1 Drug Quality in the 21 st Century Janet Woodcock, M.D. Director, Center for Drug Evaluation and Research May 11, 2010
Mar 26, 2015
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Drug Quality in the 21st Century
Janet Woodcock, M.D.Director, Center for Drug Evaluation and
ResearchMay 11, 2010
Background of FDA’s “Pharmaceutical Quality for the
21st Century Initiative• In 2002, FDA identified a series of ongoing problems
and issues in pharmaceutical manufacturing that traditional approaches had not solved
• FDA undertook an internal and external assessment of the causes
• As a result, the agency started a major change initiative that is continuing
• Stimulating more use of PAT was an early component of initiative
State of Regulation circa 2002
• Pharmaceutical manufacturing HIGHLY regulated (e.g., compared to foods, fine chemicals)
• Cost of cGMP compliance very high• Despite this: process efficiency and
effectiveness low (high wastage and rework); and level of technology not comparable to other industries
Functional Consequences
• Inability to predict effects of scale-up
• Lack of agility – usually takes years to bring up a new production site
• Operations fragmented around globe
• Inability to understand reasons for manufacturing failures
Result: for Regulators
• Extensive oversight of manufacturing resource-intensive (in era of cost reductions and increased mandates)
• Expensive and time-consuming litigation and legal actions in cGMP area
• Need to deal with recalls and shortages of medically necessary drugs
Result: for Industry
• Culture: antithesis of “continuous improvement”• Less focus on quality, more on compliance• Regulatory burden high and costly, but not viewed
as contributing to better science• Consequences of noncompliance: potentially
catastrophic• Lack of innovation: “test but don’t tell”
Outcomes
• High cost of production for products due to– Low efficiencies in manufacturing – Waste– Long manufacturing cycle times based on
testing requirements during production• Drug shortages due to inability to
manufacture• Lack of improvements based on new
technologies• Slowed development/access for
investigational drugs• Need for intensive regulatory oversight
• More than 40 years ago, Congress required that all drugs must be produced in accordance with Current Good Manufacturing Practice (cGMP).
• Requirement was intended to address significant concerns about substandard drug manufacturing practices by applying quality assurance and quality control principles to drug manufacturing.
• Last comprehensive revisions to the regulations implementing cGMP requirements occurred over 25 years ago.
• The initiative was started in August 2002 as the Pharmaceutical cGMPs for the 21st Century - A Risk-Based Approach initiative to enhance and modernize the regulation of pharmaceutical manufacturing and product quality — to bring a 21st century focus to this critical FDA responsibility.
FDA needed to Modernize Pharmaceutical Manufacturing
Regulation
Initiative Included CBER, CDER, CVM and ORA
• Outreach and collaboration with industry• Revise regulations• Implement a “pharmaceutical inspectorate”• Change the CMC review process• Implement quality systems internally• Introduce new manufacturing science into the
regulatory paradigm• Harmonize these concepts internationally
The Desired State: A Mutual Goal of Industry, Society and the Regulators
A maximally efficient, agile, flexible pharmaceutical manufacturing sector that reliably produces high quality drug products without extensive regulatory oversight
Changing the CMC Review Process
• Multiple CMC review cycles and large number of postmarket manufacturing supplements filed to FDA—leads to delays in approval, slow incorporation of new technology, and high agency workload—thousands of supplements
• Cause: inconsistencies in application quality combined with lack of adequate pharmaceutical development information
Quality by Design
• Move from empirical assessment based on performance of clinical lots to concept of “building quality in” based on critical attributes
• Definition of pharmaceutical quality: a contamination-free product that will reproducibly deliver the performance described in the drug label
• Pursued formal and operational definitions of QbD in international context
Regulatory Changes and Manufacturing Science: Implementation of QbD in FDA
• Intensive implementation efforts across review, compliance and inspection programs:– Integration of Review and Inspection– Pharmaceutical Inspectorate (PI) Program – PAT Guidance (2004)– Public meetings, workshops and training programs– Withdrawal of FDA guidances that are not aligned with QbD vision
• CMC Pilot Program – ONDQA• Implementation of QbD for biotech products• Question-based review (QbR) for generic products
Guidance for Industry: Quality Systems Approach to Pharmaceutical CGMP Regulations
• Help manufacturers bridge between 1978 regulations and modern quality systems and risk management approaches
• Extends beyond CGMP expectations; however, does not create requirements on manufacturers. Implementation of this model should ensure compliance and encourage use of science, risk management and other principles of the 21st Century Initiative.
