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Lists of Documents that Describe The U.S. Pharmaceutical GMP Regulatory System *

* Arranged by Specific Equivalence Assessment Criteria as Contained in Appendix 4 of the Pharmaceutical GMP Annex. Copies of all documents have been provided to the EMEA.

I. Legal/Regulatory authority and structures and procedures providing for post- and pre-approval:

A. Appropriate statutory mandate and jurisdiction.

1. U.S. Federal Food, Drug, and Cosmetic Act, As Amended Feb-1998:

2. Public Health Service Act:

3. Federal Anti-Tampering Act, 18 U.S.C. 1365.

4. Administrative Procedures Act (5 U.S.C. 551, et seq.)

5. Other Enforcement Acts:

B. Ability to issue and update binding requirements on GMPs and guidance documents.
1. U.S. Federal Food, Drug, and Cosmetic Act, As Amended Feb-1998:

2. Administrative Procedures Act - Section 553 (5 U.S.C. 553).

3. Code of Federal Regulations (CFR):

C. Authority to make inspections, review and copy documents, and to take samples and collect other evidence.

1. U.S. Federal Food, Drug, and Cosmetic Act, As Amended Feb-1998:

2. Public Health Service Act - Section 351 (42 U.S.C. 262) - Regulation of Biological Products.

3. Code of Federal Regulations (CFR):

4. Compliance Policy Guides:

General

Section 100.200 - FDA Jurisdiction over Products Composed of Interstate Ingredients.
Section 100.350 - FDA Jurisdiction on Indian Reservations.
Section 100.500 - Common Carrier as a Relabeler, Repacker, Reprocessor.
Section 100.550 - Status and Responsibilities of Contract Sterilizers Engaged in the Sterilization of Drugs and Devices.
Section 160.300 - Requests for Records under Section 703.
Section 160.750 - Drug and Device Products Found in Violation of GMP Reconditioning.

Human

Section 460.100 - Hospital Pharmacies - Status as Drug Manufacturer.

5. Regulatory Procedures Manual:

Chapter 2 - FDA Authority.
Chapter 6 - Judicial Actions.
Chapter 10 - Other Procedures.

D. Ability to enforce requirements and to remove products found in violation of such requirements from the market.

1. U.S. Federal Food, Drug, and Cosmetic Act, As Amended Feb-1998:

2. Public Health Service Act:

3. Code of Federal Regulations (CFR):

4. Compliance Policy Guides:

General

120.100 - Fraud, Untrue Statements of Material Facts, Bribery, and Illegal Gratuities.
160.400 - Section 305 Meeting - Before Report of Criminal Violation.

5. Regulatory Procedures Manual:

Chapter 2 - FDA Authority.
Chapter 4 - Advisory Actions.
Chapter 5 - Administrative Actions.
Chapter 6 - Judicial Actions.
Chapter 7 - Recall and Emergency Procedures.
Chapter 9 - Import Operations/Actions.
Chapter 10 - Other Procedures.

6. Compliance Programs:
(not available on the Internet)

Human

7356.002 - Drug Process Inspections (continuing) (28-Dec-1990).
7356.002-A - Sterile Drug Process Inspections (1-Oct-1990).
7356.002-B - Drug Repackers and Relabelers (27-Dec-1993).
7356.002-F - Active Pharmaceutical Ingredients (APIs) (20-May-1998).
7356.008 - Drug Product Surveillance (7-Sep-1995).
7346.832 - Pre-Approval Inspections/Investigations (15-Aug-1994).
7346.843 - Post-Approval Inspections (15-Sep-1994).
7341.001 - Inspections of Licensed Therapeutic Drug Products (2-Mar-1999).
7345.001 - Inspections of Licensed Allergenic Products (5-Nov-1998).

Veterinary

7368.001 - Pre-Approval Inspections New Animal Drug Application (30-Sep-1998).
7371.001 - Drug Process and New Animal Drug Inspections (30-Sep-1998).
7371.004 - Medicated Feeds (30-Sep-1998).
7371.005 - Type A Medicated Articles (30-Sep-1996).

E. Substantive current good manufacturing practice requirements.

1. U.S. Federal Food, Drug, and Cosmetic Act, As Amended Feb-1998:

2. Public Health Service Act - Section 351 (42 U.S.C. 262) - Regulation of Biological Products.

3. Code of Federal Regulations (CFR):

Human and animal

Animal

Related requirement

21 CFR Part 11 - Electronic records and electronic signatures.

4. Notice: FDA's Good Guidance Practices, Volume 62 Federal Register (FR) page 8961 (27-Feb-1997).

5. Center for Drug Evaluation and Research (CDER) Manual of Policies and Procedures 4000.2 - Developing and Issuing Guidance for Industry (29-Apr-1998).

6. Center for Biologics Evaluation and Research (CBER), Manual of Standard Operating Policies and Procedures 8002 - Procedures for the Processing, Routing and Use of Guidance Documents (31-Dec-1997).

7. Center for Veterinary Medicine (CVM), Policy and Procedures Manual 1240.2000 - Establishment of Center Policies/Procedures.

