Draft Guidance for Industry; Exports and Imports Under the FDA Export Reform and Enhancement Act of 1996

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. 98D-0307]

Draft Guidance for Industry; Exports and Imports Under the FDA

Export Reform and Enhancement Act of 1996

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availability of a draft guidance document entitled, ``FDA Draft

Guidance for Industry on: Exports and Imports Under the FDA Export

Reform and Enhancement Act of 1996.'' The draft guidance document

addresses issues pertaining to the exportation of human drugs, animal

drugs, biologics, food additives, and devices as well as the

importation of components, parts, accessories, or other articles for

incorporation or further processing into articles intended for export.

DATES: Written comments on the draft guidance document may be submitted

by August 26, 1998. General comments on the agency's guidance documents

may be submitted at any time.

ADDRESSES: Submit written comments on the draft guidance document to

the Dockets Management Branch (HFA-305), Food and Drug Administration,

12420 Parklawn Dr., rm. 1-23, Rockville, MD 20857.

FOR FURTHER INFORMATION CONTACT: Philip L. Chao, Office of Policy (HF-

23), Food and Drug Administration, 5600 Fishers Lane, Rockville, MD

20857, 301-827-3380.

SUPPLEMENTARY INFORMATION: FDA is announcing the availability of a

draft guidance document entitled, ``FDA Draft Guidance for Industry on:

Exports and Imports Under the FDA Export Reform and Enhancement Act of

1996.'' Enacted and later amended in 1996, the FDA Export Reform and

Enhancement Act (Pub. L. 104-134, as amended by Pub. L. 104-180)

significantly changed the export requirements for human drugs, animal

drugs, biologics, devices, and, to a limited extent, food additives.

For example, before the law was enacted, most exports of unapproved new

drug products could only be made to 21 countries identified in section

802 of the Federal Food, Drug, and Cosmetic Act (the act), and these

exports were subject to various restrictions. The FDA Export Reform and

Enhancement Act amended section 802 of the act to allow, among other

things, the export of unapproved new drugs to any country in the world

if the drug complies with the laws of the importing country and has

valid marketing authorization from any of the following countries:

Australia, Canada, Israel, Japan, New Zealand, Switzerland, South

Africa, and the countries in the European Union (EU) and the European

Economic Area (EEA). (Currently, the EU countries are Austria, Belgium,

Denmark, Germany, Greece, Finland, France, Ireland, Italy, Luxembourg,

the Netherlands, Portugal, Spain, Sweden, and the United Kingdom. The

EEA countries are the EU countries, Iceland, Liechtenstein, and Norway.

The list of countries will expand automatically if any country accedes

to the EU or becomes a member of the EEA.)

The draft guidance document provides information on the statutory

requirements for exporting human drugs, animal drugs, biologics, and

medical devices, general requirements for products exported under

section 801 of the act (21 U.S.C. 381), labeling requirements for drugs

and biologics exported under section 801(e) of the act, export

requirements for unapproved drugs, biologics, and devices under section

802(b) of the act (21 U.S.C. 382(b)), exports of unapproved drugs and

devices for investigational use, exports of unapproved drugs and

devices in anticipation of foreign approval; exports of drugs and

devices for diagnosing, preventing, or treating a tropical disease or a

disease ``not of significant prevalence in the United States,'' export

notifications to FDA, and ``import for export.''

The draft guidance document represents the agency's current

thinking on exports and imports-for-export under sections 801 and 802

of the act. 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 statute, regulations, or both.

Interested persons may submit to the Dockets Management Branch

(address above) written comments on the draft guidance document. Two

copies of any comments are to be submitted, except that individuals may

submit one copy. Comments are to be identified with the docket number

found in brackets in the heading of this document. A copy of the draft

guidance document and received comments may be seen in the office

[[Page 32220]]

above between 9 a.m. and 4 p.m., Monday through Friday. The agency

invites comments on the following issues:

What are the draft guidance document's strengths and

weaknesses? For example, which topics might require more explanation?

Which international standards organization(s), if any,

should FDA recognize for purposes of section 802(f)(1) of the act?

