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The topic that myself and my coauthors are going to talk on today is some of the opportunities and challenges that we see specifically in raw material and starting material qualification for cell and gene therapy products. One of our key focuses within Roche around raw materials is really understanding raw material variability and how we can actually use that to control materials and drive the raw material control strategy. For those of us that have the fortune or sometimes misfortune of working at large companies, we know how many folks in global functions and stakeholders are either generating raw material knowledge or are users of it. So it is simultaneously very frustrating, I think, to have that number of stakeholders, but also quite rewarding when you get it right. Because once you get it right, you are able to really advance the understanding for many, many different folks.

What I really want to focus on today is around cell and gene therapy, the materials that are used for those products, and the expansion of the tools and the ways of working that we see within Roche that we have really had to start to think about.

When we think about raw material variability – and this has been a theme that has been touched on multiple times over the last few days – it is obviously a risk to: ● supply ● quality ● cost, and ● delivery time. And so when we think about what we are calling the science of raw material variability, what we were talking about is understanding how material attributes and their variability end up impacting processes and products.

Obviously the most common framework that we think about for that is QbD, and defining critical material attributes and how those impact CPPs [critical process parameters] and CQAs [critical quality attributes.]

Raw Material Control – CGTs Versus Conventional Biologics

What I want to do is take a step back and do a high-level view of where we think we are at around raw materials with a comparison of cell gene therapy materials and biologics. On the left panel here we have a control strategy, or an attempt of a schematic of a control strategy, where across multiple products we have data and hypotheses that are all linked together in order to be able to form what we are calling a multi-product control strategy.

The last session of the USP workshop concluded with a presentation on the opportunities and challenges in controlling raw/starting materials for CGT products, provided by Roche/Genentech Pharma Technical Innovation Principal Materials Science Engineer Stefan Yohe. The presentation encompassed: ● a comparison of raw material control for CGTs versus conventional biologics ● key enablers to understand and control CGT raw material variability, and ● applying the classification of “critical materials.” Click here for the slides

accompanying Yohe’s talk. Formatting changes and other minor edits have been made by IPQ for clarity. Expressions of thanks to the meeting organizers/attendees and disclaimers that the presentation represents the speaker’s views and not necessarily those of their organization are not included.

ROCHE/GENENTECH’S STEFAN YOHE ON CONTROLLING CGT RAW MATERIALS

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If you were looking at this from a raw materials perspective, the reason that this is largely possible is because we have a pretty long history of use of raw materials. A lot of these materials that we are using within our processes are largely compendial – certainly not totally true, but in many cases, these are not proprietary materials. Or there is a lot of literature information that is available to you to actually be able to assess those materials.

I think the other thing that is not on this [slide,] is that biologics processes have become platforms for a lot of companies. Being able to look across multiple different products and the materials used within them really allows you to generate data on a very massive scale.

If we are now turning our attention to the right-most panel here for cell and gene therapies materials, it is almost the exact opposite. We have new materials, complex materials, and proprietary materials. And because of that, we also have unknown critical attributes, new analytical methods that are either currently being established or have not quite been established yet, and then new sampling strategies.

When I say new sampling strategies, we have low volume products, and the traditional square root of n plus 1 sampling that many of us are used to in manufacturing – you really can’t have those types of sampling strategies here. And because of that, our method of data generation may actually be quite a bit different.

We have less knowledge about the patient-risk benefit. So not knowing exactly what the key CQAs are for the product, or at least not knowing how many points that we are used to for biologics makes it more challenging to define our critical material attributes.

C&GT’s Offer Unique Considerations to Understanding and C&GT’s Offer Unique Considerations to Understanding and Controlling Raw Material VariabilityControlling Raw Material Variability

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We have to address lifecycle management in a phaseless world – so thinking about how now we have materials where we may actually only have a single clinical trial, or that clinical trial may be unclear whether or not it is going to have multiple phases. So [the challenge is] being able to actually identify knowledge and risk when you actually have a lot less time, or certainly a lot more ambiguity, in terms of your ability to do that. And then finally unestablished tools and approaches – and there being opportunities to actually think about new ways and new tools that we need to generate knowledge around these materials.

Material QualificationMaterial Qualification

Looking at this from a material qualification perspective, the framework that I like to think about for material qualification is that you are really aggregating knowledge from many different sources, and taking all of that knowledge to identify form, fit, and function for that material in your specific product and process.

The reason that we are finding it so challenging around cell and gene therapy materials is a lot of the traditional mechanisms or places that you would find knowledge – suppliers knowing quite a bit about their products, internal knowledge that you have generated, industry forums like this, being able to track and trend information – there is really just a lot less of it. And because of that, there is a lot less information to drive on that initial material qualification.

On top of that you have these new avenues, where they are likely very beneficial to generate new raw material knowledge around new analytical techniques, direct linkage to patient data – and then the idea that post-approval changes in many of these products are seemingly an inevitability.

So, taking a step back and looking at all nine of these different panels, these are the things that we have identified as being why this is maybe a bit more challenging to qualify a material in cell and gene therapy versus a traditional biologic product.

