INTRODUCTION TO DRUG LAW AND REGULATION: REGULATION OF DRUG MANUFACTURING

Transcription

1 Food and Drug Law Institute's Workshop on INTRODUCTION TO DRUG LAW AND REGULATION: REGULATION OF DRUG MANUFACTURING November 8-9, 2010 Park Hyatt Hotel Washington, D.C. 1

2 REGULATION OF DRUG MANUFACTURING Presented by: Cathy L. Burgess, Esq. Crowell & Moring LLP 1001 Pennsylvania Avenue, N.W. Washington, D.C phone fax Dean R. Cirotta, MBA EAS Consulting Group, LLC 1940 Duke Street, Suite 200 Alexandria, Virginia phone fax 2

3 DRUG ESTABLISHMENT REGISTRATION AND DRUG LISTING 3

4 Authority To Require Establishment Registration And Drug Listing Initial Registration. 510(c), 21 U.S.C. 360(c); 21 C.F.R Annual Registration and Fees. 510(b), 21 U.S.C. 360(b); 736(a)(2), (3), (b)(1); 21 U.S.C. 379h (a)(2), (3), (b)(1); 21 C.F.R Semi-Annual Reports. 21 C.F.R ; 510(j)(2), 21 U.S.C. 360(j)(2) Failure to Register, List Drugs, or File Semi-Annual Reports. 505(e), 21 U.S.C. 355(e); 301(p), 21 U.S.C. 331(p) 4

5 Purpose And Scope Of Establishment Registration And Drug Listing Purpose. 510; 21 U.S.C. 360; 21 C.F.R Scope. Domestic Establishments. 21 C.F.R Establishments and Activities Requiring Registration. 21 C.F.R (a)(7-8) Private Label Distributors. 21 C.F.R (b); Forms FDA 2656, 2657, 2658 Foreign Drug Establishments. 501(i), 21 U.S.C. 360(i); 21 C.F.R (66 F.R , Nov. 26, 2002) 5

6 Exemptions From Registration Pharmacies regulated by local laws; dispensing drugs at retail. Practitioners use in professional practices. Research, teaching or chemical analysis and not for sale. Other Classes: e.g. hospitals, clinics, farmers, common carriers. 510(g); 21 U.S.C. 360(g); 21 C.F.R

7 Information Required for Registration and Drug Listing Information Required on Initial Registration of Drug Establishments (Form FDA 2656). 21 C.F.R Purpose of Form (registrant, distributor, foreign) Report Date (current) Type of Owner (sole proprietor, partnership, corporation, etc.) Reason for Submission (annual, new, private label, name change, etc. Business Type (human, veterinary) Name and Site Address (street, city, state, country) 7

8 Information Required For Registration And Drug Listing Information Required on Initial Registration - (continued) Mailing Address (if different from Site Address) Type of Ownership or Operation (partnership, corporation) Names(s) of Owner(s) Parent Company Name Name and Phone Number of submitter Other Establishment Names at same site Signature of Authorizing Official (must be signed) 8

9 Information Required For Registration And Drug Listing Amendments to Establishment Registration 21 C.F.R Changes in ownership, structure, location or activity--within five (5) days. Change in an establishment s firm name. Changes in the names of officers and directors of corporations--annual registration. 9

10 Information Required For Registration And Drug Listing Drug Product Listing (Form FDA 2657) 21 C.F.R New drugs, authority for the marketing, application number, labeling. 510(j)(1)(A); 21 U.S.C. 360(j)(1)(A) Prescription drugs subject to 503(b)(1), all labeling and representative sampling of advertisements. 510(j)(1)(B)(I); 21 U.S.C. 360(j)(1)(B)(I) Quantitative listing of active ingredient(s) 510(j)(1)(C); 21 U.S.C. 360(j)(1)(C) Quantitative listing of all ingredients as necessary. 510(j)(1)(C); 21 U.S.C. 360(j) (1)(C) Over-the-counter drugs, label, package insert, sampling of any other labeling. 510(j)(1)(C); 21 U.S.C. 360(j)(1)(C) Drug Listing Number using the National Drug Code (NDC). 21 C.F.R

