For spray dried powders, physical characterisation is a key step in the development of a formulation, process or product. Understanding the key physical characteristics can mean the difference between success and failure of a pharmaceutical product.
The following are just some important properties of powders that we routinely assess:
Particle Size
The particle size distribution in a dry powder can be critical for specific applications such as nasal or inhaled delivery. This can be measured in several different ways. For example:
A simple sieved fractionation can be useful, although the fraction sizes can be relatively wide.
Laser diffraction provides a higher fidelity measurement. This can be undertaken in the dry state (using a dispersant gas to ensure primary particles are measured) or in the wet state (in a suitable antisolvent for the material).
Ensuring a representative sample is used for measurement is vital, especially when broader size distributions are encountered.
Morphology / Shape
Particle morphology can be dependent upon the numerous formulation and process factors, all affecting the way droplets form and dry into particles. Particle size, density and morphology affect important powder properties such as flow and aerodynamics. Examples are:
SEM imaging is a qualitative measure, which allows you to observe what powder has been made. Sampling is key to ensure a representative sample is imaged.
Laser or optical techniques using single particle imaging provides a more quantitative measure; these can be used for a less subjective comparison of samples.
Density
Powder density and flow measurements are important characteristics in downstream processing, especially during automated filling. Density of particles produced may be controlled or tuned by the droplet drying process, the formulation and solvent systems used during manufacture.
Aerodynamics
Particle aerodynamics are important for product performance in inhalation delivery. The aerodynamic particle size distribution is often quite different to the geometric size distribution. Morphology and density also play a role in how well a particle may fly and be carried in to the lung or the nasal cavity. Cascade impactor testing tests the aerodynamic performance of formulations for inhaled and nasal delivery.
Thermal properties
The thermal properties of a powder should be understood, both in reaction to heat and to humidity. Considering the effects of temperature, different materials may melt or become sticky depending on whether they are crystalline or amorphous. Thermal analysis of powders by differential scanning calorimetry (DSC) and dynamic vapour sorption/desorption (DVS) will give an indication of suitable storage conditions and any packaging challenges that may need to be addressed.
DSC can give an insight to the structure of a formulation and interactions between its components. It also indicates any potential stability issues that may arise.
The relatively large surface area of powders means that the effects of humidity can be quite marked, ranging from no impact, through stickiness and aggregation to deliquescence.
Using DVS the effect of a wide range of relative humidities on a sample can be studied and the reversibility of any effect can give insight to its mechanism; such as absorption, adsorption or crystallisation.
Powder characterisation is vital to successful formulation and process development. It enables us to identify and control the parameters that affect the key powder characteristics. The techniques described above are the ones most routinely applied, but there are many others that can be used, depending upon the development stage, the formulation and the application.
Producing a spray dried powder is rarely
the end of the formulation pathway. Further processing is usually required in
order to create a dosage form that can be administered in First-in-Human (FIH)
or Proof of Concept (POC) clinical studies.
The selection of a dosage form will involve a
number of factors, for example:
Pharmacokinetics
Bioavailability
Stability under ambient climatic conditions
Excipient compatibility
The determined route of administration and the ability to achieve patient compliance
Tablets and capsules are the most common dry powder
dosage form. However, other dosage forms such as sachets (bulk powders), vials
(for reconstitution) and powders delivered via devices (inhalation and nasal)
are also required on a regular basis.
Upperton
now has the flexibility to offer all of these dosage forms to our clients
thanks to our recently granted MIA (IMP) licence.
Designing a Process for Tablet Manufacture
In general, processes for tablet manufacture require
the following 3 step processes:
Granulation
- Dry granulation (roller compaction,
slugging) is the most common technique for spray dried powders. Alternatively,
spray dried powders can be blended and subjected to direct compression.
Compression – Conventional rotary multi-station
compressing machine with dedusting and metal detection. Flexibility in
tablet size and shape can be managed using conventional and multi-tip
tooling.
Coating – Utilisation of a film or sugar coating can
be used for a variety of purposes including taste masking, improving stability
and for targeted release in the digestive tract.
Designing a Process for Capsule Manufacture
Filling spray dried powders and other API’s into
hard shell HPMC or gelatin capsules enables projects
to move more quickly into FIH or POC studies.
In many cases, it is possible to fill capsules
manually. As the trial progresses through the clinical stages.
