Notice2025-12403
Small Volume Parenteral Drug Products and Pharmacy Bulk Packages for Parenteral Nutrition: Aluminum Content and Labeling Recommendations; Draft Guidance for Industry; Availability
Primary source
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Published
July 3, 2025
Issuing agencies
Health and Human Services DepartmentFood and Drug Administration
Abstract
The Food and Drug Administration (FDA or Agency) is announcing the availability of a draft guidance for industry entitled "Small Volume Parenteral Drug Products and Pharmacy Bulk Packages for Parenteral Nutrition: Aluminum Content and Labeling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 This draft guidance is intended to clarify the key factors in calculating the aluminum content to ensure that the total aluminum exposure in parenteral nutrition (PN) does not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 Additionally, this draft guidance is intended to assist sponsors and applicants in determining the appropriate placement of information on aluminum toxicity in SVP and large volume parenteral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 This draft guidance revises and replaces the draft guidance for industry of the same name published on December 7, 2022.
Full Text
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<title>Federal Register, Volume 90 Issue 126 (Thursday, July 3, 2025)</title>
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[Federal Register Volume 90, Number 126 (Thursday, July 3, 2025)]
[Notices]
[Pages 29554-29555]
From the Federal Register Online via the Government Publishing Office [<a href="http://www.gpo.gov">www.gpo.gov</a>]
[FR Doc No: 2025-12403]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. FDA-2022-D-2301]
Small Volume Parenteral Drug Products and Pharmacy Bulk Packages
for Parenteral Nutrition: Aluminum Content and Labeling
Recommendations; Draft Guidance for Industry; Availability
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice of availability.
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SUMMARY: 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the availability of a draft guidance for industry entitled ``Small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.
DATES: 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.
ADDRESSES: You may submit comments on any guidance at any time as
follows:
Electronic Submissions
Submit electronic comments in the following way:
<bullet> Federal eRulemaking Portal: <a href="https://www.regulations.gov">https://www.regulations.gov</a>.
Follow the instructions for submitting comments. Comments submitted
electronically, including attachments, to <a href="https://www.regulations.gov">https://www.regulations.gov</a>
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 <a href="https://www.regulations.gov">https://www.regulations.gov</a>.
<bullet> If you want to submit a comment with confidential
information that you do not wish to be made available to the public,
submit the comment as a written/paper submission and in the manner
detailed (see ``Written/Paper Submissions'' and ``Instructions'').
Written/Paper Submissions
Submit written/paper submissions as follows:
<bullet> Mail/Hand Delivery/Courier (for written/paper
submissions): Dockets Management Staff (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
<bullet> For written/paper comments submitted to the Dockets
Management Staff, FDA will post your comment, as well as any
attachments, except for information submitted, marked and identified,
as confidential, if submitted as detailed in ``Instructions.''
Instructions: All submissions received must include the Docket No.
FDA-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 <a href="https://www.regulations.gov">https://www.regulations.gov</a> or at the Dockets
Management Staff between 9 a.m. and 4 p.m., Monday through Friday, 240-
402-7500.
<bullet> 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 <a href="https://www.regulations.gov">https://www.regulations.gov</a>.
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
[[Page 29555]]
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: <a href="https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf">https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf</a>.
Docket: For access to the docket to read background documents or
the electronic and written/paper comments received, go to <a href="https://www.regulations.gov">https://www.regulations.gov</a> 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 SUPPLEMENTARY INFORMATION section for electronic
access to the draft guidance document.
FOR FURTHER INFORMATION CONTACT: 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.
SUPPLEMENTARY INFORMATION:
I. Background
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:
<bullet> 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;
<bullet> 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
<bullet> 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 Content and Labeling Recommendations.'' 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. As we develop
any final guidance on this topic, FDA will consider comments on the
applicability of Executive Order 14192, per the Office of Management
and Budget (OMB) guidance M-25-20, and in particular, on any costs or
cost savings.
II. Paperwork Reduction Act of 1995
While this guidance contains no collection of information, it does
refer to previously approved FDA collections of information. The
previously approved collections of information are subject to review by
OMB under the Paperwork Reduction Act of 1995 (PRA) (44 U.S.C. 3501-
3521). The collections of information in 21 CFR part 314 have been
approved under OMB control number 0910-0001. The collections of
information in 21 CFR part 312 have been approved under OMB control
number 0910-0014. The collections of information in FDA's guidance
entitled ``Formal Meetings Between the FDA and Sponsors or Applicants
of PDUFA Products'' (available at <a href="https://www.fda.gov/media/109951/download">https://www.fda.gov/media/109951/download</a>) have been approved under OMB control number 0910-0001. The
collections of information in 21 CFR 201.56 and 201.57 have been
approved under OMB control number 0910-0572. The collections of
information in FDA's guidance entitled ``Formal Meetings Between FDA
and ANDA Applicants of Complex Products Under GDUFA'' (available at
<a href="https://www.fda.gov/media/107626/download">https://www.fda.gov/media/107626/download</a>) and in FDA's guidance
entitled ``Controlled Correspondence Related to Generic Drug
Development'' (available at <a href="https://www.fda.gov/media/109232/download">https://www.fda.gov/media/109232/download</a>)
have been approved under OMB control number 0910-0727.
III. Electronic Access
Persons with access to the internet may obtain the draft guidance
at <a href="https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs">https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs</a>, <a href="https://www.fda.gov/regulatory-information/search-fda-guidance-documents">https://www.fda.gov/regulatory-information/search-fda-guidance-documents</a>, or <a href="https://www.regulations.gov">https://www.regulations.gov</a>.
Dated: June 27, 2025.
Grace R. Graham,
Deputy Commissioner for Policy, Legislation, and International Affairs.
[FR Doc. 2025-12403 Filed 7-2-25; 8:45 am]
BILLING CODE 4164-01-P
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