List of Bulk Drug Substances for Which There Is a Clinical Need Under Section 503B of the Federal Food, Drug, and Cosmetic Act, 20531-20542 [2023-07237]

Download as PDF Federal Register / Vol. 88, No. 66 / Thursday, April 6, 2023 / Notices Partnerships and Technology Innovation, Center for Devices and Radiological Health, cdrh-pro@ fda.hhs.gov, 800–638–2041 or 301–796– 7100. SUPPLEMENTARY INFORMATION: ddrumheller on DSK120RN23PROD with NOTICES1 I. Background FDA is announcing the availability of a draft guidance for industry entitled ‘‘Patient-Focused Drug Development: Incorporating Clinical Outcome Assessments Into Endpoints for Regulatory Decision-Making.’’ This draft guidance (Guidance 4) is the fourth of a series of four methodological patientfocused drug development guidance documents that describe how stakeholders (patients, researchers, medical product developers, and others) can collect and submit patient experience data and other relevant information from patients and caregivers to be used for medical product development and regulatory decision-making. This series of guidance documents is intended to facilitate the advancement and use of systematic approaches to collect and use robust and meaningful input that can more consistently inform medical product development and regulatory decision-making. The purpose of Guidance 4 is to: (1) address methods to better incorporate clinical outcome assessment into endpoints that are considered significantly robust for regulatory decision-making; (2) address methodologies, standards, and technologies that may be used for the collection, capture, storage, and analysis of patient perspective data; and (3) identify resources that offer considerations regarding submissions of patient experience data. This draft guidance is being issued consistent with FDA’s good guidance practices regulation (21 CFR 10.115). The draft guidance, when finalized, will represent the current thinking of FDA on ‘‘Incorporating Clinical Outcome Assessments Into Endpoints for Regulatory Decision-Making.’’ It does not establish any rights for any person and is not binding on FDA or the public. You can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations. II. Paperwork Reduction Act of 1995 This guidance refers to collections of information from ‘‘individuals under treatment or clinical examination in connection with research,’’ which are not subject to review by the Office of Management and Budget (OMB) under 5 CFR 1320.3(h)(5). This guidance also refers to previously approved FDA VerDate Sep<11>2014 21:13 Apr 05, 2023 Jkt 259001 collections of information. These collections of information are subject to review by OMB under the Paperwork Reduction Act of 1995 (44 U.S.C. 3501– 3521). The collections of information in 21 CFR parts 312 and 812 for investigational new drug applications and investigational device exemptions have been approved under OMB control numbers 0910–0014 and 0910–0078, respectively. The collections of information in 21 CFR parts 314 and 601 for new drug applications and biologic license applications have been approved under OMB control numbers 0910–0001 and 0910–0338, respectively, and the collections of information in 21 CFR part 814, subparts A through E, 21 CFR part 860, subpart D, and 21 CFR part 807, subpart E, for premarket approval applications, De Novo classification requests, and premarket notifications have been approved under OMB control numbers 0910–0231, 0910–0844, and 0910–0120, respectively. III. Additional Information Section 3002 of Title III, Subtitle A of the 21st Century Cures Act (Pub. L. 114– 255) directs FDA to develop patientfocused drug development guidance to address a number of areas, including under section 3002(c)(4): methodologies, standards, and technologies to collect and analyze clinical outcome assessments for purposes of regulatory decision-making. In addition, FDA committed to meet certain performance goals under the sixth authorization of the Prescription Drug User Fee Act. These goal commitments were developed in consultation with patient and consumer advocates, healthcare professionals, and other public stakeholders, as part of negotiations with regulated industry. Section I.J.1 of the commitment letter ‘‘Enhancing the Incorporation of the Patient’s Voice in Drug Development and Decision-Making’’ (https:// www.fda.gov/media/99140/download) outlines work, including the development of a series of guidance documents and associated public workshops to facilitate the advancement and use of systematic approaches to collect and utilize robust and meaningful patient and caregiver input that can more consistently inform drug development, and, as appropriate, regulatory decision-making. IV. Electronic Access Persons with access to the internet may obtain the draft guidance at https:// www.fda.gov/drugs/guidancecompliance-regulatory-information/ guidances-drugs, https://www.fda.gov/ PO 00000 Frm 00066 Fmt 4703 Sfmt 4703 20531 regulatory-information/search-fdaguidance-documents, or https:// www.regulations.gov. Dated: April 3, 2023. Lauren K. Roth, Associate Commissioner for Policy. [FR Doc. 2023–07243 Filed 4–5–23; 8:45 am] BILLING CODE 4164–01–P DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA–2018–N–3240] List of Bulk Drug Substances for Which There Is a Clinical Need Under Section 503B of the Federal Food, Drug, and Cosmetic Act AGENCY: Food and Drug Administration, HHS. ACTION: Notice. The Food and Drug Administration (FDA, the Agency, or we) is evaluating substances that have been nominated for inclusion on a list of bulk drug substances (active pharmaceutical ingredients (APIs)) for which there is a clinical need (the 503B Bulks List). Drug products that outsourcing facilities compound using bulk drug substances on the 503B Bulks List can qualify for certain exemptions from the Federal Food, Drug, and Cosmetic Act (FD&C Act) provided certain conditions are met. This notice identifies one bulk drug substance that FDA has considered and is including on the list at this time: quinacrine hydrochloride (HCl) to compound drug products for oral use only. This notice also identifies 10 bulk drug substances that FDA has considered and is not including on the list at this time: hydroxyzine HCl, mannitol, methacholine chloride, metoclopramide HCl, nalbuphine HCl, potassium acetate, procainamide HCl, sodium bicarbonate, sodium nitroprusside, and verapamil HCl. Additional bulk drug substances nominated by the public for inclusion on this list are currently under consideration and will be the subject of future notices. DATES: The announcement of the notice is published in the Federal Register on April 6, 2023. ADDRESSES: 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, SUMMARY: E:\FR\FM\06APN1.SGM 06APN1 20532 Federal Register / Vol. 88, No. 66 / Thursday, April 6, 2023 / Notices ddrumheller on DSK120RN23PROD with NOTICES1 and/or go to the Dockets Management Staff, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852, 240–402–7500. FOR FURTHER INFORMATION CONTACT: Tracy Rupp, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 51, Silver Spring, MD 20993, 301–796–3100. SUPPLEMENTARY INFORMATION: I. Background Section 503B of the FD&C Act (21 U.S.C. 353b) describes the conditions that must be satisfied for drug products compounded in an outsourcing facility to be exempt from section 505 (21 U.S.C. 355) (concerning the approval of drugs under new drug applications (NDAs) or abbreviated new drug applications (ANDAs)), section 502(f)(1) (21 U.S.C. 352(f)(1)) (concerning the labeling of drugs with adequate directions for use), and section 582 of the FD&C Act (21 U.S.C. 360eee–1) (concerning drug supply chain security requirements).1 Compounded drug products that meet the conditions in section 503B are not exempt from current good manufacturing practice (CGMP) requirements in section 501(a)(2)(B) of the FD&C Act (21 U.S.C. 351(a)(2)(B)).2 Outsourcing facilities are also subject to FDA inspections according to a riskbased schedule, adverse event reporting requirements, and other conditions that help to mitigate the risks of the drug products they compound.3 Outsourcing facilities may or may not obtain prescriptions for identified individual patients and can, therefore, distribute compounded drugs to healthcare practitioners for ‘‘office stock,’’ to hold in their offices in advance of patient need.4 One of the conditions that must be met for a drug product compounded by an outsourcing facility to qualify for the exemptions under section 503B of the FD&C Act is that the outsourcing facility may not compound a drug using a bulk drug substance unless: (1) the bulk drug substance appears on a list established by the Secretary of Health and Human Services (the Secretary) identifying bulk drug substances for which there is a clinical need (the 503B Bulks List) or (2) the drug compounded from the bulk drug substance appears on the drug shortage list in effect under section 506E 1 Section 503B(a) of the FD&C Act. section 503A(a) of the FD&C Act (21 U.S.C. 353a(a) (exempting drugs compounded in accordance with that section)) with section 503B(a) of the FD&C Act (not providing the exemption from CGMP requirements). 3 Section 503B(b)(4) and (5) of the FD&C Act. 4 Section 503B(d)(4)(C) of the FD&C Act. 2 Compare VerDate Sep<11>2014 21:13 Apr 05, 2023 Jkt 259001 of the FD&C Act (21 U.S.C. 356e) at the time of compounding, distribution, and dispensing.5 Section 503B of the FD&C Act directs FDA to establish the 503B Bulks List by: (1) publishing a notice in the Federal Register proposing bulk drug substances to be included on the list, including the rationale for such proposal; (2) providing a period of not less than 60 calendar days for comment on the notice; and (3) publishing a notice in the Federal Register designating bulk drug substances for inclusion on the list.6 FDA has published a series of Federal Register notices addressing bulk drug substances nominated for inclusion on the 503B Bulks List.7 This notice identifies one bulk drug substance that FDA has considered and is including on the 503B Bulks List and 10 bulk drug substances that FDA has considered and is not including on the 503B Bulks List. For purposes of section 503B of the FD&C Act, bulk drug substance means an active pharmaceutical ingredient as defined in 21 CFR 207.1.8 Active pharmaceutical ingredient means any substance that is intended for incorporation into a finished drug product and is intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the body, but the term does not include intermediates used in the synthesis of the substance.9 10 5 Section 6 Section 503B(a)(2)(A) of the FD&C Act. 503B(a)(2)(A)(i)(I) to (III) of the FD&C Act. 7 See Federal Register of August 28, 2018 (83 FR 43877), March 4, 2019 (84 FR 7383), September 3, 2019 (84 FR 46014), July 31, 2020 (85 FR 46126), March 24, 2021 (86 FR 15673), and November 23, 2022 (87 FR 71642). The comment period for the July 2020 notice was reopened for 30 days on January 8, 2021 (86 FR 1515), to allow interested parties an additional opportunity to comment. FDA has not yet reached a final determination on whether the substances evaluated in the September 2019, July 2020, or March 2021 notices will be added to the 503B Bulks List. In addition, bumetanide, which was considered in the August 2018 notice, remains under consideration by the Agency. 8 See section 503B(a)(2) of the FD&C Act, which defines bulk drug substances used in compounding under section 503B according to 21 CFR 207.3(a)(4) ‘‘or any successor regulation.’’ Section 207.1 is the successor regulation. 9 Section 503B(a)(2) of the FD&C Act and 21 CFR 207.1. 10 Inactive ingredients are not subject to section 503B(a)(2) of the FD&C Act and will not be included in the 503B Bulks List because they are not included within the definition of a bulk drug substance. Pursuant to section 503B(a)(3), inactive ingredients used in compounding must comply with the standards of an applicable United States Pharmacopeia (USP) or National Formulary (NF) monograph, if a monograph exists. PO 00000 Frm 00067 Fmt 4703 Sfmt 4703 II. Methodology for Developing the 503B Bulks List A. Process for Developing the List FDA requested nominations for specific bulk drug substances for the Agency to consider for inclusion on the 503B Bulks List in the Federal Register of December 4, 2013 (78 FR 72838). FDA reopened the nomination process in the Federal Register of July 2, 2014 (79 FR 37747), and provided more detailed information on what FDA needs to evaluate nominations for the list. On October 27, 2015 (80 FR 65770), the Agency opened a new docket, FDA– 2015–N–3469, to provide an opportunity for interested persons to submit new nominations of bulk drug substances, renominate substances with sufficient information, or submit comments on nominated substances. As FDA evaluates bulk drug substances, it intends to publish notices for public comment in the Federal Register that describe its proposed position on each substance along with the rationale for that position.11 After considering any comments on FDA’s proposals regarding whether to include nominated substances on the 503B Bulks List, FDA intends to consider whether input from the Pharmacy Compounding Advisory Committee (PCAC) on the nominations would be helpful to the Agency in making its determination, and if so, it will seek PCAC input.12 Depending on its review of the docket comments and other relevant information before the Agency, FDA may finalize its proposed determination without change, or it may finalize a modification to its proposal to reflect new evidence or analysis regarding clinical need. FDA will then publish in the Federal Register a final determination identifying the bulk drug substances for which it has determined there is a clinical need and FDA’s rationale in making that final determination. FDA will also publish in the Federal Register a final determination regarding those substances it considered but found that there is no clinical need to use in compounding and FDA’s rationale in making this decision. 11 This is consistent with procedures set forth in section 503B(a)(2)(A)(i) of the FD&C Act. Although the statute only directs FDA to issue a Federal Register notice and seek public comment when it proposes to include bulk drug substances on the 503B Bulks List, we intend to seek comment when the Agency has evaluated a nominated substance and proposes either to include or not to include the substance on the list. 12 Section 503B of the FD&C Act does not require FDA to consult the PCAC before developing the 503B Bulks List. E:\FR\FM\06APN1.SGM 06APN1 Federal Register / Vol. 88, No. 66 / Thursday, April 6, 2023 / Notices FDA intends to maintain a list of all bulk drug substances it has evaluated on its website, and separately identify bulk drug substances it has placed on the 503B Bulks List and those it has decided not to place on the 503B Bulks List. This list is available at https://www.fda.gov/ media/120692/download. FDA will only place a bulk drug substance on the 503B Bulks List when it has determined there is a clinical need for outsourcing facilities to compound drug products using the bulk drug substance. If a clinical need to compound drug products using the bulk drug substance has not been demonstrated, based on the information submitted by the nominator and any other information considered by the Agency, FDA will not place a bulk drug substance on the 503B Bulks List. FDA is evaluating bulk drug substances nominated for the 503B Bulks List on a rolling basis. FDA intends to evaluate and publish in the Federal Register its proposed and final determinations in groups of bulk drug substances until all nominated substances that were sufficiently supported have been evaluated and either placed on the 503B Bulks List or identified as bulk drug substances that were considered but determined not to be appropriate for inclusion on the 503B Bulks List (Ref. 1).13 ddrumheller on DSK120RN23PROD with NOTICES1 B. Analysis of Substances Nominated for the List As noted above, the 503B Bulks List will include bulk drug substances for which there is a clinical need. The Agency is evaluating bulk drug substances that were nominated for inclusion on the 503B Bulks List, proceeding case by case, under the standard provided by the statute (Ref. 2).14 In applying this standard to make its determinations regarding the 13 In January 2017, FDA announced the availability of a revised final guidance for industry that provides additional information regarding FDA’s policies for bulk drug substances nominated for the 503B Bulks List pending our review of nominated substances under the ‘‘clinical need’’ standard entitled ‘‘Interim Policy on Compounding Using Bulk Drug Substances Under Section 503B of the Federal Food, Drug, and Cosmetic Act’’ (the ‘‘Interim Policy’’), available at https://www.fda.gov/ media/94402/download. 14 In March 2019, FDA announced the availability of a final guidance entitled ‘‘Evaluation of Bulk Drug Substances Nominated for Use in Compounding Under Section 503B of the Federal Food, Drug, and Cosmetic Act’’ (the ‘‘Clinical Need Guidance’’), available at https://www.fda.gov/ media/121315/download. This guidance describes FDA policies for developing the 503B Bulks List and the Agency’s interpretation of the phrase ‘‘bulk drug substances for which there is a clinical need’’ as it is used in section 503B. The analysis under the statutory ‘‘clinical need’’ standard described in this notice is consistent with the approach described in FDA’s guidance. VerDate Sep<11>2014 21:13 Apr 05, 2023 Jkt 259001 substances set forth in this notice, FDA interprets the phrase ‘‘bulk drug substances for which there is a clinical need’’ to mean that the 503B Bulks List may include a bulk drug substance if: (1) there is a clinical need for an outsourcing facility to compound the drug product and (2) the drug product must be compounded using the bulk drug substance. FDA does not interpret supply issues, such as backorders, to be within the meaning of ‘‘clinical need’’ for compounding with a bulk drug substance. Section 503B of the FD&C Act separately provides for compounding from a bulk drug substance under the exemptions from the FD&C Act discussed above if the drug product compounded from the bulk drug substance is on the FDA drug shortage list at the time of compounding, distribution, and dispensing. Additionally, FDA does not consider convenience in administering a particular compounded drug product (e.g., a ready-to-use form) or the cost of the compounded drug product as compared with an FDA-approved drug product when assessing ‘‘clinical need.’’ All of the bulk drug substances addressed in this notice, with the exception of quinacrine HCl, are components of FDA-approved drug products.15 FDA began its evaluation of the bulk drug substances that are components of FDA-approved drug products by asking one or both, as applicable, of the following questions: 1. Is there a basis to conclude, for each FDA-approved product that includes the nominated bulk drug substance, that (a) an attribute of the FDA-approved drug product makes it medically unsuitable to treat certain patients for a condition that FDA has identified for evaluation, and (b) the drug product proposed to be compounded is intended to address that attribute? 2. Is there a basis to conclude that the drug product proposed to be compounded must be produced from a bulk drug substance rather than from an FDA-approved drug product? The reason for question 1 is that unless an attribute of the FDA-approved drug is medically unsuitable for certain patients, and a drug product to be compounded using a bulk drug substance that is a component of the FDA-approved drug is intended to address that attribute, there is no clinical need to compound a drug product using that bulk drug substance. 