CFR Subpart A

CFR Subpart A
in effect

21 C.F.R. § 601.2 Applications for biologics licenses; procedures for filing.

(a) General. To obtain a biologics license under section 351 of the Public Health Service Act for any biological product, the manufacturer shall submit an application to the Director, Center for Biologics Evaluation and Research or the Director, Center for Drug Evaluation and Research (see mailing addresses in § 600.2(a) or (b) of this chapter), on forms prescribed for such purposes, and shall submit data derived from nonclinical laboratory and clinical studies which demonstrate that the manufactured product meets prescribed requirements of safety, purity, and potency; with respect to each nonclinical laboratory study, either a statement that the study was conducted in compliance with the requirements set forth in part 58 of this chapter, or, if the study was not conducted in compliance with such regulations, a brief statement of the reason for the noncompliance; statements regarding each clinical investigation involving human subjects contained in the application, that it either was conducted in compliance with the requirements for institutional review set forth in part 56 of this chapter; or was not subject to such requirements in accordance with § 56.104 or § 56.105, and was conducted in compliance with requirements for informed consent set forth in part 50 of this chapter. A full description of manufacturing methods; data establishing stability of the product through the dating period; sample(s) representative of the product for introduction or delivery for introduction into interstate commerce; summaries of results of tests performed on the lot(s) represented by the submitted sample(s); specimens of the labels, enclosures, and containers, and if applicable, any Medication Guide required under part 208 of this chapter proposed to be used for the product; and the address of each location involved in the manufacture of the biological product shall be listed in the biologics license application. The applicant shall also include a financial certification or disclosure statement(s) or both for clinical investigators as required by part 54 of this chapter. An application for a biologics license shall not be considered as filed until all pertinent information and data have been received by the Food and Drug Administration. The applicant shall also include either a claim for categorical exclusion under § 25.30 or § 25.31 of this chapter or an environmental assessment under § 25.40 of this chapter. The applicant, or the applicant's attorney, agent, or other authorized official shall sign the application. An application for any of the following specified categories of biological products subject to licensure shall be handled as set forth in paragraph (c) of this section: (1) Therapeutic DNA plasmid products; (2) Therapeutic synthetic peptide products of 40 or fewer amino acids; (3) Monoclonal antibody products for in vivo use; and (4) Therapeutic recombinant DNA-derived products. (b) [Reserved] (c)(1) To obtain marketing approval for a biological product subject to licensure which is a therapeutic DNA plasmid product, therapeutic synthetic peptide product of 40 or fewer amino acids, monoclonal antibody product for in vivo use, or therapeutic recombinant DNA-derived product, an applicant shall submit a biologics license application in accordance with paragraph (a) of this section except that the following sections in parts 600 through 680 of this chapter shall not be applicable to such products: §§ 600.10(b) and (c), 600.11, 600.12, 600.13, 610.53, and 610.62 of this chapter. (2) To the extent that the requirements in this paragraph (c) conflict with other requirements in this subchapter, this paragraph (c) shall supersede other requirements. (d) Approval of a biologics license application or issuance of a biologics license shall constitute a determination that the establishment(s) and the product meet applicable requirements to ensure the continued safety, purity, and potency of such products. Applicable requirements for the maintenance of establishments for the manufacture of a product subject to this section shall include but not be limited to the good manufacturing practice requirements set forth in parts 210, 211, 600, 606, and 820 of this chapter. (e) Any establishment and product license for a biological product issued under section 351 of the Public Health Service Act (42 U.S.C. 201 et seq.) that has not been revoked or suspended as of December 20, 1999, shall constitute an approved biologics license application in effect under the same terms and conditions set forth in such product license and such portions of the establishment license relating to such product. (f) Withdrawal from sale of approved biological products. A holder of a biologics license application (BLA) must report to FDA, in accordance with the requirements of §§ 207.61 and 207.65, the withdrawal from sale of an approved biological product. The information must be submitted to FDA within 30 working days of the biological product's withdrawal from sale. The following information must be submitted: The holder's name; product name; BLA number; the National Drug Code; and the date on which the product is expected to be no longer in commercial distribution. The reason for the withdrawal of the biological product is requested but not required to be submitted. (g) Master files—(1) Biologics license applications under section 351 of the Public Health Service Act not permitted to incorporate by reference drug substance, drug substance intermediate, or drug product information contained in a master file. Except as provided in paragraphs (g)(2) and (3) of this section, a biologics license application under section 351 of the Public Health Service Act may not incorporate by reference drug substance, drug substance intermediate, or drug product information contained in a master file, including a drug master file submitted under § 314.420 of this chapter, for the product, including for a biological product constituent part of a combination product. (2) Former approved applications deemed to be licenses for biological products pursuant to section 7002(e)(4) of the Biologics Price Competition and Innovation Act of 2009. An application for a biological product that: (i) Is a former approved application under section 505 of the Federal Food, Drug, and Cosmetic Act that, pursuant to section 7002(e)(4) of the Biologics Price Competition and Innovation Act of 2009, has been deemed to be a license for the biological product under section 351 of the Public Health Service Act; and (ii) At the time it was so deemed, incorporated by reference drug substance, drug substance intermediate, and/or drug product information contained in a drug master file submitted under § 314.420 of this chapter, may continue to incorporate by reference the information contained in that drug master file. Amendments and supplements to such applications may also continue to incorporate by reference the information contained in that drug master file. (3) Non-biological product constituent parts of combination products regulated under biologics license applications under section 351 of the Public Health Service Act. A biologics license application under section 351 of the Public Health Service Act may incorporate by reference drug substance, drug substance intermediate, and/or drug product information contained in a master file, including a drug master file submitted under § 314.420 of this chapter, for any non-biological product constituent part of a combination product. (4) Biologics license applications under section 351 of the Public Health Service Act permitted to incorporate by reference information contained in a master file that is not drug substance, drug substance intermediate, or drug product information. Nothing in paragraph (g)(1) of this section limits or restricts a biologics license application under section 351 of the Public Health Service Act from incorporating by reference information contained in any master file, including a drug master file submitted under § 314.420 of this chapter, that is not drug substance, drug substance intermediate, or drug product information. (5) Investigational new drug applications. Nothing in paragraph (g)(1) of this section limits or restricts an investigational new drug application for a product that would be subject to licensure under section 351 of the Public Health Service Act from incorporating by reference any information, including drug substance, drug substance intermediate, and drug product information, contained in a master file, including a drug master file submitted under § 314.420 of this chapter.