8. Judicial Decisions:

United States v. Barr Laboratories, Inc., 812 F. Supp. 458 (D.N.J. 1993). This case held that: (1) a manufacturer would be required to cease all distribution of certain drugs until current or prospective validation studies for each were completed, and the court would recall batches of drugs released on basis of successful resample; and (2) the court would also recall batches that had content uniformity and assay difficulties).
(not available on the Internet)
United States v. 789 Cases, More or Less, of Latex Surgeons' Gloves, an Article of Device, 799 F. Supp. 1275 (D.P.R. 1992). This case, which is a medical device case, also discusses the parallel pharmaceutical GMP provisions.
(not available on the Internet)
John D. Companos and Sons, Inc. v. FDA, 854 F.2d 510 (D.C. Cir. 1988). This case upheld the withdrawal of drug approval for failure to comply with GMPs.
(not available on the Internet)

(The above referenced case law provides judicial opinion that is particularly descriptive of the U.S. pharmaceutical GMP regulatory system. Many other cases exist that interpret and describe the pharmaceutical GMP requirements listed throughout this document.)

F. Accountability of the regulatory authority.

1. Executive Office of the President.

2. Office of Management and Budget - Information Collection Budget for the Federal Government; Regulations and Paperworks Review.

3. Department of Health and Human Services - Research, Policy, and Administration of HHS Agencies.

4. U.S. Constitution - Article 1, Section 8 - Powers of Congress.

5. Congressional Oversight:

Principal Authorizing and Oversight Committees:

Committee on Commerce. (now: Committee on Energy and Commerce)

Subcommittee on Oversight & Investigations.
Subcommittee on Health & Environment. (now: Subcommittee on Health)

Senate Committee on Health, Education, Labor, and Pensions
House Committee on Government Reform
Senate Committee on Governmental Affairs

Appropriations Committees:

FDA from time to time also responds to other committees with interest in FDA issues and programs, such as the Committees on the Agriculture, Judiciary, Veterans' Affairs, Small Business, and Science. Additional committees also may request information from FDA as issues arise

U.S. General Accounting Office (GAO) Audits and Evaluations of U.S. Government Programs and Activities.

6. U.S. Federal Food, Drug, and Cosmetic Act, As Amended Feb-1998:

7. Unfunded Mandates Reform Act (2 U.S.C. 1501 - 1571)

8. 2 U.S.C. 658 (5), (6), and (7) - Federal mandate.

9. Government Performance and Results Act of 1993.

10. Federal Advisory Committee Act (5 U.S.C. App. II, Sections 1-15).

11. 5 U.S.C. 552(a) - Public information; agency rules, opinions, orders, records, and proceedings.

12. 5 U.S.C. 601-612 - The analysis of regulatory function.

13. Administrative Procedures Act:

14. 18 U.S.C. Chapter 90 - Protection of Trade Secrets.

15. 18 U.S.C. Chapter 93 - Public officers and employees.

16. 42 U.S.C. 4321 - 4370d - The National Environmental Policy Act of 1969.

17. 44 U.S.C. 3501 - 3520 - Coordination of Federal information policy.

18. Transparency in U.S. Government Rulemaking -- Provided to European Commission under the Transatlantic Economic Partnership (16-Jul-1999).
(not available on the Internet)

19. Code of Federal Regulations (CFR):

20. The FDA Development, Issuance, and Use of Guidance Documents (62 FR 8961 (27-Feb-1997).

21. Annual Comprehensive list of Guidance Documents at the Food and Drug Administration (65 FR 42457) (21-Jul-2000).

22. Executive Order 12114 (4-Jan-1979)

23. Executive Order 12600 (23-Jun-1987)

24. Executive Order 12838 (10-Feb-1993)

25. Executive Order 12866 (30-Sep-1993)

26. Executive Order 12875 (26-Oct-1993)

27. Executive Order 13084 (14-May-1998)

28. Compliance Policy Guides - General - 120.100 - Fraud, Untrue Statements of Material Facts, Bribery, and Illegal Gratuities.

29. Investigations Operations Manual - Chapter 1 (Subchapters 130 and 169).

30. FDA Customer Service Plan and Customer Commitments (for consumers, for other government agencies, for health professionals, and for regulated industries).

31. FDA Listens: Consumer Forums.

32. Catalog of FDA Information for Consumers: Publications and Audiovisuals (Jul-1999).

G. Inventory of current products and manufacturers.

1. U.S. Federal Food, Drug, and Cosmetic Act, As Amended Feb-1998:

2. Code of Federal Regulations (CFR):

3. Approved Drug Products with Therapeutic Equivalence Evaluations.

4. FDA Approved Animal Drug Products.

5. Biologics Product Information.

6. Field Management Directives:

FMD 92 - Agency Establishment Registration and Control Procedures (16-Jul-1996).
FMD 100 - Field District Rosters (3-Jun-1998).
FMD 130 - OEI (Official Establishment Inventory) Development and Maintenance Procedures (16-May-1997).

