Science Diction Podcast | Generic Drugs

Erin Merritt
Generic pharmaceuticals make up nine out of every 10 prescriptions in the United States and in 2025 drugs for COPD, hypertension, high cholesterol, cancer, and many other disease conditions have expiring patents, so can be produced as generics. These drugs are as effective and work the same as the name brands, but typically cost consumers significantly less.

Dr. Alison Hart is a senior chemist. She and her team are responsible for the synthesis and process development of small molecule drug candidates for preclinical and clinical studies.

Today on the show – Generic Drugs – how they’re formulated to be effective, how they’re scaled from laboratory to manufacturing, and why they’re so important in improving access and affordability. I’m Erin Merritt and this is Science Diction from MRIGlobal.

Alison Hart, PhD
Tylenol is a name brand that is one of the most commonly used drugs on the market today. However, most individuals purchase acetaminophen, which is what the active ingredient or compound is called. The active pharmaceutical ingredient or API is the same, but the formulation may be different. This includes the color, excipients, and the casings of the drug.

Erin Merritt
Fascinating. So one question I have is when you say “excipient,” what does that mean?

Alison Hart, PhD
Excipients are basically the inactive ingredients. So it can be a filler in a pill or it can be part of the liquids that a drug or active pharmaceutical ingredient has been dissolved in.

Erin Merritt
Okay, so they have to have the same active ingredient, but they don’t have to have the same non-active ingredients. Does that then mean that the generic works the same as the brand name?

Alison Hart, PhD
Yes. So the active ingredient has to be the exact same. So basically it has to interact with the body in the same manner. The delivery system also has to be the same. So if the name brand is a pill, the generic would also be a pill. If it’s an injection or a bolus, it’ll also have to be an injection or a bolus.

Erin Merritt
So with that stipulation, why do some people have certain side effects with a name brand and not the generic or vice versa?

Alison Hart, PhD
Well, it’s most likely because there’s an inactive ingredient, so one of the excipients or the coloring or the flavorings that the patient is allergic to.

Erin Merritt
That makes sense. When initiating development of a generic drug, where do you begin?

Alison Hart, PhD
Development of a generic begins with the name brand pharmaceutical. When first developing a generic, you have to file with the FDA to show that the generic that you are developing is just as effective as the name brand. You also have to show that the manufacturer is capable of making the active pharmaceutical ingredient correctly and consistently.

Erin Merritt
So when a name brand drug comes to the market, how long do their drug patents last?

Alison Hart, PhD
Currently, drug patents last around 20 years. However, that 20 years starts at the invention of the drug, not when it hits the market. So it typically takes about 10 to 15 years after the patent has been filed and approved before the drug will actually make it to the market, which means the pharmaceutical company has to put 10 to 15 years of money into that drug before they can start to make anything off of it.

Erin Merritt
Oh, okay.

Alison Hart, PhD
For example, a client of ours filed their patent in 2019 and they’re just now getting to phase one clinical trials. During that time, we’ve had to develop an optimized synthetic pathway and scale it so that it could be repeated on kilogram scale.

We’ve also synthesized a toxicology batch for preclinical trials and develop formulation so that the drug can be dosed. We’ve also had to set up for our cGMP campaign for phase one clinicals, which we’ve just completed at our headquarters location. We’ve also had to do multiple stability studies for this pharmaceutical, some of which have been ongoing for over three years. It will probably be at least another 3-5 years before the drug makes it to the market, if it makes it to the market, because about one in 5,000 drugs makes it past clinical trials, which is why pharmaceuticals can be so expensive. The cost of the drugs that don’t make it to the market has to be included, which is why they can be so expensive.

Erin Merritt
Definitely the odds seem stacked against each pharmaceutical that comes through. With generics, do you also have to first understand how that name brand drug works?

Alison Hart, PhD
Yes. You have to know the chemical makeup of the drug, specifically what the active ingredient is, whether it’s a large molecule like a protein or a small molecule, which is what we at MRIGlobal focus on. Generic drugs and brand name medicines share that same active ingredient, but other characteristics such as the color, flavorings, and anything else that do not affect the performance, safety, or effectiveness of the drug may be different.

Erin Merritt
Do generics have to undergo the same clinical trials as the name brand drug?

Alison Hart, PhD
No, because the active pharmaceutical ingredient is the same and has already undergone rigorous testing, generics do not have to undergo clinical trials. Skipping the preclinical and clinical trials drastically decreases the cost of the drug, which is passed on to the consumer. However, the manufacturers of the generic do have to show that they can replicate the synthesis of the API and that their formulation will not have any undesired effects.

Erin Merritt
So the manufacturer has to demonstrate this. What else do they have to show in order to gain approval from the FDA?

Alison Hart, PhD
When a new prescription is ready for clinical trials, the company that is producing it must file a new drug application or an NDA. The same thing happens for the generic form of the drug called an abbreviated new drug application. And in the ANDA, the manufacturer must show that the new generic has the same active ingredient, that will be the same strength, have the same form of administration. It also must show that the inactive ingredients will have no impact and that the drug will last for the same amount of time. More importantly, the manufacturer has to show how they will be manufacturing the drug, which has to be using the same or extremely similar synthetic methods, and they must show that they can reliably make the drug, among other things.

Erin Merritt
And then once generic drugs make this ANDA application, are they regulated the same way as branded drugs?

Alison Hart, PhD
Absolutely. It’s the same active ingredient. So the regulations for the generic and the name brand remain the same.

