[Federal Register Volume 77, Number 235 (Thursday, December 6, 2012)]
[Notices]
[Pages 72869-72870]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2012-29461]
-----------------------------------------------------------------------
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. FDA-2012-D-1135]
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.
-----------------------------------------------------------------------
SUMMARY: The Food and Drug Administration (FDA) is announcing the
availability of a guidance for industry entitled ``Limiting the Use of
Certain Phthalates as Excipients in CDER-Regulated Products.'' This
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 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: Submit either electronic or written comments on Agency guidances
at any time.
ADDRESSES: Submit written requests for single copies of the 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
guidance document.
Submit electronic comments on the 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 guidance for industry
entitled ``Limiting the Use of Certain Phthalates as Excipients in
CDER-Regulated Products.'' This 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
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 and delivery
systems.
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
indicate widespread exposure of the general population to phthalates.
Humans are exposed to phthalates by multiple
[[Page 72870]]
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 guidance is being issued consistent with FDA's good guidance
practices regulation (21 CFR 10.115). The guidance represents 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 either written comments regarding
this document to the Division of Dockets Management (see ADDRESSES) or
electronic comments to http://www.regulations.gov. It is 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, and will be posted to the docket at http://www.regulations.gov.
III. The Paperwork Reduction Act of 1995
This 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: November 30, 2012.
Leslie Kux,
Assistant Commissioner for Policy.
[FR Doc. 2012-29461 Filed 12-5-12; 8:45 am]
BILLING CODE 4160-01-P