15 Specifically, hydroxyzine HCl, mannitol, methacholine chloride, metoclopramide HCl, nalbuphine HCl, potassium acetate, procainamide HCl, sodium bicarbonate, sodium nitroprusside, and verapamil HCl. PO 00000 Frm 00068 Fmt 4703 Sfmt 4703 20533 Rather, such compounding would unnecessarily expose patients to the risks associated with drug products that do not meet the standards applicable to FDA-approved drug products for safety, effectiveness, quality, and labeling and would undermine the drug approval process. The reason for question 2 is that to place a bulk drug substance on the 503B Bulks List, FDA must determine that there is a clinical need for outsourcing facilities to compound a drug product using the bulk drug substance rather than starting with an FDA-approved drug product. When it is feasible to compound a drug product by starting with an FDA-approved drug product, there are certain benefits of doing so over starting with a bulk drug substance, including that FDA-approved drugs have undergone premarket review for safety, effectiveness, and quality, and are manufactured by a facility that is subject to premarket assessment, including site inspection, as well as routine post-approval risk-based inspections. In contrast, FDA does not conduct a premarket review of the quality standards, specifications, and controls for bulk drug substances used in compounding and does not conduct a premarket assessment of the manufacturer of the bulk drug substance. If the answer to both of the above questions is ‘‘yes,’’ there may be a clinical need for outsourcing facilities to compound using the bulk drug substance, and we would evaluate the substance further, applying the factors described below. If the answer to either of these questions is ‘‘no,’’ we generally would not include the bulk drug substance on the 503B Bulks List, because there would not be a basis to conclude that there may be a clinical need to compound drug products using the bulk drug substance instead of administering an FDA-approved drug or compounding starting with an FDAapproved drug product. FDA did not answer ‘‘yes’’ to both of the threshold questions for the 10 bulk drug substances that are components of FDAapproved drug products that we are addressing in this notice. Accordingly, as explained below, we did not proceed further in our evaluation of these substances and have decided not to include them on the 503B Bulks List. With respect to the bulk drug substance addressed in this notice that is not a component of an FDA-approved drug, quinacrine HCl, we conducted a balancing test using four factors. Specifically, we considered available data relevant to each factor in the context of the other factors and balanced all four factors to determine whether the E:\FR\FM\06APN1.SGM 06APN1 20534 Federal Register / Vol. 88, No. 66 / Thursday, April 6, 2023 / Notices ddrumheller on DSK120RN23PROD with NOTICES1 statutory ‘‘clinical need’’ standard has been met. The balancing test includes the following factors: • The physical and chemical characterization of the substance; • any safety issues raised by the use of the substance in compounding; • the available evidence of effectiveness or lack of effectiveness of a drug product compounded with the substance, if any such evidence exists; and • current and historical use of the substance in compounded drug products, including information about the medical condition(s) that the substance has been used to treat and any references in peer-reviewed medical literature. The discussion below reflects FDA’s consideration of these four factors and describes how they were applied to develop FDA’s decision to include quinacrine HCl for oral use on the 503B Bulks List. C. Inclusion of a Bulk Drug Substance on the 503B Bulks List In evaluating a bulk drug substance for the 503B Bulks List, FDA has considered whether the clinical need for the bulk drug substance in the proposed compounded drug product is limited, by, for example, route of administration or dosage form. In the Federal Register notice of July 31, 2020 (85 FR 46126), FDA requested comments on the proposal to limit listings in this manner. On January 8, 2021 (86 FR 1515), the comment period for the July 2020 notice was reopened for 30 days to allow interested parties an additional opportunity to comment before FDA began to develop its final determinations. After considering the comments submitted regarding the proposal, in the Federal Register notice of January 27, 2022 (87 FR 4240), FDA listed three bulk drug substances to compound drug products for topical use only, consistent with its findings related to clinical need for those bulk drug substances. FDA has also determined that to be eligible for the statutory exemptions under section 503B, drug products compounded using a bulk drug substance that appears on the 503B Bulks List cannot contain other APIs unless those APIs have been listed in combination on the 503B Bulks List (87 FR 4240). FDA’s assessment of the clinical need for compounding with a particular bulk drug substance or combination of bulk drug substances could be affected if a bulk drug substance is commonly used in compounded drug products that contain multiple bulk drug substances (APIs). VerDate Sep<11>2014 21:13 Apr 05, 2023 Jkt 259001 The use of certain APIs in combination with other APIs in a compounded drug product could also pose a safety risk or affect the compounded drug product’s effectiveness. These considerations of the composition of a nominated compounded combination, the history of its use in compounding, and evidence of safety or effectiveness would be included in FDA’s clinical need evaluation. In accordance with these considerations and the clinical need analysis set forth below, FDA is adding one bulk drug substance—quinacrine HCl—to the 503B Bulks List to compound single-ingredient drug products for oral use only.16 III. FDA’s Determinations Regarding Substances Proposed for the 503B Bulks List In September 2019, the Agency issued a Federal Register notice in which it evaluated nine nominated bulk drug substances under the section 503B statutory standard—dipyridamole, ephedrine sulfate, famotidine, hydralazine HCl, methacholine chloride, sodium bicarbonate, sodium tetradecyl sulfate, trypan blue, and vecuronium bromide—and proposed not to include them on the 503B Bulks List (the September 2019 notice).17 In this notice, after review of the comments submitted to the docket for the September 2019 notice, FDA is making its final determination not to include methacholine chloride and sodium bicarbonate on the 503B Bulks List. At this time, FDA is not making a final determination regarding ephedrine sulfate, famotidine, hydralazine HCl, sodium tetradecyl sulfate, trypan blue, and vecuronium bromide.18 These substances remain under consideration by FDA. In July 2020, the Agency issued a Federal Register notice in which it evaluated 23 nominated bulk drug substances under the section 503B statutory standard (the July 2020 notice).19 FDA proposed to include diphenylcyclopropenone (DPCP), glycolic acid, squaric acid dibutyl ester (SADBE), and trichloroacetic acid (TCA) on the 503B Bulks List. FDA proposed not to include diazepam, dobutamine HCl, dopamine HCl, edetate calcium disodium, folic acid, glycopyrrolate, hydroxyzine HCl, ketorolac 16 In this notice, ‘‘single-ingredient’’ refers to a drug product containing one active ingredient. The drug product may also contain excipients. 17 See 84 FR 46014. 18 FDA made a final determination not to include dipyridamole on the 503B Bulks List (see 87 FR 4240). 19 85 FR 46126. PO 00000 Frm 00069 Fmt 4703 Sfmt 4703 tromethamine, labetalol HCl, mannitol, metoclopramide HCl, moxifloxacin HCl, nalbuphine HCl, polidocanol, potassium acetate, procainamide HCl, sodium nitroprusside, sodium thiosulfate, and verapamil HCl on the 503B Bulks List. In this notice, after review of the comments submitted to the docket for the July 2020 notice, FDA is making its final determination not to include hydroxyzine HCl, mannitol, metoclopramide HCl, nalbuphine HCl, potassium acetate, procainamide HCl, sodium nitroprusside, and verapamil HCl on the 503B Bulks List. FDA has previously made final determinations for DPCP, glycolic acid, SADBE, TCA, diazepam, dobutamine HCl, dopamine HCl, edetate calcium disodium, folic acid, glycopyrrolate, and sodium thiosulfate (except the topical route of administration) (87 FR 4240). At this time, FDA is not making a final determination regarding ketorolac tromethamine, labetalol HCl, moxifloxacin HCl, and polidocanol. These substances remain under consideration by FDA. In March 2021, the Agency issued a Federal Register notice in which it evaluated five bulk drug substances under the section 503B statutory standard (the March 2021 notice).20 FDA proposed to include quinacrine HCl on the 503B Bulks List to compound drug products for oral use only. FDA proposed not to include bromfenac sodium, mitomycin-C, nepafenac, and hydroxychloroquine sulfate on the 503B Bulks List. In this notice, after review of the comments submitted to the docket for the March 2021 notice, FDA is making its final determination to include quinacrine HCl on the 503B Bulks List to compound drug products for oral use only. At this time, FDA is not making a final determination regarding bromfenac sodium, mitomycin-C, nepafenac, and hydroxychloroquine sulfate. These substances remain under consideration by FDA. Additional bulk drug substances nominated by the public for inclusion on the 503B Bulks List are currently under consideration and may be the subject of future notices. A. Substance Evaluated and Included on the 503B Bulks List FDA is placing quinacrine HCl on the 503B Bulks List. FDA evaluated quinacrine HCl and proposed to include it on the 503B Bulks List in the March 2021 notice. The reasons for FDA’s proposal to place quinacrine HCl for oral use on the 503B Bulks List are 20 86 E:\FR\FM\06APN1.SGM FR 15673. 06APN1 Federal Register / Vol. 88, No. 66 / Thursday, April 6, 2023 / Notices included below (Ref. 3).21 For the reasons set forth in the proposal, FDA is now placing quinacrine HCl on the 503B Bulks List for oral use only. ddrumheller on DSK120RN23PROD with NOTICES1 Quinacrine HCl FDA considered the bulk drug substance quinacrine HCl for inclusion on the 503B Bulks List to compound drug products in oral dosage forms at strengths of 25–100 milligrams (mg) for the treatment of cutaneous lupus erythematosus (CLE), as described in the Agency’s nomination and evaluation.22 Quinacrine HCl is not a component of an FDA-approved drug product. The Agency therefore evaluated quinacrine HCl for potential inclusion on the 503B Bulks List under the clinical need standard in section 503B of the FD&C Act using the balancing test described above. FDA considered data and information regarding the physical and chemical characterization of quinacrine HCl, safety issues raised by use of this substance in compounding, available evidence of effectiveness or lack of effectiveness, and historical and current use in compounding (Ref. 3). Quinacrine HCl is well-characterized physically and chemically. Although there are concerns about its safety profile in certain patient populations, FDA believes these risks are well known within the rheumatology and dermatology specialties that most often treat CLE, and the known risks could be controlled with appropriate dosing and monitoring. Quinacrine HCl has been used for several decades to treat systemic lupus erythematosus and CLE, and there is a significant body of experience, documented in the scientific literature, that quinacrine HCl may be effective in the treatment of patients with cutaneous lupus, and patients who are not fully clinically responsive to, or are intolerant of, treatment with FDA-approved products alone. These patients may respond to the addition of quinacrine HCl to their existing therapy, or to the use of quinacrine HCl alone. On balance, the 21 In addition to FDA’s evaluation of the quinacrine HCl nomination for the 503B Bulks List, the Agency considered data and information from its earlier evaluation regarding the use of this bulk drug substance for the list of bulk drug substances that can be used in compounding under section 503A of the FD&C Act (the 503A Evaluation) (see appendices A–D in ‘‘FDA Memo to File, Clinical Need for Quinacrine Hydrochloride in Compounding Under Section 503B of the FD&C Act’’ (Ref. 3)). FDA also considered a report provided by the University of Maryland Center of Excellence in Regulatory Science and Innovation and conducted a search for relevant scientific literature and safety information, focusing on materials published or submitted to FDA since the 503A Evaluations (see appendix H in Ref. 3). 22 See appendix G in Ref. 3. VerDate Sep<11>2014 21:13 Apr 05, 2023 Jkt 259001 physical and chemical characterization, safety, effectiveness, and historical and current use of quinacrine HCl weigh in favor of including this substance on the 503B Bulks List. Two commenters supported FDA’s proposal to include quinacrine HCl on the 503B Bulks List, although one of them disagreed with FDA’s proposal to limit the entry to oral use only. No commenters opposed adding quinacrine HCl to the 503B Bulks List. Several commenters objected generally to FDA’s proposals, and these overarching concerns are addressed in section IV of this notice. Accordingly, FDA is adding quinacrine HCl to the 503B Bulks List for oral use only. The entry on the 503B Bulks List is limited in this way because, as discussed above, FDA’s evaluation only revealed a clinical need for outsourcing facilities to compound drug products containing the bulk drug substance quinacrine HCl for the oral route of administration. Due to the safety risks referred to above, FDA is making safety information about the use of quinacrine HCl available to prescribers, pharmacists, outsourcing facilities, and the public through a safety guide on FDA’s website, available at https:// www.fda.gov/drugs/human-drugcompounding/consumer-and-healthcare-professional-information. B. Substances Evaluated and Not Included on the 503B Bulks List The 10 bulk drug substances that FDA has evaluated, proposed not to include on the 503B Bulks List in a Federal Register notice, and has now decided not to place on the 503B Bulks List are: hydroxyzine HCl, mannitol, methacholine chloride, metoclopramide HCl, nalbuphine HCl, potassium acetate, procainamide HCl, sodium bicarbonate, sodium nitroprusside, and verapamil HCl. Because the substances discussed in this section are components of FDAapproved drug products, FDA considered one or both of the following questions: (1) is there a basis to conclude that an attribute of each FDAapproved drug product containing the bulk drug substance makes each one medically unsuitable to treat certain patients for a condition that FDA has identified for evaluation, and the drug product(s) proposed to be compounded is intended to address that attribute in each FDA-approved drug product, and (2) is there a basis to conclude that the drug product(s) proposed to be compounded must be compounded using a bulk drug substance. FDA considered comments to the docket submitted within the public comment period, but as explained below, none of PO 00000 Frm 00070 Fmt 4703 Sfmt 4703 20535 the comments received on these bulk drug substances provided information that led FDA to change its determination. 1. Hydroxyzine HCl Hydroxyzine HCl has been nominated for inclusion on the 503B Bulks List to compound drug products that treat alcohol withdrawal syndrome, analgesia in labor, pre- and postpartum reduction of narcotic use, and relief of anxiety, among other conditions.23 The proposed route of administration is intramuscular, the proposed dosage form is a solution, and the proposed concentration is 50 milligrams/milliliters (mg/mL). The nominators proposed to compound a preserved solution. However, they failed to acknowledge that there is a preserved formulation of hydroxyzine HCl that is FDA-approved or identify an attribute of that formulation that makes it medically unsuitable for certain patients. The nominations state that hydroxyzine HCl might also be used to compound other drug products but do not identify those products. The nominated bulk drug substance is a component of FDAapproved drug products (e.g., ANDA 087408). FDA-approved hydroxyzine HCl is marketed as a preserved 50 mg/ mL solution for intramuscular administration.24 25 26 a. Suitability of FDA-Approved Drug Product(s) The nominations do not identify an attribute of the FDA-approved preserved 50 mg/mL hydroxyzine HCl solution for intramuscular administration that makes it medically unsuitable for certain patients or identify an attribute of the FDA-approved drug products that the proposed compounded drug product is intended to address. Two commenters supported FDA’s proposal not to include hydroxyzine HCl on the 503B Bulks List. No new information supporting the clinical need for compounding from the bulk drug substance hydroxyzine HCl was provided by the commenters. Accordingly, FDA finds no basis to conclude that there is an attribute of the 23 See Docket No. FDA–2013–N–1524, document nos. FDA–2013–N–1524–2292 and FDA–2013–N– 1524–2298. 24 See, e.g., ANDA 087408 labeling available as of the date of this notice at https://www.accessdata. fda.gov/spl/data/e711ee73-c054-4f3f-a189bb3c01c7aecc/e711ee73-c054-4f3f-a189bb3c01c7aecc.xml. 25 Per the label for ANDA 087408, each mL contains hydroxyzine HCl 25 mg or 50 mg, benzyl alcohol 0.9 percent, and water for injection q.s. pH is adjusted with sodium hydroxide and/or hydrochloric acid. 26 Hydroxyzine HCl is also FDA-approved as an oral tablet and as an oral syrup. E:\FR\FM\06APN1.SGM 06APN1 20536 Federal Register / Vol. 88, No. 66 / Thursday, April 6, 2023 / Notices FDA-approved products that makes them medically unsuitable to treat certain patients for a condition that FDA has identified for evaluation and that a proposed compounded product is intended to address. b. Whether the Drug Product Must Be Compounded From a Bulk Drug Substance Because the nominations do not identify specific differences between drug products that would be compounded using hydroxyzine HCl and the FDA-approved drug product containing hydroxyzine HCl, there is nothing for FDA to evaluate under question 2. No further information was supplied on this point during the comment period. Therefore, FDA finds no basis to conclude that the drug product proposed to be compounded must be prepared using a bulk drug substance rather than an FDA-approved drug product. 2. Mannitol ddrumheller on DSK120RN23PROD with NOTICES1 Mannitol has been nominated for inclusion on the 503B Bulks List to compound drug products for treatment of acute renal failure, inhalation bronchial challenge testing, and irrigation of the urinary bladder, among other conditions.27 The proposed route of administration is intravenous, the proposed dosage form is a solution, and the proposed concentration is 25 percent. The nominators proposed to compound a preservative-free solution. However, they failed to acknowledge that there is a preservative-free formulation of mannitol that is FDAapproved or identify an attribute of that formulation that makes it medically unsuitable for certain patients. The nominations state that mannitol might also be used to compound other drug products but do not identify those products. The nominated bulk drug substance is a component of FDAapproved drug products (e.g., NDA 016269). FDA-approved mannitol is marketed as a preservative-free solution in water for injection in various concentrations, including a 25 percent concentration in a flip-top vial for administration by intravenous infusion only.28 29 30 27 See Docket No. FDA–2013–N–1524, document nos. FDA–2013–N–1524–2292 and FDA–2013–N– 1524–2298. 28 See, e.g., NDA 016269 labeling available as of the date of this notice at https://www.accessdata. fda.gov/drugsatfda_docs/label/2020/016269s056lbl. pdf. 29 Per the label for NDA 016269, the solutions contain no bacteriostat, antimicrobial agent, or added buffer (except for pH adjustment) and each is intended only as a single-dose injection. VerDate Sep<11>2014 21:13 Apr 05, 2023 Jkt 259001 a. Suitability of FDA-Approved Drug Product(s) The nominations do not identify an attribute of each of the FDA-approved 25 percent preservative-free solution products that makes them medically unsuitable for certain patients or identify an attribute of the FDAapproved drug products that the proposed compounded drug product is intended to address. Two commenters supported FDA’s proposal not to include mannitol on the 503B Bulks List. The commenters provided no new information supporting the clinical need for compounding from the bulk drug substance mannitol. Accordingly, FDA finds no basis to conclude that there is an attribute of the FDA-approved products that makes them medically unsuitable to treat certain patients for a condition that FDA has identified for evaluation and that a proposed compounded product is intended to address. b. Whether the Drug Product Must Be Compounded From a Bulk Drug Substance Because the nominations do not identify specific differences between drug products that would be compounded using mannitol and FDAapproved drug products containing mannitol, there is nothing for FDA to evaluate under question 2. No further information was supplied on this point during the comment period. Therefore, FDA finds no basis to conclude that drug products must be compounded using a bulk drug substance rather than an FDA-approved drug product. 3. Methacholine Chloride Methacholine chloride has been nominated for inclusion on the 503B Bulks List to compound drug products that aid in the diagnosis of bronchial airway hyperactivity.31 The proposed route of administration is inhalation tapering dose kits, the proposed dosage form is an inhalant, and the proposed strengths are as follows: 8 dilutions (0.125 mg/mL, 0.25 mg/mL, 0.5 mg/mL, 1 mg/mL, 2 mg/mL, 4 mg/mL, 8 mg/mL, 16 mg/mL) and 10 dilutions (0.031 mg/ mL, 0.0625 mg/mL, 0.125 mg/mL, 0.25 mg/mL, 0.5 mg/mL, 1 mg/mL, 2 mg/mL, 4 mg/mL, 8 mg/mL, 16 mg/mL). The nominated bulk drug substance is a component of an FDA-approved drug product (NDA 019193). FDA-approved methacholine chloride is marketed as a 30 Mannitol is also FDA-approved as a single ingredient as a solution for irrigation and as a powder for inhalation. 31 See Docket No. FDA–2013–N–1524, document no. FDA–2013–N–1524–2292. PO 00000 Frm 00071 Fmt 4703 Sfmt 4703 100 mg/vial powder for solution to be administered only by inhalation.32 Per its labeling, methacholine chloride is reconstituted and diluted to the following concentrations with 0.9 percent sodium chloride injection or 0.9 percent sodium chloride injection containing 0.4 percent phenol (pH 7.0): 0.025 mg/mL, 0.25 mg/mL, 2.5 mg/mL, 10 mg/mL, and 25 mg/mL. a. Suitability of FDA-Approved Drug Product The nomination does not identify an attribute of the FDA-approved drug product that makes it medically unsuitable to treat certain patients and that the proposed compounded drug products are intended to address. Specifically, the nomination does not identify an attribute of the FDAapproved 100 mg/vial powder for solution (for reconstitution) that makes it medically unsuitable for certain patients. The commenters propose to compound a ready-to-use product from a bulk drug substance to seek improved efficiency for prescribers or healthcare providers, or to address the possibility that the FDA-approved drug might be mishandled by a medical professional, neither of which falls within the meaning of clinical need to compound a drug product using a bulk drug substance.33 Several commenters supported FDA’s proposal not to include methacholine chloride on the 503B Bulks List. The commenters provided no additional information supporting the clinical need for compounding from the bulk drug substance methacholine chloride. Accordingly, FDA finds no basis to conclude that there is an attribute of the FDA-approved product that makes it medically unsuitable to treat certain patients for a condition that FDA has identified for evaluation and that a proposed compounded product is intended to address. b. Whether the Drug Product Must Be Compounded From a Bulk Drug Substance The nomination does not provide support for the position that drug products containing methacholine chloride must be compounded from a bulk drug substance rather than by diluting the FDA-approved drug 32 See, e.g., NDA 208943 labeling available as of the date of this notice at https://www.accessdata. fda.gov/spl/data/7f538d73-80e2-4c00-911adf2637e5a4d1/7f538d73-80e2-4c00-911adf2637e5a4d1.xml. 33 See, e.g., ‘‘List of Bulk Drug Substances for Which There Is a Clinical Need Under Section 503B of the Federal Food, Drug, and Cosmetic Act,’’ 87 FR 4240 at 4248. E:\FR\FM\06APN1.SGM 06APN1 Federal Register / Vol. 88, No. 66 / Thursday, April 6, 2023 / Notices ddrumheller on DSK120RN23PROD with NOTICES1 product. None of the commenters provided support for such a position during the comment period. Some commenters stated that there could be a benefit from using a bulk drug substance to compound drug products to avoid the manipulations that the FDA-approved drug products that contain methacholine chloride require before they can be administered (e.g., dilution). Commenters also contended that outsourcing facilities, as opposed to hospitals, are better able to prepare methacholine in the sterile environment that is necessary for the sterility of an injectable drug product. This is essentially an argument that the approved drug might be mishandled by a medical professional, which, as discussed above, does not fall within the meaning of clinical need to compound a drug product using a bulk drug substance. The commenters also did not establish that drug products in the relevant concentrations, including ready-to-use products, cannot be prepared from the FDA-approved drug products, which are labeled for dilution. Having considered these arguments, and because no further information was supplied regarding the clinical need for compounding from the bulk drug substance, FDA finds no basis to conclude that the methacholine chloride drug products proposed to be compounded must be prepared using a bulk drug substance rather than the FDA-approved drug product. 