The Business Case for Building the Janssen Brand AWS
Development of Real Time Release Test of Tablet Dissolution Jessica Riley, Shells Artwork from Reflections Art in Health
Sarah Nielsen, PhD Janssen Supply Chain
Recent Industry Announcements
http://www.fiercepharmamanufacturing.com/story/vertex-jj -gsk-novartis-all-working-continuous-manufacturing-facilities/2015-02-09
Though making the switch from batch to continuous manufacturing may be difficult, costly and time consuming, pharma manufacturers and CMOs should begin to consider the switch as in the long-run it will end up saving companies time, money and space, FDA’s CDER Director Janet Woodcock told congressmen in a hearing Thursday. http://www.in-pharmatechnologist.com/Processing/FDA-calls-on-manufacturers -to-begin-switch-from-batch-to-continuous-production
2
Real Time Release Testing
RTRT
Real Time Release Testing is the ability to evaluate and ensure the quality of inprocess and/or final product based on process data – Typically include a valid combination of measured material attributes and process controls -ICH Q8(R2)
Real Time Release Testing
4
Traditional Release Approach Granulation Control through LoD
Milling Drying
Real Time Release Approach Dissolution control through DoE end point
Drying time by NIR
Milling Blending Weight, Thickness, Hardness, friability
Lubrication Compression
Standard Release Tests Assay (HPLC) CU (HPLC) Physical Description Dissolution
Coating Laboratory
Blend Uniformity Control Through NIR
• NIR Assay • Dosage Uniformity • Predicted Dissolution
5
Example of Continuous Manufacturing with On-line Monitoring
FDA Perspective on Continuous Manufacturing, Sharmista Chatterjee, Ph.D. IFPAC Annual Meeting Baltimore, January , 2012 6
Janssen Continuous DP Manufacturing Line Process Data Control Strategy Residence Time Distribution In-Line Blend ID for Process Monitoring Tablet ID for Real Time Release Testing Tablet Assay Tablet Content Uniformity
Dry Blend Direct Compression Process
Roller Compaction RTRT Example
Janssen Process and Tablet Data Material Feeders
Feed Rate
Blend NIR Blend Assay
Tablet Physical Testing
Tablet NIR (RTRt)
Weight
Assay
Thickness
Identification Hardness Identification Tablet Press
Content Uniformity
9
Path to Dissolution Real Time Release
ID CQA’s
Apply at-line PAT where applicable
CU, Assay, Hardness, Thickness, etc
Process Understanding
Identify sources of variation for remaining CQA
Identify Critical Process Parameters
• Align with criticality analysis, Based on data and in-sights • Identify critical material attributes (CMA’s)
Design of Experiments
Knowledge Based
Develop Surrogate Model
Implement Real-time MVA
10
CM Dissolution Criticality Analysis (Process)
Critical Process Parameters
11
Design of Experiments
Excipient Concentration
Potential Factors to Consider Line Throughput API Concentration MgSt Mill Speed Blender Speed Feed Frame Tablet Weight Tablet Thickness Tablet Hardness Disintegration Time Raw Material Properties Granulation Water Concentration API Polymorph Conversion
Dissolution Curves CQA’s, CMA’s
12
Modeling Approaches Multivariate Statistical Analysis – Bayesian, Population Analysis
Noyes-Whitney Approach
Spectroscopic Approach
13
Dissolution Considerations Identify Critical Material and Critical Process Parameters for Formulation Excipients API Particle Size Design of Experiments Tablet Critical Quality Attributes Critical Process Parameters Run Design of Experiments Measure Dissolution Identify Contributions to Dissolution
Build Predictive Model Surrogate Dissolution Method
Validate Model with Independent Test Set
Validation of Dissolution Model • Independent batches (with representative variation) • Set acceptance criteria based on calibration samples • Determine “sampling strategy” for validation
15
Additional Considerations for Dissolution Model or Surrogate Testing Reference Method Development Model Maintenance Raw Material Supplier Changes Ongoing Verification of the Model Overall “Sampling Strategy” – USP Develop procedures for surrogate testing model maintenance including periodic challenges Strategy for handling raw material variability
16
Thank you Sarah Nielsen ([email protected])
Jessica Riley, Shells Artwork from Reflections Art in Health
Dissolution for Real Time Release Testing • Determining factors which may affect dissolution (criticality analysis) • Measuring dissolution in response to these factors (Design of Experiments) • Choosing a predictive model which incorporates PAT/tablet properties/process parameters/raw material attributes • Multivariate process and raw material model • Calibration of dissolution model • Validation of dissolution model • Dissolution Model Maintenance • Recalibration of model (when needed)
19
