Science Diction Podcast | Repository

Transcript—Repository: Defeating Cancer, HIV, and Alzheimer’s, One Critical Step at a Time

Dr. Amy Manning-Boğ

Clinical trials are typically studies in humans that test medical interventions like therapeutic pharmaceuticals with the goal of primarily ensuring safety, as well as demonstrating efficacy and ultimately contributing to our health and welfare. But before going into a clinical trial, the putative drugs for the treatment of cancer, HIV, Alzheimer’s and other disease conditions called, at this stage, the drug product must be received from the manufacturer and precisely stored and managed and then shipped to their destination for use in that trial.

As director of pharmaceutical sciences at MRIGlobal, Dr. Jon White leads a team that facilitates this critical step of the supply chain for clinical trial testing, along with other tests and assays of drug products. Today, we’re going to pull back the curtain on the repository. I’m Amy Manning-Boğ, and this is Science Diction from MRIGlobal.

Dr. Jon White

So many times when people think about drugs, they think about the end drug product. That’s the material that their physician is prescribing to them or maybe that a pharmacist is dispensing. Regardless of how the drug ends up in the hands of a patient, there’s a tremendous amount of work that goes on behind the scenes to create the drug itself. And there’s always a need for guiding new drugs through development and regulatory approvals because it’s a complex process and it’s especially challenging for small and virtual companies who may not have the resources at their disposal to move these drugs through those areas. And that’s really where the repository comes in. 

Dr. Amy Manning-Boğ

What makes this work, this facility, unique, John?

Dr. Jon White 

Because of the work that we conduct for the government and given many of their programs span decades, the repository is home to a diverse collection of materials that have been studied for use to either treat or prevent disease. It also serves to store and distribute materials for clinical trials. These are called clinical trial materials, as the name implies. And so we do a lot of clinical trial materials management and supply chain logistics out of the repository that come to us from a variety of biotechnology companies as well as from government programs that we operate.

Dr. Amy Manning-Boğ

It’s pretty clear that the repository is far more than a shipping and receiving warehouse.

Dr. Jon White

Yeah, absolutely. It does that as one of the functions, but it has a lot of additional features. Some of those things are done to ensure that the materials are managed properly, that they’re stored correctly, and that they’re distributed to the places that they need to go to. But as part of the pharmaceutical process, it has to adhere to good manufacturing practices or GMP.

Dr. Amy Manning-Boğ

Could you explain a bit more about GMP, please?

Dr. Jon White

It stands for good manufacturing practices and it’s a set of regulations… designed to ensure that the products are consistently produced and controlled and according to set standards, specifically set quality standards. The main risk with drugs is that they can have contaminants in them. They can also be, if they’re made incorrectly, have the incorrect purity. So that might be either higher or lower than what’s intended. The labels may not be correct, and there’s a variety of other factors that the GMP are designed to protect against.

To ensure that the GMPs are followed, we in a repository have detailed written procedures and systems in place to cover our work. We must document what we do to have evidence that it was done correctly and also an auditable record that folks can go back and take a look at to ensure that the procedures were consistently followed every time a product is made.

Dr. Amy Manning-Boğ

It sounds like also that you’re holding on to these drug products, these clinical trial products for quite a while. Can you tell me about the storage conditions?

Dr. Jon White

Yeah, the storage conditions are really important and not all of them are the same. So we have to have a variety of storage conditions to hold the materials in a manner that’s going to ensure that the integrity of the drugs are not compromised. We will have things like Ln2 or liquid nitrogen storage conditions. So that’s around -195 degrees centigrade, very cold. And then we’ll also have storage conditions that are still pretty cold, -80 degrees C will have -20, which is a typical freezer condition, 2 to 8 degrees, which is a refrigerator. And then we also hold materials at what we call controlled room temperature or CRT storage, which is around 20 to 25 degrees C. So this ensures that the drugs that we’re holding not only maintain their integrity and that they don’t degrade, but they’re also held securely for the duration that they’re needed for supporting these clinical trials.

Dr. Amy Manning-Boğ

And I imagine that there must be FDA regulations associated with their storage and with these conditions.

Dr. Jon White

So pharmaceuticals at all stages of investigation and use are highly regulated and then regulated by the Food and Drug Administration or the FDA. This is done to make sure that drugs are safe for human use and that they’re also effective. 

Dr. Amy Manning-Boğ

For decades it has been this level of expertise and our facilities that have differentiated us while benefiting commercial and government clients, including the National Institute for Allergies and Infectious Disease, The National Institute for Neurological Disorders and Stroke, and the National Cancer Institute.

