tained for evaluation by the Food and Drug Administration The tests necessary to resolve whatever safety or effectiveness questions exist shall be described.

(4) The full report or reports of the panel to the Commissioner of Food and Drugs.

The summary minutes of the panel meeting or meetings shall be made available to Interested persons upon request. Any interested person may, within 60 days after publication of the proposed order in the FEDERAL REGISTER, file with the Hearing Clerk of the Food and Drug Administration written comments in quintuplicate. Comments may be accompanied by a memorandum or brief in support thereof. All comments may be reviewed at the office of the Hearing Clerk during regular working hours, Monday through Friday.

(g) Final order. After reviewing the comments, the Commissioner of Food and Drugs shall publish in the FEDERAL REGISTER a final order on the matters covered in the proposed order. The final order shall become effective as specified in the order.

(h) Additional studies. (1) Within 30 days following publication of the final order, each licensee for a biological product designated as requiring further study to justify continued marketing on an interim basis, pursuant to paragraph (f) (3) of this section, shall satisfy the Commissioner of Food and Drugs in writing that studies adequate and appropriate to resolve the questions raised about the product have been undertaken, or the Federal Government may undertake the studies. The Commissioner may extend this 30-day period if necessary, either to review and act on proposed protocols or upon indication from the licensee that the studies will commence at a specified reasonable time. If no such commitment is made, or adequate and appropriate studies are not undertaken, the product license or licenses shall be revoked.

(2) A progress report shall be filed on the studies every January 1 and July 1 until completion. If the progress report is inadequate or if the Commissioner of Food and Drugs concludes that the studies are not being pursued promptly and diligently, or if interim results indicate the potential benefits do not outweigh the potential risks, the product license or licenses shall be revoked.

(3) Promptly upon completion of the studies undertaken on the product, the Commissioner of Food and Drugs will review all available data and will either

retain or revoke the product license or licenses involved. In making this review and evaluation the Commissioner may again consult the advisory review panel which prepared the report on the product, or other advisory committees, professional organizations, or experts. The Commissioner shall take such action by notice published in the FEDERAL REGISTER.

(1) Court Appeal. The final order(s) published pursuant to paragraph (g) of this section, and any notice published pursuant to paragraph (h) of this section, constitute final agency action from which appeal lies to the courts. The Food and Drug Administration will request consolidation of all appeals in a single court. Upon court appeal, the Commissioner of Food and Drugs may, at his discretion, stay the effective date for part or all of the final order or notice, pending appeal and final court adjudication. [38 FR 32052, Nov. 20. 1973 as amended at 39 FR 11535, Mar. 29, 1974; 40 FR 13498, Mar. 27, 1975]

Subpart D-Licensing of Foreign
Establishments and Products

§ 601.30

an

Licenses required; products for controlled investigation only. Any biological or trivalent organic arsenical manufactured in any foreign country and intended for sale, barter or exchange shall be refused entry by collectors of customs unless manufactured in establishment holding an unsuspended and unrevoked establishment license and license for the product. Unlicensed products which are not imported for sale, barter or exchange and which are intended solely for purposes of controlled investigation are admissible only if in accord with section 505 of the Federal Food, Drug, and Cosmetic Act, as amended, and the regulations thereunder.

licensees shall notify each person in the United States to whom such a product is thus sent, carried, or brought, to keep such records of distribution as are required of domestic licensed establishments. Failure to give such notice to maintain records shall constitute ground for revocation of license.

§ 601.32 Form of license.

Licenses for establishments located in foreign countries shall be in form similar to that for domestic establishments except that they shall authorize manufacture for sending, carrying, or bringing for sale, barter or exchange from the foreign country designated in the license into any State or possession of the United States and shall specify that it is issued upon the condition that the licensee will permit the inspection during all reasonable hours of the establishment by any officer, agent, or employee of the Department of Health, Education, and Welfare authorized by the Secretary for such purpose.

§ 601.33 Samples for each importation.

Random samples of each importation, obtained by the District Director of Customs and forwarded to the Director, Bureau of Biologics, shall be at least two final containers of each lot of product. A copy of the associated documents which describe and identify the shipment shall accompany the shipment for forwarding with the samples to the Director, Bureau of Biologics. For shipments of 20 or less final containers, samples need not be forwarded, provided a copy of an official release from the Bureau of Biologics accompanies each shipment.

Subpart E-Suspension of Licenses and Appeals Procedure

§ 601.40 Summary suspension.

Whenever the Commissioner of Food and Drugs has reasonable ground to believe that an establishment or product for which a license has been issued fails to conform to the standards prescribed in the regulations in this subchapter, and that by reason of such failure and of failure of the manufacturer to take prompt corrective measures on notice thereof, the distribution or sale of a licensed product would constitute a danger to health, or that the establishment and manufacturing methods have been so changed as to require in order to protect the public health a new showing that the establishment or product

meets the standards prescribed in the regulations in this subchapter, he may recommend to the Secretary that the license for the establishment or the product be summarily suspended and the manufacturer be required (a) to notify the selling agents and distributors to whom such product or products have been delivered of such suspension, (b) to furnish complete records of such deliveries and notice of suspension, and (c) to show cause within 60 days or such other period as may be specified in the order why the license should not be revoked.

