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Method SelectionHow does understanding ‘why’ measurements are made affect the process of analytical method development?
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What is Quality by Design?
August 13, 2019Title of the presentation2
“A systematic approach to development that begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management…”ICH Q8 (R2)
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What does Quality by Design avoid?
August 13, 2019Title of the presentation3
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Applying QbD to drug product development
Define QTPP
Identify CQAs
Risk Assessment: define CMAs / CPPs
Design Space Definition
Control Strategy
Life Cycle Management
Patient NeedsQTTP: Quality Target Product Profile
CQA: Critical Quality Attributes
Drug Product ControlMaintain QTTP through continuous
assessment of CMAs / CPPs
Drug Product DesignCMA: Critical Material Attributes
CPP: Critical Process Parameters
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Applying QbD to analytical method development
Define QTPP
Identify CQAs
Risk Assessment: define CMAs / CPPs
Design Space Definition
Control Strategy
Life Cycle Management
Analytical Target Profile
Identify Critical Method Attributes
Risk Assessment
Method Design Space Definition
Control Strategy
Life Cycle Management
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Laser diffraction particle size analysis
August 13, 20196
Particle scattering pattern
• Wide measurement range• 10nm – 3.5mm
• Rapid data acquisition rate• Aids understanding of device operation• Provides a good screening technique
Emulsion, suspension and dry powder analysis
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Step 1: Identify Analytical Target Profile
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When is particle size considered a CMA?
No further action
Critical to dissolution, solubility or bioavailability?
Critical to product stability?
Critical to product content uniformity?If ‘yes’ to any of these, measure particle size.
Critical to drug product processability?
Solid dosage formor liquid suspension?
No
Yes
ICH Q6ADecision Tree 3
Critical to maintaining product appearance?
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When is particle size considered a CMA?
BCS Classification Scheme MCS Classification Scheme
Answers the question: do the physical properties of the API fit with bioavailability requirements.
Answers the question: do the physical properties of the API fit with process requirements
Particle size can be predictive within each classification scheme
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When is particle size considered a CMA?
• Focus on continuous manufacturing is increasing
• Move to continuous manufacturing changes the paradigm for OSD product development:
• Old approach: customised processes were designed to fit the specific product, as blockbuster model assumed capital costs for manufacturing system development could be written off over product lifetime
• New approach: standardised processes are applied as this enables lifecycle costs to be minimised.
• Outcome: candidate drug products will not proceed through development if the formulations do not fit available continuous processing methods
13 August 201910
Shift to continuous manufacturing for Oral solid dose products
ConsiGma™ Continuous Tableting Line
‘ConsiGma was developed in compliance with the FDA’s QbD initiative. It satisfies the
industry’s need for reduced risk and higher quality while avoiding lengthy and
costly validation and scale-up to bring products to market faster and cheaper.’
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Step 2: Identify Critical Method Attributes
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Identify Critical Method Attributes
Dr. Henk Merkus, “Quality Assurance in Particle Size Measurement”
Sampling and Dispersion
Analytical Target Profile
Identify Critical Method Attributes
Risk Assessment
Method Design Space Definition
Control Strategy
Life Cycle Management
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Critical Method AttributesSampling
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Critical Method AttributesSampling: mass required for reproducible measurements
Particle size / m
0 500 1000 1500 2000 2500 3000
Min
imum
mas
s / g
0
20
40
60
80
100
density = 1.5g/cm3
Sample mass required to give 95% confidence in the Dv90
Method Estimated max error RSD
Cone & Quartering 22.7% 6.81%
Scoop Sampling 17.1% 5.14%
Table Sampling 7.0% 2.09%
Shute Riffler 3.4% 1.01%
Spinning Riffler 0.42% 0.146%
Random Variation 0.25% 0.075%
From: T. Allen. Particle Size Measurement. Chapman and Hall. 4th Edition, 1993, Page 39. Figures based on 60:40 coarse (420-500µm) : fine (120-250µm) sample mixture
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Critical Method Attributes
Agglomerated Dispersed
Dispersion
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Critical Method Attributes
• Step 1: Chose an appropriate dispersant• Must wet the particles being measured• May require the use of surfactants
• Step 2: Add energy to improve dispersion• Apply ultrasound energy• Use additives to prevent re-agglomeration
• Step 3: Confirm results using an orthogonal method • Image analysis provides a good reference for laser diffraction
Dispersion of samples in liquids
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Critical Method Attributes
• Step 1: control the powder feed rate (concentration)
• Step 2: determine how energy input changes the particle size
• Step 3: Compare the results to an orthogonal technique• A liquid dispersion result or image analysis provides a good reference for
dry powder laser diffraction methods
Dry Powder Dispersion
Dry powder disperser
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Step 3: Risk assessment and MODR definition
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Risk assessment and design space definitionWhen is the performance of a method realistic?
