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11
In-Process Particle Size Analysis:
Regulatory Perspective
Zhigang Sun, Ph.D.
Office of Generic Drugs
OPS/CDER/FDA
Opinions expressed in this presentation are those of the speaker and do not necessarily reflect the views or policies of the FDA
PQRI Workshop on Sample Sizes for Decision Making in New Manufacturing Paradigms
Bethesda, MD /September 13, 2011
2
Outline Introduction
In-Process Particle Size Analysis
Regulatory Considerations
Concluding Remarks
3
Particle Size in Pharmaceutics
How do we describe a 3D particle with one parameter only?
Dispersion process and complex shapes of particles make particle size analysis more difficult.
4
Equivalent Particle Diameter
Alan Rawle, The Basic Principles of Particle Size Analysis
Each diameter represents a specific property of the particle.
Do not compare particle sizes measured by different techniques.
Choose right particle sizing technique for your application.
5
Particle Size Distribution
In general, narrow particle size distribution (PSD) is desired
– Segregation occurs primarily as a result of size differences.
For a broad size distribution, it is important to control the whole PSD rather than mean size only.
– Fine particles: agglomeration, poor flowability, dust etc.
– Coarse particles: low dissolution, content uniformity etc.
Differential Distribution Cumulative
Distribution
Frequency Distribution
6
Outline Introduction
In-Process Particle Size Analysis (PSA)
Regulatory Considerations
Concluding Remarks
7
Why In-Process PSA Needed?Pre-Mixing
Wet Granulation
Roller Compaction
Drying Milling
Blending
ExcipientsAPI
Compression (Coating)
Tablets
SievingSieving
Combination of Particles of Different Components
Particle Size Enlargement
Particle Size Reduction
Separation of Particles with Different Sizes
In-situ, real-time information PAT to facilitate QbD Process monitoring and control
8
Where to Perform in-Process PSA?Pre-Mixing
Wet Granulation
Roller Compaction
Drying/Milling Milling/Sieving
Blending
ExcipientsAPI
Compression (Coating)
Tablets
In-process PSA
In-process PSA
Inconsistent endpoint
Poor FlowSegregation
Inconsistent PSD
Inconsistent Dissolution
Poor Content Uniformity
FDA Guide to Inspections of Oral Solid Dosage Forms (1994): Particle size profile of granules are recommended as an important parameter to demonstrate equivalence between batches.
Inconsistent PSD
9
In-Process PSA: Continuous Manufacturing
API
Excipients
In-Process PSA
Conceptual Example from Christine More’s presentation
Poor FlowSegregation
Inconsistent PSD
Variable PSDSegregation
Variable PSDSegregation
Inconsistent Dissolution Poor Content Uniformity
Tablets
10
Techniques for In-Process PSA Focused Beam Reflectance
Measurement (FBRM)
Laser Diffraction (LD)
Imaging Analysis
Spatial Filter Velocimetry (SFV)
Acoustic Emission
Near Infrared Spectroscopy (NIRS)
11
FBRM: Pharmaceutical Applications• Drug Substance
• Crystallization
• Wet Milling
• Drying
• Drug Product
• Roller Compaction
• High-Shear Granulation
• Fluid Bed Granulation
• Drug and ER coating
Many applications found in literature
Regulatory submissions Crystallization Wet milling
Process development
No implementation for commercial production
12
LD: Pharmaceutical Applications• Drug Substance
• Milling/Micronization
• Drug Product
• Roller Compaction
• Spray Drying
• High-Shear Granulation
• Fluid Bed Granulation
• Drug and ER coating
Many applications found in literature
Regulatory submission: Roller compaction spray drying
Implementation for routine commercial production
13
Challenges for Routine Implementation Complex System configuration for commercial
manufacturing process
• System set-up, process integration ….
• Communication, data access, analysis, and exchange…
Insufficient to achieve demanding process control targets
• Particle sizes are closely monitored but optimal process control is not achieved.
• Size information collected is not linked in a way that maximizes its usefulness.
