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STREAMLINE YOUR
FREEZE-DRYING R&D
Contents
• History
• BTL’s mission
• Products handled
• Principles of freeze-drying
• Typical issues & consequences
• Product critical temperatures
• Instruments: Lyostat and its operation
• Instruments: Lyotherm for frozen state analysis
• Product Characterisation
• Development Services
• Formulation Development
• Cycle Development
• Optimisation and scale up
• Post-process Analysis
• Troubleshooting
• Typical timelines
• BTL’s Research
• Training
• Meet the Team
• Our facilities
• Main Laboratory
• Potent compounds’ Suite
• Freeze-Drying capacity
• Partnering with BTL
• Case Studies
History
• Started in 1997 with laboratory services
• Historically supported BPS sales of equipment
as supplier in UK & Ireland
• Since 2011, with the set-up of a commercial
arm, has expanded internationally with
representation in 8 territories
• In 2012, opened a negative pressure facility
for handling potent compounds
BTL’s Mission
• Quantitative approach to process development
• Product characterisation: empirical foundation for development
• Holistic view: Product, process, scale and equipment
• Post-process analysis
• Championing the establishment of a QbD approach
• Expert support the freeze drying industries
• Ongoing collaborative research in science of freeze drying
Products Handled
Small Molecules
25%
-Traditional Drugs
-Small Peptides
Large Molecules
50%
-Large peptides / polypeptides
-Enzymes and other proteins
-Mono / polyclonal antibodies
-DNA-based reagents
-Antibody based diagnostics
Structured
Materials 15%
-Collagen matrices
-Nanoparticulates, hydrogels, microspheres
-Foods and artefacts
Cellullar &
Organisms 10%
-Bacteria
-Tissue samples
-Purified body fluids for personalised medicines
-Red blood cells
Principles of Freeze Drying
Freeze drying ideal to produce:
• Stable product
• High levels of activity
• Homogeneous powder or cake
• Rapid reconstitution
• Controllable batch production
• Batch consistency
Typical issues & Consequences
Clients can experience issues with:
• Poor characterisation
• Batch reproducibility
• Poor stability, activity or reconstitution
• Inconsistent dryness across samples
• Cycle control
• Breakage of vials and containers
• Product quality failure
• Long, expensive cycles
Typical issues & Consequences (Continued)
Consequences:
• Financial inefficiencies
• Quality and regulatory drawbacks
• Operational setbacks
Product Critical Temperatures
• Freeze-drying success depends on knowledge of
critical temperatures
• Provide empirical basis for R&D and scale-up
• Collapse (Tc) most important.
• Also, glass transition (Tg’) or eutectic point (Te)
and other frozen-state events affect processing
Product Critical Temperatures (continued)
• Freeze drying without empirical data leads to:
– Poorly defined and justified process’ parameters
– Loss of product or batch recall
– Mismatch between process and equipment
– Lack of quantified, well characterised product and
cycle, detrimental to any regulatory submissions
Instruments
• BTL helped develop 2 instruments for freeze-
drying specific analyses:
– Lyostat freeze drying microscope (FDM): real-time
analysis of freezing and drying events
– Lyotherm frozen-state analysis: combines DTA and
impedance analysis
Lyostat Freeze Drying
Microscope (FDM)
Lyostat
• Acts as a micro-freeze dryer
• Observation of freezing and drying under
microscope
• FDM is the only technique that identifies
collapse temperature (Tc)
• Also used to investigate the effects of annealing
• Available for purchase at BTL
Lyostat Operation
• Requires just 2µl sample
• Set freezing temperature and hold to ensure
complete freezing
• Turn on vacuum pump to initiate drying
• Sublimation front will move from one side of
the sample to the other. Raising the
temperature will cause the sample to
eventually collapse.
