Quality by Design Trevor Schoerie

Slide 2

Guidelines

• Please contribute and ask questions

• Please relax and enjoy yourself

• Phone on silent / mute?

• Native presentation can be emailed.

Slide 3

Agenda

What is QbD? 1

2

Why are we talking about QbD? 3

Where will QbD be applicable? 4

Who is driving QbD?

The what, who, why, where, when but not the how of QbD

When will we need to adopt QbD? 5

How do we do QbD? 6

Slide 4

What is QbD?

The quality by design (QbD) principle can be simply stated as follows:

Once a system has been tested to the extent that the test results are predictable, further testing can be replaced by establishing that the system was operating within a defined design space.

Slide 5

Who is driving QbD?

“As we’ve said many, many times, FDA Office of Generic Drugs expects QbD applications starting January 2013. You heard right, full implementation of QbD in January 2013.” FDA’s Lawrence Yu, deputy director for science and chemistry in the Office of Generic Drugs Joint EU / US QbD program.

Slide 6

Why are we talking about QbD?

QbD

ICH Q8, Q9 Q10 and Q11

Other documents

•Case studies

•PDA & FDA

GMP’s

•EU

•US FDA

•PIC/S

Design space

Risk

Quality Targeted Product Profiles QTPP

Control strategy

Design of experiments

DOE

Critical Process

Parameters CPP

Critical Quality

Attributes (CQA)

Product Lifecycle

Slide 7

Where will QbD be applicable?

Lifecycle concept, but QbD is at the start of the product lifecycle, i.e. product design, R&D

FDA Process Validation - 3 stages

1. Process Design = Quality by Design

2. Process Qualification (National Validation Forum)

3. Continued Process Verification

National Validation Forum 1 http://www.pharmout.com.au/events/validation-forum.shtml

National Validation Forum 2 http://pharmout.com.au/events/validation-forum2.shtml

Slide 8

When will we need to adopt QbD?

1987 | 2000 |2002 | 2004 | 2006 | 2008 2010 | 2011 | 2013

FDA Guide to Process Validation

EU Annex

15

FDA: Pharmaceutical cGMPs For The

21st Century

ICH Q9

FDA: Quality System

Approach to Pharmaceutical

cGMP

PICS VMP

ICH Q10

ICH Q11

ISPE C&Q Baseline 5

Guide

ISPE 21st Century

Qualification White Paper

ICH Q8

FDA Process

Val. Guidance

US Law

as from

1st Jan

2013?

ASTM E2500-

07

Slide 9

Australian GMPs - Risk

Year GMP reference x times risk mentioned

1971 First TGA code of GMP 3

1990 TGA GMP code (Blue Book) 20

2002 First PIC/S code adopted in Australia 57

2008 Current – 2009 version of the PIC/S GMP code 390

ICH ICH Title x times risk mentioned

Q8 Pharmaceutical Development (2006) 10

Q9 Quality Risk Management (June 2006) 279

Q10 Pharmaceutical Quality System (April 2009) 34

Q11 Development & Manufacture of Drug Substances (May 2012) 51

Slide 10

What is QbD?

Quality by Design (QbD) is a concept first outlined by Juran

ICH - concepts

1. Quality by Design

2. Design Space

3. Design of Experiments

4. Critical Quality Attributes (CQA)

5. Critical Process Parameters (CPP)

6. Control Strategy

Slide 11

“Dosage form Design”

“A rational approach to dosage form design requires a complete understanding of the physicochemical and biopharmaceutical properties of the drug substance.”

DOSAGE FORM DESIGN: A PHYSICOCHEMICAL APPROACH. Michael B. Maurin (DuPont Pharmaceuticals Company, Wilmington, Delaware, U.S.A.), Anwar A. Hussain and Lewis W. Dittert (University of Kentucky, Lexington, Kentucky, U.S.A.)

FDA Publication - Quality by Design: Next Steps to Realize Opportunities? Ajaz S. Hussain, Ph.D.

Office of Pharmaceutical Sciences, CDER, FDA, 17 September 2003

Slide 12

FDA Process Validation

PharmOut White Paper on FDA http://www.pharmout.com.au/downloads/white_pape

r_fda_process_validation_guidance_final.pdf

ICH Q11 discusses the

Enhanced vs Traditional

approach

Slide 13

FDA PV Stages

Stage 1 – Process Design: The commercial manufacturing process is defined during this stage based on knowledge gained through development and scale-up activities.

Stage 2 – Process Qualification: During this stage, the process design is evaluated to determine if the process is capable of reproducible commercial manufacturing.

Stage 3 – Continued Process Verification: Ongoing assurance is gained during routine production that the process remains in a state of control.