Scale up of batch size is managed through
automation, into semi-automated capsules fillers (Profill
range) and then onto fully automated capsule filling machines capable of producing
several thousand capsules per hour.
When developing the approach to capsule filling,
consideration should be given to the target formulation, powder properties and
the dose required. This will essentially dictate the method of manufacture, in
particular;
Is a simple floodfill with the spray dried powder possible?
Is a bulking agent required to enhance
powder handing/filling operations?
Is a Precision fill of the spray dried powder
directly into the capsule more appropriate?
Drugs that have short half-lives or are rapidly
metabolized often require dosing three or four times a day to maintain drug
levels in the required therapeutic range. In such cases, sustained-release
dosage forms can reduce the frequency of dosing.
The selection and use of specifically designed capsule coatings can create sustained-release
products that can reduce the frequency of drug administration; improving
compliance and the therapeutic effectiveness of the drug by maintaining a more
constant drug plasma level than can be obtained using traditional dosage forms.
Upperton
Pharma Solutions are one of the very few CDMO’s that have a bespoke, fully
equipped non-GMP pilot plant designed to reduce the timelines and the costs for
scale up and transfer of spray drying processes into GMP.
Spray Drying Development and Scale up
Formulation and early process
development studies are performed in the Upperton spray drying development
suite on one of our laboratory-scale Büchi B290 spray dryers.
These are excellent spray dryers for early development studies; enabling us to
produce stable formulations to meet our customers' requirements. They also
allow us to define the process design space for producing the spray dried
formulation using a DoE approach.
The next step towards clinical manufacture is transfer of the process onto one of the GMP-compliant spray dryers, housed in our non-GMP pilot plant.
Depending upon the scale eventually required for clinical manufacture, the
process may be transferred onto our ProCepT 4M8-TriX spray dryer or it may be
scaled up onto our GEA Niro Mobile Minor spray dryer which can be used to produce
batches of up to ~3kg spray dried product.
The Upperton pilot plant is equipped with exactly the same spray dryers as our
GMP facility. This allows us to produce kilogram quantities of non-GMP material
to support toxicology and stability studies at a fraction of the cost of GMP
manufacture.
Once tech transfer / scale up studies are completed: A Master Batch Record
can be produced, Chemistry, Manufacturing and Controls (CMC) batches can be
manufactured and the process is ready to be transferred directly into the GMP
facility for clinical manufacture.
Engineered Powders for Enhanced Pulmonary Delivery
Upperton is continuing to invest in its combined spray
drying and micronisation technology in order to meet
increased demand. This emerging processing technology has been developed to
enable the production of larger quantities of dry powder formulations suitable
for pulmonary delivery.
The expansion of this service has been driven by growing
demand for this exciting next generation pulmonary delivery technology
particularly from customers requiring GMP manufacturing to support clinical
trials.
Producing dry powders with the optimum aerodynamic particle
size distribution of 1-5 µm for pulmonary delivery is fairly
straightforward on a laboratory scale spray dryer. Feedstocks of low solids
concentration are typical; processing rates are kept relatively low and high
atomisation gas pressures are employed in order to generate the very small
particles needed for high levels of deposition and uptake in the alveoli.
Challenges arise when larger quantities of material are
required and a scaled-up, commercially viable process is essential.
Particles in the 1-5 µm range are notoriously difficult to produce and
collect efficiently on larger pilot or commercial scale spray dryers. Size
distributions can often creep upwards, and product yields can plummet. This is
particularly bad news for high value APIs!
The Upperton approach is to optimise the spray drying process
for product yield, with particle size no longer the primary focus. The
feedstock concentration and processing rate can both be increased;
significantly reducing both manufacturing time and cost. The spray dried
particles are then reduced to the target particle size distribution, using a
carefully controlled dry powder milling process. The result is a much faster,
more efficient process producing large quantities of powders with excellent
aerolisation properties.
Impaction testing of our model pulmonary formulations shows that we can
reproducibly generate dry powders with an aerodynamic particle size
distribution of 1-5 µm, with fine particle fraction in excess of 70% when
formulated powders are delivered from commercially available DPI’s.
There is growing interest in the use of spray drying to
create biotherapeutic dry powder formulations. Spray drying is becoming
increasingly viewed as a more cost-effective method for enhancing the stability of thermo-sensitive molecules (such as proteins, peptides, monoclonal
antibodies and vaccines).
