technobis crystallization workshop · 2018-10-15 · solution crystallization controlled via...
TRANSCRIPT
© 2018 Alkermes. All rights reserved.
© 2018 Alkermes. All rights reserved.
Particle size control during
recrystallization and scale-up Naomi Briggs, Jacklyn O’Neil, Anthony Moffa,
Technobis Crystallization workshop
October 3rd 2018
© 2018 Alkermes. All rights reserved.
Background:
Me, particle size control, crystallization
Problem Statement
Solution: Crystallization development
Scale-up considerations
Drug product: consideration & performance
Summary
2
Outline
© 2018 Alkermes. All rights reserved.
Focused on developing innovative
medicines for the treatment of
central nervous system (CNS)
diseases
Diversified commercial product
portfolio and a substantial clinical
pipeline of product candidates
Research and development
center located in Waltham,
Massachusetts
− Headquarters in Dublin, Ireland
− Research and manufacturing
facility in Athlone, Ireland
− Manufacturing facility
in Wilmington, Ohio
Approximately 2,100 employees
Nasdaq: ALKS
Alkermes: A Global Biopharmaceutical Company 3
Wilmington, OH
Waltham, MA
Dublin, Ireland
Athlone, Ireland
© 2018 Alkermes. All rights reserved.
4
Background - Me
Undergraduate: M.Sci Forensic and Analytical Chemistry
Department of Pure and Applied Chemistry, University of Strathclyde, Glasgow.
Sept. 2006 - June 2010
- Industrial Placement, Reading Science Services, July 2008-2009
- Masters thesis: A structural database for salt selection studies.
Postgraduate: Pharmaceutical Science PhD
Strathclyde Institute of Pharmacy and Biomedical Sciences,
University of Strathclyde, Sept. 2010 – Sept. 2014
Polymorph Control of Pharmaceuticals within a Continuous Oscillatory Baffled Crystalliser
Postdoctoral: Massachusetts Institute of Technology
DARPA Pharmacy on demand (POD) June 2015 – November 2017
Lead Engineer II: Alkermes, Waltham, Massachusetts,
Process development drug substance, November 2017 – Present
© 2018 Alkermes. All rights reserved.
5
Background – Particle size control
Why is it important?
Bioavailability, stability, processability
Typical routes of control:
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6
Background – Crystallization
𝜎 = 𝐶 − 𝐶∗
𝐶∗ C = solution conc. C∗ = equilibrium solution conc. @ constant T & P
𝐽 = 𝑘𝑏𝑆𝑏 𝐺 = 𝑘𝑔𝑆𝑔
Step 1: Nucleation (1y) Step 2: Growth
Approach A
𝐽 = 𝑘𝑏𝑆𝑏 𝐺 = 𝑘𝑔𝑆𝑔
Step 1: Nucleation (1y) Step 2: Growth
Approach B (simplified)
Nucleation controlled through seed addition
Solution crystallization controlled via supersaturation (𝜎) most commonly by temperature and/or antisolvent addition.
𝑱 & 𝑮 are both complex processes
Considerations; Seed generation; Size dependent growth; Breakage (collision breeding/micro attrition); 𝐽 2y (surface breading); Agglomeration
𝑮 is a complex processes
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The Challenge 7
Reactive Crystallization: Base + Acid = Salt (Compound A)
PSD overlay of Compound A manufactured at 2 sites
No PSD control = processability challenges for drug product
© 2018 Alkermes. All rights reserved.
100 μm
The Challenge… Continued.... 8
Jet Mill Sieve fraction
Uni-modal distribution Uni-modal distribution dv50 ~100μm suitable DP processing characteristics
10 μm
10 μm
How to: • Produce uni-modal dv50 ~100μm • Scale the process
Accelerated degradation during stability
Approach: • Controlled recrystallization
Sieving = ~80% material unused per batch
© 2018 Alkermes. All rights reserved.
Crystallization Development 9
1) Identify solvent system (Crystal 16)
Solu
bili
ty (
mg/
ml)
3) Detailed 3D solubility (Crystalline)
2) Kinetic information (Crystalline)
Large MSZW ~25 ˚C (𝜎 1.2)
R2 of 0.987
Solvents
Co-solvent system identified
© 2018 Alkermes. All rights reserved.
Crystallization Development… Continued.... 10
Step 1: Nucleation (1y) Step 2: Growth
Approach A
Large MSZW ~25 ˚C (𝜎 1.2) Investigated: • Various process volumes and operating conditions Result: • Agglomerated product - not individual particles
© 2018 Alkermes. All rights reserved.
Crystallization Development… Continued.... 11
Step 1: Nucleation (1y) Step 2: Growth
Approach B (simplified)
Nucleation controlled through seed addition
𝑮 is a complex processes
Investigated: • Various process volumes and operating conditions Result: • Not individual particles 𝑚𝑖𝑐𝑟𝑜𝑛𝑖𝑧𝑒𝑑
𝑺𝒆𝒆𝒅 𝒎𝒂𝒕𝒆𝒓𝒊𝒂𝒍
𝑛𝑜𝑛 − 𝑚𝑖𝑐𝑟𝑜𝑛𝑖𝑧𝑒𝑑
© 2018 Alkermes. All rights reserved.
