Federal Register / Vol. 73, No. 185 / Tuesday, September 23, 2008 / Notices 54829 

1A ‘‘person’’ includes individuals, partnerships, 

corporations, or associations (21 U.S.C. 321(e)). 

been designed to (1) communicate the 

current state of knowledge on hazards to 

workers’ health from dermal exposures, 

(2) address the conceptual shortcomings 

of the current NIOSH skin notation 

represented by the symbol [skin], (3) 

recognize the health risks associated 

with contact of the skin with chemicals 

beyond dermal absorption, and (4) 

increase the transparency of the process 

for assigning the new NIOSH skin 

notations. The CIB can be found at: 

http://www.cdc.gov/niosh/review/ 

public/109. 

Public Meeting Time and Date: 9 

a.m.–4 p.m. EDT, November 6, 2008. 

Place: NIOSH, Robert A. Taft 

Laboratories, Taft Auditorium, 4676 

Columbia Parkway, Cincinnati, Ohio 

45226. 

Status: The forum will include 

scientists and representatives from 

various government agencies, industry, 

labor, and other stakeholders, and is 

open to the public, limited only by the 

space available (the room 

accommodates approximately 80 

people). Due to limited space, 

notification of intent to attend the 

meeting must be made to the NIOSH 

Docket Officer, no later than October 22, 

2008. The NIOSH Docket Officer can be 

reached at (513) 533–8611 or by e-mail 

at niocindocket@cdc.gov. Requests to 

attend the meeting will be 

accommodated on a first-come basis. 

Non-U.S. Citizens: Because of CDC 

Security Regulations, any non-U.S. 

citizen wishing to attend this meeting 

must provide the following information 

in writing to the NIOSH Docket Officer 

at the address below no later than 

October 15, 2008. 

1. Name: 

2. Gender: 

3. Date of Birth: 

4. Place of Birth (city, province, state, 

country): 

5. Citizenship: 

6. Passport Number: 

7. Date of Passport Issue: 

8. Date of Passport Expiration: 

9. Type of Visa: 

10. U.S. Naturalization Number (if a 

naturalized citizen): 

11. U.S. Naturalization Date (if a 

naturalized citizen): 

12. Visitor’s Organization: 

13. Organization Address: 

14. Organization Telephone Number: 

15. Visitor’s Position/Title within the 

Organization: 

This information will be transmitted 

to the CDC Security Office for approval. 

Visitors will be notified as soon as 

approval has been obtained. 

Purpose of the Meeting: To discuss 

and obtain comments on the draft CIB, 

‘‘A Strategy for Assigning the New 

NIOSH Skin Notations for Chemicals.’’ 

Special emphasis will be placed on 

discussion of the following issues: 

1. Are the proposed classes of skin 

notations appropriate? 

2. Are the proposed criteria for 

assigning each type of skin notation 

appropriate? 

3. Is the proposed assignment of 

multiple skin notations useful for 

protecting workers from dermal 

hazards? 

4. Should the sensitizing effects (SEN) 

notation apply strictly to allergic contact 

dermatitis or is it appropriate to assign 

the SEN notation for other immunemediate responses, such as respiratory 

sensitization, airway hyperactivity and 

mucosal inflammation, associated with 

dermal exposure to a compound? 

5. Does the proposed harmonization 

scheme found in Appendix G.2 link the 

new NIOSH skin notations and The 

Globally Harmonized System of 

Classification and Labeling of Chemicals 

(GHS) assignments sufficiently? 

6. Should additional information be 

included within document? If so, what? 

7. Do the data cited support the 

objectives of the document? 

8. Are the conclusions appropriate in 

light of the current understanding of the 

toxicological data? 

This document may be found at: 

http://www.cdc.gov/niosh/review/ 

public/109/. 

Written comments may be submitted 

to the NIOSH Docket Officer, Robert A. 

Taft Laboratories, 4676 Columbia 

Parkway, M/S C–34, Cincinnati, OH 

45226, telephone (513) 533–8611, 

facsimile (513) 533–8230. Comments 

may also be submitted via e-mail to 

niocindocket@cdc.gov. All electronic 

comments should be formatted as 

Microsoft Word. Comments must be 

submitted to NIOSH no later than 

November 7, 2008, and should reference 

docket number NIOSH–109 in the 

subject heading. Oral comments made at 

the public meeting must also be 

submitted to the docket in writing in 

order to be considered by the Agency. 