Analytical Target Profile
Identify Critical Method Attributes
Risk Assessment
Method Design Space Definition
Control Strategy
Life Cycle Management
• General advice regarding method reproducibility:
• ISO13320:2009• Take at least 5 readings• Dv50: RSD < 3%• Dv10 and Dv90: RSD < 5%• Below 10 µm, double these values.
• USP <429> and EP 2.9.13• Take at least 6 readings• Dv50: RSD <10%• Dv10 and Dv90: RSD<15%• Below 10 µm, double these values.
• Actual limits should be set based on the requirements for control of the product’s critical quality attributes
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Risk assessment and design space definition
Sampling method
Weighing method Laser alignment
Optical properties
Sonication power / time
Equilibration time following sonication
Measurement time
Humidity
Temperature
Sample transfer to instrument
Sample source / lot
Verification materials
Instrument model
Analysis range
Cleanliness
Sample quantityDispersant source
Particle Sizing
Method
Laser obscuration
Sample preparation
Pump / stirrer speedPre-dispersion method
Dispersant gradeOrthogonal method
Analysis settings
Define experimentallyControlNoise factor
Risk assessment for liquid dispersion methods
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Risk assessment and design space definitionDispersion of samples in liquids: dispersion using ultrasound
after ultrasound
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Risk assessment and design space definitionDispersion of samples in liquids: dispersion using ultrasound
after ultrasound
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Risk assessment and design space definitionDispersion of samples in liquids: dispersion using ultrasound
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4
5
6
7
8
9
20 30 40 50 60 70 80 90 100 110
Dv9
0 (µ
m)
Sonication time (sec)
Risk assessment and design space definitionLiquid dispersion: sonication power and time
UAL
LAL
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Risk assessment and design space definition
August 13, 2019Title of the presentation25
Liquid dispersion: stirrer speed
60
80
100
120
140
160
500 1000 1500 2000 2500 3000 3500
Dv9
0 / µ
m
Stirrer Speed / rpm
UAL
LAL
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Risk assessment and design space definition
August 13, 2019Title of the presentation26
Liquid dispersion: measurement duration
0
1
2
3
4
5
6
7
8
0 5 10 15 20 25
% R
SD (D
v50)
Measurement duration / s
UAL
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Risk assessment and design space definition
Define experimentallyControlNoise factor
Risk assessment for dry powder dispersion methods
Sampling method
Weighing method
Laser alignment
Optical properties
Dispersion pressure
Feed rate
Measurement time
Extraction
Humidity
Temperature
Sample transfer to Instrument
Sample source / lot
Verification materials
Instrument model
Analysis range
Cleanliness
Air supply
Sample quantityAir quality
Particle Sizing
Method
Laser obscuration
Orthogonal method
Analysis settings
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Risk assessment and design space definitionDry powder dispersion: standard disperser pressure titration
Pressure / bar
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0
Size
/ µm
0
100
200
300
400
500
600Dv10Dv50Dv90
Orthogonal method Dv90
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Risk assessment and design space definitionDry powder dispersion: standard disperser pressure titration
Pressure / bar
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0
Size
/ µm
0
100
200
300
400
500
600Dv10Dv50Dv90
Orthogonal method Dv90
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Step 4: Control
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Method ControlUSP<429> guidance for methods validation
Analytical Target Profile
Identify Critical Method Attributes
Risk Assessment
Method Design Space Definition
Control Strategy
Life Cycle Management
• The system’s accuracy should be assessed using a certified reference material
• The precision and robustness of the method should be assessed
• Assurance should be provided that the data generated are reproducible and control the product’s quality.
