Draft Guidance for Industry on Limiting the Use of Certain Phthalates as Excipients in Center for Drug Evaluation and Research-Regulated Products; Availability, 12852-12853 [2012-5069]
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Federal Register / Vol. 77, No. 42 / Friday, March 2, 2012 / Notices
Ave., Silver Spring, MD 20993–0002,
301–796–1571.
SUPPLEMENTARY INFORMATION:
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Draft Guidance for Industry on Limiting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.
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availability of a draft guidance for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 This draft
guidance provides the pharmaceutical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(2ethylhexyl) 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particular, the draft guidance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considers your comment on this draft
guidance before it begins work on the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on the draft guidance by May 31, 2012.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single copies of the draft guidance to the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access to the draft guidance document.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draft guidance to https://
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
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SUMMARY:
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Jkt 226001
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 entericcoatings 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
PO 00000
Frm 00061
Fmt 4703
Sfmt 4703
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 CDERregulated 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
E:\FR\FM\02MRN1.SGM
02MRN1
Federal Register / Vol. 77, No. 42 / Friday, March 2, 2012 / Notices
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
https://www.fda.gov/Drugs/Guidance
ComplianceRegulatoryInformation/
Guidances/default.htm or https://
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]
BILLING CODE 4160–01–P
DEPARTMENT OF HEALTH AND
HUMAN SERVICES
Food and Drug Administration
[Docket No. FDA–2011–D–0618]
Draft Guidances Relating to the
Development of Biosimilar Products;
Public Hearing; Request for Comments
AGENCY:
Food and Drug Administration,
HHS.
Notice of public hearing; request
for comments.
ACTION:
The Food and Drug
Administration (FDA) is announcing a
1-day public hearing to obtain input on
recently issued draft guidances relating
to the development of biosimilar
products (draft guidances). These draft
guidances were issued by FDA as part
of the implementation of the Biologics
Price Competition and Innovation Act of
2009 (the BPCI Act). The BPCI Act
establishes an abbreviated licensure
pathway for biological products that are
demonstrated to be biosimilar to, or
interchangeable with, a reference
product. FDA will consider the
information it obtains from the public
hearing in the finalization of these
guidances. In addition, FDA is soliciting
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SUMMARY:
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17:01 Mar 01, 2012
Jkt 226001
public input regarding topics for future
policies regarding biosimilars.
DATES: The public hearing will be held
on May 11, 2012, from 8:30 a.m. to 5
p.m. Individuals who wish to present at
the public hearing must register by
April 11, 2012. Section V of this
document provides attendance and
registration information. Electronic or
written comments will be accepted after
the public hearing until May 1, 2012.
ADDRESSES: The public hearing will be
held at FDA’s White Oak Campus,
10903 New Hampshire Ave., Bldg. 31,
Rm. 1503, Silver Spring, MD 20993.
Submit electronic comments to https://
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. Identify
comments with the corresponding
docket number found in brackets in the
heading of this document.
Transcripts of the public hearing will
be available for review at the Division
of Dockets Management and on the
Internet at https://www.regulations.gov
approximately 30 days after the public
hearing (see section VIII of this
document).
A live Web cast of this public hearing
may be seen at https://www.fda.gov/
Drugs/NewsEvents/ucm265628.htm on
the day of the public hearing. A video
record of the public hearing will be
available at the same Web address for
1 year.
FOR FURTHER INFORMATION CONTACT:
Sandra J. Benton, Center for Drug
Evaluation and Research, Food and
Drug Administration, 10903 New
Hampshire Ave., Bldg. 51, Rm. 6340,
Silver Spring, MD 20993, 301–796–
1042, Fax: 301–847–3529, email:
biosimilarspublicmtg@fda.hhs.gov.
SUPPLEMENTARY INFORMATION:
I. Background
On March 23, 2010, President Obama
signed into law the Patient Protection
and Affordable Care Act (Affordable
Care Act) (Pub. L. 111–148). The
Affordable Care Act contains the BPCI
Act that amends the Public Health
Service Act (the PHS Act) and other
statutes to create an abbreviated
licensure pathway for biological
products shown to be biosimilar to, or
interchangeable with, a reference
product (see sections 7001 through 7003
of the Affordable Care Act).
The implementation of an abbreviated
licensure pathway for biological
products can present challenges given
the scientific and technical complexities
that may be associated with the larger
and often more complex structure of
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Frm 00062
Fmt 4703
Sfmt 4703
12853
biological products, as well as the
processes by which such products are
manufactured. Most biological products
are produced in a living system such as
a microorganism, or plant or animal
cells, whereas small molecule drugs are
typically manufactured through
chemical synthesis.
Among other things, section 351(k) of
the PHS Act (42 U.S.C. 262(k)), added
by the BPCI Act, sets forth the
requirements for an application for a
proposed biosimilar biological product.
Section 351(k) defines biosimilarity to
mean ‘‘that the biological product is
highly similar to the reference product
notwithstanding minor differences in
clinically inactive components’’ and
that ‘‘there are no clinically meaningful
differences between the biological
product and the reference product in
terms of the safety, purity, and potency
of the product.’’ A 351(k) biosimilar
application must contain, among other
things, information demonstrating that
the biological product is biosimilar to a
reference product based upon data
derived from analytical studies, animal
studies and a clinical study or studies,
unless FDA determines that an element
described here is unnecessary in a
351(k) application.
II. Previous Public Hearing on
Biosimilar Pathway
As part of our commitment to public
outreach, FDA held a 2-day public
hearing on the ‘‘Approval Pathway for
Biosimilar and Interchangeable
Biological Products’’ on November 2
and 3, 2010 (75 FR 61497, October 5,
2010) (November 2010 public hearing).
The purpose of that public hearing was
to seek comments on a number of issues
relating to the implementation of the
BPCI Act. Over 40 speakers presented at
the public hearing. In addition to the
presentations, FDA has received more
than 60 public comments to the docket,
which closed on December 31, 2010.
Information on this prior public hearing,
including the Federal Register notice,
meeting transcripts, and public
comments can be found at https://
www.regulations.gov (Docket No. FDA–
2010–N–0477). FDA carefully
considered the presentations and public
comments as it was developing the
recently issued draft guidances (see
section III of this document).
III. Draft Guidances
FDA has issued the following three
draft guidances as part of its initial
implementation of the BPCI Act based
on public input at the November 2010
public hearing regarding priorities for
issuing guidances:
E:\FR\FM\02MRN1.SGM
02MRN1
Agencies
[Federal Register Volume 77, Number 42 (Friday, March 2, 2012)]
[Notices]
[Pages 12852-12853]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 2012-5069]
[[Page 12852]]
-----------------------------------------------------------------------
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.
-----------------------------------------------------------------------
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 https://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
[[Page 12853]]
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 https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm or https://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]
BILLING CODE 4160-01-P