Repeal of Regulation Requiring an Approved New Drug Application for Drugs Sterilized by Irradiation, 46121-46126 [2018-19845]

Download as PDF daltland on DSKBBV9HB2PROD with PROPOSALS Federal Register / Vol. 83, No. 177 / Wednesday, September 12, 2018 / Proposed Rules be kept within the amount authorized in the Order. A review of historical information and preliminary information pertaining to the upcoming fiscal year indicates that the average grower price for the 2018– 2019 season should be approximately $296 per ton of pears for processing. Therefore, the estimated assessment revenue for the 2018–2019 fiscal period as a percentage of total grower revenue would be about 2.4 percent ($7.15 per ton assessment divided by $296 per ton grower price). This proposed action would decrease the assessment obligation imposed on handlers for the 2018–2019 and subsequent fiscal periods. Assessments are applied uniformly on all handlers, and some of the costs may be passed on to producers. However, decreasing the assessment rate would reduce the burden on handlers, and may reduce the burden on producers. The Committee’s meetings were widely publicized throughout the Oregon and Washington processed pear industry. All interested persons were invited to attend the meetings and participate in Committee deliberations on all issues. Like all Committee meetings, the May 30, 2018, meeting was a public meeting and all entities, both large and small, were able to express views on this issue. Finally, interested persons are invited to submit comments on this proposed rule, including the regulatory and information collection impacts of this action on small businesses. In accordance with the Paperwork Reduction Act of 1995 (44 U.S.C. chapter 35), the Order’s information collection requirements have been previously approved by OMB and assigned OMB No. 0581–0189. No changes in those requirements would be necessary because of this action. Should any changes become necessary, they would be submitted to OMB for approval. This proposed rule would not impose any additional reporting or recordkeeping requirements on either small or large Oregon and Washington processed pear handlers. As with all Federal marketing order programs, reports and forms are periodically reviewed to reduce information requirements and duplication by industry and public sector agencies. AMS is committed to complying with the E-Government Act, to promote the use of the internet and other information technologies to provide increased opportunities for citizen access to Government information and services, and for other purposes. VerDate Sep<11>2014 16:21 Sep 11, 2018 Jkt 244001 USDA has not identified any relevant Federal rules that duplicate, overlap, or conflict with this proposed rule. A small business guide on complying with fruit, vegetable, and specialty crop marketing agreements and orders may be viewed at: https://www.ams.usda.gov/ rules-regulations/moa/small-businesses. Any questions about the compliance guide should be sent to Richard Lower at the previously mentioned address in the FOR FURTHER INFORMATION CONTACT section. 46121 [Docket No. FDA–2017–N–6924] The Food and Drug Administration (FDA, the Agency, or we) is proposing to repeal a regulation that requires an FDA-approved new drug application (NDA) or abbreviated new drug application (ANDA) for any drug product that is sterilized by irradiation (the irradiation regulation). Repealing the irradiation regulation would mean that over-the-counter (OTC) drug products that are generally recognized as safe and effective, that are not misbranded, and that comply with all applicable regulatory requirements can be marketed legally without an NDA or ANDA, even if they are sterilized by irradiation. FDA is proposing to take this action because the irradiation regulation is out of date and unnecessary. The technology of controlled nuclear radiation for sterilization of drugs is now well understood, and our regulations require that OTC drugs be manufactured in compliance with current good manufacturing practices (CGMPs). Appropriate and effective sterilization of drugs, including by irradiation, is adequately addressed by the CGMP requirements. This action is part of FDA’s implementation of Executive Orders (EOs) 13771 and 13777. Under these EOs, FDA is comprehensively reviewing existing regulations to identify opportunities for repeal, replacement, or modification that will result in meaningful burden reduction while allowing the Agency to achieve our public health mission and fulfill statutory obligations. DATES: Submit either electronic or written comments on the proposed rule by November 13, 2018. ADDRESSES: You may submit comments as follows. Please note that late, untimely filed comments will not be considered. Electronic comments must be submitted on or before November 13, 2018. The https://www.regulations.gov electronic filing system will accept comments until midnight Eastern Time at the end of November 13, 2018. Comments received by mail/hand delivery/courier (for written/paper submissions) will be considered timely if they are postmarked or the delivery service acceptance receipt is on or before that date. RIN 0910–AH47 Electronic Submissions List of Subjects in 7 CFR Part 927 Marketing agreements, Pears, Reporting and recordkeeping requirements. For the reasons set forth in the preamble, 7 CFR part 927 is proposed to be amended as follows: PART 927—PEARS GROWN IN OREGON AND WASHINGTON 1. The authority citation for 7 CFR part 927 continues to read as follows: ■ Authority: 7 U.S.C. 601–674. 