OFFICE OF REGULATORY AFFAIRS FIELD OPERATIONS CDR Thomas R. Berry, RPh, PharmD FDA, Senior Regulatory Review Officer DEN

1. OFFICE OF REGULATORY AFFAIRS FIELD OPERATIONS CDR Thomas R. Berry, RPh, PharmD FDA, Senior Regulatory Review Officer DEN-DO / SWR / ORA

2. Information Disclaimer: The information provided is only intended to be general summary information. It is not intended to take the place of either the written law or regulations. Opinion Disclaimer: The comments and opinions expressed are those solely of the presenter. They are not intended to take the place of either the written law or regulations

3. FDA • Center for Drug Evaluation and Research (CDER) • Center for Biological Evaluation and Research (CBER) • Center for Devices and Radiological Health (CDRH) • Center for Food Safety and Applied Nutrition (CFSAN) • Center for Veterinary Medicine (CVM) • National Center for Toxicological Research (NCTR) • Office of Regulatory Affairs (ORA) • Center for Tobacco Products (CTP)

4. FDA Leadership Commissioner Margaret A. Hamburg, MD Principle Deputy Commissioner Joshua Sharfstein, MD Associate Commissioner for Regulatory Affairs Dara Corrigan, Esquire

5. Commissioner’s Initial Steps Toward Effective Enforcement and Public Health • Set post-inspection deadlines • Streamline the warning letter process • Work more closely with our regulatory partners • Prioritize follow-up on warning letters and other enforcement actions • Be prepared to take immediate action in response to public health risks • Develop and implement a formal warning letter “close-out” process

6. FDA Resources • For FY 2010 FDA’s budget was $3.2 billion which represented a 19% increase over 2009. • President Obama’s FY 2011 budget request for FDA is nearly $4 billion which represents a 6% increase to $2.51 billion. (Percentage discrepancy due to anticipated collection of user fees from the food, tobacco and drug industries. • This budget would increase the agency FTE ceiling by approximately 1,250, bringing the workforce total to 13,586.

7. Dara Corrigan, Esq., ACRA • DHHS - Associate Deputy Assistant Secretary for Health Policy in the Office of the Assistant Secretary for Planning and Evaluation. Managed thirty economists and public health experts to provide leadership and address policy concerns about Medicare, Medicaid, children’s health, the uninsured, and public health. • Arnold Porter (DC-based international law firm) - Partner, FDA and Health Care Policy Group • DHHS - Acting Inspector General and Principal Deputy Inspector General in Office of the Inspector General. • Assistant U.S. Attorney at the Department of Justice • Deputy Chief Counsel for CMS in the Office of General Counsel at HHS • Director of Program integrity at the Centers for Medicare and Medicaid Services. • Dara earned her JD at the University of Virginia School of Law, and her bachelor’s degree at Baylor University in Texas.

8. ORA Regulating almost 124,000 business establishments that annually produce, warehouse, import and transport $1 trillion worth of consumer goods is no small task. The FDA devotes to this crucial task, which is directed by the Office of Regulatory Affairs (ORA), about one-third of the agency's personnel. Stationed in more than 160 offices, resident posts and laboratories from coast to coast and in Puerto Rico, ORA's highly trained staff provides the eyes, ears and the long arm of the agency that ensures the implementation of the FDA's high public health standards.

9. Southwest Region

10. Director Compliance Branch Director Investigations Branch Compliance Officers Supervisory Consumer Safety Officers Consumer Safety Officers / Investigators DEN-DO Organizational Chart District Director Director Denver Laboratory

12. National Domestic and Import Investigator Experience Levels

13. Denver District Investigator Experience Levels

14. The Changing Face of the Denver District Office

15. FDA Science Initiative Significant increase in sample analysis using high throughput methodology

16. Consumer Safety Officer What is fieldwork?

17. Compliance Officer • Reviews and evaluates evidence and findings indicating a possible lack of compliance with Agency enforced laws and regulations. • Analyzes data samples and documented information gathered during inspections and investigations • Determines whether an investigation is complete or what additional work may be required • Recommends legal action to Headquarters, the Office of Chief Counsel, the responsible U.S. Attorney • Maintains working liaison with the U.S. Attorney’s Office and U.S. Marshal’s Service in implementing approved actions • Ensures that non-compliant establishments make necessary changes to meet the regulations. Enforcement includes official correspondence as well as legal actions taken in a court of law

18. Consumer Safety Officers • Credentialed Federal Officers Food, Drug and Cosmetic Act (FD&C)This Act, passed in 1938, remains FDA’s main legal basis. It greatly enlarged the agency’s mission and authority by: • requiring that new drugs be shown to be safe before marketing. • extending FDA’s control to cosmetics and therapeutic devices. • authorizing factory inspections and standards of identity for food staples. • eliminating a requirement to prove intent to defraud in drug misbranding cases. • adding court injunctions to the previous penalties of seizures and prosecutions.

19. Major Inspection Programs • Imports • Food • Drug • Biomedical Monitoring • Biologics • Medical Device Training & Location International

20. Food Safety Enhancement Act of 2009 Approved by the House FDA Food Safety Modernization Act Under review in the Senate

21. Drug • The term “drug” means (A) articles recognized in the official USP, official Homeopathic Pharmacopeia of the United States, or official National Formulary, or any supplement to any of them; and (B) articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals; and (C) articles (other than food) intended for use as a component of any articles specified in clause (A), (B), or (C).

