How Formulation Scientists View Drug Delivery With Yogesh Bachhav

Videocast host Tom von Gunden talks with Yogeshwar Bachhav, CMC consultant for AiCuris AG Germany, about scientific and technical considerations in the alignment of drug formulations with routes of administration and related delivery systems during product development. Topic coverage includes delivery considerations related to viscosity, permeability, solubility, safety, usability, packaging, and supply chain.

Episode Transcript 

Tom von Gunden, Chief Editor, Drug Delivery Leader:

Welcome to another episode of Sit and Deliver. My name is Tom von Gunden, Chief Editor at Drug Delivery Leader and your host for the series. Today, I am pleased to be joined by Yogesh Bachhav, who is an independent CMC consultant for AiCuris AG Germany.

Welcome, Yogesh.

Yogeshwar Bachhav, CMC Consultant, AiCuris AG Germany:

Thank you, Tom, for the kind introduction and invitation. It’s a pleasure to be here.

Well, it's my pleasure to have you here. So, let's go ahead and dive in.

So, folks in the audience, I want to frame this up a bit. I have invited Yogesh here because I was very much interested in hearing his perspectives — representing the perspectives of formulation scientists — as it relates to thinking about drug delivery, all the way through the product development life cycle.

So, Yogesh, let's start at the point in an organization — a biopharma organization: Let's imagine that a lead molecule has been identified, and we're beginning to think about the formulation and dosing considerations that would ultimately lead to a decision about delivery route of administration.

So, at that [stage of] just on the verge of moving into product development from lead molecule identification, what are some of the formulation science considerations that come into play with delivery — either front of mind or, at least, back of mind —at that point?

That is a very interesting question. So, to give a background: During the hit-to-lead stage in the drug discovery process, often they start with hundreds of compounds. And by the time you have a lead, you have maybe one front compound [and] two to three backup compounds.

At that point, the challenge is really to develop the formulations, to do some preclinical studies in order to understand how the molecule behaves in vivo in terms of the efficacy.

And, at that point, the information available to the formulation scientist is very limited. So, in order to develop the formulation, the formation scientist really needs to understand: What is the ionization constant of the molecule? What is the lipophilicity of the molecule? How stable is the molecule into the aqueous media, simulated gastric media, the intestinal media? How stable is it into the solid state and solution state? These are the basic properties, or the tests, the formation scientists must do.

Once we know the solubility of the lead molecule into the simulated media, like a 0.1 normal HCl, or maybe simulated gastric fluid, the intestinal pH, like pH 7.4 phosphate buffer, or simulated intestinal fluid: that gives a fair idea if the molecule has a desired solubility [or] that it can achieve the desired bioavailability. If the molecule is too lipophilic, maybe then we have good chances to come up with a lipid-based drug delivery system. It has good potential to cross the intestinal barriers due to the lipophilicity.

Stability is also quite an important factor because, if the molecule is inherently unstable, then that is the right time that formulation scientists can go back to the chemists and tell them, hey, guys, this molecule is not very stable, maybe a good idea to replace some of the functional groups without changing its efficacy so that we have the potential to move this molecule across the different development phases.

Another important aspect we need to consider is the solid state that the molecule must possess — good solid-state properties, like a stable polymorphic form, the flow properties.  Because at the end of the day, we need to develop the first-in-human and later on commercial formulation. And if the molecule does not have those properties, then maybe it does not make sense to develop it all the way. And that is the right time we can change the properties of the molecule so that it can be formulated into the given process form.

So, these are some of the aspects we try to address when the molecule is really coming to the lead stage, and we are asked to develop suitable preclinical formulations.

Gotcha. Of course, we know that the ultimate route of administration or delivery method may be several stages later before that becomes definitive. But is there anything that happens in these early stages which does influence at least the basic yes/no or go/no-go decisions about certain routes of administration?  In other words, are there things that happen that would rule some of them out, or one of them out, but keep others in the potential mix?