4. Metoclopramide HCl Metoclopramide HCl has been nominated for inclusion on the 503B Bulks List to compound drug products that treat chemotherapy-induced nausea and vomiting, diabetic gastroparesis, gastroesophageal reflux disease, and postoperative nausea and vomiting, among other conditions.34 The proposed routes of administration are intravenous and intramuscular, the proposed dosage form is a suspension, and the proposed concentration is 5 mg/mL. The nominators proposed to compound both preservative-free and preserved suspensions. However, they failed to acknowledge that there is a preservative-free formulation of metoclopramide HCl that is FDAapproved or identify an attribute of that formulation that would be medically unsuitable for certain patients. The nominations state that metoclopramide HCl might also be used to compound other drug products but do not identify those products. The nominated bulk 34 See Docket No. FDA–2013–N–1524, document nos. FDA–2013–N–1524–2292 and FDA–2013–N– 1524–2298. VerDate Sep<11>2014 21:13 Apr 05, 2023 Jkt 259001 drug substance is a component of FDAapproved drug products (e.g., ANDA 073118). FDA-approved metoclopramide HCl is marketed as a preservative-free 10 mg/2 mL (5 mg/mL) solution for intravenous or intramuscular administration.35 36 37 a. Suitability of FDA-Approved Drug Product(s) The nominations do not identify an attribute of each of the FDA-approved preservative-free 10 mg/2 mL (5 mg/mL) solution products for intravenous or intramuscular administration that makes them medically unsuitable for certain patients or identify an attribute of the FDA-approved drug products that the proposed compounded drug product is intended to address. In particular, the nominations do not identify any data or information indicating that there are some patients who need a preserved product rather than the FDA-approved preservative-free products. In addition, the nominations do not identify any data or information indicating that there are some patients who need a suspension rather than a solution for intravenous and intramuscular administration. Two commenters supported FDA’s proposal not to include metoclopramide HCl on the 503B Bulks List. Commenters provided no new information supporting the clinical need for compounding from the bulk substance metoclopramide HCl. Accordingly, FDA finds no basis to conclude that there is an attribute of the FDA-approved products that makes them medically unsuitable to treat certain patients for a condition that FDA has identified for evaluation and that a proposed compounded product is intended to address. b. Whether the Drug Product Must Be Compounded From a Bulk Drug Substance Because the nominations have not identified an attribute of the FDAapproved drug product that makes it medically unsuitable for certain patients, FDA has not evaluated whether the proposed drug products containing metoclopramide HCl must be compounded from bulk drug substances rather than using the FDA-approved drug product. No further information was supplied on this point during the 35 See, e.g., ANDA 073118 labeling available as of the date of this notice at https://www.accessdata. fda.gov/spl/data/d693380f-94fa-46df-ad374ecf3c59b8b8/d693380f-94fa-46df-ad374ecf3c59b8b8.xml. 36 Per the label for ANDA 073118, the solution is preservative-free and is intended for intravenous or intramuscular administration. 37 Metoclopramide is also FDA-approved as an oral solution, metered nasal spray, and tablet. PO 00000 Frm 00072 Fmt 4703 Sfmt 4703 20537 comment period. Therefore, FDA finds no basis to conclude that the drug products proposed to be compounded must be prepared using a bulk drug substance rather than an FDA-approved drug product. 5. Nalbuphine HCl Nalbuphine HCl has been nominated for inclusion on the 503B Bulks List to compound drug products that are used for general anesthesia and to treat moderate to severe pain as a preoperative, postoperative, and obstetrical analgesia.38 The proposed routes of administration are intravenous, intramuscular, and subcutaneous, the proposed dosage form is a solution, and the proposed concentrations are 10 mg/mL and 20 mg/mL. The nominators proposed to compound a preservative-free solution and a preserved solution. However, they failed to acknowledge that there are both a preservative-free solution formulation and a preserved solution formulation of nalbuphine HCl that are FDA-approved or identify an attribute of those formulations that makes them medically unsuitable for certain patients. The nominations state that nalbuphine HCl might also be used to compound other drug products but do not identify those products. The nominated bulk drug substance is a component of FDA-approved drug products (e.g., ANDAs 070914 and 070918). FDA-approved nalbuphine HCl is marketed as both preservative-free and as preserved 10 mg/mL and 20 mg/ mL solutions for intravenous, intramuscular, and subcutaneous administration.39 40 a. Suitability of FDA-Approved Drug Product(s) The nominations do not identify an attribute of each of the FDA-approved 10 mg/mL and 20 mg/mL nalbuphine HCl solutions for intravenous, intramuscular, and subcutaneous administration that makes them medically unsuitable for certain patients or identify an attribute of the approved drug products that the proposed compounded drug products are 38 See Docket No. FDA–2013–N–1524, document nos. FDA–2013–N–1524–2298 and FDA–2013–N– 1524–2292. 39 See, e.g., ANDA 070914 and 070918 labeling available as of the date of this notice at https:// www.accessdata.fda.gov/spl/data/f118d0a9-270f4ced-ba4c-c62e32e0d635/f118d0a9-270f-4ced-ba4cc62e32e0d635.xml and https://www.accessdata. fda.gov/spl/data/0e1346b6-7c47-4957-b0be849a84b18a89/0e1346b6-7c47-4957-b0be849a84b18a89.xml, respectively. 40 Per the labels for ANDA 070914 and 070918, single-dose products contain no bacteriostat or antimicrobial agent and unused portions must be discarded. E:\FR\FM\06APN1.SGM 06APN1 20538 Federal Register / Vol. 88, No. 66 / Thursday, April 6, 2023 / Notices intended to address. Two commenters supported FDA’s proposal not to include nalbuphine HCl on the 503B Bulks List. The commenters provided no new information supporting the clinical need for compounding from the bulk substance nalbuphine HCl. Accordingly, FDA finds no basis to conclude that there is an attribute of the FDA-approved products that makes them medically unsuitable to treat certain patients for a condition that FDA has identified for evaluation and that a proposed compounded product is intended to address. ddrumheller on DSK120RN23PROD with NOTICES1 b. Whether the Drug Product Must Be Compounded From a Bulk Drug Substance Because the nominations do not identify specific differences between drug products that would be compounded using nalbuphine HCl and approved drug products containing nalbuphine HCl, there is nothing for FDA to evaluate under question 2. No further information was supplied on this point during the comment period. Therefore, FDA finds no basis to conclude that the drug products proposed to be compounded must be prepared using a bulk drug substance rather than an FDA-approved drug product. 6. Potassium Acetate Potassium acetate has been nominated for inclusion on the 503B Bulks List to compound drug products that facilitate electrolyte management.41 The proposed route of administration is intravenous, the proposed dosage form is a solution, and the proposed concentration is 2 milliequivalents per milliliter (mEq/mL). The nominators proposed to compound a preservativefree solution. However, they failed to acknowledge that there is a preservative-free formulation of potassium acetate that is FDA-approved or identify an attribute of that formulation that makes it medically unsuitable for certain patients. The nominations state that potassium acetate might also be used to compound other drug products but do not identify those products. The nominated bulk drug substance is a component of FDAapproved drug products (e.g., NDA 018896). FDA-approved potassium acetate is marketed as a 40 mEq/20 mL (2 mEq/mL) preservative-free solution for intravenous administration.42 43 41 See Docket No. FDA–2013–N–1524, document nos. FDA–2013–N–1524–2292 and FDA–2013–N– 1524–2298. 42 See, e.g., NDA 018896 labeling available as of the date of this notice at https:// www.accessdata.fda.gov/spl/data/28f98aef-8865- VerDate Sep<11>2014 21:13 Apr 05, 2023 Jkt 259001 a. Suitability of FDA-Approved Drug Product(s) The nominations do not identify an attribute of each of the FDA-approved 2 mEq/mL preservative-free solution products that makes them medically unsuitable for certain patients or identify an attribute of the approved drug products that the proposed compounded drug product is intended to address. Two commenters supported FDA’s proposal not to include potassium acetate on the 503B Bulks List. The commenters provided no new information supporting the clinical need for compounding from the bulk substance potassium acetate. Accordingly, FDA finds no basis to conclude that there is an attribute of the FDA-approved products that makes them medically unsuitable to treat certain patients for a condition that FDA has identified for evaluation and that a proposed compounded product is intended to address. b. Whether the Drug Product Must Be Compounded From a Bulk Drug Substance Because the nominations do not identify specific differences between drug products that would be compounded using potassium acetate and approved drug products containing potassium acetate, there is nothing for FDA to evaluate under question 2. No further information was supplied on this point during the comment period. Therefore, FDA finds no basis to conclude that the drug products proposed to be compounded must be prepared using a bulk drug substance rather than an FDA-approved drug product. 7. Procainamide HCl Procainamide HCl has been nominated for inclusion on the 503B Bulks List to compound drug products that treat ventricular arrhythmia.44 The proposed routes of administration are intramuscular and intravenous, the proposed dosage form is a solution, and the proposed concentrations are 100 mg/mL and 500 mg/mL. The nominators proposed to compound a preserved solution. However, they failed to acknowledge that there is a preserved formulation of procainamide HCl that is FDA-approved or identify an attribute of 4faf-b491-a77b56513d5d/28f98aef-8865-4faf-b491a77b56513d5d.xml. 43 Per the label for NDA 018896, the potassium acetate solution contains no bacteriostat, antimicrobial agent, or added buffer but may contain acetic acid for pH adjustment. 44 See Docket No. FDA–2013–N–1524, document nos. FDA–2013–N–1524–2292 and FDA–2013–N– 1524–2298. PO 00000 Frm 00073 Fmt 4703 Sfmt 4703 that formulation that makes it medically unsuitable for certain patients. The nominations state that procainamide HCl might also be used to compound other drug products but do not identify those products. The nominated bulk drug substance is a component of FDAapproved drug products (e.g., ANDA 089069). FDA-approved procainamide HCl is marketed as 100 mg/mL and 500 mg/mL preserved solutions for intramuscular and intravenous administration.45 46 a. Suitability of FDA-Approved Drug Product(s). The nominations do not identify an attribute of each of the FDA-approved 100 mg/mL and 500 mg/mL preserved solutions that makes them medically unsuitable for certain patients or identify an attribute of the approved drug products that the proposed compounded drug products are intended to address. Two commenters supported FDA’s proposal not to include procainamide HCl on the 503B Bulks List. Commenters provided no new information supporting the clinical need for compounding from the bulk drug substance procainamide HCl. Accordingly, FDA finds no basis to conclude that there is an attribute of the FDA-approved products that makes them medically unsuitable to treat certain patients for a condition that FDA has identified for evaluation and that a proposed compounded product is intended to address. b. Whether the Drug Product Must Be Compounded From a Bulk Drug Substance Because the nominations do not identify specific differences between drug products that would be compounded using procainamide HCl and approved drug products containing procainamide HCl, there is nothing for FDA to evaluate under question 2. No further information was supplied on this point during the comment period. Therefore, FDA finds no basis to conclude that the drug products proposed to be compounded must be prepared using a bulk drug substance rather than an FDA-approved drug product. 45 See, e.g., ANDA 089069 labeling available as of the date of this notice at https://www.accessdata. fda.gov/spl/data/6918f728-6c39-4be9-b0f66eb5f12bbcaf/6918f728-6c39-4be9-b0f66eb5f12bbcaf.xml. 46 Per the label for ANDA 089069, each milliliter of the 2 mL vial contains procainamide hydrochloride 500 mg, methylparaben 1 mg, and sodium metabisulfite 1.8 mg added in water for injection, and may contain hydrochloric acid and/ or sodium hydroxide for pH adjustment. E:\FR\FM\06APN1.SGM 06APN1 Federal Register / Vol. 88, No. 66 / Thursday, April 6, 2023 / Notices 8. Sodium Bicarbonate Sodium bicarbonate has been nominated for inclusion on the 503B Bulks List to compound drug products that treat various conditions, including metabolic acidosis, certain drug intoxications, severe diarrhea, and indigestion.47 The proposed route of administration is intravenous, the proposed dosage forms are an injectable solution and injection solutions, and the proposed strengths range from 4.2 percent to 8.4 percent. The nominators proposed to compound a preservativefree solution. However, they failed to acknowledge that there is an FDAapproved preservative-free formulation of sodium bicarbonate or identify an attribute of that formulation that makes it medically unsuitable for certain patients. The nominations state that sodium bicarbonate might also be used to compound other drug products but do not identify those products. The nominated bulk drug substance is a component of FDA-approved drug products (e.g., ANDAs 203449 and 202494). FDA-approved sodium bicarbonate is a single-dose, preservative-free 1 mEq/mL (8.4 percent) solution for intravenous administration. 48 49 50 ddrumheller on DSK120RN23PROD with NOTICES1 a. Suitability of FDA-Approved Drug Product The nominations do not identify an attribute of the FDA-approved drug products, including the single-dose, preservative-free 1 mEq/mL (8.4 percent) solution, that makes them medically unsuitable to treat certain patients and that the proposed compounded drug products are intended to address. Two commenters supported FDA’s proposal not to include sodium bicarbonate on the 503B Bulks List. Commenters provided no new information supporting the clinical need for compounding from the bulk drug substance sodium bicarbonate. Accordingly, FDA finds no basis to conclude that there is an attribute of the FDA-approved product that makes it 47 See Docket No. FDA–2013–N–1524, document nos. FDA–2013–N–1524–2292 and FDA–2013–N– 1524–2298; see also Docket No. FDA–2015–N–3469, document no. FDA–2015–N–3469–0095. 48 See, e.g., ANDA 203449 labeling available as of the date of this notice at https://www.accessdata. fda.gov/spl/data/0e955d36-928c-4f09-9b340cc954e5b1f4/0e955d36-928c-4f09-9b340cc954e5b1f4.xml. 49 Per the label for ANDA 203449, the solutions contain no bacteriostat, antimicrobial agent, or added buffer and are intended only for use as a single-dose injection. 50 Sodium bicarbonate is also FDA-approved in combination with other ingredients as an injectable, solution for irrigation, and various oral formulations. VerDate Sep<11>2014 21:13 Apr 05, 2023 Jkt 259001 medically unsuitable to treat certain patients for a condition that FDA has identified for evaluation and that the proposed compounded product is intended to address. b. Whether the Drug Product Must Be Compounded From a Bulk Drug Substance The nominations do not provide support for the position that the proposed sodium bicarbonate products with concentrations at or below 8.4 percent (1 mEq/mL) must be compounded from bulk drug substances rather than by diluting the FDAapproved drug product. Because no data or information was submitted supporting the need for a higher concentration, we have not considered whether a bulk drug substance must be used to compound a sodium bicarbonate drug product at concentrations higher than 8.4 percent. No comments provided support for the position that the proposed sodium bicarbonate products with concentrations at or below 8.4 percent (1 mEq/mL) must be compounded from bulk drug substances rather than by diluting the FDAapproved drug product. Several commenters stated that the ability to compound sodium bicarbonate using a bulk drug substance was crucial to address persistent drug shortages. However, as explained above, section 503B of the FD&C Act already provides for compounding from a bulk drug substance if the drug product compounded from such bulk drug substance is on the FDA drug shortage list at the time of compounding, distribution, and dispensing. The Agency does not interpret supply issues, such as shortages and backorders, to be within the meaning of ‘‘clinical need’’ for compounding with a bulk drug substance.51 Other commenters asserted that there could be a benefit from using the bulk drug substance sodium bicarbonate to compound drug products to avoid the manipulations that the FDA-approved drug products that contain sodium bicarbonate require before they can be administered (e.g., dilution or drawing the drug into a syringe before administration). One commenter proposes to compound ready-to-use products from bulk drug substances to seek improved efficiency for prescribers or healthcare providers and to address the possibility that the approved drug might be mishandled by a medical professional, neither of which 51 See, e.g., ‘‘List of Bulk Drug Substances for Which There Is a Clinical Need Under Section 503B of the Federal Food, Drug, and Cosmetic Act,’’ 87 FR 4240 at 4248. PO 00000 Frm 00074 Fmt 4703 Sfmt 4703 20539 falls within the meaning of clinical need to compound a drug product using a bulk drug substance. Having considered these arguments, and because no further information was supplied regarding the clinical need for compounding from the bulk drug substance, FDA finds no basis to conclude that the drug products proposed to be compounded must be prepared using a bulk drug substance rather than an FDA-approved drug product. 9. Sodium Nitroprusside Sodium nitroprusside has been nominated for inclusion on the 503B Bulks List to compound drug products to treat acute decompensated heart failure and acute hypertension.52 The proposed route of administration is an injection, the proposed dosage form is a solution, and the proposed concentration is 12.5 mg/mL. The nomination states that sodium nitroprusside might also be used to compound other drug products but does not identify those products. The nominated bulk drug substance is a component of FDA-approved drug products (e.g., ANDA 209493). FDAapproved sodium nitroprusside is marketed as a 50 mg/2 mL (25 mg/mL) solution that must be diluted prior to injection. 53 54 a. Suitability of FDA-Approved Drug Products Although the nominator proposes to make a drug product that has a lower concentration than the approved drug product with the same API, the nomination does not identify an attribute of each of the FDA-approved 50 mg/2 mL solution for dilution products that makes them medically unsuitable for certain patients or identify an attribute of the FDAapproved drug products that the proposed compounded drug product is intended to address. Two commenters supported FDA’s proposal not to include sodium nitroprusside on the 503B Bulks List. Commenters provided no new information supporting the clinical need for compounding from the bulk drug substance sodium nitroprusside. Accordingly, FDA finds no basis to conclude that there is an attribute of the FDA-approved products 52 See Docket No. FDA–2015–N–3469, document no. FDA–2015–N–3469–0238. 53 See, e.g., ANDA 209493 labeling available as of the date of this notice at https://www.accessdata. fda.gov/spl/data/37060217-1ad1-462b-a1d07271c68ed881/37060217-1ad1-462b-a1d07271c68ed881.xml. 54 Sodium nitroprusside is also FDA-approved as a solution for intravenous administration. E:\FR\FM\06APN1.SGM 06APN1 20540 Federal Register / Vol. 88, No. 66 / Thursday, April 6, 2023 / Notices that makes them medically unsuitable to treat certain patients for a condition that FDA has identified for evaluation and that a proposed compounded product is intended to address. b. Whether the Drug Product Must Be Compounded From a Bulk Drug Substance The nomination does not provide support for the position that drug products containing sodium nitroprusside must be compounded from bulk drug substances rather than using the FDA-approved drug products. No further information was supplied on this point during the comment period. Therefore, FDA finds no basis to conclude that the drug products proposed to be compounded must be prepared using a bulk drug substance rather than an FDA-approved drug product. 