14
How to Deal with Large Sample Sizes? Data preprocessing to fit the purpose
• Data pretreatment for dynamic noise reduction
• Data transformation for modeling and control
Chart from Alon Vaisman’s presentation
15
How to Deal with Large Sample Sizes? Process Modeling
• Deep understanding of process and product
• Knowledge can be transferable
Empirical /Statistical Approaches
• Population balance model
• Multivariate model
• Regression model
16
Outline Introduction
In-Process Particle Size Analysis (PSA)
Regulatory Considerations
Concluding Remarks
17
Submissions for In-Process PSA
Testing method
Analytical Procedure
Method Validation
Acceptance Criteria
18
Testing Methods Laser Diffraction (LD): USP<429>
Imaging Analysis: USP<776>
Acoustic Emission: USP <1005>
Near Infrared Spectroscopy (NIRS) : USP<1119>
Focused Beam Reflectance Measurement (FBRM)
Spatial Filter Velocimetry (SFV)
19
Analytical Procedure Statement of purpose,
principle, & summary
• Method suitability
• Method development report recommended
System description
• Instrument (hardware & software)
• System setup & process integration FBRM*
INSITEC*
* Pictures from internet
20
Analytical Procedure Sampling and sample
preparation
• Sensor location
• Interface cleanness
• Sampling accessories
• Sample dispersion
INSITEC Sampling System*
* From Malvern website
1. Sample probe2. Eductor dispersion3. Measuring zone4. Sample return5. Air purge system6. Valves for background
measurement or routine maintenance
How to obtain representative samples should be clarified
21
Analytical Procedure
• Acquisition Time & Frequency
• Data pretreatment & Modeling
• Reporting of Results
Acquisition time << process time constant to resolve the process dynamic changes.
Data acquisition and analysis
Data reduction to fit purpose.
Meet/fail acceptance criteria
Chart from Alon Vaisman’s presentation
22
Analytical Procedure
• Documented In the manufacturer's quality system
• High level overview recommended to be included in regulatory submissions
– How to detect and deal with in-process equipment failure?
– How to deal with OOS detected by in-process method?
– How to perform continuous performance verification?
– …..
Maintenance of In-process PSA
23
Submissions for In-Process PSA
Testing method
Analytical Procedure
Method Validation
Acceptance Criteria
24
Critical for evaluation of in-process PSA• In-process PSA proposed is suitable for its intended purpose
ICH Q2 (R1): Validation of Analytical Procedures • Particle sizing methods are not specifically addressed
FDA Draft Guidance: Analytical Procedures and Method Validation• Validation of particle sizing methods is not the same as Validation
of other analytical methods such as HPLC
• Usually involves evaluation of intermediate precision and Robustness
Online or inline particle sizing methods?
Method Validation
25
• Specificity
• Range (size)
• Detection limit
• Quantification limit
Method Validation: In-Process LD
Not required generally Method development Image analysis is
helpful for suitability assessment
• Accuracy Not required Verification/Qualification Reference Standard Acceptance criteria
26
• Linearity– Non-linear response to
particle size (Mie theory)
– Sample concentration (obscuration) effect.
Method Validation: In-Process LD
Sample concentration (obscuration) range should be specified
Concentration
Turbidity
Particle size analysis should be performed in the linear range
• Precision– Repeatability
– Intermediate precision
– Reproducibility
Required
Not required
Required
27
• Robustness– Instrument robustness (air pressure, measurement time, etc.)
– System robustness (sensor location, sample size, flow condition etc.)
– Environment conditions (temperature, humidity etc.)
Method Validation: In-Process LD
• Reference Method– Off-line particle sizing method
– Correlation between on-line and off-line measurements
Variation effects on sample representativity and stability
28
Submissions for In-Process PSA
Testing method
Analytical Procedure
Method Validation
Acceptance Criteria
29
Product Dependent– Dissolution, bioavailability, content uniformity, stability etc.
Process Dependent– Segregation & aggregation
– Flowability, blend uniformity, compactibility,etc.
Control Strategy Dependent– Feed-back vs. feed-forward controls
– Process monitoring (Qualitative vs. Quantitative)
Acceptance Criteria
30
Flexible with appropriate justification
– Proposed control strategy
– Current product and process understanding
Changeable as enhanced process and product understanding
– Continues improvement through its life cycle
Acceptance Criteria
3131
Concluding Comments Use of in-process particle size analyzer for
pharmaceutical applications increases rapidly.
Few applications have been included in the regulatory submissions, especially for routine commercial manufacturing process.
Appropriate submission package will facilitate evaluation of in-process PSA– Complete information for analytical procedures
– Method validation
– Acceptance criteria with adequate justification
3232
AcknowledgementOffice of Generic Drugs (OGD)
• David Skanchy
• Naiqi Ya
• Robert Iser
• Lawrence Yu
• Keith Webber
Office of New Drug Quality Assessment (ONDQA)
• Charmista Chatterjee
• Brian Rogers
• Bogdan Kurtyka
• Christine Moore