A Practical Guide toQbD Product Development

APTI Webinar Series, 2020

Trainers

C H A N D R A M O U L I RKAV I T H A A N

• A s s o c i a t e P ro f . , Kr u p a n i d h i

C o l l e g e o f P h a r m a c y B a n g a l o re ,

( 2 0 0 8 - t h r u p re s e n t )

• 7 ye a rs o f Q b D e x p e r i e n c e

• H ave g u i d e d 5 M P h a r m P ro j e c t s

• P ro f e s s o r & H e a d , D e p t . o f QA ,

Kr u p a n i d h i C o l l e g e o f P h a r m a c y

• 5 Ye a rs o f I n d . e x p. ( QA & C R O )

• 1 3 ye a rs o f P G t e a c h i n g E x p.

• 2 5 P ro j e c t s g u i d e d i n QA d o m a i n

• S A S C e r t i f i e d A d va n c e d P ro g r a m m e r

c re d e n t i a l

• P R I N C E 2 p ro j e c t m g t . c re d e n t i a l

• 5 ye a rs o f c o n s u l t i n g e x p. a s

s t a t i s t i c i a n

• E x p e r t Fa c u l t y, Fa c u l t y o f

P h a r m a c y, R G U H S , KA

TO

PIC

HIG

HL

IGH

TS OUTLINE

100 years of Quality

Origins

Evolution of QbD

QbD & ICH

QbD applied to product development

Process understanding

Intro to QbD Software

Example case study

FISHER, BOX & WILSON

Fisher founded DOE, Box & Wilson -

Optimization | 1920 - 60

ICI - SHWARTZ - RSM- JURAN

Merck, RSM application to Pharma

FDA - ICH AND BEYOND

Woodcock adoption at USFDA |

2002 till now

ORIGINS

"a maximally efficient, agile,

flexible pharmaceutical

manufacturing sector that

reliably produces high-

quality drug

products without extensive

regulatory oversight"

JANET WOODCOCK

Fmr. D i rector CDER USFDA

Evolution of QbD

ICH QbD timeline

A FRAMEWORK FOR QBD

.

De

fin

itio

n o

f Q

bD

ICH Q8

“Systematic approach to

development that begins

with predefined objectives,

emphasizes product and

process understanding and

process control, and is

based on sound science and

quality risk management”

ICH Q8–Q12

ICH Q8 (R2) – ‘Pharmaceutical Development’

ICH Q9 – ‘Qual ity Risk Management’

ICH Q10 – ‘Pharmaceutical Qual ity System’

ICH Q11 – ‘Development and Manufacture of Drug Substances

(Chemical Entit ies and Biotechnological/Biological Entit ies’

ICH Q12 – Concept paper – ‘Technical and Regulatory

Considerations for Pharmaceutical Product Li fecycle Management’

ICH GUIDELINE BRIEFS -1

ICH Q8 (R2) – ‘PHARMACEUTICAL DEVELOPMENT’

• principles of using science for development of a drug product. It

was the f irst ICH document to use the term ‘enhanced, Quality by

Design’ approach. It includes two Parts and two Appendices.

• Part 1 is Pharmaceutical Development; Part 2 Pharmaceutical

Quality by Design gives the Elements of Pharmaceutical

Development, also introducing the terms laid out

• Appendix 1 is about di f fering approaches and gives examples of

‘minimal’ and ‘enhanced, Quality by Design’approaches ; Appendix 2

is I l lustrative Examples.

ICH GUIDELINE BRIEFS -2

ICH Q9 – ‘QUALITY RISK MANAGEMENT’

• ICH Q9 lays out a framework on approaches for qual ity r isk

management, including r isk init iat ion, assessment, control , review,

communication and the tools to use

ICH Q10, ‘PHARMACEUTICAL QUALITY SYSTEMS’,

• lays out the fundamentals of what a qual ity system should cover,

including management responsibi l i ty, and continual improvement

of process performance and product qual ity and also of the qual ity

system itself.

QbD Terminology

• Quality target product profile (QTPP).

• Critical quality attribute (CQA).

• Critical process parameter (CPP).

• Critical materials attribute (CMA).

• Introduction to Quality by Design (QbD)

• Design space (DS).

• Control strategy (CS).

• Lifecycle.

QbD process applied to pharmaceutical product development 1

Define the quality

target product

profile (QTPP) as

it relates to

quality, safety‚

and efficacy,

considering, for

example, the route

of administration,

dosage form,

bioavailability,

strength, and

stability

STEP 1 STEP 2 STEP 3

Identify the

approach to drug

product

formulation/manu

facturing process

Identify potential

critical quality

attributes (CQAs)

of the drug

substance/raw

materials/

drug product, so

that those

characteristics

having an impact

on product quality

can be

studied and

controlled.

