Lawrence Yu, Ph.D. Deputy Director, Office of Pharmaceutical Quality FDA Center for Drug Evaluation and Research

Future of Pharmaceutical Quality and the Path to Get There

3rd PQRI/FDA Conference on Advancing Product Quality, March 22-24, 2017

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Early 2000s: FDA Embarks upon Pharmaceutical Quality for 21st Century

Initiative

Vision “A maximally efficient, agile, flexible pharmaceutical manufacturing sector that reliably produces high quality drugs without extensive regulatory oversight”

-Dr. Janet Woodcock

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2002: Pharmaceutical cGMPs for the 21st Century

2004: PAT Guidance

2006: ICH Q9

2008: ICH Q10

2009: ICH Q8

2011: Process Validation Guidance

2012: ICH Q11

2013: Emerging

Technology Quality Metrics

FDA CDER’s Quality Journey

Building the Science and Risk-Based Foundation for the Regulation of Pharmaceutical Quality

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Drivers for Modernizing Pharmaceutical Manufacturing

• Quality issues account for 2/3 of drug shortages

• Surge in drug product recalls due to quality issues

• The supply chain is globalized at an

unprecedented level

• Major advances in the scientific landscape are pressuring existing regulatory paradigms, especially around biosimilars, precision medicine, combination products and the use of real-world data

35%

31%

14%

8% 2%

6% 4% Quality: Facility RemediationEfforts

Quality: Product ManufacturingIssues

Discontinuation of Product

Raw Materials (API) Shortage

Other Component Shortage

Increased Demand

Loss of Manufacturing Site

Class 1 Drug Product Recalls

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Future of Pharmaceutical Quality

A Six Sigma Capable Process is Expected to Have No More than 3.4 Defects per Million Opportunities

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Path to Get 6 Sigma

• Economic Driver • Performance-based Regulation • Emerging Technologies • Quality by Design • Continuous Improvement and Operational

Excellence

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Economic and Technological Drivers of Generic Sterile Injectable Drug Shortages

• The fundamental problem we identify is the inability of the market to observe and reward quality. This lack of reward for quality can reinforce price competition and encourage manufacturers to keep costs down by minimizing quality investments...

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Woodcock, J; Wocinska, M. Clin. Pharmacol. & Thera. 93:170-176 (2013)

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Path to Get 6 Sigma

Economic Driver • Performance-based Regulation • Emerging Technologies • Quality by Design • Continuous Improvement and Operational

Excellence

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Performance-based Regulation

• A regulatory approach that focuses on desired, measurable outcomes, rather than prescriptive processes, techniques, or procedures. Performance-based regulation leads to defined results without specific direction regarding how those results are to be obtained

• At the Nuclear Regulatory Commission, performance-based regulatory actions focus on identifying performance measures that ensure an adequate safety margin and offer incentives to improve safety without formal regulatory intervention by the agency

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Types of Regulations

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• Pharmaceutical regulation should be designed to improve the performance of individual and organizational behavior in ways that protect and promote public health

Coglianese, C., & Lazer, D. (2003) Law & Society Review, 37(4), 691-730.

Planning Acting Outputs (both good and bad)

Stage of Production

Type of Regulation

Management Based

Technology Based

Performance Based

Stages of Organizational Production and Types of Regulation

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Types of Regulations

Coglianese, C., & Lazer, D. (2003) Law & Society Review, 37(4), 691-730.

Low High

High

Management-Based Regulation

Technology-Based Regulation

Performance-Based Regulation

PHARMACEUTICAL REGULATION

Homogeneity of Regulated Entities

Capa

city

to A

sses

s Out

put

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FDA is Moving to Clinically Relevant Specification

• Quality by Testing – Specification acceptance criteria are based on one or

more batch data – Testing must be made to release batches

• Quality by Design – Specification acceptance criteria are based on clinical

performance – Testing itself may not be necessary to release batches

We Need to Decouple Acceptance Criteria from Process Variability

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FDA Quality Metrics Program

• Goals: Objective measures – Quality of a drug product – Quality of a site

• Vision – Patients/consumers expect and deserve quality drugs – FDA and manufacturers have the shared responsibility to

make sure that quality drugs are available – The FDA’s quality metrics program improves the quality of

drugs, accessibility of quality drugs, and effectiveness of the FDA regulatory oversight

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Path to Get 6 Sigma

Economic Driver Performance-based Regulation • Emerging Technologies • Quality by Design • Continuous Improvement and Operational

Excellence

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Guidance for Industry PAT — A Framework for Innovative

Pharmaceutical Development, Manufacturing, and Quality

Assurance U.S. Department of Health and Human Services

Food and Drug Administration Center for Drug Evaluation and Research (CDER)