2. In § 927.237 revise the intro paragraph text and paragraph (a) to read as follows: ■ § 927.237 Assessment rate. On and after July 1, 2018, the following base rates of assessment for pears for processing are established for the Processed Pear Committee: (a) $7.15 per ton for any or all varieties or subvarieties of pears for canning classified as ‘‘summer/fall’’ excluding pears for other methods of processing; * * * * * Dated: September 6, 2018. Bruce Summers, Administrator, Agricultural Marketing Service. [FR Doc. 2018–19683 Filed 9–11–18; 8:45 am] BILLING CODE 3410–02–P DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration 21 CFR Part 310 Repeal of Regulation Requiring an Approved New Drug Application for Drugs Sterilized by Irradiation AGENCY: Food and Drug Administration, HHS. ACTION: PO 00000 Proposed rule. Frm 00003 Fmt 4702 Sfmt 4702 SUMMARY: Submit electronic comments in the following way: • 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 E:\FR\FM\12SEP1.SGM 12SEP1 46122 Federal Register / Vol. 83, No. 177 / Wednesday, September 12, 2018 / Proposed Rules daltland on DSKBBV9HB2PROD with PROPOSALS the 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. • If you want to submit a comment with confidential information that you do not wish to be made available to the public, submit the comment as a written/paper submission and in the manner detailed (see ‘‘Written/Paper Submissions’’ and ‘‘Instructions’’). Written/Paper Submissions Submit written/paper submissions as follows: • Mail/Hand delivery/Courier (for written/paper submissions): Dockets Management Staff (HFA–305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852. • For written/paper comments submitted to the Dockets Management Staff, FDA will post your comment, as well as any attachments, except for information submitted, marked and identified, as confidential, if submitted as detailed in ‘‘Instructions.’’ 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. • Confidential Submissions—To submit a comment with confidential information that you do not wish to be made publicly available, submit your comments only as a written/paper submission. You should submit two copies total. One copy will include the information you claim to be confidential with a heading or cover note that states ‘‘THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.’’ The Agency will review this copy, including the claimed confidential information, in its consideration of comments. The second copy, which will have the claimed confidential information redacted/blacked out, will be available VerDate Sep<11>2014 16:21 Sep 11, 2018 Jkt 244001 for public viewing and posted on https://www.regulations.gov. Submit both copies to the Dockets Management Staff. If you do not wish your name and contact information to be made publicly available, you can provide this information on the cover sheet and not in the body of your comments and you must identify this information as ‘‘confidential.’’ Any information marked as ‘‘confidential’’ will not be disclosed except in accordance with 21 CFR 10.20 and other applicable disclosure law. For more information about FDA’s posting of comments to public dockets, see 80 FR 56469, September 18, 2015, or access the information at: https://www.gpo.gov/ fdsys/pkg/FR-2015-09-18/pdf/201523389.pdf. Docket: For access to the docket to read background documents or the electronic and written/paper comments received, go to https:// www.regulations.gov and insert the docket number, found in brackets in the heading of this document, into the ‘‘Search’’ box and follow the prompts and/or go to the Dockets Management Staff, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852. FOR FURTHER INFORMATION CONTACT: Sudha Shukla, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 51, Rm. 5198, Silver Spring, MD 20993–0002, 301– 796–3345. SUPPLEMENTARY INFORMATION: Table of Contents I. Executive Summary II. Background and Discussion A. The History of the Irradiation Regulation B. Sterilization by Irradiation C. The OTC Drug Monograph System and Current Good Manufacturing Practices D. Conclusion III. Legal Authority IV. Proposed Effective Date V. Economic Analysis of Impacts VI. Analysis of Environmental Impact VII. Paperwork Reduction Act of 1995 VIII. Federalism IX. Consultation and Coordination With Indian Tribal Governments X. References I. Executive Summary This proposed rule would repeal the irradiation regulation, which provides that any drug sterilized by irradiation is a new drug. This action, if finalized, would mean that OTC drugs marketed pursuant to the OTC Drug Review that are generally recognized as safe and effective, that are not misbranded, and that comply with all applicable regulatory requirements can be marketed legally without an FDA- PO 00000 Frm 00004 Fmt 4702 Sfmt 4702 approved NDA or ANDA, even if the drugs are sterilized by irradiation. FDA is taking this action 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. In addition, drugs that are marketed pursuant to the OTC Drug Review must be manufactured in compliance with CGMPs. Appropriate and effective sterilization of drugs, including by irradiation, is adequately addressed by the CGMP requirements. Repealing the irradiation regulation would eliminate a requirement that is no longer necessary, and will not diminish public health protections. The estimated one-time costs of this rule range from $120 to $150. Avoiding the unnecessary preparation and review of a premarket drug application will generate an estimated one-time cost savings that range from about $395,000 to $2,076,000. Over 10 years with a 7 percent discount rate, the annualized net cost savings range from $0.05 million to $0.28 million, with a primary estimate of $0.06 million; with a 3 percent discount rate, the annualized net cost savings range from $0.04 million to $0.24 million, with a primary estimate of $0.05 million. Over an infinite horizon, we assume that one sponsor will benefit from this deregulatory action every 10 years; the present value of the net cost savings over the infinite horizon range from $0.83 million to $4.37 million with a 7 percent discount rate and from $1.58 million to $8.30 million with a 3 percent discount rate. II. Background and Discussion 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. E:\FR\FM\12SEP1.SGM 12SEP1 Federal Register / Vol. 83, No. 177 / Wednesday, September 12, 2018 / Proposed Rules daltland on DSKBBV9HB2PROD with PROPOSALS A. The History of the Irradiation Regulation 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 1996, FDA proposed to revise the statement and consolidate it with similar provisions into a single list of drugs that have been determined by previous rulemaking procedures to be new drugs within the meaning of section 201(p) of the FD&C Act (61 FR 29502 at 29503 to 29504 (June 11, 1996)). The Agency proposed to remove any existing background information describing the Agency’s basis for determination of new drug status from the regulatory text. 