7. Compliance Program - 7356.014 - Drug Listing (14-Jun-1995).
(not available on the Internet)

8. Compliance Policy Guides:

Human

400.100 - Drugs, Human - Failure to Register.

Animal

625.500 - Failure to register and/or drug list (animal).

H. System for maintaining or accessing inspection reports, samples and other analytical data, and other firm/product information relating to matters covered by this Sectoral Annex.

1. Investigations Operations Manual:

Chapter 4 - Sampling (Subchapter 430 - Documentation & C/R).
Chapter 5 - Establishment Inspection (Subchapter 590 - Reporting).

2. Laboratory Procedures Manual.

3. FDA Staff Manual Guide - SMG 2460.2 - Description and Use of the FDA Records Control Schedule (29-May-1986).
(not available on the Internet)

4. Regulatory Procedures Manual - Chapter 10 - Other Procedures.

5. Field Management Directives - FMD 130 - OEI (Official Establishment Inventory) Development and Maintenance Procedures (16-May-1997).

II. Mechanisms in place to assure appropriate professional standards and avoidance of conflicts of interest.

1. U.S. Constitution, Article I, Section 9, Clause 8.

2. U.S. Federal Food, Drug, and Cosmetic Act, As Amended Feb-1998:

3. 18 U.S.C. 201 - Bribery of public officials and witnesses.

4. 18 U.S.C. 202 - Definitions.

5. 18 U.S.C. 203 - Compensation to Members of Congress, officers, and others in matters affecting the Government.

6. 18 U.S.C. 205 - Activities of officers and employees in claims against and other matters affecting the Government.

7. 18 U.S.C. 207 - Restrictions on former officers, employees, and elected officials of the executive and legislative branches.

8. 18 U.S.C. 208 - Acts affecting a personal financial interest.

9. 18 U.S.C. 209 - Salary of Government officials and employees payable only by United States.

10. 18 U.S.C. 216 - Penalties and injunctions.

11. 18 U.S.C. 218 - Voiding transactions in violation of chapter; recovery by the United States.

12. 18 U.S.C. 219 - Officers and employees acting as agents of foreign principals.

13. 18 U.S.C. 1905 - Disclosure of confidential information generally.

14. 5 U.S.C. App. 7, 7342 - Receipt and disposition of foreign gifts and decorations.

15. 22 U.S.C. 611- Definitions.

16. 22 U.S.C. 612 - Registration statement.

17. 22 U.S.C. 613 - Exemptions.

18. 22 U.S.C. 614 - Filing and labeling of political propaganda.

19. 15. 22 U.S.C. 615 - Books and records.

20. 22 U.S.C. 616 - Public examination of official records; transmittal of records and information.

21. 22 U.S.C. 617 - Liability of officers.

22. 22 U.S.C. 618 - Enforcement and penalties.

23. 22 U.S.C. 619 - Territorial applicability of subchapter.

24. 22 U.S.C. 620 - Rules and regulations.

25. 22 U.S.C. 621 - Reports to Congress.

26. 31 U.S.C. 1353 - Acceptance of travel and related expenses from non-Federal sources.

27. Executive Order 12674 (12-Apr-1989).

28. Executive Order 12731 (17-Oct-1990).

29. Executive Order 12834 (20-Jan-1993).

30. Code of Federal Regulations (CFR):

31. Annual Ethics Training, ver. 1998, Department of Health and Human Services.
(not available on the Internet)

32. Office of Government Ethics Informal Advisory Letters and Memoranda and Formal Opinions File Library.

33. Investigations Operations Manual - Chapter 1 - Administration (Subchapter 160 - Public Relations, Ethics & Conduct).

34. FDA Staff Manual Guide - SMG 2342.1 - Acceptance of Payment for Travel Expenses from Non-Federal Sources (31-May-1990).
(not available on the Internet)

35. CDER Manual of Policies and Procedures:

36. CBER Standard Operating Procedures and Policies:
(not available on the Internet)

7201 - Participation in or Planning of Outside Regulatory and Scientific Events.
7202 - Approval of Outside Activities.
7203 - Political Activities.
7204 - Post-Employment Restrictions.
7205 - Negotiating Employment with Non-Federal Organizations.
7206 - Conflicts of Interest.

37. CVM Program Policy and Procedure Manual - 2600 - Standards of Conduct.
(not available on the Internet)

38. Regulatory Procedures Manual - Chapter 10 - Other Procedures (Application Integrity Policy) (Mar-1998).

III. Administration of the regulatory authority:

A. Standards of education/qualification and training.

1. U.S. Federal Food, Drug, and Cosmetic Act, As Amended Feb-1998:

2. 5 U.S.C. 4101 - Part III Employees, Training.

3. Position description for Consumer Safety Officer (GS-696).

4. ORA Investigational Training Manual.
(not available on the Internet)

Chapter 1 - Objectives.
Chapter 6 - Interviewing Techniques.
Chapter 7 - Evidence Development.
Chapter 12 - Quality.
Chapter 13 - Report Writing.
Chapter 16 - Investigations and Emergencies.