Center for Veterinary Medicine (CVM) Office of Regulatory Affairs (ORA)

September 2004 Pharmaceutical CGMPs

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Control Strategy Implementation Options

Traditional Approach

Enhanced Approach

Level 3

End product testing + Tightly constrained

material attributes and process parameters

Level 2 Reduced end product testing + Flexible critical material attributes and critical

process parameters within design space

Level 1 Real - time automatic control +

Flexible process parameters to respond

to variability in the input material attributes

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Impact of Active Control

Variable Input

Fixed Process

Variable Output

Variable Process

Variable Input

Uniform Output

PAT

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Continuous Manufacturing

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(1) Batch

(2) Hybrid

(3) End-to-End

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Trends in Continuous Manufacturing

• Vertex’s ORKAMBI™ (lumacaftor/ivacaftor) – 1st NDA approval for using a continuous manufacturing technology for

production of the Cystic Fibrosis drug (tablets) (July 2015)

• Prezista (darunavir) – 1st NDA supplement approval for switching from batch manufacturing to

continuous manufacturing process for an FDA-approved HIV drug (tablet) (April 2016)

• Over 15 ETT-Industry meetings – Drug substance – Drug product – Small-molecule and biotechnology products – Control strategy utilizing models

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Path to Get 6 Sigma

Economic Driver Performance-based Regulation Emerging Technologies • Quality by Design • Continuous Improvement and Operational

Excellence

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Quality by Design • ICH Q8(R2)

– Pharmaceutical Quality by Design (QbD) is 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

• Quality by Design Tools – Prior knowledge – Risk assessment – Design of experiments (DOE) and data analysis – Process analytical technology (PAT) tools

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Quality by Design: Objectives

• To achieve meaningful product specifications that are based on clinical performance

• To increase process capability and reduce product variability and defects by enhancing product and process design, understanding, and control

• To increase product development and manufacturing efficiencies

• To enhance post-approval change management

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Relationship of CMA, CPP, and CQA

Pharmaceutical Unit

Operation Input Materials

Output Materials or Product

CPPs

CMAs CQAs

A CQA of an output material may become a CMA if it becomes an input material of another unit operation

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STEP 6 Develop a control strategy

STEP 5 Analyze the experimental data

STEP 4 Design and conduct experiments, using DOE when appropriate

STEP 3 Identify levels or ranges of these high risk attributes or parameters

STEP 2 Identify high risk attributes or parameters based on risk assessment and scientific knowledge

STEP 1 Identify all possible material attributes and process parameters

Continuous Improvement

Product & Process Understanding

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QbD Improves Product Quality

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Path to Get 6 Sigma

Economic Driver Performance-based Regulation Emerging Technologies Quality by Design • Continuous Improvement and Operational

Excellence

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ICH Q10 Pharmaceutical Quality System

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McKinsey: “Flawless: From measuring failures to building quality robustness in pharma” •“There’s…the challenge of shifting mind-sets across industry that has focused predominantly on compliance rather than on truly knowing the root causes and effects on quality issues”

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Creating a Culture of Quality S. Srinivasan and B. Kurey, Harvard Business Review, 2014

• Culture of quality: An environment in which employees not only follow quality guidelines but also consistently see others taking quality-focused actions, hear others talking about quality, and feel quality all around them

• Four Essentials of Quality – Maintaining a leadership emphasis on quality – Ensuring message credibility – Encouraging peer involvement – Increasing employee ownership and empowerment

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Characteristics of Culture for Quality • Clearly visible, engaged and unwavering senior

management support for quality • Clearly articulated vision and values • Active and ongoing engagement with customers to

continually identify and address current and evolving needs

• Clearly stated quality goals • Performance expectations for all individuals throughout

the company that clearly link to quality goals • Appropriate incentives—which can favor monetary or

recognition-based awards, depending on individual circumstances.

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Continuous Improvement

• Leaders must take the lead in quality improvement • Investments in quality improvement must be

substantial • Modern tools for improvement must be put to use • Flawless execution, focusing on quality, not

compliance/enforcement • Communications among industry, patients, and

regulators must be open and carefully maintained

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Yu et al. The Use of Process Capability to Ensure Product Quality

Pharm. Eng. (2015)

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A Sustained Focus on Quality Risk Management Has Delivered Improvements in Product Quality

©2014 Eli Lilly and Company 38

Comparison of 2013 Performance to 2007 Baseline

Activity Indicators

Productivity Improvement

Performance Improvement

PQRI – October 2015

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Path to Get 6 Sigma

Economic Driver Performance-based Regulation Emerging Technologies Quality by Design Continuous Improvement and Operational

Excellence