Understanding and Controlling RMV For C&GT Products Requires ‘Full’ Understanding and Controlling RMV For C&GT Products Requires ‘Full’ Utilization of a Lifecycle Management ApproachUtilization of a Lifecycle Management Approach

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Another way to think about differences is that we don’t think that risk is managed much differently for cell and gene therapy materials. You are still using a risk-based framework. You are still using a science and risk-based approach. But really the key differences seem to be the stage gates in which you are actually assessing knowledge and risk, and how often you should actually be assessing knowledge and risk during the development lifecycle.

The Journey to CGT Material ControlThe Journey to CGT Material Control

With this idea of less knowledge or different knowledge, in addition to the way that you manage risk at different time points at a different cadence, these are the areas that we are really focused on in the rest of this talk – to describe what we really need to do to actually get to a point where we are qualifying materials and able to really understand the knowledge and risk of them in a robust way. Another way to frame that is: What is the journey to determine, monitor, and control cell and gene therapy materials?

When I think about material qualification, I think about the initial point of material qualification – that is the ‘determine’ part in the top left corner here, where we are doing the initial determination of attributes and specifications, and initial assessment of how those impact your process and product.

But the lifecycle management of that material requires constant scrutiny of that material qualification – where you are actually monitoring raw material variability within your process and within your raw material, and then using that variability to help continue to drive additional controls and updated controls for those materials.

Where we are in the biologics and small molecule world is probably getting to a point of maturity on this space on the left. But for cell and gene therapy, I think we are really just starting to think about how we will do this.

The Journey to Determine, Monitor, & Control for C&GT MaterialsThe Journey to Determine, Monitor, & Control for C&GT Materials

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Key Enablers to Control Raw Material Variability

What I will walk through now is key enablers that we view as being quite important to understanding control of variability – how we should actually apply those to cell gene therapy materials – and then lastly, going through starting, critical and raw materials. I think that last point will actually speak quite well to the talk which we just heard by [Cellgenix’ Patricia Chimot-Marolle, who provided an ancillary material manufacturer’s perspective on the issues].

Generic Case Study for CAR-T ProcessGeneric Case Study for CAR-T Process

The way that I have framed this is coming up with a generic case study for a CAR-T process. This is something that has many complex new and proprietary raw materials. You have patient Leukopak, which you are receiving from a clinic. You have cell isolation reagents that are used within the T-cell purification process. As far as transduction, you have DNA, Cas9 and other gene editing reagents.

And then as far as expansion, you have cytokines and human serum albumin. Then of course there are many other materials that would be used throughout this as well.

On top of all the new materials that we are using, I think we have similar actors to what we are used to in other modalities – so known risks around trace elements. And of course, we have heard about the risks that trace elements have in several talks over the last few days. I think the big question here for trace elements is: We have developed a pretty large knowledge base around them over the last 10-20 years, but how are they going to impact T-cells in a totally different process?

‘Case Study’: Cell Therapies Have New and Complex Raw Materials ‘Case Study’: Cell Therapies Have New and Complex Raw Materials that Require Key Enablers to Understand and Control RMVthat Require Key Enablers to Understand and Control RMV

CAR-T process schematic from https://chemometec.com/clinical-manufacturing-car-t-cells-adoptive-immunotherapy/

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Another example that I am doing here is single-use assemblies – so same materials, maybe similar assemblies, tubing kits, flasks. But if the extractable/leachable profiles change, we are not quite sure. But I think more importantly, even if you have an extractable/leachable profile that is identical to what you have had in a biologics process, how does that end up impacting your CAR-T process here?

Six Key EnablersSix Key Enablers

From our vantage point, these are the six enablers that we see as being really crucial to our future understanding of raw material qualification and really having a robust understanding of knowledge and risk:

● Number one here is early engagement across internal functions and with key suppliers. I suspect that this one is probably a bit obvious to folks. But I will say that, especially around the area of proprietary materials, we have found that our ability to understand and control materials is quite challenged if we did not have a strategic partnership with our suppliers early on to help share knowledge with our suppliers and allow our suppliers to share knowledge with us. So I think this is quite crucial.

● Number two is unique approaches to DOEs [design of experiments]. The example I use specifically around cell therapies is, of course, their materials and our process – usually patient derived that are going to have inherent variability that you do not have the ability to control. With that being a factor of these processes, being able to take DOEs and design them in a way to isolate variability becomes quite challenging.

One of the ways that we have found to be quite helpful is examples like using surrogate materials in your process development to be able to isolate variability – to determine other materials and other process variables that end up impacting your overall CPPs and your CQAs. It is something to think about as far as surrogate materials, but also the analytical tools and statistical tools that we have found that are useful are actually also quite a bit different.

● Number three is this idea of the agile material attribute and specification lifecycle. One of the things that I think is quite important here is really identifying, not only that you have to be agile, but the points in which you are actually going to have critical data to allow you to go back and look at that data and define whether or not attributes and specifications can be revised.

I really think that points number three and number four here speak quite well to one another, where the approach that you are taking around design of experiments and knowledge building really should reflect when you actually will be getting that data and being able to think a bit more about your attributes and specifications.