Which international standards should be used and for which products?

Under section 802(f)(1) of the act, all drugs and devices exported

under section 802 of the act must be in substantial conformity with

current good manufacturing practice requirements or meet

``international standards as certified by an international standards

organization recognized'' by FDA.

Section 802(e) of the act requires an application to

export a drug or device intended to treat a tropical disease or a

disease that is not of significant prevalence in the United States. FDA

may approve exportation if it finds that the drug or device will not

expose patients in the foreign country to an unreasonable risk of

illness or injury and that the probable health benefits from using the

drug or device under its labeled conditions of use outweigh the risk of

injury or illness from its use, ``taking into account the probable

risks and benefits of currently available drug or device treatment.''

What should the application contain so that FDA may make these

findings? How many applications might be submitted?

The draft guidance document, with a table of contents and ``quick

locator guide,'' can be accessed electronically at http://www.fda.gov/

opacom/fedregister/frexport.html. The full text of the draft guidance

document, without the table of contents and quick locator guide (due to

reformatting and pagination changes in the Federal Register), follows:

FDA Guidance for Industry on: Exports and Imports Under the FDA

Export Reform and Enhancement Act of 1996

I. Introduction

This guidance document is intended to summarize and to explain the

basic requirements and procedures for exporting and importing human

drugs, animal drugs, biologics, devices, food additives, color

additives, and dietary supplements that may not be sold or distributed

in the United States under the FDA Export Reform and Enhancement Act of

1996 (Pub. L. 104-134, and amended by Pub. L. 104-180). \1\ This law

amended sections 801 and 802 of the Federal Food, Drug, and Cosmetic

Act (the act), as well as section 351(h) of the Public Health Service

Act, simplifying the requirements for exporting unapproved human drugs,

biologics, and devices. \2\ In addition, the FDA Export Reform and

Enhancement Act substantially reduced the requirements for exporting

unapproved new animal drugs, provided a new option for exporting

unapproved devices, and added a new provision, at section 801(d)(3) of

the act that permits the import of certain components, parts, and

accessories of human drugs, biologics, devices, food additives, color

additives, and dietary supplements for further processing or

incorporation into products intended for export.

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\1\ This guidance document may be supplemented by other guidance

documents on specific topics.

\2\ If a product meets the requirements for sale in the United

States, the act has no restrictions on its exportation.

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This guidance document does not address export certificates and

fees. Information on these subjects can be found in Compliance Policy

Guide 7150.01, ``Certification for Exports.''

Please note that a firm or product may be subject to additional

statutory or regulatory requirements beyond those described in this

guidance. For example, depending on the type of products it

manufactures, a firm may be subject to registration requirements under

section 510 of the act (21 U.S.C. 360).

This guidance document represents the agency's current thinking

with respect to the exportation of various products under the FDA

Export Reform and Enhancement Act of 1996 and replaces FDA's previous

guidance on exports entitled, ``A Review of FDA's Implementation of the

Drug Export Amendments of 1986.'' 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 statute, regulations, or both.

II. Terms Used in This Guidance

This guidance uses the following terms:

``act'' means the Federal Food, Drug, and Cosmetic Act. Citations

to specific sections of the act will use the numerical sequence

specified in the act rather than the section numbers used in the U.S.

Code.

``cGMP'' means current good manufacturing practice. For drugs and

biologics, cGMP regulations can be found at parts 210 and 211 (21 CFR

parts 210 and 211). For devices, cGMP regulations can be found at part

820 (21 CFR part 820). For blood and blood components, additional

regulations can be found at part 606 (21 CFR part 606).

``FDA'' or ``agency'' means the Food and Drug Administration.

``IDE'' means an investigational device exemption application.

These are applications containing requests to use an unapproved device

in clinical tests using human subjects. The regulations are authorized

under section 520(g) of the act (21 U.S.C. 360(g)), and the

implementing regulations can be found at part 812 (21 CFR part 812).