5. CBER Inspection Manual (Nov-1992).
(not available on the Internet)

6. Field Management Directive - FMD 101- ORA System and Criteria for Selecting Employees for Training (10-Aug-1994).

7. Laboratory Procedures Manual.

8. FDA Staff Manual Guide:
(not available on the Internet)

SMG 3120.1 - FDA Training and Staff Development Policy (General) (16-Aug-1972).
SMG 3120.2 - Staff Development and Training Responsibilities (22-Aug-1972).
SMG 3112.2 - Policy and Procedures for Pre-employment Suitability Checks (20-May-1971).

9. CDER Manual of Policies and Procedures - 4550.3 - Employee Training and Development (13-Mar-1997).

10. Team Biologics - A Plan for Reinventing FDA's Ability to Optimize Compliance of Regulated Biologics Industries (30-Jul-1997).

B. Effective quality assurance systems measures to ensure adequate job performance.

1. U.S. Federal Food, Drug, and Cosmetic Act, As Amended Feb-1998:

2. ORA Investigational Training Manual.
(not available on the Internet)

3. CDER Manual of Policies and Procedures:

4. Laboratory Procedures Manual.

C. Appropriate staffing and resources to enforce laws and regulations.

1. FY 1998 Office of Management and Systems Annual Performance Report.

2. FY 1999 Office of Management and Systems Annual Performance Plan.

3. FY 2000 Budget Request.

4. FDA organizational charts for ORA/Offices of Compliance.

5. CDER organizational chart and directory.

6. CBER organizational chart and directory.

7. CVM organizational chart and directory.

IV. Conduct of Inspections:

A. Adequate pre-inspection preparation, including appropriate expertise of investigator/team, review of firm/product and databases, and availability of appropriate inspection equipment.

1. U.S. Federal Food, Drug, and Cosmetic Act, As Amended Feb-1998 - Section 742 (21 U.S.C. 379l) - Education.

2. Compliance Policy Guides:

680.200 - Current GMP Regulations for Medicated Feeds - Daily Inventory Requirements.
680.400 - Medicated Feeds - Combined Batches.
680.500 - Unsafe Contamination of Animal Feed from Drug Carryover.
680.600 - Sequencing as a Means to Prevent Unsafe Drug Contamination in the Production, Storage and Distribution of Feeds.

3. Investigations Operations Manual - Chapter 5 - Establishment Inspection.

4. Compliance Programs:
(not available on the Internet)

Human

7356.002 - Drug Process Inspections (continuing) (28-Dec-1990).
7356.002-A - Sterile Drug Process Inspections (1-Oct-1990).
7356.002-B - Drug Repackers and Relabelers (27-Dec-1993).
7356.002-F - Active Pharmaceutical Ingredients (APIs) (20-May-1998).
7356.008 - Drug Product Surveillance (7-Sep-1995).
7346.832 - Pre-Approval Inspections/Investigations (15-Aug-1994).
7346.843 - Post-Approval Inspections (15-Sep-1994).
7341.001 - Inspections of Licensed Therapeutic Drug Products (2-Mar-1999).
7345.001 - Inspections of Licensed Allergenic Products (5-Nov-1998).
Veterinary
7368.001 - Pre-Approval Inspections New Animal Drug Application (30-Sep-1998).
7371.001 - Drug Process and New Animal Drug Inspections (30-Sep-1998).
7371.004 - Medicated Feeds (30-Sep-1998).
7371.005 - Type A Medicated Articles (30-Sep-1996).

5. Field Management Directives:

FMD 112A - Prior Notification to FDA Regulated Industries of Impending Inspections; Under Review.
FMD 135 - Pre-operational Reviews of Manufacturing Facilities (4-Dec-1995).
FMD 142 - Technical Inspection Assistance (1-Sep-1995).

6. List of Inspection Technical Guides.

7. Inspection Guides:

Biotechnology Inspection Guide (Nov-1991).
Infectious Disease Market Testing Facilities (Jun-1996).
Viral Clearance Processes for Plasma Derivatives.
Guide to Inspection of Computerized Systems in Drug Establishments (Feb-1983).
Glossary Computerized Systems Software Development Terminology (Aug-1995).
Bulk Pharmaceutical Chemicals (Sep-1991).
High Purity Water Systems (Jul-1993).
Lyophilization of Parenterals (Jul-1993).
Microbiological Pharmaceutical Quality Control Labs (Jul-1993).
Pharmaceutical Quality Control Laboratories (Jul-1993).
Validation of Cleaning Processes (Jul-1993).
Dosage Form Drug Manufacturers - CGMP's (Oct-1993).
Oral Solid Dosage Forms Pre/Post Approval Issues (Jan-1994).
Sterile Drug Substance Manufacturers (Jul-1994).
Topical Drug Products (Jul-1994).
Oral Solutions and Suspensions (Aug-1994).

8. Guidances to Industry:

B. Adequate conduct of inspection, including statutory access to facilities, effective response to refusals, depth and competence of evaluation of operations, systems, and documentation; collection of evidence; appropriate duration of inspection and completeness of written report of observations to firm management.

