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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

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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

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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

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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

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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

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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)

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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

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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

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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.

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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

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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

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Outline Introduction

In-Process Particle Size Analysis (PSA)

Regulatory Considerations

Concluding Remarks

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Submissions for In-Process PSA

Testing method

Analytical Procedure

Method Validation

Acceptance Criteria

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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)

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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

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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

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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

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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

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Submissions for In-Process PSA

Testing method

Analytical Procedure

Method Validation

Acceptance Criteria

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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

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• 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

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• 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

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• 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

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Submissions for In-Process PSA

Testing method

Analytical Procedure

Method Validation

Acceptance Criteria

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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

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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

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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

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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