21 C.F.R. § 601.3 Complete response letter to the applicant.

(a) Complete response letter. The Food and Drug Administration will send the biologics license applicant or supplement applicant a complete response letter if the agency determines that it will not approve the biologics license application or supplement in its present form. (1) Description of specific deficiencies. A complete response letter will describe all of the deficiencies that the agency has identified in a biologics license application or supplement, except as stated in paragraph (a)(2) of this section. (2) Inadequate data. If FDA determines, after a biologics license application or supplement is filed, that the data submitted are inadequate to support approval, the agency might issue a complete response letter without first conducting required inspections, testing submitted product lots, and/or reviewing proposed product labeling. (3) Recommendation of actions for approval. When possible, a complete response letter will recommend actions that the applicant might take to place its biologics license application or supplement in condition for approval. (b) Applicant actions. After receiving a complete response letter, the biologics license applicant or supplement applicant must take either of the following actions: (1) Resubmission. Resubmit the application or supplement, addressing all deficiencies identified in the complete response letter. (2) Withdrawal. Withdraw the application or supplement. A decision to withdraw the application or supplement is without prejudice to a subsequent submission. (c) Failure to take action. (1) FDA may consider a biologics license applicant or supplement applicant's failure to either resubmit or withdraw the application or supplement within 1 year after issuance of a complete response letter to be a request by the applicant to withdraw the application or supplement, unless the applicant has requested an extension of time in which to resubmit the application or supplement. FDA will grant any reasonable request for such an extension. FDA may consider an applicant's failure to resubmit the application or supplement within the extended time period or request an additional extension to be a request by the applicant to withdraw the application. (2) If FDA considers an applicant's failure to take action in accordance with paragraph (c)(1) of this section to be a request to withdraw the application, the agency will notify the applicant in writing. The applicant will have 30 days from the date of the notification to explain why the application or supplement should not be withdrawn and to request an extension of time in which to resubmit the application or supplement. FDA will grant any reasonable request for an extension. If the applicant does not respond to the notification within 30 days, the application or supplement will be deemed to be withdrawn.

21 C.F.R. § 601.4 Issuance and denial of license.

(a) A biologics license shall be issued upon a determination by the Director, Center for Biologics Evaluation and Research or the Director, Center for Drug Evaluation and Research that the establishment(s) and the product meet the applicable requirements established in this chapter. A biologics license shall be valid until suspended or revoked. (b) If the Commissioner determines that the establishment or product does not meet the requirements established in this chapter, the biologics license application shall be denied and the applicant shall be informed of the grounds for, and of an opportunity for a hearing on, the decision. If the applicant so requests, the Commissioner shall issue a notice of opportunity for hearing on the matter pursuant to § 12.21(b) of this chapter.

