[Code of Federal Regulations]
[Title 21, Volume 1]
[Revised as of April 1, 2001]
From the U.S. Government Printing Office via GPO Access
[CITE: 21CFR26.21]

[Page 255-258]
 
                        TITLE 21--FOOD AND DRUGS
 
CHAPTER I--FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN 
                                SERVICES
 
   PART 26--MUTUAL RECOGNITION OF PHARMACEUTICAL GOOD MANUFACTURING PRACTICE REPORTS, MEDICAL DEVICE QUALITY SYSTEM AUDIT REPORTS, AND CERTAIN MEDICAL DEVICE PRODUCT EVALUATION REPORTS: UNITED STATES AND THE EUROPEAN COMMUNITY--Table of Contents
 
     Subpart A--Specific Sector Provisions for Pharmaceutical Good 
                         Manufacturing Practices
 
Sec. 26.21   Safeguard clause.

    Each party recognizes that the importing country has a right to 
fulfill its legal responsibilities by taking actions necessary to ensure 
the protection of human and animal health at the level of protection it 
deems appropriate. This includes the suspension of the distribution, 
product detention at the border of the importing country, withdrawal of 
the batches and any request for additional information or inspection as 
provided in Sec. 26.12.

      Appendix A to Subpart A of Part 26--List of Applicable Laws, 
               Regulations, and Administrative Provisions

                   1. For the European Community (EC):

    [Copies of EC documents may be obtained from the European Document 
Research, 1100 17th St. NW., suite 301, Washington, DC 20036.

[[Page 256]]

EC documents may be viewed on the European Commission Pharmaceuticals 
Units web site at ``http://dg3.eudra.org''.]
Council Directive 65/65/EEC of 26 January 1965 on the approximation of 
provisions laid down by law, regulation, or administrative action 
relating to proprietary medicinal products as extended, widened, and 
amended.
Council Directive 75/319/EEC of 20 May 1975 on the approximation of 
provisions laid down by law, regulation or administrative action 
relating to proprietary medicinal products as extended, widened and 
amended.
Council Directive 81/851/EEC of 28 September 1981 on the approximation 
of the laws of the Member States relating to veterinary medicinal 
products, as widened and amended.
Commission Directive 91/356/EEC of 13 June 1991 laying down the 
principles and guidelines of good manufacturing practice for medicinal 
products for human use.
Commission Directive 91/412/EEC of 23 July 1991 laying down the 
principles and guidelines of good manufacturing practice for veterinary 
medicinal products.
Council Regulation EEC No 2309/93 of 22 July 1993 laying down Community 
procedures for the authorization and supervision of medicinal products 
for human and veterinary use and establishing a European Agency for the 
Evaluation of Medicinal Products.
Council Directive 92/25/EEC of 31 March 1992 on the wholesale 
distribution of medicinal products for human use.
Guide to Good Distribution Practice (94/C 63/03).
Current version of the Guide to Good Manufacturing Practice, Rules 
Governing Medicinal Products in the European Community, Volume IV.

                        2. For the United States:

    [Copies of FDA documents may be obtained from the Government 
Printing Office, 1510 H St. NW., Washington, DC 20005. FDA documents, 
except the FDA Compliance Program Guidance Manual, may be viewed on 
FDA's Internet web site at ``http://www.FDA.gov''.]
Relevant sections of the United States Federal Food, Drug, and Cosmetic 
Act and the United States Public Health Service Act.
Relevant sections of Title 21, United States Code of Federal Regulations 
(CFR) Parts 1-99, Parts 200-299, Parts 500-599, and Parts 600-799.
Relevant sections of the FDA Investigations Operations Manual, the FDA 
Regulatory Procedures Manual, the FDA Compliance Policy Guidance Manual, 
the FDA Compliance Program Guidance Manual, and other FDA guidances.

         Appendix B to Subpart A of Part 26--List of Authorities

1. For the United States: In the United States, the regulatory authority 
                  is the Food and Drug Administration.

2. For the European Community: In the European Community, the regulatory 
                     authorities are the following:

Belgium: Inspection generale de la Pharmacie, Algemene Farmaceutische 
Inspectie.
Denmark: Laegemiddelstyrelsen.
Germany: Bundesministerium fur Gesundheit for immunologicals: Paul-
Ehrlich-Institut, Federal Agency for Sera and Vaccines.
Greece: 



, Ministry of Health and Welfare, National Drug Organization (E.O.F).
Spain: For medicinal products for human use: Ministerio de Sanidad y 
Consumo, Subdireccion General de Control Farmaceutico. For medicinal 
products for veterinary use: Ministerio de Agricultura, Pesca y 
Alimentacion (MAPA), Direccion General de la Produccion Agraria.
France: For medicinal products for human use: Agence du Medicament. For 
veterinary medicinal products: Agence Nationale du Medicament 
Veterinaire.
Ireland: Irish Medicines Board.
Italy: For medicinal products for human use: Ministero della Sanita, 
Dipartimento Farmaci e Farmacovigilanza. For medicinal products for 
veterinary use: Ministero della Sanita, Dipartimento alimenti e 
nutrizione e sanita pubblica veterinaria-Div. IX.
Luxembourg: Division de la Pharmacie et des Medicaments.
Netherlands: Staat der Nederlanden.
Austria: Bundesministerium fur Arbeit, Gesundheit und Soziales.
Portugal: Instituto da Farmacia e do Medicamento (INFARMED).
Finland: Laakelaitos/Lakemedelsverket (National Agency for Medicines).
Sweden: Lakemedelsverket-Medical Products Agency.
United Kingdom: For human use and veterinary (non-immunologicals): 
Medicines Control Agency. For veterinary immunologicals: Veterinary 
Medicines Directorate.
European Community: Commission of the European Communities. European 
Agency for the Evaluation of Medicinal Products (EMEA).