Sure. So, maybe I can give you an example. Imagine there's a drug which is to be developed for the oral route. But if you see that the molecule does not have any permeability across the GI tract and also the solubility is bad. These are typically the BCS Class IV molecules, the Biopharmaceutical Classification System Class 4. And even if the dose is high, because normally such a basic Class IV molecule uses penetration enhancers, those penetration enhancers naturally do not come with all safety profiles. Often they try to impair GI permeability.

In this case, if the dose is high, and the permeability is also bad, then formulation scientists may come back and tell the medicinal chemists, hey guys, this molecule cannot be developed for the oral route. Okay, next question, can you develop for the IV route?

But, as I said before, maybe if the dose is high, its solubility is also bad. Then, the amount of excipients you will need to develop an IV formulation or parenteral formulation, the quantities are so high that it is not approved by or is not acceptable by the FDA IIG [Inactive Ingredients] database. And then you come to the conclusion that this molecule may not be developed either for the oral or the parenteral route. That is one example.

Second example, if the molecule possesses not very acceptable stability in the presence of the liver enzymes, like high first-pass metabolism, then this is also sort of no-go for oral tablets. Maybe then other options can be explored, like sublingual tablets, or maybe the parenteral route.

So, these types of scenarios we do come across. And depending on the problem and then the solutions, we have to decide [through] which path we should take it forward.

Gotcha. Well, thanks for that foundational explanation of some of those key early-stage considerations. That's all about the science, so to speak.

But we know that, in a biopharma organization, it's also about the business. And so, I'm going to just throw a handful of what comes to my mind when I think about business and market considerations. And you can speak to any of them or others as you feel free.

I'm thinking of things — do any of these considerations come into play in the stages we’re talking about? Things such as competitive differentiation or cost of product, either for the company developing it and or for the ultimate patient, desire to accelerate speed to market or, perhaps, alignment with a company's current core competencies. Or perhaps the company wants to [leverage], or is already leveraging, platform technologies and would like to repeat [that] with new products, if possible. So, [for] any of those business and market approach considerations, how do they enter the thinking of formulation folks, if they do at all?

So, that's also quite an interesting question, Tom. Again, there are two aspects you mentioned. Accelerating the speed of drug discovery, that is one thing. At the same time, we want to use the existing platforms of the company.

Frankly, if you have the lead candidate and you want to reach for the first-in-human formulation, you try to keep [it] as simple as possible. Then maybe a simple powder-filled capsule can also work. If there are no delivery challenges, [if the] molecule is highly soluble and it's highly permeable, then you have those answers needed for first-in-human studies. It could be a simple oral solution, for example. As long as it is palatable, it can work. That allows you to start your first-in-human studies on time because drug discovery time is very crucial. That is one thing.

But in the background, maybe you can do all supporting pre-formulation studies, which are suitable to the existing platform technologies of the company. Imagine a company has a benchmark technology, like a lipid-based drug delivery system, for example. The formulation scientists can do all the basic pre-formulation studies, like solubility on those lipids, the stability of the drugs in contact with those lipids, formulating in that particular benchmark delivery system to check its resolution, the in vivo PK studies, in order to have all those answers ready. But this can go hand in hand.

So, once your first-in-human studies are done using very simple formulations, in parallel then you try to do some bridging studies. And maybe then you have the chance to use your own technology in the Phase 2 studies, for example, then there's a switchover. But of course, any company will try to use their platform technology because they have made a lot of investment. And it makes sense because they have everything ready to make it commercialized. So, that perfectly makes sense.

Gotcha. So, I'm going to layer on another obvious aspect of biopharma product development to what we've been talking about. And that's the regulatory pathway component.

When I think of formulation, what comes to my mind are things like patient safety, product stability, primary packaging — some of the various components that would have to be run through regulatory submission and approval processes.

So, [about] those or others, talk about what comes to your mind or the minds of formulation folks when it comes to regulatory.