• Describes a comprehensive quality system model and how CGMP regulations link to QS elements
“When fully developed and effectively managed, a quality system will lead to consistent, predictable processes that ensure that
pharmaceuticals are safe, effective, and available for the consumer.”
Quality Systems : Implementation and International Development as the PQS
• Manufacturers with a robust quality system and appropriate process knowledge can implement many types of improvements and take responsibility for quality– Eliminate most of the burden of CMC post approval regulatory
submissions– Allow for more focused and fewer FDA inspections– Adoption by industry is starting to take hold – fewer deviations, cost
savings in manufacturing• ICH adopted this concept as Q 10 Pharmaceutical Quality
System (PQS) to fulfill the ICH Quality Vision – Covers the product lifecycle from pharmaceutical development, tech
transfer, commercial manufacturing, to discontinuation– Focuses on the commercial manufacturing process, predicted by
development and utilizes knowledge for process improvement and future development
International Harmonization
• In addition to Q10, Quality Systems:• Q8 Pharmaceutical Development• Q9 Quality Risk Management
This Was the State of Development in January 2008
Heparin was a Wakeup Call
• Up to 30% contamination of finished product• Present worldwide in various APIs: many
countries affected• Undetected by acceptance and release testing• Persisted in drug supply until serious adverse
events triggered investigation• Brought home the need for vigilance
throughout supply chain and in all global settings
Globalization of Pharmaceutical Manufacturing Poses Significant
Threats to US Drug Supply
• Safety and quality of US drug supply long taken for granted
• FDA not organized to oversee a global enterprise
• Shift to developing nations means shift away from regions with strong regulatory presence
• Sheer volume of new players challenging• New opportunities for criminal activity
Drug Postmarket Manufacturing Surveillance Circa 1990’s
• Domestic focus of inspectorate—FDA field – Organized around US districts– Obtaining foreign inspection rather difficult– FD&C Act required biennial inspection of domestic firms but silent on
foreign sites• Start of international harmonization efforts
– ICH-International Conference on Harmonization of Technical Requirements for Pharmaceuticals
– Spurred by multi-national Pharma– Successful but manufacturing not prominent– Exception “Q7A”—GMPs for APIs guidance
• Beginning of movement of production outside traditional regions—began with APIs
Oversight of Non-US Production
• No unique identifiers for foreign establishments
• Little regulatory focus on supply chain• Minimal Congressional/Administration
interest in the problem• “Porous” borders--FDA required to
demonstrate a problem to stop a drug entry
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Circa 1990s: Screening at Border
• Much burden on FDA
• Relies on paperwork accompanying shipments
• Little information known about most raw materials presented at borders– Presumes articles presented for importation can be traced back to
the source– API firms must register with FDA and provide drug/site information
(no analogous registration requirement for excipient manufacturers)
• Number of line items/day (food & drug) growing continuously– Which shipments should be scrutinized?– Which shipments contain drug ingredients?
• Limited assurance of traceability back to manufacturer
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International Mail Branches (14 total) Express Consignment Facilities (29 total)Number of Ports in State (312 total)
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Globalization: Significant Challenges for Maintaining Pharmaceutical
Quality• Increased complexity of supply chains; extensive
outsourcing• Greater potential for exploitation (e.g., counterfeits,
terrorism)• Global regulatory system fragmented• (US) Erosion of inspectional coverage over last
several decades• (US) Lack of modern IT (e.g., registration and listing
systems, inspection tracking, imports)
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““Data from FDA suggest that the agency may inspect Data from FDA suggest that the agency may inspect about 7 percent of foreign [drug] establishments in a about 7 percent of foreign [drug] establishments in a given year. At this rate, it would take FDA more than 13 given year. At this rate, it would take FDA more than 13 years to inspect each foreign establishment once . . . .” years to inspect each foreign establishment once . . . .” November 2007 GAO report on drug safetyNovember 2007 GAO report on drug safety
Mission v. Challenges Mission v. Challenges Manufacturing of Many FDA-Regulated Drug Products Manufacturing of Many FDA-Regulated Drug Products
Has Moved OverseasHas Moved Overseas
The Current State of Globalized Manufacturing
• Dispersed drug production: “world travelers”– APIs– Excipients/packaging/container-closures– Finished pharmaceuticals
• Weak/absent regulatory oversight in developing countries
• Lack of local tradition of quality management• Economically motivated fraud/counterfeits– Diffusion of science and scientific personnel enables
Trajectory of Globalization
• Expect ever increasing proportion of APIs to be from developing world
• Rapid increase in finished pharmaceuticals, especially generics
• Rise of innovator industries in Asia particularly• FDA not able to inspect all these sites on a
regular basis
