Source: https://www.federalregister.gov/documents/2018/09/12/2018-19845/repeal-of-regulation-requiring-an-approved-new-drug-application-for-drugs-sterilized-by-irradiation
Timestamp: 2020-07-09 09:50:40
Document Index: 479988472

Matched Legal Cases: ['§\u2009310', '§\u2009310', '§\u2009310', '§\u2009330', '§\u2009330', 'arts 210', 'arts 210', '§\u2009310', 'art 133', '§\u2009310', 'art 1', 'art 2', 'art 3', '§\u2009310', '§\u2009310', '§\u2009310', '§\u20093', 'art 349']

Federal Register :: Repeal of Regulation Requiring an Approved New Drug Application for Drugs Sterilized by Irradiation
A Proposed Rule by the Food and Drug Administration on 09/12/2018
83 FR 46121
46121-46126 (6 pages)
Docket No. FDA-2017-N-6924
0910-AH47
FDA-2017-N-6924
Reference 8 508 - RIA repeal of regulation requiring an...
https://www.federalregister.gov/d/2018-19845
Federal eRulemaking Portal: https://www.regulations.gov. Follow the instructions for submitting comments. Comments submitted electronically, including attachments, to https://www.regulations.gov will be posted to Start Printed Page 46122the docket unchanged. Because your comment will be made public, you are solely responsible for ensuring that your comment does not include any confidential information that you or a third party may not wish to be posted, such as medical information, your or anyone else's Social Security number, or confidential business information, such as a manufacturing process. Please note that if you include your name, contact information, or other information that identifies you in the body of your comments, that information will be posted on https://www.regulations.gov.
Instructions: All submissions received must include the Docket No. FDA-2017-N-6924 for “Repeal of Regulation Requiring an Approved New Drug Application for Drugs Sterilized by Irradiation.” Received comments, those filed in a timely manner (see ADDRESSES), will be placed in the docket and, except for those submitted as “Confidential Submissions,” publicly viewable at https://www.regulations.gov or at the Dockets Management Staff between 9 a.m. and 4 p.m., Monday through Friday.
On February 24, 2017, E.O. 13777, “Enforcing the Regulatory Reform Agenda” (https://www.gpo.gov/​fdsys/​pkg/​FR-2017-03-01/​pdf/​2017-04107.pdf) was issued. One of the provisions in the E.O. requires Agencies to evaluate existing regulations and make recommendations to the Agency head regarding their repeal, replacement, or modification, consistent with applicable law. As part of this initiative, FDA is proposing to repeal the irradiation regulation as specified in this rule.
In addition, in a citizen petition dated August 14, 2014, Richard O. Wood of The Wood Burditt Group LLC requested that the irradiation regulation be revoked. FDA has responded to Mr. Wood's citizen petition. A copy of the response is available at: https://www.regulations.gov under Docket No. FDA-2014-P-1784.Start Printed Page 46123
In the November 29, 1955, issue of the Federal Register, FDA issued a statement of interpretation relating to the sterilization of drugs by irradiation (20 FR 8747 to 8748).[1] In the statement, FDA explained that there was an interest in the utilization of newly developed sources of radiation for the sterilization of drugs. The Agency went on to state that it was necessary in the interest of protecting the public health to establish by adequate investigations that the irradiation treatment does not cause the drug to become unsafe or otherwise unsuitable for use. For this reason, all drug products sterilized by irradiation would be regarded as new drugs within the meaning of section 201(p) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), which would mean that an effective new drug application would be required for such products.
In 1997, FDA finalized these provisions, now located in 21 CFR 310.502, entitled “Certain drugs accorded new drug status through rulemaking procedures.” (62 FR 12084 at 12084 (March 14, 1997).) Paragraph 310.502(a) sets forth a list of drugs that have been determined by rulemaking procedures to be “new drugs” within the meaning of section 201(p) of the FD&C Act. Included on the list is sterilization of drugs by irradiation (§ 310.502(a)(11) (21 CFR 310.502(a)(11)). Because this regulation reflects an FDA determination that the drugs on the list are “new drugs,” an NDA or ANDA must be submitted and approved by FDA before they can be marketed legally. For a non-prescription drug that could otherwise be legally marketed without an approved NDA or ANDA in effect pursuant to the OTC Drug Review, the effect of § 310.502(a)(11) is that, if the drug is sterilized by irradiation, an approved NDA or ANDA is necessary.
