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Joël Richard VP, Peptides for Ipsen on Formulation Challenges for Biological Drug Products

Contributor: Joël Richard
Posted: 02/03/2013
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In this industry interview Joël Richard Vice President, Peptides for Ipsen, speaks to Andrea Charles from Pharma IQ, about formulation challenges for biological drug products.

Pharma IQ: Can you briefly explain your current role and responsibilities?

J Richard: I'm presently the Vice-President, Peptides, for Ipsen, which means that I'm leading all the activities that are called CMC activities, which are actually product development activities for peptide-related drugs, including of course all the API, formulation, novel formulation development, analytical and industrialization activities.

Pharma IQ: What are some of the biggest challenges in getting formulation right for peptide drugs?

J Richard: I would say there are many different challenges. One of the main challenges today is to develop formulations that provide a specific functionality, for instance, sustained-release formulation for very long periods of time. Today, peptides on the market have either immediate release formulations, or sustained-release up to six months.  As regards proteins, on the contrary there's only one product on the market for a relatively short period of time - only one week-, which is a recombinant growth hormone already commercialized in Korea and being in the process of filing in other countries.  All the other long-lasting products are modified proteins, like PEGylated or fusion proteins.  And actually developing and bringing to the market sustained- release formulations of proteins over long periods of time is today one of the main challenges. 

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Another challenge is to find an alternative route of administration. All the biotech products are parenteral products today; they are administered chronically, for instance, every day or many times a week for biologics.  And most likely if an alternative route of administration, for instance oral administration or transdermal administration, would be available, there would most likely be a big interest from the market and from the patients to shift to this new type of formulations for peptides and proteins. 

So, as a summary, these are the main focus of development in the field of novel formulations for peptides and proteins today. 

Pharma IQ: From your wealth of experience, what would be your top tip for facilitating best practice in formulations?

J Richard: One of the main things is to first understand the physical chemical properties of a peptide or a protein in solutions. I think that in the process of developing new formulations the understanding of the solubility, precipitation, aggregation properties, of a peptide or a protein in various buffers or aqueous media is one of the key concepts, and of course using many different analytical techniques to investigate the behaviour of molecules in solution.  I mean not only using chromatographic methods, since they can only assay the soluble parts of a peptide or protein in solution.

But also I would say methods that can especially be used to evidence higher molecular weights, and also particles in the nano- and micro-range for instance.  I think this is one of the key points.  As a summary, it’s about: “First, know well your molecule”.  The second point is you have to define the target product profile, which means what type of product you would like to get in terms of dose strength, volume of injection, stability, and also the real need and importance of a device for administration,  as well as easiness for use. 

For instance, would you consider a reconstitution product where re-dispersion of microparticles, for instance, or re-dissolution of a lyophilized formulation before administration is necessary, or not?  Do you absolutely need to have a ready-to-use liquid formulation in a prefilled syringe, for instance?  So I think it's a key point to really and precisely define what the target product profile is, before starting the development project. 

This would involve a lot of various actors from marketing, from also the clinical team, the manufacturing people; so it's really a team work to agree on what a product should be.  These are maybe the two key points to set best practices for formulation development.  There might be other ones, but I don’t pretend to be fully exhaustive here. 

Pharma IQ: What's the danger of working with high concentration formulations?

J Richard: High concentration formulations, this is another very good topic! So, actually if you look at the trend of the market, I would say people are working on high concentration formulations most of the time for monoclonal antibodies (mAbs). Today most of the monoclonal antibodies are administered by IV and do not require high concentration formulations.  But there's a general trend, for various reasons related to patient compliance, also to the cost of the treatment, to get subcutaneous administration of monoclonal antibodies.  And for this reason, of course you need high concentration formulations, not to have a too high injection volume. 

The main hurdles could be related to stability of the formulation.  It's clear that if the concentration of proteins/mAbs in the formulation is high - we are talking here of concentrations higher than 200 milligrams per mL-, then the interactions between the protein molecules are much more frequent and then they can lead to formation of multimers, and aggregation, with a much higher probability than in diluted formulations.  This is one of the first concerns. 

Second point and maybe this is the major one, it's about injectability, because of course when you increase the concentration of a formulation you also dramatically increase the viscosity of the solution - even faster if you are working with mAbs, for which molecular weight is in the 150 kiloDalton range, so a very high molecular weight.  As you know, molecules with a very high molecular weight in a high concentration display a very high viscosity in liquid formulations. And then injectability is reduced because, of course, you would need very high syringe injection force to administer the formulation, even with a large diameter needle.  And this can be a show stopper.  So I think this might be the most important point for developing high concentration formulations, the more that you are working with high molecular weight compounds like mAbs. 

Pharma IQ: You are going to be speaking at the Global Formulation & Drug Delivery Summit taking place on 23rd to 24th April in Amsterdam. What are you most looking forward to the event and can you just give us a brief overview of your presentation?

J Richard:
So, my presentation actually will address still one of the major challenges of protein delivery for the parenteral route, which is about: “What are the available tools and successful technologies today to achieve long-lasting or sustained-release formulations of proteins”.  Actually, there are typically two different types of technologies. I mean first, technologies based on the modification of a protein, some of them have been quite successful in the past years with PEGylation technology and also fusion proteins.  But they also have their limitations because today nobody has really been able with PEGylation to get very long sustained-release formulations, and ultimately PEG is not biodegradable and can accumulate in some tissues. 

And the second one is getting a long-lasting effect and a sustained-release effect only by formulation of a protein without any modification; I mean any chemical modification or any modification by fusion with another molecule. And actually this is a quite challenging domain.  As I've already said, there's only today one product of this type on the market.  A lot of various technologies are investigated at the present time, and some of them are in clinical development, but they have not been so successful until now. 

So my talk will point out what the requirements for a purely formulation-based approach are to be successful, based on, I would say, past experience. For instance, people have tried a lot of formulation technologies based on polymers, PLGA copolymers for instance, and solvent-based approach, and this does not really work for proteins.  We have to think more of, solvent-free processes and water-based processes.  And so my talk will be about these aspects, about showing that, well, there has been a lot of work carried out, we have to learn from it and if we really want to develop new sustained-release formulations of proteins, we have to focus on some very specific processes. 

Pharma IQ: Looking to the future, what are the expectations for parenteral biologics delivery in the next two to five years?

J Richard: I think that as regards high concentration formulations for mAbs, for instance, there will be significant progress.  I know some companies are working on, for instance, increasing the concentration by working on dispersions of mAbs particles or protein crystals, because these dispersions display a much lower viscosity for the same protein concentration in the formulation. So, I think this would be one of the progresses expected. 

I would also expect that as more and more formulations and products from originators are going to fall in the public domain, there will be progresses in the field of life cycle management of these formulations, which means the development of sustained-release formulations based on adequate processes, as mentioned before.  This is an area where maybe not so many companies have really put significant efforts in the last five to ten years, and my suggestion would be that they should really look at this more carefully. 

I would also expect new compounds to come to the market, which is more about compound discovery, and is not really related to formulation, except if they would bring new formulation challenges related to poor stability or solubility. I think these are the main aspects.  There will also be progresses in the field of alternative routes of administration; this is likely more progressed in the field of peptides where already the oral route is in clinical Phase III, and also there are some interesting developments for transdermal delivery.  Yes, I would say these are the main expectations in the next few years. 

Thank you for giving me the opportunity to express my view on formulation challenges for biological drug products.

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