and how this how this might apply to the what and the when of phase appropriateness.
In my section of the talk, I'm really going to be focusing on phase appropriate assays as applied to potency testing. And in particular, I'll introduce some concepts with respect to potency testing of cell and gene therapy products.
I'll introduce the idea of a potency matrix and then go into a discussion about what is meant by a more biological potency assay as opposed to more early stage assays. And then I'll provide some examples of how you might implement this phase appropriate potency assay strategy.
Regulatory Environment for Potency
Brent Morse: Alright. So when we discuss potency testing with clients, you know, there's inevitably a lot of questions that come up with respect to how much validation do we need? And when? You know how rugged do we need to approach this, what guidelines apply? And when?
So in the context of potency, given the complexity of it, you know, these questions start to converge, and it really can be a source of difficulty to contend with, particularly if you don't address it early. So this is something that you know, we've had a lot of experience and a lot of need to address in the industry. And this is something that we've gotten a lot of experience addressing.
So I think first, the first place to start is with the regulatory environment itself. So in relationship to perhaps the wider cell and gene therapy space, there is quite a bit of regulatory guidance with respect to potency assays. So whether it's FDA or EMA, or some of the ICH and USP type of guidelines, there is a fair amount, body of work and a fair body of information that you can draw upon as you think about putting together your potency assay.
It should be noted, however, that particularly with cell and gene therapy, the mechanism of actions can be quite complex. And also these can be, you know it can be difficult to apply the particulars of your situation within the framework of what can be some fairly vague guidances.
Potency Matrix Concept
Brent Morse: One of the first things you should consider when you're thinking about what types of potency assays you want to implement is that it really needs to be a matrix, right? So your product is going to have a lot of biological effects on the system. And so your panel of assays really needs to account for ideally all of them or certainly as many of them as you can.
And so what we've placed in this slide is just an example of different approaches you might take with respect to the matrix, the assay matrix for different types of products. So you can see with a viral vector product, maybe it's primarily infectivity and titer early on, and you know, perhaps in later phases or ideally, in early phases you implement a biological potency assay.
In the modified cell based therapy space, whether that's by gene editing or viral vectors, the types of assays may differ. So for a gene editing product, maybe early on, an on target editing assay may be a good surrogate for early phases. Likewise you may look at a percent of a cell surface marker that may be affected by your gene editing process.
And again, particularly for later phases, you're going to want to implement a biological potency assay. Now, when you think of viral vectors that can combine both the gene editing and some of the aspects of viral vector types of products. So you might have a percent, you know, percent positive cells. You might look at things like transduction efficiency, or transgene expression early on. VCN could be a surrogate potency assay.
And then ultimately, as with the other modalities you are going to need ultimately a biological potency assay. So the overall, the theme I want to impress upon everyone is that for these products, these complex products, you're going to need to consider a number of different assays. They're going to need to be tailored to your product.
And ultimately they're all going to need to have a biologically relevant assay that's consistent with the product's proposed mechanism of action.
Biological Potency Assay Characteristics
Brent Morse: And so before we go too much further, what do we mean by biological potency assay? So as defined in the guidance, this really is an assessment of the ability of your product to exert a biological effect in a biological system at a specific dose.
But on this slide what we have are some other features of this assay that we need to take into account. So your assay needs to be quantitative. And so that's because at some point you're going to need to have a numerical acceptance criteria.
Later on, if you need to use this for comparability, you're going to need to have, it's going to need to be quantitative so that you can set quantitative criteria. You're going to need to set product specifications that are quantitative.
So you really need to focus on the quantitative aspect. It's going to need to be, as Josh mentioned in the early part of the talk, it's going to need to be qualified, qualifiable, and validatable in later stages.
The assay needs to be tech transferable, and it needs to be able to be applied in a QC setting.
Now we can move to some of the should or nice to haves. And these in most cases they are also must haves in most contexts. Things like a potency matrix, not an absolute requirement in most cases. But functionally, it's something that you more or less, will need to have to hedge against the possibility of an assay failing later in development.
It needs to align with the biological mechanism of action. It should be stability indicating. There needs to be a correlation, at least to some extent between the clinical data and your potency results.
