Three Top Tips for Evaluating the Potential of New Drug Delivery Technologies

Dr. Keith Horspool, Vice President, Pharmaceutical Development US at Boehringer Ingelheim, joins Andrea Charles from Pharma IQ, to discuss strategies to reduce time spent in R&D and recent trends in the adoption of novel drug delivery technologies.

Pharma IQ: How has the global market for pharmaceutical R&D evolved in recent years?

K Horspool: Clearly it’s a much tougher environment than it was, say, five or ten years ago and right now there’s quite a lot of focus on productivity and costs within the industry, and for me, I’ve seen quite profound changes in pharmaceutical development to try and balance the investment with the potential success of a product and particularly efforts to try and minimise the effort and cost in phases of development that are associated with high compound attrition. So several companies have been looking at somewhat streamlined early development, for example, which has, I think, had quite significant change.

The other thing that’s happening is several pharma companies have evolved to what I call a more decentralised research operation, so rather than having a worldwide research centre, if you will, research R&D, there’s now specific business units that are tasked to act somewhat independently to progress, say, a portfolio for a particular therapeutic area. So, again, that’s quite a profound change.

And then, thirdly, there’s obviously, as I mentioned earlier, efforts to try and streamline within development the activities and there are a number of scenarios being promoted for very accelerated truncated development whereby clinical studies are compressed, or some studies are eliminated, to try and get safe effective medicines to patients as quickly as possible.

Now, all of these things, all of these new approaches, demand a completely different approach from the main support lines such as, say, a pharmaceutical development function or an analytical function or pharmacokinetics and metabolisms functions, so that we can match our output in terms of speed, quality and resources with the specific requirements of either the therapeutic area business unit or a... say, for example, an oncology unit may require a much faster, leaner development paradigm than, say, a cardiovascular therapeutic area unit and , again, that strategy within departments like pharmaceutical development will also have to be flexible to accommodate these alternative development models which may require a lot less clinical time and therefore may compress the time we have to do what was traditional formulation. We may have to think differently to respond to those changes in other parts of the business.

Pharma IQ: Why are changes needed to current preformulation and formulation practices?

K Horspool: Well, I think I mentioned a few reasons there and I think the main change for me that we need to do is just one word, and that’s flexibility. We have got these changes in early development as I mentioned and through development, so there’s not only change at the front end, but there are also other changes going on within our industry in terms of more later stage considerations. I’m thinking now of the regulatory environment where there are concepts such as quality by design, which requires a more fundamental approach to product designs throughout, not only later but throughout early and later stage development. For me, those are some of the drivers and so I think preformulation and formulation needs to become more predictive, more scientifically driven than empirical, particularly scale up work, and I think in early development, early work, some of the unfocused screening activities again don’t always give you the best return on investment. So, again, I think a more fundamental approach and more predictive in nature is what needs to be progressed.

The other big trend in the industry that I think will change practice is the growth of new biological entities, NBEs, and the influence they’re going to bring to preformulation and formulation development which will need to be redefined, I believe, to advance the science of new technologies to bring these types of molecules into routine developments as opposed to being somewhat unusual activities for some companies. So, again, there are efforts to have more focussed groups or skills centres who address the increasing prevalence of NBEs, but I think there’s going to be an increased need to have more widespread capabilities to deliver these molecules and develop them, because they are going to become a greater part of the portfolio and, again, that goes back to having a flexible workforce and flexible capabilities that can basically manage a greater diversity of molecules within development. And I think with that there may also be an increased need to have selected outsourcing to manage this diversity of demand in the future.

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Pharma IQ: You mentioned selective outsourcing. Which strategies are pharmaceutical companies employing to reduce the time spent in R&D?