Since the paragraph now reflected at § 310.502(a)(11) was published in 1955, the technology of controlled nuclear radiation for sterilization of drugs has become well understood. Gamma ray irradiation has been recognized as a method of sterilizing drug products for half a century (Refs. 1 and 2). Electron beam and x-ray irradiation are also recognized methods for sterilizing drugs (Ref. 1).
Information and data on whether a particular drug can safely and effectively be sterilized by irradiation are available in the scientific literature (Ref. 1). The United States Pharmacopeial Convention (USP) has provided guidance on irradiation sterilization of drug products since 1965 (Refs. 1 and 3). This includes chapter <1229> on “Sterilization of Compendial Articles,” which sets forth principles that may be applied to the sterilization of compendial and non-compendial drug products, and chapter <1229.10> on “Radiation Sterilization,” which sets forth guidelines on validation of sterilization by irradiation (Refs. 3 and 4). The American National Standards Institute, the Association for the Advancement of Medical Instrumentation, ASTM International, and the International Organization for Standardization (ISO) have also published standards on the irradiation of medical products, including drugs (Ref. 1). ISO standard 11137, which sets forth several methods that can be used to determine the appropriate radiation dose for health care products, was first published in 1984 [2] (Ref. 1).
USP chapter <1229.10> states that the methods set forth in ISO 11137 typically guide the choice of radiation dose (Ref. 3). Relevant factors include a drug's pre-sterilization level of microbial contamination (sometimes referred to as its bioburden) and the desired sterility assurance level (Ref. 1). Once the dose is selected, USP General Chapter <1229.10> states that all materials exposed to radiation, especially the drug product and its primary container, should be evaluated for immediate and long-term effects, and “[p]roduct stability, safety, and functionality should be confirmed over the product's intended use period” (Ref. 3). Among the advantages of sterilizing drug products by irradiation is that due to radiation's high penetrability, drug products can be irradiated after they are placed in their final containers (Ref. 1). Known as terminal sterilization, this provides a greater degree of sterilization assurance than aseptic processing and, where feasible, its use is preferable to relying solely on aseptic processing to ensure sterility (Ref. 5). Other advantages to irradiation sterilization of drugs include low chemical reactivity; the very low rise in temperature associated with radiation, which allows for its use on heat-sensitive products; that irradiation sterilization has fewer process variables than other methods, which translates into fewer sterility rejections; and that radiation does not leave behind any sterilant residuals (Refs. 1 and 6).
The OTC Drug Review was established to evaluate the safety and effectiveness of OTC drug products marketed in the United States before May 11, 1972. As set forth in 21 CFR 330.10, it is a multiphase public rulemaking process (each phase requiring a Federal Register publication) resulting in the establishment of monographs for OTC therapeutic drug classes. OTC drug monographs, which can be found in Title 21, chapter I, subchapter D of the Code of Federal Regulations, cover acceptable ingredients, doses, formulations, other conditions, and labeling for certain OTC drugs. A company can legally make and market an OTC product that meets each of the conditions contained in an applicable monograph and, in addition, each of the general conditions set forth in § 330.1. Among the general conditions that apply to all drug products marketed under the OTC Drug Review is the requirement set forth in § 330.1(a) that they be manufactured in compliance with current good manufacturing practices, as established by parts 210 and 211 of this chapter. The CGMP requirements in parts 210 and 211 Start Printed Page 46124encompass sterilization, including by irradiation.[3]
In 1955, when the determination with respect to drugs sterilized by irradiation (now reflected in § 310.502(a)(11)) was made, neither the OTC drug monograph system nor the CGMP requirements existed. The authorizing legislation that the CGMP regulations implement, section 501(a)(2)(B) of the FD&C Act (21 U.S.C. 351(a)(2)(B)), was enacted in 1962 (Drug Amendments of 1962, October 10, 1962, Pub. L. 87-781, Title I, sec. 101), and the first CGMP regulations followed in 1963 (Part 133—Drugs; Current Good Manufacturing Practice in Manufacture, Processing, Packing, or Holding, 28 FR 6385 (June 20, 1963) available at: https://www.loc.gov/​item/​fr028120/​). The regulations creating procedures for establishing OTC drug monographs were issued in 1972 (37 FR 9464 (May 11, 1972)) available at: https://www.loc.gov/​item/​fr037092/​). Because of these subsequent statutes and regulations, § 310.502(a)(11) can be revoked and manufacturers will still be obligated to ensure that, if they use radiation: (1) The drug products that they purport to be sterile are in fact sterile and (2) their use of radiation does not have a detrimental effect on their drug products' identity, strength, quality, purity, or stability.
