nanomaterial
Quality by Design of Drug Products Containing Nanomaterials
Anthony J. Hickey RTI International Research Triangle Park, NC
Overview
Introduction Complexity of product manufacturing Quality considerations Drug Delivery Conclusions
PRODUCTION PROCESS
PRODUCT QUALITY
IN-VITRO, IN-VIVO PERFORMANCE
EFFICACY
T. Crowder, A. Hickey, M. Louey and N. Orr, Introduction to Pharmaceutical Particulate Science, CRC Press, 2003
Statistics/Control Wisdom Knowledge Information Data
Use of statistical method to monitor products Operational control
Overview
Introduction Complexity of product manufacturing Quality considerations Drug delivery Conclusions
Monitoring and Control of elements of the Manufacturing Process Related to Product Quality
A.J. Hickey and D. Ganderton, in Pharmaceutcal Process Engineering, Informa Healthcare, NY, 2010, p206
Product Complexity Nanomaterials are individually complex in terms of: – Components – Function – Performance
As a general category of therapeutic dosage form Nanomaterials – – – – –
Drug (small or large molecular weight) Core/Matrix Components (inorganic/organic) Targeting moieties Solid or liquid state Delivered by any route of administration
Structures Drug Adsorption Or Encapsulation Core
Matrix
Coating
Decoration with Targeting or other moeities
NANOMATERIAL CHARACTERIZATION
Individual nanoparticles exist in • POPULATION (P) of particles • ENVIRONMENT (E)
N
P
E
Observed Characteristic = ƒ(P,E) Additional considerations: • • • • •
Individual Particle Population/sampling Environment Time Measurement technique
= ƒ(P,E,T,M…) 9
LOOKING ACROSS THE CHARACTERIZATION DATA MEASUREMENT PROPERTIES Reference Materials
· · · · · ·
Medical Applications
Meta Data
Toxicological Studies
Environmental Studies
· Particle Size · Size distribution · Surface area · Shape · Composition · Aggregation/ Agglomeration state
Purity Surface chemistry Surface charge Surface reactivity Solubility Stability
PCC Data
12 Physical and Chemical Characteristics
Protocal & Parameters
Information about instrumentation settings
Best Practice Questions
Meta data about measurement technique
A controlled vocabulary of PCC & measurands have been identified 10 I (https://www.nanomaterialregistry.com/resources/Glossary.aspx)
Minimal Information About Nanomaterials
PCC
PCC
Compositio n
Measurement Measurement Type Type DLS Protocols and Technique Parameters (for DLS)
Parameters
Best Practice Questions
Shape
Size
Algorithm used
Surface Area
Size Distribution
Diameter
Size
Aggregation/ Agglomeratio n State
Surface Chemistry
pH of suspensio n
Surface Charge
Stability
Mean Hydrodynamic Diameter
Mean Aerodynamic Diameter
Molecular Weight
Medium Sample type conc.
Viscosity
Surface Reactivity
Size
Temperatur e of suspension
Dispersin g agent
Purity of dispersin g agent
Mean Hydrodynami c Diameter
Number Avg. Molecular Weight
Dispersing agent Concentration of dispersing agent
Sample concentration
Mediu m type
Weight Avg. Molecular Weight
Dispersin g agent
pH
Solubility
Volume Avg. Molecular Weight
Ionic Strength
Purity
Nanomaterial State
… + 9 more Sonication/ Milling power
Sonication/ Milling time
Parameters
Were replicates done? Were controls used? Were protocols used? Was instrument calibrated?