1. U.S. Federal Food, Drug, and Cosmetic Act, As Amended Feb-1998

2. Investigations Operations Manual:

Chapter 1 - Administration.
Chapter 5 - Establishment Inspection.
Chapter 9 - Investigations.

3. Compliance Programs:
(not available on the Internet)

Human

7356.002 - Drug Process Inspections (continuing) (28-Dec-1990).
7356.002-A - Sterile Drug Process Inspections (1-Oct-1990).
7356.002-B - Drug Repackers and Relabelers (27-Dec-1993).
7356.002-F - Active Pharmaceutical Ingredients (APIs) (20-May-1998).
7356.008 - Drug Product Surveillance (7-Sep-1995).
7346.832 - Pre-Approval Inspections/Investigations (15-Aug-1994).
7346.843 - Post-Approval Inspections (15-Sep-1994).
7341.001 - Inspections of Licensed Therapeutic Drug Products (2-Mar-1999).
7345.001 - Inspections of Licensed Allergenic Products (5-Nov-1998).

Veterinary

7368.001 - Pre-Approval Inspections New Animal Drug Application (30-Sep-1998).
7371.001 - Drug Process and New Animal Drug Inspections (30-Sep-1998).
7371.004 - Medicated Feeds (30-Sep-1998).
7371.005 - Type A Medicated Articles (30-Sep-1996).

4. Field Management Directives:

FMD 86 - Establishment Inspection Report Conclusions and Decisions, Revised (31-Jul-1996).
FMD 120 - FDA-483, Inspectional Observations Under Review 145 Procedure for Release of Establishment Inspection Report to the Inspected Establishment.

5. Compliance Policy Guides:

General

130.100 - Inspectional Authority; Refusal to Permit Inspection.
130.200 - Inspection of Firms when Legal Action is pending.
130.300 - FDA Access to Results of Quality Assurance Program Audits and Inspections.
130.400 - Use of Microfiche and/or Microfilm for Method of Records Retention.
160.300 - Requests for Records under Section 703.
160.750 - Drug and Device Products (Including Biologics and Animal Drugs) Found in Violation of GMPRs - Reconditioning.
160.800 - Y2K Computer Compliance.
160.850 - Enforcement Policy: 21 CFR Part 11; Electronic Records and Electronic Signatures.

6. CBER Manual of Standard Operating Procedures and Policies:

7. Inspection Guides:

Biotechnology Inspection Guide (Nov-1991).
Infectious Disease Market Testing Facilities (Jun-1996).
Viral Clearance Processes for Plasma Derivatives.
Guide to Inspection of Computerized Systems in Drug Establishments (Feb-1983).
Glossary Computerized Systems Software Development Terminology (Aug-1995).
Bulk Pharmaceutical Chemicals (Sep-1991).
High Purity Water Systems (Jul-1993).
Lyophilization of Parenterals (Jul-1993).
Microbiological Pharmaceutical Quality Control Labs (Jul-1993).
Pharmaceutical Quality Control Laboratories (Jul-1993).
Validation of Cleaning Processes (Jul-1993).
Dosage Form Drug Manufacturers - CGMP's (Oct-1993).
Oral Solid Dosage Forms Pre/Post Approval Issues (Jan-1994).
Sterile Drug Substance Manufacturers (Jul-1994).
Topical Drug Products (Jul-1994).
Oral Solutions and Suspensions (Aug-1994).

8. Guidances to Industry:

9. Index of FDA Enforcement Reports.

C. Adequate post-inspection activities, including completeness of inspector's report, inspection report review where appropriate, and conduct of follow-up inspections and other activities where appropriate, assurance of preservation and retrieval of records.

1. U.S. Federal Food, Drug, and Cosmetic Act, As Amended Feb-1998:

2. Investigations Operations Manual - Chapter 5 - Establishment Inspection.

3. Field Management Directives:

FMD 17 - Field Assignment Issuances; Guidelines for Headquarters Offices. Revised (20-Sep-1995).
FMD 17B - Management of Compliance Programs by the Field, Revised (5-Feb-1988).
FMD 71 - Field Distribution of Hardcopy Reports to Headquarters Units, Revised (5-Sep-1995).
FMD 145 - Procedure for Release of Establishment Inspection Report to the Inspected Establishment, Original (1-Apr-1997).
FMD 147 - Procedure for Release of Analytical Results Pursuant to Section 704(d), Original (1-Oct-1997).

4. Compliance Programs:
(not available on the Internet)

Human

7356.002 - Drug Process Inspections (continuing) (28-Dec-1990).
7356.002-A - Sterile Drug Process Inspections (1-Oct-1990).
7356.002-B - Drug Repackers and Relabelers (27-Dec-1993).
7356.002-F - Active Pharmaceutical Ingredients (APIs) (20-May-1998).
7356.008 - Drug Product Surveillance (7-Sep-1995).
7346.832 - Pre-Approval Inspections/Investigations (15-Aug-1994).
7346.843 - Post-Approval Inspections (15-Sep-1994).
7341.001 - Inspections of Licensed Therapeutic Drug Products (2-Mar-1999).
7345.001 - Inspections of Licensed Allergenic Products (5-Nov-1998).

