12852 Federal Register / Vol. 77, No. 42 / Friday, March 2, 2012 / Notices 

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Draft Guidance for Industry on Limiting 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availability of a draft guidance for 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particular, the draft guidance 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on the draft guidance by May 31, 2012.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single copies of the draft guidance to the 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access to the draft guidance document.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draft guidance to http:// 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 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 

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 


tkelley on DSK3SPTVN1PROD with NOTICES
Federal Register / Vol. 77, No. 42 / Friday, March 2, 2012 / Notices 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 

http://www.fda.gov/Drugs/Guidance

ComplianceRegulatoryInformation/ 

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] 

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. 

ACTION: Notice of public hearing; request 

for comments. 

SUMMARY: 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 

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 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. 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 http://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 http://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 

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 http:// 

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: 


tkelley on DSK3SPTVN1PROD with NOTICES