Quality by Design Concept

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Dr. Yafit Stark

Vice President, TEVA Pharmaceutical Industries, Ltd.

R&D Quality and Pharma Sciences

6-7 June, 2012

QbD in Clinical Research - Where Can

QbD Impact Clinical Research Practices?

Quality by Design Concept

New concept for drug development and approvable process

Creates a road map for designing new compounds

Quality is easily transferable throughout development

Allows more flexibility in development and regulatory approach

Understanding and optimizing:

• How designing and manufacturing of a product may affect the product’s quality, its clinical safety and effectiveness

• How the product’s safety and effectiveness will affect its design and quality

Moving towards a more scientific, risk-based, holistic and

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Why Do We Need Quality by Design?

Why Do Projects Fail?

On time

or ahead of time

Quality

meets expectations,

fulfils purpose

Cost

on or under budget

Success and failure are defined according to 3 main dimensions:

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Can Failure Be Prevented?

“Prevention” is dependent on the extent to which we

can anticipate and manage risk

The goal of Quality by Design is to build quality in prospectively,

rather than “test it in”

retrospectively

This means identifying in advance where the risks to quality lie and planning to avoid or

mitigate them

Failure Prevention by Implementation of QbD

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7 Target Product Profile

Product Design

Process Design

Process Performance

Product Development Material Science &

API Development

Process Development

& Tech Transfer

Continuous Process Verification

People, Equipment and Facilities

Continual Improvement Product Enhancement Ph 1 Ph II Ph III -NDA- Commercial Manufacture

Process Analytical Technology Knowledge management Quality Risk Management

What is QbD?

In Vitro In Vivo Correlation

A Work Plan

Janet Woodcock, 2004:

FDA concluded “Basic research isn’t enough;

we have to look at the critical path that the product must follow before it is introduced to market44 The science required to evaluate new product safety and efficacy.”

The outgrowth of that effort was the critical path concept:

• We are accelerating the pace of introducing the new science and technology

• More from empirically derived trial and error methods to rigorous mechanistically based and statistically run processes

FDA View: How Can We Make It Differently?

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The QbD Process

Streamline the clinical development of innovative drugs

Better understanding the product early on will lead to better science

Improve product reliability and reproducibility

Making available new products, including targeted therapies

Maximizing efficacy while minimizing safety hurdles to patients

Increase productivity of drug development

Establishing a clear linkage between safety and efficacy of the drug product in the patients

Quality of the product is linked back to the process of its preparation

QbD requires:

• Clinical understanding: link between the product and its safety and efficacy in humans

• Process understanding: link between the drug product and process attributes

FDA Viewpoints: QbD

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EMA “Roadmap” Outlines Drug Regulation/Vision

Vision for future EU regulatory environment

Regulators and Industry start working together earlier on in policy for new drug development process

Speed up availability of certain drugs

• Addressing public health needs

• Improving access to medicines

• Optimizing the safe use of medicines

Possible QbD Clinical Approach

Determine:

• Target indication

• Route of administration

• Target patient population

What’s ahead:

• Advancing reliable new methodologies to harness the potential of the clinical product development

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Clinical Deliverables

Definition and design of clinical criteria that will evaluate potential and biological relevance of the product early on in development

Explore alternatives to large clinical studies (in- silico patients)

Design and implement innovative clinical design protocols during clinical development

Quality should be built in by design

Information from clinical development as the basis for quality risk management

Click to edit Master title styleTransition Toward A Mechanistic Based Approach

Trial and Error Empirical Testing Patient Exposure Based Assessment of Efficacy &

Adverse Events

Mechanistic Based Approach Predictive Evaluation Based On a

New Molecular Knowledge About the Mechanisms of Disease and

Products

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A New Product Development Toolkit is Urgently Needed

New predictive tools:

• Improve predictability and efficiency along the critical path

–Early identification of product candidate with greatest efficacy against molecular and biological processes

–Early evaluation of product safety

New evaluative tools:

