Designing Amorphous Formulations and Manufacturing ...
Transcript of Designing Amorphous Formulations and Manufacturing ...
Designing Amorphous Formulations and Manufacturing Processes for Challenging Compounds
Michael Grass | Principal Scientist, Lonza - Bend
Michael Grass | 8th American DDF Summit | 2018 SEP 11
• a
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Flexible Model Across the Product Development Cycle
Small Molecule Technologies
DESIGNSmall / Lab-Scale (non-GMP)
DEVELOPClinical Scale
MANUFACTURECommercial Scale
Drug Substance Intermediates – early and GMP intermediates
Drug substances – full range of API inclusive of HPAPI, cytotoxic payloads for ADC’s
Drug Product Intermediates – multiparticulates (MP), micronized API, spray dried dispersions
Drug Products - tablets (IR and MR), encapsulated powder and MP, soft gels, liquid-fill hard caps
> 300Projects
> 200Products
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Our Global Development & Manufacturing Network
3 Regions | 8 Sites
• Full Chemistry Capability
• Integrated Drug Product Development
APAC
Nansha, China
Europe
Edinburgh, UK
Ploermel, France
Molinazzo, Switzerland
Visp, Switzerland
North America
Bend, OR
Quakertown, PA
Tampa, FL
DPI and Drug Product
API
Problem Statement Definition
Michael Grass | 8th American DDF Summit | 2018 SEP 11
Formulation Selection
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Low Bioavailability Has Many Causes
Barriers to Absorption
P.B. Shekhawat, V.B. Pokharkar. Acta Pharmaceutica Sinica B, 2017, 7 (3), 260 - 280
• Solubility
• Dissolution rate
• Unstirred water layer (UWL) diffusion
• Epithelial membrane permeability
• Efflux
• Metabolism
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70-80% of drugs in pharmaceutical pipeline are low solubility
Biopharmaceutical Classification System
2008;7:255–270
IIA Dissolution Rate
Limited
IIB Solubility Limited
Butler, J., Dressman, J. J. Pharm. Sci., 2010
500
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Important Considerations for Pre-formulation Assessment
Solubility1. Crystalline Aqueous
2. Amorphous Aqueous3. Crystalline Organic
Aqueous Solubility Challenge1. Lipophilicity/Micelle partitioning
2. Melting point/Crystal lattice energy (i.e. “brick dust”)
Permeability1. Molecular Descriptors
(e.g. MW, rotatable bonds, charge state)
2. Caco-23. Perfusion
Metabolism/Efflux
Pharmacokinetics Absolute BA
1.BA dose dependence2.Food effect
3. Gastric pH effect
Target Product Profile1. Dose
2. Dosing Frequency3. In vivo model (e.g. rat,
dog, monkey, human, etc.)
Chemical Stability1. Labile functional groups
2. Forced degradation
Physical Stability1. Thermal Properties
(e.g. Tm, Tc, Tg)2. Water Uptake
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Goal: efficiently arrive at product development with certainty of approach
Problem Statement Definition Guides Technology Choice
SDD
LIPIDIC
NXSTAL
Product Concept
Molecular Properties
Predictions
Technology & Formulation
In vitro, in silico, & in vivo testing
Problem Statement
HME
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Many Enabling Technologies Are Available
H.D. Williams et al. “Strategies to Address Low Solubility in Discovery and Development,” Pharmacol. Rev., 65(2013)315-499
Amorphous
• Solid dispersions
• SDD
• HME
• Lyophiles
• Drug/polymer nanoparticles
• Pure amorphous drug
Size Reduction
•Micronization
• Sub-micron crystals (100 to 800 nm)
• Nanocrystals (<100 nm)
• Cosolvents
• Surfactants
• Cyclodextrins
• Lipids:
• Oils
• SEDDS/SMEDDS
• Lipid Multiparticulates
Solvation
• Polymorphs
• Cocrystals
• Salts
Crystal Form
•Molecular modification
• Pro-drugs
Molecular Design
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Conceptual Guidance Map for Technology Selection Based on Molecular Properties and Dose
H.D. Williams et al. “Strategies to Address Low Solubility in Discovery and Development,” Pharmacol. Rev., 65(2013), 315-499
Historic focus on defining key parameters
impacting choice of technology in meeting target product
profiles
Thousands of compounds studied and modeled over 20+ years
Multiple reference maps developed for key API and formulation
parameters
Specialized in-vitro test methods developed
to characterize candidate compounds
Rapid technology selection methodologies reduce
empirical testing and API requirements
Solu
bili
ty (
mg
/mL)
LogP
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Performance
ManufactureStability
Formulation Selection Criteria
Performance:• Prediction of in vivo performance• Can the technology achieve required PK
performance?• Dose, dosage form, etc.