[FDA Guidance for Industry Process Validation: General Principles and Practices, Jan 2011]

Slide 14

FDA Stage 1

Stage Intent Typical activities

Process design

To define the commercial process on knowledge gained through development and scale up activities The outcome is the design of a process suitable for routine manufacture that will consistently deliver product that meets its critical quality attributes

A combination of product and process design (Quality by Design) Product development activities Experiments to determine process parameters, variability and necessary controls Risk assessments Other activities required to define the commercial process Design of Experiment testing

Slide 15

FDA Stage 2

Stage Intent Typical activities

Process Qualification

To confirm the process design as capable of reproducible commercial manufacturing

Facility design Equipment & utilities qualification Process Performance qualification (PPQ)* Strong emphasis on the use of statistical analysis of process data to understand process consistency and performance

* Note: The term “Process Performance Qualification” or PPQ has been carried over from the 1987

guidance. This term is analogous with the traditional concept of ‘process validation’, as multiple batches of

product made at commercial scale under commercial manufacturing conditions. It is not the same as the

concept of ‘equipment performance qualification’.

Slide 16

FDA Stage 3

Stage Intent Typical activities

Continued Process Verification

To provide ongoing assurance that the process remains in a state of control during routine production through quality procedures and continuous improvement initiatives.

Product review SOP data collection from every batch Data trending and statistical analysis Equipment and facility maintenance Calibration Management review and production staff feedback Improvement initiatives through process experience

Slide 17

FDA and Industry publications

• Quality by Design for ANDAs: An Example for Immediate-Release Dosage Forms April 2012 http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/AbbreviatedNewDrugApplicationANDAGenerics/UCM304305.pdf

• Quality by Design for ANDAs: An example for Modified Release Dosage Forms Dec 2011 http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/AbbreviatedNewDrugApplicationANDAGenerics/UCM286595.pdf

• Applying Quality by Design to Vaccines CMC-Vaccines Working Group May 2012 http://www.pda.org/Home-Page-Content/CMC-VWG-A-VAX.asp

Slide 18

ICH

• ICH Q8, Q9, Q10 & Q11are designed as separate but linked in a series of documents exploring pharmaceutical products lifecycle

• ICH Q8 Pharmaceutical Development

• ICH Q9 Quality Risk Management

• ICH Q10 Pharmaceutical Quality System

• ICH Q11 - Development and Manufacture of Drug Substances

Slide 19

ICH Q8 Concepts

Design Space

CQA

Variable 1

CQA Variable 2

CDQ

Variable 3

CQA Variable 4

Critical Process Parameter (CPP) Control strategy

Design Space

Acceptable Range

Most profitable

Slide 20

Pharmaceutical Development ICH Q8

Slide 21

Pharmaceutical Development ICH Q8

Quality by Design (QbD)

A systematic approach to development that begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management.

Slide 22

Pharmaceutical Development ICH Q8

Critical Quality Attribute (CQA)

– Quality attributes that must be controlled within pre defined limits

– Assurance that product meets its intended safety, efficacy, stability and performance

Slide 23

Pharmaceutical Development ICH Q8

Critical Process Parameter (CPP)

a process parameter that must be controlled within pre defined limits

– Assurance the product meets its pre defined quality attributes

Slide 24

Quality Risk Management ICH Q9

PIC/S code of GMP, PE009-8, January 2009

Slide 25

Pharmaceutical Quality Systems Q10

• Knowledge Management

• Describes systems that facilitate establishment and maintenance of a state of control for process performance and product quality.

• Facilitates innovation and continual improvement

• Applies to drug substance and drug product throughout product lifecycle

• Control strategy

Slide 26

Pharmaceutical Quality System (PQS) ICH Q10

Good Manufacturing Practice

Pharmaceutical Development

Technology Transfer

Commercial Manufacturing

Product Discontinuation

Investigational

products

Management Responsibilities

Process Performance & Product Quality Monitoring System

Corrective Action / Preventative Action System

Change Managements System

Management review

Knowledge Management

Quality Risk Management Enablers

PQS

elements

Slide 27

Development and Manufacture of Drug Substances - ICH Q11

Provides further clarification on the principles and concepts described in ICH guidelines on -

• Pharmaceutical Development (Q8),

• Quality Risk Management (Q9)

• Pharmaceutical Quality Systems (Q10)

as they pertain to the development and manufacture of drug substance.

Slide 28

Development and Manufacture of Drug Substances - ICH Q11

Traditional approach

– Set points & operating ranges

– Process reproducibility and testing to meet acceptance criteria

Enhanced approach

– Risk management & science.

– process parameters and unit operations that impact on CQA

– Further studies, design space & control strategies over the lifecycle.

Slide 29

Development and Manufacture of Drug Substances - ICH Q11

A company can choose to follow different approaches in developing a drug substance.

