Future of Pharmaceutical Quality and the Path to Get...
Transcript of Future of Pharmaceutical Quality and the Path to Get...
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
2
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
3
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
4
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
5
Future of Pharmaceutical Quality
A Six Sigma Capable Process is Expected to Have No More than 3.4 Defects per Million Opportunities
6
Path to Get 6 Sigma
• Economic Driver • Performance-based Regulation • Emerging Technologies • Quality by Design • Continuous Improvement and Operational
Excellence
7
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...
7
Woodcock, J; Wocinska, M. Clin. Pharmacol. & Thera. 93:170-176 (2013)
8
Path to Get 6 Sigma
Economic Driver • Performance-based Regulation • Emerging Technologies • Quality by Design • Continuous Improvement and Operational
Excellence
9
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
9
10
Types of Regulations
10
• 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
11
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
12
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
13
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
13
14
Path to Get 6 Sigma
Economic Driver Performance-based Regulation • Emerging Technologies • Quality by Design • Continuous Improvement and Operational
Excellence
15
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
17 17
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
18
Impact of Active Control
Variable Input
Fixed Process
Variable Output
Variable Process
Variable Input
Uniform Output
PAT
21
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
22
Path to Get 6 Sigma
Economic Driver Performance-based Regulation Emerging Technologies • Quality by Design • Continuous Improvement and Operational
Excellence
23
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
24
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
26
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
28
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
30
Path to Get 6 Sigma
Economic Driver Performance-based Regulation Emerging Technologies Quality by Design • Continuous Improvement and Operational
Excellence
32
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”
33
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
34
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.
35
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
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