● Now looking at the bottom row – advanced data analytics: We have spoken a bit about that over the last few days. And of course this is a hot topic around many companies right now, where a lot of the analytical tools that have been used in other industries and have become quite mature are now being applied in the pharmaceutical world.

I think in this case in particular the tools will probably differ a little bit, in the sense that we have cell therapy products that may be for a single patient. And the processing will be quite a bit different than the way we are able to analyze our biologics processes.

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The concept is the same – that we have got data coming from multiple different sources, we have multiple statistical tools that we are able to leverage, and we want to be able to create models of that data to be able to continue to refine our understanding of our raw materials.

● Linked pretty directly to that, is this idea of linkage directly to clinical data. This is the first time, at least in my career, where it seems to be that there is tremendous value linking the entire data value chain, from clinical biomarkers for raw material data, to manufacturing data, all the way to clinical outcomes. Of course this pairs very well with the advanced data analytics capabilities. But being able to link all that data in a way that is actually accessible and digestible is, I think, going to be very important.

● And then lastly, this again may be a bit obvious, but I want to reflect on this for just a moment: When we think about raw material variability and we think about risk, we are usually linking directly to critical quality attributes of our drug product and how the CQAs end up impacting the patient.

There is really a need to reflect on that quite a bit more and to confirm that the CQA model is the most appropriate model for use in specific attributes for raw materials. Because of the change in processes and because of the change in the way that these products are manufactured, there is really going to be a lot more scrutiny on raw materials and their ability to directly impact patients.

What I am highlighting here specifically is making sure that our risk assessments are tied directly to patients, as opposed to some intermediate input.

‘Case Study’: Cell Therapies Have New and Complex Raw Materials ‘Case Study’: Cell Therapies Have New and Complex Raw Materials that Require Key Enablers to Understand and Control RMVthat Require Key Enablers to Understand and Control RMV

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Applying the Classification of ‘Critical Materials’

One last content slide and then I will wrap up and hopefully be on time. One of the things that we have had a bit of challenge with internally – I think that began with Patricia’s talk, it seems like this is something that is being experienced by others as well – is really the classification of materials. That is driving quite a bit of how we actually manage those materials, how we control them, how risky they are, etc.

And so what I am showing here is that internally within Roche right now we have elected to create this intermediate grouping of raw materials called ‘critical materials.’ And I do think that this speaks pretty well to a lot of the existing regulations and guidances out there, including USP <1043>. These are materials that are not considered to be starting, but do have a direct function in the process for defining the final ATMP. What I left off in this classification is that oftentimes they are biologically derived but may also be biologically active.

So this sits right between ‘starting materials,’ which we are classifying as a significant structural fragment that is a structure of the product, or from which the product is directly derived. And then in this case we are calling everything else that is not bucketed by starting materials and critical materials as being ‘raw.’

To spend a moment on why we created this definition – there are a set of materials in our processes that are so crucial that to call something a raw material and simply defining critical material attributes did not seem to be an adequate level of scrutiny that we were placing on these materials.

Use of “Critical Material” Classification for C&GT Materials Has Improved Use of “Critical Material” Classification for C&GT Materials Has Improved Communication about Risk, Knowledge, and Controls within RocheCommunication about Risk, Knowledge, and Controls within Roche

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So what we have done with this classification is to make sure that just because something does not meet the current regulatory guidelines for a starting material, that we put this together to make sure that we as a company are providing enough knowledge and risk around these materials. And that we are working with our suppliers in an adequate way – thinking about what we are submitting with regulatory filings. Some of these are listed down here in the bottom portion of the slide. What is interesting about these classifications is that – and I think this was mentioned in some of the earlier talks on day one – we said that risk is really hard to bucket, when you create a single bucket of risks. This is risky, this is not. This is a critical material, this is not.

I think risk is clearly on a spectrum, and what we have tried to show down here in the slide bars is – even though we are calling things ‘starting’ or ‘critical’ or ‘raw’ – if you look at the subcomponents of what would force something into each of those different buckets, there is still overlap between different categories of material. I think that that is important to highlight.

Closing ThoughtsThese are just some closing thoughts:

● I am certainly not the first person to make this analogy [see slide #11], but it does seem like we are much closer in the cell and gene therapy world to when the biologics industry started. So simultaneously very exciting, but also a lot of unknowns and things to figure out.

● The idea that we should have early strategic relationships with your suppliers and partners has been brought up multiple times during the last three days. I think that this is something that especially with cell and gene therapies, especially with complex new proprietary materials, is quite essential.

● These new tools, incredibly important. Knowledge sharing and noncompetitive environments within USP, within other industry forums, are incredibly important.

● And then one last thing to comment on, and this is not directed at a specific guidance or regulation: With the amount of unknown unknowns right now with cell and gene therapies, I think that we do need to be a little bit cautious about being overly prescriptive in guidances and regulations before we actually know a bit more.

I know that these are ongoing discussions within USP and other forums, but our perspective is that we have found, specifically with cell and gene therapy, that there are guidances that exist right now that may not be necessarily appropriate or adequate. It actually ends up being a bit challenging to maneuver around or identify how you are going to meet those expectations when they may not have been fit for function.