Title 21

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

21:1.0.1.1.20.1.63.22.1 : Appendix A

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. 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

21:1.0.1.1.20.1.63.22.2 : Appendix B

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 générale de la Pharmacie, Algemene Farmaceutische Inspectie. Denmark: Laegemiddelstyrelsen. Germany: Bundesministerium für Gesundheit for immunologicals: Paul-Ehrlich-Institut, Federal Agency for Sera and Vaccines. Greece: Εθνικως Ωργανισμως Φαρμακωυ, Ministry of Health and Welfare, National Drug Organization (E.O.F). Spain: For medicinal products for human use: Ministerio de Sanidad y Consumo, Subdirección General de Control Farmacéutico. For medicinal products for veterinary use: Ministerio de Agricultura, Pesca y Alimentación (MAPA), Dirección General de la Producción Agraria. France: For medicinal products for human use: Agence du Médicament. For veterinary medicinal products: Agence Nationale du Médicament Vétérinaire. Ireland: Irish Medicines Board. Italy: For medicinal products for human use: Ministero della Sanità, Dipartimento Farmaci e Farmacovigilanza. For medicinal products for veterinary use: Ministero della Sanità, Dipartimento alimenti e nutrizione e sanità pubblica veterinaria-Div. IX. Luxembourg: Division de la Pharmacie et des Médicaments. Netherlands: Staat der Nederlanden. Austria: Bundesministerium für Arbeit, Gesundheit und Soziales. Portugal: Instituto da Farmácia e do Medicamento (INFARMED). Finland: Lääkelaitos/Läkemedelsverket (National Agency for Medicines). Sweden: Läkemedelsverket-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

21:1.0.1.1.20.1.63.22.3 : Appendix C

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 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

21:1.0.1.1.20.1.63.22.4 : Appendix D

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.

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

21:1.0.1.1.20.1.63.22.5 : Appendix E

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:Food and Drug Administration, Center for Biologics Evaluation and Research, Document Control Center, 10903 New Hampshire Ave., Bldg. 71, Rm. G112, Silver Spring, MD 20993-0002, telephone: 240-402-9153, FAX: 301-595-1302. Human Drugs: Director, Office of Compliance, 10903 New Hampshire Ave., Silver Spring, MD 20993-0002, phone: 301-796-3100, fax: 301-847-8747. 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. [63 FR 60141, Nov. 6, 1998, as amended at 69 FR 48775, Aug. 11, 2004; 74 FR 13112, Mar. 26, 2009; 80 FR 18090, Apr. 3, 2015]

Appendix A to Subpart B of Part 26 - Relevant Legislation, Regulations, and Procedures.

21:1.0.1.1.20.2.63.21.6 : Appendix A

Appendix A to Subpart B of Part 26 - Relevant Legislation, Regulations, and Procedures. 1. For the European Community (EC) the following legislation applies to § 26.42(a) of this subpart:

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

a. Council Directive 90/385/EEC of 20 June 1990 on active implantable medical devices OJ No. L 189, 20.7. 1990, p. 17. Conformity assessment procedures. Annex 2 (with the exception of section 4) Annex 4 Annex 5 b. Council Directive 93/42/EEC of 14 June 1993 on Medical Devices OJ No. L 169,12.7.1993, p.1. Conformity assessment procedures. Annex 2 (with the exception of section 4) Annex 3 Annex 4 Annex 5 Annex 6 2. For the United States, the following legislation applies to § 26.32(a):

[Copies of FDA documents may be obtained from the Government Printing Office, 1510 H St. NW., Washington, DC 20005. FDA documents may be viewed on FDA's Internet web site at http://www.fda.gov.]

a. The Federal Food, Drug and Cosmetic Act, 21 U.S.C. 321 et seq. b. The Public Health Service Act, 42 U.S.C. 201 et seq. c. Regulations of the United States Food and Drug Administration found at 21 CFR, in particular, Parts 800 to 1299. d. Medical Devices; Third Party Review of Selected Premarket Notifications; Pilot Program, 61 FR 14789-14796 (April 3, 1996). e. Draft Guidance Document on Accredited Persons Program, 63 FR 28392 (May 22, 1998). f. Draft Guidance for Staff, Industry and Third Parties, Third Party Programs under the Sectoral Annex on Medical Devices to the Agreement on Mutual Recognition Between the United States of America and the European Community (MRA), 63 FR 36240 (July 2, 1998). g. Guidance Document on Use of Standards, 63 FR 9561 (February 25, 1998).

Appendix B to Subpart B of Part 26 - Scope of Product Coverage

21:1.0.1.1.20.2.63.21.7 : Appendix B

Appendix B to Subpart B of Part 26 - Scope of Product Coverage 1. Initial Coverage of the Transition Period Upon entry into force of this subpart as described in § 26.80 (it is understood that the date of entry into force will not occur prior to June 1, 1998, unless the parties decide otherwise), products qualifying for the transitional arrangements under this subpart include: a. All Class I products requiring premarket evaluations in the United States - see Table 1. b. Those Class II products listed in Table 2. 2. During the Transition Period The parties will jointly identify additional product groups, including their related accessories, in line with their respective priorities as follows: a. Those for which review may be based primarily on written guidance which the parties will use their best efforts to prepare expeditiously; and b. Those for which review may be based primarily on international standards, in order for the parties to gain the requisite experience. The corresponding additional product lists will be phased in on an annual basis. The parties may consult with industry and other interested parties in determining which products will be added. 3. Commencement of the Operational Period a. At the commencement of the operational period, product coverage shall extend to all Class I/II products covered during the transition period. b. FDA will expand the program to categories of Class II devices as is consistent with the results of the pilot, and with FDA's ability to write guidance documents if the device pilot for the third party review of medical devices is successful. The MRA will cover to the maximum extent feasible all Class II devices listed in Table 3 for which FDA-accredited third party review is available in the United States. 4. Unless explicitly included by joint decision of the parties, this part does not cover any U.S. Class II-tier 3 or any Class III product under either system.

[The lists of medical devices included in these tables are subject to change as a result of the Food and Drug Administration Modernization Act of 1997.]