11 Information Required For Registration And Drug Listing Updating Drug Listing Information. 21 C.F.R Updates semi-annually, in June and December Information to be submitted in the updates: Drugs not on a previously submitted list; Drugs that have been discontinued; Reintroduction of discontinued drugs; Material change in previously submitted information; and No changes; no report. 11

12 Public Inspection Of Registrations And Drug Listings; 21 C.F.R ; 510(f), 21 U.S.C. 360(f) Registration of Drug Establishment (Form FDA 2656) is publicly available at Drug Listing Branch, CDER and FDA District Offices. (21 C.F.R ) Types of Information Available for Public Disclosure include: List of all drug products List of all drug products by labeled indications or pharmacological category Drug products listed by manufacturer List of active ingredients Discontinued drugs, newly marketed drugs and drugs for which marketing is resumed Labeling Advertising 12

13 Public Inspection Of Registrations And Drug Listings; 21 C.F.R ; 510(f), 21 U.S.C. 360(f) Information Not Available for Public Disclosure Basis for determination not subject to drug provisions of the Act. Drug product s inactive ingredients. 502(e)(i)(A)(iii) Drugs containing a particular inactive ingredient. 13

14 Adulteration/Misbranding and GMPs 14

15 Adulterated Drugs (21 U.S.C. 351) Drug is deemed adulterated if: contains any filthy or decomposed substance (FDCA 501(a)(1), 21 U.S.C. 351(a)(1)); prepared, packed or held under unsanitary conditions (FDCA 501(a)(2)(A), 21 U.S.C. 351(a)(2)(A); methods used do not conform to good manufacturing practices (FDCA 501 (a)(2), 21 U.S.C. 351 (a)(2)(b), 21 CFR Part 210 & 211); 15

16 Adulterated Drugs (21 U.S.C. 351) container composed of poisonous or deleterious substance may cause contents to be injurious to health (FDCA 501 (a)(3), 21 U.S.C. 351 (a)(3)); contains an unsafe coloring additive ( 501 (a)(4), 21 U.S.C. 351 (a)(4)); strength, quality or purity falls below compendial standards 501 (b), 21 U.S.C. 351 (b)); strength or purity falls below what it purports to possess ( 501 (c), 21 U.S.C. 351 (c)); mixed or packaged to reduce quality or strength ( 501 (d), 21 U.S.C. 351 (d)). 16

17 MISBRANDING of DRUG PRODUCTS (21 U.S.C. 331) A drug is deemed misbranded if: labeling is false or misleading (FDCA 502 a), 21 U.S.C. 352(a)); label fails to bear the name and place of business, an accurate statement of contents, weight, measure or numerical count (FDCA 502(b), 21 U.S.C. 352(b)); labeling required is not prominently displayed and understandable (FDCA 502(c), 21 U.S.C. 352(c)); 17

18 DEEMED MISBRANDED - continued labeling does not contain the established name and names and quantities of active ingredients (FDCA 502(e), 21 U.S.C. 352(e); labeling does not prominently display the established name at least half as large as the proprietary name (FDCA 502(e)(1)(B), 21 U.S.C. 352(e)(1)(B)); labeling doesn t bear adequate directions for use (FDCA 502(f), 21 U.S.C. 352(f)); not packaged or labeled as prescribed in the official compendium (FDCA 502(g), 21 U.S.C. 352(g)). 18

19 Misbranding Of Drug Products Reference to Registration or Registration Number denoting FDA s approval of firm or products. 21 C.F.R Manufacture in a Non-Registered Establishment. 502(o) 21 U.S.C. 352(o) Drugs Not Included in Drug Listing. 502(o); 21 U.S.C. 352(o); 21 U.S.C. 510(j) 19

