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CORPORATE OVERVIEW
QbD/PAT Implementation: The Road to RTR From Science to Compliance
Quality by Design China 2013 April 17-18, 2013 Shanghai, China
Pedro Hernandez, PhD 何盼多博士 Senior Director Quality Assurance - China
http://www.frontagelab.com [email protected]
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CORPORATE OVERVIEW
QbD/PAT Implementation: The Road to RTR From Science to Compliance
Background
Development Overview
Quality Risk Assessment
FMEA
Risk Prioritization Matrix
Pareto Chart
Ishikawa diagram
PAT Implementation Strategy
Process Flow - Opportunities
Blending - NIR
Instrumentation, Technology and Development
Roller Compactor/Milling - LLD
Instrumentation, Technology and Development
Compression - NIR
Fette 3090 Tablet Press Control Loops
Instrumentation, Technology and Development
Strategy for Implementation
Conclusions
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CORPORATE OVERVIEW
QbD/PAT Implementation: The Road to RTR From Science to Compliance
Product Summary
Relatively High Dose Compound
Extended Release Formulation Required for Once-a-Day Dosing
HPMC based formulation
Dissolution Rate Controlled by
• HPMC Concentration
• Surface Area/Volume Ratio
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CORPORATE OVERVIEW
QbD/PAT Implementation: The Road to RTR From Science to Compliance
Design Space: Multi-dimensional space that encompasses combinations of product design, manufacturing process design, manufacturing process parameters and component attributes that provide assurance of suitable product quality and performance.
Control Space: Multi-dimensional space that encompasses process operating parameters and component quality measurements that assure process or product quality. The Control space is a sub-set of the design space.
Control Strategy : A strategy/methodology to mitigate the risks associated with the batch failure when the critical and non-critical parameters fall outside the control space but within the design space.
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CORPORATE OVERVIEW
QbD/PAT Implementation: The Road to RTR From Science to Compliance
Defined experimental design space dimension for HPMC
Viscosity
Polymer substitution
Water content
Defined roller compaction design space dimension
Roll force
Roll gap
Polymer concentration
Defined tablet compression design space dimension
Pre-compression force
Compression force
Tableting speed
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CORPORATE OVERVIEW
QbD/PAT Implementation: The Road to RTR From Science to Compliance
Design Space
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CORPORATE OVERVIEW
QbD/PAT Implementation: The Road to RTR From Science to Compliance
Manufacturing design space based on DOE has been established and discussed
Next step in implementation process: Incorporation of PAT techniques into the manufacturing process.
Goal: Real Time Release of drug product based on QbD principles and real time monitoring of the manufacturing process
Summary
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CORPORATE OVERVIEW
QbD/PAT Implementation: The Road to RTR From Science to Compliance
Background
Development Overview
Quality Risk Assessment
FMEA
Risk Prioritization Matrix
Pareto Chart
Ishikawa diagram
PAT Implementation Strategy
Process Flow - Opportunities
Blending - NIR
Instrumentation, Technology and Development
Roller Compactor/Milling - LLD
Instrumentation, Technology and Development
Compression - NIR
Fette 3090 Tablet Press Control Loops
Instrumentation, Technology and Development
Strategy for Implementation
Conclusions
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CORPORATE OVERVIEW
QbD/PAT Implementation: The Road to RTR From Science to Compliance
Fish bone or Ishikawa diagram
Solid dosage quality risk assessment uses Failure Mode and Effect Analysis (FMEA)
FMEA: Risk scores based on probability, severity, and detectability
Risk Prioritization Matrix
Pareto Chart
Quality Risk Assessment (QRA)
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CORPORATE OVERVIEW
QbD/PAT Implementation: The Road to RTR From Science to Compliance
Compression
Roller Compaction
Raw Material Blending
Environmental Material Transfer
Hardness of Tablet (Friability)
Pre & Post Compression Press speed
Feeder speed Material addition
Feed frame setting Fill Weight
Cam selection Tooling
Roll Gap Roll force
Porosity (den) PSD
Ribbon strength
API HPMC
TALC Mg. Stea
Temp. Humidity
Blend time Blend rpm
Order of ddn. Fill Vol.