Stability• Chemical stability• Physical/performance
stability• Stability risk (ability to
model with accelerated studies)
Manufacturability• Scale-up considerations• Cost of goods• Required batch size
Formulation Feasibility
Formulation Dev.
In-Vitro Tests
Stability Mapping
Identify
CQA and CPP Relationship
Fix Formulation
Formulation and Process History
RISK ASSESSMENTS
Scale-up
ID Commercial
Process
Define Commercial Operating
Space
Scale-Up
Knowledge
Pro
cess C
on
trol
Strategy
Co
mp
ou
nd
P
rop
erti
es
Small Scale Experiments
Predictive Models
(Performance, Stability,
manufacturing)
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Spray Dried Amorphous Dispersions
Simplified Product Development Flow Chart
Animal Studies Clinical Studies
- Formulation Optimization
- Dose
- Dosage Form
Late Stage Clinical
- Commercial Quantity
- Commercial Image
- Business Drivers
- Cost of Goods
- Filing Strategy
Pre-Clinical Phase 1/2A Phase 2B/3 Commercial
- Biomodel
- Lead Compound ID
- Physical form
- Process Validation
- Process Monitoring
- Process Verification
Commercial Readiness
Spray Drying at Lonza - Bend
Michael Grass | 8th American DDF Summit | 2018 SEP 11
Spray Dryer Scales
Solv
ent
Excipients API
SolventTank
SolutionTank
Process Heater
Condenser
Baghouse / Police Filter
System Gas Blower
Cyclone
ProductCollection
System Gas Blower
Feed Pump
DryingChamber
Atomizer
Secondary Dryer
Closed Loop / Recycle Equipment
0 1 2 3 40%
1%
2%
3%
4%
Drying Time [hours]
Wt%
So
lve
nt
SolventPolymer
Active
Solution TankSolvent Tank
Feed Pump
Cyclone BaghouseDrying
Chamber
Process Heater
Condenser
Product
Collection
System Gas
Blower
System Gas
Blower
Atomization
Drying Kinetics
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Spray-Dried Dispersion Equipment and Process Schematic
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A Spray dryer is a spray dryer……
Spray Dryer Scalability – Why is it important?
• Feasibility and formulation screening dryers often have limited operating space (Small particles and fast drying)
• Ideally the manufacturability assessment happens as close to discovery as practical and may be strongly coupled with the formulation selection process• Understanding limitations early can reduce scale-up surprises later• Custom equipment designed for feasibility to keep properties in same ball park of future
clinical/commercial expectations• Offline tools and models for scale-up for larger scale spray dryers
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Spray-Dried Dispersion (SDD): Equipment Scale Range
Late Stage Clinical/CommercialProcess DevelopmentToxicology and Early-Phase Clinical Supplies
FormulationIdentification
Mini Spray Dryer25 mg → 1 g
Lab Spray Dryer(<35 kg drying gas/hr)
0.5 g → 100 g
Lab to Pilot Scale (“PSD-1” <150 kg drying gas/hr)
5 g → 5 kg
Pilot to Commercial (“PSD-2” < 750 kg drying gas/hr)
kgs → tons
Pilot to Commercial (NGD <200 kg drying gas/hr)
kgs → tons
Confidential | 28 August 2018
High On-timeSmall Footprint
Continuous Solution Prep
Case Study #1
Michael Grass | 8th American DDF Summit | 2018 SEP 11
Amorphous Itraconazole Formulations: Room
for Improvement?