``IND'' means an investigational new drug application. These

applications are required for persons who intend to conduct clinical

investigations involving products subject to section 505 of the act (21

U.S.C. 355) or to the licensure provisions of the Public Health Service

Act (42 U.S.C. 262). The IND regulations are authorized by section

505(i) of the act and are found at part 312 (21 CFR part 312).

``1986 Amendments'' means the Drug Export Amendments Act of 1986

(Pub. L. 99-960). Most provisions in the 1986 Amendments were revised

or eliminated by the 1996 Amendments.

``1996 Amendments'' means the FDA Export Reform and Enhancement Act

of 1996 (Pub. L. 104-134 and amended by Pub. L. 104-180).

``PHS Act'' means the Public Health Service Act (42 U.S.C. 201 et

seq.). Citations to specific sections of the PHS Act will use the

numbers specified in the PHS Act rather than the section numbers used

in the U.S. Code.

``PMA'' means a premarket approval application. This is a marketing

application for certain devices under section 515 of the act. The

regulation for PMA's can be found at 21 CFR part 814.

``312 Program'' means the regulatory program used by FDA for

permitting the exportation of investigational drugs or biologics for

clinical use in foreign countries. The principal statutory authority

for the 312 Program is section 505(i) of the act, and the regulation

can be found at Sec. 312.110.

III. Statutory Background

Some background information on the statutory requirements that

existed before the enactment of the 1996 Amendments is helpful to

understand why the 1996 Amendments were enacted.

A. Exports of Drugs and Biologics That May Not be Sold in the United

States

The export provision in the act had its origins in 1906 as part of

the Federal Food and Drugs Act (Pub. L. 59-384).

[[Page 32221]]

Section 2 of the 1906 Federal Food and Drugs Act stated that:

* * * no article shall be deemed misbranded or adulterated

within the provisions of this act when intended for export to any

foreign country and prepared or packed according to the

specifications or directions of the foreign purchaser when no

substance is used in the preparation or packing thereof in conflict

with the laws of the foreign country to which said article is

intended to be shipped; but if said article shall be in fact sold or

offered for sale for domestic use or consumption, then this proviso

shall not exempt said article from the operation of any of the other

provisions of this act.

This export provision remained essentially unchanged in the Federal

Food, Drug, and Cosmetic Act of 1938 (Pub. L. 75-717), where it was

codified as section 801(d). Section 801(d) of the 1938 Act stated that:

A food, drug, device, or cosmetic intended for export shall not

be deemed to be adulterated or misbranded under this Act if it (1)

accords to the specifications of the foreign purchaser, (2) is not

in conflict with the laws of the country to which it is intended for

export, (3) is labeled on the outside of the shipping package that

it is intended for export, and (4) is not sold or offered for sale

in domestic commerce * * *.

The 1938 act, however, also defined the terms, ``drug,'' and ``new

drug,'' and these definitions led to the conclusion that section

801(d)(1) of the act did not apply to new drugs. (See, e.g., United

States v. An Article of Drug, etc. * * * Ethionamide-INH, No. 67 C 288

(E.D. N.Y., Aug. 19, 1967); United States v. Yaron Laboratories, Inc.,

365 F.Supp. 917, 919 (N.D. Cal. 1972); Compliance Policy Guide 7132c.01

(Oct. 1, 1980).) As a result, the act was interpreted as permitting the

export of approved drugs, but not the export of unapproved new drugs.

This interpretation was viewed as imposing hardships on the

pharmaceutical industry (by impairing its ability to compete in

international markets) without any accompanying public health benefits

(see S. Rept. 99-225, 99th Cong., 2d sess. 5-6 (1985)).

To remedy the situation, Congress enacted the Drug Export

Amendments Act of 1986 (Pub. L. 99-960). Insofar as human drug products

and biologics were concerned, the 1986 Amendments created section 802

of the act and established three separate ``tracks'' for exporting

unapproved drugs and unlicensed biologics. Under ``track 1,'' FDA was

authorized to approve an application for the export of new human and

animal drugs and biologics that were not approved in the United States,

so long as the drug contained the same active ingredient(s) as a

product for which marketing approval in the United States was being

sought or the biological product was one for which licensing was

actively being pursued. Exports under ``track 1'' were confined to 21

specific countries listed in section 802 of the act. Those countries

were: Australia, Austria, Belgium, Canada, Denmark, the Federal

Republic of Germany, Finland, France, Iceland, Ireland, Italy, Japan,

Luxembourg, the Netherlands, New Zealand, Norway, Portugal, Spain,

Sweden, Switzerland, and the United Kingdom.