Discharge rate Surface
Discharge Storage
Moisture Transport
Ishikawa: Fishbone Diagram
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CORPORATE OVERVIEW
QbD/PAT Implementation: The Road to RTR From Science to Compliance
Process
Steps
Potential Failure
Mode
Potential Effect of
Failure
SEV Cause of Failure OCR Current Process Control DET RPN Recommended
Action
Roller
Compaction
No Roll Gap
Control
Reject Batch 3 Porosity & Roll gap
not controlled
4 Control particle size 3 36 PAT for porosity
control
Reject batch 3 API particle size;
morphology
2 Raw material physical
characteristics
1 6 Moisture, double
sampling
Reject Batch 3 Flow of blend 3 Raw material
characteristics
2 27 Reduce roll speed
to improve
densification
Milling/ Granulation Reject Batch 3 Flow issues of blend;
excess fines
3 Monitor particle size, use
of force feeder
2 18 Control particle
size; control roll
gap
Tablet
Compression
Loss in Hardness Reject Batch 4 Loss in
compressibility; over
lubrication
4 Control particle size;
compressibility & lube
time
3 48 PAT- porosity
control
Weight Variation Scrap batch 2 Flow & fill weight
variability due to
PSD
3 In-Process sampling 3 18 Double sampling
Control PSD
Sticking of tablets Reject 4 Over lubrication,
feeder causing over
lubrication
3 Control Lube times 3 36 Feeder speed &
setting control.
FMEA for Roller Compaction and Compression
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CORPORATE OVERVIEW
QbD/PAT Implementation: The Road to RTR From Science to Compliance
Risk Prioritization Matrix
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CORPORATE OVERVIEW
QbD/PAT Implementation: The Road to RTR From Science to Compliance
0.00%
2.00%
4.00%
6.00%
8.00%
10.00%
12.00%
14.00%
HP
MC
K 1
00 C
R
PO
RO
SIT
Y
PR
ES
S S
PE
ED
CO
MP
RE
SS
ION
FO
RC
E
FE
ED
ER
SP
EE
D
LU
BE
TIM
E
PS
D O
F IN
TR
A-
GR
AN
ULA
R B
LE
ND
AP
I P
AR
TIC
LE
SIZ
E
BLE
ND
TIM
E
PR
E-C
OM
P F
OR
CE
EX
CIP
IEN
T
PA
RT
ICLE
SIZ
E
Pareto Chart: Relative Importance of Inputs
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CORPORATE OVERVIEW
QbD/PAT Implementation: The Road to RTR From Science to Compliance
Background
Development Overview
Quality Risk Assessment
FMEA
Risk Prioritization Matrix
Pareto Chart
Ishikawa diagram
PAT Implementation Strategy
Process Flow - Opportunities
Blending - NIR
Instrumentation, Technology and Development
Roller Compactor/Milling - LLD
Instrumentation, Technology and Development
Compression - NIR
Fette 3090 Tablet Press Control Loops
Instrumentation, Technology and Development
Strategy for Implementation
Conclusions
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CORPORATE OVERVIEW
Compression Initial Blend
Roller
Compactor
Milling
QbD
` All raw materials are released and dispensed against
established specifications to
verify identity and quality. NIR
Monitoring
Blend Uniformity of
API and HPMC
Fette Control Loops
Monitoring Weight
and NIR Monitoring
Identity and Assay of
API and HPMC Laser Diffraction
Monitoring Particle Size
PAT Pyramid PAT
Process Stage
Quality Control or PAT
Control of
Manufacturing
Ingredients
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CORPORATE OVERVIEW
QbD/PAT Implementation: The Road to RTR From Science to Compliance
Stage 1: Identify and develop a feasibility (proof of principle) study for PAT use in critical steps of the drug product manufacturing process
Stage 2: Application development to further refine the technique and demonstrate its robustness to assure data quality
Stage 3: Monitor and analyze data of at commercial scale to demonstrate applicability of the PAT techniques
Stage 4: Formal submission to agency to allow for real time release of the finished drug product and implementation of Continual Process Improvement
Implementation Strategy
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CORPORATE OVERVIEW
QbD/PAT Implementation: The Road to RTR From Science to Compliance
Background
Development Overview
Quality Risk Assessment
FMEA
Risk Prioritization Matrix
Pareto Chart
Ishikawa diagram
PAT Implementation Strategy
Process Flow - Opportunities
Blending - NIR
Instrumentation, Technology and Development
Roller Compactor/Milling - LLD
Instrumentation, Technology and Development
Compression - NIR
Fette 3090 Tablet Press Control Loops
Instrumentation, Technology and Development
Strategy for Implementation
Conclusions
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CORPORATE OVERVIEW
QbD/PAT Implementation: The Road to RTR From Science to Compliance
NIR data can serve as a surrogate for dissolution performance (i.e. ratio of API/HPMC).
