Stability Testing - 2011 Pharma IQ Resource Pack

Stability Testing
Industry Overview

Pharma IQ Sector Report & Resources:
Interviews with Industry Experts
June 2011

In Association With

STABILITY TESTING
Pharma IQ Resource Pack 2011

Contents

3
Getting to Grips with Stability Testing and Regulatory
Compliance
6
Stability Data in the Cold Chain
7
Predicting Physical Stability of Amorphous Solid Dispersions
9
3 Tips on Overcoming Poor Aqueous Solubility and Stability
11
Additional Resources
12
Stability Testing Training Online 2011

Authors: Andrea Charles & Helen Winsor Pharma IQ 2010 - 2011

STABILITY TESTING

Getting to Grips with Stability Testing and Regulatory Compliance
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: 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.

STABILITY TESTING

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?

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.

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.

STABILITY TESTING

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.

STABILITY TESTING

Stability Data in the Cold Chain
Cornelia Nopitsch-Mai, scientist for the Federal Institute for Drugs and Medical Devices in Germany,
discusses good distribution practices in cold chain management.

To listen to the full interview go to How to Implement Cool Chain Regulations Effectively in Order to Ensure
Full Compliance.

Pharma IQ: What are the current key initiatives for good distribution practices in cold chain management?

C Nopitsch-Mai: I think in this case it's the Inspectorate. It doesn't belong to the quality assessment. It's
clearly stated that this is the good distribution practice which belongs also to good manufacturing practice
and therefore the Inspector has to look for the regulatory issues. It's not a quality issue at that time; it
belongs more to the Inspectorate.

However, if we can see that something is transported or shipped from let's say one outside Europe, from
one climatic zone to another climatic zone, maybe in this case we will ask something about the shipping
conditions, but only in these cases and not regularly. It's not a requirement for the quality assessment.

Pharma IQ: Regulatory compliance is key; what would be your top tips for implementing cold chain
regulations effectively?

C Nopitsch-Mai: First it's the stability data which supports the need of cold chain transportation and to
provide also data at accelerated conditions, let's say for short time, for example at five degrees, and also to
provide also data on stress testing, like product stability or data under heat and humidity.

Pharma IQ: What are the key stability issues for pharmaceutical bulk products and how should we seek to
overcome them?

C Nopitsch-Mai: I think it's necessary to give details of storage conditions and also on container closure
systems, because these are the main issues we have to look for for stability data. So we have the
guidelines on stability data on new drug products and new drug substances and also for existing drug
substances and drug products.

In this guideline no conditions are mentioned for the shipping conditions or cold chain conditions, they are
not mentioned or only some parts, some issues are mentioned in these guidelines. But mainly it's up to the
pharmaceutical company to establish such kinds of conditions and to describe the condition that the bulk-
ware, for example, has been stored and also, of course, the container closure system.

Pharma IQ: Cornelia, what do you think the future holds for European pharmaceutical cold chain
distribution?

C Nopitsch-Mai: I think maybe it will become an issue which has to be assessed also by quality assessors
and not only by inspectors, so to work closely together with inspectors. I think this may become, in the
future, one of the issues regarding stability data.

STABILITY TESTING

Stéphanie Greco, Analyst Scientist, Pharmaceutical Science Department, Sanofi-aventis, joined Pharma IQ
to discuss predicting physical stability of amorphous solid dispersions.

Pharma IQ: Please could you tell us about your previous achievements and current work at Sanofi-
aventis?

S Greco: I've been working for Sanofi for seven years, just after my PhD, and I spent six years in the
Physical Quality Service where I was in charge of a laboratory of physical analysis. My main task was to
support the teams developing processes of drug's physical treatment, such as milling, micronisation, nano-
milling and amorphisation by spray drying.

One of my projects has been to actively participate to the development of an amorphous dispersion, and
particularly in the screening of a polymer carrier, to improve the stability of this amorphous form. So this
project gave me the opportunity to study extensively the physical stability of amorphous dispersions.

One year ago I moved to the Pharmaceutical Engineering Service, and I'm now developing formulation and
processes for extremely poorly-soluble drugs in the nanotechnology domain. For instance, I'm specialised
in processes like nano-milling or nano-precipitation.

Pharma IQ: Commentators have suggested that the number of poorly-soluble drugs on the market is
increasing. Why do you think this is?

S Greco: Indeed it is one of the most important challenges we are facing in the Pharmaceutical Science
department for the development of new drugs. I have heard that 40% of candidates in development are
stopped because of the lack of solubility, but it was some years ago, and this number might be under the
reality now.

Pharma IQ: At the 7th Annual Improving Solubility Summit in June, you are going to be delivering a talk on
practical methods to predict physical stability of amorphous solid dispersions. Why did you choose
amorphous solid dispersions as a method of improving solubility?

S Greco: It is well known for a very long time, that a drug isolated in its amorphous state gets a much
higher dissolution rate in water, than its most stable crystalline form. So it seems very interesting to use this
property in order to improve the bio availability of poorly-soluble drugs. Unfortunately the development of
amorphous drugs was blocked, I think during a long time, because of some technical challenges, such as
the poor physical and chemical stability of amorphous compounds.