Under ``track 2,'' FDA was authorized to approve the export of

drugs and biologics intended for the treatment of tropical diseases.

Persons seeking to export a drug under track 2 had to submit an

application to FDA, and FDA had to find, based on ``credible scientific

evidence,'' that the drug would be safe and effective in the country to

which it would be exported in the prevention or treatment of a tropical

disease in that country.

``Track 3'' applied to partially processed biological products and

amended section 351 of the PHS Act. FDA was authorized to approve the

export of partially processed human biological products intended for

further manufacture in any of the 21 listed countries, but the final

product had to be approved or in the process of receiving approval from

the foreign country.

Additionally, the 1986 Amendments added a new section 801(d) of the

act (regarding importation of drugs), and renumbered the existing

section 801(d) as a new section 801(e)(1) of the act. \3\

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\3\ The 1986 Amendments did not alter the export requirements

for insulin and antibiotics. These products remained subject to the

basic export requirements that are now seen in section 801(e)(1) of

the act, and so exports could occur without prior FDA approval.

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The 1986 Amendments, however, presented several problems and

concerns. One significant problem was that the 1986 Amendments limited

exports of unapproved drugs and biologics to 21 countries. Although the

1986 Amendments provided criteria for adding more countries to the

list, it did not provide any administrative mechanism for doing so.

Consequently, exports to countries that were not on the list were not

permitted.

The requirement that the drug contain the same active ingredient as

a drug for which marketing approval in the United States was being

``actively pursued'' also caused some concern in the industry.

Questions arose concerning the degree to which the active ingredient

had to be the ``same'' or how ``actively'' the manufacturer had to be

seeking approval.

The concept in the 1986 Amendments which required FDA approval

before a product could be exported generated criticism and debate as

well. The 1986 Amendments required a person to file an application to

export a drug at least 90 days before the date on which the applicant

proposed to export the drug; required FDA to publish a notice in the

Federal Register identifying the applicant, the drug to be exported,

and the country to which the drug was being exported (for Track 1

exports only); and established requirements for the application as well

as the agency's action on an application. For example, if the agency

decided to disapprove an application, it had to provide a written

statement to the applicant describing deficiencies that the applicant

must correct and give the applicant 60 days to correct those

deficiencies. Some firms charged that this approval process took too

long; others questioned why the United States should have to approve

the export of a product to a foreign country, particularly when the

foreign country had its own public health authorities or had approved

the product for marketing.

B. Exports of Animal Drugs That May Not be Sold in the United States

As stated earlier, section 801(e) of the act was construed as not

applying to the exportation of unapproved new human drugs. This

interpretation also covered unapproved new animal drugs, and was made

explicit in 1968 as part of the Animal Drug Amendments of 1968 (Pub. L.

90-399). Although the initial Congressional bill would have permitted

exportation of unapproved new animal drugs, Congress, at the request of

the then-Department of Health, Education, and Welfare, elected to amend

section 801 of the act to prevent the exportation of unapproved new

animal drugs and animal feed containing unapproved new animal drugs

(see S. Rept. 1308, 90th Cong., 2d sess., 1968 U.S. Code Cong. & Admin.

News 2160). The legislative history explained that the amendment's

purpose was to ``preserve, essentially, the status quo with respect to

the export exemption'' (id.).

The Drug Export Amendments Act of 1986 altered the export

requirements for unapproved new animal drugs in the same manner that it

changed the export requirements for unapproved new human drugs (such as

limiting exports to 21 countries and requiring the exporter to be

pursuing product approval in the United States as a condition for

allowing exportation). Consequently, an unapproved new

[[Page 32222]]

animal drug could be exported under section 802 of the act.

