Drug Quality in the
st
21
Century
Janet Woodcock, M.D.
Director, Center for Drug Evaluation and
Research
May 11, 2010
1
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
FDA needed to Modernize
Pharmaceutical Manufacturing
Regulation
• 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.
Initiative Included CBER, CDER, CVM
and ORA
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•
•
•
•
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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
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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VT 7
14
4
19
3
11
15
6
1
1
13
8
1
1
1
2
5
RI
7
1
3 NJ
DE
3
MD
4
1
4
22
4 CT
5
1
4
2
4
6
6
4
1
2
8
9 MA
1
2
1
3
3
6
16
11
4
1
(Guam)
2
International
Mail Branches (14 total)
Express Consignment Facilities (29
total)
Number of Ports
3
in State (312 total)
5
(Puerto
Rico)
(Virgin Islands)
23
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)
Mission v. Challenges
Manufacturing of Many FDA-Regulated Drug Products
Has Moved Overseas
“Data from FDA suggest that the agency may inspect about 7
percent of foreign [drug] establishments in a given year. At this
rate, it would take FDA more than 13 years to inspect each foreign
establishment once . . . .” November 2007 GAO report on drug
25
safety
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
50,000
Cumulative Listings
Expon. (Cumulative Listings)
45,000
42,983
Number of Active Products
40,000
37,256
35,000
31,530
30,000
26,917
25,000
23,099
20,249
20,000
17,558
15,000
10,000
5,000
0
CY01
CY02
CY03
CY04
Data Source: FDA/CDER Drug Registration and Listing System
Calendar Year
* Finished drugs, intermediates and APIs; Products active on 3/18/2007
CY05
CY06
CY07
28
Number of Inspections Has Increased but Inspection Rate has
Declined by 41 Percent
3,000
Foreign Facilities
2,782
Foreign Facilities
2,534
2,500
Number of Active Sites
2,253
1,973
2,000
1,729
1,452
1,500
1,252
1,000
500
249
211
260
189
255
325
212
0
2001
2002
2003
2004
2005
2006
2007
Fiscal Year
29
* Data Source: FDA Drug Registration and Listing. Sites active on 3/18/2008
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
30
– 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
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
36
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
37
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
38
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
39
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
40
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
41
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
42