K Horspool: Well, I think most of it at the moment is mostly around trying to delay early investment, as I said, so trying to limit the amount of work that’s done until there’s a clear indication that the compound or the project is going to be viable. So this really means achieving a positive proof of concept in clinical study and not investing a lot of effort in development until that milestone has been delivered. So the key thing is to quickly get through to a positive proof of clinical concept or a decision on the mechanism, and to not invest a great deal until you’ve reached that point. So that typically right now looks like oral solutions being used for as long as possible in the early phases of clinical development and I think that definitely reduces some of the costs for sure.

The downside though with this is that if the clinical results do come out positive, then if no solid dosage form studies are worked to given an understanding of what the solid dosage form challenges could be, there’s a risk that straight after receiving a positive clinical outcome, formulation development becomes rate [?] limiting and could create quite a hiatus to the overall programme. So the other scenario rather than completely delaying most of the activity is to try and use smarter, very efficient formulation type studies, so materials characterisation and what some companies call material-sparing dosage form design whereby the rapid prototype solid oral formulations can be designed at a more fundamental level with very small amounts of material in very small periods of time. So I’m talking grams to hundreds of grams rather than kilos and weeks or months rather than going on for years.

The other thing for me, I think, that is encouraging to see is there’s a lot of attention being placed on being more predictive with regard to how dosage forms are going to behave in clinical studies because clearly they are expensive. There’s huge costs associated with clinical trials, so anything we can do to better predict outcomes with regard to performance in terms of delivering the right profile, in terms of delivering bio-equivalent profiles, for example, if we’re doing switches, then I think those things are going to be very important. So I think increased knowledge and the location specificity of transporters through to advanced dissolution methods and mathematical simulations are all going to be very helpful to deal with some of these challenges and, as I mentioned before, NBEs will require also specific attention to try and accelerate how we develop those types of agents which are not only you will want to get them through to patients as quickly as possible, they’re obviously hugely expensive in terms of the API costs. So, again, efforts are needed to try and reduce the amount of API consumed to get early or late formulation development completed as effectively and as efficiently as possible.
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Pharma IQ: What trends are you currently seeing in the adoption of novel drug delivery technologies?

K Horspool: Dealing with highly crystalline poorly soluble drugs remains a big challenge and there’s clearly a lot of interest still in this area. As well as the different formulation approaches that are out there, there’s sustained interest in the actual different processing of those types of systems which is a very important consideration for scale up, so spray drying and hot melt extrusion appear to be very important areas right now and seem to be receiving a lot of attention. And there are several companies that are out there to help provide such services, and I imagine we’re going to see small or midsized companies and probably some larger pharma going to such companies to be able to supply these types of systems. Obviously some big pharma may want to internalise the technology if it’s important to a big new product, but, again, it’s going to require investment so I think there will be a mix of interest in that area.

I think with any new technology, it’s always a challenge at times to perhaps introduce it into late stage operations, but again with more manufacturing being sent outside of companies, big companies, then I think it gives those companies more opportunity to explore new technology and to bring these systems in, which again will help establish them and make them a more routine part of our business, I hope, for the future.

The other areas that I think are of interest from my perspective are technologies that facilitate any life cycle management opportunities for existing products such as fixed dose combinations. There seems to be a lot of interest in opportunity there and there are issues such as how to achieve, say, multi-phasic delivery profiles, how to ensure compatibility and stability of your triple combination therapies, for example, dealing with the high drug loads that may be required and so these are all interesting challenges that are looking for solutions from novel drug delivery.

Paediatric development is also an interesting area right now, particularly around improving the taste masking of such formulations for the paediatrics. And, again, not to forget the importance of NBEs and particularly technologies that decrease the frequency of administration, improve toleration and if injectable, those systems that allow patients to self administer such therapies efficiently and effectively.

I actually think it’s quite interesting talking about biologicals, if you will. I was intrigued to see recently there have been a couple of reports of some pharma companies making investments into oral delivery of insulin. Obviously that’s been a challenge for decades, so I’m very interested to see whether these new investments can actually prove successful in cracking what’s been a very, very challenging drug delivery issue, so that’s an interesting area for me in terms of watching the outcome of those investments.