And you really should consider engagement early and often with regulatory agencies, to advance the particular assay. That'll be critical to understanding what the agencies are expecting in this context.
Now, if we now going to what the assay won't be, it's likely not going to be a platform method. These typically, are very complex assays or complex assays that are trying to model complex mechanisms of action.
And with few exceptions, you're going to have to specifically tailor it to your drug.
And then the qualification and validation probably isn't going to be a straightforward process. So that's why it's very important to start this whole process early on.
Starting with QTPP
Brent Morse: And so where do we start? So the place to start is actually as early as possible in development. So this begins with the QTPP.
And so your quality target product profile should define those attributes, those quality attributes of your product that you're aiming for. And one of them, of course, will be potency. Now early on, you may or may not have all the idea, a precise idea of all the different potency attributes that you may want to measure. But you at least will know, have some idea of how you're going to apply this assay. And this typically is, these assays are typically used for release, characterization and stability. So the intended use of this assay will do a lot to inform your potency assay, the overall strategy.
So whether you have a more thorough QTPP or you apply the more recent guidance of actually establishing the analytical target profile, either way, at some point you're going to come into the situation where you are starting to more thoroughly define what you're looking for in terms of potency, and that'll be very much dictated by your modality as well as the indication.
So in this particular example, we have an AAV gene therapy for epidermolysis bullosa. And so this is a disease characterized by blistering and fragility of the skin. So understanding what your product is, and you know what types of attributes you might want in the product that can lead you to a reasonable first estimate of what types of assays you may want to employ. So you may want to look at infectivity and transgene expression to account for the AAV vector piece. And then things like wound healing and cell migration, growth factor release for the more biological mechanism of action aspect of this particular type of drug.
Implementation Timeline
Brent Morse: And then when we lay this on to thinking about how this is going to proceed through development, I come back to the development timeline that was introduced by Josh, and so we may have a number of different assays that may be contending as our primary potency assay. And so we keep in mind that early in development, you know, through maybe phase 2, we still may be defining what is our mechanism of action, and precisely defining those quality control attributes.
So we want to start early in development with evaluating a number of assays, keeping in mind that these may fail at various phases. So in this particular example, we are, you know, we may have failures. You could, it could fail early on as you try to optimize it, it could fail even qualification, maybe even at the clinical stage. So that's where you really need to have multiple shots on goal and multiple approaches that you can take so you can have a backup.
And when you're implementing an approach like this you really need to keep in mind that you don't need to, that things don't need to be fully validated upfront. This is a process of development. And you're qualifying at later stages. So you can bring these assays along and make decisions as you need to, whether to implement them or to keep them as characterization assays.
Common Waterfall Approach
Brent Morse: Now, what's more typical and what we more often see is that sponsors typically don't start with a panel of assays early in development, they follow more of a waterfall approach. And that's exemplified by this slide. And so you might have your favorite assay that you're starting early in development and focus exclusively on that.
And you know if it gets you all the way to commercial, great. Typically, that doesn't happen. And so you will need to pivot and go to different assays at some point, and whether that's because your assay fails, or because you're not completely accounting for all the different mechanisms of action of the product.
And so if you wait to do that later on, your timelines are inherently compressed. And so that's putting stress on the organization, that's putting stress on the program. In some cases can lead to failures of programs. And it can even put the overall health of the companies at risk. So this is more typical of what we see. But the example on the preceding slide is more where you want to be, is where you're at least starting to look at a broad cross section of assays early on, carrying them through development. And so that gives you more time to react.
CAR-T Case Study
Product Overview
Brent Morse: Now, we're going to go into a mini case study and start to think about how we might apply this to something closer to a real-world situation. And so this is a CAR-T product. And so this product, you know, we introduce a CAR construct into a T cell, and this can affect, so the intent here is to target either a tumor cell or whatever cell type you might be looking at.
And typically the mechanism of action would be more associated with clearing the tumor. And so that's mostly through killing the tumor. So in one way or another, so that might be upon binding your target, you might release cytokine to kill, you might release something like perforin or granzymes, which may affect the integrity of the cell membrane. But ultimately you're looking for direct killing.