C. Exports of Devices That May Not be Sold in the United States

As stated earlier, then-section 801(d) of the Federal Food, Drug,

and Cosmetic Act of 1938 (now codified at section 801(e)) stated that a

food, drug, device, or cosmetic intended for export would not be

considered adulterated or misbranded if the product: (1) Met the

foreign purchaser's specifications; (2) was not in conflict with the

laws of the country to which it was being exported; (3) was labeled on

the outside of the shipping package that the product was intended for

export; and (4) was not sold or offered for sale in domestic commerce.

This authority remained unchanged until 1976 when, as part of the

Medical Device Amendments Act of 1976 (Pub. L. 94-295), Congress

amended the provision to state that the four criteria did not apply to

any device that did not comply with an applicable requirement under

sections 514 (performance standards) or 515 (premarket approval) of the

act, to devices that were exempt from sections 514 or 515 of the act

under section 520(g) of the act (devices subject to an IDE), and to

banned devices (under section 516 of the act) unless, in addition to

requiring compliance with section 801(e)(1) of the act, the agency

determined that exportation of the device would not be contrary to the

public health and safety and the device had the approval of the foreign

country that would receive the device. In other words, most unapproved

devices could not be exported unless the agency determined that

exportation would not be contrary to the public health or safety and

that the foreign country approved of the device. This provision was,

and remains, codified at section 801(e)(2) of the act (21 U.S.C.

381(e)(2)).

As in the case of FDA drug export approvals, the statutory

requirement that FDA approve device exports began to generate criticism

from the device industry. The device industry criticized the agency for

the time FDA took to determine whether an export request met the

statutory criteria. FDA reduced the average time for processing device

export requests from an average of 91 days in 1992 to 10 days in 1995,

yet, despite this significant reduction in processing time, the

statute's export approval requirements were seen as adversely affecting

the ability of U.S. firms to enter or to compete in foreign markets.

D. Enactment of the FDA Export Reform and Enhancement Act of 1996

The FDA Export Reform and Enhancement Act of 1996 (Pub. L. 104-134,

and amended by Pub. L. 104-180) addressed industry's problems and

concerns. For human drugs and biologics that may not be sold in the

United States, the 1996 Amendments:

Amended section 801(d) of the act to allow import of

components of drugs and biologics into the United States that do not

comply with other provisions in the act where those components are

intended for incorporation or further processing by the initial owner

or consignee into a drug or biologic that will be exported under

section 801(e) or section 802 of the act or section 351(h) of the PHS

Act.

Amended section 801 of the act to allow exports of

approved drugs (except for insulin and antibiotics) to countries that

have different or additional labeling requirements. The new provision,

at section 801(f) of the act, requires such drugs to be labeled in

accordance with the requirements and conditions for use in the foreign

country and to be labeled in accordance with the act. If the drug's

labeling includes conditions of use that are not approved in the United

States, the labeling must state that such conditions for use have not

been approved under the act.

Replaced section 802 of the act in its entirety with a new

section 802 of the act that:

Eliminated the requirement for prior FDA approval of

exports of unapproved drugs (in most cases),

Significantly expanded the list of countries to which

unapproved products can be exported without prior FDA approval (and

also provided administrative mechanisms for the Secretary of Health

and Human Services (the Secretary) to add countries to the list and

for FDA to permit exports of specific products to unlisted

countries),

Authorized exports of unapproved drugs and biologics

intended for use in clinical investigations in any of 25 countries

identified in section 802(b)(1)(A) of the act,

Authorized the export of unapproved products to a

listed country in anticipation of marketing approval in that

country,

Created a simple notification process for most exported

products (as opposed to the application process required under the

1986 Amendments). Notification is not required for drugs exported

for investigational use in a listed country or drugs exported in

anticipation of marketing authorization in a listed country, and

Authorized FDA to permit the export of unapproved

products intended to treat tropical or other diseases that are ``not

of significant prevalence in the United States.''

