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

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 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 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.”

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 22 22

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)

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)

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

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

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

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

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.

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

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

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

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

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

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

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