Freeze-Drying and Optimising Formulation Development for Biologicals

Andrea Charles

Dr. Paul Matejschuk, Principal Scientist at the National Institute for Biological Standards and Control, joined Pharma IQ to discuss optimal formulation development, ahead of Lyophilisation for Biologicals 2011, taking place in Belgium from the 23rd- 25th January.

Pharma IQ: What would you say are the key drivers of the lyophilisation market?

P Matejschuk: I think that certainly in the areas of commercial processes – I mean, our activities are not commercial in that sense, our scales are not commercial, but I would have said that they are either therapeutic or diagnostic – the key drivers are shortened cycles while maintaining the reactivity of the biological material that you’re drying, so as to reduce what is essentially an expensive unit processing step to the minimum you can get away with and still maintain the quality of your product. Consistent product quality and defining and implementing quality by design are also big drivers, and the new products on the market, high concentration protein products, syringe formats, novel vaccine delivery systems, all of which require development.  So I think those are the things that are hot at the moment in the lyophilisation area.

Pharma IQ: What are the key challenges to be addressed in optimal formulation development?

P Matejschuk:  I think fundamental to any formulation development is to know the thermal properties of the formulation that you choose, so determinations of glass transition temperatures/collapse temperatures, and optimising your cycles accordingly in the light of that data.  There are a lot of people at the moment seem to be challenged by making even higher protein formulations, so it’s in the 50/100 per mil solutions of proteins to therapeutics, which can be a challenge to freeze-dry because of the resistance to flow when you try and sublime them; and finding formulations that will stabilise difficult situations such as liposomes and gene therapy factors and things like that – cell systems, maybe, even - and avoiding the pitfalls of already patented technology.

Pharma IQ:
How have the laboratories in the freeze-drying impacted on formulation development?

P Matejschuk: I think the technology – I mean, for many years some of the techniques like freeze-drying microscopy were available, but they were the techniques of the specialists who often had home-built equipment and were sort of consultants in the field; and now with the commercialisation of those kind of techniques you can easily buy a freeze-drying microscope for a modest sum of money these days, and the supporting software and everything makes those kinds of techniques accessible to everybody.

I think you’ll now find that most people with any serious commitment to development of freeze-drying cycles will have those kinds of techniques to hand.  I think that is really what has transformed the formulation development for freeze-drying.  But there are certain areas where there’s not so much development but also quality control issues using non-invasive methods to confirm things like moisture, confirm their headspace integrity and things like that, and there again they’re becoming more accessible through the commercialisation of effective and cost effective pieces of equipment.

Pharma IQ:
There is much emphasis on accelerating lyophilisation cycle development: what methods are the industry employing and considering, to do this?

P Matejschuk:   Essentially, you can apply the principles of design by experiment, and enable you to rapidly screen lots of different formulations and come up with the ones that seem most effective quickly, and in that way powerful, and also actually in terms of monitoring your process while you’ve got the freeze-drier running there’s a lot of new technologies; traditional ones like microbalance and things will enable you to determine sublimation rates.

But those have been supplemented by people looking at the use of near-infrared reflectance – Rahman, and techniques like that - and those are quite…  There’s quite interesting ways of determining when sublimation is over and how the rate of sublimation can be influenced by the conditions that you choose that even optimise your cycle a modest scale, sort of pilots, or large laboratory scale, and then take that forward with an understanding, because what you really need to do is understand the sublimation rate before you can scale up with confidence.

Pharma IQ:
How can you utilise accelerated degradation studies to better protect product stability?

P Matejschuk:  Although obviously accelerated degradation studies are no replacement for real time stability data, and certainly when you take in the submission you will need to be expected to have the real-time data before you’ll get a suitable shelf life for your products. They are very useful in identifying the breakdown products that are likely to occur, so what degradation pathways are crucial for your biological material are, identifying worst-case stability conditions so you can use accelerated degradation studies early in your formulation development when you have maybe one or two promising formulations to actually see which one is the best by subjecting your material to quite stringent and quite harsh accelerated degradation studies, looking for the degradation that you see, and therefore selecting the formulation which gives you best protection.

Pharma IQ:
Looking to the future, what developments do you think we will witness across the freeze-drying equipment market?

P Matejschuk: I think there has been in the last two decades a growth in the degree of automation, and I’m sure that’s the way it’s going, and people are building new plants, there will be ever increasing degrees of automation of the freeze-drying process.  And that’s fine at large-scale, but I think where the most interesting developments are coming are in the application of techniques that enable you to understand the sublimation of your product and such as monitoring the flux rate through the whole process, whether that’s by laser infra-red methods, or whether that’s by other vapour study methods, mass-spectrometry methods.

But I think those will become increasingly commonly used because you’ll fit those on medium-sized freeze-driers, and that will enable people to be able to develop cycles which are – you can use, which will give you more responsive – so that you can adjust your process to meet the… to developing online, on the fly, if you like – to be able to modify cycles to get optimal processing times.  And I think that’s probably where the biggest growth will occur over the next ten years, will be the application of those and the benefits that they will bring to shortening cycles in production processes.

Pharma IQ: To anyone interested in attending Lyophilisation for Biologicals, what will be your key take-home message?

P Matejschuk: I think it’s got a very good programme of international speakers, certainly with Michael Pikal and others, world-renowned speakers in the area of freeze-drying, but also an interesting group of people looking at new spectroscopic methods – I think they will be very interested to listen to them and say, at least analytical methods are being applied more and more now to pilot scale driers.  There’s also some presentations on upcoming areas – spray freeze-drying, and the application of PAT tools to actually, process analytical tools, to actually define the design space for processes.

So I think anyone coming along will learn a lot about where the state of the art is at the moment, and also how they can come home, go back and apply those techniques into their own freeze-drying processes.  So I think it’s a very valuable meeting for people to come along to learn where the state of the art is in lyophilisation process monitoring, and to pick up those lessons and take them back and implement them in their own freeze-drying applications.

Interview conducted by: Andrea Charles