• Improve the performance of clinical trials and treatment choices

Better Evaluative & Predictive Tools

• Advancing Use of Biomarkers &

Next Generation Technologies

• Disease

• Safety

• Efficacy

Streamlining Clinical Trial Process Innovative Clinical Development Plan

• Adaptive & Exploratory Design

Ensure Efficacy & Success Early Stage Decision Making Developing Drugs Faster Smaller Patient Population Lower Costs

More Certainty

Innovative Drug Development to Ensure Efficacy & Success

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A New Era of Drug Development

Decreasing productivity

Increasing cost per successful trial

Slow incremental change in processes

Paradigm shift underway towards:

Learn/Confirm Structure

Innovative Trial Design/Adaptive Clinical Trials

Click to edit Master title styleEmploying Novel Paradigms in Clinical Development

Preclinical Phase I Phase II Phase III Phase IV LCM Discovery

Pre

clinical Exploratory Registrational Commercialization Discovery

Biomedical Sciences

• Early Development

• Bimarkers Strategy

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Moving Forward

Moving forward for the patient’s benefit requires:

• Methods based on understanding, knowledge and good science

• Selection/application of the right tool for the right purpose

• Studies based on and developed with QbD principles

Regulatory Basis and Context for Quality Risk Management (QRM)

Main focus to date has been on CMC

Gradual shift to apply concept to clinical drug development, focusing on highly regulated areas:

• GCP

• Clinical trials

• Pharmacovigilance

ICH Q8 (Pharmaceutical 4), Q9 (QRM) final in 2005, Q10 (Quality Systems) final 2008

FDA Quality by Design: Pharmaceutical Quality for the 21^stCentury A Risk-Based Approach

http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm128080.htm

• 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

Concern about practical implementation of Q9-10 into GCP

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FDA:

• Can’t “inspect in” quality retrospectively – need to build in prospectively

• Expect shift from data-heavy NDA/BLA submissions to

“knowledge-rich”, i.e. with insights gained from QRM approaches

• Involve regulators proactively in agreeing quality definitions for programs

EU:

• Identify risks prospectively

• Comprehensive/holistic approach:

• Organizational level

• Project level

• In clinical program, apply concept at early program design stage, before individual trials are running

Expectations of Regulatory Authorities for QRM

How can QbD Help in Mitigating the Clinical Drug Risk of Development

Quality by Design adds value anywhere where time, cost or quality matters:

Designing optimal infrastructure

Optimizing processes and systems

De-risking clinical programs and individual studies

“Fit-for-purpose” training and communication

Enhancing GCP compliance and reducing audit/inspection findings

Meeting health authority expectations

Reducing costly errors

Getting it right first time – minimizing need for laborious

“fixes”

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Project Risk Management Plan

Ideally, should be included in project management plan

Can be simple, informal, e.g.

• Risk sources reviewed

• Risks identified

• Mitigation plans

Formal risk management plan should contain plans and procedures for:

• Sources of risk and risk identification

• Risk analysis (impact, probability, detectability)

• Risk response planning

• Risk monitoring and control

Conclusions

Innovations in study designs are critical for success of clinical development:

• Simulations

• Adaptive Designs

• Bayesian Networks

New initiatives to translate animal data into early human testing are underway (IVIVC)

More management maturity (on the Quality Ladder)

Expanded application of QbD in pharmaceutical industry

Build in quality in advance instead of fixing things afterwards

Evan a simple risk management plan is better than nothing

Start as far “upstream” as possible and think holistically

Update the project RMP periodically, e.g. at milestones/phase transitions

Use project RMP in communications with management

Use project RMP in de-brief at project end

Structured RMP for all projects allows systemic findings across organization

Establish a culture of proactive risk management and “what if”

thinking

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Conclusions

(contd.)

Quality by Design in Clinical Development – Do we wish to have a new concept?

• Foster clinical development

• Maximize success in clinical development

• Ensure safety and effectiveness making successful drugs available for unmet needs

QbD is a strategic/systemic approach in improving product development to maximize the success of getting new products to the market:

faster

safer

smarter

and for less!!!