For animal drugs that may not be sold in the United States, the

1996 Amendments:

Again restricted the authority to export an unapproved new

animal drug to section 801 of the act. \4\ However, unlike the

situation that existed from 1968 to 1986, an unapproved new animal drug

can be exported if it is: Intended for export; accords to the

specifications of the foreign purchaser; is not in conflict with the

laws of the importing country; is labeled on the outside of the

shipping package that it is intended for export; and is not sold or

offered for sale in interstate commerce (see section 801(e)(1) of the

act).

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\4\ Animal drugs cannot be exported under section 802 of the act

because that section pertains to biologics, devices, and human

drugs.

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The only unapproved new animal drugs that cannot be

exported under section 801 of the act are ``banned'' animal drugs (see

section 801(e)(3) of the act). Neither the statute nor the legislative

history explains what a ``banned'' animal drug is, and FDA is working

on an interpretation as to what constitutes a ``banned'' animal drug.

For devices that may not be sold in the United States, the 1996

Amendments:

Amended section 801(d) of the act to permit the import of

component parts, accessories, or other articles of a device that do not

comply with other provisions in the act, if those component parts,

accessories, or other articles are intended for incorporation or

further processing by the initial owner or consignee into a device that

will be exported under section 801(e) or section 802 of the act or

section 351(h) of the PHS Act;

Amended section 801 of the act to permit exportation of

devices under section 801(e) of the act or under section 802 of the

act;

Replaced section 802 of the act in its entirety with a new

section 802 of the act that:

Eliminated the requirement for prior FDA approval for

exports (for devices approved in a listed country or destined for

clinical investigations in a listed country),

Created administrative mechanisms for the Secretary to

add countries to the list and for FDA to approve exports of specific

products to unlisted countries,

Authorized exports of unapproved devices intended for

use in clinical investigations in any of 25 countries identified in

section 802 of the act,

Authorized the export of unapproved devices to a listed

country in anticipation of marketing approval in that country,

Created a simple notification process for exported

devices (as opposed to the application process under section

801(e)(2) of the act). Notification is not required for devices

exported for investigational use to a listed country or devices

exported in

[[Page 32223]]

anticipation of marketing authorization in the listed country, and

Authorized FDA to permit the export of unapproved

devices intended to treat tropical diseases or other diseases that

are ``not of significant prevalence in the United States.''

Additionally, the 1996 Amendments permit importation of food

additives, color additives, and dietary supplements into the United

States if those articles are intended for incorporation or further

processing by the initial owner or consignee into a drug, biologic,

device, food, food additive, color additive, or dietary supplement that

will be exported.

This document describes the requirements for drugs (both human and

animal), biologics, and devices under sections 801 and 802 of the act

and section 351(h) of the PHS Act, as amended by the 1996 Amendments.

It begins with a discussion of the principal export requirements under

sections 801 and 802 of the act and section 351(h) of the PHS Act,

followed by a discussion of the ``import-for-export'' requirements

under section 801 of the act.

IV. General Requirements for Products Exported Under Section

801(e)(1) of the Act

Section 801(e)(1) of the act contains general requirements for any

food, drug, device, or cosmetic that may not be sold in the United

States and is intended for export. These requirements apply regardless

of whether the product is exported under section 801(e) or section 802

of the act or section 351(h) of the PHS Act. \5\ (Additional

requirements apply to products exported under section 802 of the act

and to devices exported under section 801(e)(2) of the act; those

requirements are described later in this document).

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\5\ The requirements in section 801(e)(1) of the act apply to

all products exported under section 802 of the act due to section

802(f)(3) of the act. That section prohibits exportation of a

product under section 802 of the act if the requirements in section

801(e)(1)(A) through (e)(1)(D) of the act are not met. The

requirements in section 801(e)(1) of the act also apply to partially

processed biologics exported under section 351(h) of the PHS Act.

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Section 801(e)(1) of the act states that a food, drug, device, or

cosmetic intended for export shall not be deemed to be adulterated or

misbranded if the product: Accords to the specifications of the foreign

purchaser; is not in conflict with the laws of the country to which it

is intended for export; is labeled on the outside of the shipping

package that it is intended for export; and is not sold or offered for

sale in domestic commerce.

