spray drying for inhaled dosage forms · spray-drying equipment scales at lonza - bend david k....
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Spray Drying for Inhaled
Dosage Forms
CPHI | DAVID K. LYON, PH.D. | OCTOBER 25, 2017
Market Drivers
David K. Lyon, PH.D. | CPHI | October 25, 2017
“Although MDIs are the market leader with 48% of retail sales in Europe versus 39% for DPIs and only 13% for nebulisers, they are gradually losing their popularity to be replaced by technically superior and more ecofriendly DPIs”.
Inhaled Drug Products DPI technology
• large & growing prevalence of COPD / Asthma
• utilization of lung’s absorptive capacity for treating systemic conditions
• attractive delivery alternative for some large molecule / biologics
• high barrier to generic competition due to proprietary devices
• can be superior to pMDI from drug delivery efficiency perspective
• ease of use
• ecofriendly vs. traditional pMDI using aerosols
• offers life cycle management / delivery alternative vs. pMDI, nebulizers
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Major Challenges of Pulmonary Delivery
David K. Lyon, PH.D. | CPHI | October 25, 2017
• Delivery level of the nominal dose or level of actual lung deposition
• Lack of reproducibility in the deposition site of the administered dose
• Particle size, shape, surface is key for product performance
• Reduce kinetic speed of small dense particles - settlement in upper airways
• Expiration or mucocillary transport – membrane interaction
• Inhaler misuse by the patient, exacerbated by the specialty, tailored nature of devices
• Overall cost per treatment
A very different situation in comparison to greater surface uniformity of the small intestine.
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Next Generation of Pulmonary Delivered Drugs Does Require Novel Approaches
David K. Lyon, PH.D. | CPHI | October 25, 2017
Today, formulations are dominated by carrier blend formulations
• Micronized API (jet milling) to range of 2 to 5 microns , 80-90% Fine Particle Fraction (FPF)
Next Generation product challenges
• Complex biologiocal material (peptides, proteins, olionucleotides, cell and gene therapy)
• Molecules that cannot be milled• Incompatibility with lactose/excipient
flexibility• Solubility or stability with water/HFA• Very high dose (up to 1500 mg/day)• Need to tune PK / stability based on
amorphous or crystalline format• Need for drug sparing processes during
feasibility and scale-up• Compatibility with wide range of DPI
devices (reservoir, blister or capsule-based)
Inhalation product using porous particlesExample: Tobramycin
(TOBI®, Novartis)
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Particle Engineering for Traditional Lactose Blends
David K. Lyon, PH.D. | CPHI | October 25, 2017
• Full range of spiral jet mill micronizing equipment
• Vertical, horizontal and loop milling
• Experience in routinely meeting required PSD
• Provides the > 80% fine particle fraction (FPF) desired
• Particle size uniformity to targeted 2.5 micron
•High containment micronization for highly potent or sensitive compounds
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Spray Dry Formulation Technology for DPI-based Formulations
David K. Lyon, PH.D. | CPHI | October 25, 2017
SD technology offers several advantages vs. historic lactose blend technology used in DPI based formulations
• Efficiency – more drug delivered / less wastage
• Tighter particle size distribution / 80-90% fine particle fraction (FPF) desired
• Greater particle size uniformity to targeted 2.5 micron
• Flexibility – fewer formulation dependencies
• Not dependent upon crystalline drugs
• Not dependent upon lactose compatibility
• Not dependent on aerosol compatibility
• Not dependent upon jet milling
• Can deliver proteins (avoids Maillard reaction)
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Complete Inhalation Platform
David K. Lyon, PH.D. | CPHI | October 25, 2017 7
Starting with Product Design
David K. Lyon, PH.D. | CPHI | October 25, 2017
Product concept starts with knowing the molecules attributes and target profile
Depicted figures from:Hastedt ed al. AAPS Open (2016) 2:1DOI 10.1186/s41120-015-0002-x
PRODUCT DESIGN
Permeability/Dissolution/Form Mechanism of action Location
Solubility/Dose in Lung Fluid Dose/Technology
BCS Classifications
Solubility / Dissolution
CLASS ILow Retention
Amorphous – FastCrystalline - Fast
CLASS IVBiologics
Amorphous – FastCrystalline - Fast
CLASS IIIDose limited
Amorphous – SlowCrystalline - Slow
CLASS IIDose limited
Amorphous – FastCrystalline - Slow
Pe
rmea
bili
ty
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Compound Properties and PK Drive the Formulation Design
David K. Lyon, PH.D. | CPHI | October 25, 2017
• Modulating particle properties through formulation and or process design
• Understand impacts for PK, physical stability etc.