All information received in response 

to this notice will be available for public 

examination and copying at the NIOSH 

Docket Office, 4676 Columbia Parkway, 

Cincinnati, Ohio 45226. 

Contact Person for Technical 

Information: Scott Dotson, Industrial 

Hygienist, NIOSH, CDC, telephone (513) 

533–8540, M/S C–32, Robert A. Taft 

Laboratories, 4676 Columbia Parkway, 

Cincinnati, Ohio 45226. 

Dated: September 15, 2008. 

James D. Seligman, 

Chief Information Officer, Centers for Disease 

Control and Prevention. 

[FR Doc. E8–22190 Filed 9–22–08; 8:45 am] 

BILLING CODE 4163–19–P 

DEPARTMENT OF HEALTH AND 

HUMAN SERVICES 

Food and Drug Administration 

[Docket No. FDA–2008–N–0482] 

Ophthalmic Balanced Salt Solutions 

for Ocular Surgical Procedures; 

Enforcement Action Dates 

AGENCY: Food and Drug Administration, 

HHS. 

ACTION: Notice. 

SUMMARY: The Food and Drug 

Administration (FDA) is announcing its 

intention to take enforcement action 

against unapproved ophthalmic 

balanced salt solutions for irrigation of 

the eye during surgery and persons1

who manufacture or cause the 

manufacture of such products or their 

shipment in interstate commerce. 

Unapproved ophthalmic balanced salt 

solutions have been associated with 

adverse events, some of them leading to 

permanent loss of visual acuity, because 

of contamination of the product or other 

product defects. Ophthalmic balanced 

salt solutions are new drugs that require 

approved applications because they are 

not generally recognized as safe and 

effective. Two firms have approved 

applications to market these products. 

Manufacturers who wish to market 

ophthalmic balanced salt solutions must 

obtain FDA approval of a new drug 

application (NDA) or an abbreviated 

new drug application (ANDA). 

DATES: This notice is effective 

September 23, 2008. For information 

about enforcement dates, see 

SUPPLEMENTARY INFORMATION, section 

III.B. 

ADDRESSES: All communications in 

response to this notice should be 

identified with Docket No. FDA–2008– 

N–0482 and directed to the appropriate 

office listed as follows: 

Regarding applications under section 

505(b) of Federal Food, Drug, and 

Cosmetic Act (the act) (21 U.S.C. 

355(b)): Division of Anti-Infective and 

Ophthalmology Products, Office of New 

Drugs, Center for Drug Evaluation and 

Research, Food and Drug 

Administration, 10903 New Hampshire 


jlentini on PROD1PC65 with NOTICES
54830 Federal Register / Vol. 73, No. 185 / Tuesday, September 23, 2008 / Notices 

2 Data in the current system date back to 1969, 

when FDA first implemented an adverse event 

reporting system. 

3McDermott, M.L., H.F. Edelhauser, H.M. Hack, 

and R.H.S. Langston, ‘‘Ophthalmic Irrigants: A 

Current Review and Update,’’ Ophthalmic Surgery, 

19(10):724 733, 1988; Briggs, R.B. and D.L. 

McCartney, ‘‘Balanced Salt Solution Infusion 

Alert,’’ Archives of Ophthalmology, 106:718, 1988. 

4The agency’s general approach for dealing with 

these products in an orderly manner is spelled out 

in the Marketed Unapproved Drugs CPG. That CPG, 

however, provides notice that any product that is 

being marketed illegally, and the persons 

responsible for causing the illegal marketing of the 

Ave., Bldg. 22, Silver Spring, MD 

20993–0002. 

Regarding applications under section 

505(j) of the act: Office of Generic 

Drugs, Center for Drug Evaluation and 

Research (HFD–600), Food and Drug 

Administration, 7500 Standish Pl., 

Rockville, MD 20855. 

All other communications: Jennifer 

Devine, Center for Drug Evaluation and 

Research (HFD–310), Food and Drug 

Administration, 10903 New Hampshire 

Ave., Bldg. 51, rm. 5240, Silver Spring, 

MD 20993–0002. 

