Download - QbD Overview.pdf

7/23/2019 QbD Overview.pdf

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The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.

Quality by Design (QbD)


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Why QbD?

Higher level of assurance of product quality

Cost saving and efficiency for industry and regulators

Increase efficiency of manufacturing process and reduce manufacturing cost

and product rejects

Minimize/eliminate potential compliance actions, costly penalties & recalls

Enhance opportunities for first cycle approval

Streamline post approval manufacturing changes and regulatory processes


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FDA View on QbD

Quality by Design is: Scientific, risk-based, holistic and proactive approach to

pharmaceutical development

Deliberate design effort from product conception through

commercialization

Full understanding of how product attributes and process relate to

product performance

QbD informat ion and conc lus ions shou ld be shared wi th FDA,required start ing in 2013


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QbD System

Define desiredproduct performance

upfront;

identify product CQAs

Design formulation andprocess to meet

product CQAs

Understand impact ofmaterial attributes andprocess parameters on

product CQAs

Identify and controlsources of variability

in material andprocess

Continually monitorand update

process to assureconsistent quality

Risk assessment and risk control

Product & process design and development


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Approaches to Pharmaceutical Development

Aspects Traditional QbD

Pharmaceuticaldevelopment

Empirical; typically univariateexperiments

Systematic; multivariate experiments

Manufacturingprocess

Fixed; validation on 3 initial full-scalebatches; focus on reproducibility

Adjustable within design space;continuous verification within designspace; focus on control strategy androbustness

Process control In-process testing for go/no-go; offlineanalysis w/ slow response

All critical process variables understood

Productspecification

Primary means of quality control;based on batch data

Part of the overall quality controlstrategy; based on desired productperformance

Control strategyMainly by intermediate and endproduct testing

Risk-based; controls shifted upstream;real-time release

Lifecyclemanagement

Reactive to problems & OOS; post-approval changes needed

Continual improvement enabled withindesign space


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Designing a Robust Process

Problemsdetected after they occur,

through

product testing andinspection

Reproducible process

within

narrow operatingranges

Robust & reproducible

process

Low High

Low

High

PROCESS UNDERSTANDING

PROCESS

CONTROL

High potential

for failures


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Quality by DesignThe Desired State

Product quality and performance achieved and assured by design ofeffective and efficient manufacturing processes

Product specifications based on mechanistic understanding of howformulation and process factors impact product performance

An ability to affect continuous improvement and continuous real timeassurance of quality


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Quality by DesignThe Way Forward

Identify and control all sources of

variability

Raw materials

Process

Environmental

Manage variability through the

process

Uncertainty the inability to determine or

the ambiguity in the true state of a system

caused by a combination of variability and

incomplete knowledge (ICH Q9)

Reduce UNCERTAINTY Control VARIABILITY

Mitigate risk

Knowledge transfer to manufacturing and regulatory bodies


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Quality Risk Assessment (QRA)

Risk scores based on probability, severity, and detectability Risk Prioritization Matrix

Quality Function Deployment

Fish bone or Ishikawa diagram

Pareto Chart


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Risk Prioritization Matrix

Process and Formulation Inputs

QUALITYATTRIBUTES

WEIGHTED

AVERAGE

HPMCK100CR

CONCENTRAT

ION

BLENDTIME

LUBETIME

APIPARTICLE

SIZE

PRE-

COMPRESSION

FORCE

COMPRESSING

FORCE

MACHINESPE

ED

FEEDERSPE

ED

POROSITYO

F

RIBBON/ROLL

GAP

EXCIPIENT

PARTICLESIZE

PSDOFINTR

A-

GRANULAR

BLEND

REGULATOR

Y

MANUFACTUR

ING

DISSOLUTION 10 10 1 1 1 1 1 1 1 1 1 1 10 3

ASSAY/

POTENCY9 3 1 5 5 1 1 1 1 7 1 1 10 1

UNIFORMITY 7 1 7 1 5 1 1 5 7 7 3 5 5 1

HARDNESS 10 5 5 10 5 7 10 7 7 10 5 5 10 10

THICKNESS 5 3 1 1 1 7 10 3 1 1 1 1 1 5

FLOW 4 7 5 1 3 1 1 3 7 5 5 7 3 1

APPEARANCE 4 5 1 3 3 3 5 3 5 5 5 5 1 1

STABILITY 2 1 1 1 1 1 1 1 1 1 1 1 3 1

YIELD 7 1 1 1 1 1 1 10 3 3 1 3 7 10

TOTALS 256 156 192 178 156 209 235 200 236 144 180

PERCENTIMPORTANCE

11.95 7.28 8.96 8.31 7.28 9.76 10.97 9.34 11.01 6.72 8.40


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Tablet Hardness

Basic risk facilitation methods

Cause EffectDiagram

for Tablet

Hardness

Compression

Roller Compaction

Raw MaterialBlending

EnvironmentalMaterial

Transfer

Hardness of Tablet

(Friability)

Pre & Post CompressionPress speed

Feeder speedMaterial addition

Feed frame settingFill Weight

Cam selectionTooling

Roll GapRoll force

Porosity (den)PSD

Ribbon strength

APIHPMC

TALCMg. Stea

Temp.Humidity

Blend time

Blend rpm

Order of ddn.Fill Vol.

Discharge rateSurface

DischargeStorage

MoistureTransport


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Pareto Chart: Relative Importance of Inputs

0.00%

2.00%

4.00%

6.00%

8.00%

10.00%

12.00%

14.00%

HPMC

K100CR

POROSITY

PRESSSPEED

COMPRESSIO

N

FORCE

FEEDER

SPEE

D

LUBETIME

PSD

OFINTRA-

GRANULAR

BLEND

APIPARTICLESIZ

E

BLEND

TIME

PRE-COMPFORC

E

EXCIPIENT

PARTICLESIZE


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Control/Design Space Critical Process Parameters

Critical Process Parameters (CPP) identified using a risk analysis investigatedextensively using a DOE.

Design Space

Established on the basis of the DOE and experience duringmanufacture of clinical/registration batches

In certain cases where response of critical quality attributestudied/investigated was insignificant, extrapolation was used toexpand/establish design space

Control Space

Subset of design space established on the basis of process

capability, prior knowledge Intent is to stay within the control space during commercial manufacturing


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Control/Design Space Non-Critical Process Parameters

Non-Critical Process Parameters those identified as low risk which

lead to low probability of product failure

Design Space

Established on the basis of range studies (in some cases

DOEs) and manufacturing experience at various scales

Control Space

Subset of design space established on the basis of process

capability, prior knowledge

Intent is to stay within the control space during commercial

manufacturing


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Design Space and Control Space

Design Space

Multi-dimensional space that encompasses combinations of product design,manufacturing process design, critical manufacturing process parameters andcomponent attributes that provide assurance of suitable product quality andperformance

Control Space

Multi-dimensional space that encompasses process operating parameters andcomponent quality measurements that assure process or product quality. It is asubset of the design space

Control Strategy

Strategy/Methodology to mitigate risks associated with the batch when thecritical and non-critical process parameters fall outside the control space butwithin the design space


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Quality by Design (QbD)