Veterinary

7368.001 - Pre-Approval Inspections New Animal Drug Application (30-Sep-1998).
7371.001 - Drug Process and New Animal Drug Inspections (30-Sep-1998).
7371.004 - Medicated Feeds (30-Sep-1998).
7371.005 - Type A Medicated Articles (30-Sep-1996).

5. FDA Staff Manual Guide - SMG 2460.2 - Description and Use of the FDA Records Control Schedule (29-May-1986).
(not available on the Internet)

6. Regulatory Procedures Manual:

Chapter 6 - Judicial Actions.
Chapter 10 - Other Procedures.

V. Execution of regulatory enforcement actions to achieve corrections, designed to prevent future violations, and to remove products found in violation of requirements from the market.

1. U.S. Federal Food, Drug, and Cosmetic Act, As Amended Feb-1998:

2. Code of Federal Regulations (CFR):

3. Archive of Product Recalls, Alerts, and Warnings.

4. Biologics Recalls/Withdrawals/Safety Issues.

5. "FDA Consumer; The Magazine of the U.S. Food and Drug Administration" See section: Summaries of Court Actions (from 1985-present).

6. Laboratory Procedures Manual.

7. Compliance Policy Guides:

General

120.100 - Fraud, Untrue Statements of Material Facts, Bribery, and Illegal Gratuities.

Human

400.200 - Consistent Application of CGMP Determinations.
410.100 - Finished Dosage Form Drug Products in Bulk Containers - Applications of Current Good Manufacturing Practice Regulations.
420.400 - Performance of Tests for Compendial Requirements on Compendial Products.
425.100 - Computerized Drug Processing; CGMP Applicability to Hardware and Software.
425.200 - Computerized Drug Processing; Vendor Responsibility.
425.300 - Computerized Drug Processing; Source Code for Process Control Application Programs.
425.400 - Computerized Drug Processing; Input/Output Checking.
425.500 - Computerized Drug Processing; Identification of "Persons" on Batch Production and Control Records.
430.200 - Repacking of Drug Products - Testing/Examination under CGMPs.
446.100 - Regulatory Action Regarding Approved New Drug and Antibiotic Drug Products Subjected to Additional Processing or other Manipulations.
448.100 - Reconditioning of New Drugs Which Do Not Have Approved NDAs/ANDAs.
450.100 - CGMP Enforcement Policy - OTC vs Rx Drugs.
450.500 - Tamper-Resistant Packing Requirements for Certain Over-the-Counter (OTC) Human Drug Products.
450.550 - Control and Accountability of Labeling Associated with Tamper-Resistant Packaging of Over-the-Counter Drug Products.
454.100 - OTC Ear Drop Preparations.
460.600 - Content Uniformity Testing of Tablets and Capsules.
460.700 - Controlled Release Dosage Form Drugs - Rate of Release of Active Ingredients.
470.100 - Orders for Post-Approval Record Reviews.
480.100 - Requirements for Expiration Dating and Stability Testing.
480.200 - Expiration Dating of Unit Dose Repackaged Drugs.
480.300 - Lack of Expiration Date of Stability Data.
490.100 - Process Validation Requirements for Drug Products Subject to Pre-Market Approval.

8. 56 Federal Register 46191-46200,10-Sep-1991, Final Notice Fraud, Untrue Statements of Material Facts, Bribery, and Illegal Gratuities.

9. Points to Consider for Internal Reviews and Corrective Action Operating Plan, Office of Enforcement (Jun-1991).

10. Regulatory Procedures Manual:

Chapter 4 - Advisory Actions.
Chapter 5 - Administrative Actions.
Chapter 6 - Judicial Actions.
Chapter 7 - Recall and Emergency Procedures.
Chapter 9 - Import Operations/Actions.
Chapter 10 - Other Procedures (Application Integrity Policy) (Mar-1998).

11. CBER Annual Report.

12. CDER 1998 Report to the Nation: Improving Public Health through Human Drugs.

VI. Effective Use of Surveillance Systems:

A. Sampling and analysis.

1. U.S. Federal Food, Drug, and Cosmetic Act, As Amended Feb-1998:

2. Code of Federal Regulations (CFR):

3. Investigations Operations Manual - Chapter 4 - Sampling.

4. Laboratory Procedures Manual.

5. Compliance Policy Guides:

General

150.100 - Requests for Portions of Intermediate or End Products Resulting from FDA Sample Analysis.
150.500 - Analytical Methodology Used by FDA - Drugs.