Sure. If you see the specific guidances by the regulatory authorities, like FDA and EMA, the focus always remains around patient safety and efficacy. So, safety is really at the forefront. The formulation scientists really need to make sure that whatever delivery system we are developing remains safe to the patient and. at the same time, efficacious.

So, the first thing we have to consider is: What are the excipients we are using? They must be approved by the FDA. The quantities we are using must be within the IIG database. The quantities, because they give all the details about what is acceptable per day. And we have to make sure that the quantities remain below those certified quantities.

At the same time, if any excipient is approved for the oral route, it does not mean we can use it for the IV route. In some cases, we may have to use it. But, in that case, we have to make sure that all the toxicological studies must be done using that concentration of the excipient for that particular route to demonstrate that the excipient remains safe. So, that is about excipients.

The second thing is about packaging. For example, if it is an ophthalmic product, or maybe a parental product, then we must demonstrate that there is no adsorption of the active onto the primary packaging. At the same time, there are no unacceptable leachables coming out of the primary packaging into the delivery system.

So, these are the considerations we have to make sure with respect to the impurities, because all the specifications are set with respect to the different degradation products or impurities. So, we must develop the product in such a way that the API degradation is within control, and the formation of the impurities must be within the specified limits. Otherwise, then we have to demonstrate if any degradation product or impurity is going out of specification, then that must be shown to the authorities at that particular concentration there is no toxicity, and that [it] is acceptable.

So, these are the typical regulatory considerations the formulation scientists must observe during development of any delivery system.

Gotcha. That brings to mind a question I have — not necessarily regulatory specific. When we're talking about patient safety, and we're talking about packaging and thinking about stability, what comes to mind from a formulation standpoint [related] to the actual supply chain and distribution process, even storing something before it gets into the hands of the patients? I'm interested in that aspect of what we were just talking about, regulatory or otherwise.

So, there are two aspects, again. You see a lot of biologicals or macromolecules that are not stable at room temperature. The cold supply chain is very important in that case. But then it puts huge burden onto the supply chain. It’s very expensive.

Imagine I have a liquid product, which can be shipped under cold supply chain, for obvious reasons. It is stable under cold supply chain, but the amount of investment or the expenses are so high, [the] company may ask, “Can you just come up with some lyophilized or dry formulation?” Although the technology is more expensive than a liquid formulation, that certainly makes sense, because that lyophilized product can be shipped at room temperature without the need of a cold supply chain. It just needs to be re-constituted before administration.

So, these are the criteria or considerations formulation scientists can also think [about] to reduce the burden on the supply chain.

Gotcha. Well, thank you for allowing me to interject that follow-up. So, as you know, there's certainly a lot of  demand and interest and need for ways to transition formulations from particular routes of administration to others — especially, getting things from IV and infusions in clinical settings out into decentralized settings, even including at-home patient self-administration.

So, when it comes to transitioning from IV to injection or, say, injection to oral, what are some of the formulation considerations that come to mind when those needs and demands and hopes are on the table?

So, I can give you an example. In hospital settings, often drugs are administered by IV infusion, and these volumes are quite big — 200 to 300 mL, for example. So, the large volume is getting injected. So, naturally, the drug is diluted, so we are not worried about the viscosity. Also, the pH of the plasma is 7.4, so it remains physiological.

But the moment the patient is discharged from the hospital to the residence, he has the possibility to switch from the IV infusions to autoinjectors, maybe subcutaneous. But, in that case, the volumes are changing from 200 mL to 1.5 mL. So, all the drug you have to accumulate within 1.5 mL, and that becomes so viscous. So then, the formulation scientists need to think differently. Can we use some viscosity modification agents to make it less viscous?

At the same time, in the case of IV infusions, the drug is diluted into the entire blood circulation. In the case of self-administration, it's some local tissue injection. So, the risk of tissue irritation is much higher. So, that is also one consideration the formulation scientist has to take into account, how we can reduce the local tissue irritation when a high amount of dose will be injected there. How can we adjust the pH? That is about IV to subcutaneous.