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17,558
20,249
23,099
26,917
31,530
37,256
42,983
0
5,000
10,000
15,000
20,000
25,000
30,000
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CY01 CY02 CY03 CY04 CY05 CY06 CY07
Calendar Year
Nu
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Cumulative Listings Expon. (Cumulative Listings)
Data Source: FDA/CDER Drug Registration and Listing System* Finished drugs, intermediates and APIs; Products active on 3/18/2007
29
1,252
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1,973
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Fiscal Year
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Foreign Facilities Foreign Facilities
* Data Source: FDA Drug Registration and Listing. Sites active on 3/18/2008
Number of Inspections Has Increased but Inspection Rate has Declined by 41 Percent
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Different Facilities Pose Different Product Quality Risks
• CDER using risk-based approach to determine inspection priorities
• We also factor in the information received from other countries’ regulators
• Factors Determining Risk include (examples):– Manufacturer’s technical expertise – knowledge of FDA regulatory requirements, e.g. Good Manufacturing
Practices (GMPs)– Maturity of regulatory system in foreign “home” country– Complexity/ contamination risk of product– Level of exposure of US population
Corporate Responsibility
• Qualify and oversee component suppliers• Ensure security of supply chain• Have adequate testing methods and controls to
guard against substitutions/poor quality ingredients
• Consider total costs/liabilities to firm when choosing suppliers and sites—be prepared to provide level of support needed
Significant Challenges for Both Manufacturers and FDA
• Explosion of globalized manufacturing• Increased complexity of supply chains• Greater potential for exploitation (e.g.,
counterfeits, terrorism)• Global regulatory system still fragmented• (US) Erosion of inspectional coverage over last
several decades• (US) Lack of modern IT (e.g., registration and
listing systems, inspection tracking, imports)
Where We Need to Go
• Seamless, effective global regulatory collaboration– World wide safety net– Increase effectiveness of inspectorates in developing
countries• Fully harmonized quality standards (ICH and non-ICH
regions)• Manufacturing modernization• Harmonized pharmacopeial standards• Agreed-upon methods for supply chain security/integrity• IT: Better automation/standardization of global
inventory
Improvements Started in 21st Century Initiative are Critical
• Global harmonization of manufacturing standards
• Continuous improvement in manufacturing science
• Application of quality risk management• Quality by design
Quality by Design
• Requires strong quality management system• Requires monitoring and good change
control by manufacturer• Allows innovation• Frees up FDA inspectional resources to focus
on those at greater risk of problems
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Quality by Design and 21st Century Pharmaceutical Quality Initiative
• Quality by design continues to be a major goal
• Implementation is moving forward in all three product Offices of OPS
• Implementation of a Quality Management System within CDER will further support this initiative
Role of This PAT Workshop
• Gathering of academics, pharmaceutical industry, FDA, PAT equipment manufacturers
• Goal: update on use of the technology, present case studies, understand barriers to more widespread adoption
• Understanding of how PAT fits into the future of quality by design
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Role of This Workshop• FDA has been working intensively on QbD, quality
management systems, and our own internal processes
• PAT was a stimulating concept for the 21st Century Initiative: we want to continue our emphasis on the use of modern analytical technology
• Can help address many of the challenges discussed above
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FDA’s Internal Initiatives
• Reorganization within ONDQA to reflect multidisciplinary team approach to QbD submission review. OBP and OGD also addressing QbD in review
• Development of a quality management system for CDER: OPS in forefront
• Better coordination across OPS, CDER Office of Compliance and ORA
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Design of Workshop
• Hear from experts in the field who have successfully implemented PAT applications
• Hear from FDA—inspectors, compliance staff and reviewers—about how we work with PAT in submissions
• Case histories to illustrate practical aspects and (hopefully) decrease regulatory concerns
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Summary• The public expects their drugs to be of reliable high
quality• Tradition of empirical development of formulation and
manufacturing process makes reliability a challenge• Globalization introduces more risks of quality problems• FDA introduced “Pharmaceutical Quality for 21st Century”
to address these challenges
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Summary• Improved manufacturing science (QbD), when paired with
a robust quality system, is the key to reliable drug quality• Technologies such as PAT are crucial to implementing the
knowledge gained from QbD in a meaningful and efficient way
• FDA encourages adoption of these technologies, and is modifying its own processes in order to facilitate this change
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