Joint Pharmaceutical Analysis Group / Academy of Pharmaceutical Sciences
Material functionality and fitness for purpose in solid dosage forms
Speakers from the pharmaceutical industry presented the drivers for
the development of materials science. In the past, said Lesley Mackin,
of
AstraZeneca, limited characterisation was driven by regulatory expectations
which tended to be concerned with safety and efficacy and hence issues
of chemical purity; insufficient attention was given to the physical
properties of the solids, which can be extremely important for a dosage
form. For example, it can be shown that micronisation increases the surface
energy and exposes more acidic groups on the material surface. The surface
energy then significantly decreases with time, probably because of the
recrystallisation of amorphous material generated during micronisation.
Currently, the industry has a better record in linking material properties
to drug product performance and reliability. Thus it ensures that quality
by design takes into account material properties such as crystal form
and mechanical properties of the solid state, flow density and electrostatic
charge of the bulk material, the size distribution, shape and porosity
of particles, and the area, energetics, wetting, disorder, roughness
and vapour sorption of surfaces. Looking to the future, Dr Mackin envisaged
better control of properties, and prediction and design of formulations
and processes. This would include predicting surface energetics using
molecular modelling.
The traditional disciplines of pharmaceutical research and development — chemistry,
analysis and formulation — have now been joined by materials science,
said Bob Docherty, of Pfizer Global R&D. Materials science, or solid
state chemistry, is at the heart of new product development, having significant
contributions to make in delivery characteristics (salt and polymorph
screening, and biopharmaceutics), manufacturing efficiency (crystallisation
development and particle engineering) and product quality (dissolution
properties, stability and homogeneity). Materials science has evolved
in the past decade from delivering routine characterisation of drug substance
and drug product batches to on-line and at-line enhanced crystallisation
and physical characterisation and more importantly to be one of the foundations
of quality by design. “Chemists are from Mars, formulators are
from Venus,” claimed Dr Docherty.
In recent years there has been a shift towards the use of risk-based
quality systems to regulate product development, said Anthony Taylor,
of GlaxoSmithKline R&D. Although the primary focus is on understanding
the manufacturing process and its impact on product quality, current
guidance also has implications for the material science, physical properties
and supply of raw materials, including excipients. A scenario could be
constructed where the active pharmaceutical ingredient in a formulation
has all the right parameters as regards pharmacokinetics, pharmacodynamics
and biopharmaceutics, but could be undone by insufficient attention to
the interactions of excipients. The quality by design concept works on
the understanding that the control space operates within the design space
which operates within the knowledge space — but this can be inverted
if the knowledge space is shrunk as would be the situation where little
is known about variations in the excipient.
To be able to demonstrate the interaction and impact on the drug product
of variation in the input material properties, it is necessary to work
in close partnership with excipient suppliers to identify the properties
that may be important, understand the pattern of variation, and obtain
supplies at the extremes of the variation to establish the impact on
both the manufacturing process and drug product. The outcome will be
the creation of the scientific knowledge to confirm the design space
and if necessary allow the setting of rational functional specifications,
which may be additional to those in the pharmacopoeial monographs, concluded
Mr Taylor.
Understanding the structures of materials
Particles can be custom engineered with the intelligent use of micronisation,
claimed Linda Green of Phoqus Pharmaceuticals, a drug delivery company
providing a range of innovative drug delivery systems. Electrostatic
dry powder deposition is a proven technology exemplified by the photocopying
principle. The active compound may be in the core to be coated or
in the coating powder, or both. The technology allows accurate and
precise deposition of powders onto the core in predefined patterns
and thicknesses. The coat powder must have specific properties in
order to function in the electrostatic system and must maintain the
required functionality once formed into a coat. The components of
the powder may include polymers, plasticisers and colouring agents
as well as active ingredient. These components are melted together
in the preparation of the coating powder. Ingredients that do not
melt, such as carbon black, could be efficiently dispersed in the
mixture. The key to the ability to customise the powder, explained
Dr Green, lies in a micronisation step followed by the use of a rotary
classifier to ensure a narrow particle size distribution. The technology
can produce tailored modified release drug delivery solutions (fast
dissolve or controlled release), anticounterfeit and product-branded
tablets, and as a new solution for formulation issues encountered
with low dose actives and combination therapies.
Fiona Clarke, of Pfizer Global Manufacturing, emphasised the need
to understand the matrix in manipulating how solids are processed.
The
matrix of pharmaceutical solid dosage forms can be evaluated using imaging
instrumentation. The workhorse for such studies is near infrared microscopy,
with other techniques, such as tetrahertz pulsed imaging, also being
used. These chemical images are generated based on spectral information
collected across a specific sample area. Chemical imaging allows the
distribution and size of components to be examined so that matrix exploration
can be used to understand the impact of a change in material properties
on the final dose. Dr Clarke used case studies to illustrate the approach,
demonstrating the impact on the tablet matrix upon changing the input
particle size of dibasic calcium phosphate, and the result of variability
in the hydration state of magnesium stearate or age of input raw materials
on component distribution in the final solid dosage form. Having the
ability to examine the matrix distribution of components provides a
means to identify attributes critical to quality. This allows greater
understanding of what the impact is on the dosage form following a change
to input raw materials, concluded Dr Clarke.
Pharmaceutical manufacturing is devoted to making particles, modifying
their properties and turning them into structured products, said Robert
Price, of the University of Bath, yet the pharmaceutical technologies
used to manufacture drug particles can at best be described as primitive.