21 C.F.R. § 601.5 Revocation of license.

(a) A biologics license shall be revoked upon application of the manufacturer giving notice of intention to discontinue the manufacture of all products manufactured under such license or to discontinue the manufacture of a particular product for which a license is held and waiving an opportunity for a hearing on the matter. (b)(1) The Commissioner shall notify the licensed manufacturer of the intention to revoke the biologics license, setting forth the grounds for, and offering an opportunity for a hearing on the proposed revocation if the Commissioner finds any of the following: (i) Authorized Food and Drug Administration employees after reasonable efforts have been unable to gain access to an establishment or a location for the purpose of carrying out the inspection required under § 600.21 of this chapter, (ii) Manufacturing of products or of a product has been discontinued to an extent that a meaningful inspection or evaluation cannot be made, (iii) The manufacturer has failed to report a change as required by § 601.12 of this chapter, (iv) The establishment or any location thereof, or the product for which the license has been issued, fails to conform to the applicable standards established in the license and in this chapter designed to ensure the continued safety, purity, and potency of the manufactured product, (v) The establishment or the manufacturing methods have been so changed as to require a new showing that the establishment or product meets the requirements established in this chapter in order to protect the public health, or (vi) The licensed product is not safe and effective for all of its intended uses or is misbranded with respect to any such use. (2) Except as provided in § 601.6 of this chapter, or in cases involving willfulness, the notification required in this paragraph shall provide a reasonable period for the licensed manufacturer to demonstrate or achieve compliance with the requirements of this chapter, before proceedings will be instituted for the revocation of the license. If compliance is not demonstrated or achieved and the licensed manufacturer does not waive the opportunity for a hearing, the Commissioner shall issue a notice of opportunity for hearing on the matter under § 12.21(b) of this chapter.

21 C.F.R. § 601.6 Suspension of license.

(a) Whenever the Commissioner has reasonable grounds to believe that any of the grounds for revocation of a license exist and that by reason thereof there is a danger to health, the Commissioner may notify the licensed manufacturer that the biologics license is suspended and require that the licensed manufacturer do the following: (1) Notify the selling agents and distributors to whom such product or products have been delivered of such suspension, and (2) Furnish to the Center for Biologics Evaluation and Research or the Center for Drug Evaluation and Research, complete records of such deliveries and notice of suspension. (b) Upon suspension of a license, the Commissioner shall either: (1) Proceed under the provisions of § 601.5(b) of this chapter to revoke the license, or (2) If the licensed manufacturer agrees, hold revocation in abeyance pending resolution of the matters involved.

21 C.F.R. § 601.7 Procedure for hearings.

(a) A notice of opportunity for hearing, notice of appearance and request for hearing, and grant or denial of hearing for a biological drug pursuant to this part, for which the exemption from the Federal Food, Drug, and Cosmetic Act in § 310.4 of this chapter has been revoked, shall be subject to the provisions of § 314.200 of this chapter except to the extent that the notice of opportunity for hearing on the matter issued pursuant to § 12.21(b) of this chapter specifically provides otherwise. (b) Hearings pursuant to §§ 601.4 through 601.6 shall be governed by part 12 of this chapter. (c) When a license has been suspended pursuant to § 601.6 and a hearing request has been granted, the hearing shall proceed on an expedited basis.

21 C.F.R. § 601.8 Publication of revocation.

The Commissioner, following revocation of a biologics license under 21 CFR 601.5(b), will publish a notice in the Federal Register with a statement of the specific grounds for the revocation.

21 C.F.R. § 601.9 Licenses; reissuance.

(a) Compliance with requirements. A biologics license, previously suspended or revoked, may be reissued or reinstated upon a showing of compliance with requirements and upon such inspection and examination as may be considered necessary by the Director, Center for Biologics Evaluation and Research or the Director, Center for Drug Evaluation and Research. (b) Exclusion of noncomplying location. A biologics license, excluding a location or locations that fail to comply with the requirements in this chapter, may be issued without further application and concurrently with the suspension or revocation of the license for noncompliance at the excluded location or locations. (c) Exclusion of noncomplying product(s). In the case of multiple products included under a single biologics license application, a biologics license may be issued, excluding the noncompliant product(s), without further application and concurrently with the suspension or revocation of the biologics license for a noncompliant product(s).

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