We can also think about IV to oral. In ICU settings, that drug is given by infusion. But, to continue the medication, maybe patients need to be given oral tablets. In that case, we have to make sure because, in the case of IV administration, the entire drug is into systemic circulation. But, in case of oral, then first it has to pass through the gastric pH, then the intestinal pH, then we have to really make sure the drug remains stable within the gastric pH and intestinal pH, [that] the drug has a very good permeability, so that it is also reaching the systemic circulation.

And that needs to be demonstrated through the dissolution studies, the permeability studies, followed by the bioavailability studies — [that] the desired PK levels, pharmacokinetic levels, can be achieved after formulating the drug into the oral dosage form.

Gotcha. Well, all along, we've either been overtly or implicitly talking about the ultimate recipients of these products, and those are the patients.

So, for our final segment, Yogesh, let's talk a little bit about the way that formulation folks need to be thinking about — not the breadth of everything out in the patient population, we could talk for hours and days on target indications and how to get there and that sort of thing. But I'm thinking about particularly challenged or unique populations where there might be considerations that wouldn’t need to be thought of for broader populations. For example, geriatric patients or pediatric patients.

Are there any particular patient populations that come to mind that would illustrate how you might need to adjust the thinking when it comes to formulation for delivery?

I think you have rightly highlighted the geriatric and pediatric population. There, we need to think differently because the pediatric population is not exactly the ideal population because there are difficulties with respect to taste. The children have more taste buds, so the tendency to reject any formulation is much higher due to the taste.

So, we really have to make sure that whatever formulation we are developing is palatable. There is no taste to the population, and they may reject the therapy. And they are not able to swallow the tablets. So basically, we have to either come up with some suspension formulation. Or maybe the tablet can be dispersed into the given vehicle. Even the mental order can work for that matter, as long as you're able to disperse the tablet. But the resulting suspension must be acceptable, so taste needs to be masked. That is something very important about pediatric formulations.

For the geriatric [population], again, it's the same issue. Their swallowing capacity is reduced. They [may] have difficulties, due to arthritis or tremors, opening or breaking the child-resistant barriers. So, we have to also keep the primary packaging as simple as possible for the geriatric population.

With respect to the taste, it is the same challenge. It should be acceptable to them during administration.

The third important problem with the geriatric population: For a long time, they may be taking different medications, including the proton pump innovators. Normally, the pH of the geriatric population is much more basic compared to the normal adult population. So, a lot of drugs having high acid solubility may show reduced bioavailability for the geriatric population.

So, this has to be checked upfront, whether with the geriatric population we are able to get the same bioavailability using the given population. If not, then what can be adjusted to make sure that the dissolution profile, the absorption profile, remains the same with the geriatric population?

Well, Yogesh, I want to thank you for joining me and sharing your excellent perspectives on the alignment of formulation thinking with delivery choices and the thinking that goes on there. And I also want to thank our Drug Delivery Leader audience for joining for another episode of Sit and Deliver. And we'll see you next time.

About The Featured Guest

Dr. Yogeshwar Bachhav has over 19 years of experience in drug development, spanning R&D, CMC, regulatory strategy, and business development. From his experience working at Pantec Biosolutions AG, DebioPharm, and AiCuris AG, and as a founder and director of Adex Pharma, he has contributed to the CMC development of several drug candidates from discovery to clinical and commercial phases. Currently, he also serves as an independent consultant at AiCuris Anti-infective Cures AG, Germany, leading formulation design, outsourcing, and regulatory documentation across global markets. Dr. Bachhav holds an M. Pharm in Pharmaceutical Chemistry and a Ph.D. in Pharmaceutics from ICT (Mumbai). With 27 peer-reviewed publications, 7 international patents, more than 50 invited talks, 6 book chapters, and as an editor of 4 books, Dr. Bachhav continues to leverage his deep scientific expertise to help advance pharmaceutical innovation.