But during the past several years, high improvements have been made to withdraw these technological
locks, for example, with the use of a polymer carrier to increase the stability, or the addition of surfactants to
improve solubility. And the number of drugs developed as an amorphous form has increased significantly.

But the amorphous dispersion is not the only way to increase drugs solubility, for example reducing the
drug’s particle size to the nano scale can also give good results. For the project I will present at the
conference, in-vivo pharmacokinetic studies demonstrated a better exposure with an amorphous
dispersion, compared to the micronised drug or even a nano-suspension. And that was the reason why the
amorphous dispersion was the formulation selected for the development of this drug.

STABILITY TESTING

There are several criteria that are important to discriminate different formulation strategies for poorly-
soluble drugs, but I think that the direct measurement of bio availability, by in-vivo studies, must always be
the crucial point for the final choice.

Pharma IQ: What would you say are the main challenges that you face with using amorphous solid
dispersions, and how have you overcome them?

S Greco: As I've just said, I think that the main challenge that is usually faced when developing amorphous
dispersion is the lack of physical stability of such formulations. Indeed the better solubility is directly linked
to the metastability of the amorphous form. An amorphous drug is more soluble because it is less stable.

The solution to overcome this problem is well known: it is to make a solid solution between the amorphised
drug and an excipient, generally a polymer that is called a polymer carrier.

The main role of this polymeric matrix is to prevent the crystallisation of the drug, but not only. During the
screening of best polymer carrier for a given drug, it is important to keep in mind that it must be selected
according at least three criteria
this polymer has to improve the chemical stability of the drug, so there must be a good compatibility
between the drug and this polymer.

Secondly, it has to improve the long-term physical stability of the drug, since the final amorphous dispersion
has to be stable at least two years.

At last, it has also to prevent the recrystallisation of the drug in the stomach, or in the gastrointestinal tract,
and this can be determined by appropriate in vitro biopharmaceutical tests.

It is only when all these criteria are evaluated at the same time that a good choice will be made for the
polymer carrier.

The process of amorphisation by spray drying can also pose technical difficulties. Handling organic
solvents, for instance, in a pharmaceutical environment is not straightforward. It requires double skills
between chemical and pharmaceutical areas.

So to conclude, the development of amorphous dispersion is a quite complex technology, but all the
technical difficulties can find appropriate solutions.

STABILITY TESTING

Rene Holm, Head of Preformulation at H Lundbeck A/S, joins Pharma IQ to discuss the benefits of early
stage preformulation, how advances in drug delivery devices have impacted on formulations, and strategies
for enhancing solubility.

Pharma IQ: Please could you tell us a bit about your current role?

R Holm: I am currently involved in preformulation, both in discovery and development and troubleshooting
based on preformulation things in production, and therefore we have a perspective that covers the entire
lifecycle of the compound here at Lundbeck.

Pharma IQ: Early stage preformulation is a hot topic in formulation development. What are the benefits?

R Holm: The benefits of preformulation are to, early on, identify formulation risks; early on help to facilitate
and identify a formulation strategy, basically. Those are the two main things. So you need to figure out
which strategy to go for and which would work, most probably, and which will not.

Furthermore, you need to tell management that you may not be the slacking one here. There may be a
scientific reason why this may take longer time. You have to follow the standards, sell the project, perhaps.
Preformulation data can actually help with that discussion.

Pharma IQ: How have advances in drug delivery devices impacted on formulations?

R Holm: On devices, I’m not sure if it has done anything. It has done a lot on pulmonary delivery, but not
orally, in my perspective. It’s a more specialised delivery form where it has had any impact.

Pharma IQ: And what strategies are companies employing for enhancing solubility?

R Holm: In reality, enhancing solubility is not that difficult. You have two main things you can do: either you
can increase the solution rate or you can just present it in that form. That can be done by relatively
developed strategies.

The well-known way of increasing mobility rate is salt formation, but things that are used much more are
the solid solution sensation of amorphous form, lipid based formulations, that kind of stuff. But actually it is
relatively well described in literature what can be done for these compounds. The tricky thing, of course, is
to do it and also to get it in a GP way and in a commercial scale.

Pharma IQ: In your view, what are the industrial obstacles to the use of lipid based formulations?

R Holm: The main obstacle, as I see it, is encapsability. That’s the one thing. And then solubility in lipids.
We would normally use a lipid based formulation where we have a low soluble compound, but there is no
link between low… increased solubility and high lipid solubility. So although the compounds are low soluble
in water, they may still also have a low solubility in lipids, and we need to solubilise the lipids in order to use
that formulation system.

Secondly, in the lipids excipients we see impurities that may lead to degradation and oxidation and that
encapsability with the compound is also a major. Lipid based formulations really, really possess huge
power to increase solubility on those compounds where it works.

STABILITY TESTING

Pharma IQ: How exactly is the industry seeking to overcome these problems?

