Spray Drying for Inhaled Dosage Forms CPHI DAVID K. LYON, PH.D. OCTOBER 25, 2017
Market Drivers 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 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 DPI technology 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 2
Major Challenges of Pulmonary Delivery 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. 3
Next Generation of Pulmonary Delivered Drugs Does Require Novel Approaches 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 capsulebased) Inhalation product using porous particles Example: Tobramycin (TOBI, Novartis) 4
Particle Engineering for Traditional Lactose Blends 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 5
Spray Dry Formulation Technology for DPIbased Formulations 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) 6
Complete Inhalation Platform 7
Permeability Starting with Product Design Product concept starts with knowing the molecules attributes and target profile Permeability/Dissolution/Form Mechanism of action Location CLASS II Dose limited Amorphous Fast Crystalline - Slow CLASS III Dose limited Amorphous Slow Crystalline - Slow BCS Classifications CLASS I Low Retention Amorphous Fast Crystalline - Fast CLASS IV Biologics Amorphous Fast Crystalline - Fast Solubility / Dissolution Solubility/Dose in Lung Fluid PRODUCT DESIGN Dose/Technology Depicted figures from: Hastedt ed al. AAPS Open (2016) 2:1 DOI 10.1186/s41120-015-0002-x 8
Compound Properties and PK Drive the Formulation Design 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 9
Complete Inhalation Platform Building on SD expertise to optimize pulmonary drug delivery and bring advanced inhalation therapeutics to market 11
Droplet Surface Spray Dryer Process Overview Atomization Define target particle size ƒ (geometry, pressure) Atomizer Spray Solution Stability versus process time Shear, ph, concentration, interactions Drying nitrogen Drying Conditions Product morphology Water content Physical state ƒ (T In T out M soln M gas ) Drying Chamber Cyclone Collection Efficiency High Value Product ƒ (geometry, product properties) Droplet Spray Solution Surface-active excipients CONFIDENTIAL Hot drying gas contacts droplet Engineered Dry Powder Particles 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 12
Rationale for Excipient Selection Ideally nothing Safety paramount in selection; keep it simple Rationale for Excipients (If Needed) Bulking agent dilution for dose/fill API stabilization Physical Stability Particle dispersability* Bulking or Stabilizing High Tg Sugar Key Properties Nonhygroscopic Competes at air/liquid interfaces, H-bonding to stabilize from heat, shear or water displacement Buffer salts to chemically stabilize product Nonhygroscopic, high T g to limit mobility Hydrophobic component at surface of particle Surface Modification Lactose Trehalose L-Leucine 1,2-Distearoyl-sn-glycero-3-phosphocholine (DSPC) CONFIDENTIAL *Lechuga-Ballasteros et al. J. Pharm. Sci. 2008, 97(1), 287-302 13
Inhalation Platform Breadth of Approaches Heated solvents to drive crystallization and process Organic Solvent for active use water as anti solvent to drive crystallization Aqueous Spray Drying Crystalline Product Heated Solvents To Drive Process Efficiency Suspension Sprays In-line Mixing or Organic Only Aqueous/Organic Co- Solvent Amorphous product Aqueous Spray Drying Amorphous Product 14
Spray-Drying Equipment Scales at Lonza - Bend 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 15
Complete Inhalation Platform Building on SD expertise to optimize pulmonary drug delivery and bring advanced inhalation therapeutics to market 16
DPI Specific Analytical Platform Analytical Tool Kit 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) Product Profile 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 Chemical Stability Laser Diffraction Aerosol Testing 17
Complete Inhalation Platform 18
Encapsulation Development and Scale-up Pre-Clinical Process Development and Early-Phase Clinical Supplies Late Stage Clinical/Commercial Xcelodose 600s 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% Harro Hofliger ModUC MS 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 19
DPI Capsule Customization According to Formulation & Device Multidisciplinary team to support polymer selection and critical parameter specifications according to formulation and device: Polymer Science Production & QC Technical service Regulatory Affairs 20
Capsule for Inhaled Drugs a Customized Approach Wide Polymer Option Customization Services Moisture content Gelatin HPMC + Gelling agent (Vcaps) Stricter microbio limits Gelatin + PEG HPMC (Vcaps Plus) Reduced lubricant Customized weight Tolerance Components enhancing flexibility Customized design for optimal puncturing 21
Summary Integrated Lonza Inhalation Offering Advanced particle engineering expertise based on either jet milling or spray drying Formulation expertise in small Capabilities / Infrastructure 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 Value added services 22
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