Federal Register / Vol. 65, No. 103 / Friday, May 26, 2000 / Rules and Regulations 34081

Dated: May 16, 2000.

Margaret H. McFarland,

Deputy Secretary.

[FR Doc. 00–12756 Filed 5–25–00; 8:45 am]

BILLING CODE 8010–01–P

DEPARTMENT OF HEALTH AND

HUMAN SERVICES

Food and Drug Administration

21 CFR Part 176

[Docket No. 00F–0813]

Indirect Food Additives: Paper and

Paperboard Components

AGENCY: Food and Drug Administration,

HHS.

ACTION: Final rule.

SUMMARY: The Food and Drug

Administration (FDA) is amending the

food additive regulations to provide for

the safe use of sodium xylenesulfonate

as a component of paper and

paperboard intended to contact food.

This action is in response to a petition

filed by Tritex Co., Inc.

DATES: This rule is effective May 26,

2000. Submit written objections and

requests for a hearing by June 26, 2000.

ADDRESSES: Submit written objections to

the Dockets Management Branch (HFA–

305), Food and Drug Administration,

5630 Fishers Lane, rm. 1061, Rockville,

MD 20852.

FOR FURTHER INFORMATION CONTACT:

Mark A. Hepp, Center for Food Safety

and Applied Nutrition (HFS–215), Food

and Drug Administration, 200 C St. SW.,

Washington, DC 20204, 202–418–3098.

SUPPLEMENTARY INFORMATION: In a notice

published in the Federal Register of

March 7, 2000 (65 FR 12015), FDA

announced that a food additive petition

(FAP 0B4719) had been filed by Tritex

Co., Inc., 1001 Boul. Industriel, SaintEustache (Quebec), CANADA J7R 6C3

(zip code was incorrectly identified as

J7H 6C3 in the March notice). The

petition proposed to amend the food

additive regulations in § 176.170

Components of paper and paperboard

in contact with aqueous and fatty foods

(21 CFR 176.170) to provide for the safe

use of sodium xylene sulfonated as a

component of paper and paperboard

intended to contact food. Although the

additive was identified as sodium

xylene sulfonated in the notice of filing,

FDA feels that it is more appropriately

listed as sodium xylenesulfonate in this

final rule.

FDA has evaluated data in the

petition and other relevant material.

Based on this information, the agency

concludes that the proposed use of the

additive is safe, that the additive will

achieve its intended technical effect,

and therefore, that the regulations in

§ 176.170 should be amended as set

forth below.

In accordance with § 171.1(h) (21 CFR

171.1(h)), the petition and the

documents that FDA considered and

relied upon in reaching its decision to

approve the petition are available for

inspection at the Center for Food Safety

and Applied Nutrition by appointment

with the information contact person

listed above. As provided in § 171.1(h),

the agency will delete from the

documents any materials that are not

available for public disclosure before

making the documents available for

inspection.

The agency has previously considered

the potential environmental effects of

this rule as announced in the notice of

filing for FAP 0B4719. No new

information or comments have been

received that would affect the agency’s

previous determination that there is no

significant impact on the human

environment and that an environmental

impact statement is not required.

This final rule contains no collections

of information. Therefore, clearance by

the Office of Management and Budget

under the Paperwork Reduction Act of

1995 is not required.

Any person who will be adversely

affected by this regulation may at any

time file with the Dockets Management

Branch (address above) written

objections by June 26, 2000. Each

objection shall be separately numbered,

and each numbered objection shall

specify with particularity the provisions

of the regulation to which objection is

made and the grounds for the objection.

Each numbered objection on which a

hearing is requested shall specifically so

state. Failure to request a hearing for

any particular objection shall constitute

a waiver of the right to a hearing on that

objection. Each numbered objection for

which a hearing is requested shall

include a detailed description and

analysis of the specific factual

information intended to be presented in

support of the objection in the event

that a hearing is held. Failure to include

such a description and analysis for any

particular objection shall constitute a

waiver of the right to a hearing on the

objection. Three copies of all documents

are to be submitted and are to be

identified with the docket number

found in brackets in the heading of this

document. Any objections received in

response to the regulation may be seen

in the Dockets Management Branch

between 9 a.m. and 4 p.m., Monday

through Friday.

