Small Volume Parenteral Drug Products and Pharmacy Bulk Packages for Parenteral Nutrition: Aluminum Content and Labeling Recommendations; Draft Guidance for Industry; Availability

<NOTICE> DEPARTMENT OF HEALTH AND HUMAN SERVICES <SUBAGY>Food and Drug Administration</SUBAGY> <DEPDOC>[Docket No. FDA-2022-D-2301]</DEPDOC> <SUBJECT>Small Volume Parenteral Drug Products and Pharmacy Bulk Packages for Parenteral Nutrition: Aluminum Content and Labeling Recommendations; Draft Guidance for Industry; Availability</SUBJECT> <HD SOURCE="HED">AGENCY:</HD> Food and Drug Administration, HHS. <HD SOURCE="HED">ACTION:</HD> Notice of availability. <SUM> <HD SOURCE="HED">SUMMARY:</HD> The Food and Drug Administration (FDA or Agency) is announcing the availability of a draft guidance for industry entitled “Small Volume Parenteral Drug Products and Pharmacy Bulk Packages for Parenteral Nutrition: Aluminum Content and Labeling Recommendations.” This draft guidance is intended to clarify the key factors in calculating the aluminum content to ensure that the total aluminum exposure in parenteral nutrition (PN) does not exceed an acceptable threshold. It also provides FDA's recommendations regarding the aluminum concentration limits for small volume parenterals (SVPs) packaged as single doses or SVPs packaged in pharmacy bulk packages (PBPs). Additionally, this draft guidance is intended to assist sponsors and applicants in determining the appropriate placement of information on aluminum toxicity in SVP and large volume parenteral (LVP) Prescribing Information and container and carton labeling. This draft guidance revises and replaces the draft guidance for industry of the same name published on December 7, 2022. </SUM> <DATES> <HD SOURCE="HED">DATES:</HD> Submit either electronic or written comments on the draft guidance by September 2, 2025 to ensure that the Agency considers your comment on this draft guidance before it begins work on the final version of the guidance. </DATES> <HD SOURCE="HED">ADDRESSES:</HD> You may submit comments on any guidance at any time as follows: <HD SOURCE="HD2">Electronic Submissions</HD> Submit electronic comments in the following way: • <E T="03">Federal eRulemaking Portal: https://www.regulations.gov.</E> Follow the instructions for submitting comments. Comments submitted electronically, including attachments, to <E T="03">https://www.regulations.gov</E> will be posted to the docket unchanged. Because your comment will be made public, you are solely responsible for ensuring that your comment does not include any confidential information that you or a third party may not wish to be posted, such as medical information, your or anyone else's Social Security number, or confidential business information, such as a manufacturing process. Please note that if you include your name, contact information, or other information that identifies you in the body of your comments, that information will be posted on <E T="03">https://www.regulations.gov.</E> • If you want to submit a comment with confidential information that you do not wish to be made available to the public, submit the comment as a written/paper submission and in the manner detailed (see “Written/Paper Submissions” and “Instructions”). <HD SOURCE="HD2">Written/Paper Submissions</HD> Submit written/paper submissions as follows: • <E T="03">Mail/Hand Delivery/Courier (for written/paper submissions):</E> Dockets Management Staff (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852. • For written/paper comments submitted to the Dockets Management Staff, FDA will post your comment, as well as any attachments, except for information submitted, marked and identified, as confidential, if submitted as detailed in “Instructions.” <E T="03">Instructions:</E> All submissions received must include the Docket No. FDA-2022-D-2301 for “Small Volume Parenteral Drug Products and Pharmacy Bulk Packages for Parenteral Nutrition: Aluminum Content and Labeling Recommendations.” Received comments will be placed in the docket and, except for those submitted as “Confidential Submissions,” publicly viewable at <E T="03">https://www.regulations.gov</E> or at the Dockets Management Staff between 9 a.m. and 4 p.m., Monday through Friday, 240-402-7500. • Confidential Submissions—To submit a comment with confidential information that you do not wish to be made publicly available, submit your comments only as a written/paper submission. You should submit two copies total. One copy will include the information you claim to be confidential with a heading or cover note that states “THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.” The Agency will review this copy, including the claimed confidential information, in its consideration of comments. The second copy, which will have the claimed confidential information redacted/blacked out, will be available for public viewing and posted on <E T="03">https://www.regulations.gov.