When deemed advisable by the Commissioner of Food and Drugs, in matters involving the safety, purity, and potency of licensed products or products for which an application for license is pending, the reports of inspection and laboratory examinations, together with any pertinent data the establishment may submit, shall be passed upon by a special board of three officers appointed by the Commissioner of Food and Drugs for that purpose. The board shall report its findings to the Commissioner of Food and Drugs who will forward its report, together with his findings and recommendations, to the Secretary. § 601.42

Opportunity for hearing.

Any manufacturer whose application for a license has been denied, or whose establishment or product license has been summarily suspended, without prior opportunity for hearing, may appeal from such denial or suspension and shall be entitled to a hearing thereon before a review body constituted as provided in § 601.41. The Commissioner of Food and Drugs, upon review of the record, may affirm, reverse, or modify the findings of the review board, or may direct the taking of further testimony, and shall forward his determinations and recommendations to the Secretary.

§ 601.43 Suspension and

publication.

revocation;

Notice of suspension or revocation of license, with statement of cause therefor, may be published by the Secretary. § 601.44 Licenses; reissuance.

(a) Compliance with standards. An establishment or product license, previously suspended or revoked, whether upon application, or for failure to com

ply with standards or changes in standards prescribed in the regulations in this subchapter, may be reissued or reinstated upon a showing of compliance with required standards and upon such inspection and examination as may be considered necessary by the Director of the Bureau of Biologics.

(b) Exclusion of noncomplying location. An establishment or product 11cense, excluding a location or locations that fail to comply with prescribed standards, may be issued without further application and concurrently with the suspension or revocation of the license for noncompliance at the excluded location or locations.

Subpart F-Confidentiality of Information

AUTHORITY: Pub. L. 90-23, 81 Stat. 54-56, as amended by 88 Stat. 1561-1564 (5 U.S.C. 552).

§ 601.50 Confidentiality of data and 'nformation in an investigational new drug notice for a biological product. (a) The existence of an IND notice for a biological product will not be disclosed by the Food and Drug Administration unless it has previously been publicly disclosed or acknowledged.

(b) The availability for public disclosure of all data and information in an IND file for a biological product shall be handled in accordance with the provisions established in § 601.51.

(c) Notwithstanding the provisions of $ 601.51, the Food and Drug Administration shall disclose upon request to an individual on whom an investigational biological product has been used a copy of any adverse reaction report relating to such use.

[39 FR 44656, Dec. 24, 1974]

§ 601.51 Confidentiality of data and information in applications for establishment and product licenses.

(a) For purposes of this section the "biological product file" includes all data and information submitted with or incorporated by reference in any application for an establishment or product license, IND's incorporated into any such application, master files, and other related submissions. The availability for public disclosure of any record in the biological product file shall be handled in accordance with the provisions of this section.

(b) The existence of a biological product file will not be disclosed by the Food

and Drug Administration before a product license has been sent to the applicant, unless it has previously been publicly disclosed or acknowledged. The Director of the Bureau of Biologics will maintain a list available for public disclosure of biological products for which a license has been issued.

(c) If the existence of a biological product file has not been publicly disclosed or acknowledged, no data or information in the biological product file is available for public disclosure.

(d) If the existence of a biological product file has been publicly disclosed or acknowleged before a license has been issued, no data or information contained in the file is available for public disclosure before such license is issued, but the Commissioner may, in his discretion, disclose a summary of such selected portions of the safety and effectiveness data as are appropriate for public consideration of a specific pending issue, e.g., at an open session of a Food and Drug Administration advisory committee or pursuant to an exchange of important regulatory information with a foreign government.

(e) After a license has been issued, the following data and information in the biological product file are immediately available for public disclosure unless extraordinary circumstances are shown:

(1) All safety and effectiveness data and information.

(2) A protocol for a test or study, unless it is shown to fall within the exemption established for trade secrets and confidential commerical or financial information in § 4.61 of this chapter.

(3) Adverse reaction reports, product experience reports, consumer complaints, and other similar data and information, after deletion of:

(i) Names and any information that would identify the person using the product.

(ii) Names and any information that would identify any third party involved with the report, such as a physician or hospital or other institution.

(4) A list of all active ingredients and any inactive ingredients previously disclosed to the public, as defined in § 4.81 of this chapter.

(5) An assay method or other analytical method, unless it serves no regulatory or compliance purpose and it is shown to fall within the exemption established in § 4.61 of this chapter.

(6) All correspondence and written summaries of oral discussions relating to the biological product file, in accordance with the provisions of Part 4 of this chapter.

(7) All records showing the manufacturer's testing of a particular lot, after deletion of data or information that would show the volume of the drug produced, manufacturing procedures and controls, yield from raw materials, costs, or other material falling within $ 4.61 of this chapter.

(8) All records showing the testing of and action on a particular lot by the Food and Drug Administration.