A key aspect in the successful development of dry powder formulations is
identifying suitable analytical techniques to evaluate the biologic in
question. These tests will be needed to: aid formulation development, determine the impact of different spray drying parameters on the product and to determine stability profile. There are a wide range of assays available so it is important to choose suitable assays that can provide insight into two important aspects of the final powders produced, namely assays that show:
The biologic in question retains its structure and activity both during the spray drying process and on subsequent storage.
The spray drying process is generating powders with the necessary physical properties required for powder handling, reconstitution and storage stability.
There is a range of potential assays that can be used
to evaluate the spray dried formulation, the list is extensive therefore,some of the key tests that practitioners might want to consider have been highlighted. The assays have been divided into two groups: those used to evaluate the physical properties of the spray dried powders and those assays designed to evaluate the structure, function and chemical properties of the biologic itself.
Physical properties of the spray dried powder
Test
Rationale
Particle size analysis (Laser light scattering, impaction by ACI/NGI)
Particle
sizing will give an insight into powder handling requirements, storage
stability and performance in delivery devices such as dry powder inhalers.
Residual moisture (loss on drying,
Karl Fischer)
Tight control of residual moisture is an important read out in the optimisation of spray drying conditions and tight specification will be needed in order to meet storage stability targets.
Thermal properties DSC/DVS)
Thermal properties, such as moisture uptake, melting points or glass transition temperatures of the powders produced will impact on handling and storage stability.
Powder flow properties (Bulk/tapped density, angle of repose)
One of the major challenges of spray drying is engineering powders that have suitable handling and flow characteristics.
Electron microscopy (scanning, transmission)
Important
for evaluating particle morphology, evidence of any crystallinity and
retention of physical structure of biologic (e.g. virosomes).
Structure, function and chemical properties of the biologic
Test
Rationale
HPLC analysis (size exclusion, reverse phase)
Established technique for evaluating aggregation of biologic molecules (during spray drying and on storage) and for evaluating chemical modification(s) of specific amino acids.
Gel electrophoresis (denaturing/non-denaturing, Western blotting)
Technique
for evaluating covalent and non-covalent molecular weight changes of
structural components (including aggregation, dissociation and scission).
Testing
the activity of the molecule being formulated is an important test of the
molecule's integrity during spray drying and on subsequent storage.
Mass spectroscopy
Sensitive
technique especially useful for detecting oxidation and deamidation of amino
acid side chains that can occur during spray drying and on storage.
Spectrophotometric assays (reconstituted
powder)
Assess
reconstitution time, presence of insoluble material (aggregation), substrate
binding studies.
Circular Dichroism
Used
to determine protein folding, looking at secondary and tertiary structures.
Dry powder formulations of Biotherapeutics eliminate the
need for expensive cold chain storage and facilitate supply chain management.
Lyophilisation is traditionally used for the drying process, but in recent
years the semi-continuous, robust and scalable qualities of spray drying have
made it the drying process of choice.
With expert formulation and process development, even the most delicate
biomolecule can be spray dried with little or no loss of activity.
To understand this, it is useful to consider the spray drying process: The
solution is first pumped into the drying chamber through a two-fluid nozzle, at
the tip of which it is atomised into droplets by a flow of compressed air. The
design of the nozzle means that the cool atomisation air protects the liquid
from the high temperature of the drying gas right up until the point of
atomisation. Once the solution is atomised, the droplets dry very quickly in
the heated drying airstream; again, the biomolecule is protected from the heat
by an evaporative-cooling effect as the droplets dry. Once in the dry form,
biomolecules are generally much more robust than in solution, and the total
residence time within the spray dryer is only a matter of seconds, depending
upon the size of the dryer.
Biotherapeutic Formulation Development
Formulation development is important to ensure the stability
of biomolecules at three critical points during and after processing: on
solution atomisation, during the drying process, and on storage after drying.
Surfactants, such as polysorbates or poloxamers, offer protection at the
liquid-air interface during the atomisation stage, preventing protein
aggregation or denaturation.
Stabilisation during the drying process is achieved by the use of excipients
that can form hydrogen-bonds with the biomolecule. Sugars such as trehalose, raffinose, or dextran are commonly used, due to their high glass transition temperatures; offering enhanced
storage stability of the bioformulations. Combinations of amino acids such as
histidine, glycine, proline and arginine, can be tailored to offer effective
stabilisation; resulting in dry powder bioformulations with excellent stability
characteristics.