QbD process applied to pharmaceutical product development 2

Identify potential

critical process

parameters

STEP 4 STEP 5 STEP 6

Using risk

assessment and

experimental

approaches,

determine the

functional

relationships that

link raw material

CQAs and unit

operations critical

process

parameters

(CPPs)

to drug product

CQAs.

Optimise the

formulation and

manufacturing

process in an

iterative fashion

to meet the

QTPP defined in

step 1 of this list

QbD process applied to pharmaceutical product development 3

Establish the

design space and

control strategy.

STEP 7

Building

blocks

of QbD

.

Developing

the Model

Y=f(X)

Enables

Prediction

of Future

Process

Performance

.

Developing

and Using

Process

Understanding

.

Routes

to Process

Understanding

.

Tools for

Developing Process

Understanding

.

DOE

Decision Tree

.

Development of Novel Lipid Based

Drug Delivery System in a QbD

framework

SEDDS- Self Emulsifying Drug Delivery

System

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Formulation components of

SEDDS

• Drug

• Oil

• Surfactant

• Cosurfactant/Cosolvent

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Why SEDDS?

Enhanced drug

absorption

Prolongation of Gastric Residence

time

Reduced metabolism and efflux

activity

Promotion of intestinal lymphatic transport

Affecting permeability

In vivo solubilization

of drug

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Formulation

development through

QbD approach• Defining the QTPP and CQAs

• Justification for the CQAs

• Risk assessment/QRM matrix

• Solubility study

• Pseudo ternary phase diagram

• Design of Experiment

• Model fit

• Design validation/Verification

• Optimization of formulation

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Defining the QTPP

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QTPP Elements Target Justification

Dosage type Lipid based formulation Bioavailability improvement

Dosage form Capsule Ease of administration

Dosage strength 150 mg Target dose of 150 mg essential to

target viral load

Route of administration Oral Most convenient route for AIDS

patients(Patient acceptability)

Packaging Alu – Alu Blister Acts as a permeation and photo

barrier

Pharmacokinetics Tmax, Cmax, AUC For attaining MIC in the target site

Stability As per the conditions of

ICH Q1B Long term stability

studies

To assess degradatory pattern of the

Drug and Excipients used in the

formulation

Justification for the CQAs

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Quality Attributes of

product

Target CQA Justification

Physical

attributes

Color Acceptable to patient No The physical attributes were not directly related to

the efficacy and safety of the productOdor

Appearance

Drug content (mg) NLT 150 mg per unit

dose

Yes 150 mg per unit dose essential to combat the

CD4 viral load

Transmittance (%) ˃ 95 % Yes Clarity of the product ensures the minimization of

the globule size

Droplet size (nm) ˂ 200 nm Yes Smaller and consistent globule size essential for

stability and bioavailability of the formulation.

Zeta potential (mEv) Stearically stable Yes Target zeta potential essential to ensure stability

of the dispersed system

Emulsification efficiency

(seconds)

˂ 120 Yes Direct correlation with onset of action, and

influences the size of the dispersed globules

Drug release at 15 min ˃ 80 % Yes Has direct correlation with bioavailability

Permeability (45 mins) NLT 45 mins Yes f ≥ 80%

Ishikawa/Fish bone

diagram

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Risk Assessment/REM

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CMA /CPP

CQAs

Oil Surfactant Cosurfactant Stirring

speed

Stirring

time

Stirring

temperature

Drug content High High High Low Low Low

Droplet size High High High Medium Medium Medium

Zeta potential High High High Low Low Low

Emulsification Time High High High Medium Medium Medium

Drug release at 15

min

High High High Low Low Low

Permeability (45

mins)

High High High Low Low Low

Construction of Pseudo

Ternary Diagram

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Design of ExperimentCritical Material Attributes (CMA)

✓Oil

✓Surfactant

✓Cosurfactant

Critical Process Parameters (CPP)

✓Stirring speed (rpm)

✓Stirring Temperature

✓Stirring time (min)

Critical Quality Attributes (CQAs)

✓Drug loading (mg/ml)

✓Particle size (nm or µm or mm)

✓Poly dispersity index (PDI)

✓% Transmittance

✓Emulsification time (sec)

✓% Drug release

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Mixture Design• Independent Variables

✓Oil- Capryol 90

✓Surfactant- Tween 80

✓Cosurfactant – Transcutol HP

• Dependent variables✓Droplet size in nm

✓Emulsification time in seconds

✓Drug loading mg/ml

✓% Drug release at 15 min

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Model Fit

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Verification/Validation of model

Ternary mixture profiler

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Optimization of Formulation

Contour Profiler Report

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Prediction Profiler

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Predicted and Experimental values obtained for VF and

OF-SMEDDS

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Transition from Knowledge to Design Space

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