List of Subjects in 21 CFR Part 176

Food additives, Food packaging.

Therefore, under the Federal Food,

Drug, and Cosmetic Act and under

authority delegated to the Commissioner

of Food and Drugs, and redelegated to

the Director, Center for Food Safety and

Applied Nutrition, 21 CFR part 176 is

amended as follows:

PART 176—INDIRECT FOOD

ADDITIVES: PAPER AND

PAPERBOARD COMPONENTS

1. The authority citation for 21 CFR

part 176 continues to read as follows:

Authority: 21 U.S.C. 321, 342, 346, 348,

379e.

2. Section 176.170 is amended in the

table in paragraph (b)(2) by

alphabetically adding an entry under

the headings ‘‘List of substances’’ and

‘‘Limitations’’ to read as follows:

§ 176.170 Components of paper and

paperboard in contact with aqueous and

fatty foods.

* * * * *

(b) * * *

(2) * * *

List of substances Limitations

*******

Sodium xylenesulfonate (CAS Reg. No. 1300–72–7) For use only in paper and paperboard coatings at levels not to exceed

0.01 percent by weight of the finished paper and paperboard.

*******

34082 Federal Register / Vol. 65, No. 103 / Friday, May 26, 2000 / Rules and Regulations

* * * * *

Dated: May 11, 2000.

L. Robert Lake,

Director of Regulations and Policy, Center

for Food Safety and Applied Nutrition.

[FR Doc. 00–13209 Filed 5–25–00; 8:45 am]

BILLING CODE 4160–01–F

DEPARTMENT OF HEALTH AND

HUMAN SERVICES

Food and Drug Administration

21 CFR Part 200

[Docket No. 96N–0048]

RIN 0910–AA88

Sterility Requirement for AqueousBased Drug Products for Oral

Inhalation

AGENCY: Food and Drug Administration,

HHS.

ACTION: Final rule.

SUMMARY: The Food and Drug

Administration (FDA) is amending its

regulations to require that all

prescription and over-the-counter (OTC)

aqueous-based drug products for oral

inhalation be manufactured sterile. This

rule applies to aqueous-based oral

inhalation drug products in both singledose and multiple-use primary

packaging. Pressurized metered-dose

inhalers are not subject to this rule.

Based on reports of adverse drug

experiences from contaminated

nonsterile inhalation drug products and

recalls of these products, FDA is taking

this action to help ensure the safety and

effectiveness of these products.

DATES: This rule is effective May 27,

2002.

FOR FURTHER INFORMATION CONTACT:

Peter H. Cooney, Center for Drug

Evaluation and Research (HFD–160),

Food and Drug Administration, 5600

Fishers Lane, Rockville, MD 20857,

301–443–5818.

SUPPLEMENTARY INFORMATION:

I. Background

In the Federal Register of September

23, 1997 (62 FR 49638), FDA proposed

to amend its regulations to require that

all inhalation solutions for nebulization

be manufactured sterile. This action was

proposed to help ensure the safety and

effectiveness of these drug products.

Drug products for oral inhalation are

used to treat a variety of breathing

disorders and are frequently

administered to patients who are

immunocompromised, have cystic

fibrosis, or have chronic obstructive

airway disease. Aqueous-based oral

inhalation drug products either in

single-dose or multiple-use packaging

are administered by oral inhalation into

the lungs as a mist or spray created by

a nebulizer device. The majority of

inhalation drug products on the market

are manufactured to be sterile. Those

products not manufactured to be sterile

are often manufactured under assigned

microbial count limits, but current

manufacturing methods and safeguards

have not prevented dangerous microbial

contamination.