Erin Merritt
And how does your team support that process?

Alison Hart, PhD
Medicinal chemistry combines chemistry, biology, and pharmacology to design and develop new drugs and improve existing ones. The synthesis team at MRIGlobal assists in developing synthetic routes for target molecules that will hopefully make it to clinical trials. We optimize procedures that are for medicinal chemistry routes, which are basically when you make something on a very, very small scale within the milligram range. We do this so that they can be replicated on manufacturing scale, so kilogram synthesis or metric ton. So you’re looking at a hundred-to-thousand-fold scale.

Erin Merritt
Tell me more about this.

Alison Hart, PhD
Typically, chemists will screen several chemicals that have shown promise with whatever disease they’re researching. Once they get a hit, they then start to develop a library of similar compounds with the same basic structure. This can go on for multiple rounds, optimizing different areas of the molecule so that it’ll interact with whatever enzyme or interaction that the body has with the drug. Throughout this time, they’re only synthesizing each compound on that milligram scale as they don’t need much for the initial testing. The procedures that they are using may not be optimized and have really poor yields. Once a major hit has been found, that’s when process optimization occurs, which is where MRIGlobal can come in.

Erin Merritt
And how does this optimization of the chemical reactions improve the production process?

Alison Hart, PhD
So optimizing reactions can target several criteria to make the synthesis more efficient and cost effective. A few of the main areas that we target for optimization include removing harsh or dangerous chemicals, using better or fewer solvents that don’t have adverse health effects, and rerouting the chemistry to have fewer steps.

Erin Merritt
Are there any drugs of particular interest that you’re working on now?

Alison Hart, PhD
Actually, we just finished a cGMP manufacturing campaign for a phase one clinical trial for the treatment of methamphetamine use disorder. Additionally, our team is working on developing new routes for the treatment of tuberculosis and familial dysautonomia. In the past, we have worked on several drugs that involve the treatment of different cancers, as well as Alzheimer’s disease. I’m always excited for the next project to come in to see what we’ll be working on.

Erin Merritt
Working in the laboratory to replicate name brand pharmaceuticals is the first step in developing generics, but they also then have to be scaled to work in manufacturing, which presents its own challenges.

Alison Hart, PhD
Initially we perform reactions on the milligram to gram scale, and once we get something to work really well, we then scale our reactions by increasing them to 10 to 50 times the original size.

Erin Merritt
So in the lab, you’re working with very small quantities. How do you then scale that process to work in manufacturing?

Alison Hart, PhD
So if we start with one gram, the next reaction might be 50 grams once we get something to work. This allows us to determine if our reactions are going to work as we scale them without wasting too much of our synthetic intermediates. Once we have shown that we can successfully synthesize materials on the kilogram scale, we then start working on providing materials for toxicology and clinical trials.

Erin Merritt
Are there challenges that you face in doing so?

Alison Hart, PhD
Absolutely. There are challenges in everything that we do. Some of the ones that we face include the formation of undesired products in the reactions that can increase as
we scale the reactions or we can form new ones. We also have issues that cause our reactions to stall or just stop working. Additionally, when we use a catalyst, there’s something called catalyst exhaustion. A catalyst is a reagent that interacts with our products, and then after it’s done reacting, it then becomes regenerated so it can be used again, which means we don’t have to use as much of it. However, when you’re scaling up these reactions, sometimes a catalyst can become exhausted to where it basically stops working or it doesn’t keep regenerating as it should.

Erin Merritt
Are there any new trends that also pose an additional challenge in your work?

Alison Hart, PhD
So currently the industry is making great advances in something called green chemistry initiatives, and that’s where we really have to be cognizant of what’s going into a reaction. The solvents we use, the reagents we use, and we really want to make sure that what we’re putting into a reaction we’re getting out, which is also called atom economy. So certain solvents, we have to be really cognizant about what we use because they do have toxic traits.

Alison Hart, PhD
In fact, the EPA designated last year that methylene chloride or dichloromethane has increased hazards. And so MRIGlobal is doing what it can to remove the practice of using
methylene chloride in our synthetic procedures.

Erin Merritt
Are there other groups within MRIGlobal that your team is able to support or collaborate with given your skillsets?

Alison Hart, PhD
Absolutely. At MRIGlobal, we’re a team that solves problems together, and I have collaborated with almost every single department, whether that’s our Integrated Defense Solutions team, as well as our Integrated Health Surveillance and Diagnostics teams. In fact, we assist our CBRNE team by synthesizing dangerous drugs of interest such as fentanyl and its derivatives. They use these in their testing and evaluation of drug detection equipment.

Erin Merritt
Alright. Getting back to the generics themselves, why are they so important in improving access and affordability for people?

Alison Hart, PhD
Well, approximately 90 percent of the prescription drug market is generic drugs. At an 80 –87 percent decrease in costs compared to their name brand pharmaceuticals, generic drugs really increase the access to pharmaceuticals that are needed. If consumers only had access to name brands, then there would be a lot of people who would not be able to afford the medications that they need.

Erin Merritt
And why is doing so so personal to you and your work?

Alison Hart, PhD
Well, I feel like I’m doing my part in making the world a better place, but also, almost every single person you know is on some type of medication, and some of those medications can cost thousands of dollars just for one month. So when a generic comes out, instead of costing a thousand dollars, it might only cost a hundred dollars for that month, which really increases the affordability. There’s always a sense of satisfaction that something I’ve worked on might make it to the market, which could potentially help thousands of people.