Moisture Mapping of Freeze Dryer
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Transcript of Moisture Mapping of Freeze Dryer
Moisture mapping using headspace moisture analysis
Isobel Cook BSc MRSCPrincipal ScientistBiopharma Technology Limited – specialists in freeze drying research and development
www.btl-solutions.net
Importance of residual moistureThe moisture content within a freeze dried material has a direct effect on
the glass transition (Tg) of the material.
The Tg is the point at which a material can be observed to undergo
structural change, this has a direct effect on the
• Long term stability
• Storage temperature
Incorrect drying /moisture too high
Moisture in the freeze dried product
Establishing moisture content uniformity is an important quality
control tool
Moisture is commonly measured by Karl Fischer (KF), other methods
include, TGA, NIR, though KF analysis is often considered the industry
standard
• Measure the total water!
• Labour intensive
• Destroy the sample
• Toxic reagents
Sampling product for moisture analysis
• Sample from different positions on shelf….and from different shelves
• Useful to sample vials with different dried product appearance (esp. for R&D)
• Obviously any method that could allow 100%inspection has many advantages
Frequency Modulation Spectroscopy (FMS)
FMS-1400 (Lighthouse Instruments)
Measures water and pressure within the headspace of the vial
• The laser light tuned to match internal water absorption frequency
• Laser light absorbed is proportional to the water vapour concentration
Mahajan et al, J. Pharmaceutical Technology, Data and Review, 83, (2005)
FMS / KF moisture correlationWater can have different association/affinity within the freeze dried material which varies with the formulation
For amorphous sucrose the intercept is at 1% w/w by KF
Indicate moisture retained in cake when none observed in headspace.
This is not unsurprising given the hygroscopicity of sucrose
Moisture mapping for Sucrose
Direct shelf contact
• Uniform headspace moisture (HSM)• Lowest 0.2 torr / 1% water KF• Highest 1.0 torr / 1.8% water KF• Average 0.49 torr / 1.3% KF• Standard deviation 0.15
Sucrose-Headspace Moisture
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• Primary drying conducted at -40°C, Vacuum set at 50 mtorr
Shelf front
Moisture mapping for Sucrose
Sucrose-Headspace Moisture
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No direct shelf contact (tray)
• High variation in HSM• Lowest 0.4 torr / 1.2% water KF• Highest 3.2 torr / 4.0% water KF• Average 1.05 torr / 1.9% KF• Standard deviation 0.49
• Primary drying conducted at -40°C, Vacuum set at 50 mtorr
Shelf front
Vial heat transfer in a freeze dryer
Vapour escapes through gap in stopper
Top layer dries first
Freeze dryer shelf
Heat transfer by direct conduction from the shelf to the vial and product Heat transfer by gaseous
convection
Heat transfer by radiation from side Walls of the freeze dryer
Central vials have greater shielding from side wall radiation
This observation can be explained by radiation and shielding effects Edge vial effects bigger at lower temperatures
Factors affecting moisture variationHeat transfer by• Conduction• Gaseous convection
Degree of shelf contact• Tray• Direct shelf contact• Sample container
Radiative heating• Freeze dryer door• Freeze dryer walls• Extent of shielding
• Cycle/processing conditions responsible for observed differences
Samples in a tray
Direct shelf contact
FMS and Karl Fischer moisture correlations
Water may be present in a variety of “forms”/locations – free, adsorbed, chemically bound, hydration shells (e.g. proteins), water of crystallisation
Intercept and gradient vary with the formulation based on intrinsic properties of excipients and active
Moisture mapping variations for Mannitol
Primary drying conducted at -5°C after annealing, vacuum set at 1000 mTorr
• Direct shelf contact• Average Torr 5.24 / ~ 2 % KF• Standard deviation 2.31
• No direct shelf contact (Tray)• Average Torr 4.72 / ~ 2 % KF• Std deviation 1.30
Significant variation within each sample setTray samples have a lower standard deviation – slower cooling rate!Similar moisture content – gaseous convection plays a role!
Moisture mapping variations for Mannitol
Mannitol-Headspace Moisture (Direct)
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Mannitol-Headspace Moisture (Tray)
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Primary drying at -40°C after annealing, vacuum set at 50 mTorr, shortened secondary drying
• Direct shelf contact• Average Torr 10.31 ~ 5%KF• Standard deviation 2.79
• No direct shelf contact (Tray)• Average Torr 9.69 ~5%KF• Standard deviation 2.12
Sample sets have similar moisture content – gaseous convection not a factor
Significant variation within each tray
Mannitol – Frozen structure• Annealing – involves cooling and re-warming of the frozen structure• Encourages crystallisation and growth of larger ice crystals
(slower cooling larger ice crystals)
Structure reduces impact of heat transfer variation due to shelf contact
Gaseous convection not observed as open structure allows for efficient drying
Material structure and treatment can have large impact on moisture
Mannitol – further investigationsFreeze dried mannitol can exist in several forms
• Amorphous mannitol • Crystalline hydrate(s) of mannitol • Anhydrous crystalline mannitol - Alpha (α), beta (β) and delta (δ)
Further analysis and closer inspection of the KF/FMS correlation revealed a deviation and lack of correlation for some samples
This variation appeared to be related to a change in the mannitol form (observed by comparing FMS data over several days)
Mannitol KF vs FMS
y = 0.3191x - 0.0673
R2 = 0.6003
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FMS (torr)
KF
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Mannitol – FMS ratio variations
• Direct shelf contact• Higher ratio change• Random spread
(highest ratio change
towards front half of
tray)
• High level of variation observed• Standard deviation 2.31
• Indicate headspace moisture variation within a shelf could be related to the different proportion
of mannitol crystalline forms
Ratio change= Day 3 / Day 1
Mannitol – FMS ratio variations• No direct contact• Lower ratio change• Random spread
(Higher ratio changes
towards tray edge)
• Lower level of variation observed• Standard deviation 1.30
• Indicate slower heat transfer results in more controlled crystallisation / smaller variation in mannitol form
Ratio change= Day 3 / Day 1
Factors affecting moisture variation
Excipients/active material• Excipients play a critical role in dynamics of water exchange
Processing factors
• Heat transfer efficiency– conduction, convection, container
• Degree of shelf contact e.g. tray/no tray, container shape
• Radiative heating – larger shelves = fewer vials exposed
• Annealed or non-annealed - ice crystal size, pathways for vapour to escape
• Cooling and re-warming rates
• Assess stopper type and treatment (autoclave, sterilisation, drying times)
FMS summary
• Important to fully understand what the moisture result is telling you
• Headspace moisture analysis is a non-destructive method allowing long term monitoring
• Understand moisture variation due to
processing and material choices.
• 100% inspection can assist in
validation and scale up/transfer
Thank you
Any questions?
Isobel CookPrincipal Scientist BSc MRSCBiopharma Technology Limited – specialists in freeze drying research and development
www.btl-solutions.net
Presented during “Emerging Technologies in Freeze Drying”, Cambridge, 11th May 2011. Event
organised by BPS and BTL, www.biopharma.co.uk
www.btl-solutions.net