𝐽 = 𝑘𝑏𝑆𝑏
Step 1: Nucleation (1y) Step 2: Growth
Crystallization Development… Continued.... 12
x10
x4
x4
After seeding x4 Seed slurry x4
x4
Seed Aggregation
Growth of
agglomerates
Thermal de-
agglomeration
Primary particle
growth
Approach C
+ Step 4: Growth Step 3: Heat +
De- agglomeration? Individual particles?
© 2018 Alkermes. All rights reserved.
Background:
Me, particle size control, crystallization
Problem Statement
Solution: Crystallization development
Scale-up considerations
Drug product: consideration & performance
Summary
13
Outline
© 2018 Alkermes. All rights reserved.
Scale-up Considerations: Mixing 14
Other important considerations: • Plant and equipment tolerances • Sensitivity of the process – critical steps? NOR/PAR • Complexity of the process – can it be simplified?
© 2018 Alkermes. All rights reserved.
Scale-up Considerations: Tolerances 15
0:00:00 0:28:48 0:57:36 1:26:24 1:55:12 2:24:00
Tem
pe
ratu
re (
C)
Time (hours)
“holding” at seed temp °C
6°C
1°C
Low σ High σ
Antisolvent - +
Solvent + -
API (Compound A) - +
Seed temperature + -
Normal charge 0.05 0.68
Critical charge 0.17 0.51
Temperature:
Charges:
- Under charge/ low T, + Over charge/ high T
• Seed T was dropped based on risk
of dissolving seed
• Critical charges narrow σ
• Co-solvent system a challenge, but
possible
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16
Scale-up Considerations: Operation
• GMP requirement for Polish filtration: - Operation driven by solubility & kinetic’s
- max ΔT with solvent composition change
%Antisolvent T Sol. °C ΔT °C
0 >40 50 51 14
67 42 23 75 60 5
Vo
l (%
)
Size (µm)
Dry seeding product
• Ruled out dry seeding • Simplified seed solvent preparation
• Seeding method: - Historically seed with saturated solution - Dry v wet (& wet solvent choice) assessed
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17
Scale-up Considerations: Equipment and mixing
Desire: Mixing insensitive process and/or well understood effect on CQA’s Reality: Mixing effects are complex and not always easy to understand Other considerations:
• CMO Vessel availability • Equipment variation across manufacturing sites
EasyMax 2 L 20 L 115 L
General rule of thumb for efficient mixing: • D/T = ~ 1/2 • C/D = ~ 1/2 • H/D > 1.5 Second impeller should be used D = Impeller diameter T = Tank diameter H= Liquid height C = off bottom clearance.
Handbook of industrial mixing, Science and Practice, E.L. Paul, V. A. Atiemo-Obeng, S. M. Kresta, Wiley, 2004
380 L
H
C
T
D
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18
Scale-up: 2 L mixing study
EasyMax 2 L
20 x scale-up
Size (µm)
Vo
l (%
)
Min Mid Max
Just suspended Mid point Before
cavitation 240 rpm 360 rpm 540 rpm
Transitional Transitional Turbulent
Initial scale-up mixing study suggested mixing insensitivity for the recrystallization process
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19
Scale-up: 20 L mixing study
rpm baffled D50 Yield (%) 120 no - - 250 no 103.9 82.8 250 no 106.4 80.8 210 yes 115.1 72.2 120 yes 129.4 83.0
2 L 20 L
Size (µm)
Vo
l (%
)
10 x scale-up
Build up in 20 L vessel, 120 rpm, baffled, prior to antisolvent addition
© 2018 Alkermes. All rights reserved.
20
Scale-up: Pilot plant production
20 L 115 L
5 x scale-up
Target 100µm Target 100µm
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21
Scale-up: Mixing study 2L
• 3 best trending mixing descriptors • How to inform further scale-up?
HYD RCI PBT
HYD RCI PBT
HYD
RCI
PBT
HYD
RCI
PBT
© 2018 Alkermes. All rights reserved.
22
Scale-up: 30 kg batch
115 L 380 L
4 x scale-up
Target 100µm
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23
Scale-up: 30 kg batch PSD Illustrate some data on improved processability here e.g flow function comparison
Batch 1
Batch 2
Batch 3
Batch 4
Batch 5
Batch 6
© 2018 Alkermes. All rights reserved.
Background:
Me, particle size control, crystallization
Problem Statement
Solution: Crystallization development
Scale-up considerations
Drug product: consideration & performance
Summary
24
Outline
© 2018 Alkermes. All rights reserved.
Various options for isolation and drying during production:
− e.g. clam shell, agitated filter driers, tray drying
− Comilling identified as and addition step prior to packaging
Brief investigation on tip speed and screen size
25
Drug product considerations: De-lumping
Size (µm)
Vo
l (%
)
Size (µm)
Vo
l (%
)
© 2018 Alkermes. All rights reserved.
Drug product: Production improvements 26
Material characterization directing drug product processability include:
PSD, Surface Area, Bulk and Tapped Density, Flow Function, Wall Friction, Permeability
Applied Normal Stress kPa
Perm
eab
ility
x 1
0^9
cm
2
Lot Se
gre
gati
on
an
d
flu
idiz
atio
n r
isk
fact
or
© 2018 Alkermes. All rights reserved.
An addition recrystallization step added for PSD control
Utilized heat cycled for de-agglomeration to insure
production of single particles
Simplified some process steps to reduce manufacturing
risk
Mixing studies to inform best scale-up descriptor
Improved particle properties for drug product
processability
27
Summary
© 2018 Alkermes. All rights reserved.
28
Thank-you!