QbD/PAT Implementation: The Road to RTR...QbD/PAT Implementation: The Road to RTR From Science to...

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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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


Compression - NIR

Fette 3090 Tablet Press Control Loops


Strategy for Implementation

Conclusions

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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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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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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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Design Space

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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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Background



FMEA


Pareto Chart

Ishikawa diagram



Blending - NIR




Compression - NIR




Conclusions

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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


Pareto Chart

Quality Risk Assessment (QRA)

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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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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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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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Background



FMEA


Pareto Chart

Ishikawa diagram



Blending - NIR




Compression - NIR




Conclusions

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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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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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Background



FMEA


Pareto Chart

Ishikawa diagram



Blending - NIR




Compression - NIR




Conclusions

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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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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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NIR spectra: 90% (blue) and 100% (red) strength

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HPMC NIR spectra

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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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Background



FMEA


Pareto Chart

Ishikawa diagram



Blending - NIR




Compression - NIR




Conclusions

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Roll force

Roll gap

Roller Compaction

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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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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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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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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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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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Background



FMEA


Pareto Chart

Ishikawa diagram



Blending - NIR




Compression - NIR




Conclusions

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NIR will be used to assess tablet assay of API and HPMC

Bruker Optics Model MPA FT-NIR

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Tablet NIR Spectra of Calibration Standards: First Derivative/MSC*

*Multiplicative Scatter Correction

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API Model Prediction versus calibration tablets

API

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HPMC Model Prediction versus calibration tablets

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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

CORPORATE OVERVIEW


Background



FMEA


Pareto Chart

Ishikawa diagram



Blending - NIR




Compression - NIR




Conclusions

CORPORATE OVERVIEW


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


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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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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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· 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.


Risk Analysis Feasibility Monitoring Implementation Application

Development

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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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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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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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Background



FMEA


Pareto Chart

Ishikawa diagram



Blending - NIR




Compression - NIR




Conclusions

CORPORATE OVERVIEW


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

CORPORATE OVERVIEW


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


070337.pdf

Guidance for Industry: Q9 Quality Risk Management, June 2006


073511.pdf

Guidance for Industry: Q8(R2) Pharmaceutical Development Revision 2, November 2009


073507.pdf

Guidance for Industry: Q10 Pharmaceutical Quality System,April 2009


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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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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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]

QbD/PAT Implementation: The Road to RTR...QbD/PAT Implementation: The Road to RTR From Science to...

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