Polymers, for example: cyclodextrin, PVP, methyl-cellulose and eudragits may be used in bioformulations, both for enhanced
stability and for other purposes (controlled release, taste masking and enteric
coating).
Other commonly used excipients include:
·
Salts for increasing ionic strength of solution,
minimising electrostatic interactions, and control of pH
·
Antioxidants
·Divalent metal ions, such as zinc, to form
dimers and reduce protein aggregation
·Amino acids, such as Leucine, and surfactants
such as Phophatidylcholine, for improved powder flow and aerosolization
·Mucoadhesives such as chitosan in formulations for nasal delivery
Process Development
Spray drying processing parameters can have a profound
effect on the properties of dry powder bioformulations, and the process development
phase is of critical importance.
In optimising the drying temperature, a balance must often be struck between
the need for a low residual moisture level in the product for optimum storage
stability, and a drying temperature that the biomolecule can withstand. The
drying temperature can also affect the stickiness of the product, depending
upon the glass transition temperature of the formulation.
Particle size and morphology have an impact on powder flow and aerosolisation properties, which are especially important
in formulations for inhaled or nasal delivery. These can be controlled by
optimisation of a range of process parameters: Feed solution concentration,
liquid feed rate, atomisation airpressure and air flow rate,
have the biggest impact on particle size. Drying air flow rate and temperature
affect the rate of drying and so can be used to change the morphology of the
dried particles.
Characterisation of Spray Dried Bioformulations
Upperton has a wide range of analytical techniques that can
be used to investigate the chemical and physical properties of dry powder
bioformulations. These include HPLC, gel electrophoresis, activity assays,
particle size analysis by laser diffraction and impaction (ACI/NGI), residual
moisture determination, differential scanning calorimetry, dynamic vapour
sorption, powder flow measurements, and scanning electron microscopy.
Upperton Pharma Solutions now has a fully commissioned
60 square metre non-GMP pilot plant, mirroring our GMP manufacturing facility.
The pilot plant is equipped for three scales of spray drying:
•ProCept 4M8-Trix for batch sizes of up to 300g
•Upperton
Intermediate Spray Dryer for batch sizes of up to 1kg
•GEA
Niro Mobile Minor for batch sizes of up to 3kg
In addition, the pilot plant has all of the powder
handling and processing capabilities offered in our GMP manufacturing facility,
for downstream processing of spray dried powders into final dosage forms.
Formulations and processes optimised in our R&D
laboratories can be quickly scaled up to produce non-GMP material for
toxicology and stability studies and CMC batches. The mirroring of our GMP
capability enables a rapid seamless transfer of processes into clinical
manufacture, along with all of the expertise and formulation-specific know-how
built up during the development stages.
In 2014, Upperton Pharma Solutions was awarded a
prestigious Horizon 2020 grant as part of a European consortium led by Mymetics, a pioneering company at the forefront of the development
of virosome-based vaccines.
The MACIVIVA goal was to develop dry powder, thermostable, cold-chain
independent virosomal vaccine formulations for non-invasive needle-free
administration. Such solid form vaccines should reduce the cost and improve safety
and compliance in National Immunisation Programs, particularly in the developing
world.
The Upperton formulation development team successfully developed spray dried
formulations of HIV virosomal vaccines for both oral and nasal delivery routes.
The optimised processes were scaled up and transferred into the company’s GMP
clean room facility, where batches of both the Oral and the Nasal formulation
were manufactured.
Retained virosome structure and
particle size on spray drying
Preserved antigenicity in the
final solid vaccine forms
Retained the initial vaccine
immunogenicity after storage for three months at 40°C / 75%RH
Both nasal and oral formulations
were successfully dosed in animal models
The immunogenicity of the nasal
solid vaccine form was comparable to subcutaneous injection of the
reference liquid vaccine
Participation in the MACIVIVA
project has enabled Upperton to expand their technical capabilities to include
GMP manufacture of solid form virosomal vaccines.
Successful Completion of N2 Business Growth Grant
In October 2017, Upperton was delighted to be awarded grant
funding by the Nottinghamshire-based N2 Business Growth Fund to support
investment into a capital project leading to business growth and the creation
of new sustainable jobs. Upperton used the funds to support the establishment
of a GMP clinical manufacturing capability at its Nottingham site.