Process Unit Granulation Tablet Compression
Critical Quality Attribute Blend Uniformity Assay and ID (AP I and HPMC)
Instrument Brimrose: Luminar 4030 Bruker: MPA
Process AOTF-NIR FT-NIR
Mode Reflectance Transmission
Range 1100 – 2300 nm 833 – 1111 nm
Scans 50 per revolution 128 per tablet
Chemometric PLS, First Derivative PLS, First Derivative
NIR Tools
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CORPORATE OVERVIEW
QbD/PAT Implementation: The Road to RTR From Science to Compliance
NIR Tools
Proper blending is critical to consistent product quality in solid dose manufacturing.
NIR spectroscopy provides a real time window into your blending process for improved end-point determination even with variability in raw materials.
Brimrose: Luminar 4030 NIR Brimrose: Luminar 5030 NIR
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CORPORATE OVERVIEW
QbD/PAT Implementation: The Road to RTR From Science to Compliance
NIR spectra: 90% (blue) and 100% (red) strength
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CORPORATE OVERVIEW
QbD/PAT Implementation: The Road to RTR From Science to Compliance
HPMC NIR spectra
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CORPORATE OVERVIEW
QbD/PAT Implementation: The Road to RTR From Science to Compliance
Benefits
Real time monitoring of the blending process and End Point determination.
Non-invasive and non-intrusive.
No sampling or sample preparation artifacts to affect the data.
Summary
Method development validated the NIR method(s) for
monitoring Blend Uniformity (API and HPMC)
NIR for Blend Uniformity
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CORPORATE OVERVIEW
QbD/PAT Implementation: The Road to RTR From Science to Compliance
Background
Development Overview
Quality Risk Assessment
FMEA
Risk Prioritization Matrix
Pareto Chart
Ishikawa diagram
PAT Implementation Strategy
Process Flow - Opportunities
Blending - NIR
Instrumentation, Technology and Development
Roller Compactor/Milling - LLD
Instrumentation, Technology and Development
Compression - NIR
Fette 3090 Tablet Press Control Loops
Instrumentation, Technology and Development
Strategy for Implementation
Conclusions
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CORPORATE OVERVIEW
QbD/PAT Implementation: The Road to RTR From Science to Compliance
Roll force
Roll gap
Roller Compaction
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CORPORATE OVERVIEW
QbD/PAT Implementation: The Road to RTR From Science to Compliance
Design of Experiments and Design Space
The multidimensional combination and interaction of input variables (e.g., material attributes)
and process parameters that have been demonstrated to provide assurance of quality. ICH Q8 (R2)
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CORPORATE OVERVIEW
QbD/PAT Implementation: The Road to RTR From Science to Compliance
There was good control of key attributes within the design space studied.
DOE demonstrates robustness of tablet compressibility within the manufacturing design space
Variation in roller compaction force and tablet compression force gave essentially the same dissolution
Batches manufactured outside of the roll compaction design space are within the clinical pharmacokinetic design space but fail tablet compression (Failure mode – did not achieve desired hardness)
Tablet Development - Summary of DoE
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CORPORATE OVERVIEW
QbD/PAT Implementation: The Road to RTR From Science to Compliance
System Description
The system consists of a computer, an Automation Control Panel, and Interface Panel and a bypass arrangement using a venturi eductor to draw a small amount of particulate from the discharge of the roller compactor.
The eductor also provides a dispersion mechanism for the powder to separate agglomerated particles. Material drawn out of the process flow is returned to the process flow downstream from the sampling point.
Malvern Insitec: Laser Diffraction for On-line Particle Size Analysis
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CORPORATE OVERVIEW
QbD/PAT Implementation: The Road to RTR From Science to Compliance
0
5
10
15
20
25
30
35
40
% > 1
000m
(%)
840m
> 10
00m
(%)
350m
> 84
0m (%
)
177m
> 35
0m (%
)
149m
> 17
7m (%
)
74m
> 149
m (%
)
44m
> 74m
(%)
% < 4
4m (%
)
PS RANGE
% in
RA
NG
E
A +
A -
B +
B -
C +
C -
D +
D -
Particle Size Distribution: Range by Dose
Maximum: (+), Minimum (-)
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CORPORATE OVERVIEW
QbD/PAT Implementation: The Road to RTR From Science to Compliance
Benefits
Particle Size Analysis in real time
Non-destructive sampling.
Flow problems can be visually monitored and addressed
Summary
Each formulation has its own PSD profile but all four exhibit a similar bimodal profile.
The axis for the bimodal distribution is in the 149-177 microns in all four doses.
Control of particle size at the roller compaction stage of the process may be needed for processing purposes (i.e. manufacturability).