10. Verapamil HCl ddrumheller on DSK120RN23PROD with NOTICES1 Verapamil HCl has been nominated for inclusion on the 503B Bulks List to compound drug products that treat atrial fibrillation and flutter, hypertension, and paroxysmal supraventricular tachycardia, among other conditions.55 The proposed route of administration is intravenous, the proposed dosage form is a solution, and the proposed concentration is 2.5 mg/ mL. The nominators proposed to compound a preservative-free solution. However, they failed to acknowledge that there is a preservative-free formulation of verapamil HCl that is FDA-approved or identify an attribute of that formulation that makes it medically unsuitable for certain patients. The nominations state that verapamil HCl might also be used to compound other drug products but do not identify those products. The nominated bulk drug substance is a component of FDAapproved drug products (e.g., ANDA 070737). FDA-approved verapamil HCl is marketed as a preservative-free 5 mg/ 2 mL (2.5 mg/mL) solution for intravenous administration. 56 57 58 55 See Docket No. FDA–2013–N–1524, document nos. FDA–2013–N–1524–2298 and FDA–2013–N– 1524–2292. 56 See, e.g., ANDA 070737 labeling available as of the date of this notice at https://www.accessdata. fda.gov/spl/data/072b89b5-6d71-4f63-9686d715d9256241/072b89b5-6d71-4f63-9686d715d9256241.xml. 57 Per the label for ANDA 070737, the solution contains no bacteriostat or antimicrobial agent, is intended for single-dose intravenous administration, and may contain hydrochloric acid for pH adjustment. 58 Verapamil HCl is also FDA-approved in various oral capsule and tablet formulations. VerDate Sep<11>2014 21:13 Apr 05, 2023 Jkt 259001 a. Suitability of FDA-Approved Drug Products The nominations do not identify an attribute of each of the FDA-approved preservative-free 5 mg/2 mL (2.5 mg/ mL) solution products for intravenous administration that makes them medically unsuitable for certain patients or identify an attribute of the FDAapproved drug products that the proposed compounded drug products are intended to address. Two commenters supported FDA’s proposal not to include verapamil HCl on the 503B Bulks List. Commenters provided no new information supporting the clinical need for compounding from the bulk drug substance verapamil HCl. Accordingly, FDA finds no basis to conclude that there is an attribute of the FDA-approved products that makes them medically unsuitable to treat certain patients for a condition that FDA has identified for evaluation and that a proposed compounded product is intended to address. b. Whether the Drug Product Must Be Compounded From a Bulk Drug Substance Because the nominations do not identify specific differences between drug products that would be compounded using verapamil HCl and FDA-approved drug products containing verapamil HCl, there is nothing for FDA to evaluate under question 2. No further information was supplied on this point during the comment period. Therefore, FDA finds no basis to conclude that drug products proposed to be compounded must be prepared using a bulk drug substance rather than an FDAapproved drug product. IV. Other Issues Raised in Nominations and Comments Two commenters expressed concern that nominations submitted before FDA issued the Clinical Need Guidance in March 2019 are disadvantaged in demonstrating clinical need because the nominators might not have fully understood FDA’s thinking on clinical need when they submitted their nominations.59 In addition, one commenter expressed concern that FDA is evaluating bulk drug substances for clinical need pursuant to a non-binding guidance document. FDA disagrees with these comments. First, as explained in section II.B of this notice, FDA is evaluating bulk drug 59 See 84 FR 7383, which is available at https:// www.federalregister.gov/documents/2019/03/04/ 2019-03807/evaluation-of-bulk-drug-substancesnominated-for-use-in-compounding-under-section503b-of-the. PO 00000 Frm 00075 Fmt 4703 Sfmt 4703 substances nominated for inclusion on the 503B Bulks List under the ‘‘clinical need’’ standard provided by the FD&C Act, as amended by the Drug Quality and Security Act in 2013.60 The analysis under the statutory ‘‘clinical need’’ standard described in this notice is consistent with the approach described in FDA’s Clinical Need Guidance. Second, the commenters fail to note the many opportunities that nominators and interested members of the public had to provide information supporting a clinical need to compound drug products containing the bulk drug substances that are the subject of this notice. As explained in section II.A, a public docket, FDA–2015–N–3469, is available for interested persons to submit nominations, including updated or revised nominations, or comments on nominated substances. Furthermore, during the comment periods for the September 2019 and July 2020 Federal Register notices, commenters had an additional opportunity to submit comments to the docket associated with those notices to provide additional supporting information for the bulk drug substances that are the subject of this notice, and many did so. Moreover, in response to a request from a commenter, FDA reopened the comment period on the July 2020 Federal Register notice for an additional 30 days to allow interested persons yet another opportunity to submit additional comments. Three commenters on the bulk drug substances addressed in this notice asserted that FDA is regulating and interfering with the practice of medicine by not placing bulk drug substances on the 503B Bulks List despite some physicians wanting to prescribe drug products compounded from those bulk drug substances. FDA disagrees with these comments. The Agency’s evaluation under the clinical need standard only regulates the ability of certain compounded drug products to reach the market and is well within the Agency’s authorities.61 The Agency is fulfilling its statutory mandate of regulating outsourcing facilities’ 60 See Public Law 113–54, section 102(a) (2013), which is available at https://www.govinfo.gov/ content/pkg/PLAW-113publ54/pdf/PLAW113publ54.pdf. 61 See United States v. Evers, 643 F.2d 1043, 1048 (5th Cir. 1981) (‘‘[W]hile the [FDCA] was not intended to regulate the practice of medicine, it was obviously intended to control the availability of drugs for prescribing by physicians.’’); United States v. Regenerative Scis., LLC, 741 F.3d 1314, 1319–20 (D.C. Cir. 2014); (citing Evers and noting that the FDCA ‘‘regulate[s] the distribution of drugs by licensed physicians’’); Gonzales v. Raich, 545 U.S. 1, 28 (2005) (‘‘the dispensing of new drugs, even when doctors approve their use must await federal approval.’’). E:\FR\FM\06APN1.SGM 06APN1 ddrumheller on DSK120RN23PROD with NOTICES1 Federal Register / Vol. 88, No. 66 / Thursday, April 6, 2023 / Notices production and distribution of compounded drug products, not interfering with physicians’ clinical decisions regarding which drug products to prescribe. Indeed, a Federal court considered the very claim raised in these comments and determined that FDA’s evaluation under the clinical need standard ‘‘regulates the type of drug that reaches the marketplace,’’ a decision that ‘‘rests well within FDA’s regulatory authority under the FDCA . . . and . . . does not intrude on the practice of medicine.’’ 62 Several commenters expressed concern that FDA is promoting the offlabel use of FDA-approved drug products. FDA disagrees with this comment. In performing the clinical need evaluation, FDA asks a limited, threshold question to determine whether there might be a clinical need for a compounded drug product, by asking what attributes of the approved drug product the proposed compounded drug product would change and why. Asking this question helps ensure that if a bulk drug substance is included on the 503B Bulks List, it is to compound drug products that include a needed change to an approved drug product rather than to compound drug products without such a change. We do not suggest that the approved drug product or products prepared from it are approved for the use proposed by the nomination being evaluated. One commenter expressed concern with FDA’s decision to evaluate clinical need in the context of the specific drug products proposed to be compounded in the nomination. This commenter stated that requiring nominators to provide information on specific drug products is unnecessary to determine whether there is a clinical need for the bulk drug substance. This commenter also asserted that FDA should not evaluate bulk drug substances in the context of finished dosage forms for drug products. FDA disagrees with these comments. As explained in section I of this notice, section 503B of the FD&C Act limits the bulk drug substances that outsourcing facilities can use in compounding to those that are used to compound drugs in shortage or that appear on a list developed by FDA of bulk drug substances for which there is a clinical need.63 Section 503B of the FD&C Act includes this limitation, among others, to help ensure that outsourcing facilities do not grow into conventional manufacturing operations making 62 Athenex Inc. v. Azar, 397 F. Supp. 3d 56, 72 (D.D.C. 2019). 63 Section 503B(a)(2(A)(i) and (ii) of the FD&C Act. VerDate Sep<11>2014 21:13 Apr 05, 2023 Jkt 259001 unapproved new drug products without complying with critical requirements, such as new drug approval. Outsourcing facilities, as opposed to other compounders, may compound and distribute drug products for ‘‘office stock’’ without first receiving a prescription for an individually identified patient 64 and without conditions on interstate distribution that are applicable to other compounded drugs (Ref. 4).65 Because of these differences and others, section 503B of the FD&C Act places different conditions on drugs compounded by outsourcing facilities, including limitation on the outsourcing facilities’ use of bulk drug substances, which are more stringent than those placed on other compounders’ use of bulk drug substances.66 The clinical need standard 64 By contrast, to qualify for the exemptions in section 503A of the FD&C Act, drug products compounded by licensed pharmacists in Statelicensed pharmacies or Federal facilities, or by licensed physicians, must be compounded based on the receipt of a valid prescription for an individually identified patient. This means that for drug products compounded under section 503A to meet the conditions of that section and qualify for the exemptions in the statute, the pharmacist or physician compounding under section 503A of the FD&C Act must compound either: (1) after receiving a valid prescription for an identified, individual patient or (2) before receiving a patient-specific prescription, in limited quantities, based on a history of receiving valid orders generated solely within the context of an established relationship with the patient or prescriber. See FDA’s final guidance for industry ‘‘Prescription Requirement Under Section 503A of the Federal Food, Drug, and Cosmetic Act’’ (December 2016). 65 For drug products compounded under section 503A of the FD&C Act to meet the conditions of that section and qualify for the exemptions in the statute, drug products must be compounded in a State: (i) that has entered into a memorandum of understanding with the Secretary which addresses the distribution of inordinate amounts of compounded drug products interstate and provides for appropriate investigation by a State agency of complaints relating to compounded drug products distributed outside such State; or (ii) that has not entered into the memorandum of understanding described in clause (i) and the licensed pharmacist, licensed pharmacy, or licensed physician distributes (or causes to be distributed) compounded drug products out of the State in which they are compounded in quantities that do not exceed 5 percent of the total prescription orders dispensed or distributed by such pharmacy or physician (see section 503A(b)(3)(a)(B)(i) and (ii) of the FD&C Act). 66 Licensed pharmacies and physicians who compound drugs under the conditions of section 503A of the FD&C Act, including the requirement to compound drugs only pursuant to a prescription for an identified individual patient, may use many bulk drug substances by operation of the statute, without action by FDA. See section 503A(b)(1)(A)(i)(I) and (II) of the FD&C Act (providing that a drug product may be compounded consistent with the exemptions in section 503A of the FD&C Act if the licensed pharmacist or licensed physician compounds the drug product using bulk drug substances that comply with the standards of an applicable USP or NF monograph, if a monograph exists, and the USP chapters on pharmacy compounding; or if such a monograph PO 00000 Frm 00076 Fmt 4703 Sfmt 4703 20541 in section 503B of the FD&C Act requires FDA to perform a sorting function—to distinguish bulk drug substances for which there is a clinical need from those for which there is not— and this requires FDA to apply its expertise to consider whether there is a need for the finished drug product that would be compounded from the bulk drug substance. Indeed, a Federal court considered the very claim raised in these comments and determined that ‘‘[o]nly when ‘clinical need’ is assessed against the availability and suitability of an approved drug does the term perform the classifying function that Congress intended.’’ In reaching this view, the court found that only when the clinical need evaluation ‘‘considers the actual way in which the active pharmaceutical ingredient supplies a therapeutic benefit—by its administration as a finished drug product—does the inquiry produce the categorization that Congress surely envisioned’’ in enacting section 503B of the FD&C Act.67 FDA’s clinical need assessments help limit patient exposure to compounded drug products that have not been demonstrated to be safe and effective to those situations in which the compounded drug product is necessary for patient treatment. In addition, FDA’s assessments preserve the incentives for applicants to invest in the research and testing required to obtain FDA approval and continue to manufacture FDA-approved drug products, thereby helping to maintain a supply of high-quality, safe, and effective drugs. Some of the bulk drug substance nominations and comments discussed above asserted that there could be a benefit from using a bulk drug substance to compound drug products to avoid the manipulations that the FDA-approved drug products that contain these bulk drug substances require before they can be administered (e.g., dilution or drawing the drug into a syringe before administration). As explained above, when a bulk drug substance is a component of an FDA-approved drug, we ask whether there is a basis to conclude that an attribute of each FDAapproved drug product makes each one medically unsuitable to treat certain patients for their condition, an interpretation that protects patients and the integrity of the drug approval process. The nominations proposing to compound drug products in ready-touse form containing bulk drug substances in one or more FDAapproved drug products do not show does not exist, are drug substances that are components of drugs approved by the Secretary). 67 Athenex Inc. at 65. E:\FR\FM\06APN1.SGM 06APN1 ddrumheller on DSK120RN23PROD with NOTICES1 20542 Federal Register / Vol. 88, No. 66 / Thursday, April 6, 2023 / Notices that the FDA-approved drug product, when not manufactured in the ready-touse form, is medically unsuitable for certain patients. Nor do the nominations and comments establish that drug products in the relevant concentrations, including ready-to-use products, cannot be prepared from the FDA-approved drug products. Rather, they propose to compound a ready-to-use product from bulk drug substances to seek improved efficiency for prescribers or healthcare providers, or to address the possibility that the FDA-approved drug might be mishandled by a medical professional, neither of which falls within the meaning of clinical need to compound a drug product using a bulk drug substance. Two commenters requested changes to the Interim Policy. These comments are outside the scope of FDA’s bulk drug substance evaluations and decisions that are the subject of this notice. FDA welcomes public comments on its guidance documents that address human drug compounding. Comments on the Interim Policy may be submitted to the docket for the guidance, Docket No. FDA–2015–D–3539, at any time at https://www.regulations.gov. Act,’’ January 2017 (available at https:// www.fda.gov/media/94402/download). 2. FDA, Guidance for Industry, ‘‘Evaluation of Bulk Drug Substances Nominated for Use in Compounding Under Section 503B of the Federal Food, Drug, and Cosmetic Act,’’ March 2019 (available at https://www.fda.gov/media/121315/ download). 3. FDA Memorandum to File, ‘‘Clinical Need for Quinacrine Hydrochloride in Compounding Under Section 503B of the FD&C Act,’’ March 2021. 4. FDA Guidance for Industry, ‘‘Prescription Requirement Under Section 503A of the Federal Food, Drug, and Cosmetic Act,’’ December 2016 (available at https:// www.fda.gov/media/97347/download). V. Conclusion For the reasons stated above, we find that there is a clinical need for outsourcing facilities to compound drug products using the bulk drug substance quinacrine HCl for oral use only, and therefore we are now including it on the 503B Bulks List. In addition, we find that there is no clinical need for outsourcing facilities to compound using the bulk drug substances hydroxyzine HCl, mannitol, methacholine chloride, metoclopramide HCl, nalbuphine HCl, potassium acetate, procainamide HCl, sodium bicarbonate, sodium nitroprusside, and verapamil HCl, and therefore we are not including these bulk drug substances on the 503B Bulks List. Pursuant to section 10(d) of the Federal Advisory Committee Act, as amended, notice is hereby given of the following meeting. The meeting will be closed to the public in accordance with the provisions set forth in sections 552b(c)(4) and 552b(c)(6), Title 5 U.S.C., as amended. The grant applications and the discussions could disclose confidential trade secrets or commercial property such as patentable material, and personal information concerning individuals associated with the grant applications, the disclosure of which would constitute a clearly unwarranted invasion of personal privacy. VI. References The following references are on display at 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. FDA, Guidance for Industry, ‘‘Interim Policy on Compounding Using Bulk Drug Substances Under Section 503B of the Federal Food, Drug, and Cosmetic VerDate Sep<11>2014 21:13 Apr 05, 2023 Jkt 259001 Dated: April 3, 2023. Lauren K. Roth, Associate Commissioner for Policy. [FR Doc. 2023–07237 Filed 4–5–23; 8:45 am] BILLING CODE 4164–01–P DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Institute of Dental and Craniofacial Research; Notice of Closed Meeting Name of Committee: National Institute of Dental and Craniofacial Research Special Emphasis Panel; Practice-Based Research in Dental Schools. Date: May 11, 2023. Time: 9:00 a.m. to 7:00 p.m. Agenda: To review and evaluate grant applications. Place: National Institute of Dental and Craniofacial Research, 6701 Democracy Boulevard, Bethesda, MD 20892 (Virtual Meeting). Contact Person: Yun Mei, MD, Scientific Review Officer, Scientific Review Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, 6701 Democracy Boulevard, Bethesda, MD 20892, (301) 827–4639, yun.mei@nih.gov. (Catalogue of Federal Domestic Assistance Program No. 93.121, Oral Diseases and Disorders Research, National Institutes of Health, HHS) PO 00000 Frm 00077 Fmt 4703 Sfmt 4703 Dated: April 3, 2023. Melanie J. Pantoja, Program Analyst, Office of Federal Advisory Committee Policy. [FR Doc. 2023–07217 Filed 4–5–23; 8:45 am] BILLING CODE 4140–01–P DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Cancer Institute; Notice of Closed Meetings Pursuant to section 10(d) of the Federal Advisory Committee Act, as amended, notice is hereby given of the following meetings. The meetings will be closed to the public in accordance with the provisions set forth in sections 552b(c)(4) and 552b(c)(6), Title 5 U.S.C., as amended. The grant applications and contract proposals and the discussions could disclose confidential trade secrets or commercial property such as patentable material, and personal information concerning individuals associated with the grant applications and contract proposals, the disclosure of which would constitute a clearly unwarranted invasion of personal privacy. Name of Committee: National Cancer Institute Special Emphasis Panel; FFRDC Review Meeting. Date: May 4–5, 2023. Time: 9:00 a.m. to 6:00 p.m. Agenda: To review and evaluate contract proposals. Place: National Cancer Institute Shady Grove, 9609 Medical Center Drive, Room 7W530, Rockville, Maryland 20850 (Telephone Conference Call). Contact Person: Shamala K. Srinivas, Ph.D., Associate Director, Office of Referral, Review, and Program Coordination, Division of Extramural Activities, National Cancer Institute, NIH, 9609 Medical Center Drive, Room 7W530, Rockville, Maryland 20850, 240–276–6442, ss537t@nih.gov. Name of Committee: National Cancer Institute Special Emphasis Panel; NCI SPORE (P50) Review SEP–I. Date: May 18, 2023. Time: 9:00 a.m. to 6:30 p.m. Agenda: To review and evaluate grant applications. Place: National Cancer Institute Shady Grove, 9609 Medical Center Drive, Room 7W244, Rockville, Maryland 20850 (Telephone Conference Call). Contact Person: John Paul Cairns, Ph.D., Scientific Review Officer, Research Programs Review Branch, Division of Extramural Activities, National Cancer Institute, NIH, 9609 Medical Center Drive, Room 7W244, Rockville, Maryland 20850, 240–276–5415, paul.cairns@nih.gov. E:\FR\FM\06APN1.SGM 06APN1

