According to Nigel Langley (chair of IPEC – Americas), the new drugs that have yet to be developed and approved might need more than the excipients that are in our hands now. Many emerging treatments very likely will need novel excipients in order to succeed.
Langley will cover the topic on May 17 at 4:15 pm during his presentation “Novel Excipient Pilot Program” at CPhI North America. Outsourcing-Pharma connected with him to get a preview of the session, and to discuss the US Food and Drug Administration (FDA) program, current and emerging challenges, and what is happening with excipients currently in review.
OSP: Why is there a need for new, novel excipients?
NL: If you look at pipelines of pharmaceutical companies the percentage of very poorly water-soluble drugs is far higher than it was 20-30 years ago. In fact, up to 90% of the small molecules can be really intractable, and very poorly soluble.
To put this in context, in some cases these compounds are less soluble than marble is in water. So, the challenge is to deliver these poorly soluble drugs so that they have efficacy in the patient. After all, if it's not dissolved, it's not absorbed and will just pass through the body and have no beneficial effect.
You put this together and it becomes clear in an age of limited new excipients, they are conversely needed more than ever to help overcome this significant formulation challenge.
OSP: Where are we starting from in terms of bringing in new materials?
NL: It's important to remember that there is a strong need for new materials because many of today's excipients were not developed for pharmaceutical applications. They've come from either cosmetics, food, or other industries, so they were not designed specifically for any formulation need.
I've already mentioned poorly soluble small molecules, but there are also problems on the biologics side around the agglomeration and stability of proteins. Plus, there are challenges around different dosage forms, for example, different patient populations, like pediatrics and geriatrics, where taste masking of bitter drugs is critical if you're taking an oral form that's not a traditional tablet – and around 40% of active pharmaceutical ingredients (APIs) are bitter in taste.
In addition, new modalities have grown exponentially over the last ten years and excipients really haven't kept up. So, you've got excipients that are generally between 30 and 70 years old, and you've got new modalities for which you've got to try and come up with some new solution. As a consequence, sometimes the options are very limiting.
Our mantra is, therefore. 'The drugs tomorrow can't all be formulated with the excipients of yesterday!'
OSP: How did the FDA review process start?
NL: We formed a partnership between IPEC Americas and the IQ Consortium (The International Consortium for Innovation and Quality in Pharmaceutical Development) as far back as 2015, as we felt this would give us a better chance to discuss this topic with the FDA.
Then in 2017, we had a pivotal meeting with the FDA where we first proposed a novel excipient review program. As a result of this meeting, the USP developed a global questionnaire aimed at the formulators to assess whether there was a need for novel excipients, what the challenges were, and if a program was actually developed in the future, would that resonate with them?
There was overwhelming support for a program to enable more access to these materials in the future and this stimulated the FDA into issuing a docket for a public response in 2019. This was for a pilot review process and was warmly welcomed, but things then went quiet because of the pandemic; the FDA had other priorities which is completely understandable.
Fast forward to September of last year and they announced that they would be introducing a pilot program and this would involve the opportunity to evaluate four novel excipients, two each year for two years. Although there are a lot of different types of novel excipients that fall under the definition given by the FDA for novel excipients, the focus of this pilot will really be on new chemical entities, like brand new chemistries for novel excipients.
OSP: Do you know if four candidates were submitted?
Nigel: The closing date for the submissions was, around December 7, 2021, and we're still waiting for feedback from the FDA to see if they received four candidates. Certain criteria were set within this assessment and the first necessitated a fairly high-level document to be submitted. If it looks to be of interest and gets through that first phase, then the second phase would require the full toxicity data as defined by the FDA guidance on novel excipient development, which typically takes about three years to complete.
My own opinion is that I do think the four have been submitted, possibly a few more. These may have come from different suppliers and, possibly, even universities or start-ups. Whether they have the full tox data package is a good question, as I don't think there's physically enough time to actually generate that information to satisfy the requirements of the program.
OSP: Let's assume four novel excipients are being taken forward; will these have to be part of a commercial drug that's going to come to market to get that tox data?
NL: When you develop a novel excipient, you should really follow the current guidelines set by the FDA. It generally takes two or three years to complete all the necessary tox data. Although developers may be interested in trying a new excipient, prior to this pilot program, the reticence has always been that it might be blocked at some point during that process because of the perceived risk of taking something through that's not been through a clinical assessment before.