Now on the more CD4 centric type of approach or activity, some of the other mechanisms of action that you may consider are things like cytokine release that may lead to more proliferation or activation of T cells, it could recruit other immune cells.
And so across the different potential mechanisms, there are multiple opportunities for establishing markers of activity, keeping in mind that the primary mechanism here that you're going for is ultimately killing of these tumor cells. With these surrogate markers, you're going to, if you're going to implement them, you're at least going to need to attempt to establish a correlation to killing in some manner.
Matrix Implementation
Brent Morse: And so now, when we start to put it all together, applying the concepts of phase appropriateness, and a matrix approach to this biological potency assay.
In this particular situation, you know, maybe early, we start developing a number of different assays. And one thing I want to point out, is this matrix approach, you are applying a matrix across the different types of potential mechanisms of action.
But you're also applying the matrix within a single mechanism of action. For example, here in the cytotoxic assays, you may consider more than one, because all you know, these different assay platforms may not all be things that you can carry through development. So you really need to increase your shots on goal, you really need to consider both the breadth of assays across the different mechanisms. But also consider multiple approaches within a particular mechanism.
So in this example, you know, you start off with your focus to at least for release on your IL-2 ELISA. You know it works fine for you all the way into validation, and where it fails.
If you have these other assays, that perhaps early on you use for characterization. And you're developing these. And earlier in development, you're keeping them in maybe a qualified fit for purpose type of status, as characterization assays. You can imagine that you can easily slide these in and they can become your release assay. If you've been implementing them early on, and you have been gathering the appropriate data on their performance.
And so, yeah, you probably will need to do method bridging studies. You certainly will need to do method bridging studies. But if you've been developing these assays the whole time, and you've been testing your clinical samples throughout the clinical program, you should be in a place where ideally it's much more straightforward to implement an alternative assay than it would be if you had waited and maybe not considered the full breadth of assays.
Keys to Success and Takeaways
Critical Success Factors
Brent Morse: And so as we start to wrap up, I do want to kind of really reiterate some of the keys to success that we've touched on. So you really need to consider these strategies and approaches early. So you need to implement assays as soon as possible, and you should really start to consider, you should go into it with a prospective approach and try to be proactive instead of reactive. It'll save your organization a lot of stress. And it'll really mitigate risk.
As we discussed this needs to be quantitative. Now, we couldn't necessarily, we didn't go into a ton of data or a ton of examples on comparability. But this is for comparability and for specification setting, quantitative, a quantitative assay is a must and so you really need to consider that in your strategy.
We didn't touch on regulatory compliance. So from the earliest stage, your approach needs to comply with the regulations. You should get buy in early and often, active communication, because these there is a huge amount of complexity, and you know, keeping that discussions early and often with the regulators are key.
And then, finally, keeping abreast of industry standards will be in your best interest, so there may be a lot of different approaches you can take with respect to how you, you know what assays you may choose to evaluate, and so casting the widest net possible will improve your chances of success.
Overall Takeaways
Brent Morse: And then overall takeaways. When we consider phase appropriate analytical development, so we pointed out that phase appropriate analytical testing is a strategic approach. And it really optimizes drug development. It's a balance between the need for reliable data consistent with regulatory needs while maintaining as much as possible resource efficiency and speed. It's really a risk mitigation approach. But you need to be aware of, and you need to educate yourself on what is needed and when.
And then the concept of phase appropriateness can be used as a tool to help implement, you know, matrix approaches to potency assay development. And again, this ultimately reduces overall program risk.
And then with that, I just want to, I'll reiterate what Josh said early on, a lot of these concepts, you know, we could touch on in a broad sense, hopefully, as we continue the discussion. Perhaps in future webinars, we can go a little deeper on some of these topics. But stay tuned for that, and thank you all for your attention, and we are happy to answer questions.
Q&A Session
Oliver Ball: So, Brent, I think there's a number of questions that have popped up throughout the talk there. You want to stop your screen share, and we can have a look through them.
Brent Morse: Sure.
Oliver Ball: So I think the first one that came in there, Brent, is what the key differences are between characterization and release testing, especially for flow based immunophenotyping assays, for example.