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Amorphous Itraconazole (ITZ) is well absorbed relative to
crystalline ITZ
Amorphous RFP – Sporanox® (HPMC SLD)
Amorphous Dispersion (Soluplus HME)
Nanocrystals
Bulk Crystals
Is there room at the top?
Zhang et al. Eur J Pharmaceutics Biopharmaceutics (2013) 85 (3), 1285-1292
Itraconazole pH 6.5 Solubility (µg/mL)
Buffer FaSSIF
Crystalline < 10-3 0.07
Amorphous < 1 7 - 10
100x Amorphous Enhancement
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Dimensionless numbers can predict impact of solubility, permeability or dissolution rate in vivo
FaCS Ref: Sugano, K., et al., J Pharm Sci. (2015), 104, 2777-2788
Solubility-permeability limited
Τ𝑃𝑛 𝐷𝑜 < 𝐷𝑛 & 𝐷𝑜 > 1
𝑃𝑛 < 𝐷𝑛 & 𝐷𝑜 < 1
Permeability-limited
𝐷𝑛 < 𝑃𝑛/𝐷𝑜
Dissolution-limited
Amorphous Itraconazole
ItraconazoleBCS II basepKa = 3.7cLogP = 6.3
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Can a “better” amorphous dispersion be made via formation of nanoparticles?
Room at the Top?
Itraconazole pH 6.5 Solubility (µg/mL)
Buffer FaSSIF
Crystalline < 10-3 0.07
Amorphous < 1 7 - 10
100x Amorphous Enhancement
Mucus layer diffusion α r-1
100 nm
5 nm
1 nm
Dissolved drug
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Amorphous spray dried dispersions (SDDs) of Itraconazole(ITZ) dosed to rats
+ItraconazoleBCS II basepKa = 3.7cLogP = 6.3
OH
H
CH2OR
H
ORH
OR H
OH
H
H
ORH
OR
CH2OR
H
O
O
n
R= -H-CH3-COCH3
-COCH2CH2CO2H-CH2CH(OH)CH3
-CH2CHCH3
OCOCH3
-CH2CHCH3
OCOCH2CH2CO2H
Hydroxypropyl MethylcelluloseAcetate Succinate (HPMCAS)
Formulations dosed to ratsSprague-Dawley (n=6), fastedDose: 50 mg/kgDosing vehicle: 0.5% Methocel A4Min H2ODosing route: oral gavage
Stewart, A.M., et al. Mol Pharmaceutics (2017), 14 (7), 2437-2449
25% activeHydrophilic SDDAffinisol 716HP
25% activeHydrophobic SDDAffinisol 126HP
or
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Material sparing in vitro membrane flux test can assess solubility-permeability limited absorption
Accurel PP 1E membrane (55% porous, 100 µm thickness)
50 µL lipid (20% phospholipid in dodecane)
Feed Volume: 5 mLReceiver Volume: 10 mL
SA: 4.9 cm2
SA/V = 1.0 cm-1
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Hydrophilic SDD has the highest flux in vitro
Flux (µg/min/cm2) Colloid (µg/ml)
1.18 602
0.85 150
0.53 0
No. Formulation Dispersion polymer
1 25% ITZ/75% HPMCAS SDD AFFINISOL 716HP
2 25% ITZ/75% HPMCAS SDD AFFINISOL 126HP
3 Sporanox® spray layered dispersion HPMC
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Hydrophilic SDD shows the fastest absorption in rats – rank orders with in vitro performance
Case Study #2
Michael Grass | 8th American DDF Summit | 2018 SEP 11
Spray Drying Poly(methyl methacrylate-co-
methacrylic acid), PMMAMA [Eudragit L and S]Dr. Kim Shepard
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Enabling improved physical stability and higher loading amorphous formulations
Eudragit L100: A high Tg enteric polymer
Improved Physical Stability Higher Loading, Improved Performance