Agencies

[Federal Register Volume 88, Number 66 (Thursday, April 6, 2023)]
[Notices]
[Pages 20531-20542]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2023-07237]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2018-N-3240]

List of Bulk Drug Substances for Which There Is a Clinical Need
Under Section 503B of the Federal Food, Drug, and Cosmetic Act

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA, the Agency, or we) is
evaluating substances that have been nominated for inclusion on a list
of bulk drug substances (active pharmaceutical ingredients (APIs)) for
which there is a clinical need (the 503B Bulks List). Drug products
that outsourcing facilities compound using bulk drug substances on the
503B Bulks List can qualify for certain exemptions from the Federal
Food, Drug, and Cosmetic Act (FD&C Act) provided certain conditions are
met. This notice identifies one bulk drug substance that FDA has
considered and is including on the list at this time: quinacrine
hydrochloride (HCl) to compound drug products for oral use only. This
notice also identifies 10 bulk drug substances that FDA has considered
and is not including on the list at this time: hydroxyzine HCl,
mannitol, methacholine chloride, metoclopramide HCl, nalbuphine HCl,
potassium acetate, procainamide HCl, sodium bicarbonate, sodium
nitroprusside, and verapamil HCl. Additional bulk drug substances
nominated by the public for inclusion on this list are currently under
consideration and will be the subject of future notices.

DATES: The announcement of the notice is published in the Federal
Register on April 6, 2023.

ADDRESSES: 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,

[[Page 20532]]

and/or go to the Dockets Management Staff, 5630 Fishers Lane, Rm. 1061,
Rockville, MD 20852, 240-402-7500.

FOR FURTHER INFORMATION CONTACT: Tracy Rupp, Center for Drug Evaluation
and Research, Food and Drug Administration, 10903 New Hampshire Ave.,
Bldg. 51, Silver Spring, MD 20993, 301-796-3100.

SUPPLEMENTARY INFORMATION:

I. Background

Section 503B of the FD&C Act (21 U.S.C. 353b) describes the
conditions that must be satisfied for drug products compounded in an
outsourcing facility to be exempt from section 505 (21 U.S.C. 355)
(concerning the approval of drugs under new drug applications (NDAs) or
abbreviated new drug applications (ANDAs)), section 502(f)(1) (21
U.S.C. 352(f)(1)) (concerning the labeling of drugs with adequate
directions for use), and section 582 of the FD&C Act (21 U.S.C. 360eee-
1) (concerning drug supply chain security requirements).\1\
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\1\ Section 503B(a) of the FD&C Act.
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Compounded drug products that meet the conditions in section 503B
are not exempt from current good manufacturing practice (CGMP)
requirements in section 501(a)(2)(B) of the FD&C Act (21 U.S.C.
351(a)(2)(B)).\2\ Outsourcing facilities are also subject to FDA
inspections according to a risk-based schedule, adverse event reporting
requirements, and other conditions that help to mitigate the risks of
the drug products they compound.\3\ Outsourcing facilities may or may
not obtain prescriptions for identified individual patients and can,
therefore, distribute compounded drugs to healthcare practitioners for
``office stock,'' to hold in their offices in advance of patient
need.\4\
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\2\ Compare section 503A(a) of the FD&C Act (21 U.S.C. 353a(a)
(exempting drugs compounded in accordance with that section)) with
section 503B(a) of the FD&C Act (not providing the exemption from
CGMP requirements).
\3\ Section 503B(b)(4) and (5) of the FD&C Act.
\4\ Section 503B(d)(4)(C) of the FD&C Act.
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One of the conditions that must be met for a drug product
compounded by an outsourcing facility to qualify for the exemptions
under section 503B of the FD&C Act is that the outsourcing facility may
not compound a drug using a bulk drug substance unless: (1) the bulk
drug substance appears on a list established by the Secretary of Health
and Human Services (the Secretary) identifying bulk drug substances for
which there is a clinical need (the 503B Bulks List) or (2) the drug
compounded from the bulk drug substance appears on the drug shortage
list in effect under section 506E of the FD&C Act (21 U.S.C. 356e) at
the time of compounding, distribution, and dispensing.\5\
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\5\ Section 503B(a)(2)(A) of the FD&C Act.
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Section 503B of the FD&C Act directs FDA to establish the 503B
Bulks List by: (1) publishing a notice in the Federal Register
proposing bulk drug substances to be included on the list, including
the rationale for such proposal; (2) providing a period of not less
than 60 calendar days for comment on the notice; and (3) publishing a
notice in the Federal Register designating bulk drug substances for
inclusion on the list.\6\
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\6\ Section 503B(a)(2)(A)(i)(I) to (III) of the FD&C Act.
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FDA has published a series of Federal Register notices addressing
bulk drug substances nominated for inclusion on the 503B Bulks List.\7\
This notice identifies one bulk drug substance that FDA has considered
and is including on the 503B Bulks List and 10 bulk drug substances
that FDA has considered and is not including on the 503B Bulks List.
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\7\ See Federal Register of August 28, 2018 (83 FR 43877), March
4, 2019 (84 FR 7383), September 3, 2019 (84 FR 46014), July 31, 2020
(85 FR 46126), March 24, 2021 (86 FR 15673), and November 23, 2022
(87 FR 71642). The comment period for the July 2020 notice was
reopened for 30 days on January 8, 2021 (86 FR 1515), to allow
interested parties an additional opportunity to comment. FDA has not
yet reached a final determination on whether the substances
evaluated in the September 2019, July 2020, or March 2021 notices
will be added to the 503B Bulks List. In addition, bumetanide, which
was considered in the August 2018 notice, remains under
consideration by the Agency.
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For purposes of section 503B of the FD&C Act, bulk drug substance
means an active pharmaceutical ingredient as defined in 21 CFR
207.1.\8\ Active pharmaceutical ingredient means any substance that is
intended for incorporation into a finished drug product and is intended
to furnish pharmacological activity or other direct effect in the
diagnosis, cure, mitigation, treatment, or prevention of disease, or to
affect the structure or any function of the body, but the term does not
include intermediates used in the synthesis of the
substance.^{9 10}
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\8\ See section 503B(a)(2) of the FD&C Act, which defines bulk
drug substances used in compounding under section 503B according to
21 CFR 207.3(a)(4) ``or any successor regulation.'' Section 207.1 is
the successor regulation.
\9\ Section 503B(a)(2) of the FD&C Act and 21 CFR 207.1.
\10\ Inactive ingredients are not subject to section 503B(a)(2)
of the FD&C Act and will not be included in the 503B Bulks List
because they are not included within the definition of a bulk drug
substance. Pursuant to section 503B(a)(3), inactive ingredients used
in compounding must comply with the standards of an applicable
United States Pharmacopeia (USP) or National Formulary (NF)
monograph, if a monograph exists.
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II. Methodology for Developing the 503B Bulks List

A. Process for Developing the List

FDA requested nominations for specific bulk drug substances for the
Agency to consider for inclusion on the 503B Bulks List in the Federal
Register of December 4, 2013 (78 FR 72838). FDA reopened the nomination
process in the Federal Register of July 2, 2014 (79 FR 37747), and
provided more detailed information on what FDA needs to evaluate
nominations for the list. On October 27, 2015 (80 FR 65770), the Agency
opened a new docket, FDA-2015-N-3469, to provide an opportunity for
interested persons to submit new nominations of bulk drug substances,
renominate substances with sufficient information, or submit comments
on nominated substances.
As FDA evaluates bulk drug substances, it intends to publish
notices for public comment in the Federal Register that describe its
proposed position on each substance along with the rationale for that
position.\11\ After considering any comments on FDA's proposals
regarding whether to include nominated substances on the 503B Bulks
List, FDA intends to consider whether input from the Pharmacy
Compounding Advisory Committee (PCAC) on the nominations would be
helpful to the Agency in making its determination, and if so, it will
seek PCAC input.\12\ Depending on its review of the docket comments and
other relevant information before the Agency, FDA may finalize its
proposed determination without change, or it may finalize a
modification to its proposal to reflect new evidence or analysis
regarding clinical need. FDA will then publish in the Federal Register
a final determination identifying the bulk drug substances for which it
has determined there is a clinical need and FDA's rationale in making
that final determination. FDA will also publish in the Federal Register
a final determination regarding those substances it considered but
found that there is no clinical need to use in compounding and FDA's
rationale in making this decision.
---------------------------------------------------------------------------

\11\ This is consistent with procedures set forth in section
503B(a)(2)(A)(i) of the FD&C Act. Although the statute only directs
FDA to issue a Federal Register notice and seek public comment when
it proposes to include bulk drug substances on the 503B Bulks List,
we intend to seek comment when the Agency has evaluated a nominated
substance and proposes either to include or not to include the
substance on the list.
\12\ Section 503B of the FD&C Act does not require FDA to
consult the PCAC before developing the 503B Bulks List.

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[[Page 20533]]

FDA intends to maintain a list of all bulk drug substances it has
evaluated on its website, and separately identify bulk drug substances
it has placed on the 503B Bulks List and those it has decided not to
place on the 503B Bulks List. This list is available at https://www.fda.gov/media/120692/download. FDA will only place a bulk drug
substance on the 503B Bulks List when it has determined there is a
clinical need for outsourcing facilities to compound drug products
using the bulk drug substance. If a clinical need to compound drug
products using the bulk drug substance has not been demonstrated, based
on the information submitted by the nominator and any other information
considered by the Agency, FDA will not place a bulk drug substance on
the 503B Bulks List.
FDA is evaluating bulk drug substances nominated for the 503B Bulks
List on a rolling basis. FDA intends to evaluate and publish in the
Federal Register its proposed and final determinations in groups of
bulk drug substances until all nominated substances that were
sufficiently supported have been evaluated and either placed on the
503B Bulks List or identified as bulk drug substances that were
considered but determined not to be appropriate for inclusion on the
503B Bulks List (Ref. 1).\13\
---------------------------------------------------------------------------

\13\ In January 2017, FDA announced the availability of a
revised final guidance for industry that provides additional
information regarding FDA's policies for bulk drug substances
nominated for the 503B Bulks List pending our review of nominated
substances under the ``clinical need'' standard entitled ``Interim
Policy on Compounding Using Bulk Drug Substances Under Section 503B
of the Federal Food, Drug, and Cosmetic Act'' (the ``Interim
Policy''), available at https://www.fda.gov/media/94402/download.
---------------------------------------------------------------------------

B. Analysis of Substances Nominated for the List

As noted above, the 503B Bulks List will include bulk drug
substances for which there is a clinical need. The Agency is evaluating
bulk drug substances that were nominated for inclusion on the 503B
Bulks List, proceeding case by case, under the standard provided by the
statute (Ref. 2).\14\ In applying this standard to make its
determinations regarding the substances set forth in this notice, FDA
interprets the phrase ``bulk drug substances for which there is a
clinical need'' to mean that the 503B Bulks List may include a bulk
drug substance if: (1) there is a clinical need for an outsourcing
facility to compound the drug product and (2) the drug product must be
compounded using the bulk drug substance. FDA does not interpret supply
issues, such as backorders, to be within the meaning of ``clinical
need'' for compounding with a bulk drug substance. Section 503B of the
FD&C Act separately provides for compounding from a bulk drug substance
under the exemptions from the FD&C Act discussed above if the drug
product compounded from the bulk drug substance is on the FDA drug
shortage list at the time of compounding, distribution, and dispensing.
Additionally, FDA does not consider convenience in administering a
particular compounded drug product (e.g., a ready-to-use form) or the
cost of the compounded drug product as compared with an FDA-approved
drug product when assessing ``clinical need.''
---------------------------------------------------------------------------

\14\ In March 2019, FDA announced the availability of a final
guidance entitled ``Evaluation of Bulk Drug Substances Nominated for
Use in Compounding Under Section 503B of the Federal Food, Drug, and
Cosmetic Act'' (the ``Clinical Need Guidance''), available at
https://www.fda.gov/media/121315/download. This guidance describes
FDA policies for developing the 503B Bulks List and the Agency's
interpretation of the phrase ``bulk drug substances for which there
is a clinical need'' as it is used in section 503B. The analysis
under the statutory ``clinical need'' standard described in this
notice is consistent with the approach described in FDA's guidance.
---------------------------------------------------------------------------

All of the bulk drug substances addressed in this notice, with the
exception of quinacrine HCl, are components of FDA-approved drug
products.\15\ FDA began its evaluation of the bulk drug substances that
are components of FDA-approved drug products by asking one or both, as
applicable, of the following questions:
---------------------------------------------------------------------------

\15\ Specifically, hydroxyzine HCl, mannitol, methacholine
chloride, metoclopramide HCl, nalbuphine HCl, potassium acetate,
procainamide HCl, sodium bicarbonate, sodium nitroprusside, and
verapamil HCl.
---------------------------------------------------------------------------

1. Is there a basis to conclude, for each FDA-approved product that
includes the nominated bulk drug substance, that (a) an attribute of
the FDA-approved drug product makes it medically unsuitable to treat
certain patients for a condition that FDA has identified for
evaluation, and (b) the drug product proposed to be compounded is
intended to address that attribute?
2. Is there a basis to conclude that the drug product proposed to
be compounded must be produced from a bulk drug substance rather than
from an FDA-approved drug product?
The reason for question 1 is that unless an attribute of the FDA-
approved drug is medically unsuitable for certain patients, and a drug
product to be compounded using a bulk drug substance that is a
component of the FDA-approved drug is intended to address that
attribute, there is no clinical need to compound a drug product using
that bulk drug substance. Rather, such compounding would unnecessarily
expose patients to the risks associated with drug products that do not
meet the standards applicable to FDA-approved drug products for safety,
effectiveness, quality, and labeling and would undermine the drug
approval process. The reason for question 2 is that to place a bulk
drug substance on the 503B Bulks List, FDA must determine that there is
a clinical need for outsourcing facilities to compound a drug product
using the bulk drug substance rather than starting with an FDA-approved
drug product. When it is feasible to compound a drug product by
starting with an FDA-approved drug product, there are certain benefits
of doing so over starting with a bulk drug substance, including that
FDA-approved drugs have undergone premarket review for safety,
effectiveness, and quality, and are manufactured by a facility that is
subject to premarket assessment, including site inspection, as well as
routine post-approval risk-based inspections. In contrast, FDA does not
conduct a premarket review of the quality standards, specifications,
and controls for bulk drug substances used in compounding and does not
conduct a premarket assessment of the manufacturer of the bulk drug
substance.
If the answer to both of the above questions is ``yes,'' there may
be a clinical need for outsourcing facilities to compound using the
bulk drug substance, and we would evaluate the substance further,
applying the factors described below. If the answer to either of these
questions is ``no,'' we generally would not include the bulk drug
substance on the 503B Bulks List, because there would not be a basis to
conclude that there may be a clinical need to compound drug products
using the bulk drug substance instead of administering an FDA-approved
drug or compounding starting with an FDA-approved drug product. FDA did
not answer ``yes'' to both of the threshold questions for the 10 bulk
drug substances that are components of FDA-approved drug products that
we are addressing in this notice. Accordingly, as explained below, we
did not proceed further in our evaluation of these substances and have
decided not to include them on the 503B Bulks List.
With respect to the bulk drug substance addressed in this notice
that is not a component of an FDA-approved drug, quinacrine HCl, we
conducted a balancing test using four factors. Specifically, we
considered available data relevant to each factor in the context of the
other factors and balanced all four factors to determine whether the

[[Page 20534]]

statutory ``clinical need'' standard has been met. The balancing test
includes the following factors:
The physical and chemical characterization of the
substance;
any safety issues raised by the use of the substance in
compounding;
the available evidence of effectiveness or lack of
effectiveness of a drug product compounded with the substance, if any
such evidence exists; and
current and historical use of the substance in compounded
drug products, including information about the medical condition(s)
that the substance has been used to treat and any references in peer-
reviewed medical literature.
The discussion below reflects FDA's consideration of these four
factors and describes how they were applied to develop FDA's decision
to include quinacrine HCl for oral use on the 503B Bulks List.