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 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: https://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/. VerDate Sep<11>2014 16:21 Sep 11, 2018 Jkt 244001 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. B. Sterilization by Irradiation 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 presterilization level of microbial contamination (sometimes referred to as its bioburden) and the desired sterility assurance level (Ref. 1). Once the dose 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. PO 00000 Frm 00005 Fmt 4702 Sfmt 4702 46123 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). C. The OTC Drug Monograph System and Current Good Manufacturing Practices 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 E:\FR\FM\12SEP1.SGM 12SEP1 46124 Federal Register / Vol. 83, No. 177 / Wednesday, September 12, 2018 / Proposed Rules daltland on DSKBBV9HB2PROD with PROPOSALS encompass 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. CGMP regulations require manufacturers to take steps to ensure that sterile drug products are free of objectionable microorganisms. (See, e.g., 21 CFR 211.28(a), 211.42(b) and (c), 211.67(a), 211.84(c), 211.110(a), 211.113(b), 211.165(b), 211.167(a).) The CGMP regulations also include provisions that ensure that irradiation or any other sterilization processes do not have a detrimental effect on a drug product’s identity, strength, quality, purity, or stability. (See, e.g., 21 CFR 211.22, 211.25(b), 211.68, 211.100, 211.160(b), 211.165, 211.166.) Numerous records relating to the manufacture of the drug product must be maintained and made available for 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). VerDate Sep<11>2014 16:21 Sep 11, 2018 Jkt 244001 inspection (21 CFR part 211, subpart J). FDA conducts inspections at manufacturing facilities, including irradiation facilities, to ensure that the CGMP regulations are followed. Inspection findings are reviewed and, when appropriate, action may be recommended against manufacturers observed to be out of compliance. Choosing the sterilization process that is suitable for a particular drug product is the responsibility of the manufacturer and is an important part of pharmaceutical development. To guide them in choosing an appropriate method of sterilization and otherwise complying with the CGMP requirements, manufacturers can turn to voluntary consensus standards that are widely-known by industry and recognized by FDA for the development, validation, and routine control of the sterilization of drugs by irradiation. As noted previously in this document, ISO publishes standards that address the different doses of radiation that are appropriate depending on the type and amount of microbiological contamination and the necessary degree of sterility assurance (Ref. 3). These include the following: • 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). D. Conclusion 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. III. Legal Authority FDA is issuing this proposed rule under the drugs and general administrative provisions of the FD&C PO 00000 Frm 00006 Fmt 4702 Sfmt 4702 Act (sections 201, 301, 501, 502, 503, 505, 510, 701, 702, and 704 (21 U.S.C. 321, 331, 351, 352, 353, 355, 360, 371, 372, and 374)) and under section 361 of the Public Health Service Act (PHS Act) (42 U.S.C. 264). The FD&C Act gives us the authority to issue and enforce regulations designed to help ensure that drug products are safe, effective, and manufactured according to current good manufacturing practices, while section 361 of the PHS Act gives us the authority to issue and enforce regulations designed to prevent the introduction, transmission, or spread of communicable diseases. IV. Proposed Effective Date 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. V. Economic Analysis of Impacts 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 Regulatory Flexibility Act requires us to analyze regulatory options that would minimize any significant impact of a rule on small entities. Because few entities will be affected and the net effect will be cost savings to affected firms, we propose to certify that the proposed rule, if finalized, will not have a significant economic impact on a substantial number of small entities. 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 E:\FR\FM\12SEP1.SGM 12SEP1 46125 Federal Register / Vol. 83, No. 177 / Wednesday, September 12, 2018 / Proposed Rules adjustment for inflation is $150 million, using the most current (2017) Implicit Price Deflator for the Gross Domestic Product. This proposed rule would not result in an expenditure in any year that meets or exceeds this amount. Table 1 summarizes our estimate of the annualized costs and benefits of the proposed rule. TABLE 1—SUMMARY OF BENEFITS, COSTS AND DISTRIBUTIONAL EFFECTS OF THE RULE [$ million] Units Category Benefits: Annualized, Monetized $millions/year .................. Annualized Quantified ........................................... Primary estimate Low estimate High estimate $0.06 0.05 .................. .................. $0.05 0.04 .................. .................. $0.28 0.24 .................. .................. 2016 2016 2016 2016 7 3 7 3 10 10 10 10 Benefits are cost savings. Benefits are cost savings. 0.00 0.00 .................. .................. 0.00 0.00 .................. .................. 0.00 0.00 .................. .................. 2016 2016 2016 2016 7 3 7 3 10 10 10 10 Costs total less than $100. Costs total less than $100. 0.14 0.12 0.14 0.12 0.14 0.12 2016 2016 7 3 10 10 User Fee. User Fee. 2016 2016 7 3 10 10 Year dollars Discount rate (%) Period covered (years) Notes Qualitative Costs: Annualized Monetized $millions/year ................... Annualized Quantified ........................................... Qualitative Transfers: Federal Annualized Monetized $millions/year ...... From: Other Annualized Monetized $millions/year ......... .................. .................. To: .................. .................. .................. .................. From: To: Effects: State, Local or Tribal Government: None Small Business: None Wages: None Growth: None Because the proposed rule will repeal an outdated regulation and generate net cost savings, we consider this action a deregulatory action under E.O. 13771. Table 2 presents a summary of the E.O. 13771 impacts of the proposed rule over an infinite horizon. For this estimate, we assume that one sponsor will benefit from this deregulatory action every 10 years. TABLE 2—E.O. 13771 SUMMARY [In $ millions 2016 dollars, over an infinite horizon] Primary (7%) daltland on DSKBBV9HB2PROD with PROPOSALS Present Value of Costs ............................ Present Value of Cost Savings ................ Present Value of Net Costs ..................... Annualized Costs ..................................... Annualized Cost Savings ......................... Annualized Net Costs .............................. $0.00 0.97 (0.97) $0.00 $0.07 (0.07) 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. VerDate Sep<11>2014 16:21 Sep 11, 2018 Jkt 244001 Lower bound (7%) Upper bound (7%) $0.00 0.83 (0.83) $0.00 $0.06 (0.06) Primary (3%) $0.00 4.37 (4.37) $0.00 $0.31 (0.31) $0.00 1.84 (1.84) $0.00 $0.06 (0.06) Lower bound (3%) $0.00 1.58 (1.58) $0.00 $0.05 (0.05) Upper bound (3%) $0.00 8.30 (8.30) $0.00 $0.25 (0.25) VI. Analysis of Environmental Impact VII. Paperwork Reduction Act of 1995 We have determined under 21 CFR 25.30(h) and 25.31(a) that this action is of a type that does not individually or cumulatively have a significant effect on the human environment. Therefore, neither an environmental assessment nor an environmental impact statement is required. 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 PO 00000 Frm 00007 Fmt 4702 Sfmt 4702 E:\FR\FM\12SEP1.SGM 12SEP1 46126 Federal Register / Vol. 83, No. 177 / Wednesday, September 12, 2018 / Proposed Rules approved under OMB control number 0910–0139. VIII. Federalism We have analyzed this proposed rule in accordance with the principles set forth in E.O. 13132. We have determined that this proposed rule does not contain policies that have substantial direct effects on the States, on the relationship between the National Government and the States, or on the distribution of power and responsibilities among the various levels of government. Accordingly, we conclude that the rule does not contain policies that have federalism implications as defined in the E.O. and, consequently, a federalism summary impact statement is not required. daltland on DSKBBV9HB2PROD with PROPOSALS IX. Consultation and Coordination With Indian Tribal Governments We have analyzed this proposed rule in accordance with the principles set forth in E.O. 13175. We have tentatively determined that the rule does not contain policies that would have a substantial direct effect on one or more Indian Tribes, on the relationship between the Federal Government and Indian Tribes, or on the distribution of power and responsibilities between the Federal Government and Indian Tribes. The Agency solicits comments from tribal officials on any potential impact on Indian Tribes from this proposed action. 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/guidance complianceregulatoryinformation/ guidances/ucm070342.pdf. 6. United States Pharmacopeial Convention (USP 40), Sterilization and Sterility Assurance of Compendial Articles <1211>, 2017. 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. List of Subjects in 21 CFR Part 310 Administrative practice and procedure, Drugs, Labeling, Medical devices, Reporting and recordkeeping requirements. Therefore, under the Federal Food, Drug, and Cosmetic Act and the Public Health Service Act and under authority delegated to the Commissioner of Food and Drugs, it is proposed that 21 CFR part 310 be amended as follows: X. References The following references are on display in the Dockets Management Staff (see ADDRESSES) and are available for viewing by interested persons between 9 a.m. and 4 p.m., Monday through Friday; they are also available electronically at https:// www.regulations.gov. FDA has verified the website addresses, as of the date this document publishes in the Federal Register, but websites are subject to change over time. PART 310—NEW DRUGS 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. 3. United States Pharmacopeial Convention (USP 40), Radiation Sterilization <1229.10>, 2017. 4. United States Pharmacopeial Convention (USP 40), Sterilization of Compendial Articles <1229>, 2017. § 310.502 Certain drugs accorded new drug status through rulemaking procedures. VerDate Sep<11>2014 16:21 Sep 11, 2018 Jkt 244001 1. The authority citation for part 310 continues to read as follows: ■ 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: ■ (a) The drugs listed in this paragraph have been determined by rulemaking procedures to be new drugs within the meaning of section 201(p) of the Federal Food, Drug, and Cosmetic Act. An approved new drug application under section 505 of the Federal Food, Drug, and Cosmetic Act and part 314 of this chapter is required for marketing the following drugs: * * * * * (11) [Reserved] * * * * * PO 00000 Frm 00008 Fmt 4702 Sfmt 4702 Dated: September 7, 2018. Scott Gottlieb, Commissioner of Food and Drugs. [FR Doc. 2018–19845 Filed 9–11–18; 8:45 am] BILLING CODE 4164–01–P ENVIRONMENTAL PROTECTION AGENCY 40 CFR Part 261 [EPA–R10–RCRA–2018–0538; SW–FRL– 9982–05—Region 10] Hazardous Waste Management System; Proposed Exclusion for Identifying and Listing Hazardous Waste Environmental Protection Agency (EPA). ACTION: Proposed rule and request for comment. AGENCY: The Environmental Protection Agency (also, ‘‘the Agency’’ or ‘‘we’’ in this preamble) is proposing to grant a petition submitted by Sandvik Special Metals (Sandvik), in Kennewick, Washington to exclude (or ‘‘delist’’) up to 1,500 cubic yards of F006 wastewater treatment sludge per year from the list of federal hazardous wastes. The Agency is proposing to grant the petition based on an evaluation of waste-specific information provided by Sandvik. This proposed decision, if finalized, conditionally excludes the petitioned waste from the requirements of hazardous waste regulations under the Resource Conservation and Recovery Act. We conclude that Sandvik’s petitioned waste is nonhazardous with respect to the original federal listing criteria and that there are no other factors (including additional constituents) other than those for which the waste was listed that would warrant retaining the waste as a hazardous waste. Subject to state-only requirements within the state of Washington, or federally-authorized or state-only requirements in other states where the subject wastes may be disposed of, Sandvik’s petitioned waste may be disposed of in a Subtitle D landfill which is permitted, licensed, or registered by a State to manage industrial solid waste. DATES: Comments must be received on or before October 12, 2018. Requests for an informal hearing must reach the EPA by September 27, 2018. ADDRESSES: Submit your comments, identified by Docket ID No. EPA–R10– RCRA–2018–0538 by one of the following methods: SUMMARY: E:\FR\FM\12SEP1.SGM 12SEP1