FOR FURTHER INFORMATION CONTACT: 

Jennifer Devine, Office of Compliance, 

Division of New Drugs and Labeling 

Compliance, Center for Drug Evaluation 

and Research (HFD–310), Food and 

Drug Administration, 10903 New 

Hampshire Ave., Bldg. 51, rm. 5240, 

Silver Spring, MD 20993–0002, 301– 

796–3347, e-mail: 

Jennifer.Devine@fda.hhs.gov. 

SUPPLEMENTARY INFORMATION: 

I. Background 

Ophthalmic balanced salt solutions 

are sterile, isotonic irrigating solutions 

used during surgical procedures on the 

eye. Prior to the 1960s, saline was the 

ophthalmic irrigating solution most 

commonly used to replace small 

amounts of intraocular fluid and wet the 

external eye. Balanced salt solutions for 

use during ocular surgery were 

developed in the 1960s to provide a 

temporary replacement for the aqueous 

humor, physiologically supporting the 

cornea until sufficient fluid is replaced 

by the ciliary body. These products 

enable the conduct of complex 

intraocular surgery techniques that 

require the replacement of large 

amounts of aqueous and vitreous 

humor. Some of the products marketed 

today are designed for use in surgical 

procedures of limited duration, while 

others are appropriate for use in 

procedures of any expected duration. 

Two firms—Alcon Laboratories and 

Akorn, Inc. (Adorn),—have approved 

applications for ophthalmic balanced 

salt solutions. Alcon’s approved 

products are marketed under the names 

BSS (NDA 20–742), intended for 

surgeries of under 60 minutes, and BSSplus (NDA 18–469), intended for 

surgery of any expected duration. 

Akorn’s approved products include 

Balanced Salt Solution (ANDA 75–503) 

and Endosol Extra (NDA 20–079). BSS, 

BSS-plus, and Endosol Extra have been 

designated as reference listed drugs, 

meaning that FDA can accept ANDAs 

referencing these products and filed 

under section 505(j) of the Federal, 

Food, Drug, and Cosmetic Act (act). In 

addition, the agency is aware that other 

firms market unapproved ophthalmic 

balanced salt solutions. 

II. Safety Issues Associated With 

Ophthalmic Balanced Salt Solutions. 

Serious safety concerns associated 

with ophthalmic balanced salt solutions 

are mentioned in adverse drug events 

reported to the agency and in the 

literature. Through January 31, 2008,2

FDA had received over 300 spontaneous 

reports of serious adverse events 

associated with all ophthalmic balanced 

salt solution products. Adverse events 

associated with these products that have 

been reported to FDA include toxic 

anterior segment syndrome (TASS) (a 

noninfectious inflammation of the 

anterior segment of the eye), bacterial 

endophthalmitis, corneal edema, and 

corneal opacity (clouding). In some 

cases, these adverse events have 

resulted in permanent loss of visual 

acuity. Because the adverse event 

reports sometimes include limited 

information on the product used, it is 

often difficult to establish whether an 

adverse event was caused by a 

particular product. In some instances, 

adverse events may be the result of 

improperly manufactured products. 

Product defects affecting the safety and 

performance of ophthalmic balanced 

salt solutions include contaminants 

(such as bacteria, endotoxins, fungi, or 

particulates) and variations in pH and 

osmolality.3 In 2006, for example, 

contamination with endotoxins of 

unapproved products made by one 

manufacturer was associated with 

several hundred reports of adverse 

events (both serious and nonserious), 

including TASS. Given the safety 

concerns described previously, FDA’s 

review of the individual applications 

and application supplements for 

ophthalmic balanced salt solutions, 

including their manufacturing methods 

and controls, is essential to ensuring the 

safety, efficacy, and quality of these 

products. 

III. Legal Status 

A. Ophthalmic Balanced Salt Solutions 

Are New Drugs Requiring Approved 

Applications 

As described previously, ophthalmic 

balanced salt solution products used for 

irrigation of the eye during surgery are 

not generally recognized as safe and 

effective under section 201(p) of the act 

(21 U.S.C. 321(p)). Therefore, 

ophthalmic balanced salt solution 

products are regarded as new drugs as 

defined in section 201(p) of the act and 

are subject to the requirements of 

section 505 of the act. As set forth in 

this notice, approval of an NDA or an 

ANDA under section 505 of the act is 

required as a condition for 

manufacturing or marketing all 

ophthalmic balanced salt solutions. 