Brent Morse: Yeah, I think for that, the main differences are can be how they're applied. So typically when we think of characterization, you would be looking at particular attributes of the drug product or in process, maybe early on would be earlier in the process and would be, could be early on, it could be just for information gathering, and later on it would be to set an in-process specification.
Functionally, there may not be necessarily a difference in how the assay is run. Perhaps if you're thinking about validating later on, it may be with respect to what matrices you're looking at, so matrices and potentially robustness. So those would be key considerations to think about in terms of differences.
I don't know, Josh, if you have anything else to add there.
Joshua Beckett: Oh, yeah, that sounds good. I think, really kind of what I was thinking is characterization is more, you know, final product testing.
And then I think there's a definition of suitable material for qualification. Again, I think this one's going to vary in the definition can vary from sponsor to sponsor. But really, when I think of it, as you know, it's representative material of your process. And I know that's not a great definitive answer. But you know it's material that is representative of your process.
Brent Morse: And then, I see a question. Does the method need to be re-qualified and revalidated if the manufacturing processes change? Is product specific qualification and validation a better idea?
I would say that it's not necessarily that you need to re-qualify or revalidate if the process changes. I think it in large part depends on what the matrix is of the final product.
If you're certainly, if you're moving, if part of that manufacturing change is a change in manufacturing site, and you're not using the same site to run the method, then, yeah, I think that's a case where you need to carefully think about transferring and establishing method equivalence at least. Now, whether the method necessarily has to change, probably not. But you need to at least show that the methods are, if you're establishing a method at a new location, it needs to be comparable and give similar results. And if the matrix is changing, you just need to verify that the matrix isn't going to affect your assays. That's true of potency, but it's also true of some of the safety assays as well.
Joshua Beckett: Okay, so I mentioned that validation protocols need to be pre-approved prior to execution of validation. And this person asked if that means pre-approval by agencies, or to have buy in, or just internal quality pre-approval. I was saying, you know, internal quality pre-approval. But you know we always recommend that you get your buy in from the agencies, for you know your qualification validation protocols, for sure.
Brent Morse: Yeah, particularly, that's true in later stages, and if you are, if you know, if you're working with a complicated assay. But you know, agencies are, the agency is certainly happy to, and they want you to succeed as well. And they're happy to you know, discuss these types of things with you. So they, I think through maybe a type C mechanism or other interactions, you can get that kind of feedback.
And then it says, we have contract labs working under GMP conditions, you know, at which stage an assay has to be performed under GMP conditions.
Brent, do you want to take that one first?
Brent Morse: Yeah, I think the concept of GMP, there can be a little wiggle room in what's meant by GMP. I think, you know the way I would approach it is that your assay needs to be well controlled and needs to be well documented. So following the spirit of GMP, so you know, personnel that's trained, records are appropriately, so things are documented. Records are appropriately kept. There's a sufficient level of oversight. That's what I would focus on. This might be a topic we can go into in one of our quality focused webinars as well. We could address this in more detail, perhaps.
I see a question. So you say potency assays must be quantitative, which is clearly desirable and essential by late stage. But I've experienced early stage potency assays that are semi-quantitative at best, more some are more, some or none. Obviously this has been risk based on patient need, etc. Has DHC had different experience?
So I think the attributes I was discussing, so these are certainly aspirational for late stage. Early stage, you can certainly get away with a lot more, and you know there is leeway, because you know, you may not fully understand your product. It may have a very complicated mechanism of action. The assays that you have at your disposal may not be, may not be, you know there may not be many available.
So you can get away with perhaps using assays that are semi-quantitative in some cases that can even go into late stage. But you just need to keep in mind what you're risking when you take that approach. And you know the first thing that comes to mind are things like, how are you going to set specs if it's semi-quantitative.
Are you going to be able to set a meaningful specification that ultimately will be able to correlate with patient data. If you want to change manufacturing sites, potency typically is one of the critical parameters of a comparability assessment. You know, you may find yourself in deep water trying to justify specifications to the degree your potency assays aren't quantitative. So yes, it can be done. But you just need to be aware of what the risks are, and really think it through.
I see a question, is there a move towards molecular based potency assays and QC testing overall? For example, NGS, away from functional live cell assays.