For the purpose of this guideline, the terms “traditional” and “enhanced” are used to differentiate two possible approaches.

Slide 30

ICH Q11 Example – Linking Material Attributes & process parameters to a Drug CQA

At Step F – Temp reflux

Only 1 impurity is formed –

hydrolysis_impurity

t = c, Conc. = c, H2O = c

hydrolysis_impurity = <0.30% hydrolysis_impurity

Slide 31

ICH Q11 Example – Linking Material Attributes & process parameters to a Drug CQA

Slide 32

ICH Q11 Example – Linking Material Attributes & process parameters to a Drug CQA

Traditional Approach:

Set a proven acceptable

range for % water and time

that achieves the

acceptance criteria for the

hydrolysis impurity of

0.30% in intermediate F.

Dry Intermediate E to a

water content < 1.0%.

Target reflux time of 1.5

hours and a maximum

reflux time of 4 hours

Slide 33

ICH Q11 Example – Linking Material Attributes & process parameters to a Drug CQA

Enhanced Approach:

Where:

[F]o refers to the initial concentration of intermediate F,

[H20] o refers to the initial concentration of water,

M=[F]o/ [H20] o refers to the ratio of the initial concentration of intermediate F

to the initial concentration of water, and

XF refers to the time-dependent concentration of the hydrolysis

degradant of intermediate F.

Slide 34

ICH Q11 Example – Linking Material Attributes & process parameters to a Drug CQA

Summary:

While both the traditional

and enhanced approach

provide ranges of water

content and time to control

the formation of the

hydrolysis impurity, the

enhanced approach allows

more manufacturing

flexibility.

Slide 35

Control Strategy

Planned set of controls, derived from current product and process understanding that assures process performance and product quality

A control strategy can include, but is not limited to, the following:

• Material attributes (raw materials, starting materials, intermediates, reagents, primary packaging materials)

• Controls are implicit in the design of the manufacturing process

• In-process controls

• Controls on drug substance

Slide 36

Control strategy table Drug Substance CQA (3.2.S.2.6) / Limit In Drug Substance

In process Controls (Including In-process testing and process parameters)

Controls on material attributes (raw materials / starting materials / intermediates)

Impact of Manufacturing Process Design

Is CQA tested on drug substance / Included in Drug Substance specification (3.2.S.4.1)

Organic Purity

Impurity X NMT 0.15%

Impurity Y

NMT 0.20%

Any individual unspecified impurity

NMT 0.10%

Design space of the reflux unit operation composed of a combination of % water in Intermediate E and the reflux time in step 5 that delivers Intermediate F with Hydrolysis Impurity ≤0.30% (3.2.S.2.2)

Process parameters step 4 (3.2.S.2.2)

P(H2) ≥2 barg

T <50°C

In-process test step 4 (3.2.S.2.4)

Impurity Y ≤0.50%

Specs for starting material D (3.2.S.2.3)

Yes/Yes

Yes/Yes

Yes/Yes

Total impurities

NMT 0.50%

Enantiomeric purity

S-enantiomer

NMT 0.50%

Specs for starting material D (3.2.S.2.3)

S-enantiomer ≤0.50%

Stereocentre is shown not to racemize; (3.2.S.2.6)

Yes/Yes

No/No

Residual Solvent

Ethanol

NMT 5000 ppm

In-process test during drying after final purification step (3.2.S.2.4)

LOD ≤0.40%

In-process results correlated to test results on drug substance

No/Yes

Slide 37

Extracted from the FDA IM release worked example

http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/Abbreviat

edNewDrugApplicationANDAGenerics/UCM304305.pdf

Slide 38

Submission of Control Strategy Information

The information provided on the control strategy should include detailed descriptions of the individual elements of the control strategy plus, when appropriate, a summary of the overall drug substance control strategy.

ICH M4Q recommends ….

• Description of Manufacturing Process and Process Controls (3.2.S.2.2)

• Control of Materials (3.2.S.2.3)

• Controls of Critical Steps and Intermediates (3.2.S.2.4)

• Container Closure System (3.2.S.6)

• Control of Drug Substance (3.2.S.4)

Slide 39

Common Technical Document (CTD) - Quality (ICH M4Q) guideline

Regional Admin

Information

Module 1

Nonclinical Overview

Nonclinical Summary

Clinical Overview

Clinical Summary

Quality Overall

Summary

Quality Nonclinical

Study Reports Clinical

Study Reports

Module 3 Module 4 Module 5

Module 2

Not Part of the CTD

The CTD

Slide 40

Thanks

http://au.linkedin.com/in/schoerie

1. What is QbD?

2. Who is driving QbD?

3. Why are we talking about QbD?

4. Where will QbD be applicable?

5. When will we need to adopt QbD?

6. How do we do QbD?