Appendix C to Subpart A of Part 26--Indicative List of Products Covered 
                              by Subpart A

Recognizing that precise definition of medicinal products and drugs are 
to be found in

[[Page 257]]

the legislation referred to above, an indicative list of products 
covered by this arrangement is given below:
    --human medicinal products including prescription and 
nonprescription drugs;
    --human biologicals including vaccines, and immunologicals;
    --veterinary pharmaceuticals, including prescription and 
nonprescription drugs, with the exclusion of veterinary immunologicals 
(Under 9 CFR 101.2 ``veterinary immunologicals'' are referred to as 
``veterinary biologicals'');
    --premixes for the preparation of veterinary medicated feeds (EC), 
Type A medicated articles for the preparation of veterinary medicated 
feeds (United States);
    --intermediate products and active pharmaceutical ingredients or 
bulk pharmaceuticals (United States)/starting materials (EC).

 Appendix D to Subpart A of Part 26--Criteria for Assessing Equivalence 
                        for Post- and Preapproval

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

A. Appropriate statutory mandate and jurisdiction.
B. Ability to issue and update binding requirements on GMP's and 
guidance documents.
C. Authority to make inspections, review and copy documents, and to take 
samples and collect other evidence.
D. Ability to enforce requirements and to remove products found in 
violation of such requirements from the market.
E. Substantive current good manufacturing requirements.
F. Accountability of the regulatory authority.
G. Inventory of current products and manufacturers.
H. System for maintaining or accessing inspection reports, samples and 
other analytical data, and other firm/product information relating to 
matters covered by subpart A of this part.

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

            III. Administration of the regulatory authority:

A. Standards of education/qualification and training.
B. Effective quality assurance systems measures to ensure adequate job 
performance.
C. Appropriate staffing and resources to enforce laws and regulations.

                       IV. Conduct of inspections:

A. Adequate preinspection preparation, including appropriate expertise 
of investigator/team, review of firm/product and databases, and 
availability of appropriate inspection equipment.
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.
C. Adequate postinspection activities, including completeness of 
inspectors' report, inspection report review where appropriate, and 
conduct of followup inspections and other activities where appropriate, 
assurance of preservation and retrieval of records.

 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.

               VI. Effective use of surveillance systems:

A. Sampling and analysis.
B. Recall monitoring.
C. Product defect reporting system.
D. Routine surveillance inspections.
E. Verification of approved manufacturing process changes to marketing 
authorizations/approved applications.

     VII. Additional specific criteria for preapproval inspections:

A. Satisfactory demonstration through a jointly developed and 
administered training program and joint inspections to assess the 
regulatory authorities' capabilities.
B. Preinspection preparation includes the review of appropriate records, 
including site plans and drug master file or similar documentation to 
enable adequate inspections.
C. Ability to verify chemistry, manufacturing, and control data 
supporting an application is authentic and complete.
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.
E. Ability to verify conformity of the onsite processes and procedures 
with those described in the application.
F. Review and evaluate equipment installation, operational and 
performance qualification data, and evaluate test method validation.

[[Page 258]]

    Appendix E to Subpart A of Part 26--Elements to be Considered in 
                    Developing a Two-Way Alert System

                            1. Documentation

--Definition of a crisis/emergency and under what circumstances an alert 
is required
--Standard Operating Procedures (SOP's)
--Mechanism of health hazards evaluation and classification
--Language of communication and transmission of information

                       2. Crisis Management System

--Crisis analysis and communication mechanisms
--Establishment of contact points
--Reporting mechanisms

                        3. Enforcement Procedures

--Followup mechanisms
--Corrective action procedures

                       4. Quality Assurance System

--Pharmacovigilance programme
--Surveillance/monitoring of implementation of corrective action

                            5. Contact Points

For the purpose of subpart A of this part, the contact points for the 
alert system will be:

                     A. For the European Community:

the Executive Director of the European Agency for the Evaluation of 
Medicinal Products, 7, Westferry Circus, Canary Wharf, UK - London E14 
4HB, England. Telephone 44-171-418 8400, Fax 418-8416.

                       B. For the United States :

Biologics: Director, Office of Compliance and Biologics Quality (HFM-
600), 1401 Rockville Pike, Rockville, MD 20852, phone: 301-827-6190, 
fax: 301-594-1944.
Human Drugs: Director, Office of Compliance (HFD-300), MPN I, 7520 
Standish Pl., Rockville, MD 20855-2737, phone: 301-594-0054, fax: 301-
594-2114.
Veterinary Drugs: Director, Office of Surveillance and Compliance (HFV-
200), MPN II, 7500 Standish Pl., Rockville, MD 20855-2773, phone: 301-
827-6644, fax: 301-594-1807.