[Federal Register Volume 87, Number 234 (Wednesday, December 7, 2022)]
[Notices]
[Pages 75052-75054]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2022-26564]


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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Recommendations; Draft Guidance for Industry; Availability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the availability of a draft guidance for industry entitled ``Small 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This draft guidance is intended to clarify the key factors in 
determining the appropriate aluminum content in a small volume 
parenteral (SVP) drug product and/or a pharmacy bulk package (PBP) 
intended as a component of parenteral nutrition (PN) and provide FDA's 
recommendations regarding the concentration of aluminum in SVP drug 
products and PBPs for PN. Additionally, this guidance is intended to 
assist applicants in determining the appropriate content and placement 
of information on aluminum in SVP and PBP human prescription drug 
product labeling.

DATES: Submit either electronic or written comments on the draft 
guidance by February 6, 2023 to ensure that the Agency considers your 
comment on this draft guidance before it begins work on the final 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:
     Federal eRulemaking Portal: https://www.regulations.gov. 
Follow the instructions for submitting comments. Comments submitted 
electronically, including attachments, to https://www.regulations.gov 
will be posted to the docket unchanged. Because your comment will be 
made public, you are solely responsible for ensuring that your comment 
does not include any confidential information that you or a third party 
may not wish to be posted, such as medical information, your or anyone 
else's Social Security number, or confidential business information, 
such as a manufacturing process. Please note that if you include your 
name, contact information, or other information that identifies you in 
the body of your comments, that information will be posted on https://www.regulations.gov.
     If you want to submit a comment with confidential 
information that you do not wish to be made available to the public, 
submit the comment as a written/paper submission and in the manner 
detailed (see ``Written/Paper Submissions'' and ``Instructions'').

Written/Paper Submissions

    Submit written/paper submissions as follows:
     Mail/Hand Delivery/Courier (for written/paper 
submissions): Dockets Management Staff (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
     For written/paper comments submitted to the Dockets 
Management Staff, FDA will post your comment, as well as any 
attachments, except for information submitted, marked and identified, 
as confidential, if submitted as detailed in ``Instructions.''
    Instructions: All submissions received must include the Docket No. 
FDA-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 https://www.regulations.gov 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

[[Page 75053]]

second copy, which will have the claimed confidential information 
redacted/blacked out, will be available for public viewing and posted 
on https://www.regulations.gov. Submit both copies to the Dockets 
Management Staff. If you do not wish your name and contact information 
to be made publicly available, you can provide this information on the 
cover sheet and not in the body of your comments and you must identify 
this information as ``confidential.'' Any information marked as 
``confidential'' will not be disclosed except in accordance with 21 CFR 
10.20 and other applicable disclosure law. For more information about 
FDA's posting of comments to public dockets, see 80 FR 56469, September 
18, 2015, or access the information at: https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf.
    Docket: For access to the docket to read background documents or 
the electronic and written/paper comments received, go to https://www.regulations.gov and insert the docket number, found in brackets in 
the heading of this document, into the ``Search'' box and follow the 
prompts and/or go to the Dockets Management Staff, 5630 Fishers Lane, 
Rm. 1061, Rockville, MD 20852, 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, 241-308-2929.

SUPPLEMENTARY INFORMATION:

I. Background

    FDA 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.'' 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, foods, and drugs, aluminum's oral bioavailability is poor, so 
healthy individuals typically face little risk of toxicity. Despite 
that, aluminum toxicity has been documented in medical literature for 
more than 30 years, with manifestations that include osteomalacia and 
reduced bone mineralization, neurological dysfunction and dialysis 
encephalopathy, microcytic hypochromic anemia, and cholestasis.
    A long-implicated, major source of aluminum exposure is PN, 
resulting from contamination of ingredients. Patients with underlying 
renal impairment who receive prolonged courses of PN support are at 
greatest risk of exposure to toxic levels of aluminum from PN. Preterm 
neonates and infants who often require many days of PN support and have 
immature kidneys that are incapable of excreting aluminum efficiently 
are at particularly high risk.
    Research indicates that patients with renal impairment, including 
premature neonates, who receive parenteral levels of aluminum at 
greater than 4 to 5 microgram/kilogram/day (mcg/kg/day) accumulate 
aluminum at levels associated with central nervous system and bone 
toxicity. Because patients with renal impairment, including all preterm 
neonates, comprise a major portion of those requiring PN support, we 
recommend that the total aluminum exposure (TAE) from PN uniformly 
should not exceed 5 mcg/kg/day. To determine TAE, one must consider all 
sources of aluminum content in PN, including each large volume 
parenteral and each SVP drug product and PBP in PN. This guidance 
describes an approach to deriving the recommended aluminum 
concentration limit in an SVP drug product for PN, based on the 
proposed clinical dose, concentration of drug or dose volume, and the 
known or estimated contribution of aluminum from other products in the 
PN.
    Additionally, this guidance is intended to assist applicants in 
determining the appropriate content and placement of information on 
aluminum in SVP and PBP human prescription drug product labeling. This 
guidance provides recommendations to help ensure that information on 
the aluminum content is appropriate and placed in the proper sections 
and subsections within the Highlights of Prescribing Information and on 
the container label and carton labeling. This will help to assure that 
the information is clear and accessible to healthcare practitioners and 
includes content that guides the safe and effective use of the drug 
product.
    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.

II. Paperwork Reduction Act of 1995

    While this guidance contains no collection of information, it does 
refer to previously approved FDA collections of information. Therefore, 
clearance by the Office of Management and Budget (OMB) under the 
Paperwork Reduction Act of 1995 (PRA) (44 U.S.C. 3501-3521) is not 
required for this guidance. The previously approved collections of 
information are subject to review by OMB under the PRA. 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 
https://www.fda.gov/media/109951/download) have been approved under OMB 
control numbers 0910-0001 and 0910-0429. 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 https://www.fda.gov/media/107626/download) 
have been approved under OMB control number 0910-0718. The collections 
of information in FDA's guidance entitled ``Controlled Correspondence 
Related to Generic Drug Development'' (available at https://www.fda.gov/media/109232/download) have been approved under OMB control 
number 0910-0797.

III. Electronic Access

    Persons with access to the internet may obtain the draft guidance 
at https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs, https://www.fda.gov/regulatory-information/search-fda-guidance-documents, or https://www.regulations.gov.


[[Page 75054]]


    Dated: December 1, 2022.
Lauren K. Roth,
Associate Commissioner for Policy.
[FR Doc. 2022-26564 Filed 12-6-22; 8:45 am]
BILLING CODE 4164-01-P


