Joint Pharmaceutical Analysis Group / Academy of Pharmaceutical Sciences
The role of materials characterisation techniques in pharmaceutical quality
Introducing the symposium, Tony Moffat, from the School of Pharmacy,
University of London, emphasised the importance of recognising that quality
for a pharmaceutical product must be built in at the start of the manufacturing
process.
Speakers addressed the subject of how the solid form of a pure ingredient
should be selected. Jim McCabe, of AstraZeneca, explained that once a
pharmacological entity has been chosen for development, the solid chemical
form needs to be one which can be robustly formulated and, in turn, this
means selection of the most stable salt or polymorph which has favourable
properties related to crystallisation, filtration, particle size control
and compaction, all contributing to ease of manufacture. An efficient
system of screening large numbers of possibilities is therefore required.
Dr McCabe described a 96-well screening plate containing salts of the
candidate drug, prepared at different temperatures and with different
crystallisation solvents. These can be scanned and computed for optimum
crystallinity in as little as 10 minutes. Because salt preparation, analysis
and reporting can be automated and streamlined, this screening is ideal
for early rapid assessment of the probability of obtaining a crystalline
solid form and a selection of suitable solid forms for further screening
and consideration.
Polymorphism, the ability of a substance to crystallise with different
molecular packing, must also be assessed because different polymorphs
have different physical properties, such as solubility; a particular
polymorph may be more suited for development than another. For polymorph
screening, a large number of experiments may be performed in parallel
and analysed in situ. However most screens do not give specific information
on which conditions will yield a particular form, and it is more efficient
to pay attention to the design of the experiments to ensure a full coverage
of possibilities. Important variables in directing polymorph production
include solvent, temperature, concentration, evaporation rate, pH and
the presence and nature of impurities. Rational and controllable polymorph
screening generates final data containing much information allowing prediction
of the most stable polymorph, even if such a polymorph is not observed
in early development of the candidate, concluded Dr McCabe.
Neil Feeder, of Pfizer, developed this theme and described the intelligent
use of informatics in selection of polymorphs. Ostwald’s Law of
Stages states that, if the supersaturated state has been established,
a less stable phase will be formed instead of a solid phase which is
thermodynamically stable. Thus, it is important to seek out the most
stable form.
Dr Feeder described current efforts to exploit the perspective that the
crystal structure gives to enable predictions on polymorph stability.
In particular, crystallographic database mining methods illustrate how
the notion of solid-state structural informatics can be applied to the
management and selection of the solid form in the pharmaceutical industry.
Ab initio crystal structure prediction appears promising but is not yet
ready for application to all solid forms. Knowledge-based hydrogen bond
propensity describes a model which can be used to articulate the probability
of finding a more stable polymorph.
Applying materials characterisation to product and process scale-up
The manufacturing best practice associated with the batch crystallisation
of pharmaceutical materials, together with its underpinning process
engineering science, is surprisingly weak, contended Kevin Roberts,
from the University of Leeds. However, the stringent quality enhancement
demands of the regulatory bodies, are providing a driver for future
research.
Significant activity is being directed in the area of improving fundamental
understanding and hence control of crystallisation processes with the
aim of reducing product variability and improving quality, even if
this ambition is on a collision course with others to cut drug costs
and drug
development costs. Among several process analytical techniques available,
the in-process monitoring of crystal shape was impressively demonstrated.
Stroboscopic digital videomicroscopy for crystal shape monitoring,
developed by GlaxoSmithKline in Harlow, has enabled the examination
of crystal
shape during batch processing at the one-litre scale. The combined
and synergistic use of molecular modelling for morphological prediction
with
online image analysis for morphological monitoring can lead to improved
product purity.
Consideration should be given to the quality attributes of incoming
materials, and their processability for each unit operation, in the
spirit of the
process analytical technology guidelines, said Niklas Sandler, of AstraZeneca.
Physical and mechanical attributes of pharmaceutical ingredients have
not always necessarily been well understood and consequently the undetected
variability of raw materials may be manifested in the final product.
To understand those quality attributes which are critical to product
quality, the establishment of effective processes for managing physical
attributes of raw and in-process materials is essential. Dr Sandler
described the use of quality risk analysis to highlight some possible
impacts of
the active pharmaceutical ingredient (API) on a roller-compacted product.
In this context the influence of API properties on product manufacturability
was studied by assessing the flow properties of the formulation during
different processing steps. In another example, design of experiments
was used to study the effects of process parameters in a fluidised
bed granulation process to obtain suitable particle size distributions
of
granules. Further, the study showed how granule characteristics could
be linked to tableting quality. The evaluation of segregation tendency
of granules could also be demonstrated. Basically, the performed measurements
provide information for the creation of a design space to meet the
quality attributes for the final tablet (weight uniformity, disintegration,
tensile
strength, segregation tendency). Thorough knowledge of the material
together with process monitoring and process understanding combined
with efficient
data analysis enables the definition of operating space for producing
high quality products.
Developing a fundamental knowledge of functional material properties
is an essential component in the development of a robust drug product
formulation and processing route, concluded Dr Sandler.
Techniques used for materials characterisation
There are a number of spectroscopic techniques that are well established
for the characterisation of pharmaceutical drugs and formulations,
including nuclear magnetic resonance, mass spectrometry and vibrational
spectroscopy. These techniques probe characteristic molecular features
and are generally used for the elucidation and quantification of structure.
Mike Claybourn, of AstraZeneca, focused on the application of two spectroscopic
technologies that use long-wavelength radiation for material characterisation:
solid-state NMR and electron paramagnetic resonance (EPR).