Particle size distribution does not impact dissolution
Laser Diffraction for Particle Size Analysis
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CORPORATE OVERVIEW
QbD/PAT Implementation: The Road to RTR From Science to Compliance
Background
Development Overview
Quality Risk Assessment
FMEA
Risk Prioritization Matrix
Pareto Chart
Ishikawa diagram
PAT Implementation Strategy
Process Flow - Opportunities
Blending - NIR
Instrumentation, Technology and Development
Roller Compactor/Milling - LLD
Instrumentation, Technology and Development
Compression - NIR
Fette 3090 Tablet Press Control Loops
Instrumentation, Technology and Development
Strategy for Implementation
Conclusions
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CORPORATE OVERVIEW
QbD/PAT Implementation: The Road to RTR From Science to Compliance
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CORPORATE OVERVIEW
QbD/PAT Implementation: The Road to RTR From Science to Compliance
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CORPORATE OVERVIEW
QbD/PAT Implementation: The Road to RTR From Science to Compliance
NIR will be used to assess tablet assay of API and HPMC
Bruker Optics Model MPA FT-NIR
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CORPORATE OVERVIEW
QbD/PAT Implementation: The Road to RTR From Science to Compliance
Tablet NIR Spectra of Calibration Standards: First Derivative/MSC*
*Multiplicative Scatter Correction
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CORPORATE OVERVIEW
QbD/PAT Implementation: The Road to RTR From Science to Compliance
API Model Prediction versus calibration tablets
API
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CORPORATE OVERVIEW
QbD/PAT Implementation: The Road to RTR From Science to Compliance
HPMC Model Prediction versus calibration tablets
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CORPORATE OVERVIEW
QbD/PAT Implementation: The Road to RTR From Science to Compliance
NIR for Assay of core tablets
Benefits
Identity and Assay in real time
Non-destructive sampling.
The final coating stage is for cosmetic purposes and dose differentiation, and has no impact on product performance.
Desired Objective: NIR analysis at the compression stage on uncoated tablets will eventually replace current HPLC release testing.
Summary
The NIR methods has been validated for identity and assay for for both, API and HPMC
In summary, NIR will be used to assess tablet assay of API and HPMC
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CORPORATE OVERVIEW
QbD/PAT Implementation: The Road to RTR From Science to Compliance
Background
Development Overview
Quality Risk Assessment
FMEA
Risk Prioritization Matrix
Pareto Chart
Ishikawa diagram
PAT Implementation Strategy
Process Flow - Opportunities
Blending - NIR
Instrumentation, Technology and Development
Roller Compactor/Milling - LLD
Instrumentation, Technology and Development
Compression - NIR
Fette 3090 Tablet Press Control Loops
Instrumentation, Technology and Development
Strategy for Implementation
Conclusions
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CORPORATE OVERVIEW
QbD/PAT Implementation: The Road to RTR From Science to Compliance
PAT deployment during the monitoring stage
In-line blend uniformity measurements Using NIR
On-Line Particle size monitoring using Laser Light Diffraction
At-line NIR measurements for API and HPMC content in tablets (n = 90) NIR Assay: n= average of 10 tablets beginning, middle and end
Tablets weights using an automatic weight checker
Over 180 batches monitored
Strategy for Implementation
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CORPORATE OVERVIEW
QbD/PAT Implementation: The Road to RTR From Science to Compliance
Feasibility Application
Development Monitoring
1Q
Implementation
Brimrose Luminar 4030/5030 NIR
On-Line Monitoring of Blend Uniformity
Bruker MPA NIR
At-Line Monitoring of ID, Assay and API to HPMC ratio
Malvern Insitec T Particle Size Analyzer
In-Line Monitoring of Particle Size in the
Roller Compactor/Milling Process
PAT TOOLS
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CORPORATE OVERVIEW
QbD/PAT Implementation: The Road to RTR From Science to Compliance
Fit For Purpose Development cGMP
Risk Analysis
Feasibility
Monitoring
Implementation
Identify Critical Process Steps and PAT Technologies
Proof of Concept for the Technology
Method/Technology optimization
Continual Improvement and Process Control
In Process Application Development/Deployment
Process Data gathering for statistical analysis
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CORPORATE OVERVIEW
QbD/PAT Implementation: The Road to RTR From Science to Compliance
· Specificity
· Linearity
· Range
· Accuracy
· Precision
· Repeatability
· Intermediate Precision
· Robustness
· Detection Limit
· Quantitation Limit
General Method Validation Requirements per ICH Q2A & Q2B
These requirements are Scientific and Fit for Purpose, they are not based in a
compliance status. The compliance status is determined by the environment.