Agencies

[Federal Register Volume 83, Number 177 (Wednesday, September 12, 2018)]
[Proposed Rules]
[Pages 46121-46126]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2018-19845]

=======================================================================
-----------------------------------------------------------------------

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 310

[Docket No. FDA-2017-N-6924]
RIN 0910-AH47

Repeal of Regulation Requiring an Approved New Drug Application
for Drugs Sterilized by Irradiation

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

-----------------------------------------------------------------------

SUMMARY: The Food and Drug Administration (FDA, the Agency, or we) is
proposing to repeal a regulation that requires an FDA-approved new drug
application (NDA) or abbreviated new drug application (ANDA) for any
drug product that is sterilized by irradiation (the irradiation
regulation). Repealing the irradiation regulation would mean that over-
the-counter (OTC) drug products that are generally recognized as safe
and effective, that are not misbranded, and that comply with all
applicable regulatory requirements can be marketed legally without an
NDA or ANDA, even if they are sterilized by irradiation. FDA is
proposing to take this action because the irradiation regulation is out
of date and unnecessary. The technology of controlled nuclear radiation
for sterilization of drugs is now well understood, and our regulations
require that OTC drugs be manufactured in compliance with current good
manufacturing practices (CGMPs). Appropriate and effective
sterilization of drugs, including by irradiation, is adequately
addressed by the CGMP requirements. This action is part of FDA's
implementation of Executive Orders (EOs) 13771 and 13777. Under these
EOs, FDA is comprehensively reviewing existing regulations to identify
opportunities for repeal, replacement, or modification that will result
in meaningful burden reduction while allowing the Agency to achieve our
public health mission and fulfill statutory obligations.

DATES: Submit either electronic or written comments on the proposed
rule by November 13, 2018.

ADDRESSES: You may submit comments as follows. Please note that late,
untimely filed comments will not be considered. Electronic comments
must be submitted on or before November 13, 2018. The https://www.regulations.gov electronic filing system will accept comments until
midnight Eastern Time at the end of November 13, 2018. Comments
received by mail/hand delivery/courier (for written/paper submissions)
will be considered timely if they are postmarked or the delivery
service acceptance receipt is on or before that date.

Electronic Submissions

Submit electronic comments in the following way:
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

[[Page 46122]]

the 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.
If you want to submit a comment with confidential
information that you do not wish to be made available to the public,
submit the comment as a written/paper submission and in the manner
detailed (see ``Written/Paper Submissions'' and ``Instructions'').