Requirements for Dissolution and Things to Consider ICH Guidelines Guidance for Industry (FDA) USP Monograph for Dissolution BCS Classification System
20
Sarah Nielsen, PhD Janssen Supply Chain
Recent Industry Announcements
http://www.fiercepharmamanufacturing.com/story/vertex-jj -gsk-novartis-all-working-continuous-manufacturing-facilities/2015-02-09
Though making the switch from batch to continuous manufacturing may be difficult, costly and time consuming, pharma manufacturers and CMOs should begin to consider the switch as in the long-run it will end up saving companies time, money and space, FDA’s CDER Director Janet Woodcock told congressmen in a hearing Thursday. http://www.in-pharmatechnologist.com/Processing/FDA-calls-on-manufacturers -to-begin-switch-from-batch-to-continuous-production
2
Real Time Release Testing
RTRT
Real Time Release Testing is the ability to evaluate and ensure the quality of inprocess and/or final product based on process data – Typically include a valid combination of measured material attributes and process controls -ICH Q8(R2)
Real Time Release Testing
4
Traditional Release Approach Granulation Control through LoD
Milling Drying
Real Time Release Approach Dissolution control through DoE end point
Drying time by NIR
Milling Blending Weight, Thickness, Hardness, friability
Lubrication Compression
Standard Release Tests Assay (HPLC) CU (HPLC) Physical Description Dissolution
Coating Laboratory
Blend Uniformity Control Through NIR
• NIR Assay • Dosage Uniformity • Predicted Dissolution
5
Example of Continuous Manufacturing with On-line Monitoring
FDA Perspective on Continuous Manufacturing, Sharmista Chatterjee, Ph.D. IFPAC Annual Meeting Baltimore, January , 2012 6
Janssen Continuous DP Manufacturing Line Process Data Control Strategy Residence Time Distribution In-Line Blend ID for Process Monitoring Tablet ID for Real Time Release Testing Tablet Assay Tablet Content Uniformity
Dry Blend Direct Compression Process
Roller Compaction RTRT Example
Janssen Process and Tablet Data Material Feeders
Feed Rate
Blend NIR Blend Assay
Tablet Physical Testing
Tablet NIR (RTRt)
Weight
Assay
Thickness
Identification Hardness Identification Tablet Press
Content Uniformity
9
Path to Dissolution Real Time Release
ID CQA’s
Apply at-line PAT where applicable
CU, Assay, Hardness, Thickness, etc
Process Understanding
Identify sources of variation for remaining CQA
Identify Critical Process Parameters
• Align with criticality analysis, Based on data and in-sights • Identify critical material attributes (CMA’s)
Design of Experiments
Knowledge Based
Develop Surrogate Model
Implement Real-time MVA
10
CM Dissolution Criticality Analysis (Process)
Critical Process Parameters
11
Design of Experiments
Excipient Concentration
Potential Factors to Consider Line Throughput API Concentration MgSt Mill Speed Blender Speed Feed Frame Tablet Weight Tablet Thickness Tablet Hardness Disintegration Time Raw Material Properties Granulation Water Concentration API Polymorph Conversion
Dissolution Curves CQA’s, CMA’s
12
Modeling Approaches Multivariate Statistical Analysis – Bayesian, Population Analysis
Noyes-Whitney Approach
Spectroscopic Approach
13
Dissolution Considerations Identify Critical Material and Critical Process Parameters for Formulation Excipients API Particle Size Design of Experiments Tablet Critical Quality Attributes Critical Process Parameters Run Design of Experiments Measure Dissolution Identify Contributions to Dissolution
Build Predictive Model Surrogate Dissolution Method
Validate Model with Independent Test Set
Validation of Dissolution Model • Independent batches (with representative variation) • Set acceptance criteria based on calibration samples • Determine “sampling strategy” for validation
15
Additional Considerations for Dissolution Model or Surrogate Testing Reference Method Development Model Maintenance Raw Material Supplier Changes Ongoing Verification of the Model Overall “Sampling Strategy” – USP Develop procedures for surrogate testing model maintenance including periodic challenges Strategy for handling raw material variability
16
Thank you Sarah Nielsen ([email protected])
Jessica Riley, Shells Artwork from Reflections Art in Health
Dissolution for Real Time Release Testing • Determining factors which may affect dissolution (criticality analysis) • Measuring dissolution in response to these factors (Design of Experiments) • Choosing a predictive model which incorporates PAT/tablet properties/process parameters/raw material attributes • Multivariate process and raw material model • Calibration of dissolution model • Validation of dissolution model • Dissolution Model Maintenance • Recalibration of model (when needed)
19
Requirements for Dissolution and Things to Consider ICH Guidelines Guidance for Industry (FDA) USP Monograph for Dissolution BCS Classification System
20