B. Recall monitoring

1. Code of Federal Regulations (CFR): 21 CFR Part 7 - Enforcement Policy, Subpart C - Recalls.

2. Regulatory Procedures Manual - Chapter 7 - Recall and Emergency Procedures.

3. Investigations Operations Manual - Chapter 8 - Recall Activities.

4. Field Management Directive - FMD 128 - Field Management of Recall Operations (17-May-1995).

5. Compliance Policy Guides - Human - 400.900 - Class I Recalls of Prescription Drugs.

C. Product defect reporting system

1. Code of Federal Regulations (CFR):

2. Field Management Directive - FMD 119 - Consumer Products Complaint System (12-Jan-1994).

3. Compliance Programs:
(not available on the Internet)

7353.001 - Enforcement of Postmarketing Adverse Drug Experience Reporting (11-Jun-1997).
7356.021 - Drug Quality Reporting System (DQRS); NDA Field Alert Reporting (11-May-1995).

4. CDER Adverse Events Reporting System

5. CDER Manual of Policies and Procedures - 4723.1 - Standing Operating Procedures for NDA/ANDA Field Alert Reports (30-Oct-1998).

6. CBER Manual of Standard Operating Procedures and Policies - 8501 - Emergency Operations (14-Apr-1992).

7. Biologics Error and Accident Report Summaries.

8. Guidance to Industry: How to Complete the Vaccine Adverse Reporting System Form (8-Sep-1998).

9. Guidance to Industry: Postmarketing Adverse Experience Reporting for Human Drug and Licensed Biological Products: Clarification of What to Report (27-Aug-1997).

D. Routine surveillance inspections.

1. U.S. Federal Food, Drug, and Cosmetic Act, As Amended Feb-1998:

2. Compliance Programs:
(not available on the Internet)

Human

7356.021 - Drug Quality Reporting System (DQRS); NDA Field Alert Reporting (11-May-1995).
7356.002 - Drug Process Inspections (continuing) (28-Dec-1990).
7356.002-A - Sterile Drug Process Inspections (1-Oct-1990).
7356.002-B - Drug Repackers and Relabelers (27-Dec-1993).
7356.002-F - Active Pharmaceutical Ingredients (APIs) (20-May-1998).
7356.008 - Drug Product Surveillance (7-Sep-1995).
7346.843 - Post-Approval Inspections (15-Sep-1994).
7341.001 - Inspections of Licensed Therapeutic Drug Products (2-Mar-1999).
7345.001 - Inspections of Licensed Allergenic Products (5-Nov-1998). Veterinary
7368.001 - Pre-Approval Inspections New Animal Drug Application (30-Sep-1998).
7371.001 - Drug Process and New Animal Drug Inspections (30-Sep-1998).
7371.004 - Medicated Feeds (30-Sep-1998).
7371.005 - Type A Medicated Articles (30-Sep-1996).

3. Investigations Operations Manual.

E. Verification of approved manufacturing process changes to marketing authorizations/approved applications.

1. U.S. Federal Food, Drug, and Cosmetic Act, As Amended Feb-1998:

2. Code of Federal Regulations (CFR):

3. Compliance Programs:
(not available on the Internet)

Human

7356.002 - Drug Process Inspections (continuing) (28-Dec-1990).
7356.002-A - Sterile Drug Process Inspections (1-Oct-1990).
7356.002-B - Drug Repackers and Relabelers (27-Dec-1993).
7356.002-F - Active Pharmaceutical Ingredients (APIs) (20-May-1998).
7346.843 - Post-Approval Inspections (15-Sep-1994).
7341.001 - Inspections of Licensed Therapeutic Drug Products (2-Mar-1999).
7345.001 - Inspections of Licensed Allergenic Products (5-Nov-1998). Veterinary
7368.001 - Pre-Approval Inspections New Animal Drug Application (30-Sep-1998).
7371.001 - Drug Process and New Animal Drug Inspections (30-Sep-1998).
7371.004 - Medicated Feeds (30-Sep-1998).
7371.005 - Type A Medicated Articles (30-Sep-1996).

4. Compliance Policy Guides - Human - 470.100 - Orders for Post Approval Record Reviews (25-Jun-1992).

VII. Additional specific criteria for pre-approval inspections.

A. Satisfactory demonstration through a jointly developed and administered training program and joint inspections to assess the authorities capabilities.

[To be carried out under Equivalence Assessment Plans of FDA and EC.]

B. Pre-inspection preparation includes the review of appropriate records, including site plans and drug master file or similar documentation to enable adequate inspections.

1. Code of Federal Regulations (CFR) - 21 CFR 314.420 - Drug Master Files.

2. Compliance Programs:
(not available on the Internet)

Human

7356.002 - Drug Process Inspections (continuing) (28-Dec-1990).
7356.002-A - Sterile Drug Process Inspections (1-Oct-1990).
7356.002-B - Drug Repackers and Relabelers (27-Dec-1993).
7356.002-F - Active Pharmaceutical Ingredients (APIs) (20-May-1998).
7346.832 - Pre-Approval Inspections/Investigations (15-Aug-1994).

Veterinary

7368.001 - Pre-Approval Inspections New Animal Drug Application (30-Sep-1998).
7371.001 - Drug Process and New Animal Drug Inspections (30-Sep-1998).
7371.004 - Medicated Feeds (30-Sep-1998).
7371.005 - Type A Medicated Articles (30-Sep-1996).