• Key Properties to Consider
• Aqueous and organic solvent solubility (or lack thereof for anti-solvent concepts)
• Preferred physical form
• Hydrophobicity
• Tm, Tg, and pkA
• Dose
Formulation Approach Based on Compound Properties
Formulation Approach Based on PK
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David K. Lyon, PH.D. | CPHI | October 25, 2017
Building on SD expertise to optimize pulmonary drug delivery and bring advanced inhalation therapeutics to market
Complete Inhalation Platform
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Spray Dryer Process Overview
David K. Lyon, PH.D. | CPHI | October 25, 2017 | CONFIDENTIAL
AtomizationDefine target particle sizeƒ (geometry, pressure)
Drying Conditions• Product morphology• Water content
• Physical state• ƒ (TIn Tout Msoln Mgas)
SpraySolution
Surface-active excipients
Droplet
Atomizer
Drying Chamber
Spray SolutionStability versus process timeShear, pH, concentration, interactions
Drying nitrogen
Collection EfficiencyHigh Value Productƒ (geometry, product properties)Cyclone
Engineered Dry Powder Particles
Dro
ple
t Su
rfac
e Hot drying gas contacts droplet
Neat API
Amorphous API/Excipient
Crystalline API/Excipient
Mixed Approaches
Single Solvent Solution
Single Co-Solvent Solution
Single, Dual, or Variable Process Settings – Solution or Suspension
Single, Dual, or Variable Process Settings – Solution or Suspension
12David K. Lyon, PH.D. | CPHI | October 25, 2017
Rationale for Excipient Selection
Surface Modification
David K. Lyon, PH.D. | CPHI | October 25, 2017 | CONFIDENTIAL
Rationale for Excipients (If Needed) Key Properties
Bulking agent – dilution for dose/fill Nonhygroscopic
API stabilization Competes at air/liquid interfaces,H-bonding to stabilize from heat, shear or water displacementBuffer salts to chemically stabilize product
Physical Stability Nonhygroscopic, high Tg to limit mobility
Particle dispersability* Hydrophobic component at surface of particle
Bulking or Stabilizing High Tg Sugar
Ideally nothing – Safety paramount in selection; keep it simple
Lactose Trehalose L-Leucine 1,2-Distearoyl-sn-glycero-3-phosphocholine (DSPC)
*Lechuga-Ballasteros et al. J. Pharm. Sci. 2008, 97(1), 287-302
13David K. Lyon, PH.D. | CPHI | October 25, 2017
Inhalation Platform – Breadth of Approaches
David K. Lyon, PH.D. | CPHI | October 25, 2017
Heated SolventsTo Drive Process Efficiency
Aqueous Spray DryingAmorphous
Product
Heated solvents to drive crystallization and process
Organic Solvent for active – use water as anti solvent to drive
crystallization
Aqueous Spray Drying Crystalline
Product
Aqueous/Organic Co- SolventAmorphous product
Suspension Sprays
In-line Mixing or Organic Only
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Spray-Drying Equipment Scales at Lonza - Bend
David K. Lyon, PH.D. | CPHI | October 25, 2017
Modular Facility Design
• Modular spray dryer
• Designed for inhalation spray drying
• 0.2g to tons: no scale-up pre-clinical through commercial)
• High on time – Run longer
• Niche high value product and/or Variable commercial volumes/estimates
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Complete Inhalation Platform
David K. Lyon, PH.D. | CPHI | October 25, 2017
Building on SD expertise to optimize pulmonary drugdelivery and bring advanced inhalation therapeutics to market
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DPI Specific Analytical Platform
David K. Lyon, PH.D. | CPHI | October 25, 2017
Imaging• Optical microscopy
