Academy of Pharmaceutical Sciences (Inhalation Group)
Regulatory agencies work with industry to develop field of inhaled medicines
Representatives from the pharmaceutical industry were united in welcoming
the initiatives of regulatory agencies to improve collaboration with the
industry. Steve Nichols, of Sanofi Aventis, described how regulatory groups
surround the work environment. These include the major government agencies,
such as the Food and Drug Administration in the US and the European Agency
for the Evaluation of Medicinal Products (EMEA).
The EMEA, for example, publishes comments it receives on its guidelines
along with its response to any comments, on its website. Inhalanda is one
of the working groups of the European Pharmacopoeia, and comprises experts
on inhalation preparations from major European member states. It works
on revising monographs and test chapters, including those addressing aqueous
delivery inhalers, nasal products and impactor screening. For Inhalanda
to be useful to industry, it is essential for the industry to put forward
information, ideas, proposals and methods, said Dr Nichols.
The industry itself has a variety of discussion groups working together
on issues relevant to the development of inhalation products and devices.
The Global Harmonization Task Force is a voluntary group of representatives
from national medical device regulatory authorities and the regulated industry,
similar to the International Conference on Harmonisation (ICH), but concentrating
mainly on devices. The Product Quality Research Institute (PQRI) is a collaborative
process involving the FDA Center for Drug Evaluation and Research, industry
and academia. The mission of PQRI is to conduct research to generate specific
scientific information that should be submitted in a regulatory filing.
The International Pharmaceutical Aerosol Consortium represents leading
manufacturers of metered-dose inhalers, and member companies are now in
the forefront of developing a new class of metered-dose inhalers for respiratory
medicines. The European Pharmaceutical Aerosol Group is a voluntary non-profit
making consortium open to European pharmaceutical companies that develop
new products for humans to be delivered by the pulmonary or nasal route.
Members share non-confidential information. Many of these groups were set
up to meet specific political needs, said Dr Nichols, and although mergers
would be desirable, this is unlikely in the near future.
Paul Lucas, of Pfizer, explained that, as with all European initiatives,
the regulation of medicines was driven by the concept of free movement
of trade. This has now evolved into considerations of quality, safety and
efficacy. There have been significant developments in the regulation of
inhalation products in the past five years, said Dr Lucas, with collaboration
on standards with Health Canada (the Canadian federal department responsible
for helping Canadians maintain their health) being seen as a positive step.
The welcome changes in the regulatory climate will create opportunities
and challenges for orally inhaled and nasal drug products, he concluded.
Japan is the third largest market for Western pharmaceutical products,
said Richard Malley, of GlaxoSmithKline. Although it is part of the ICH,
Japan still offers interesting technical, regulatory and cultural challenges.
The Pharmaceutical Affairs Law dates back to 1943, but it is changes introduced
in 2005 that have the most impact on chemical manufacturing controls and
Mr Malley reviewed the specific requirements for Japanese registration
of new products. It was advisable to consider and build Japan-specific
requirements into development plans from an early point, he said, because
understanding the submission process makes for a more efficient application
and a higher probability of success.
Creating medicines is a high-risk journey, said David Roblin, of Pfizer.
It was noted that research and development has been moving out of Europe
and the EC challenged the industry to identify bottlenecks to innovation.
The industry’s response was to set up the Innovative Medicines Initiative
(IMI), identifying four key areas of exploration: predictive safety, predictive
efficacy, knowledge management, and education and training. IMI does not
develop new medicines but provides the framework that is needed across
the industry. Thus the IMI is concerned with research and development processes
from target identification to pharmacovigilance, and with tools and understanding,
not medicinal products. The ultimate beneficiaries are all European citizens,
concluded Dr Roblin.
Rosemary Leak, of GlaxoSmithKline agreed with the concept of collaboration
of industrial groups on non-product related issues. In particular, the
complexity of inhalation products is such that no single company can afford
the resources to negotiate regulatory hurdles, and shared experience is
useful. Older manufacturing processes entailed the acceptance of variable
starting materials subjected to a fixed procedure resulting in variable
product.