ISO 11137-1:2006: Sterilization of health care products—Radiation—Part 1: Requirements for development, validation and routine control of a sterilization process for medical devices;
ISO 11137-2:2013: Sterilization of health care products—Radiation—Part 2: Establishing the sterilization dose;
ISO 11137-3:2006: Sterilization of health care products—Radiation—Part 3: Guidance on dosimetric aspects; and
ISO/TS 13004:2013: Sterilization of health care products—Substantiation of selected sterilization dose: Method VDmaxSD.
The USP also provides guidance on irradiation sterilization, including in chapter <1229.10>, which specifically addresses the topic (Ref. 3).
We propose the repeal of § 310.502(a)(11) because the Agency no longer concludes that drugs sterilized by irradiation are necessarily new drugs. The technology of controlled nuclear radiation for sterilization of drugs is now well understood and sterilization is a manufacturing process that is adequately addressed by the regulations governing the OTC drug monograph system and CGMPs.
Any final rule that results from this proposed rule will be effective 30 days after the date of the final rule's publication in the Federal Register.
We have examined the impacts of the proposed rule under E.O. 12866, E.O. 13563, E.O. 13771, the Regulatory Flexibility Act (5 U.S.C. 601-612), and the Unfunded Mandates Reform Act of 1995 (Pub. L. 104-4). EOs 12866 and 13563 direct us to assess all costs and benefits of available regulatory alternatives and, when regulation is necessary, to select regulatory approaches that maximize net benefits (including potential economic, environmental, public health and safety, and other advantages; distributive impacts; and equity). E.O. 13771 requires that the costs associated with significant new regulations “shall, to the extent permitted by law, be offset by the elimination of existing costs associated with at least two prior regulations.” We believe that this proposed rule is not a significant regulatory action as defined by E.O. 12866.
The Unfunded Mandates Reform Act of 1995 (section 202(a)) requires us to prepare a written statement, which includes an assessment of anticipated costs and benefits, before proposing “any rule that includes any Federal mandate that may result in the expenditure by State, local, and tribal governments, in the aggregate, or by the private sector, of $100,000,000 or more (adjusted annually for inflation) in any one year.” The current threshold after Start Printed Page 46125adjustment for inflation is $150 million, using the most current (2017) Implicit Price Deflator for the Gross Domestic Product. This proposed rule would not result in an expenditure in any year that meets or exceeds this amount.
Table 1—Summary of Benefits, Costs and Distributional Effects of the Rule
Table 2—E.O. 13771 Summary
[In $ millions 2016 dollars, over an infinite horizon]
We have developed a comprehensive Economic Analysis of Impacts that assesses the impacts of the proposed rule. The full analysis of economic impacts is available in the docket for this proposed rule (Ref. 8) and at: https://www.fda.gov/​AboutFDA/​ReportsManualsForms/​Reports/​EconomicAnalyses/​default.htm.
