Getting to Grips with Stability Testing and Regulatory Compliance

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Find out more about the challenges in pre-and post-release stability testing and formulation. In this Pharma IQ interview, Claire Willsher, head of analytical development at Lifecycle Pharma, discusses the technologies being employed by Lifecycle Pharma to pre-empt these challenges. Willsher also offers her perspective on Quality by Design, cost-cutting and how to achieve regulatory compliance.

Pharma IQ: Claire Willsher, head of analytical development at Lifecycle Pharma, joins Pharma IQ today to discuss stability testing requirements. Welcome, Claire. Thank you for joining us.

C Willsher: Hello.

Pharma IQ: So, Claire, just to start off, where do you think the main challenges are in pre-stability testing at the moment?

C Willsher: I think the main challenge at the moment in pre-stability testing is the fact that we tend to focus a lot on chemicals, for the chemical side, for the chemical stability. And we don’t really look at the physical attributes so much in pre-stability. And I think that this is an area that we really need to work on. We need to work hard to look at polymorph and active pharmaceutical ingredients (APIs), excipients, etc, and that kind of thing. And I think that that’s the main challenge at the moment.

Pharma IQ: What are the key challenges in stability testing and formulation, and also, what technology do you employ in order to pre-empt these different challenges?

C Willsher: Challenges in stable formulation, making a stable formulation - that’s a challenge in itself - or, in reality, the key challenge. So, identify your most stable formulation as early as possible during development. We want to do this to avoid formulation changes at a later stage, that can lead to really costly bioequivalent studies. So, during formulation of your products, it’s important to identify early on compatible excipients; and know the degradation pathways, so that you understand your API as much as possible, then that way you can identify the best formulation routes and initiate any stabilising compounds where you can see that there may be possibility issues.

There are a number of tools available for you to look at this kind of thing, and I think those utilised most are forced degradation of excipient compatibility and stability as early as possible. One thing again I’d comment on is to remember to monitor both the chemical and physical attributes, especially when you’re using fluid systems. As I said, we tend to focus on the chemical stability, and it can lead to some not-so-nice surprises at a later stage. To do those kinds of things, obviously you need have an effective chromatography system in place. It needs to be a stability indicating method. At the early stages, it doesn’t have to be as vigorously qualified as it does at later stages, but you still want to ensure that you can monitor all impurities and get reliable results.

All the challenges include the normal cost versus stage of development, return on number of samples – that kind of thing. And when to perform those kind of analysis varies from company to company. The use of ultra high pressure liquid chromatography and improved common chemistry nowadays means that sample volume is becoming less of an issue. I think in research and development it’s always going to come down to where we can get the most information for the smallest cost, both monetary and resource. What we do have to remember is that we need to be disciplined and avoid the temptation to say, oh well, it’s not so stable, but we can do something about the packaging to do that. We need to choose our most stable formulation; it might not always be the nicest formulation, but I think the best companies, they have the best decision-making skills, and they’re not afraid for the quick-kill approach.

Pharma IQ: There is a lot of hype in the market about Quality by Design throughout the product lifecycle. Now, specifically within stability testing, is Quality by Design something that you think will provide benefit?
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C Willsher: Quality by Design - or QbD, as we know it - is the new buzzword. The authorities undergo cutbacks just like the rest of us. They’re looking for features that can assist them and make their lives easier - something that we all do. I can see the benefits within manufacturing of employing Quality by Design or PAT testing; however, specifically within stability, I’m not so sure that it’s something new that will revolutionise the way that we do things.

If you look at what is QbD really, it’s a way of looking at factorial design of experiments, and using your scientific knowledge to ensure that your product quality is maintained, and what you’re putting in is a quality product. However, if you look at ICH (International Conference on Harmonisation) guidelines, in particular Q1D, this discusses how to utilise bracketing and matrixing to minimise the amount of samples required to gain your maximum amount of knowledge about your product. This guidance has been around for nearly a decade or so now. I’m not sure how that differs from the description of what Quality by Design is. I think within stability, we’re already doing Quality by Design as much as possible.

If you took the absolute description of Quality by Design to its absolute maximum extent, you perform the majority of your stability on scientific knowledge: one strength may be a couple of pack configurations, tutorial designers, five or six strengths in three or four pack configurations. Do we really think that the authorities are going to approve our product? So, I don’t know if it’s true. I’m not sure that Quality by Design is something that’s going to be new and revolutionise the way we do things in stability.

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Pharma IQ: What are the main challenges in maintaining regulatory compliance for post-approval pharma products?