11
DATA INSTANCE OF CHARACTERIZATION
METADATA
PCC MIAN IOC #1 · Time Point (e.g.As As Received) Received) (e.g. · Predecessor Study Data
· Nanomaterial State · Manufacturer Name · As Synthesized Data Record · Laboratory Name · As Received · Product Name · As Processed A, B, C.. · Lot Number PCC MIAN IOC #2 #2· Synthesis Method IOC · DOI Reference to Synthesis (e.g.As As Processed) Processed) (e.g. Study Data · Processing Type TYPES OF IOC
12 I
Overview
Introduction Complexity of product manufacturing Quality considerations Drug delivery Conclusions
Design Space Development
A.J. Hickey and D. Ganderton, Statistical Experimental Design in Pharmaceutical Process Engineering, Informa Healthcare, NY, 2010, p201
Batch/Continuous Processes Unit operations have historically been batch processes where each step introduces a source of error impacting the quality of the product. Continuous processes could be adopted where appropriate where design space dictated by process control dictate product quality.
Overview
Introduction Complexity of Product Manufacturing Quality considerations Drug Delivery Conclusions
Effect of a controlled continuous process
A particle engineering approach was
adopted to achieve optimal morphology and physicochemical characteristics correlating to: (i)controlled aerosol delivery; (ii) controlled dissolution rate and thereby; (ii) controlled action in a guinea pig model of bronchoconstriction
Example – Design Space Development Desired Attributes Biological Effect Modulated Bronchodilatation
Necessary Attributes Encapsulated Primary Particles Aerodynamically Suitable Particles
Drug Substance Attributes Bronchodilator e.g. Ipratropium Bromide
Project Goals Generation of engineered particles of ipratropium bromide (an anticholinergic agent) suitable for aerosol inhalation Develop sustained release properties for particles Targeted delivery of particles to tracheobronchial region of lung Demonstrate modulated bronchodilatation
Sustained Release Strategies Matrix Approach – Soln of hydrophobic excipient in acetone; IPB, glycine in water (50:50) – DPPC, PLGA, PLA
Coating Approach – Suspension of hydrophilic primary particle (IPB/glycine) in acetone with hydrophobic excipient solubilized – DPPC, PLGA, PLA
Buchi Spray Dryer/ Spray Coater Drying
Process Variables
Feedback
Feedback
Feed
B
O2 Sensor
Temp. Heater
Gas Supply
Atomizer
Feed Solns
Condenser Purge Pin
Temp.
Main Drying Chamber
Liquid Collection Vessel
A Cyclone Separator
Collection Vessel (Coarse)
Collection Vessel (Fines)
Feed Conc: • 0.5-5.0%w/v Feed Flow Rate: • 5-16mL/min Atom. Pressure: • 2-4 bar Nozzle Size: • 0.5,0.7,1.0mm Inlet Temp.: • 80-100°C
Taylor et al., 2006 Taylor, MK; Hickey, AH; Van Oort,M. Manufacture,Characterization, and Pharmacodynamic Evalualtion of Engineered Ipratroopium Bromide Particles. Phar Dev Tech, 11:321-336,2006
(a) 5% and (b) 30% PLA Spray Coated SEM Images (a)
(b)
Process Variable Map for Desired Particle Characteristics Overlay Plot 1.00
DESIGN EXPERT Plot
Actual Factors: X = Feedconc
0.50
Y = Feedflow
Feedflow
0.00
Feedflow -1
0
1
5.2
12.6 20
Surface Area: 2.5 -0.50
Particle S2.78731 Surface Ar2.85851 0.97 Particle Size: 3 X Y -0.86
Feedconc -1 0.5
0
Particle S2.81493 Surface Ar3.57414 X -0.98 Y -0.76
1
Particle Size: 2.5 Surface Area: 3.6
2.75 5.0 -1.00
-1.00
-0.50
0.00
Feedconc
0.50
1.00
Taylor et al., 2006
Spray Dried Particles used in Guinea Pig Experiments
Sample
Dissolution T50 (min)
Dissolution T90 (min)
% Released at 1.5min
% Released at 9 min
IPB Neat Drug 5% PLA 15% PLA
1.5 6 55
6 >120 >120
50 27 10
90 50 18
Konzett Roessler Study Design GP* (1) (2) (3) (4)
Treatment ABCD BDAC CADB DCBA
GP* (5) (6) (7) (8)
Treatment ABCD BDAC CADB DCBA
where treatments are as follows: A: 5% PLA Coated Particle – MKT9946 B: 5% Placebo Negative Control – 5% Coated glycine particles C: 30% PLA Coated Particles – MKT9951 D: 30% Placebo Negative Control – 30% Coated glycine particles *guinea-pig
Pulmonary Inflation Pressure Results for Bronchoconstriction * 80
70
60
54
Time (min)
50
40
Time of Onset Duration of Effect 30
Mean,n=3 20
13.5 11
* 9.78
10
1.67
0.33 0 IPB
5% PLA
Particles
30%PLA
