[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]


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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.

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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