Written/Paper Submissions

Submit written/paper submissions as follows:
Mail/Hand delivery/Courier (for written/paper
submissions): Dockets Management Staff (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
For written/paper comments submitted to the Dockets
Management Staff, FDA will post your comment, as well as any
attachments, except for information submitted, marked and identified,
as confidential, if submitted as detailed in ``Instructions.''
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.
Confidential Submissions--To submit a comment with
confidential information that you do not wish to be made publicly
available, submit your comments only as a written/paper submission. You
should submit two copies total. One copy will include the information
you claim to be confidential with a heading or cover note that states
``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' The Agency will
review this copy, including the claimed confidential information, in
its consideration of comments. The second copy, which will have the
claimed confidential information redacted/blacked out, will be
available for public viewing and posted on https://www.regulations.gov.
Submit both copies to the Dockets Management Staff. If you do not wish
your name and contact information to be made publicly available, you
can provide this information on the cover sheet and not in the body of
your comments and you must identify this information as
``confidential.'' Any information marked as ``confidential'' will not
be disclosed except in accordance with 21 CFR 10.20 and other
applicable disclosure law. For more information about FDA's posting of
comments to public dockets, see 80 FR 56469, September 18, 2015, or
access the information at: https://www.gpo.gov/fdsys/pkg/FR-2015-09-18/pdf/2015-23389.pdf.
Docket: For access to the docket to read background documents or
the electronic and written/paper comments received, go to https://www.regulations.gov and insert the docket number, found in brackets in
the heading of this document, into the ``Search'' box and follow the
prompts and/or go to the Dockets Management Staff, 5630 Fishers Lane,
Rm. 1061, Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: Sudha Shukla, Center for Drug
Evaluation and Research, Food and Drug Administration, 10903 New
Hampshire Ave., Bldg. 51, Rm. 5198, Silver Spring, MD 20993-0002, 301-
796-3345.

SUPPLEMENTARY INFORMATION:

Table of Contents

I. Executive Summary
II. Background and Discussion
A. The History of the Irradiation Regulation
B. Sterilization by Irradiation
C. The OTC Drug Monograph System and Current Good Manufacturing
Practices
D. Conclusion
III. Legal Authority
IV. Proposed Effective Date
V. Economic Analysis of Impacts
VI. Analysis of Environmental Impact
VII. Paperwork Reduction Act of 1995
VIII. Federalism
IX. Consultation and Coordination With Indian Tribal Governments
X. References

I. Executive Summary

This proposed rule would repeal the irradiation regulation, which
provides that any drug sterilized by irradiation is a new drug. This
action, if finalized, would mean that OTC drugs marketed pursuant to
the OTC Drug Review that are generally recognized as safe and
effective, that are not misbranded, and that comply with all applicable
regulatory requirements can be marketed legally without an FDA-approved
NDA or ANDA, even if the drugs are sterilized by irradiation. FDA is
taking this action 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. In addition, drugs that are marketed pursuant to the OTC
Drug Review must be manufactured in compliance with CGMPs. Appropriate
and effective sterilization of drugs, including by irradiation, is
adequately addressed by the CGMP requirements. Repealing the
irradiation regulation would eliminate a requirement that is no longer
necessary, and will not diminish public health protections.
The estimated one-time costs of this rule range from $120 to $150.
Avoiding the unnecessary preparation and review of a premarket drug
application will generate an estimated one-time cost savings that range
from about $395,000 to $2,076,000. Over 10 years with a 7 percent
discount rate, the annualized net cost savings range from $0.05 million
to $0.28 million, with a primary estimate of $0.06 million; with a 3
percent discount rate, the annualized net cost savings range from $0.04
million to $0.24 million, with a primary estimate of $0.05 million.
Over an infinite horizon, we assume that one sponsor will benefit from
this deregulatory action every 10 years; the present value of the net
cost savings over the infinite horizon range from $0.83 million to
$4.37 million with a 7 percent discount rate and from $1.58 million to
$8.30 million with a 3 percent discount rate.

II. Background and Discussion

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.

[[Page 46123]]

A. The History of the Irradiation Regulation

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.
---------------------------------------------------------------------------

\1\ Available at: https://www.loc.gov/item/fr020231/. A month
later, this provision was included at Sec. 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: https://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/.
---------------------------------------------------------------------------

In 1996, FDA proposed to revise the statement and consolidate it
with similar provisions into a single list of drugs that have been
determined by previous rulemaking procedures to be new drugs within the
meaning of section 201(p) of the FD&C Act (61 FR 29502 at 29503 to
29504 (June 11, 1996)). The Agency proposed to remove any existing
background information describing the Agency's basis for determination
of new drug status from the regulatory text.
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 (Sec. 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 Sec. 310.502(a)(11) is that, if the drug is
sterilized by irradiation, an approved NDA or ANDA is necessary.

B. Sterilization by Irradiation

Since the paragraph now reflected at Sec. 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).
---------------------------------------------------------------------------

\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.
---------------------------------------------------------------------------

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).