R Holm: If it’s done right, especially by the excipient deliverance, you can purchase a specialty high purity
grade different oils, etc, and that is a way to do it. And then the use of antioxidants, etc. But it is very much
to work on the excipient income, in reality, and that’s also what’s been done.

Pharma IQ: And how do you plan a robust formulation strategy?

R Holm: Quality by design. That’s how we would do it normally. First of all, your formulation strategy will be
defined by your preformulation input. The knowledge you have about the compound, its behaviour, its
solubilities and its physical parameters, they will define what strategy or strategies you think you’ll go for.

Then, to get it robust, at least from a pharmaceutical point of view, you would define a design space and
that design space can also be transferred into a clinical design space. That’s normally how we would do it.
You would use the thinking and the thoughts that are included in quality by design.

Pharma IQ: What would be your top three tips for overcoming poor aqueous solubility instability, Rene?

R Holm: The best still is to get a soluble compound. Having said that, I’m well aware that whenever you
select a compound in pharmaceutical industries, physical parameters normally has a lower rank than
pharmacology.

This, of course, makes sense, because if it doesn’t work there’s no need to use the time... Internally, in the
company, you need to define what relatively generic strategy can be used for these kinds of compounds –
what are we going for. Are we going for solidification of the amorphous form, which can be among the
different classes of compounds.

At least, I would also consider internally which scientific capabilities we have in-house to produce this. We
have to have the equipment so we can do it both on a lab scale and on a GP scale. We don’t need to do it
on a high scale level. All we need is to identify inventors that can help us to do that. But we need to find
what our priorities are and make the formulations.

On solubility it is a bit more tricky because it depends much more what is the instability problem. You need
to define the formulation solution to the specific compound, and that is one of the major measures. Look at
the compound, look at what you know, and fit the formulation and the work to the compounds.

STABILITY TESTING

Additional Resources

INTERVIEW
Establishing an Effective and Efficient Stability Testing Programme
With Shekhar Natarajan, Senior Executive-CMC Regulatory Affairs, Johnson & Johnson

In this podcast, Shekhar Natarajan, Senior Executive-CMC Regulatory Affairs,
Johnson & Johnson discusses current challenges in meeting stability requirements
and how to overcome them.

VIDEO
European Regulatory Guidelines Controlled or Ambient
Temperatures, Stability Data and Compliance
With Ian Holloway, Manager, Defective Medicines Report Centre, Medicines and
Healthcare Products Regulatory Agency (MHRA)

There is more regulatory interest in ambient products and growing opportunities
for solution providers to enter this market. In this presentation Ian Holloway,
Manager, Defective Medicines Report Centre, Medicines and Healthcare
Products Regulatory Agency (MHRA), discusses the expectations and
documenting for ambient or CRT products, regulatory expectations for
qualification or validation and stability studies versus shipping studies.

VIDEO
Drug Discovery and the Market Today: Critical Thoughts on Stability
With Dr. David Elder,Externalization Director,GlaxoSmithKline

Dr. David Elder is the Externalization Director for GlaxoSmithKline. Here, he talks
exclusively to Pharma IQ on his perspective across the industry, including CROs,
regulations, and strategising for efficiency.

STABILITY TESTING

No travel costs, no time out of the office, flexible learning for your whole team!

Stability Testing Training Online 2011

Access 5 hours of direct learning with a leading industry expert to understand the new ICH guidelines and ensure long
term quality and first time regulatory approval

With companies worldwide failing to get market access due to insufficient stability data the pressure to ensure that
the regulatory requirements for stability testing are fulfilled, first time, has never been higher with the pharmaceutical
industry as a whole focusing on cutting margins and avoiding recalls.

ICH has created guidelines to regulate the major markets, however the WHO is pushing to amending those guidelines
in favour of global harmonisation.

Coupled with the trend towards global supply chains and working in climatic zones there are many challenges when it
comes to assessing humidity and temperature levels in different supply zones - are you fully prepared for these
changes?

Being involved in stability testing, you are well aware that high standards have to be maintained whilst dealing with
significant budget and time constraints. Establishing an effective and efficient stability testing programme is key to
ensuring regulations are upheld whilst staying within your margins.

Pharma IQ's Stability Training Course has been constructed to give you the tools to achieve this -
all at the comfort of your own desk!

Secure your spot on the only interactive, online course addressing the ICH guidelines.
This offer is available for a limited time!

We have 5 interactive modules and for those participants interested in accreditation, we offer an official exam. This
will be internet based and available upon completion of the training course. Materials can be completed in your own
time, all of which will arm you with the necessary skills to develop a robust stability testing programme.

Train your whole team and save up to €550 per person! Click Here
Meet Your Course Leader: Dr Manuel Zahn 3R Pharma Consulting
Speaking on:
Understanding the Regulatory Aspects of Stability Testing
Implementing an Effective Stability by Design Prgramme
Evaluation of Stability Data
Stability Testing for Global Markets
Temperature Monitoring during Shipment

STABILITY TESTING
View the full Module List Click Here Resource Pack 2011
Pharma IQ

Stability Testing - 2011 Pharma IQ Resource Pack

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Stability Testing - 2011 Pharma IQ Resource Pack