C. Inclusion of a Bulk Drug Substance on the 503B Bulks List

In evaluating a bulk drug substance for the 503B Bulks List, FDA
has considered whether the clinical need for the bulk drug substance in
the proposed compounded drug product is limited, by, for example, route
of administration or dosage form. In the Federal Register notice of
July 31, 2020 (85 FR 46126), FDA requested comments on the proposal to
limit listings in this manner. On January 8, 2021 (86 FR 1515), the
comment period for the July 2020 notice was reopened for 30 days to
allow interested parties an additional opportunity to comment before
FDA began to develop its final determinations. After considering the
comments submitted regarding the proposal, in the Federal Register
notice of January 27, 2022 (87 FR 4240), FDA listed three bulk drug
substances to compound drug products for topical use only, consistent
with its findings related to clinical need for those bulk drug
substances.
FDA has also determined that to be eligible for the statutory
exemptions under section 503B, drug products compounded using a bulk
drug substance that appears on the 503B Bulks List cannot contain other
APIs unless those APIs have been listed in combination on the 503B
Bulks List (87 FR 4240). FDA's assessment of the clinical need for
compounding with a particular bulk drug substance or combination of
bulk drug substances could be affected if a bulk drug substance is
commonly used in compounded drug products that contain multiple bulk
drug substances (APIs). The use of certain APIs in combination with
other APIs in a compounded drug product could also pose a safety risk
or affect the compounded drug product's effectiveness. These
considerations of the composition of a nominated compounded
combination, the history of its use in compounding, and evidence of
safety or effectiveness would be included in FDA's clinical need
evaluation.
In accordance with these considerations and the clinical need
analysis set forth below, FDA is adding one bulk drug substance--
quinacrine HCl--to the 503B Bulks List to compound single-ingredient
drug products for oral use only.\16\
---------------------------------------------------------------------------

\16\ In this notice, ``single-ingredient'' refers to a drug
product containing one active ingredient. The drug product may also
contain excipients.
---------------------------------------------------------------------------

III. FDA's Determinations Regarding Substances Proposed for the 503B
Bulks List

In September 2019, the Agency issued a Federal Register notice in
which it evaluated nine nominated bulk drug substances under the
section 503B statutory standard--dipyridamole, ephedrine sulfate,
famotidine, hydralazine HCl, methacholine chloride, sodium bicarbonate,
sodium tetradecyl sulfate, trypan blue, and vecuronium bromide--and
proposed not to include them on the 503B Bulks List (the September 2019
notice).\17\ In this notice, after review of the comments submitted to
the docket for the September 2019 notice, FDA is making its final
determination not to include methacholine chloride and sodium
bicarbonate on the 503B Bulks List. At this time, FDA is not making a
final determination regarding ephedrine sulfate, famotidine,
hydralazine HCl, sodium tetradecyl sulfate, trypan blue, and vecuronium
bromide.\18\ These substances remain under consideration by FDA.
---------------------------------------------------------------------------

\17\ See 84 FR 46014.
\18\ FDA made a final determination not to include dipyridamole
on the 503B Bulks List (see 87 FR 4240).
---------------------------------------------------------------------------

In July 2020, the Agency issued a Federal Register notice in which
it evaluated 23 nominated bulk drug substances under the section 503B
statutory standard (the July 2020 notice).\19\ FDA proposed to include
diphenylcyclopropenone (DPCP), glycolic acid, squaric acid dibutyl
ester (SADBE), and trichloroacetic acid (TCA) on the 503B Bulks List.
FDA proposed not to include diazepam, dobutamine HCl, dopamine HCl,
edetate calcium disodium, folic acid, glycopyrrolate, hydroxyzine HCl,
ketorolac tromethamine, labetalol HCl, mannitol, metoclopramide HCl,
moxifloxacin HCl, nalbuphine HCl, polidocanol, potassium acetate,
procainamide HCl, sodium nitroprusside, sodium thiosulfate, and
verapamil HCl on the 503B Bulks List. In this notice, after review of
the comments submitted to the docket for the July 2020 notice, FDA is
making its final determination not to include hydroxyzine HCl,
mannitol, metoclopramide HCl, nalbuphine HCl, potassium acetate,
procainamide HCl, sodium nitroprusside, and verapamil HCl on the 503B
Bulks List. FDA has previously made final determinations for DPCP,
glycolic acid, SADBE, TCA, diazepam, dobutamine HCl, dopamine HCl,
edetate calcium disodium, folic acid, glycopyrrolate, and sodium
thiosulfate (except the topical route of administration) (87 FR 4240).
At this time, FDA is not making a final determination regarding
ketorolac tromethamine, labetalol HCl, moxifloxacin HCl, and
polidocanol. These substances remain under consideration by FDA.
---------------------------------------------------------------------------

\19\ 85 FR 46126.
---------------------------------------------------------------------------

In March 2021, the Agency issued a Federal Register notice in which
it evaluated five bulk drug substances under the section 503B statutory
standard (the March 2021 notice).\20\ FDA proposed to include
quinacrine HCl on the 503B Bulks List to compound drug products for
oral use only. FDA proposed not to include bromfenac sodium, mitomycin-
C, nepafenac, and hydroxychloroquine sulfate on the 503B Bulks List. In
this notice, after review of the comments submitted to the docket for
the March 2021 notice, FDA is making its final determination to include
quinacrine HCl on the 503B Bulks List to compound drug products for
oral use only. At this time, FDA is not making a final determination
regarding bromfenac sodium, mitomycin-C, nepafenac, and
hydroxychloroquine sulfate. These substances remain under consideration
by FDA. Additional bulk drug substances nominated by the public for
inclusion on the 503B Bulks List are currently under consideration and
may be the subject of future notices.
---------------------------------------------------------------------------

\20\ 86 FR 15673.
---------------------------------------------------------------------------

A. Substance Evaluated and Included on the 503B Bulks List

FDA is placing quinacrine HCl on the 503B Bulks List. FDA evaluated
quinacrine HCl and proposed to include it on the 503B Bulks List in the
March 2021 notice. The reasons for FDA's proposal to place quinacrine
HCl for oral use on the 503B Bulks List are

[[Page 20535]]

included below (Ref. 3).\21\ For the reasons set forth in the proposal,
FDA is now placing quinacrine HCl on the 503B Bulks List for oral use
only.
---------------------------------------------------------------------------

\21\ In addition to FDA's evaluation of the quinacrine HCl
nomination for the 503B Bulks List, the Agency considered data and
information from its earlier evaluation regarding the use of this
bulk drug substance for the list of bulk drug substances that can be
used in compounding under section 503A of the FD&C Act (the 503A
Evaluation) (see appendices A-D in ``FDA Memo to File, Clinical Need
for Quinacrine Hydrochloride in Compounding Under Section 503B of
the FD&C Act'' (Ref. 3)). FDA also considered a report provided by
the University of Maryland Center of Excellence in Regulatory
Science and Innovation and conducted a search for relevant
scientific literature and safety information, focusing on materials
published or submitted to FDA since the 503A Evaluations (see
appendix H in Ref. 3).
---------------------------------------------------------------------------

Quinacrine HCl
FDA considered the bulk drug substance quinacrine HCl for inclusion
on the 503B Bulks List to compound drug products in oral dosage forms
at strengths of 25-100 milligrams (mg) for the treatment of cutaneous
lupus erythematosus (CLE), as described in the Agency's nomination and
evaluation.\22\
---------------------------------------------------------------------------

\22\ See appendix G in Ref. 3.
---------------------------------------------------------------------------

Quinacrine HCl is not a component of an FDA-approved drug product.
The Agency therefore evaluated quinacrine HCl for potential inclusion
on the 503B Bulks List under the clinical need standard in section 503B
of the FD&C Act using the balancing test described above. FDA
considered data and information regarding the physical and chemical
characterization of quinacrine HCl, safety issues raised by use of this
substance in compounding, available evidence of effectiveness or lack
of effectiveness, and historical and current use in compounding (Ref.
3).
Quinacrine HCl is well-characterized physically and chemically.
Although there are concerns about its safety profile in certain patient
populations, FDA believes these risks are well known within the
rheumatology and dermatology specialties that most often treat CLE, and
the known risks could be controlled with appropriate dosing and
monitoring. Quinacrine HCl has been used for several decades to treat
systemic lupus erythematosus and CLE, and there is a significant body
of experience, documented in the scientific literature, that quinacrine
HCl may be effective in the treatment of patients with cutaneous lupus,
and patients who are not fully clinically responsive to, or are
intolerant of, treatment with FDA-approved products alone. These
patients may respond to the addition of quinacrine HCl to their
existing therapy, or to the use of quinacrine HCl alone. On balance,
the physical and chemical characterization, safety, effectiveness, and
historical and current use of quinacrine HCl weigh in favor of
including this substance on the 503B Bulks List. Two commenters
supported FDA's proposal to include quinacrine HCl on the 503B Bulks
List, although one of them disagreed with FDA's proposal to limit the
entry to oral use only. No commenters opposed adding quinacrine HCl to
the 503B Bulks List. Several commenters objected generally to FDA's
proposals, and these overarching concerns are addressed in section IV
of this notice. Accordingly, FDA is adding quinacrine HCl to the 503B
Bulks List for oral use only. The entry on the 503B Bulks List is
limited in this way because, as discussed above, FDA's evaluation only
revealed a clinical need for outsourcing facilities to compound drug
products containing the bulk drug substance quinacrine HCl for the oral
route of administration.
Due to the safety risks referred to above, FDA is making safety
information about the use of quinacrine HCl available to prescribers,
pharmacists, outsourcing facilities, and the public through a safety
guide on FDA's website, available at https://www.fda.gov/drugs/human-drug-compounding/consumer-and-health-care-professional-information.

B. Substances Evaluated and Not Included on the 503B Bulks List

The 10 bulk drug substances that FDA has evaluated, proposed not to
include on the 503B Bulks List in a Federal Register notice, and has
now decided not to place on the 503B Bulks List are: hydroxyzine HCl,
mannitol, methacholine chloride, metoclopramide HCl, nalbuphine HCl,
potassium acetate, procainamide HCl, sodium bicarbonate, sodium
nitroprusside, and verapamil HCl.
Because the substances discussed in this section are components of
FDA-approved drug products, FDA considered one or both of the following
questions: (1) is there a basis to conclude that an attribute of each
FDA-approved drug product containing the bulk drug substance makes each
one medically unsuitable to treat certain patients for a condition that
FDA has identified for evaluation, and the drug product(s) proposed to
be compounded is intended to address that attribute in each FDA-
approved drug product, and (2) is there a basis to conclude that the
drug product(s) proposed to be compounded must be compounded using a
bulk drug substance. FDA considered comments to the docket submitted
within the public comment period, but as explained below, none of the
comments received on these bulk drug substances provided information
that led FDA to change its determination.
1. Hydroxyzine HCl
Hydroxyzine HCl has been nominated for inclusion on the 503B Bulks
List to compound drug products that treat alcohol withdrawal syndrome,
analgesia in labor, pre- and postpartum reduction of narcotic use, and
relief of anxiety, among other conditions.\23\ The proposed route of
administration is intramuscular, the proposed dosage form is a
solution, and the proposed concentration is 50 milligrams/milliliters
(mg/mL). The nominators proposed to compound a preserved solution.
However, they failed to acknowledge that there is a preserved
formulation of hydroxyzine HCl that is FDA-approved or identify an
attribute of that formulation that makes it medically unsuitable for
certain patients. The nominations state that hydroxyzine HCl might also
be used to compound other drug products but do not identify those
products. The nominated bulk drug substance is a component of FDA-
approved drug products (e.g., ANDA 087408). FDA-approved hydroxyzine
HCl is marketed as a preserved 50 mg/mL solution for intramuscular
administration.^{24 25 26}
---------------------------------------------------------------------------

\23\ See Docket No. FDA-2013-N-1524, document nos. FDA-2013-N-
1524-2292 and FDA-2013-N-1524-2298.
\24\ See, e.g., ANDA 087408 labeling available as of the date of
this notice at https://www.accessdata.fda.gov/spl/data/e711ee73-c054-4f3f-a189-bb3c01c7aecc/e711ee73-c054-4f3f-a189-bb3c01c7aecc.xml.
\25\ Per the label for ANDA 087408, each mL contains hydroxyzine
HCl 25 mg or 50 mg, benzyl alcohol 0.9 percent, and water for
injection q.s. pH is adjusted with sodium hydroxide and/or
hydrochloric acid.
\26\ Hydroxyzine HCl is also FDA-approved as an oral tablet and
as an oral syrup.
---------------------------------------------------------------------------

a. Suitability of FDA-Approved Drug Product(s)
The nominations do not identify an attribute of the FDA-approved
preserved 50 mg/mL hydroxyzine HCl solution for intramuscular
administration that makes it medically unsuitable for certain patients
or identify an attribute of the FDA-approved drug products that the
proposed compounded drug product is intended to address. Two commenters
supported FDA's proposal not to include hydroxyzine HCl on the 503B
Bulks List. No new information supporting the clinical need for
compounding from the bulk drug substance hydroxyzine HCl was provided
by the commenters.
Accordingly, FDA finds no basis to conclude that there is an
attribute of the

[[Page 20536]]

FDA-approved products that makes them medically unsuitable to treat
certain patients for a condition that FDA has identified for evaluation
and that a proposed compounded product is intended to address.
b. Whether the Drug Product Must Be Compounded From a Bulk Drug
Substance
Because the nominations do not identify specific differences
between drug products that would be compounded using hydroxyzine HCl
and the FDA-approved drug product containing hydroxyzine HCl, there is
nothing for FDA to evaluate under question 2. No further information
was supplied on this point during the comment period. Therefore, FDA
finds no basis to conclude that the drug product proposed to be
compounded must be prepared using a bulk drug substance rather than an
FDA-approved drug product.
2. Mannitol
Mannitol has been nominated for inclusion on the 503B Bulks List to
compound drug products for treatment of acute renal failure, inhalation
bronchial challenge testing, and irrigation of the urinary bladder,
among other conditions.\27\ The proposed route of administration is
intravenous, the proposed dosage form is a solution, and the proposed
concentration is 25 percent. The nominators proposed to compound a
preservative-free solution. However, they failed to acknowledge that
there is a preservative-free formulation of mannitol that is FDA-
approved or identify an attribute of that formulation that makes it
medically unsuitable for certain patients. The nominations state that
mannitol might also be used to compound other drug products but do not
identify those products. The nominated bulk drug substance is a
component of FDA-approved drug products (e.g., NDA 016269). FDA-
approved mannitol is marketed as a preservative-free solution in water
for injection in various concentrations, including a 25 percent
concentration in a flip-top vial for administration by intravenous
infusion only.^{28 29 30}
---------------------------------------------------------------------------

\27\ See Docket No. FDA-2013-N-1524, document nos. FDA-2013-N-
1524-2292 and FDA-2013-N-1524-2298.
\28\ See, e.g., NDA 016269 labeling available as of the date of
this notice at https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/016269s056lbl.pdf.
\29\ Per the label for NDA 016269, the solutions contain no
bacteriostat, antimicrobial agent, or added buffer (except for pH
adjustment) and each is intended only as a single-dose injection.
\30\ Mannitol is also FDA-approved as a single ingredient as a
solution for irrigation and as a powder for inhalation.
---------------------------------------------------------------------------

a. Suitability of FDA-Approved Drug Product(s)
The nominations do not identify an attribute of each of the FDA-
approved 25 percent preservative-free solution products that makes them
medically unsuitable for certain patients or identify an attribute of
the FDA-approved drug products that the proposed compounded drug
product is intended to address. Two commenters supported FDA's proposal
not to include mannitol on the 503B Bulks List. The commenters provided
no new information supporting the clinical need for compounding from
the bulk drug substance mannitol.
Accordingly, FDA finds no basis to conclude that there is an
attribute of the FDA-approved products that makes them medically
unsuitable to treat certain patients for a condition that FDA has
identified for evaluation and that a proposed compounded product is
intended to address.
b. Whether the Drug Product Must Be Compounded From a Bulk Drug
Substance
Because the nominations do not identify specific differences
between drug products that would be compounded using mannitol and FDA-
approved drug products containing mannitol, there is nothing for FDA to
evaluate under question 2. No further information was supplied on this
point during the comment period. Therefore, FDA finds no basis to
conclude that drug products must be compounded using a bulk drug
substance rather than an FDA-approved drug product.
3. Methacholine Chloride
Methacholine chloride has been nominated for inclusion on the 503B
Bulks List to compound drug products that aid in the diagnosis of
bronchial airway hyperactivity.\31\ The proposed route of
administration is inhalation tapering dose kits, the proposed dosage
form is an inhalant, and the proposed strengths are as follows: 8
dilutions (0.125 mg/mL, 0.25 mg/mL, 0.5 mg/mL, 1 mg/mL, 2 mg/mL, 4 mg/
mL, 8 mg/mL, 16 mg/mL) and 10 dilutions (0.031 mg/mL, 0.0625 mg/mL,
0.125 mg/mL, 0.25 mg/mL, 0.5 mg/mL, 1 mg/mL, 2 mg/mL, 4 mg/mL, 8 mg/mL,
16 mg/mL). The nominated bulk drug substance is a component of an FDA-
approved drug product (NDA 019193). FDA-approved methacholine chloride
is marketed as a 100 mg/vial powder for solution to be administered
only by inhalation.\32\ Per its labeling, methacholine chloride is
reconstituted and diluted to the following concentrations with 0.9
percent sodium chloride injection or 0.9 percent sodium chloride
injection containing 0.4 percent phenol (pH 7.0): 0.025 mg/mL, 0.25 mg/
mL, 2.5 mg/mL, 10 mg/mL, and 25 mg/mL.
---------------------------------------------------------------------------