C Willsher: I think there are a number of challenges in post-approval compliance, and I think that many of them are area-specific; whether it be chemistry, manufacturing and control or clinical, we have different challenges. One of those that a lot of people trip up on is the constant improvement of analytical technology, and everybody wants to be cutting-edge. If it’s not broken, don’t fix it. It’s not always a great idea to constantly change your methods or your processes just to keep up with the new trend. However I think for me, personally, what I find the most challenging is classifying what is a major change, what is a moderate change, what is a minor change to the product, and then how to handle that change with respect to your filing or contacting the authorities. Both the Food and Drug Administration and the European Medicines Agency do have a general description of what the changes should be classified as in their guidance for post-approval requirements; however, these descriptions are a little vague and they’re not very specific. So, that’s where I find the most challenge.

Pharma IQ: Please can you explain some of the different approaches you have used in the past to achieve constant compliance?

C Willsher: I think the simplest thing that you can use is a good change control system. Other valuable tools, I found, are REMS – the risk mitigation evaluation strategy – the use of decision trees to lead to creations and documentation evaluations, and finally, the actual implementation of the change, I think, helps in many situations. There’s one thing that I really like about this process – and it’s really interesting and often very inspiring – it’s the meeting of minds from different viewpoints.

Often in these processes you have representation from a number of different departments or specialities, and it could be really interesting to see how the different people from the different viewpoints can brainstorm and bring things forward that you don’t necessarily see or you hadn’t even thought about. I’m not saying it’s always easy, but it definitely helps that process along. Again, the final piece of that process - the implementation of the change - is eased along by a good change control system. I’m sure there are very many other valuable tools out there, and I think the ideal one is to find something that works for you.

Pharma IQ: Obviously at the moment stability testing is an area where there are a lot of cost-cutting pressures. What do you see as areas where you can cut costs and what different measures can you take?

C Willsher: I think in today’s financial climate with big company mergers and small biotechs folding under the strain of cost-cutting, it’s part of everyday life. When you compare the cost of a phase three clinical trial to the corresponding stability support or primary stability, the cost concerned with stability, it’s a drop in the ocean. However, it’s often the stability that is the place where you have to find ways to save money. To maximise your cost efficiency, you’ve got to look at a number of things, I think, including the possibility of outsourcing large chunks of your studies.

Sometimes that gives you advantages compared to utilising the resources you have in-house. Where this may seem contradictory within itself, if you’ve got a good relationship with your contract manufacturing organisation (CMO), then for large amounts of work they’ll provide reasonable rates, especially at the moment. They’re also feeling the effects of this financial climate and they’re also looking for work. One thing I do want to point out here is that there are a number of CMOs being started at the moment in the wake of all these redundancies in the business, where I would say the majority of them are really good. There are an increasing number of not-so-good ones, shall we say. So, I’d say, when you’re outsourcing your stability, cheapest is not always necessarily the best. Also, looking at the quality requirement, and the study that you’re performing, often you can charge less for GMP studies, but still perform according to ISO or GLP, and it’s worth taking advantage of that, if you don’t require full GMP requirement.

I’d say that also one of the things that we have to focus on during the lifecycle of development is learning the difference between the nice-to-have and the need-to-have. I’m an analyst, and I know as an analyst, all formulators, they want to put everything onto stability, and one formulator can, on average, create enough work for at least two or three analysts. When your cost-cutting measures are imposed, they’re nice to have if they take on less priority, as much as, myself included, we all hate to go against our scientific interest. We need to leave those exciting, interesting studies behind, and focus on the resource we have, both monetary and time and personnel and on the absolute studies required to move your product towards filing, because at the end of the day we all need to have a return of interest, and to do that, we need our product marketed.

Pharma IQ: Yes, indeed. Finally, to round off, I understand that you’ll be presenting at the upcoming Pharmaceutical Stability Testing conference taking place from 14th - 16th September 2010 in London. Now, for anyone interested in the event, what would be the key learning point to be gained from your presentation?

C Willsher: The key learning point for my presentation, I think, would be the recent changes in NDA stability. I’m also going to be looking at comparator stability. So, anybody who is working in late phase and post-approval will get lots of information on when to perform, what to perform, and what’s actually required with the new changing strategies.

Pharma IQ: We look forward to your presentation. Well, Claire, thank you so much for your time today. It’s been a real pleasure talking to you.

C Willsher: Thank you very much for asking me to do the podcast, and I hope to see lots of people at the conference.

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