Lyostat
Screenshots of Lyostat analysis, showing frozen product (1), dried with good
structure (2) and collapse (3)
1
2
3
Lyotherm Frozen State
Analysis
Lyotherm Frozen State
Analysis
• Developed in collaboration with Dr Louis Rey
• Exclusive to BTL
• Combines Differential Thermal Analysis and
Impedance Analysis
• Identifies glass transition (Tg’), eutectic,
melting, and any other endo- or exothermic
events.
Lyotherm Frozen State
Analysis
• On-site installation and training by an
experienced scientist
• Supplied validated against reference solutions
• Measurable temperature range -190°C to
+60°C
• Accuracy 0.05°C, resolution ±0.05°C
• Easy export of data directly into Microsoft
Excel
Product Characterisation
• To develop process, product characterisation
is essential
• Lyostat and Lyotherm analysis enable
identification of critical temperatures
• BTL provides full report
• The report can be incorporated into any
customer’s documentation and regulatory
submissions
Development Services
• Many products and processes developed by trial-and-error
• As a result, cycles can be inefficient, expensive, process poorly
• Collapse can occur invisibly
• Developing formulations to avoid critical temperatures being too low
• If critical temperatures are too low, cycles are too long, energy intensive and expensive
• All cycles need validation for batch uniformity
Development Services
• Favourable thermal characteristics by optimal
excipients selection
• Different excipients provide different lyo- and
cryo-protective attributes
• Product & process development with freeze
drying in mind from the start
• Yet, pre-existing formulations and cycles can
be optimised
Formulation Development
• BTL has worked with over 1000 products
• Significant experience with a multitude of excipients, their various qualities and suitability
• Empirical characterisation of products and its optimisation to yield ideal product for processing and subsequent use
Cycle Development
• Cycles best developed for each product
formulation
• Cycles tailored for the specific equipment,
batch size, container
• Using data cycle development can be
streamlined
• BTL completes a cycle development with 3
trial runs, and a confirmatory run
Cycle Development
Example of a typical freeze drying cycle
Cycle Optimisation & Scale-Up
• Equipment dimensions, chamber dimensions, container type, fill depth, and batch size affect: Heat transfer, moisture capture rate, vapour flow
• These can all affect the rate of drying
• Cycles need to be reassessed when scaling up and/or changing equipment
• Process validation provides documented evidence for parameters specified
Post-Process Analysis
• Post-process characterisation
of great value for batch quality
assurance and covers at least:
• Moisture determination by Karl
Fischer Titration
• BTL, in collaboration with
Imperial College, can perform
Mechanical tests of cake
Post-Process Analysis
• mDSC provides glass transition in dry state (Tg) which is necessary to specify appropriate storage conditions
• Non-destructive complete batch analysis or long-term studies can be conducted using FMS
• Other product-specific analyses can be provided for physical, chemical and biological parameters, e.g. SEM, DVS, XRD
Moisture mapping of
an entire freeze dryer
shelf, using FMS
Troubleshooting
• Issues can occur unexpectedly at any stage:
development or manufacture
• BTL expert at addressing multitude of products,
different stages of development and makes and
models of equipment
• Experience and science-led investigation makes
us ideally placed to timely problem resolution
• Empirical data provides foundations of QbD and
explanation of rectifications
Typical Timelines
Characterisation: typically 1-2 weeks, but same-day analysis
can arranged for urgent requirements
Formulation Development: 1-4 weeks, depending on
number of formulations and testing required
Cycle Development: Typically 4-8 weeks
Process Scale-Up / Optimisation: Typically 2-10 weeks
Troubleshooting: Up to 6 weeks
BTL’s Research Projects
• We engage in collaborative
research to further the field of
freeze drying
• We remain at the cutting edge
• Examples: red blood cells,
collagen implants, probiotic
bacteria, fusion proteins,
headspace moisture analysis,
polymorphism in herbicides
Training
• Part of our mission is to educate on freeze
drying
• Since 1997 we have run more than 120
courses and trained more than 2500 people
• Courses held regularly in UK, mainland
Europe and USA
• Courses are regularly updated with new
technologies and concepts
Training
• Latest courses include practical workshop in BTL’s laboratory allowing hands-on experience of equipment
• Courses can also be offered at customer site and include consultancy on customer’s product and equipment
Meet the Team
• Management:
Dr Kevin Ward PhD FRSC
• Director of R&D – Joined in 2000
Dr Laura Ciccolini PhD, MEng Hons, Dean Listed
• Commercial Director – Joined in 2011
Meet the Team
• Science Team:
– Isobel Cook MSC Principal Research Scientist & QA
Manager
– Nicholas White MChem Senior Scientists and
Workflow Manager
– David Banks Senior Scientist
– Mervyn Middleton BSc Research Scientist
– Magdalena Witek MSc Research Scientist
– Thomas Codd MChem Research Assistant
Meet the Team
• Sales Team:
– Nektaria Servi MBA Business Development
Executive & Instruments Product Manager
– Elysabeth Sheppard Business Development
Executive & Training Courses Manager
Our Facilities
• We operate two laboratories, one standard
freeze drying laboratory and one standalone
laboratory for potent materials.