It has really only been considered when every other formulation approach using existing excipients has failed – at which point they are forced to abandon a target or use novel excipients. So, in a nutshell, that's the dynamic we want to break – and encourage innovation of excipients to be more universal.
OSP: How will the program change NDA submissions?
NL: The program has been introduced because at the moment the FDA doesn't review the novel excipient until the drug company submits an NDA at the final stage, and then the new drug would be assessed. Or the formulation including the novel excipient will be assessed at that time and the company will hope the drug will get approved after phase three containing the novel excipient.
Currently, you need at least two drugs that have been approved before that novel excipient will eventually appear on the FDA inactive ingredient database. That's really the indication to the market that it’s a safe bet with a new drug application.
Now what is so exciting about the pilot program is that it will allow the excipient to be submitted for early review by the FDA. They will look at the data and evaluate safety, which they've never done before in a formal way.
If any novel excipient comes through that – i.e. they don't have any concerns about the safety integrity of the new material – they will then add it to their website as, in their opinion, it is suitable for clinical testing. By doing so, we hope that formulators and various pharmaceutical companies will be able to have a little bit more confidence in using novel excipients and will potentially pick those in addition to existing tried and tested older excipients. It’s essentially leveled the playing field for the use of these pre-reviewed novel excipients with anything else. It’s a big perceived barrier to entry removed and de-risks the process of the innovator.
OSP: Will this new approach incentivize the development and use of novel excipients?
NL: Absolutely, as in the past, the incentive to develop before the program was very low, as it could take seven or eight years to develop a new chemical entity novel excipient, and then basically hope for the best when you launch. So it could then take another 10 or 15 years before you got any commercial return on your investment. That doesn't work very well for any sort of company.
OSP: What about the role of co-processed excipients?
NL: That’s another area we are pushing actively for. We want to challenge the way co-processed excipients are viewed by the FDA, especially if they're specifically developed. Imagine a scenario where you have two or three known excipients that are in the FDA inactive ingredient database and you're using them at levels no more than stated in that database.
Then you know the safety risk is fairly minimal, but at the moment there’s a lot of perceived risk for even adopting co-processed excipients. And that's something that we need to address as I would say that's probably where a lot of innovation will come from, rather than developing new chemistry from the beginning.
The good news is that the FDA is very supportive in the area of continuous manufacturing, as co-processed excipients provide an excellent opportunity to improve the efficiency of continuous manufacturing processes. So, for example, rather than feeding in four different excipients into a continuous process, you could possibly combine these as a single co-processed excipient and just feed that in, leading to increased functionality and efficiency.
OSP: Will we see a lot more blue-sky thinking from the excipient manufacturers?
NL: The whole point of our joint activity is to stimulate innovation on the excipient side. We've got a tremendous amount of innovation going on in API, modes of delivery, and lots of other areas, but excipients need to play a role in all of these. Excipients need to be considered as an integral part of the puzzle, rather than the lesser science that is sometimes the current perception.
Our goal is to stimulate an innovative culture around excipients and create an environment in which excipient companies and pharmaceutical companies collaborate much more formally and closely together. Rather than the onus being all on the excipient company, as it has been in the past, with the view that: 'You generate some innovation and come back to us when somebody else has actually had this product approved in their drug and we'd be interested to use it'. We want to flip that paradigm and say 'tell us what your needs are and work closely with us'.
With this approach, patients crucially stand to benefit as they will get a formulation that is as optimum as it can be, rather than just something that's just okay. It will give developers more options for the excipients, and empower them to make even better products.
OSP: Do you think excipients are definitively on the up in the industry, and there is more interest than now than, say, five years ago?
NL: The very fact we have this session, and we are talking about it in the media shows how far we have come, but I want us to build on this and go much, much further. Yes, there's definitely more collaboration all across the industry from CDMOs and CROs to academics and of course the formulators and regulators. I see real potential to get good returns on the investment, while at the same time creating the opportunity for formulators to talk to suppliers more collaboratively.
I think everybody will win if we can make this pilot program a success – and I am very optimistic that when the news does come out from the FDA on these 4 applications, it will be positive. It will mean together we have taken another step forward in developing better medicines for patients.
CPhI North America is scheduled online May 9-27 and in-person in Philadelphia May 17-19.