(f) The following data and information in a biological product file are not available for public disclosure unless they have been previously disclosed to the public as defined in $ 4.81 of this chapter or they relate to a product or ingredient that has been abandoned and they no longer represent a trade secret or confidential commercial or financial information as defined in § 4.61 of this chapter:

(1) Manufacturing methods or processes, including quality control procedures.

(2) Production, sales, distribution, and similar data and information, except that any compilation of such data and information aggregated and prepared in a way that does not reveal data or information which is not available for public disclosure under this provision is available for public disclosure.

(3) Quantitative or semiquantitative formulas.

(g) For purposes of this regulation, safety and effectiveness data include all studies and tests of a biological product on animals and humans and all studies and tests on the drug for identity, stability, purity, potency, and bioavailability.

[39 FR 44656, Dec. 24, 1974]

610.64

Divided manufacturing responsibility

to be shown.

Name of selling agent or distributor. 610.65 Products for export.

AUTHORITY: Sec. 215, 58 Stat. 690, as amended; 42 U.S.C. 216. Sec. 351, 58 Stat. 702, as amended; 42 U.S.C. 262, unless otherwise noted.

SOURCE: 38 FR 32056, Nov. 20, 1973, unless otherwise noted.

· CROSS REFERENCES. For U.S. Customs Service regulations relating to viruses, serums, and toxins, see 19 CFR 12.21-12.23. For U.S. Postal Service regulations relating to the admissibility to the United States mails see 39 CFR Parts 124 and 125, esp. § 125.2. Subpart A-Release Requirements § 610.1

Tests prior to release required for each lot.

No lot of any licensed product shall be released by the manufacturer prior to the completion of tests for conformity with standards applicable to such product. Each applicable test shall be made on each lot after completion of all processes of manufacture which may affect compliance with the standard to which the test applies. The results of all tests performed shall be considered in determining whether or not the test results meet the test objective, except that a test result may be disregarded

when it is established that the test is invalid due to causes unrelated to the product.

§ 610.2 Requests for samples and protocols; official release.

Samples of any lot of any licensed product, together with the protocols showing results of applicable tests, may at any time be required to be sent to the Director, Bureau of Biologics. Upon notification by the Director, Bureau of Biologics, a manufacturer shall not distribute a lot of a product until the lot is released by the Director, Bureau of Biologics: Provided, That the Director shall not issue such notification except when deemed necessary for the safety, purity or potency of the product.

Subpart B-General Provisions

Tests for potency shall consist of either in vitro or in vivo tests, or both, which have been specifically designed for each product so as to indicate its potency in a manner adequate to satisfy the interpretation of potency given by the definition in § 600.3 (s) of this chapter.

§ 610.11 General safety.

In addition to specified safety tests prescribed in this subchapter for individual products, a general safety test shall be performed in final container material. from each filling of each lot of all products intended for administration to man, either after the labels have been affixed to the final container, or affixed, both outside and inside, to the multiple container storage receptacle just prior to its sealing for storage purposes. Exceptions to this procedure may be authorized by the Director, Bureau of Biologics, when more than one lot is processed each day. The general safety test shall consist of the parenteral injection of the maximum volume tolerated into each of two mice weighing approximately 20 gms. each and into each of two guinea pigs weighing approximately 350 gms. each but no more than 0.5 ml. need be inoculated into each mouse and no more than 5.0 ml. need be inoculated into each guinea pig. After injection the animals shall be observed for a period of no less than seven days and if neither significant symptoms nor death results during the observation period, the product meets

the requirements for general safety. Variations of this test, either in the volume injected or in the species of test animal used shall be made whenever required because of the human dose level demanded of the product or because of any individual demands of the product itself.

§ 610.11a

Inactivated influenza vaccine, general safety test.

For inactivated influenza vaccine, the general safety test shall be conducted in the manner indicated in § 610.11 of this chapter except that, with reference to guinea pigs, the test shall be satisfied if the product provides satisfactory results using either the subcutaneous or intraperitoneal injection of 5.0 milliliters of inactivated influenza vaccine into each guinea pig. The requirements for general safety for inactivated influenza vaccine shall not be considered to be satisfied unless each lot of influenza vaccine is assayed for endotoxin in comparison to a reference preparation provided by the Food and Drug Administration, and such lot is found to contain no more endotoxin than the reference preparation. 139 FR 40016, Nov. 13, 1974] § 610.12

Sterility.

Except as provided in paragraphs (f) and (g) of this section, the sterility of each lot of each product shall be demonstrated by the performance of the tests prescribed in paragraphs (a) and (b) of this section for both bulk and final container material.

(a) The test. Bulk material shall be tested separately from final container material and material from each final container shall be tested in individual test vessels as follows:

(1) Using Fluid Thioglycollate Medium―(1) Bulk and final container material. The volume of product, as required by paragraph (d) of this section (hereinafter referred to also as the "inoculum"), from samples of both bulk and final container material, shall be inoculated into test vessels of Fluid Thioglycollate Medium. The inoculum and medium shall be mixed thoroughly and incubated at a temperature of 30° to 32° C. for a test period of no less than 14 days and examined visually for evidence of growth on the third, fourth, or fifth day and on the seventh or eighth