The success of the project was easily measured:
In November 2018 Upperton Pharma Solutions’ manufacturing facilities passed
inspection by the UK Medicines and Healthcare products Regulatory Agency. The
MHRA licence allows the company to develop pharmaceutical formulations for
oral, nasal and pulmonary delivery right through from early feasibility studies
to scale up and Phase I & II clinical manufacture, all from its Nottingham
Science and Technology Park site.
Upperton Pharma Solutions’ new pharmaceutical spray drying manufacturing facilities at Nottingham Science and Technology Park have successfully passed inspection by the UK
Medicines and Healthcare products Regulatory Agency (MHRA).
A pharmaceutical spray drying contract development and manufacturing organisation (CDMO),
Upperton Pharma Solutions moved to its new facilities on Nottingham Science and Technology Park from its previous headquarters at BioCity Nottingham in March 2018, as part of a planned expansion of its services.
The company has invested heavily in the new facilities both in terms of building enhancements and in the expansion of its processing and analytical
capabilities.
The successful MHRA inspection provides Upperton Pharma Solutions with the
necessary MHRA licenses for manufacture, downstream processing into capsules
and tablets, as well as release of spray dried formulations of Biotherapeutics and small molecule APIs for clinical trials.
The company is now able to develop pharmaceutical formulations for oral, nasal and pulmonary delivery from early feasibility studies to Phase I & II clinical manufacture, from its Nottingham Science and Technology Park site.
Richard Johnson, CEO and Founder of Upperton Pharma Solutions, said: “We are absolutely delighted with the expansion of our capabilities in GMP clinical manufacturingand look forward to seeing our clients’ projects progress within Upperton, from early formulation development studies right through to clinical manufacture.”
“The positive endorsement by the MHRA will enable a seamless transition from R&D to GMP manufacture within the organisation, ensuring that all of the
project-specific knowledge and expertise developed in R&D will flow through to the GMP manufacturing processes.”
Paul Kelsall, Director of Clinical Trials Manufacturing commented: “This is a great opportunity for our business and is a result of our team’s commitment to
achieve the targets and aspirations of our business. We are looking forward to working with our clients and offering services from early stage development
through to clinical manufacture. These are exciting times for Upperton as we
continue to move forward and expand our capabilities.”
About
Upperton Pharma Solutions: At a time when the global CDMO market place is consolidating, Upperton Pharma Solutions remains as one of the few independent CDMO service providers with a specific focus on developing pharmaceutical
dosage forms using its specialised spray drying capabilities. Upperton provides a range of integrated services to the pharmaceutical and biotech sectors around the world. The services include: early feasibility studies, formulation
development for both small molecule APIs and Biotherapeutics for a range of
final dosage forms and GMP manufacture of materials for Phase I & II
clinical trials. Full analytical support, including ICH stability studies,
is offered.
The company is a privately-owned
organisation that has grown organically over almost 20 years and now employs 24 highly skilled personnel. Upperton Pharma Solutions has its headquarters in
Nottingham, UK.
Contact:
Klara Fisken
Business Development Associate
Upperton Pharma Solutions, Albert Einstein Centre, Nottingham Science & Technology Park
Nottingham NG7 2TN
T: +44 (0) 115 855 7050 (Monday to Friday 8.30am – 4.30pm)
Upperton Pharma Solutions will be exhibiting at AAPS
PharmSci360 for the first time, with this year’s event running from November
5th – 7th in Washington, D.C.
·CEO & Founder Dr Richard Johnson and
Business Development Executive Annette Kleiser
will
be available at booth 1643 to discuss how Upperton can support your development
programme from early feasibility to clinical trials manufacturing
·Richard will also be presenting a scientific
poster titled “Developing Cold Chain Independent Vaccines - Spray-drying of
Virosomes to Produce Dry Powder Formulations”, on Tuesday
6th November
·This presentation will be based on the work of
the MACIVIVA project which has the end goal of producing pioneering virosome-based vaccines against life threatening dise
ases
Find Richard at Booth 1643 or arrange a meeting by contacting us.
With over 20 years of experience we have successfully spray dried, formulated and characterised a vast range of pharmaceutical and biotechnology products for companies across the globe.