Fit For Purpose Development cGMP
Risk Analysis Feasibility Monitoring Implementation Application
Development
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CORPORATE OVERVIEW
QbD/PAT Implementation: The Road to RTR From Science to Compliance
Fit For Purpose Development cGMP
Risk Analysis Feasibility Monitoring Implementation Application
Development
PAT Development
Methods, SOPs and trainings are developed, verified and
implemented with team inputs from R&D, TT, PPU, Quality,
Regulatory, IT, Engineering and EHS support.
Proof of Concept
with R&D
During TT
PAT Deployment
at Manufacture
Installation,
IQ/OQ/CSV
SOPs
Method
Optimization
Validation
Update
Real Time
Release
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CORPORATE OVERVIEW
QbD/PAT Implementation: The Road to RTR From Science to Compliance
Risk assessment
Tool selection
NIR - Blend uniformity of API and HPMC
Particle size - Roller Compactor
NIR – compression potency determination
Feasibility protocol / report
Experimental studies (lab. Scale)
Build up chemometric models “robustness”
Monitoring @ commercial scale
Data analysis / process variability
Training strategy
Determine other process variables that can indirectly support product release testing
Revise SOP’s / product spec as applicable for reduce testing
PAT development report
Feasibility Application Development Monitoring
TASKS
PAT Implementation Plan
Method development
Plan and build up chemometric models “robustness”
Application development report
PAT Comparability Protocol for FDA
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CORPORATE OVERVIEW
QbD/PAT Implementation: The Road to RTR From Science to Compliance
PAT Implementation Plan
Start System Integration
Process Understanding Deployment
TASKS
Ownership Transition
Technology to PPU/Quality
Monitoring @ commercial scale
System integration for blend stage only. End point determination.
Operation strategy, revise SOP
Training strategy
PAT and critical process data will be reviewed.
Revise SOP’s / product spec as applicable for reduced testing and Update PBR/MES
Define Data Custody Chain based on level of integration and compliance requirements
Approve SOPs for Data Custody Chain
Write and Submit Comparability Protocol
Real Time Release
Degradation every 10 lots
Continuous process monitoring
Define future integration on a need and ROI basis
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CORPORATE OVERVIEW
QbD/PAT Implementation: The Road to RTR From Science to Compliance
Background
Development Overview
Quality Risk Assessment
FMEA
Risk Prioritization Matrix
Pareto Chart
Ishikawa diagram
PAT Implementation Strategy
Process Flow - Opportunities
Blending - NIR
Instrumentation, Technology and Development
Roller Compactor/Milling - LLD
Instrumentation, Technology and Development
Compression - NIR
Fette 3090 Tablet Press Control Loops
Instrumentation, Technology and Development
Strategy for Implementation
Conclusions
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CORPORATE OVERVIEW
QbD/PAT Implementation: The Road to RTR From Science to Compliance
Optimal Design Space Criteria for Hypromellose ensures consistent performance
Blend monitoring by NIR will insure consistent uniformity of the granulation
Particle Size distribution monitoring will insure processability of the granulation
Compression NIR monitoring of Identity and Assay of API and HPMC together with Weight Analysis assures that quality is built into the product
“QbD + PAT = Real Time Release”
THE DESIRED STATE FOR QUALITY BY DESIGN MANUFACTURING
Conclusions
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CORPORATE OVERVIEW
QbD/PAT Implementation: The Road to RTR From Science to Compliance
Guidance for Industry: PAT —A Framework for Innovative Pharmaceutical Development,
Manufacturing, and Quality Assurance, September 2004
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm
070305.pdf
Guidance for Industry: Quality Systems Approach to Pharmaceutical Current Good
Manufacturing Practice Regulations, September 2006
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm
070337.pdf
Guidance for Industry: Q9 Quality Risk Management, June 2006
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm
073511.pdf
Guidance for Industry: Q8(R2) Pharmaceutical Development Revision 2, November 2009
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm
073507.pdf
Guidance for Industry: Q10 Pharmaceutical Quality System,April 2009
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm
073517.pdf
Guidance for Industry: Process Validation: General Principles and Practices, January 2011
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM
070336.pdf
References
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CORPORATE OVERVIEW
谢谢
Guayama-PR
Ernesto Perez Reinaldo Vazquez
Hector Garcia Gladys Collazo
Lind Claudio Carlos Conde
Collegeville-PA
Dominic Ventura Doug Becker
Lou Sivieri T.G. Venkateshwaran
Pearl River-NY
Carl Longfellow Saeed Hashemi
Peter Larkin Eileen Fruhling
Shailesh Singh
Acknowledgments
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CORPORATE OVERVIEW
问题?
Hesitating to act because the whole vision
might not be achieved,
or because others do not yet share it,
is an attitude that only hinders progress.
M. K. Gandhi
http://www.frontagelab.com [email protected]