This proposed rule refers to previously approved collections of information that are subject to review by the Office of Management and Budget (OMB) under the Paperwork Reduction Act of 1995 (44 U.S.C. 3501-3520). The collections of information resulting from compliance with CGMPs have been Start Printed Page 46126approved under OMB control number 0910-0139.
1. Jacobs, G., “Validation of the Radiation Sterilization of Pharmaceuticals.” In: J. Agalloco and F. J. Carleton (eds.), Validation of Pharmaceutical Processes (3rd Ed.) Informa USA, New York, 2007.
2. Microbiology Sub-Committee, Radiation Sterilization Task Force, Parenteral Drug Association, Technical Report No. 11, “Sterilization of Parenterals by Gamma Radiation,” Journal of Parenteral Science and Technology, 42 (3S), 1988, available at: https://store.pda.org/​ProductCatalog/​Product.aspx?​ID=​1170.
5. FDA Guidance for Industry on “Sterile Drug Products Produced by Aseptic Processing—Current Good Manufacturing Practice,” September 2004; available at https://www.fda.gov/​downloads/​drugs/​guidancecomplianceregulatoryinformation/​guidances/​ucm070342.pdf.
7. FDA Drug Safety Communication, “FDA Requests Label Changes and Single-Use Packaging for Some Over-the-Counter Topical Antiseptic Products to Decrease Risk of Infection,” November 13, 2013; available at https://www.fda.gov/​Drugs/​DrugSafety/​ucm374711.htm.
8. FDA Preliminary Regulatory Impact Analysis, Repeal of Regulation Requiring an Approved New Drug Application for Drugs Sterilized by Irradiation; https://www.fda.gov/​AboutFDA/​ReportsManualsForms/​Reports/​EconomicAnalyses/​default.htm.
Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 360b-360f, 360j, 360hh-360ss, 361(a), 371, 374, 375, 379e, 379k-1; 42 U.S.C. 216, 241, 242(a), 262.
2. In § 310.502, revise paragraph (a) introductory text and remove and reserve paragraph (a)(11) to read as follows:
§ 310.502
Certain drugs accorded new drug status through rulemaking procedures.
1. Available at: https://www.loc.gov/​item/​fr020231/​. A month later, this provision was included at § 3.45 in the republication of chapter 21 of the Code of Federal Regulations in the Federal Register. See 20 FR 9525 at 9554 (December 20, 1955), available at: http://cdn.loc.gov/​service/​ll/​fedreg/​fr020/​fr020246/​fr020246.pdf. In 1975, FDA republished and re-codified the rule at 21 CFR 200.30. See 40 FR 13996 at 13997 (March 27, 1975), available at: https://www.loc.gov/​item/​fr040060/​.
2. ISO 11137-1 specifies standards for the development, validation, and routine control of a radiation sterilization process for medical devices, while ISO 11137-2 specifies dose establishment and dose audit methods and defines product family approaches for dose establishment and dose audits. Additional target sterilization doses are covered in ISO Technical Information Report (TIR) 13004. Neither ISO 11137-2 nor TIR 13004 is explicitly limited to medical devices. In addition, both ISO 11137-2 and ISO TIR 13004 reference ISO 11137-1 as “indispensable for the application of this document.” This implies that the concepts in ISO 11137-1 may be applied to sterilization of drug products.
3. We note that sterilization is not generally a condition specifically covered by OTC monographs. Currently, the monograph for ophthalmic drug products at 21 CFR part 349 is the only monograph that incorporates a sterility condition. There are, however, OTC products covered by a monograph or tentative final monograph that are not required to be sterile, but which manufacturers may choose to sterilize. These may include consumer and healthcare antiseptics, such as consumer hand washes, body washes, and hand rubs, first aid antiseptics, health care personnel hand washes and hand rubs, surgical hand scrubs and rubs, and patient preoperative skin preparations. In 2013, FDA asked manufacturers to voluntarily revise the product labels for topical antiseptics to indicate whether the product is manufactured as a sterile or nonsterile product (Ref. 7).