C. The OTC Drug Monograph System and Current Good Manufacturing
Practices

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 Sec. 330.1. Among the general conditions that apply to
all drug products marketed under the OTC Drug Review is the requirement
set forth in Sec. 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

[[Page 46124]]

encompass sterilization, including by irradiation.\3\
---------------------------------------------------------------------------

\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).
---------------------------------------------------------------------------

In 1955, when the determination with respect to drugs sterilized by
irradiation (now reflected in Sec. 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, Sec.
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.
CGMP regulations require manufacturers to take steps to ensure that
sterile drug products are free of objectionable microorganisms. (See,
e.g., 21 CFR 211.28(a), 211.42(b) and (c), 211.67(a), 211.84(c),
211.110(a), 211.113(b), 211.165(b), 211.167(a).) The CGMP regulations
also include provisions that ensure that irradiation or any other
sterilization processes do not have a detrimental effect on a drug
product's identity, strength, quality, purity, or stability. (See,
e.g., 21 CFR 211.22, 211.25(b), 211.68, 211.100, 211.160(b), 211.165,
211.166.)
Numerous records relating to the manufacture of the drug product
must be maintained and made available for inspection (21 CFR part 211,
subpart J). FDA conducts inspections at manufacturing facilities,
including irradiation facilities, to ensure that the CGMP regulations
are followed. Inspection findings are reviewed and, when appropriate,
action may be recommended against manufacturers observed to be out of
compliance.
Choosing the sterilization process that is suitable for a
particular drug product is the responsibility of the manufacturer and
is an important part of pharmaceutical development. To guide them in
choosing an appropriate method of sterilization and otherwise complying
with the CGMP requirements, manufacturers can turn to voluntary
consensus standards that are widely-known by industry and recognized by
FDA for the development, validation, and routine control of the
sterilization of drugs by irradiation. As noted previously in this
document, ISO publishes standards that address the different doses of
radiation that are appropriate depending on the type and amount of
microbiological contamination and the necessary degree of sterility
assurance (Ref. 3). These include the following:
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).

D. Conclusion

We propose the repeal of Sec. 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.

III. Legal Authority

FDA is issuing this proposed rule under the drugs and general
administrative provisions of the FD&C Act (sections 201, 301, 501, 502,
503, 505, 510, 701, 702, and 704 (21 U.S.C. 321, 331, 351, 352, 353,
355, 360, 371, 372, and 374)) and under section 361 of the Public
Health Service Act (PHS Act) (42 U.S.C. 264). The FD&C Act gives us the
authority to issue and enforce regulations designed to help ensure that
drug products are safe, effective, and manufactured according to
current good manufacturing practices, while section 361 of the PHS Act
gives us the authority to issue and enforce regulations designed to
prevent the introduction, transmission, or spread of communicable
diseases.

IV. Proposed Effective Date

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.

V. Economic Analysis of Impacts

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 Regulatory Flexibility Act requires us to analyze regulatory
options that would minimize any significant impact of a rule on small
entities. Because few entities will be affected and the net effect will
be cost savings to affected firms, we propose to certify that the
proposed rule, if finalized, will not have a significant economic
impact on a substantial number of small entities.
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

[[Page 46125]]

adjustment 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 summarizes our estimate of the annualized costs and
benefits of the proposed rule.

Table 1--Summary of Benefits, Costs and Distributional Effects of the Rule
[$ million]
--------------------------------------------------------------------------------------------------------------------------------------------------------
Units
------------------------------------
Category Primary Low High Period Notes
estimate estimate estimate Year Discount covered
dollars rate (%) (years)
--------------------------------------------------------------------------------------------------------------------------------------------------------
Benefits:
Annualized, Monetized $millions/ $0.06 $0.05 $0.28 2016 7 10 Benefits are cost savings.
year.
0.05 0.04 0.24 2016 3 10 Benefits are cost savings.
Annualized Quantified.............. .......... .......... .......... 2016 7 10
.......... .......... .......... 2016 3 10 .......................................
----------------------------------------------------------------------------------------------------------------
Qualitative
--------------------------------------------------------------------------------------------------------------------------------------------------------
Costs:
Annualized Monetized $millions/year 0.00 0.00 0.00 2016 7 10 Costs total less than $100.
0.00 0.00 0.00 2016 3 10 Costs total less than $100.
Annualized Quantified.............. .......... .......... .......... 2016 7 10
.......... .......... .......... 2016 3 10
--------------------------------------------------------------------------------------------------------------------------------------------------------
Qualitative
--------------------------------------------------------------------------------------------------------------------------------------------------------
Transfers:
Federal Annualized Monetized 0.14 0.14 0.14 2016 7 10 User Fee.
$millions/year.
0.12 0.12 0.12 2016 3 10 User Fee.
----------------------------------------------------------------------------------------------------------------
From:
To:
----------------------------------------------------------------------------------------------------------------
Other Annualized Monetized .......... .......... .......... 2016 7 10
$millions/year.
.......... .......... .......... 2016 3 10
----------------------------------------------------------------------------------------------------------------
From:
To:
--------------------------------------------------------------------------------------------------------------------------------------------------------
Effects:
--------------------------------------------------------------------------------------------------------------------------------------------------------
State, Local or Tribal Government: None.............................................................................................................
Small Business: None................................................................................................................................
Wages: None.........................................................................................................................................
Growth: None........................................................................................................................................
--------------------------------------------------------------------------------------------------------------------------------------------------------

Because the proposed rule will repeal an outdated regulation and
generate net cost savings, we consider this action a deregulatory
action under E.O. 13771. Table 2 presents a summary of the E.O. 13771
impacts of the proposed rule over an infinite horizon. For this
estimate, we assume that one sponsor will benefit from this
deregulatory action every 10 years.