3. CBER Manual of Standard Operating Procedures and Policies - 8410 - Determining when Pre-License/Pre-Approval Inspections are Necessary.

C. Ability to verify chemistry, manufacturing, and control data supporting an application is authentic and complete.

1. U.S. Federal Food, Drug, and Cosmetic Act, As Amended Feb-1998:

2. Public Health Service Act - Section 351 (42 U.S.C. 262) - Regulation of Biological Products.

3. Code of Federal Regulations (CFR):

4. Compliance Programs:
(not available on the Internet)

Human

7356.002 - Drug Process Inspections (continuing) (28-Dec-1990).
7356.002-A - Sterile Drug Process Inspections (1-Oct-1990).
7356.002-B - Drug Repackers and Relabelers (27-Dec-1993).
7356.002-F - Active Pharmaceutical Ingredients (APIs) (20-May-1998).
7346.832 - Pre-Approval Inspections/Investigations (15-Aug-1994).

Veterinary

7368.001 - Pre-Approval Inspections New Animal Drug Application (30-Sep-1998).
7371.001 - Drug Process and New Animal Drug Inspections (30-Sep-1998).
7371.004 - Medicated Feeds (30-Sep-1998).
7371.005 - Type A Medicated Articles (30-Sep-1996).

D. Ability to assess and evaluate research and development data as scientifically sound, especially transfer technology of pilot, scale up, and full scale production batches.

1. U.S. Federal Food, Drug, and Cosmetic Act, As Amended Feb-1998:

2. Public Health Service Act - Section 351 (42 U.S.C. 262) - Regulation of Biological Products.

3. Compliance Programs:
(not available on the Internet)

Human

7356.002 - Drug Process Inspections (continuing) (28-Dec-1990).
7356.002-A - Sterile Drug Process Inspections (1-Oct-1990).
7356.002-B - Drug Repackers and Relabelers (27-Dec-1993).
7356.002-F - Active Pharmaceutical Ingredients (APIs) (20-May-1998).
7346.832 - Pre-Approval Inspections/Investigations (15-Aug-1994).

Veterinary

7368.001 - Pre-Approval Inspections New Animal Drug Application (30-Sep-1998).
7371.001 - Drug Process and New Animal Drug Inspections (30-Sep-1998).
7371.004 - Medicated Feeds (30-Sep-1998).
7371.005 - Type A Medicated Articles (30-Sep-1996).

E. Ability to verify conformity of the on site processes and procedures with those described in the application.

1. U.S. Federal Food, Drug, and Cosmetic Act, As Amended Feb-1998:

2. Public Health Service Act - Section 351 (42 U.S.C. 262) - Regulation of Biological Products.

3. Code of Federal Regulations (CFR) - 21 CFR 314.50 (l)(3) - Field copy of application.

4. Compliance Programs:
(not available on the Internet)

Human

7356.002 - Drug Process Inspections (continuing) (28-Dec-1990).
7356.002-A - Sterile Drug Process Inspections (1-Oct-1990).
7356.002-B - Drug Repackers and Relabelers (27-Dec-1993).
7356.002-F - Active Pharmaceutical Ingredients (APIs) (20-May-1998).
7346.832 - Pre-Approval Inspections/Investigations (15-Aug-1994).

Veterinary

7368.001 - Pre-Approval Inspections New Animal Drug Application (30-Sep-1998).
7371.001 - Drug Process and New Animal Drug Inspections (30-Sep-1998).
7371.004 - Medicated Feeds (30-Sep-1998).
7371.005 - Type A Medicated Articles (30-Sep-1996).

F. Review and evaluate equipment installation, operational and performance qualification data, and evaluate test method validation.

1. U.S. Federal Food, Drug, and Cosmetic Act, As Amended Feb-1998:

2. Public Health Service Act - Section 351 (42 U.S.C. 262) - Regulation of Biological Products.

3. Compliance Programs:
(not available on the Internet)

Human

7356.002 - Drug Process Inspections (continuing) (28-Dec-1990).
7356.002-A - Sterile Drug Process Inspections (1-Oct-1990).
7356.002-B - Drug Repackers and Relabelers (27-Dec-1993).
7356.002-F - Active Pharmaceutical Ingredients (APIs) (20-May-1998).
7346.832 - Pre-Approval Inspections/Investigations (15-Aug-1994).

Veterinary

7368.001 - Pre-Approval Inspections New Animal Drug Application (30-Sep-1998).
7371.001 - Drug Process and New Animal Drug Inspections (30-Sep-1998).
7371.004 - Medicated Feeds (30-Sep-1998).
7371.005 - Type A Medicated Articles (30-Sep-1996).

4. Laboratory Procedures Manual.

5. Compliance Policy Guides - Human - 490.100 - Validation Requirements for Drug Products Subject to Pre-Market Approval.

6. Inspection Guides - Oral Solid Dosage Forms Pre/Post Approval Issues (Jan-1994).

(Hypertext updated by mev DEC-22-2002)

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