• Scanning electron microscopy (SEM)
Particle Size/Aerosol Performance• Laser diffraction (GPSD)
• Impaction (NGI)
• Dose Content Uniformity
Hygroscopicity• Dynamic vapor sorption (DVS)
• Karl Fischer (KF)
Thermal• Modulated Differential Scanning
Calorimetry mDSC
• pXRD
• Iso-calorimetry (TAM)
Morphology• Lack of agglomeration
• Surface morphology
Particle Size • Geometric Particle Size – 1.5 to 3.5µm
• Aerosol Performance – Product dependent deposition profile
Water Analysis• Water Uptake Equilibrium
• Water Content ~ 2-6%
Physical stability• Amorphous versus Crystalline
• Crystal size
• Predictive Stability
Analytical Tool Kit Product Profile
Chemical Stability
LaserDiffraction
AerosolTesting
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Complete Inhalation Platform
David K. Lyon, PH.D. | CPHI | October 25, 2017 18
Late Stage Clinical/Commercial
Encapsulation Development and Scale-up
• Suitable for early clinical development (Ph. 1 to 2a)
• 200-300 CPH for engineered particles
• Gravimetric filling mechanism (100% weight check)
• Bulk sparing
• Early phase dose range flexibility (e.g. same process/equipment can fill multiple doses)
• ~1mg to 10’s of mgs
• RSD <3%
• Suitable for late stage through commercial
• 72,000 CPH
• Volumetric drum microdosing (~5mg to 10s of mgs)
• Ideally suited for cohesive engineered particles with difficult handling properties
• In-line capacitance weight monitoring, with individual lane diagnostics
• RSD <3%
• Suite with <10%RH control
David K. Lyon, PH.D. | CPHI | October 25, 2017
Xcelodose 600s Harro Hofliger ModUC MS
Process Development and Early-Phase Clinical SuppliesPre-Clinical
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DPI Capsule Customization According to Formulation & Device
David K. Lyon, PH.D. | CPHI | October 25, 2017
Multidisciplinary team to support polymer selection and critical parameter specifications according to formulation and device:
• Polymer Science
• Production & QC
• Technical service
• Regulatory Affairs
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Capsule for Inhaled Drugs – a Customized Approach
David K. Lyon, PH.D. | CPHI | October 25, 2017
Wide Polymer Option Customization Services
Gelatin Gelatin + PEG
HPMC + Gelling agent (Vcaps)
HPMC (Vcaps Plus)
Stricter microbio limits
Reduced lubricant
Customized design for optimal puncturing
Components enhancingflexibility
Customized weight Tolerance
Moisture content
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SummaryIntegrated Lonza Inhalation Offering
• Advanced particle engineering expertise based on either jet milling or spray drying
• Formulation expertise in small
• molecules and biologics using SD technology
• PSD capacity to scale, from POC to commercial manufacture
• High potency handling / isolation capability
• Comprehensive specialized analytical / CMC platform
• Dedicated Xcelodose 600 System for POC / Ph. II studies
• Dedicated HH system for late clinical & commercial encapsulation
• Integrated product development based on SD technology
• Feasibility / POC studies
• Clinical and commercial manufacture of SD-based product concepts
• Clinical and commercial encapsulation
• Specialized product characterization
• Micronization for carrier-based inhalation formulations
• Specialized DPI capsules
David K. Lyon, PH.D. | CPHI | October 25, 2017
Capabilities / Infrastructure Value added services
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Three Sisters at DawnBend, Oregon USA