</E> Submit both copies to the Dockets Management Staff. If you do not wish your name and contact information to be made publicly available, you can provide this information on the cover sheet and not in the body of your comments and you must identify this information as “confidential.” Any information marked as “confidential” will not be disclosed except in accordance with 21 CFR 10.20 and other applicable disclosure law. For more information about FDA's posting of comments to public dockets, see 80 FR 56469, September 18, 2015, or access the information at: <E T="03">https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf.</E> <E T="03">Docket:</E> For access to the docket to read background documents or the electronic and written/paper comments received, go to <E T="03">https://www.regulations.gov</E> and insert the docket number, found in brackets in the heading of this document, into the “Search” box and follow the prompts and/or go to the Dockets Management Staff, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852, 240-402-7500. You may submit comments on any guidance at any time (see 21 CFR 10.115(g)(5)). Submit written requests for single copies of the draft guidance to the Division of Drug Information, Center for Drug Evaluation and Research, Food and Drug Administration, 10001 New Hampshire Ave., Hillandale Building, 4th Floor, Silver Spring, MD 20993-0002. Send one self-addressed adhesive label to assist that office in processing your requests. See the <E T="02">SUPPLEMENTARY INFORMATION</E> section for electronic access to the draft guidance document. <FURINF> <HD SOURCE="HED">FOR FURTHER INFORMATION CONTACT:</HD> Thao Vu, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 22, Rm. 5232, Silver Spring, MD 20993-0002, 240-402-2690. </FURINF> <SUPLINF> <HD SOURCE="HED">SUPPLEMENTARY INFORMATION:</HD> <HD SOURCE="HD1">I. Background</HD> FDA is announcing the availability of a revised draft guidance for industry entitled “Small Volume Parenteral Drug Products and Pharmacy Bulk Packages for Parenteral Nutrition: Aluminum Content and Labeling Recommendations.” Aluminum, one of the most abundant metallic elements on earth, occurs naturally in several minerals, ores, oxides, and silicates. Although humans are exposed to aluminum through drinking water, food, and drugs, absorption of aluminum through the gastrointestinal tract (oral bioavailability) is low; therefore, healthy individuals typically face little risk of aluminum toxicity. However, in the settings of chronic kidney failure or prolonged PN treatment in neonates, aluminum toxicity has manifested as osteomalacia and reduced bone mineralization, neurological dysfunction including dialysis encephalopathy, microcytic hypochromic anemia, and cholestasis. A long-implicated, major source of aluminum exposure is PN, resulting from contamination of ingredients or leaching through the container during manufacturing. Patients with underlying renal impairment who receive prolonged courses of PN are at greatest risk of exposure to toxic levels of aluminum from PN. Preterm neonates and infants, who have immature kidneys that are incapable of excreting aluminum efficiently and may require weeks of PN before transitioning to oral nutrition, are at particularly high risk. This draft guidance is intended to clarify the key factors in calculating the aluminum content to ensure that the total aluminum exposure in PN does not exceed an acceptable threshold. It also provides FDA's recommendations regarding the aluminum concentration limits for SVPs packaged as single doses or SVPs packaged in PBPs. Additionally, this draft guidance is intended to assist sponsors and applicants in determining the appropriate placement of information on aluminum toxicity in SVP and LVP Prescribing Information and container and carton labeling; it revises and replaces the draft guidance for industry of the same name published on December 7, 2022 (87 FR 75052). Interested parties' comments were considered, and the following key changes were made: • Revised the Introduction section to clarify the intended purpose; the key factors in calculating the aluminum content; the need for aluminum mitigation and control strategies for SVP, PBP, and LVP development; and labeling considerations for aluminum toxicity in SVPs, PBPs, and LVPs; • Clarified the examples showing the calculations of total aluminum exposure, individual aluminum exposure, and aluminum concentration limits, as well as the data supporting FDA's recommendation for total aluminum exposure; and • Added section VI to provide advice regarding implementation of this guidance, particularly steps manufacturers should take if a drug shortage arises. 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 “Small Volume Parenteral Drug Products and Pharmacy Bulk Packages for Parenteral Nutrition: Aluminum Co ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Preview showing 10k of 12k characters. Full document text is stored and available for version comparison. ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━