*
Summary Spray drying/coating methods used to generate hollow, spherical, porous IPB/glycine particles within respirable range (1-5m). Engineered, sustained release particles were crystalline, demonstrated excellent physicochemical stability and a broad range of release profiles (patent application submitted)
Experimental design techniques were utilized to identify critical manufacturing variables and optimize process to yield desirable particle attributes. In vivo evaluation showed bronchoprotection trends for time of onset, duration of effect for PLA coated particles vs. positive, negative controls
(a) Rifampicin-PLGA (80:20) Lyophilized Nanoparticles. Spray Dried Nanoparticle Shell Porous Particles (b) High and (c) Low Magnification
(a)
(b)
(c) Sung, J. C. et al Pharm Res, 26 (2009) 1847-55.
Conclusion The objective of all development programs is to present the therapeutic agent in a uniform and reproducible manner that is both safe and efficacious. Nanomaterial products are complex and are subject to large testing protocols to establish quality. – The most significant difference from conventional dosage forms is in the controls on the intial stages of production.
Statistical approaches to monitoring and ultimately to control can be adopted. – An example of the influence of one controlled processon a bronchodilator has been given that can be extrapolated to other cases.
Acknowledgements
Michael Taylor, PhD, Michiel VanOort, PhD, Jean Sung, PhD, David Edwards, PhD Lucila Garcia Contreras, PhD Karmann Mills
Anthony J. Hickey RTI International Research Triangle Park, NC
Overview
Introduction Complexity of product manufacturing Quality considerations Drug Delivery Conclusions
PRODUCTION PROCESS
PRODUCT QUALITY
IN-VITRO, IN-VIVO PERFORMANCE
EFFICACY
T. Crowder, A. Hickey, M. Louey and N. Orr, Introduction to Pharmaceutical Particulate Science, CRC Press, 2003
Statistics/Control Wisdom Knowledge Information Data
Use of statistical method to monitor products Operational control
Overview
Introduction Complexity of product manufacturing Quality considerations Drug delivery Conclusions
Monitoring and Control of elements of the Manufacturing Process Related to Product Quality
A.J. Hickey and D. Ganderton, in Pharmaceutcal Process Engineering, Informa Healthcare, NY, 2010, p206
Product Complexity Nanomaterials are individually complex in terms of: – Components – Function – Performance
As a general category of therapeutic dosage form Nanomaterials – – – – –
Drug (small or large molecular weight) Core/Matrix Components (inorganic/organic) Targeting moieties Solid or liquid state Delivered by any route of administration
Structures Drug Adsorption Or Encapsulation Core
Matrix
Coating
Decoration with Targeting or other moeities
NANOMATERIAL CHARACTERIZATION
Individual nanoparticles exist in • POPULATION (P) of particles • ENVIRONMENT (E)
N
P
E
Observed Characteristic = ƒ(P,E) Additional considerations: • • • • •
Individual Particle Population/sampling Environment Time Measurement technique
= ƒ(P,E,T,M…) 9
LOOKING ACROSS THE CHARACTERIZATION DATA MEASUREMENT PROPERTIES Reference Materials
· · · · · ·
Medical Applications
Meta Data
Toxicological Studies
Environmental Studies
· Particle Size · Size distribution · Surface area · Shape · Composition · Aggregation/ Agglomeration state
Purity Surface chemistry Surface charge Surface reactivity Solubility Stability
PCC Data
12 Physical and Chemical Characteristics
Protocal & Parameters
Information about instrumentation settings
Best Practice Questions
Meta data about measurement technique
A controlled vocabulary of PCC & measurands have been identified 10 I (https://www.nanomaterialregistry.com/resources/Glossary.aspx)
Minimal Information About Nanomaterials
PCC
PCC
Compositio n
Measurement Measurement Type Type DLS Protocols and Technique Parameters (for DLS)
Parameters
Best Practice Questions
Shape
Size
Algorithm used
Surface Area
Size Distribution
Diameter
Size
Aggregation/ Agglomeratio n State
Surface Chemistry
pH of suspensio n
Surface Charge
Stability
Mean Hydrodynamic Diameter
Mean Aerodynamic Diameter
Molecular Weight
Medium Sample type conc.