• Method precision assessment from USP<429>• Take at least 6 readings• Dv50: RSD <10%• Dv10 and Dv90: RSD<15%• Below 10 µm, double these values.
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Method controlUSP<1225> guidance for method validation
• USP<1225>: elements of validation for compendial procedures
Particle sizing methods
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Method control
Sample Dv10 / µm Dv50 / µm Dv90 / µm1 1.22 23.68 63.23
2 1.17 23.77 60.02
3 1.09 22.79 56.59
4 1.16 23.63 62.55
5 1.11 22.26 59.68
6 1.18 22.78 65.36
7 1.12 23.41 61.47
Mean 1.15 23.19 61.27RSD (%) 3.95 2.50 4.63
Sample Dv10 / µm Dv50 / µm Dv90 / µm1 1.06 22.92 61.01
2 1.08 22.08 56.54
3 1.04 21.66 62.17
4 0.97 22.55 60.23
5 1.04 22.74 57.98
6 0.99 23.58 59.86
7 0.95 22.11 62.78
Mean 1.02 22.52 60.08RSD (%) 4.79 2.83 3.69
Control: precision for different operators
Pooled data Dv10 Dv50 Dv90Mean / µm 1.08 22.85 60.68
Standard Deviation 0.082 0.68 2.52RSD (%) 7.6% 3.0% 4.2%
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Method controlSetting product control limits
How to Establish Manufacturing Specifications, Donald J. Wheeler, Statistical Process Controls Inc. Posted on spcpress.com
Particle SizeProduct Specification
Measurement Specification
Upper Product Acceptance Limit
Lower Product Acceptance Limit
Lower Measurement Limit
Upper Measurement Limit
σσσ = measurement error
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Method control
• Must tighten specifications to account for measurement variation:
• USP<429>: 10% for any central value15% for any value at the distribution edges
• D[4,3]: (80 x 1.1 = 88) Spec > 88 microns• Dv10: (30 x 1.15 = 34.5) Spec > 34.5 microns• Dv90: (1000 x 0.85 = 850) Spec < 850 microns
Evolutions in Direct Compression, Douglas McCormick, Pharmaceutical Technology, April 2005. Pg 52-62
Setting product control limits
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Summary
• Realistic method definition
• Improved method robustness
• Increased probability of method transfer success
• Ease of lifecycle management• Regulatory flexibility for method adjustments within
the Method Design space• Reduced risk of specification changes during
equipment upgrades
Benefits of applying AQbD
Analytical Target Profile
Identify Critical Method Attributes
Risk Assessment
Method Design Space Definition
Control Strategy
Life Cycle Management
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References
• Quality by design in analytical method development and validation• Priyanka P. Pande et al, J Environ Life Sci. June 2017; Vol. 2 (Issue 2): 39-45.
• Using the Analytical Target Profile to Drive the Analytical Method Lifecycle• Phil Borman et al, Analytical Chemistry, January 2019
• Quality by Design Approaches to Analytical Methods - FDA Perspective • Yubing Tang, Ph.D., FDA/CDER/ONDQA. AAPS, Washington DC, October 25, 2011
• A Quality by Design Approach for Particle Size Analysis of an Active Pharmaceutical Ingredient• Julie T. Adamson, Ph.D., American Pharmaceutical Review, July 2, 2013.
• Analytical Quality by Design (AQbD) in Pharmaceutical Development• George L. Reid, Ph.D et al, American Pharmaceutical Review, August 27, 2013.
• Implementation of QbD Approach to the Analytical Method Development and Validation for the Estimation of Propafenone Hydrochloride in Tablet Dosage Form• Monika L. Jadhav and Santosh R. Tambe, Chromatography Research International Volume 2013, Article ID 676501
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