20 Regulation of Drug Manufacturing Current Good Manufacturing Practices (cgmps) History First Regulations - June 20, 1963 (28 FR 6385) Now codified as 21CFR parts 210 through 226 Major revisions to regulations January 15, 1971 (36 FR 601) September 29, 1978 (43 FR 45014) January 20, 1995 (60 FR 4087) December 8, 2008 (73 FR 51919) 20

21 Regulation of Drug Manufacturing Current Good Manufacturing Practice (cgmp) Principles: (1) Quality, safety, and effectiveness must be designed and built into a product; (2) Quality cannot be inspected or tested into a finished product; and (3) Each step of the manufacturing process must be controlled to maximize the likelihood that the finished product will be acceptable. 21

22 Regulation of Drug Manufacturing Current Good Manufacturing Practice (cgmp) Regulations Drugs Generally 21 CFR Parts 210 and 211 Blood and Blood Components 21 CFR Part 600 et seq. Note: For Blood Establishments, Parts 210 through 226 and Parts 600 through 680 supplement rather than supersede each other. 22

23 Regulation of Drug Manufacturing Current Good Manufacturing Practice (cgmp) Case Law United States v. Barr Labs, Inc. 812 F. Supp. 458 (D.N.J. 1993) Established cgmp Standards for industry 23

24 Regulation of Drug Manufacturing Current Good Manufacturing Practice (cgmp) Guidance Proposed cgmp regulations (May 3, 1996, Based on Barr Labs decision; Withdrawn December 4, 2007) Draft Guidance on OOS Results (Based on Barr Labs decision) Guidelines for Quality Assurance in Blood Establishments (July 11, 1995) Guidance on OOS Results (October 2006) 24

25 Regulation of Drug Manufacturing Current Good Manufacturing Practice (cgmp) Pharmaceutical cgmps for the 21 st Century Risk Based Model for Prioritizing Sites for Manufacturing Inspections Science Based Regulation of Product Quality Guidance on Quality Systems Approach to Pharmaceutical cgmps (September 2006) Amendments to Current Good Manufacturing Practice Regulations for Finished Pharmaceuticals. (73 FR 51919) Effective December 8,

26 FDA Inspections 26

27 Statutory Authority to Conduct Establishment Inspections Section U.S.C. 374; 21 U.S.C. 360(h) Reasonableness of the Inspection (time, limits, manner) Frequency of Inspections 21 U.S.C. 360(h) Consent Unnecessary Search Warrant Unnecessary Miranda Warnings Unnecessary Inspection Warrants 27

28 Scope of Inspection FDA Authority To Inspect FDA may not inspect: Financial data. Sales data other than shipping figures. Pricing data. Personnel data other than information establishing the qualifications of technical and professional personnel. Certain research data except to the extent such information may be required to be made available for inspection or submitted to FDA for particular products. 28

29 Scope of Inspection FDA Authority To Inspect No general subpoena authority, but in certain civil proceedings FDA may issue a subpoena for production of evidence and records. If FDA initiates an enforcement action, records are available under the rules of discovery. During a criminal investigation the Justice Department can subpoena records relevant to an ongoing grand jury investigation. 29

30 Scope of Inspection FDA s Authority to Inspect Records of Interstate Shipment by Common Carriers and Recipients Section 703 If requested in writing Sample Types Official sample Documentary sample (DOC sample) 301(k) sample Post-seizure sample Investigational sample (INV sample) Induced sample 30

31 Scope of Inspection What FDA is Not Expressly Authorized to Obtain, but May Attempt to Obtain In-plant photographs Not specifically authorized * Dow Chemical Co. * Acri Wholesale Grocery Co Affidavits from individuals Interview of employees FDCA does not expressly authorize investigators to interview a company s employees; with/without company s counsel: * Managerial employees * Non-managerial employees 31

