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

16

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