Inhalation drug products

contaminated with microorganisms are

likely to cause lung infections because

the contaminating organisms are

introduced with the drug product

directly into the lungs through the

mouth. Thus, microbial contamination

of these products may result in serious

health consequences. Microbial

contamination of these products may

also cause degradation of the drug

product.

Because of contamination problems

with several different aqueous-based

drug products for oral inhalation and for

the reasons explained in the proposed

rule, FDA has determined that current

manufacturing methods and safeguards

against contamination, including

microbial limits tests, have not

prevented dangerous microbial

contamination of nonsterile aqueousbased drug products for oral inhalation.

The final rule reflects FDA’s

determination that all aqueous-based

drug products for oral inhalation be

manufactured sterile. Once the final rule

becomes effective, failure to comply

with the sterility requirement will result

in a finding that the drug product is

adulterated under section 501(a)(2)(B) of

the Federal Food, Drug, and Cosmetic

Act (the act) (21 U.S.C. 351(a)(2)(B)),

and misbranded under section 502(j) of

the act (21 U.S.C. 352(j)). Failure to

comply with the sterility requirement

will also result in the agency’s refusal to

approve a new or abbreviated

application for a product, under section

505(d)(1), (d)(2), (d)(3), and (j)(4)(A) of

the act (21 U.S.C. 355(d)(1), (d)(2),

(d)(3), and (j)(4)(A)).

II. Highlights of the Final Rule

This final rule amends the regulations

governing requirements for specific

classes of drugs to include new § 200.51

for aqueous-based drug products for oral

inhalation. Section 200.51(a) requires

that all prescription and OTC aqueousbased drug products for oral inhalation

be manufactured sterile. FDA is taking

this action to prevent the public health

consequences of the distribution of

contaminated aqueous-based drug

products for oral inhalation and to help

ensure the safety and effectiveness of

these products.

In the Federal Register of October 11,

1991 (56 FR 51354), FDA proposed to

require that manufacturers use a

terminal sterilization process when

preparing a sterile drug unless the

process adversely affects the drug

product. The October 11, 1991,

proposed rule would require that

manufacturers include in their

applications a written justification for

not using terminal sterilization if such

process is not appropriate. The agency

plans to issue a final rule regarding

terminal sterilization. When the

proposed requirement for terminal

sterilization becomes final,

manufacturers of aqueous-based drug

products for oral inhalation will be

subject to its requirements.

The agency has revised the proposed

regulation in response to comments

received on the proposed rule. The

comments and responses are discussed

in section III of this document,

‘‘Comments on the Proposed Rule.’’ The

agency is revising the title of proposed

§ 200.51 from ‘‘Sterility Requirements

for Inhalation Solution Drug Products’’

to ‘‘Aqueous-Based Drug Products for

Oral Inhalation.’’ The new title names

the specific class of drugs subject to the

rule in conformance with the

established format of part 200 (21 CFR

part 200), subpart C of the regulations.

The agency is removing the phrases

‘‘inhalation solution drug products’’ and

‘‘inhalation solutions for nebulization’’

from proposed § 200.51. These phrases

are replaced by the phrase ‘‘aqueousbased drug products for oral

inhalation.’’ The agency has added the

phrase ‘‘for oral inhalation’’ to clarify

that the rule applies to orally

administered inhalation drug products

and not nasal sprays. The agency has

added the modifier ‘‘aqueous-based’’ to

the type of drug products covered to

exclude metered-dose inhalers from

coverage. In addition, the agency has

made minor edits to the final rule in

response to the President’s June 1, 1998,

memorandum on plain language in

government writing. The agency has

increased the amount of time for

manufacturers to comply with the

sterility requirement from 1 year to 2

years. All manufacturers of nonsterile

aqueous-based drug products for oral

inhalation will have until 2 years after

the date of publication of the final rule

to comply with the sterility

requirement. As discussed in section IV

of this document, ‘‘Effective Date,’’ the

agency believes this effective date more

realistically reflects the time