Main Laboratory
• 3 research-scale freeze dryers with
4-10 shelves each, stoppering and
process monitoring
• Lyostat freeze drying microscope
• Lyotherm frozen-state analyser
• mDSC, Karl Fischer
• Filling, labelling & capping services
Toxic Compounds’ Suite
• Product analysis, cycle and
formulation development
• Small-scale production
• Dedicated, negative pressure
suite: no cross-contamination
with other products
FREEZE-DRYING CAPACITY
• Pilot Scale Genesis: offers 4 shelves, with processing capacity range from
• 1mL product (in 2mL vial) over 4 shelves = 1824 vials (1.824 L )
• to 20ml (in 50mL vial) over 4 shelves = 165 vials (3.3 L)
• Small production scale runs
• Ultra: offers 10 shelves, with processing capacity range from • 1mL product in 2mL vials, over 10 shelves = 4560 vials (4.56 L)
• 20mL product in 50mL vials, over 10 shelves = 412 vials (8.25 L)
• Or, bulk trays can offer 3L per shelf, yielding:• Genesis: 12L (4 trays)
• Ultra: 30L (10 trays)
Partnering with BTL
• Gain access to our process expertise
• Experience with a wide range of product types and process challenges
• Science-led practice for streamlined development and data-backed recommendations
• At the cutting edge of QbD in the field
• ISO 9001 with comprehensive QA documentation and procedures
CASE STUDIES
Formulation Development
Case Study• Customer needed to develop a freeze drying cycle but
the product had a low collapse temperature of -42°C. Low collapse temperatures require slow,lengthy and energy intensive cycles.
• BTL reformulated the product, as this was allowed, to replace some of the sucrose with dextran. Dextran can affect biological products but the small amount used ensured there were no detrimental effects to the active ingredient.
• The final formulation had an overall collapse temperature of -23°C, a significant improvement over the original.
Cycle Development : A Case
Study• A company had been progressing their product through clinical
trials, but the EMEA highlighted the absence of lyophilisation parameters from their DMF.
• BTL analysed the product with Lyostat, Lyotherm and mDSC. It was found that the existing cycle was far more conservative than it needed to be, adding unnecessary energy costs (to produce colder temperatures) and time.
• The analysis results were used to propose a new cycle which was then tested. The product dried well, but was visually inconsistent due to contents settling out.
• A revised cycle included a faster freezing step to prevent settling out and new handling procedures specified greater care during loading. The new cycle was significantly shorter than the original.
• A more thorough DMF was submitted and the product received EMEA approval.
Cycle Optimisation: A Case
StudyA client wanted to reduce their cycle time of 61 hours.
Lyostat analysis identified a collapse range of -8.6°C to -17.4°C.
Lyotherm analysis indicated a softening event at
-25°C.
A cycle was designed to keep the product below -30°C, allowing a 5°C safety margin below the lowest critical temperature.
The new cycle, once tested, refined and validated, was 45 hours long representing a significant saving in time and process costs.