\31\ See Docket No. FDA-2013-N-1524, document no. FDA-2013-N-
1524-2292.
\32\ See, e.g., NDA 208943 labeling available as of the date of
this notice at https://www.accessdata.fda.gov/spl/data/7f538d73-80e2-4c00-911a-df2637e5a4d1/7f538d73-80e2-4c00-911a-df2637e5a4d1.xml.
---------------------------------------------------------------------------

a. Suitability of FDA-Approved Drug Product
The nomination does not identify an attribute of the FDA-approved
drug product that makes it medically unsuitable to treat certain
patients and that the proposed compounded drug products are intended to
address. Specifically, the nomination does not identify an attribute of
the FDA-approved 100 mg/vial powder for solution (for reconstitution)
that makes it medically unsuitable for certain patients. The commenters
propose to compound a ready-to-use product from a bulk drug substance
to seek improved efficiency for prescribers or healthcare providers, or
to address the possibility that the FDA-approved drug might be
mishandled by a medical professional, neither of which falls within the
meaning of clinical need to compound a drug product using a bulk drug
substance.\33\ Several commenters supported FDA's proposal not to
include methacholine chloride on the 503B Bulks List. The commenters
provided no additional information supporting the clinical need for
compounding from the bulk drug substance methacholine chloride.
---------------------------------------------------------------------------

\33\ See, e.g., ``List of Bulk Drug Substances for Which There
Is a Clinical Need Under Section 503B of the Federal Food, Drug, and
Cosmetic Act,'' 87 FR 4240 at 4248.
---------------------------------------------------------------------------

Accordingly, FDA finds no basis to conclude that there is an
attribute of the FDA-approved product that makes it medically
unsuitable to treat certain patients for a condition that FDA has
identified for evaluation and that a proposed compounded product is
intended to address.
b. Whether the Drug Product Must Be Compounded From a Bulk Drug
Substance
The nomination does not provide support for the position that drug
products containing methacholine chloride must be compounded from a
bulk drug substance rather than by diluting the FDA-approved drug

[[Page 20537]]

product. None of the commenters provided support for such a position
during the comment period. Some commenters stated that there could be a
benefit from using a bulk drug substance to compound drug products to
avoid the manipulations that the FDA-approved drug products that
contain methacholine chloride require before they can be administered
(e.g., dilution). Commenters also contended that outsourcing
facilities, as opposed to hospitals, are better able to prepare
methacholine in the sterile environment that is necessary for the
sterility of an injectable drug product. This is essentially an
argument that the approved drug might be mishandled by a medical
professional, which, as discussed above, does not fall within the
meaning of clinical need to compound a drug product using a bulk drug
substance. The commenters also did not establish that drug products in
the relevant concentrations, including ready-to-use products, cannot be
prepared from the FDA-approved drug products, which are labeled for
dilution.
Having considered these arguments, and because no further
information was supplied regarding the clinical need for compounding
from the bulk drug substance, FDA finds no basis to conclude that the
methacholine chloride drug products proposed to be compounded must be
prepared using a bulk drug substance rather than the FDA-approved drug
product.
4. Metoclopramide HCl
Metoclopramide HCl has been nominated for inclusion on the 503B
Bulks List to compound drug products that treat chemotherapy-induced
nausea and vomiting, diabetic gastroparesis, gastroesophageal reflux
disease, and postoperative nausea and vomiting, among other
conditions.\34\ The proposed routes of administration are intravenous
and intramuscular, the proposed dosage form is a suspension, and the
proposed concentration is 5 mg/mL. The nominators proposed to compound
both preservative-free and preserved suspensions. However, they failed
to acknowledge that there is a preservative-free formulation of
metoclopramide HCl that is FDA-approved or identify an attribute of
that formulation that would be medically unsuitable for certain
patients. The nominations state that metoclopramide HCl might also be
used to compound other drug products but do not identify those
products. The nominated bulk drug substance is a component of FDA-
approved drug products (e.g., ANDA 073118). FDA-approved metoclopramide
HCl is marketed as a preservative-free 10 mg/2 mL (5 mg/mL) solution
for intravenous or intramuscular administration.^{35 36 37}
---------------------------------------------------------------------------

\34\ See Docket No. FDA-2013-N-1524, document nos. FDA-2013-N-
1524-2292 and FDA-2013-N-1524-2298.
\35\ See, e.g., ANDA 073118 labeling available as of the date of
this notice at https://www.accessdata.fda.gov/spl/data/d693380f-94fa-46df-ad37-4ecf3c59b8b8/d693380f-94fa-46df-ad37-4ecf3c59b8b8.xml.
\36\ Per the label for ANDA 073118, the solution is
preservative-free and is intended for intravenous or intramuscular
administration.
\37\ Metoclopramide is also FDA-approved as an oral solution,
metered nasal spray, and tablet.
---------------------------------------------------------------------------

a. Suitability of FDA-Approved Drug Product(s)
The nominations do not identify an attribute of each of the FDA-
approved preservative-free 10 mg/2 mL (5 mg/mL) solution products for
intravenous or intramuscular administration that makes them medically
unsuitable for certain patients or identify an attribute of the FDA-
approved drug products that the proposed compounded drug product is
intended to address. In particular, the nominations do not identify any
data or information indicating that there are some patients who need a
preserved product rather than the FDA-approved preservative-free
products. In addition, the nominations do not identify any data or
information indicating that there are some patients who need a
suspension rather than a solution for intravenous and intramuscular
administration. Two commenters supported FDA's proposal not to include
metoclopramide HCl on the 503B Bulks List. Commenters provided no new
information supporting the clinical need for compounding from the bulk
substance metoclopramide HCl.
Accordingly, FDA finds no basis to conclude that there is an
attribute of the FDA-approved products that makes them medically
unsuitable to treat certain patients for a condition that FDA has
identified for evaluation and that a proposed compounded product is
intended to address.
b. Whether the Drug Product Must Be Compounded From a Bulk Drug
Substance
Because the nominations have not identified an attribute of the
FDA-approved drug product that makes it medically unsuitable for
certain patients, FDA has not evaluated whether the proposed drug
products containing metoclopramide HCl must be compounded from bulk
drug substances rather than using the FDA-approved drug product. No
further information was supplied on this point during the comment
period. Therefore, FDA finds no basis to conclude that the drug
products proposed to be compounded must be prepared using a bulk drug
substance rather than an FDA-approved drug product.
5. Nalbuphine HCl
Nalbuphine HCl has been nominated for inclusion on the 503B Bulks
List to compound drug products that are used for general anesthesia and
to treat moderate to severe pain as a preoperative, postoperative, and
obstetrical analgesia.\38\ The proposed routes of administration are
intravenous, intramuscular, and subcutaneous, the proposed dosage form
is a solution, and the proposed concentrations are 10 mg/mL and 20 mg/
mL. The nominators proposed to compound a preservative-free solution
and a preserved solution. However, they failed to acknowledge that
there are both a preservative-free solution formulation and a preserved
solution formulation of nalbuphine HCl that are FDA-approved or
identify an attribute of those formulations that makes them medically
unsuitable for certain patients. The nominations state that nalbuphine
HCl might also be used to compound other drug products but do not
identify those products. The nominated bulk drug substance is a
component of FDA-approved drug products (e.g., ANDAs 070914 and
070918). FDA-approved nalbuphine HCl is marketed as both preservative-
free and as preserved 10 mg/mL and 20 mg/mL solutions for intravenous,
intramuscular, and subcutaneous administration.^{39 40}
---------------------------------------------------------------------------

\38\ See Docket No. FDA-2013-N-1524, document nos. FDA-2013-N-
1524-2298 and FDA-2013-N-1524-2292.
\39\ See, e.g., ANDA 070914 and 070918 labeling available as of
the date of this notice at https://www.accessdata.fda.gov/spl/data/f118d0a9-270f-4ced-ba4c-c62e32e0d635/f118d0a9-270f-4ced-ba4c-c62e32e0d635.xml and https://www.accessdata.fda.gov/spl/data/0e1346b6-7c47-4957-b0be-849a84b18a89/0e1346b6-7c47-4957-b0be-849a84b18a89.xml, respectively.
\40\ Per the labels for ANDA 070914 and 070918, single-dose
products contain no bacteriostat or antimicrobial agent and unused
portions must be discarded.
---------------------------------------------------------------------------

a. Suitability of FDA-Approved Drug Product(s)
The nominations do not identify an attribute of each of the FDA-
approved 10 mg/mL and 20 mg/mL nalbuphine HCl solutions for
intravenous, intramuscular, and subcutaneous administration that makes
them medically unsuitable for certain patients or identify an attribute
of the approved drug products that the proposed compounded drug
products are

[[Page 20538]]

intended to address. Two commenters supported FDA's proposal not to
include nalbuphine HCl on the 503B Bulks List. The commenters provided
no new information supporting the clinical need for compounding from
the bulk substance nalbuphine HCl.
Accordingly, FDA finds no basis to conclude that there is an
attribute of the FDA-approved products that makes them medically
unsuitable to treat certain patients for a condition that FDA has
identified for evaluation and that a proposed compounded product is
intended to address.
b. Whether the Drug Product Must Be Compounded From a Bulk Drug
Substance
Because the nominations do not identify specific differences
between drug products that would be compounded using nalbuphine HCl and
approved drug products containing nalbuphine HCl, there is nothing for
FDA to evaluate under question 2. No further information was supplied
on this point during the comment period. Therefore, FDA finds no basis
to conclude that the drug products proposed to be compounded must be
prepared using a bulk drug substance rather than an FDA-approved drug
product.
6. Potassium Acetate
Potassium acetate has been nominated for inclusion on the 503B
Bulks List to compound drug products that facilitate electrolyte
management.\41\ The proposed route of administration is intravenous,
the proposed dosage form is a solution, and the proposed concentration
is 2 milliequivalents per milliliter (mEq/mL). The nominators proposed
to compound a preservative-free solution. However, they failed to
acknowledge that there is a preservative-free formulation of potassium
acetate that is FDA-approved or identify an attribute of that
formulation that makes it medically unsuitable for certain patients.
The nominations state that potassium acetate might also be used to
compound other drug products but do not identify those products. The
nominated bulk drug substance is a component of FDA-approved drug
products (e.g., NDA 018896). FDA-approved potassium acetate is marketed
as a 40 mEq/20 mL (2 mEq/mL) preservative-free solution for intravenous
administration.^{42 43}
---------------------------------------------------------------------------

\41\ See Docket No. FDA-2013-N-1524, document nos. FDA-2013-N-
1524-2292 and FDA-2013-N-1524-2298.
\42\ See, e.g., NDA 018896 labeling available as of the date of
this notice at https://www.accessdata.fda.gov/spl/data/28f98aef-8865-4faf-b491-a77b56513d5d/28f98aef-8865-4faf-b491-a77b56513d5d.xml.
\43\ Per the label for NDA 018896, the potassium acetate
solution contains no bacteriostat, antimicrobial agent, or added
buffer but may contain acetic acid for pH adjustment.
---------------------------------------------------------------------------

a. Suitability of FDA-Approved Drug Product(s)
The nominations do not identify an attribute of each of the FDA-
approved 2 mEq/mL preservative-free solution products that makes them
medically unsuitable for certain patients or identify an attribute of
the approved drug products that the proposed compounded drug product is
intended to address. Two commenters supported FDA's proposal not to
include potassium acetate on the 503B Bulks List. The commenters
provided no new information supporting the clinical need for
compounding from the bulk substance potassium acetate. Accordingly, FDA
finds no basis to conclude that there is an attribute of the FDA-
approved products that makes them medically unsuitable to treat certain
patients for a condition that FDA has identified for evaluation and
that a proposed compounded product is intended to address.
b. Whether the Drug Product Must Be Compounded From a Bulk Drug
Substance
Because the nominations do not identify specific differences
between drug products that would be compounded using potassium acetate
and approved drug products containing potassium acetate, there is
nothing for FDA to evaluate under question 2. No further information
was supplied on this point during the comment period. Therefore, FDA
finds no basis to conclude that the drug products proposed to be
compounded must be prepared using a bulk drug substance rather than an
FDA-approved drug product.
7. Procainamide HCl
Procainamide HCl has been nominated for inclusion on the 503B Bulks
List to compound drug products that treat ventricular arrhythmia.\44\
The proposed routes of administration are intramuscular and
intravenous, the proposed dosage form is a solution, and the proposed
concentrations are 100 mg/mL and 500 mg/mL. The nominators proposed to
compound a preserved solution. However, they failed to acknowledge that
there is a preserved formulation of procainamide HCl that is FDA-
approved or identify an attribute of that formulation that makes it
medically unsuitable for certain patients. The nominations state that
procainamide HCl might also be used to compound other drug products but
do not identify those products. The nominated bulk drug substance is a
component of FDA-approved drug products (e.g., ANDA 089069). FDA-
approved procainamide HCl is marketed as 100 mg/mL and 500 mg/mL
preserved solutions for intramuscular and intravenous
administration.^{45 46}
---------------------------------------------------------------------------

\44\ See Docket No. FDA-2013-N-1524, document nos. FDA-2013-N-
1524-2292 and FDA-2013-N-1524-2298.
\45\ See, e.g., ANDA 089069 labeling available as of the date of
this notice at https://www.accessdata.fda.gov/spl/data/6918f728-6c39-4be9-b0f6-6eb5f12bbcaf/6918f728-6c39-4be9-b0f6-6eb5f12bbcaf.xml.
\46\ Per the label for ANDA 089069, each milliliter of the 2 mL
vial contains procainamide hydrochloride 500 mg, methylparaben 1 mg,
and sodium metabisulfite 1.8 mg added in water for injection, and
may contain hydrochloric acid and/or sodium hydroxide for pH
adjustment.
---------------------------------------------------------------------------

a. Suitability of FDA-Approved Drug Product(s).
The nominations do not identify an attribute of each of the FDA-
approved 100 mg/mL and 500 mg/mL preserved solutions that makes them
medically unsuitable for certain patients or identify an attribute of
the approved drug products that the proposed compounded drug products
are intended to address. Two commenters supported FDA's proposal not to
include procainamide HCl on the 503B Bulks List. Commenters provided no
new information supporting the clinical need for compounding from the
bulk drug substance procainamide HCl. Accordingly, FDA finds no basis
to conclude that there is an attribute of the FDA-approved products
that makes them medically unsuitable to treat certain patients for a
condition that FDA has identified for evaluation and that a proposed
compounded product is intended to address.
b. Whether the Drug Product Must Be Compounded From a Bulk Drug
Substance
Because the nominations do not identify specific differences
between drug products that would be compounded using procainamide HCl
and approved drug products containing procainamide HCl, there is
nothing for FDA to evaluate under question 2. No further information
was supplied on this point during the comment period. Therefore, FDA
finds no basis to conclude that the drug products proposed to be
compounded must be prepared using a bulk drug substance rather than an
FDA-approved drug product.

[[Page 20539]]

8. Sodium Bicarbonate
Sodium bicarbonate has been nominated for inclusion on the 503B
Bulks List to compound drug products that treat various conditions,
including metabolic acidosis, certain drug intoxications, severe
diarrhea, and indigestion.\47\ The proposed route of administration is
intravenous, the proposed dosage forms are an injectable solution and
injection solutions, and the proposed strengths range from 4.2 percent
to 8.4 percent. The nominators proposed to compound a preservative-free
solution. However, they failed to acknowledge that there is an FDA-
approved preservative-free formulation of sodium bicarbonate or
identify an attribute of that formulation that makes it medically
unsuitable for certain patients. The nominations state that sodium
bicarbonate might also be used to compound other drug products but do
not identify those products. The nominated bulk drug substance is a
component of FDA-approved drug products (e.g., ANDAs 203449 and
202494). FDA-approved sodium bicarbonate is a single-dose,
preservative-free 1 mEq/mL (8.4 percent) solution for intravenous
administration. ^{48 49 50}
---------------------------------------------------------------------------

\47\ See Docket No. FDA-2013-N-1524, document nos. FDA-2013-N-
1524-2292 and FDA-2013-N-1524-2298; see also Docket No. FDA-2015-N-
3469, document no. FDA-2015-N-3469-0095.
\48\ See, e.g., ANDA 203449 labeling available as of the date of
this notice at https://www.accessdata.fda.gov/spl/data/0e955d36-928c-4f09-9b34-0cc954e5b1f4/0e955d36-928c-4f09-9b34-0cc954e5b1f4.xml.
\49\ Per the label for ANDA 203449, the solutions contain no
bacteriostat, antimicrobial agent, or added buffer and are intended
only for use as a single-dose injection.
\50\ Sodium bicarbonate is also FDA-approved in combination with
other ingredients as an injectable, solution for irrigation, and
various oral formulations.
---------------------------------------------------------------------------

a. Suitability of FDA-Approved Drug Product
The nominations do not identify an attribute of the FDA-approved
drug products, including the single-dose, preservative-free 1 mEq/mL
(8.4 percent) solution, that makes them medically unsuitable to treat
certain patients and that the proposed compounded drug products are
intended to address. Two commenters supported FDA's proposal not to
include sodium bicarbonate on the 503B Bulks List. Commenters provided
no new information supporting the clinical need for compounding from
the bulk drug substance sodium bicarbonate. Accordingly, FDA finds no
basis to conclude that there is an attribute of the FDA-approved
product that makes it medically unsuitable to treat certain patients
for a condition that FDA has identified for evaluation and that the
proposed compounded product is intended to address.
b. Whether the Drug Product Must Be Compounded From a Bulk Drug
Substance
The nominations do not provide support for the position that the
proposed sodium bicarbonate products with concentrations at or below
8.4 percent (1 mEq/mL) must be compounded from bulk drug substances
rather than by diluting the FDA-approved drug product. Because no data
or information was submitted supporting the need for a higher
concentration, we have not considered whether a bulk drug substance
must be used to compound a sodium bicarbonate drug product at
concentrations higher than 8.4 percent. No comments provided support
for the position that the proposed sodium bicarbonate products with
concentrations at or below 8.4 percent (1 mEq/mL) must be compounded
from bulk drug substances rather than by diluting the FDA-approved drug
product. Several commenters stated that the ability to compound sodium
bicarbonate using a bulk drug substance was crucial to address
persistent drug shortages. However, as explained above, section 503B of
the FD&C Act already provides for compounding from a bulk drug
substance if the drug product compounded from such bulk drug substance
is on the FDA drug shortage list at the time of compounding,
distribution, and dispensing. The Agency does not interpret supply
issues, such as shortages and backorders, to be within the meaning of
``clinical need'' for compounding with a bulk drug substance.\51\ Other
commenters asserted that there could be a benefit from using the bulk
drug substance sodium bicarbonate to compound drug products to avoid
the manipulations that the FDA-approved drug products that contain
sodium bicarbonate require before they can be administered (e.g.,
dilution or drawing the drug into a syringe before administration). One
commenter proposes to compound ready-to-use products from bulk drug
substances to seek improved efficiency for prescribers or healthcare
providers and to address the possibility that the approved drug might
be mishandled by a medical professional, neither of which falls within
the meaning of clinical need to compound a drug product using a bulk
drug substance.
---------------------------------------------------------------------------