Pharma IQ: And what would be your top three tips for evaluating the potential of new drug delivery technologies?

K Horspool: I don’t know whether it’s a tip, but I think the three words I’d use would data, data, data. At the end of the day there has to be scientific data to support the delivery concept and how it achieves the desired outcome, and there should be some evidence of proof of concept demonstrated in vivo. Obviously it would be preferable if that demanded at least some demonstration in vivo of some sort that the concept works and not only does it have to demonstrate the effectiveness of the approach, it has to actually also be put in context with how that compares with existing technology. So what’s the real benefit, the business benefit, of the system? Just because it’s scientifically superior doesn’t mean to say that it’s going to have a business benefit which is, at the end of the day, what we’re really looking for. And then in terms of those data that I’ve just been asking for, if they’re not available, they need to be achievable quickly and at relatively low cost because if you are going to achieve that as a drug delivery provider, if you can prove quickly to a client that you can make a positive impact on one of their projects or programmes quickly, there’s nothing like showing that and being able to demonstrate that with something that a company cares about. But you have to try and lower the bar to entry at that point, try and get to be able to prove a success with the technology and I think then it’s a lot easier to negotiate and partner later on.

And then just lastly with regard to data, obviously you’ve got to have data that supports an intellectual property portfolio, if you will, so there needs to be IP in many cases for technology and if there is IP and you go to a client and you mention the IP, I’d recommend that it’s clear that the IP that is there is actually relating to all aspects of the technology and not, say, just a very small part of the technology, for example, the concept. The whole delivery concept is something that may be not covered, but there is a very small process span that allows operation of a particular type of equipment under certain conditions. That clearly is going to be a lot more limited in terms of the value versus technology where there’s broad coverage on not only the processing, but the basic concepts for that delivery technology.

And then, whilst we’re on the subject of IP and information, the other aspect I’d bring with regard to data is please make sure that you don’t share any of your confidential information with other parties without having the right agreement in place. I have seen over the years people sending confidential information into companies unsolicited which is a somewhat dangerous thing to do and it can cause quite a number of issues, so that’s definitely something to avoid at all costs.

Pharma IQ: How important is the role of co-crystals in formulation design and product development?

K Horspool:I think co-crystals represent a very interesting opportunity for the industry. What I would say is like many alternative ways of doing things that come across as somewhat new and there is some debate, I know, as to how new co-crystals are, but let’s assume that it has been somewhat unusual to develop co-crystals in our industry and, as with most things, when we’re getting involved in something that’s atypical, there are benefits and weaknesses that need to be explored and understood to really maximise the application and utility of the approach, so I think there’s some great opportunities to create novel entities which have great patents opportunity by being able to improve solubility, stability and particularly crystallinity through co-crystals. The caution now we give is that there are some risks associated with these types of systems, so mainly the stability of systems, so co-crystals either alone or particularly in the presence of excipients, and associated with that is how to translate the knowledge from early formulation and early stability studies with co-crystals into commercial shelf life.

So I think there’s some work, some science, that’s needed to really better understand the long-term viability of co-crystals. I think there’s some great work that’s been done to show how to do select co-crystals and how to streamline what could be a big universe of co-formers in terms of more efficient selection, but I think the things that need to be better understood is, having isolated the co-crystal, how robust is that for the long-term development? And associated with that is, again, some of the screening technologies have certainly improved our ability to identify co-crystals. However, some of the methods for isolating or selecting co-crystals again aren’t really scalable so, again, that’s another practice for me, great opportunities and definitely something that we should all be interested in and exploring, but I think I just raise the stability aspect and the manufacturability, the scalability of some co-crystals really needs to be considered. They’re not going to be a panacea. They have a role, but that role really needs to be well defined and well understood I think to maximise their use as I mentioned earlier.

IQPC

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