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Enteric Polymers with different properties and applications
PMMAMA HPMCAS
Structure
Trade Name(s)Eudragit® L100, S100, L100-55 (Evonik
Industries)
Affinisol® 912, 716, 126 (DOW)AQOAT® HPMCAS-L, M, H (Shin Etsu)
AquaSolve™ (Ashland)
Tg (°C) 190 115 – 120
Acid Substitution (mmol/g) 4.2 – 5.6 0.7 – 1.5
MW (kg/mol) 125 50
Comparison of PMMAMA and HPMCAS
OH
H
CH2OR
H
ORH
OR H
OH
H
H
ORH
OR
CH2OR
H
O
O
n
R= -H-CH3-COCH3
-COCH2CH2CO2H-CH2CH(OH)CH3
-CH2CHCH3
OCOCH3
-CH2CHCH3
OCOCH2CH2CO2H
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Strings form during spray drying using typical spray drying conditions, leading to poor flow and powder properties
Spray Drying Eudragit L100 Using “Standard Conditions”
Lefebvre model for atomization
Sheets Filaments Droplets
◼ High MW ◼ High Tg
◼ “Skinning” occurs at a lower concentration than typical spray drying polymers
λL = 5-10 µm
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Two characteristic times govern string formation
Model-based parameters to control string formation
Droplet skinning time
Solution concentration
Drying gas temperature
Solvent Volatility
Solution Temperature
Recycle (% RS)
Droplet break-up time
Atomization pressure
Nozzle geometry
Solution viscosity
Experimental “Handles”
Strings form when tskinning < tbreakup
Droplet skinning time
Droplet break-up time
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Inlet Temperature & Solids Concentration
Adjusting String Formulation Through Process Handles
31
Increasing inlet temperature (BLD: 125, 160, 195°C)
Increasing solution concentration (NGD: 5, 7, 9%wt)
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Qualitative & Quantitative Approach to Process Design
Inlet temperatureSolution concentration
Solvent volatilityDrying gas flow rateRecycle (wet) drying gasAtomization pressure (pressure swirl)
Solution temperatureAtomization pressure (2-fluid)*
*Depends on dryer scale
Strong effect
Weakeffect
𝐷𝑆𝑃 =
𝑇𝑖𝑛𝑙𝑒𝑡−𝑇𝑏𝑜𝑖𝑙𝑇𝑏𝑜𝑖𝑙
𝐶𝑠𝑘𝑖𝑛−𝐶𝑠𝑜𝑙𝑛𝐶𝑠𝑘𝑖𝑛
1.25 ∆𝐻𝑣𝑎𝑝
540
.75
Tinlet is the inlet temperature of the drying gas, in °C Tboil is the boiling point of the solvent, in °CCskin is the concentration of the Eudragit L100 solution, in wt%, at which skinning occurs (~15% for most solvents)Csoln is the concentration of the feed solution, in wt%ΔHvap is the standard enthalpy of vaporization, in J/g. It is normalized by 540 to bring its order of magnitude close to 1 and standardize its contribution to the other terms in the equation.
Empirical Dimensionless Solvent Parameter (DSP) to guide process selection
33
Process Space for Eudragit L100 Spray Drying on a PSD-1
Constant parameters: PSD-1, Methanol, 1850 g/min gas, SK80-16 nozzle, 400psi, single-pass
34
Secondary drying Eudragit L100 SDDs at 40°C/15% RH
Problem: • Drying of solvents other than MeOH is
unacceptably slow
Solutions: • Hotter/wetter drying (if chemical
stability is acceptable)• Methanol-assisted secondary drying