32 Scope of Inspection Limitations to the Scope of Inspection Retail pharmacies Licensed practitioners Research, teaching, or chemical analysis Exempted by regulation 32

33 Procedure for Conducting Inspections Investigation Operations Manual ( Present Credentials and Notice of Inspection Inspectional Observations (Form FDA 483) Discussion with Management Establishment Inspection Report 33

34 Procedure for Conducting Inspections How FDA prepares for Inspections and Review of FDA inspection procedures compliance policy guides. Review of a firm s most recent Establishment Inspection Reports (EIRs) and responses to 483s and Warning Letters. 34

35 Refusal to Permit Entry or Inspection; Refusal to Permit Access to or Copying of Records Prohibited Acts Administrative Inspection Warrant 35

36 Reasons for Food and Drug Administration (FDA) Administrative Inspections Routine For Cause Follow Up to Warning Letter or Enforcement Action Complaints from Consumers, Industry, and Current or Former Employees Recall Effectiveness Check Pre-Approval Inspection Special Enforcement Initiative 36

37 Scope of Inspection Scope of FDA Inspections The scope of the inspection depends on the information desired, or upon the violations suspected or likely to be encountered. 37

38 Regulation of Drug Manufacturing FDA Authority To Inspect FDA may inspect and copy: records, files, papers, processes, controls and documents related to a facility s bearing on whether drugs are adulterated, misbranded or otherwise violative. 38

39 Scope of Inspection Pre-Approval Inspections CDER s Role Review data in applications(s) Establish specifications for manufacture and control based on data 39

40 Scope of Inspections Pre-Approval Inspections Districts Role: Assure cgmp compliance Data audit verify authenticity and accuracy of data submitted Report other data or information with impact on cgmp compliance Verify compliance with application commitments 40

41 Scope of Inspections Pre-Approval Inspections Inspection Teams (Investigators, Analysts, Engineers, etc.) Areas Covered: Manufacturing (Dosage form, bulk drug/api, GMP) Reprocessing (if in application) Laboratory (Equipment and Procedures qualified and validated, raw data) Components (API-supplier, source of bio-batch, clinical batch) 41

42 Pre-Approval Inspections Areas Covered (cont.): Scope of Inspections Buildings and Facilities (impact on other products, structure e.g., cross-contamination) Equipment (cleaning validated) Packaging and Labeling Controls (accountability, past mix-ups, recalls) Stability (data audit) Process Validation (including pre-approval and commercial batches. 42

43 Scope of Inspections Pre-Approval Inspections Field Recommendations: Approve (NAI, VAI) Withheld approval (OAI - with reasons why) Delay approval pending pre-approval inspection 43

44 Scope of Inspections Pre-Approval Inspections Show Stoppers Application misrepresents date or conditions relating to pre-approval batches Inconsistencies and/or discrepancies raising significant questions about the validity of records Pre-approval batches not made in cgmp compliance Failure to report adverse findings or test data without adequate justification 44

45 Procedure for Conducting Inspections How FDA Prepares For Inspections Selection of team and designation of team leader The team leader: Plans the inspection Schedules and coordinates team member pre-inspection preparations Assesses progress of the inspection Coordinates preparation of 45 investigation

46 Procedure for Conducting Inspections FDA Inspection Goals To determine a firm s compliance with FDA rules and regulations. To obtain evidence to support legal action when violations are found, or to obtain specific information as directed by counsel. 46

47 Procedure for Conducting Inspections What To Do Before An Inspection Evaluate Relationship with FDA Assess Systems, Procedures and Controls. Review Company Performance Establish Team & Plan 47

48 Procedure for Conducting Inspections What To Do During An Inspection: The Team Approach The Daily Record Entry and Observation: What is allowed Access to Documents Types of documents Reasonable access Provide what is requested Keep good records; keep copies 48

49 Procedure for Conducting Inspections Closing the Inspection The Team Approach The Exit Meeting - A Critical Part of the Inspection Presentation of Form FDA 483 written report of the Inspection Observations Discussion of a Reply 49

