1. Drug Quality in the 21st Century
Janet Woodcock, M.D.
Director, Center for Drug Evaluation and Research
May 11, 2010

2. 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

3. 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

4. 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

5. 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

6. 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”

7. 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

8. 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. 

9. 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

10. 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

11. 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

12. 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

13. 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

14. 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
30 years after implementation of 210, 211…
“This guidance describes a comprehensive quality systems model, which, if implemented, will allow manufacturers to support and sustain robust, modern quality systems that are consistent with CGMP regulations.“
Quality professionals are aware that good intentions alone will not ensure good products. 
“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.”

15. 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

16. International Harmonization
In addition to Q10, Quality Systems:
Q8 Pharmaceutical Development
Q9 Quality Risk Management

17. This Was the State of Development in January 2008

18. 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

19. 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

20. 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

21. 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

22. 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 22 22

23. VT RI 3 MA CT 4 NJ 2 DE MD 3 3 16 (Puerto Rico) 4 2 (Guam)19 24 VT 7 14 19 11 1 15 4 2 6 8 RI 3 1 9 MA 6 1 4 CT 6 1 2 4 3 NJ 1 1 1 2 1 5 DE 13 1 5 1 3 7 MD 4 2 8 4 4 1 4 3 3 22 6 16 11
International
Mail Branches (14 total)
Express Consignment Facilities (29 total)
Number of Ports
in State (312 total) 5
(Puerto
Rico) 4 1 2 3
(Guam)
(Virgin Islands)

24. 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)

25. Manufacturing of Many FDA-Regulated Drug Products
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 safety

26. 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

27. 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

28. (DRLS)
Data Source: FDA/CDER Drug Registration and Listing System
* Finished drugs, intermediates and APIs; Products active on 3/18/2007

29. Number of Inspections Has Increased but Inspection Rate has Declined by 41 Percent
(DRLS)
* Data Source: FDA Drug Registration and Listing. Sites active on 3/18/2008

30. 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
Theresa – Gregg can specifically identify for you the factors that we use to determine risk.

31. 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

32. 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)

33. 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

34. 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

35. 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

36. 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

37. 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

38. 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

39. 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

40. 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

41. 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

42. 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