Solid state NMR is now used routinely for characterising the local chemical
environment of drug molecules and polymorphs by interpreting “through-space” interactions,
to facilitate morphology studies of drug substances or drug products,
salt formation, differentiation of amorphous and crystalline material,
drug-excipient interactions, and polymeric excipients. Information is
obtained on the structure and interactions that contribute to the performance
of the material and the formulated product.
EPR is well established as a probe for paramagnetic species, especially
free radicals. Radical generation rate will depend on cross-section,
bonds likely to undergo scission, optical density, and particle size
and shape. Dr Claybourn presented results which demonstrated the use
of EPR for stability monitoring and for following degradation, and a
predictive in situ screening method was proposed for screening in the
early phase of drug development.
For characterising particle surfaces, size and shape, the traditional
areas of drug delivery research, particle science and colloidal systems
are well served, said Clive Roberts, from the University of Nottingham.
However there are new challenges due to the low solubility of many new
small molecule drugs and there is an increasing demand for nanoscale
control and characterisation of pharmaceuticals as single particles.
Professor Roberts described a multifunctional approach to the analysis
of formulations, with special emphasis on atomic force microscopy (AFM),
a mechanical probe rather than a spectroscopic one. The dissolution at
the surfaces of different planes of single aspirin crystals could be
clearly differentiated, as could the influence of modifiers on the crystal
growth of adipic acid. Using the technique to measure the force needed
to deform a surface can also provide a direct measure of Young’s
modulus for the surface, and this information can be linked to subsequent
prediction of particle behaviour.
Charley Wu, of the University of Birmingham, described the application
of two advanced imaging and visualisation techniques, positron emission
particle tracking (PEPT) and X-ray computed microtomography (XRCT), in
characterising the flow of powders during tablet manufacture. Computational
modelling of the tablet manufacturing process was also used to enhance
the understanding of the process.
PEPT can accurately determine the motion of particles during the die
filling process and the PEPT results were consistent with macroscopic
observations using high-speed video systems. The effect of air entrapment
during the manufacturing process was highlighted and it could be shown
that the phenomenon can be well captured by numerical simulations using
a coupled discrete element method and computational fluid dynamics. The
microstructure and failure of tablets were examined using XRCT and the
observed failure patterns were in excellent agreement with predictions
using finite element methods.
Experimental and numerical studies showed that the shear bands developed
at the early stage of unloading appear to be responsible for the occurrence
of tablet failure.
It was also found that the failure patterns
depend on the compact shape, concluded
Dr Wu.
Thermal analysis is the measurement of a change in a property of a sample
as that sample is subjected to a controlled temperature programme, explained
Simon Gaisford, of the School of Pharmacy, University of London. Heat
is a universal accompaniment to chemical or physical change. There are
few enthalpically neutral processes and thus we can study almost any
sample by thermal analysis, he said. The problem is only how to select
a representative sample and how to interpret the data.
The most favoured form of thermal analysis is differential scanning calorimetry.
As a sample is heated the heat absorbed is monitored and phase changes
can be detected as the crystal melts or changes its polymorphic form.
If the heating rate is significantly faster than the change in polymorphic
form then it is possible to detect all the different polymorphs present,
including the higher-melting species. For formulated materials thermal
analysis is useful for shelf-life prediction, for quantifying efficacy,
and for selection of packaging, said Dr Gaisford.
The presence of amorphous material in a formulation is probably more
significant than its quantification said Graham Buckton, of the School
of Pharmacy, University of London. Techniques available to detect it
include differential scanning calorimetry, dynamic mechanical analysis,
dielectric analysis and inverse-phase gas chromatography.
Researchers are well aware that amorphous materials are encountered regularly,
especially when the process induces disorder and will give rise to differences
in product performance as evidenced by dissolution rate, processability,
and chemical stability. They should also be aware many methods exist
to detect and quantify it, but quantification of amorphous content does
not equate to functionality, he said.
There may be substantial changes in amorphous material with time, and
this time will depend upon the material and the environment, warned Professor
Buckton.
Regulatory issues
In putting forward the regulatory viewpoint, Keith Pugh, of the Medicines
and Healthcare products Regulatory Agency,said it was important to understand
the evolution of process analytical technology (PAT) and the setting
up of the EU PAT team. Its mandate, as described
on the website,
is to provide a forum for dialogue and understanding between working
parties and inspection services to prepare a harmonised approach in Europe
on assessment of applications and inspections of products, systems and
facilities for PAT. Dr Pugh defined the concepts of “design space” and “quality
by design”, both accepted components of drug development in the
regulatory context.
The multidimensional combination and interaction of input variables (such
as material attributes) and process parameters have been demonstrated
to provide assurance of quality. Working within the design space is not
considered as a change. Movement out of the design space is considered
to be a change and would normally initiate a regulatory post-approval
change process. Design space is proposed by the applicant and is subject
to regulatory assessment and approval.
Quality by design implies a systematic approach to pharmaceutical development
and product lifecycle management including risk management principles.
It is an approach to pharmaceutical development which emphasises product
and process understanding based on mechanistic principles, and systematic
experimentation rather than empirical experimentation.
The ongoing developments offer the option for companies to take different
approaches in their development of products. This includes optimising
the design of the products, better understanding of processes, and building
quality into products. In addition to reducing the potential for batch
failure, this approach will also benefit from some regulatory flexibility.
This potentially applies to all aspects of the finished product, from
the material characteristics of the formulation input process materials
(active substance and excipients) through to the manufacturing process
of the finished product. Overall developments continue but there are
many issues still to be clarified. There are a number of challenges ahead
for both regulators and the pharmaceutical industry and there is a clear
need for a common understanding to ensure that there are no unnecessary
problems encountered during assessments. Progress may be gradual and
there is still plenty to do to make the most of the opportunities, concluded
Dr Pugh. |
The
Pharmaceutical Journal