Dr Leak described how the industry is moving towards a situation where
stricter controls at the outset, together with a flexible procedure, will
result in a consistent output. A framework for this “quality-by-design” approach
is provided by the ICH guidance on inhalation products, enabling the industry
to collaborate in the promotion by the regulatory authorities of a quality-by-design
approach for pharmaceutical products, concluded Dr Leak.
Technological solutions from particle engineering
Without excellence in engineering, success is a lottery and failure is
the most likely outcome, said Andy Fry, of Team Consulting. Engineering
for success is largely about understanding where failure can arise and
dealing with it. The pharmaceutical industry should learn from what the
rest of industry does.
Successful organisations usually establish a comprehensive and well informed
specification, understand what is required, develop a robust design to
address all specification aspects, and understand and control the manufacturing
processes that generate the product. Pharmaceuticals should also look outside
itself for new technology, Dr Fry said, for example by incorporating electronics
into inhalation products.
Batch crystallisation is the workhorse of pharmaceutical industry, said
Ivan Marziano, of Pfizer, and conventionally this purification step has
been followed by filtration and drying procedures which can affect particle
shape and particle size distribution. Subsequent procedures, such as milling,
are undertaken to provide a respirable active ingredient for a formulation.
The traditional role of the particle engineer has been to understand and
control unit operations ahead of micronisation, to mitigate the impact
of changes in the synthetic route and to understand the impact of micronisation
on the chemical’s physical properties, including regions of disorder
which may be created in the process, and which would impair the stability
of the product. The properties after micronisation depend strongly on physical
properties of the input batch of the active phamaceutical ingredient, disorder
(increase in amorphous content and interfacial instabilities), increase
in surface energy, and reduction in stability. The particle engineer will
also seek to reduce the overall number of manufacturing unit operations.
The modern particle engineer, however, will eschew processes that seek
to alter properties after the crystallisation step but will try to engineer
conditions whereby the desired characteristics are designed into the original
crystallisation. This approach is consistent with the growing awareness
of the principles of quality by design, and Dr Marziano developed the theme
of “particle engineering from solution” by considering the
mechanisms of crystallisation and the ways open to the engineer to manipulate
crystallisation conditions.
Particle formation is driven by supersaturation, he said. Particles emerge
from supersaturated solutions by processes of nucleation (molecules of
product assemble in clusters; the clusters will progressively increase
in size to become visible crystals) or by growth (the crystal size increases
by incorporating more molecules around the initial crystal nucleus).
Nucleation and growth rates both depend on supersaturation and the engineer
will balance these processes. Thus, direct particle engineering for an
inhaled chemical plans to favour nucleation over growth, by operating at
high supersaturation and lowering the activation energy. Most constructive
particle engineering methods are based on these principles. Technologies
available may be based on mixing intensification, on supercritical fluids,
or on droplet-to-particle technologies. However, every compound will have
its own associated challenge and every technology has its advantages and
drawbacks. It is unlikely that a single technology will always offer advantages
over traditional manufacturing methods, concluded Dr Marziano.
Robert Price, pharmaceutical technology lecturer at the University of Bath,
agreed that particle engineering and its processing will become critical
in pharmaceutical manufacturing. He emphasised that geometry, not surface
chemistry, is the central design principle in controlling particulate interfaces.
Dispersity was characterised by particle size, particle shape, particle
surface morphology and particle surface properties. Micronising takes care
only of the first of these and controlled crystallisation only the first
two. Incorporating sonication into a particle engineering scheme at the
point of conversion of a single droplet to a particle at ambient temperature
has been shown to be successful in producing particles in the desired size
range, with well-defined crystalline structures, sphere-like morphology
and good geometric control of surface topology.