50 Procedure for Conducting Inspections After the Inspection Report to Regulatory Affairs and Senior Management Response to Form FDA 483 is critical Provide tangible evidence that you are correcting problems Allocate necessary resources to make corrections Address major quality system or safety issues first Demonstrate that you understand issues and what corrections are necessary Follow-Up 50

51 Establishment Inspection Reports Establishment Inspection Report (EIR) report written by the investigators that summarizes all the findings from the inspection. Investigators submit EIR to the District Office for a classification decision

52 Establishment Inspection Reports District Classifications No Action Indicated (NAI) No objectionable conditions or practices were found during the inspection (or the significance of the documented objectionable conditions found does not justify further action). Voluntary Action Indicated (VAI) Objectionable conditions were found and documented but the District and/or Center is not prepared to take or recommend any of the regulatory (advisory, administrative, or judicial) actions listed below since the objectionable conditions do not meet the threshold for regulatory action. The district may use an Untitled Letter, Regulatory Meeting or other communication with responsible individuals to inform the establishment of findings that should be corrected. A written response by the establishment may be an option, but is not necessary. Any corrective action is left to the establishment to take voluntarily. Official Action Indicated (OAI) Objectionable conditions were found and one of the regulatory actions listed below should be recommended. Includes voluntary recalls where the district has decided conditions warrant regulatory (advisory, administrative, or judicial) action. Typically, an OAI classification should be made only if a FDA-483 has been issued and the documented evidence supports the action recommended.

53 Establishment Inspection Reports District Classifications Referred to State (RTS) Referred to State, local, or other federal office. This classification can be used only when either there is no federal jurisdiction over the apparent violation in question or it is determined that State action is the most efficient method of obtaining the establishment s compliance with applicable Federal Laws, Regulations or Administrative requirements. Referred to Center (RTC) This District Decision Type can only be used when the objectionable conditions or apparent violations noted constitute a compliance area for which no clear policy has been established or significant technical issues exist which require Center review and decision. An RTC classification should be made only if a FDA-483 has been issued.

54 Field Alert Reports (FAR) 21 CFR (b)(1)(i) and (ii); NDAs and ANDAs (Effective May 23, 1985) Any incident that causes the drug product or its labeling to be mistaken for, or applied to, another article 54

55 FAR - Required Reporting 21 CFR (b)(1)(ii) Bacterial contamination Significant chemical, physical or other change Product deterioration Out-of-specification batch(es) 55

56 FAR - Reporting Requirements Applicant holders are required to submit NDA/ANDA Field Alert reports on drug products manufactured or distributed within or outside the U.S. U.S. Office/Agent - responsible for reporting to FDA district office where registered/located Notify the district office within 3 working days 56

57 FAR - Reporting Requirements Information may be provided by telephone or other rapid communication means, with prompt written follow-up Form FDA 3331 Internet Availability of Form Word Format or 57

58 FAR - Timeframe: 3 Working Days Starts Firm becomes aware of a reported problem Complaint Internal testing 58

59 FAR - Firm Reporting FAR Required Further investigation required Corrective action initiated e.g., Formulation revision, labeling change Product Recall FAR Not Required Problem is resolved within 3 working days e.g., Analytical lab error 59

60 FAR - Regulatory Actions Warning Letter When appropriate Significance Previously cited Concurrence with headquarters Withdrawal of Approval - CFR (d) 60

61 FAR - Impact on Public Protection Recalls (types 21 CFR Section 7.3) Corrective Actions Discontinuation 61

62 Regulation of Drug Manufacturing Further Action by FDA Warning Letters Adverse Publicity FDA Requested Recalls (21 CFR 7.45) Suspension or Withdrawal of Product Approval Impact on Award of Government Contracts Seizures Injunctions Criminal Prosecutions 62

63 Thank You 63