Table 2--E.O. 13771 Summary
[In $ millions 2016 dollars, over an infinite horizon]
--------------------------------------------------------------------------------------------------------------------------------------------------------
Lower bound Upper bound Lower bound Upper bound
Primary (7%) (7%) (7%) Primary (3%) (3%) (3%)
--------------------------------------------------------------------------------------------------------------------------------------------------------
Present Value of Costs.................................. $0.00 $0.00 $0.00 $0.00 $0.00 $0.00
Present Value of Cost Savings........................... 0.97 0.83 4.37 1.84 1.58 8.30
Present Value of Net Costs.............................. (0.97) (0.83) (4.37) (1.84) (1.58) (8.30)
Annualized Costs........................................ $0.00 $0.00 $0.00 $0.00 $0.00 $0.00
Annualized Cost Savings................................. $0.07 $0.06 $0.31 $0.06 $0.05 $0.25
Annualized Net Costs.................................... (0.07) (0.06) (0.31) (0.06) (0.05) (0.25)
--------------------------------------------------------------------------------------------------------------------------------------------------------

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.

VI. Analysis of Environmental Impact

We have determined under 21 CFR 25.30(h) and 25.31(a) that this
action is of a type that does not individually or cumulatively have a
significant effect on the human environment. Therefore, neither an
environmental assessment nor an environmental impact statement is
required.

VII. Paperwork Reduction Act of 1995

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

[[Page 46126]]

approved under OMB control number 0910-0139.

VIII. Federalism

We have analyzed this proposed rule in accordance with the
principles set forth in E.O. 13132. We have determined that this
proposed rule does not contain policies that have substantial direct
effects on the States, on the relationship between the National
Government and the States, or on the distribution of power and
responsibilities among the various levels of government. Accordingly,
we conclude that the rule does not contain policies that have
federalism implications as defined in the E.O. and, consequently, a
federalism summary impact statement is not required.

IX. Consultation and Coordination With Indian Tribal Governments

We have analyzed this proposed rule in accordance with the
principles set forth in E.O. 13175. We have tentatively determined that
the rule does not contain policies that would have a substantial direct
effect on one or more Indian Tribes, on the relationship between the
Federal Government and Indian Tribes, or on the distribution of power
and responsibilities between the Federal Government and Indian Tribes.
The Agency solicits comments from tribal officials on any potential
impact on Indian Tribes from this proposed action.

X. References

The following references are on display in the Dockets Management
Staff (see ADDRESSES) and are available for viewing by interested
persons between 9 a.m. and 4 p.m., Monday through Friday; they are also
available electronically at https://www.regulations.gov. FDA has
verified the website addresses, as of the date this document publishes
in the Federal Register, but websites are subject to change over time.

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.
3. United States Pharmacopeial Convention (USP 40), Radiation
Sterilization <1229.10>, 2017.
4. United States Pharmacopeial Convention (USP 40), Sterilization of
Compendial Articles <1229>, 2017.
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.
6. United States Pharmacopeial Convention (USP 40), Sterilization
and Sterility Assurance of Compendial Articles <1211>, 2017.
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.

List of Subjects in 21 CFR Part 310

Administrative practice and procedure, Drugs, Labeling, Medical
devices, Reporting and recordkeeping requirements.

Therefore, under the Federal Food, Drug, and Cosmetic Act and the
Public Health Service Act and under authority delegated to the
Commissioner of Food and Drugs, it is proposed that 21 CFR part 310 be
amended as follows:

PART 310--NEW DRUGS

0
1. The authority citation for part 310 continues to read as follows:

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.

0
2. In Sec. 310.502, revise paragraph (a) introductory text and remove
and reserve paragraph (a)(11) to read as follows:

Sec. 310.502 Certain drugs accorded new drug status through
rulemaking procedures.

(a) The drugs listed in this paragraph have been determined by
rulemaking procedures to be new drugs within the meaning of section
201(p) of the Federal Food, Drug, and Cosmetic Act. An approved new
drug application under section 505 of the Federal Food, Drug, and
Cosmetic Act and part 314 of this chapter is required for marketing the
following drugs:
* * * * *
(11) [Reserved]
* * * * *

Dated: September 7, 2018.
Scott Gottlieb,
Commissioner of Food and Drugs.
[FR Doc. 2018-19845 Filed 9-11-18; 8:45 am]
BILLING CODE 4164-01-P

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