Francesca Buttini, of the University of Parma, outlined the pharmaceutical
paradox that faces the designer of respirable particles. Inhaled particles
have to be small for aerosolisation and deposition, but large enough to
allow metering during manufacture of a dosage form. A formulation strategy
to overcome the problem for budesonide was to produce ordered mixtures
with a carrier particle. The carriers were not added as a ternary component
but were coated onto the budesonide by spray-drying a drug suspension in
polymer solution.
The blend characteristics and respirability from a dry-powder inhaler were
assessed. The ability of vinyl polymers to modify the forces of adhesion
and the aerodynamic characteristics within a dry-powder inhalation formulation
could be demonstrated, concluded Dr Buttini.
Key to products is understanding the materials
John Staniforth, of PharmaKodex, gave a historical perspective on how
powders became the source of successful drug products. The development
of the Spinhaler by Fisons relied on producing particles of a defined size
whereas developments for other inhalation devices did not necessarily require
the same sized particles. Baffles introduced into air-streams were not
solely to produce turbulence but to improve the particle separation. The
concept of inhaled delivery is not confined to treating respiratory diseases
but may be developed as a means of systemic drug delivery by absorption
via the lung. However, the lung has proved inadequate in absorbing macromolecules
and most such advances have been made with small molecules. The lung can
be an efficient route for short, sharp, low-dose delivery to switch on
a clinical effect, as in Vectura’s apomorphine project for Parkinson’s
disease, concluded Professor Staniforth.
Some drugs, however, do not take well to mechanical procedures such as
milling, said Toby Payne-Cook, of Pfizer, and it is important to characterise
and understand the amorphous state that often results. Dynamic mechanical
analysis, the measurement of the response of powders to mechanical stress,
is a highly sensitive technique in detecting glass transitions and although
the sensitivity is compromised by the presence of a crystalline matrix,
the technique is considered complementary to thermal methods in the analysis
of amorphous powders.
Understanding the nature of a material is a prelude to being able to predict
the properties resulting from appropriate manipulation. Marcel de Matas,
senior lecturer in computational formulation science at the Institute of
Pharmaceutical Innovation, Bradford, applied artificial neural networks
so that in vitro measurements (particle size data, patient data) could
predict in vivo performance (biological levels of inhaled drug). He concluded
that the approach showed promise and could provide warning of bioavailability
problems during development.
Graham Buckton, professor of pharmaceutics at the School of Pharmacy, University
of London, emphasised the difficulty of obtaining in vitro/in vivo correlations
for inhalation devices because of the major variables in the systems. Of
particular importance was a clear understanding of the presence of amorphous
material and its potential effect on material properties, particularly
in recognising that different properties may be desirable for different
devices. Complementary methods may be required for useful characterisation.
For example, inverse-phase gas chromatography measures surface properties
and is a useful complement to other analysis techniques.
Teresa Carvajal, assistant professor of industrial and physical pharmacy
at Purdue University, Indiana, described how this understanding of the
surface of pharmaceutical powders could result in designing effective products.
Flow properties, surface energy, triboelectric charge and surface roughness
were measured as contributing factors. Dr Carvajal concluded that roughness
of the particles was an important reason for the differences in behaviour,
and that surface energy measurement could be used to predict segregation
of powders.
Fine powders are prone to picking up electrostatic charge during manufacture
and use, said Joanne Peart, associate professor, department of pharmaceutics,
Virginia Commonwealth University, Virginia. The deposition of the powder
on target surfaces can depend on both particle size and its electrostatic
charge, so both need to be looked at together. Using standard impactors,
the charge distribution for different fractions of inhalation products
was determined, showing that different inhalation products containing the
same active pharmaceutical ingredient had quite different patterns of electrostatic
distribution. Sometimes large particles were positively charged and small
particles were negatively charged but sometimes this was reversed, with
the totality of the charge on the whole powder also varying. Although understanding
of electrostatic interactions has been improved by these studies, said
Dr Peart, it is not yet clear whether it is crucial to product performance. |
The
Pharmaceutical Journal