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Quality by Design

Trevor Schoerie

Please contribute and ask questions
Please relax and enjoy yourself Phone on silent / mute? Native presentation can be emailed.
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The what, who, why, where, when but not the how of QbD 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?
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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.

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Who is driving QbD?

As weve 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.
FDAs Lawrence Yu, deputy director for science and chemistry in the Office of Generic Drugs

Joint EU / US QbD program.

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Why are we talking about QbD?

Other documents GMPs

Critical Quality Attributes (CQA) Critical Process Parameters CPP

Quality Targeted Product Profiles QTPP Design of experiments DOE Product Lifecycle
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Case studies PDA & FDA

ICH Q8, Q9 Q10 and Q11

Design space


Control strategy

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 National Validation Forum 2

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When will we need to adopt QbD?

Pharmaceutical cGMPs For The 21st Century
FDA Guide to Process Validation EU Annex 15 ICH Q9 FDA: FDA: Quality System Approach to Pharmaceutical cGMP PICS VMP ICH Q10 ICH Q11

1987 | 2000


| 2004

| 2006

| 2008 2010 | 2011


ISPE C&Q Baseline 5 Guide

ISPE 21st Century Qualification White Paper


ASTM E250007

FDA Process Val. Guidance

US Law as from 1st Jan 2013?

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Australian GMPs - Risk

Year 1971 1990 2002 2008 ICH Q8 Q9 Q10 Q11 GMP reference First TGA code of GMP TGA GMP code (Blue Book) First PIC/S code adopted in Australia Current 2009 version of the PIC/S GMP code ICH Title Pharmaceutical Development (2006) Quality Risk Management (June 2006) Pharmaceutical Quality System (April 2009) Development & Manufacture of Drug Substances (May 2012) x times risk mentioned 3 20 57 390 x times risk mentioned 10 279 34 51

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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
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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

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FDA Process Validation

ICH Q11 discusses the Enhanced vs Traditional approach

PharmOut White Paper on FDA r_fda_process_validation_guidance_final.pdf

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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]

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FDA Stage 1
Process design


Typical activities

To define the A combination of product and process commercial process on design (Quality by Design) knowledge gained through development Product development activities and scale up activities Experiments to determine process parameters, The outcome is the variability and necessary design of a process controls suitable for routine manufacture that will Risk assessments consistently deliver product that meets its Other activities required to define the critical quality commercial process attributes Design of Experiment testing

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FDA Stage 2
Process Qualification


Typical activities

To confirm the process Facility design design as capable of reproducible Equipment & utilities qualification commercial manufacturing 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.
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FDA Stage 3
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.

Typical activities
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

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FDA and Industry publications

Quality by Design for ANDAs: An Example for Immediate-Release Dosage Forms April 2012 pplicationANDAGenerics/UCM304305.pdf

Quality by Design for ANDAs: An example for Modified Release Dosage Forms Dec 2011 pplicationANDAGenerics/UCM286595.pdf

Applying Quality by Design to Vaccines CMCVaccines Working Group May 2012

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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

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ICH Q8 Concepts
Critical Process Parameter (CPP) Control strategy

CQA Variable 1

Design Space
CQA Variable 4 Design Space CDQ Variable 3 CQA Variable 2

Most profitable Acceptable Range

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Pharmaceutical Development ICH Q8

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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.

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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

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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

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Quality Risk Management ICH Q9

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

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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

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Pharmaceutical Quality System (PQS) ICH Q10

Pharmaceutical Development Technology Transfer Commercial Manufacturing Product Discontinuation

Investigational products

Good Manufacturing Practice

Management Responsibilities

Process Performance & Product Quality Monitoring System

PQS elements

Corrective Action / Preventative Action System Change Managements System

Management review


Knowledge Management Quality Risk Management

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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.
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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.
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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.

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

At Step F Temp reflux Only 1 impurity is formed


t = c, Conc. = c, H2O = c hydrolysis_impurity = <0.30%

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

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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

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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
M=[F]o/ [H20] o to

refers to the initial concentration of water,

refers to the ratio of the initial concentration of intermediate F the initial concentration of water, and

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refers to the time-dependent concentration of the hydrolysis degradant of intermediate F.

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.

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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

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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%

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 <50C Specs for starting material D (3.2.S.2.3)


Impurity Y NMT 0.20%


Any individual unspecified impurity NMT 0.10% Total impurities NMT 0.50% Enantiomeric purity S-enantiomer NMT 0.50% Residual Solvent Ethanol Slide 36 NMT 5000 ppm

In-process test step 4 (3.2.S.2.4) Impurity Y 0.50%


Yes/Yes 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) In-process results correlated to test results on drug substance No/No

In-process test during drying after final purification step (3.2.S.2.4) LOD 0.40%


Extracted from the FDA IM release worked example edNewDrugApplicationANDAGenerics/UCM304305.pdf

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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)

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

Regional Admin Information

Not Part of the CTD

Module 1
Nonclinical Overview Quality Overall Summary

Module 2

Clinical Overview Clinical Summary Clinical Study Reports


Nonclinical Summary Nonclinical Study Reports


Module 3
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Module 4

Module 5


1. 2. 3. 4. 5. 6.
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What is QbD? Who is driving QbD? Why are we talking about QbD? Where will QbD be applicable? When will we need to adopt QbD? How do we do QbD?