Viscosity
Surface Reactivity
Size
Temperatur e of suspension
Dispersin g agent
Purity of dispersin g agent
Mean Hydrodynami c Diameter
Number Avg. Molecular Weight
Dispersing agent Concentration of dispersing agent
Sample concentration
Mediu m type
Weight Avg. Molecular Weight
Dispersin g agent
pH
Solubility
Volume Avg. Molecular Weight
Ionic Strength
Purity
Nanomaterial State
… + 9 more Sonication/ Milling power
Sonication/ Milling time
Parameters
Were replicates done? Were controls used? Were protocols used? Was instrument calibrated?
11
DATA INSTANCE OF CHARACTERIZATION
METADATA
PCC MIAN IOC #1 · Time Point (e.g.As As Received) Received) (e.g. · Predecessor Study Data
· Nanomaterial State · Manufacturer Name · As Synthesized Data Record · Laboratory Name · As Received · Product Name · As Processed A, B, C.. · Lot Number PCC MIAN IOC #2 #2· Synthesis Method IOC · DOI Reference to Synthesis (e.g.As As Processed) Processed) (e.g. Study Data · Processing Type TYPES OF IOC
12 I
Overview
Introduction Complexity of product manufacturing Quality considerations Drug delivery Conclusions
Design Space Development
A.J. Hickey and D. Ganderton, Statistical Experimental Design in Pharmaceutical Process Engineering, Informa Healthcare, NY, 2010, p201
Batch/Continuous Processes Unit operations have historically been batch processes where each step introduces a source of error impacting the quality of the product. Continuous processes could be adopted where appropriate where design space dictated by process control dictate product quality.
Overview
Introduction Complexity of Product Manufacturing Quality considerations Drug Delivery Conclusions
Effect of a controlled continuous process
A particle engineering approach was
adopted to achieve optimal morphology and physicochemical characteristics correlating to: (i)controlled aerosol delivery; (ii) controlled dissolution rate and thereby; (ii) controlled action in a guinea pig model of bronchoconstriction
Example – Design Space Development Desired Attributes Biological Effect Modulated Bronchodilatation
Necessary Attributes Encapsulated Primary Particles Aerodynamically Suitable Particles
Drug Substance Attributes Bronchodilator e.g. Ipratropium Bromide
Project Goals Generation of engineered particles of ipratropium bromide (an anticholinergic agent) suitable for aerosol inhalation Develop sustained release properties for particles Targeted delivery of particles to tracheobronchial region of lung Demonstrate modulated bronchodilatation
Sustained Release Strategies Matrix Approach – Soln of hydrophobic excipient in acetone; IPB, glycine in water (50:50) – DPPC, PLGA, PLA
Coating Approach – Suspension of hydrophilic primary particle (IPB/glycine) in acetone with hydrophobic excipient solubilized – DPPC, PLGA, PLA
Buchi Spray Dryer/ Spray Coater Drying
Process Variables
Feedback
Feedback
Feed
B
O2 Sensor
Temp. Heater
Gas Supply
Atomizer
Feed Solns
Condenser Purge Pin
Temp.