After the dates identified in this notice, 

FDA intends to take enforcement action 

against unapproved ophthalmic 

balanced salt solutions and persons who 

cause the manufacture or interstate 

shipment of such products. Any person 

who submits an application for an 

ophthalmic balanced salt solution but 

has not received approval must comply 

with this notice. 

B. Notice of Enforcement Action 

Although not required to do so by the 

Administrative Procedure Act, the act, 

or any rules issued under its authority, 

or for any other legal reason, FDA is 

providing this notice to persons who are 

marketing unapproved ophthalmic 

balanced salt solution products that the 

agency intends to take enforcement 

action against such products and those 

who manufacture them or cause them to 

be manufactured or shipped in 

interstate commerce. 

Manufacturing or shipping 

unapproved ophthalmic balanced salt 

solution products can result in 

enforcement action, including seizure, 

injunction, or other judicial or 

administrative proceeding. Consistent 

with policies described in the agency’s 

guidance entitled ‘‘Marketed 

Unapproved Drugs—Compliance Policy 

Guide’’ (the Marketed Unapproved 

Drugs CPG), the agency does not expect 

to issue a warning letter or any other 

further warning to firms marketing 

unapproved ophthalmic balanced salt 

solution products prior to taking 

enforcement action. The agency also 

reminds firms that, as stated in the 

Marketed Unapproved Drugs CPG, any 

unapproved drug marketed without a 

required approved drug application is 

subject to agency enforcement action at 

any time. The issuance of this notice 

does not in any way obligate the agency 

to issue similar notices or any notice in 

the future regarding marketed 

unapproved drugs.4


jlentini on PROD1PC65 with NOTICES
Federal Register / Vol. 73, No. 185 / Tuesday, September 23, 2008 / Notices 54831 

product, are subject to FDA enforcement action at 

any time. 5For the purposes of this notice, the term 

‘‘commercially used or sold’’ means that the 

product has been used in a business or activity 

involving retail or wholesale marketing and/or sale. 

6 If FDA finds it necessary to take enforcement 

action against a product covered by this notice, the 

agency may take action relating to all of the 

defendant’s other violations of the act at the same 

time. For example, if a firm continues to 

manufacture or market a product covered by this 

notice after the applicable enforcement date has 

passed, to preserve limited agency resources, FDA 

may take enforcement action relating to all of the 

firm’s unapproved drugs that require applications at 

the same time (see, e.g., United States v. Sage 

Pharmaceuticals, 210 F.3d 475, 479–480 (5th Cir. 

2000) (permitting the agency to combine all 

violations of the act in one proceeding, rather than 

taking action against multiple violations of the act 

in ‘‘piecemeal fashion’’)). 

As described in the Marketed 

Unapproved Drugs CPG, the agency 

may, at its discretion, identify a period 

of time during which the agency does 

not intend to initiate an enforcement 

action against a currently marketed 

unapproved drug solely on the ground 

that it lacks an approved application 

under section 505 of the act. With 

respect to unapproved ophthalmic 

balanced salt solution products, the 

agency intends to exercise its 

enforcement discretion for only a 

limited period of time because 

ophthalmic balanced salt solution 

products are drugs with potential safety 

risks and approved ophthalmic 

balanced salt solutions for use in 

surgical procedures of both shorter and 

longer durations have been available 

since 1997. Therefore, the agency 

intends to implement this notice as 

follows. 

For the effective date of this notice, 

see the DATES section of this document. 

FDA intends to take enforcement action 

to enforce section 505(a) of the act 

against any unapproved ophthalmic 

balanced salt solution product that is 

not listed with the agency in full 

compliance with section 510 of the act 

(21 U.S.C. 360) before September 22, 

2008, and is manufactured, shipped, or 

otherwise introduced or delivered for 

introduction into interstate commerce 

by any person on or after September 23, 

2008. FDA also intends to take 

enforcement action to enforce section 

505(a) of the act against any unapproved 

ophthalmic balanced salt solution that 

is listed with FDA in full compliance 

with section 510 of the act but is not 

being commercially used or sold5 in the 

United States on September 22, 2008 

and that is manufactured, shipped, or 

otherwise introduced or delivered for 

introduction into interstate commerce 

by any person on or after September 23, 

2008. 

