[Federal Register Volume 77, Number 42 (Friday, March 2, 2012)]
[Notices]
[Pages 12852-12853]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2012-5069]
[[Page 12852]]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. FDA-2012-D-0108]
Draft Guidance for Industry on Limiting the Use of Certain
Phthalates as Excipients in Center for Drug Evaluation and Research-
Regulated Products; Availability
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice.
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SUMMARY: The Food and Drug Administration (FDA) is announcing the
availability of a draft guidance for industry entitled ``Limiting the
Use of Certain Phthalates as Excipients in CDER-Regulated Products.''
This draft guidance provides the pharmaceutical industry with the
Center for Drug Evaluation and Research's (CDER's) current thinking on
the potential human health risks associated with exposure to dibutyl
phthalate (DBP) and di(2-ethylhexyl) phthalate (DEHP). In particular,
the draft guidance recommends that the pharmaceutical industry avoid
the use of these two specific phthalates as excipients in CDER-
regulated drug and biologic products, including prescription and
nonprescription products.
DATES: Although you can comment on any guidance at any time (see 21 CFR
10.115(g)(5)), to ensure that the Agency considers your comment on this
draft guidance before it begins work on the final version of the
guidance, submit either electronic or written comments on the draft
guidance by May 31, 2012.
ADDRESSES: Submit written requests for single copies of the draft
guidance to the Division of Drug Information, Center for Drug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, 10903 New
Hampshire Ave., Bldg. 51, Rm. 2201, 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access to the draft guidance document.
Submit electronic comments on the draft guidance to http://www.regulations.gov. Submit written comments to the Division of Dockets
Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane,
Rm. 1061, Rockville, MD 20852.
FOR FURTHER INFORMATION CONTACT: Laurie Muldowney, Center for Drug
Evaluation and Research (HFD-003), Food and Drug Administration, Bldg.
51, Rm. 4154, 10903 New Hampshire Ave., Silver Spring, MD 20993-0002,
301-796-1571.
SUPPLEMENTARY INFORMATION:
I. Background
FDA is announcing the availability of a draft guidance for industry
entitled ``Limiting the Use of Certain Phthalates as Excipients in
CDER-Regulated Products.'' This draft guidance provides the
pharmaceutical industry with CDER's current thinking on the potential
human health risks associated with exposure to DBP and DEHP. In
particular, the draft guidance recommends that the pharmaceutical
industry avoid the use of these two specific phthalates as excipients
in CDER-regulated drug and biologic products, including prescription
and nonprescription products. The recommendations in this guidance do
not address the use of DBP or DEHP in other types of FDA-regulated
products or exposure to DBP or DEHP due to the presence of any of these
compounds as an impurity--including as a result of leaching from
packaging materials.
Phthalate esters (phthalates) are synthetic chemicals with a broad
spectrum of uses. Phthalates are found in certain pharmaceutical
formulations, primarily as a plasticizer in enteric-coatings of solid
oral drug products to maintain flexibility, but they also may be used
for different functions in other dosage forms. Phthalates also are
found in other products for uses such as softeners of plastics,
solvents in perfumes, and additives to nail polish, as well as in
lubricants and insect repellents.
Phthalates have been studied extensively in animals, and DBP and
DEHP have been shown to be developmental and reproductive toxicants in
laboratory animals. While the data in humans are less clear,
epidemiological studies suggest that certain phthalates may affect
reproductive and developmental outcomes. Other studies have confirmed
the presence of DBP and DEHP in amniotic fluid, breast milk, urine, and
serum.
Data from the National Health and Nutrition Examination Survey
(NHANES) indicate widespread exposure of the general population to
phthalates. Humans are exposed to phthalates by multiple routes,
including inhalation, ingestion, and to a lesser degree absorption
through the skin. Several observational human studies have reported an
association between exposure to certain phthalates and adverse
developmental and reproductive effects. The ubiquitous presence of
phthalates in the environment and the potential consequences of human
exposure to phthalates have raised concerns, particularly in vulnerable
populations such as pregnant women and infants.
Although the currently available human data are limited, the Agency
has determined that there is evidence that exposure to DBP and DEHP
from pharmaceuticals presents a potential risk of developmental and
reproductive toxicity. While it is recognized that drug products may
carry inherent risks, DBP and DEHP are used as excipients, and safer
alternatives are available. Therefore, the Agency recommends avoiding
the use of DBP and DEHP as excipients in CDER-regulated drug and
biologic products.
These recommendations apply to CDER-regulated drug and biologic
products that are under development (i.e., investigational new drugs),
nonapplication products (e.g., over the counter monograph products),
and both marketed approved products and those currently under review
for marketing consideration (i.e., new drug applications, abbreviated
new drug applications, and biologics license applications).
There are alternatives to DBP and DEHP for use as excipients in
CDER-regulated products. Manufacturers with products that contain DBP
or DEHP should consider alternative excipients and determine if the
alternative excipient they plan to use has been used in similar CDER-
approved products and at what level.
The Inactive Ingredients Database provides information on
excipients present in FDA-approved drug products, and this information
can be helpful in developing drug products. As manufacturers
reformulate their products, the listings for DBP and DEHP will be
removed from the Inactive Ingredients Database.
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 Agency's current thinking on limiting the
use of certain phthalates as excipients in CDER-regulated products. It
does not create or confer any rights for or on any person and does not
operate to bind FDA or the public. An alternative approach may be used
if such approach satisfies the requirements of the applicable statutes
and regulations.
II. Comments
Interested persons may submit to the Division of Dockets Management
(see ADDRESSES) either electronic or written comments regarding this
document. It is
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only necessary to send one set of comments. Identify comments with the
docket number found in brackets in the heading of this document.
Received comments may be seen in the Division of Dockets Management
between 9 a.m. and 4 p.m., Monday through Friday.
III. The Paperwork Reduction Act of 1995
This draft guidance refers to previously approved collections of
information found in FDA regulations. These collections of information
are subject to review by the Office of Management and Budget (OMB)
under the Paperwork Reduction Act of 1995 (44 U.S.C. 3501-3520) and
have been approved under OMB Control Numbers 0910-0014 and 0910-0001.
IV. Electronic Access
Persons with access to the Internet may obtain the document at
either http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm or http://www.regulations.gov.
Dated: February 28, 2012.
Leslie Kux,
Acting Assistant Commissioner for Policy.
[FR Doc. 2012-5069 Filed 3-1-12; 8:45 am]
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