22. Dietary Supplement • A statement for a dietary supplement may be made if – the statement claims a benefit related to a classical nutrient deficiency disease and discloses the prevalence of such disease in the United States, describes the role of a nutrient or dietary ingredient intended to affect the structure or function in humans, characterizes the documented mechanism by which a nutrient or dietary ingredient acts to maintain such structure or function, or describes general well being from consumption of a nutrient or dietary ingredient.

23. 21st Century Reality Our borders are boundaries to our jurisdiction. Borders are not barriers to • Disease • Information Flow • Product Acquisition • Challenges of Globalization . . . borders CAN NOT be barriers to FDA’s realm of activities

24. Importation of FDA Regulated Products 2006 14.98M Lines 2007 16M Lines 2008 17.9M Lines 150 countries exporting FDA products to US -130,000 US importers of record -300,000 foreign manufacturers

26. FDA’s International Presence

27. Foreign Inspection Workplan

28. Foreign Inspection/ Import Workplan

29. Domestic Inspection Workplan

30. Drug Inspection Cadre • Pre-Approval Inspections • Surveillance GMP Inspections • Compliance GMP Inspections • PADE Inspections (Phase IV) • PDMA Inspections • MedWatch Investigations • DQRS Investigations • FAR Investigations • Consumer / Trade Complaints • Pharmacy Compounding

31. Pharmacy Compounding Food and Drug Administration Modernization Act of 1997 (FDAMA) • November 1997, Section 127 added Section 503A to the FD&C Act • Congress through Section 503A provided conditions under which compounded drugs could be exempt from the adulteration, misbranding, and new drug provisions of the FD&C Act provided certain requirements were met.

32. FDA 483 Disclaimer This document lists observations made by the FDA representative(s) during the inspection of your facility. They are inspectional observations, and do not represent a final Agency determination regarding your compliance. If you have an objection regarding an observation, or have implemented, or plan to implement, corrective action in response to an observation, you may discuss the objection or action with the FDA representative(s) during the inspection or submit this information to FDA at the address above. If you have any questions, please contact the FDA at the phone number and address listed above.

33. Significant Issue #1 - 21 CFR 211.165(f) - Drug products failing to meet established standards, specifications, and quality control criteria are not rejected. If your active ingredient has not arrived and you receive an immediate order for a product containing that active ingredient, FDA still expects you to wait for the active ingredient to arrive from the supplier and put it in the product.

34. Example Observations • The event description for complaint XXXXX states “Baby started choking and screaming. Couldn’t catch his breath, was crying, applied cold water to his mouth and threw up. She then gave him 2 pumps of his inhaler. Heart racing very very fast” – no documentation of the result of the event • Formulation room XXX had a 2.5” diameter uncapped port behind formulation tank XXX exposing the Grade C area of formulation room XXX to the uncontrolled XXX room XXX. • …There is no evidence that the firm has evaluated the safety and determined the acceptability of the introduction of this new clinical product and/or its excipients into the manufacturing facility and subsequent use on commercial equipment. • Small cryogenic vessels (home units) are filled from a large (XL-50) dewar located at the stand tank. This process was used when the van with the bulk unit is not available. This supply dewar had an industrial oxygen label with another company’s name affixed.

35. Turbo EIR • Provides more consistency between inspections and investigators • Provides specific citations and examples of violations • Provides information for statistical analysis and identifies potential investigator / FDA / industry trends

36. Inspection Outcomes • NAI – No Action Indicated • VAI – Voluntary Action Indicated • OAI – Official Action Indicated • Withhold Application • Regulatory Meeting • Untitled Letter • Warning Letter • Seizure • Injunction • Prosecution

37. Top Drug Citations (2006 – 2009)

38. Drug Recalls 2008 426 2009 1742

39. Investigator’s Top Ten • 21 CFR 211.192 – Investigations of discrepancies, failures / CAPA • 21 CFR 211.22 (1) - Quality Control Unit Responsibilities and Procedures • 21 CFR 211.100 – Written production and process control procedure deviations • 21 CFR 211.160 – Scientific Sound Laboratory Controls • 21 CFR 211.67 – Written Procedures Not Followed for Cleaning & Maintenance of Equipment

40. Investigator’s Top Ten • 21 CFR 211.80 – Written Procedures Not Followed for the Receipt and Testing of Components and Drug Product Containers • 21 CFR 211.84 - Certificates of Testing (Containers, Closures) • 21 CFR 211.180 – Annual Product Reviews • 21 CFR 211.166 – Stability Program does not support expiration dates • 21 CFR 211.188 – Batch Production & Control Records

41. Investigator’s Significant Issues • Allowing a new product and/or chemical entity into a facility to include the active pharmaceutical ingredient and all excipients before documented review and approval by Quality. • Process Validation/Process Capability Understanding and Review Quality, Production, Materials Systems

42. Top Device Citations (2006 – 2009)

43. Device Recalls: 2006 - 2009

44. Device Recalls: 2006 - 2009

45. Concerns • Adequate testing programs for incoming materials (audits of suppliers, acceptance of supplier COA) • Management review of complex statistical analysis (Cp/Cpk, multivariate analysis, etc.) - Statistics vs Biostatistics - Limitations of programs • Laboratory staff - Education/Qualifications - Workload - Oversight

46. UCL ACL ALL ALL ACL LCL Statistical Review USL Target LSL

47. USL UCL Target LCL LSL Statistical Review

48. Compliance with application specifications Process capability and control Adherence to standard operating procedures Investigation initiation and subsequent Corrective/Preventative Actions Applicability to other batches Regulatory compliance (Field Alert Reports) Correct Understanding of Statistics Results Statistical Review

49. UCL UCL Statistical Review – Example 1 USL Target LCL LSL

50. UCL UCL Statistical Review – Example 2 USL Target LCL LSL