\51\ See, e.g., ``List of Bulk Drug Substances for Which There
Is a Clinical Need Under Section 503B of the Federal Food, Drug, and
Cosmetic Act,'' 87 FR 4240 at 4248.
---------------------------------------------------------------------------

Having considered these arguments, and because no further
information was supplied regarding the clinical need for compounding
from the bulk drug substance, FDA finds no basis to conclude that the
drug products proposed to be compounded must be prepared using a bulk
drug substance rather than an FDA-approved drug product.
9. Sodium Nitroprusside
Sodium nitroprusside has been nominated for inclusion on the 503B
Bulks List to compound drug products to treat acute decompensated heart
failure and acute hypertension.\52\ The proposed route of
administration is an injection, the proposed dosage form is a solution,
and the proposed concentration is 12.5 mg/mL. The nomination states
that sodium nitroprusside might also be used to compound other drug
products but does not identify those products. The nominated bulk drug
substance is a component of FDA-approved drug products (e.g., ANDA
209493). FDA-approved sodium nitroprusside is marketed as a 50 mg/2 mL
(25 mg/mL) solution that must be diluted prior to injection.
^{53 54}
---------------------------------------------------------------------------

\52\ See Docket No. FDA-2015-N-3469, document no. FDA-2015-N-
3469-0238.
\53\ See, e.g., ANDA 209493 labeling available as of the date of
this notice at https://www.accessdata.fda.gov/spl/data/37060217-1ad1-462b-a1d0-7271c68ed881/37060217-1ad1-462b-a1d0-7271c68ed881.xml.
\54\ Sodium nitroprusside is also FDA-approved as a solution for
intravenous administration.
---------------------------------------------------------------------------

a. Suitability of FDA-Approved Drug Products
Although the nominator proposes to make a drug product that has a
lower concentration than the approved drug product with the same API,
the nomination does not identify an attribute of each of the FDA-
approved 50 mg/2 mL solution for dilution products that makes them
medically unsuitable for certain patients or identify an attribute of
the FDA-approved drug products that the proposed compounded drug
product is intended to address. Two commenters supported FDA's proposal
not to include sodium nitroprusside on the 503B Bulks List. Commenters
provided no new information supporting the clinical need for
compounding from the bulk drug substance sodium nitroprusside.
Accordingly, FDA finds no basis to conclude that there is an attribute
of the FDA-approved products

[[Page 20540]]

that makes them medically unsuitable to treat certain patients for a
condition that FDA has identified for evaluation and that a proposed
compounded product is intended to address.
b. Whether the Drug Product Must Be Compounded From a Bulk Drug
Substance
The nomination does not provide support for the position that drug
products containing sodium nitroprusside must be compounded from bulk
drug substances rather than using the FDA-approved drug products. No
further information was supplied on this point during the comment
period. Therefore, FDA finds no basis to conclude that the drug
products proposed to be compounded must be prepared using a bulk drug
substance rather than an FDA-approved drug product.
10. Verapamil HCl
Verapamil HCl has been nominated for inclusion on the 503B Bulks
List to compound drug products that treat atrial fibrillation and
flutter, hypertension, and paroxysmal supraventricular tachycardia,
among other conditions.\55\ The proposed route of administration is
intravenous, the proposed dosage form is a solution, and the proposed
concentration is 2.5 mg/mL. The nominators proposed to compound a
preservative-free solution. However, they failed to acknowledge that
there is a preservative-free formulation of verapamil HCl that is FDA-
approved or identify an attribute of that formulation that makes it
medically unsuitable for certain patients. The nominations state that
verapamil HCl might also be used to compound other drug products but do
not identify those products. The nominated bulk drug substance is a
component of FDA-approved drug products (e.g., ANDA 070737). FDA-
approved verapamil HCl is marketed as a preservative-free 5 mg/2 mL
(2.5 mg/mL) solution for intravenous administration.
^{56 57 58}
---------------------------------------------------------------------------

\55\ See Docket No. FDA-2013-N-1524, document nos. FDA-2013-N-
1524-2298 and FDA-2013-N-1524-2292.
\56\ See, e.g., ANDA 070737 labeling available as of the date of
this notice at https://www.accessdata.fda.gov/spl/data/072b89b5-6d71-4f63-9686-d715d9256241/072b89b5-6d71-4f63-9686-d715d9256241.xml.
\57\ Per the label for ANDA 070737, the solution contains no
bacteriostat or antimicrobial agent, is intended for single-dose
intravenous administration, and may contain hydrochloric acid for pH
adjustment.
\58\ Verapamil HCl is also FDA-approved in various oral capsule
and tablet formulations.
---------------------------------------------------------------------------

a. Suitability of FDA-Approved Drug Products
The nominations do not identify an attribute of each of the FDA-
approved preservative-free 5 mg/2 mL (2.5 mg/mL) solution products for
intravenous administration that makes them medically unsuitable for
certain patients or identify an attribute of the FDA-approved drug
products that the proposed compounded drug products are intended to
address. Two commenters supported FDA's proposal not to include
verapamil HCl on the 503B Bulks List. Commenters provided no new
information supporting the clinical need for compounding from the bulk
drug substance verapamil HCl. Accordingly, FDA finds no basis to
conclude that there is an attribute of the FDA-approved products that
makes them medically unsuitable to treat certain patients for a
condition that FDA has identified for evaluation and that a proposed
compounded product is intended to address.
b. Whether the Drug Product Must Be Compounded From a Bulk Drug
Substance
Because the nominations do not identify specific differences
between drug products that would be compounded using verapamil HCl and
FDA-approved drug products containing verapamil HCl, there is nothing
for FDA to evaluate under question 2. No further information was
supplied on this point during the comment period. Therefore, FDA finds
no basis to conclude that drug products proposed to be compounded must
be prepared using a bulk drug substance rather than an FDA-approved
drug product.

IV. Other Issues Raised in Nominations and Comments

Two commenters expressed concern that nominations submitted before
FDA issued the Clinical Need Guidance in March 2019 are disadvantaged
in demonstrating clinical need because the nominators might not have
fully understood FDA's thinking on clinical need when they submitted
their nominations.\59\ In addition, one commenter expressed concern
that FDA is evaluating bulk drug substances for clinical need pursuant
to a non-binding guidance document.
---------------------------------------------------------------------------

\59\ See 84 FR 7383, which is available at https://www.federalregister.gov/documents/2019/03/04/2019-03807/evaluation-of-bulk-drug-substances-nominated-for-use-in-compounding-under-section-503b-of-the.
---------------------------------------------------------------------------

FDA disagrees with these comments. First, as explained in section
II.B of this notice, FDA is evaluating bulk drug substances nominated
for inclusion on the 503B Bulks List under the ``clinical need''
standard provided by the FD&C Act, as amended by the Drug Quality and
Security Act in 2013.\60\ The analysis under the statutory ``clinical
need'' standard described in this notice is consistent with the
approach described in FDA's Clinical Need Guidance. Second, the
commenters fail to note the many opportunities that nominators and
interested members of the public had to provide information supporting
a clinical need to compound drug products containing the bulk drug
substances that are the subject of this notice. As explained in section
II.A, a public docket, FDA-2015-N-3469, is available for interested
persons to submit nominations, including updated or revised
nominations, or comments on nominated substances. Furthermore, during
the comment periods for the September 2019 and July 2020 Federal
Register notices, commenters had an additional opportunity to submit
comments to the docket associated with those notices to provide
additional supporting information for the bulk drug substances that are
the subject of this notice, and many did so. Moreover, in response to a
request from a commenter, FDA reopened the comment period on the July
2020 Federal Register notice for an additional 30 days to allow
interested persons yet another opportunity to submit additional
comments.
---------------------------------------------------------------------------

\60\ See Public Law 113-54, section 102(a) (2013), which is
available at https://www.govinfo.gov/content/pkg/PLAW-113publ54/pdf/PLAW-113publ54.pdf.
---------------------------------------------------------------------------

Three commenters on the bulk drug substances addressed in this
notice asserted that FDA is regulating and interfering with the
practice of medicine by not placing bulk drug substances on the 503B
Bulks List despite some physicians wanting to prescribe drug products
compounded from those bulk drug substances. FDA disagrees with these
comments. The Agency's evaluation under the clinical need standard only
regulates the ability of certain compounded drug products to reach the
market and is well within the Agency's authorities.\61\ The Agency is
fulfilling its statutory mandate of regulating outsourcing facilities'

[[Page 20541]]

production and distribution of compounded drug products, not
interfering with physicians' clinical decisions regarding which drug
products to prescribe. Indeed, a Federal court considered the very
claim raised in these comments and determined that FDA's evaluation
under the clinical need standard ``regulates the type of drug that
reaches the marketplace,'' a decision that ``rests well within FDA's
regulatory authority under the FDCA . . . and . . . does not intrude on
the practice of medicine.'' \62\
---------------------------------------------------------------------------

\61\ See United States v. Evers, 643 F.2d 1043, 1048 (5th Cir.
1981) (``[W]hile the [FDCA] was not intended to regulate the
practice of medicine, it was obviously intended to control the
availability of drugs for prescribing by physicians.''); United
States v. Regenerative Scis., LLC, 741 F.3d 1314, 1319-20 (D.C. Cir.
2014); (citing Evers and noting that the FDCA ``regulate[s] the
distribution of drugs by licensed physicians''); Gonzales v. Raich,
545 U.S. 1, 28 (2005) (``the dispensing of new drugs, even when
doctors approve their use must await federal approval.'').
\62\ Athenex Inc. v. Azar, 397 F. Supp. 3d 56, 72 (D.D.C. 2019).
---------------------------------------------------------------------------

Several commenters expressed concern that FDA is promoting the off-
label use of FDA-approved drug products. FDA disagrees with this
comment. In performing the clinical need evaluation, FDA asks a
limited, threshold question to determine whether there might be a
clinical need for a compounded drug product, by asking what attributes
of the approved drug product the proposed compounded drug product would
change and why. Asking this question helps ensure that if a bulk drug
substance is included on the 503B Bulks List, it is to compound drug
products that include a needed change to an approved drug product
rather than to compound drug products without such a change. We do not
suggest that the approved drug product or products prepared from it are
approved for the use proposed by the nomination being evaluated.
One commenter expressed concern with FDA's decision to evaluate
clinical need in the context of the specific drug products proposed to
be compounded in the nomination. This commenter stated that requiring
nominators to provide information on specific drug products is
unnecessary to determine whether there is a clinical need for the bulk
drug substance. This commenter also asserted that FDA should not
evaluate bulk drug substances in the context of finished dosage forms
for drug products. FDA disagrees with these comments. As explained in
section I of this notice, section 503B of the FD&C Act limits the bulk
drug substances that outsourcing facilities can use in compounding to
those that are used to compound drugs in shortage or that appear on a
list developed by FDA of bulk drug substances for which there is a
clinical need.\63\ Section 503B of the FD&C Act includes this
limitation, among others, to help ensure that outsourcing facilities do
not grow into conventional manufacturing operations making unapproved
new drug products without complying with critical requirements, such as
new drug approval. Outsourcing facilities, as opposed to other
compounders, may compound and distribute drug products for ``office
stock'' without first receiving a prescription for an individually
identified patient \64\ and without conditions on interstate
distribution that are applicable to other compounded drugs (Ref.
4).\65\ Because of these differences and others, section 503B of the
FD&C Act places different conditions on drugs compounded by outsourcing
facilities, including limitation on the outsourcing facilities' use of
bulk drug substances, which are more stringent than those placed on
other compounders' use of bulk drug substances.\66\ The clinical need
standard in section 503B of the FD&C Act requires FDA to perform a
sorting function--to distinguish bulk drug substances for which there
is a clinical need from those for which there is not--and this requires
FDA to apply its expertise to consider whether there is a need for the
finished drug product that would be compounded from the bulk drug
substance. Indeed, a Federal court considered the very claim raised in
these comments and determined that ``[o]nly when `clinical need' is
assessed against the availability and suitability of an approved drug
does the term perform the classifying function that Congress
intended.'' In reaching this view, the court found that only when the
clinical need evaluation ``considers the actual way in which the active
pharmaceutical ingredient supplies a therapeutic benefit--by its
administration as a finished drug product--does the inquiry produce the
categorization that Congress surely envisioned'' in enacting section
503B of the FD&C Act.\67\ FDA's clinical need assessments help limit
patient exposure to compounded drug products that have not been
demonstrated to be safe and effective to those situations in which the
compounded drug product is necessary for patient treatment. In
addition, FDA's assessments preserve the incentives for applicants to
invest in the research and testing required to obtain FDA approval and
continue to manufacture FDA-approved drug products, thereby helping to
maintain a supply of high-quality, safe, and effective drugs.
---------------------------------------------------------------------------

\63\ Section 503B(a)(2(A)(i) and (ii) of the FD&C Act.
\64\ By contrast, to qualify for the exemptions in section 503A
of the FD&C Act, drug products compounded by licensed pharmacists in
State-licensed pharmacies or Federal facilities, or by licensed
physicians, must be compounded based on the receipt of a valid
prescription for an individually identified patient. This means that
for drug products compounded under section 503A to meet the
conditions of that section and qualify for the exemptions in the
statute, the pharmacist or physician compounding under section 503A
of the FD&C Act must compound either: (1) after receiving a valid
prescription for an identified, individual patient or (2) before
receiving a patient-specific prescription, in limited quantities,
based on a history of receiving valid orders generated solely within
the context of an established relationship with the patient or
prescriber. See FDA's final guidance for industry ``Prescription
Requirement Under Section 503A of the Federal Food, Drug, and
Cosmetic Act'' (December 2016).
\65\ For drug products compounded under section 503A of the FD&C
Act to meet the conditions of that section and qualify for the
exemptions in the statute, drug products must be compounded in a
State: (i) that has entered into a memorandum of understanding with
the Secretary which addresses the distribution of inordinate amounts
of compounded drug products interstate and provides for appropriate
investigation by a State agency of complaints relating to compounded
drug products distributed outside such State; or (ii) that has not
entered into the memorandum of understanding described in clause (i)
and the licensed pharmacist, licensed pharmacy, or licensed
physician distributes (or causes to be distributed) compounded drug
products out of the State in which they are compounded in quantities
that do not exceed 5 percent of the total prescription orders
dispensed or distributed by such pharmacy or physician (see section
503A(b)(3)(a)(B)(i) and (ii) of the FD&C Act).
\66\ Licensed pharmacies and physicians who compound drugs under
the conditions of section 503A of the FD&C Act, including the
requirement to compound drugs only pursuant to a prescription for an
identified individual patient, may use many bulk drug substances by
operation of the statute, without action by FDA. See section
503A(b)(1)(A)(i)(I) and (II) of the FD&C Act (providing that a drug
product may be compounded consistent with the exemptions in section
503A of the FD&C Act if the licensed pharmacist or licensed
physician compounds the drug product using bulk drug substances that
comply with the standards of an applicable USP or NF monograph, if a
monograph exists, and the USP chapters on pharmacy compounding; or
if such a monograph does not exist, are drug substances that are
components of drugs approved by the Secretary).
\67\ Athenex Inc. at 65.
---------------------------------------------------------------------------

Some of the bulk drug substance nominations and comments discussed
above asserted that there could be a benefit from using a bulk drug
substance to compound drug products to avoid the manipulations that the
FDA-approved drug products that contain these bulk drug substances
require before they can be administered (e.g., dilution or drawing the
drug into a syringe before administration). As explained above, when a
bulk drug substance is a component of an FDA-approved drug, we ask
whether there is a basis to conclude that an attribute of each FDA-
approved drug product makes each one medically unsuitable to treat
certain patients for their condition, an interpretation that protects
patients and the integrity of the drug approval process. The
nominations proposing to compound drug products in ready-to-use form
containing bulk drug substances in one or more FDA-approved drug
products do not show

[[Page 20542]]

that the FDA-approved drug product, when not manufactured in the ready-
to-use form, is medically unsuitable for certain patients. Nor do the
nominations and comments establish that drug products in the relevant
concentrations, including ready-to-use products, cannot be prepared
from the FDA-approved drug products. Rather, they propose to compound a
ready-to-use product from bulk drug substances to seek improved
efficiency for prescribers or healthcare providers, or to address the
possibility that the FDA-approved drug might be mishandled by a medical
professional, neither of which falls within the meaning of clinical
need to compound a drug product using a bulk drug substance.
Two commenters requested changes to the Interim Policy. These
comments are outside the scope of FDA's bulk drug substance evaluations
and decisions that are the subject of this notice. FDA welcomes public
comments on its guidance documents that address human drug compounding.
Comments on the Interim Policy may be submitted to the docket for the
guidance, Docket No. FDA-2015-D-3539, at any time at https://www.regulations.gov.

V. Conclusion

For the reasons stated above, we find that there is a clinical need
for outsourcing facilities to compound drug products using the bulk
drug substance quinacrine HCl for oral use only, and therefore we are
now including it on the 503B Bulks List. In addition, we find that
there is no clinical need for outsourcing facilities to compound using
the bulk drug substances hydroxyzine HCl, mannitol, methacholine
chloride, metoclopramide HCl, nalbuphine HCl, potassium acetate,
procainamide HCl, sodium bicarbonate, sodium nitroprusside, and
verapamil HCl, and therefore we are not including these bulk drug
substances on the 503B Bulks List.

VI. References

The following references are on display at 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. FDA, Guidance for Industry, ``Interim Policy on Compounding Using
Bulk Drug Substances Under Section 503B of the Federal Food, Drug,
and Cosmetic Act,'' January 2017 (available at https://www.fda.gov/media/94402/download).
2. FDA, Guidance for Industry, ``Evaluation of Bulk Drug Substances
Nominated for Use in Compounding Under Section 503B of the Federal
Food, Drug, and Cosmetic Act,'' March 2019 (available at https://www.fda.gov/media/121315/download).
3. FDA Memorandum to File, ``Clinical Need for Quinacrine
Hydrochloride in Compounding Under Section 503B of the FD&C Act,''
March 2021.
4. FDA Guidance for Industry, ``Prescription Requirement Under
Section 503A of the Federal Food, Drug, and Cosmetic Act,'' December
2016 (available at https://www.fda.gov/media/97347/download).

Dated: April 3, 2023.
Lauren K. Roth,
Associate Commissioner for Policy.
[FR Doc. 2023-07237 Filed 4-5-23; 8:45 am]
BILLING CODE 4164-01-P

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