I would say in my experience, no, certainly not for late phase. I think the molecular based assays, and even some surrogate assays that are, you know, really aren't using cellular material are, you know, can be justified for early stages of development. And that's certainly the case. And for some of the gene editing products, you know, you may be able to justify a potency assay that's based on percent editing or percent of some cell surface marker.
I think later in development, I think that's a harder hurdle, a more difficult hurdle to overcome, and it's much harder to justify.
Joshua Beckett: So I see one saying, is there any criteria that calls out a method you know fit for purpose, you know. Does this lie somewhere between being developed but not qualified? You know, again, this is kind of one of those dodgy words, this fit for purpose. This is going to depend on your process, your product and the method and its intended use. And a lot of times, people will, you know, partially qualify, maybe only do things like, you know, accuracy and specificity, or you know, only a few of the parameters. Kind of for that fit for purpose. But this is really kind of, you know, we'll need to be justified, based on your experience with your product and the method.
Brent Morse: So is qualification required for assays that are required for release even in phase one? Again, I think that's a function of what you're using the assay for, and how related to safety it is. And so, strictly speaking, you wouldn't need to, you don't necessarily, there's no requirement that you formally qualify assays.
But you need to take into account, you know, if those things are important. So your dosing assays may, you may need to at least establish that the precision of your assay, you know, to the extent you're measuring some in a cell based product. If there is some, you know, cellular contaminant that may come up that could represent a safety risk. If you have an assay that's measuring that you may need to establish that it's capable, and you may need to show that it's, what its detection limits are and how precise it is at a certain range. So yeah, so not formally required. But again, you need to consider, you need to consider what the intended use of the product is.
So another question. Do you think that we will ever find a potency assay that correlates to patient data in cell therapies.
So this is a good question. So I think when we say correlate, it's not necessarily the case that you're going to have a one to one correlation between potency and effect. You don't necessarily even get that for other modalities.
But what you're going to need to have is, so when you're setting your, ultimately, your specification is going to be, it's going to need to be based on what are the attributes of potency that across batches that have been demonstrated safe and effective. And if you don't have a quantitative number or way to get a quantitative result, if it's semi-quantitative that may hinder your ability to really, you know, to really provide a, you know, to arrive at a limit that you can have confidence in.
So I think that's again, it's one of those areas where as with many with potency, it's, you know there's a lot of subjectivity, and there's a lot of gray area there. None of these requirements are absolute. They tend to fall into more best practices.
Anything you want to add there, Josh?
Joshua Beckett: Nope, that works, that's good.
Another one that would be good to answer, and your thought, and is, is it okay to use commercially available reagents as reference standards for endpoint assays, or do these need to be developed in house.
Brent Morse: I would say, if you can get a commercially available reagent that you can justify, I would say, go for it. I mean the probably one of the larger burdens, particularly early in development, is trying to, you know, if you want an in-house reference standard, you may need to do an entire manufacturing run, or more, just to provide that material. So it's certainly okay. If you can find something that you can justify, I think that's great.
They just, they're not, they tend to be few and far between from what I can see. That's been my experience.
And then let's see. I think we have time for maybe one more. Is robustness study belonging to validation? I think this question has to do with the relative rigor between qualification and validation. Typically, although, again, none of these guidelines are entirely absolute, typically for qualification, you wouldn't do necessarily a lot of robustness assessment, as in your attributes, although in certain settings it may make sense. If you know that your assay is particularly finicky and temperature sensitive, or something like that, you know, it may make sense to consider that upfront, you know, even though it's not typically done. It's sort of you go back to the principle of use, the you know, as these methods are, you know, they're fit for their intended use.
Closing Remarks
Oliver Ball: Alright. Well, thank you, guys, we still have a few more open questions that unfortunately don't have time to get to. So if any of you have submitted questions that we've not answered, we're happy to speak to you offline one on one to get through them.
Just before I close out, just a reminder that we have the on demand recording available from our website following the webinar today, and also reminder, so please register for the next 2 webinars that we have in November and December. The next one in particular with the regulatory team, I think, is going to be fantastic, and our managing partner 2023 wrap up webinar in December will be very good, too. So thank you, everybody for your time today, and we will see you on the next webinar.
Joshua Beckett: Thank you.