We need to develop capabilities to characterise, control and optimise
particle properties at every step of the manufacturing process, and
to control their properties with desired and consistent micro and macro
structures. Product property is a function of dispersity as well as
chemical composition. Dispersity is characterised by particle size,
shape, morphology and surface properties. Control of interfacial interactions,
such as adhesion and cohesion, is governed by surface forces so it is
geometry, not surface chemistry, that is the central design principle
in controlling particulate interfaces. As an example of the future direction
of such functionality by design, Dr Price described the technique of
solution atomisation and crystallisation by sonication. By exploiting
the variables of solvent, spray temperature, solute concentration, flow
rate and separation distance, the functionalities of the particle can
be selected.
Functionality testing is important and will impact on active ingredients
and excipients said Graham Buckton, of the University of London School
of Pharmacy. Small differences, which may be hard to detect, can be
significant. Excipients have more variability than is generally supposed,
said Professor Buckton. Even a simple sounding chemical such as magnesium
stearate is a mixture of magnesium salts of different fatty acids consisting
mainly of stearic acid and palmitic acid with minor proportions of other
fatty acids. Additionally, commercial lots of magnesium stearate generally
consist of mixtures of crystalline forms. This variability impacts on
the product.
Lactose was used as an example to demonstrate how the amorphous content
could have an effect on the behaviour of an excipient. Because the amorphous
state is usually thermodynamically unstable, we can expect changes with
time. Since the composition is unintended and thus not studied there
will be changes between batches and extensive water absorption can direct
the site of onset of chemical degradation. Interpretation of the measured
amorphous content is important. A product may consist of a 99 per cent
crystalline core with a 1 per cent amorphous surface, or a mixture of
99 per cent crystals and 1 per cent amorphous particles. In view of
the importance of surface chemistry in the behaviour of solid materials
the distinction is critical. Small amounts — perhaps undetectable — of
a different physical form can alter the performance of drugs and excipients.
In drug development the selected excipient is often a result of company
policy and the selected source may be a commercial decision, yet the
impact of these two decisions can be enormous. The cheapest excipient
is not necessarily the most economical, warned Professor Buckton.
The importance of sampling procedures in process analytical technology
Joep Timmermans, of Pfizer Global Manufacturing, joined the meeting
by audio link to talk about the importance of sampling in the support
of process analytical technology.
“If your sample is not representative of the process or the product,
it is useless,” Dr Timmermans told the meeting. “Of the many
considerations on sampling, understanding the attribute you are trying
to measure is
critical.”
The sample must be representative of the process under investigation,
he said. The level of scrutiny must be appropriate, taking note of the
area or volume examined, the depth of penetration, and the numbers of
replicate measurements to determine the effective sample size.
For dynamic systems, the timescale of the measurements needs to be matched
with the timescale of the process. For example, there is no advantage
in taking samples at 30-second intervals for biological processes that
take place over several weeks. The impact of developing or changing a
sampling plan on existing specifications needs to be understood to appreciate
the relevance of the test, as does the need to know what the potential
impact on product performance would be if a sampling error is made.
“
The information you are gathering on your processes is only as good as
the samples you collect the information on,” emphasised Dr Timmermans.
A warning from excipient suppliers
The concept of the pharmaceutical industry working closely with excipient
suppliers to ensure sophisticated and necessary specifications for
excipients may not be as straightforward as the industry imagines,
said Kevin McGlue, of Colorcon.
Sources of starting materials for excipient manufacture are diverse,
including oil, agriculture products (maize, wheat, sugar beet and cane),
minerals (talc and kaolin) and animal products (lactose and gelatine).
Processes vary from extremely simple to highly complex and there is,
by nature, already inherent variability so, for example, agricultural
products may vary according to conditions such as temperature, humidity
and rainfall during the growing and harvesting seasons. Unlike active
pharmaceutical ingredients, excipients are not manufactured specifically
for use in medicinal products and many are made in large chemical plants
designed for producing chemicals for other industries. For example, the
pharmaceutical industry takes only 0.02 per cent of total world-wide
cellulose production. The manufacturer’s process is, therefore,
focused on chemical and physical properties for the larger market. Excipients
have a variety of functions in pharmaceuticals and are subject to unique
sophisticated tests to identify desirable properties. The excipient manufacturer
may not even be capable of running these tests or gathering representative
data. Even if identified, the required performance characteristics may
not be properties typically controlled by the excipient manufacturer’s
process.
Mr McGlue suggested there were two options. Custom grades could be manufactured
by adjusting the normal process. However, we could not then be certain
of the impact on other parameters. Batches which did not meet the desired
specification, would still meet normal specification but, if sold as
regular grade there is a risk that they may not perform in another company’s
process that required typical material, or that they may accidentally
become another company’s special grade. Alternatively, batches
could be selected by testing multiple batches from regular production
to find those that meet the required criteria. Pharmaceutical manufacturers
must be willing to consider these excipients as special premium grades
and be willing to pay premium prices. It is critical that pharmaceutical
manufacturers and excipient manufacturers frankly discuss what can and
what cannot be done during the early development phases of the formulation
and qualification process.
Barriers to progress are within the industry
In the discussion session the opinion was expressed that the barriers
to progress in the pharmaceutical industry could be found in their
own regulatory and quality assurances departments. The industry was
being policed twice, said one delegate, once by the authorities and
once by the internal structures. The Technology Forum, set up by
the Royal Pharmaceutical Society to bring together regulators and industry
scientists needs to be reconvened, said another, to ensure progress
with the appropriate analytical tools is in the right direction and
new methods are fully
exploited. |
The
Pharmaceutical Journal