Main Drying Chamber
Liquid Collection Vessel
A Cyclone Separator
Collection Vessel (Coarse)
Collection Vessel (Fines)
Feed Conc: • 0.5-5.0%w/v Feed Flow Rate: • 5-16mL/min Atom. Pressure: • 2-4 bar Nozzle Size: • 0.5,0.7,1.0mm Inlet Temp.: • 80-100°C
Taylor et al., 2006 Taylor, MK; Hickey, AH; Van Oort,M. Manufacture,Characterization, and Pharmacodynamic Evalualtion of Engineered Ipratroopium Bromide Particles. Phar Dev Tech, 11:321-336,2006
(a) 5% and (b) 30% PLA Spray Coated SEM Images (a)
(b)
Process Variable Map for Desired Particle Characteristics Overlay Plot 1.00
DESIGN EXPERT Plot
Actual Factors: X = Feedconc
0.50
Y = Feedflow
Feedflow
0.00
Feedflow -1
0
1
5.2
12.6 20
Surface Area: 2.5 -0.50
Particle S2.78731 Surface Ar2.85851 0.97 Particle Size: 3 X Y -0.86
Feedconc -1 0.5
0
Particle S2.81493 Surface Ar3.57414 X -0.98 Y -0.76
1
Particle Size: 2.5 Surface Area: 3.6
2.75 5.0 -1.00
-1.00
-0.50
0.00
Feedconc
0.50
1.00
Taylor et al., 2006
Spray Dried Particles used in Guinea Pig Experiments
Sample
Dissolution T50 (min)
Dissolution T90 (min)
% Released at 1.5min
% Released at 9 min
IPB Neat Drug 5% PLA 15% PLA
1.5 6 55
6 >120 >120
50 27 10
90 50 18
Konzett Roessler Study Design GP* (1) (2) (3) (4)
Treatment ABCD BDAC CADB DCBA
GP* (5) (6) (7) (8)
Treatment ABCD BDAC CADB DCBA
where treatments are as follows: A: 5% PLA Coated Particle – MKT9946 B: 5% Placebo Negative Control – 5% Coated glycine particles C: 30% PLA Coated Particles – MKT9951 D: 30% Placebo Negative Control – 30% Coated glycine particles *guinea-pig
Pulmonary Inflation Pressure Results for Bronchoconstriction * 80
70
60
54
Time (min)
50
40
Time of Onset Duration of Effect 30
Mean,n=3 20
13.5 11
* 9.78
10
1.67
0.33 0 IPB
5% PLA
Particles
30%PLA
*
Summary Spray drying/coating methods used to generate hollow, spherical, porous IPB/glycine particles within respirable range (1-5m). Engineered, sustained release particles were crystalline, demonstrated excellent physicochemical stability and a broad range of release profiles (patent application submitted)
Experimental design techniques were utilized to identify critical manufacturing variables and optimize process to yield desirable particle attributes. In vivo evaluation showed bronchoprotection trends for time of onset, duration of effect for PLA coated particles vs. positive, negative controls
(a) Rifampicin-PLGA (80:20) Lyophilized Nanoparticles. Spray Dried Nanoparticle Shell Porous Particles (b) High and (c) Low Magnification
(a)
(b)
(c) Sung, J. C. et al Pharm Res, 26 (2009) 1847-55.
Conclusion The objective of all development programs is to present the therapeutic agent in a uniform and reproducible manner that is both safe and efficacious. Nanomaterial products are complex and are subject to large testing protocols to establish quality. – The most significant difference from conventional dosage forms is in the controls on the intial stages of production.
Statistical approaches to monitoring and ultimately to control can be adopted. – An example of the influence of one controlled processon a bronchodilator has been given that can be extrapolated to other cases.
Acknowledgements
Michael Taylor, PhD, Michiel VanOort, PhD, Jean Sung, PhD, David Edwards, PhD Lucila Garcia Contreras, PhD Karmann Mills