However, for unapproved ophthalmic 

balanced salt solution products that are 

commercially used or sold in the United 

States, have a National Drug Code (NDC) 

number listed with FDA, and are in full 

compliance with section 510 of the act 

before September 22, 2008 (‘‘currently 

marketed and listed’’), the agency 

intends to exercise its enforcement 

discretion as follows. FDA intends to 

initiate enforcement action against any 

currently marketed and listed 

unapproved ophthalmic balanced salt 

solution product that is manufactured 

on or after November 24, 2008 or that 

is shipped on or after January 21, 2009.6

Further, FDA intends to take 

enforcement action against any person 

who manufactures or ships such 

products after these dates. Any person 

who has submitted or submits an 

application for an ophthalmic balanced 

salt solution product but has not 

received approval must comply with 

this notice. 

The agency, however, does not intend 

to exercise its enforcement discretion as 

outlined previously if the following 

apply: (1) A manufacturer or distributor 

of an unapproved ophthalmic balanced 

salt solution product covered by this 

notice is violating other provisions of 

the act, including but not limited to, 

violations related to FDA’s current good 

manufacturing practices, adverse drug 

event reporting, labeling or misbranding 

requirements or (2) it appears that a 

firm, in response to this notice, 

increases its manufacture or interstate 

shipment of ophthalmic balanced salt 

solution products above its usual 

volume during these periods. 

Nothing in this notice, including 

FDA’s intent to exercise its enforcement 

discretion, alters any person’s liability 

or obligations in any other enforcement 

action, or precludes the agency from 

initiating or proceeding with 

enforcement action in connection with 

any other alleged violation of the act, 

whether or not related to an unapproved 

drug product covered by this notice. 

Similarly, a person who is or becomes 

enjoined from marketing unapproved 

drugs may not resume marketing of 

unapproved ophthalmic balanced salt 

solution products based on FDA’s 

exercise of enforcement discretion that 

is set forth in this notice. 

Drug manufacturers and distributors 

should be aware that the agency is 

exercising its enforcement discretion as 

described previously only in regard to 

ophthalmic balanced salt solution 

products that are marketed under an 

NDC number listed with the agency in 

full compliance with section 510 of the 

act before September 22, 2008. As 

previously stated, unapproved 

ophthalmic balanced salt solution 

products that are currently marketed but 

not listed with the agency on the date 

of this notice must, as of the effective 

date of this notice, have approved 

applications prior to their shipment in 

interstate commerce. Moreover, any 

person or firm that has submitted or 

submits an application but has yet to 

receive approval for such products is 

still responsible for full compliance 

with this notice. 

C. Discontinued Products 

Some firms may have previously 

discontinued the manufacturing or 

distribution of products covered by this 

notice without removing them from the 

listing of their products under section 

510(j) of the act. Other firms may 

discontinue manufacturing or marketing 

listed products in response to this 

notice. Firms that wish to notify the 

agency of product discontinuation 

should send a letter, signed by the firm’s 

chief executive officer, fully identifying 

the discontinued product(s), including 

NDC number(s), and stating that the 

product(s) has (have) been 

discontinued. The letter should be sent 

to Jennifer Devine (see ADDRESSES). 

Firms should also update the listing of 

their products under section 510(j) of 

the act to reflect discontinuation of 

unapproved ophthalmic balanced salt 

solution products. FDA plans to rely on 

its existing records, including drug 

listing records, or other available 

information when it targets violations 

for enforcement action. 

This notice is issued under the 

Federal Food, Drug, and Cosmetic Act 

(sections 502 and 505 (21 U.S.C. 352)) 

and under authority delegated to the 

Deputy Commissioner for Policy under 

section 1410.10 of the FDA Staff Manual 

Guide. 

Dated: September 8, 2008. 

Jeffrey Shuren, 

Associate Commissioner for Policy and 

Planning. 

[FR Doc. E8–22305 Filed 9–22–08; 8:45 am] 

BILLING CODE 4160–01–S 

DEPARTMENT OF HEALTH AND 

HUMAN SERVICES 

Food and Drug Administration 

[Docket No. FDA–2008–N–0481] 

Topical Drug Products Containing 

Papain; Enforcement Action Dates 

AGENCY: Food and Drug Administration, 

HHS. 

ACTION: Notice. 


jlentini on PROD1PC65 with NOTICES