Pharmaceutical Development of Antibody Drug Conjugates - Freeze Dryer Webinar - Dr. Greg Sacha

Freeze dryer webinar on the development of antibody-drug conjugates (ADCs); selected transcript excerpts:
What makes an optimal ADC drug product formulation? Well, first, once we formulate it and we process it, that linker system must still remain stable. Again, just to mention, older linker systems which are still available, they tend to not stick as well. And what that means is that, when working with those older linker systems, you would have to work and treat it as a category four compound per safe bridge. And that means working with them in isolators. Otherwise, you risk the health of the people working with them.
The current linkers that have very good stability, we can work with them as a category three compound and work with them in our laboratory, still taking appropriate precautions just like we do with any other chemical, but we do not have to work with it only in an isolator. We want the monoclonal antibody to be stable. So throughout our studies, we're looking at potential for aggregation or potential for fragmentation or de- emanation. And the way to improve this long-term stability is often through lyophilization.
We must have good analytical methods in place, in particular stability-indicating analytical methods. We usually start with our formulation studies, solution stability studies. We want to determine, what's the best buffer? What's the dependence on pH? Is there a dependence on buffer concentration that would make a difference for the stability of this molecule? That will then provide us the basic data where we can start building our formulation for lyo development processes. And throughout all of these studies we're working in areas that we expect some failure.
We want to know where our product will fail so that we can stay away from those areas. If we can design a lot of studies where we never see any failure, we will not know if we are right on the edge of failure or not. So, it is important to be able to test that. And in lyo development, we also test for failure. I'll show you some slides later on. And then we conduct thorough secondary drying studies, where we examine the effect of residual moisture on the stability of the product. And we will provide you some case studies on that as well.
We may look at concentration, but I have never seen concentration change and it does not really represent a great stability indicating method. What we want to know is, do we see fragmentation? Do we see aggregation? Do we see anything that would relate to this not being stable over the long-term? I will show you a slide next that would include that. So part of aggregation would be SEC, DLS, Dynamic Light Scattering. Sometimes those are good to use both at the same time because DLS uses very little solution. It is almost like getting some data for “free.”
The DAR-HIC is drug antibody ratio with hydrophobic interaction chromatography. We use that to determine if we have our linker systems still in place. And as I mentioned with the newer linker systems, we never see any changes at that. So we might include that particular assay perhaps on long-term stability, just so we have that data.
Our stability indicating methods though, the most common ICE, we may look at DAR or a free drug over time, but it depends on the linker system. So really what we focus on is SEC and ICE during the early studies. We find those tell us a lot more information. Here is an example of free-drug, and this is a solution and lyophilized samples stored at 50 degrees C. We don't often store our solution samples at 50 C but for the next few examples, for some reason we did on these studies and I don't remember the exact reason why when we do, we store at 50 degrees C so that we hopefully can get some data quicker and maybe provide us some idea of what may come when we store it for longer term.
It is frequent in our early studies that we will store freeze dried samples at 50 C for one or two weeks, but also store them at 25 C and 40 C for two and four months. So this is an example of monitoring free drug. Rarely have we ever seen free drug available in the formulations when we are using these newer linker systems.
Here is also an example of the drug antibody ratio. Again, even under stressed conditions, I'm showing you here 40 C for two weeks, but we have data for 40 C for up to six or 12 months, maybe two years where you do not see any changes in the drug antibody ratio. So, it's usually just included as a check.
ICE however we do use. We use this because we do see changes over time that may show us different charge isoforms that develop due to the storage conditions, but also due to our formulation conditions. This is just an example. This is a graphic TO and then one after one week at 50 C, we see a large change. And so that tells us this will be an important stability indicating method.

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