Dr. Jon White

We’re really personally invested in what our customers are trying to achieve because these diseases affect us and our family members as well. So we work to partner with our clients and guide them through preclinical and clinical stages of development. We provide high level technical expertise, facilities and a breadth of services. It’s really our team that makes a difference. Our team are experts, and they help to guide our clients and our partners through the challenges that they see every day.

We want to make sure that we have all of the pieces of the puzzle available to folks to help them move their ideas from bench to bedside. We want to take the drug assets that they’re looking at that are going to be potentially lifesaving for folks and help facilitate those into the hands of patients.

The materials that are being produced can degrade under a variety of conditions in order to ensure that the drugs are safe and effective, we have to do analytical testing to ensure that the drugs are stable and that they’re remaining stable over time. 

Dr. Amy Manning-Boğ

It’s really interesting, John, that you mention that you’re evaluating degradation in these drug products for use in clinical trials.

Dr. Jon White 

We perform a lot of analytical stability testing on a variety of conditions, and those conditions can vary based on what the drug composition is and what the formulation for that drug might look like. As well as where the drugs are going to be used. So, for example, if the drugs are going to be used in the United States, we might want to check it under certain and stability conditions that are conducive to storage here. If it’s going to be stored in another part of the world where maybe the humidity is higher and the temperature is higher, we may want to store it under conditions that are more representative of that location.

We then periodically pull out samples and analyze them to make sure that they’re maintaining their stability and that there’s no unwanted degradants that are being formed over time. If we see that, we can alert the groups that are working with the drug to understand what the impact might be, and we could look for ways to work around it.

Dr. Amy Manning-Boğ

Now, you mentioned outside the United States. Could you elaborate on that?

Dr. Jon White

We have a lot of groups that we work with that have their materials manufactured overseas, and then they want to conduct a trial in the United States. In order to be able to do that, they have to import that drug into the United States, where we can hold it in the repository and then help support those clinical trials, whether they’re being done in the U.S. or outside of the U.S.

Dr. Amy Manning-Boğ

Do you ever see any issues with that?

Dr. Jon White 

Actually, we do. There are some instances where a drug product manufacturer or a drug substance manufacturer that’s making the active ingredient is overseas. And the materials need to come into the United States. In order to support that, there is an importation regulation that’s managed by the Food and Drug Administration. And in those cases, the U.S. Customs and Border Patrol will often ask for what’s known as an investigational new drug application that is active. So an IND, that’s active. In certain cases, folks don’t have an active IND. And in those cases, the FDA will not allow the importation of that drug. So that has to happen before the drugs are imported. 

Unfortunately, in some cases, the timing doesn’t work out and the materials still need to come to the U.S. but there’s really not a good mechanism to get them out of the U.S. soil or into a location that’s in the U.S. So MRIGlobal has come up with a solution for that. And then as we operate what’s known as a foreign trade zone. …we can hold these materials before they’re actually imported into the United States for periods of time that would be conducive to getting that IND approval in hand or just for logistical purposes, we can hold the materials there. 

Dr. Amy Manning-Boğ

Now, I’m going to embarrass you a little bit, John, because I happen to know that you hold a patent for a formulation to stabilize a breast cancer therapeutic. Would you mind talking more about the patent for that small molecule?

Dr. Jon White

So I, along with a lot of other investigators at MRIGlobal, work really hard to investigate novel therapeutics that are going to be used to treat various diseases such as breast cancer. In doing that, we often find drugs that are efficacious in one scenario for a short period of time or in one model system. But when you try to broaden out to use for a long period of time, you know, different patient population. And what you may find is that the formulation that you originally started with doesn’t quite work out or in some cases that there’s not even a formulation that’s known. So oftentimes you have to do research and development to figure out if you can develop a formulation that’s going to maintain the stability of a drug or in other cases, you may be looking at finding a way to increase the solubility of the drug or the permeation of the drug to be able to increase the bioavailability. In our specific situation, we were looking to increase the solubility and the bioavailability of a drug that really showed good effect when it was used in model systems but wasn’t holding up when we used it in more human relevant model systems. So we had to develop a novel formulation to enable that material to then be used, which we were able to successfully do. 

Dr. Amy Manning-Boğ

I can see how this is all coming together. Stability. Storage. Evaluation of degradation. You’re giving me ideas for future “Science Diction” episodes.

Dr. Jon White 

Good. Yeah. I mean, at MRIGlobal we’re unable to accomplish the missions that we set out to do without this broad, multidisciplinary team. We have a lot of experts that are really working hard day in and day out to make those ideas turn into reality. We’re all proud to play a role in a process that will ultimately improve the quality of life and frankly, save lives.