During routine inspections, FDA will evaluate whether a firm has

complied with section 801(e)(1) of the act. Consequently, records are

very important for demonstrating compliance with each element of

section 801(e)(1) of the act.

To demonstrate that the product meets the foreign purchaser's

specifications, FDA recommends that the firm exporting the product

maintain records describing or listing the product specifications

requested by the foreign purchaser. This would include details about

the product (e.g., dosage strength, dosage form, purity, quality,

operating parameters, composition, etc.) and any details concerning the

product's manufacture (e.g., type of sterilization process to be used,

compliance with a particular manufacturing standard, etc.) as requested

by the foreign purchaser. FDA recommends that the firm have an English-

language translation of the specifications document or be prepared to

translate the document into English at the time of any FDA inspection.

To demonstrate that the product does not conflict with the laws of

the importing country, FDA recommends that the firm obtain a letter

from the foreign government agency, department, or other body stating

that the product has marketing approval from the foreign government or

does not conflict with that country's laws. Letters should not be from

nongovernmental bodies or persons (such as company officials or

attorneys in the foreign country). Additionally, if the letter from the

foreign government is not in English, FDA recommends that the firm have

an English-language translation of that document or be prepared to

translate the document into English at the time of any FDA inspection.

Such translations are essential because they will enable the firm to

show, and for FDA to verify, that the product does not conflict with

the laws of the importing country.

To demonstrate that the product is labeled on the outside of the

shipping package that it is intended for export, FDA recommends that

the firm place a statement on the shipping packages themselves. A

statement such as ``For export only'' may be sufficient.

To demonstrate that the product is not sold or offered for sale in

the United States, FDA recommends that the firm maintain records

concerning the product, its labeling, and similar products sold or

offered for sale in the United States. The labeling can simply state

that the product is ``Not for sale in the United States,'' or bear a

similar statement. As for the product itself, FDA examines whether the

product (as opposed to batches, lots, or production runs of a product)

is sold or offered for sale in the United States. For example, if

company A makes five batches of a particular unapproved drug and

intends to export two batches (and sell the remaining three batches in

the United States), the fact that company A intends to export the two

batches does not mean that the product is ``not sold or offered for

sale in the United States.'' Instead, FDA considers the unapproved drug

to be sold in the United States because other batches of the same

product are sold in the United States.

The requirements in section 801(e)(1) of the act apply to foods,

drugs (both human and animal (except for ``banned'' animal drugs, which

may not be exported)), biologics, devices, and cosmetics intended for

export, whether they are exported under section 801 or section 802 of

the act or section 351(h) of the PHS Act. Furthermore, depending on the

type of product being exported and the legal authority supporting the

product's exportation, additional requirements may apply.

A. Special Requirements for Certain Devices

Some devices face additional statutory requirements before they can

be exported under section 801(e)(1) of the act. Under section 801(e)(2)

of the act, if an unapproved device does not comply with an applicable

requirement under sections 514 (performance standards) or 515

(premarket approval) of the act, is exempt from either such section

under section 520(g) of the act, or is a banned device under section

516 of the act, the device may be deemed to be adulterated or

misbranded unless, in addition to the requirements in section 801(e)(1)

of the act, FDA has determined that exportation of the device is not

contrary to the public health and safety and has the approval of the

country to which it is intended for export.

The act provides that any device introduced into interstate

commerce after May 28, 1976, is automatically considered to be a

``class III'' device requiring premarket approval under section 515 of

the act. Such devices may not be legally marketed, unless and until

FDA: (1) Classifies the device into class I or II; (2) grants marketing

clearance by issuing an order under section 513(i) of the act, in

response to a report submitted by the sponsor under section 510(k) of

the act, determining that the device is substantially equivalent to a

predicate device that does not require premarket approval (hereinafter

referred to as 510(k) marketing clearance); or (3) issues an order

under section 515(d)(1)(A) of the act approving an application for

premarket approval.

Although the act prohibits exportation of class III devices

requiring premarket

[[Page 32224]]

approval unless the criteria under section 801(e)(2) of the act are

met, \6\ FDA, in exercising its enforcement discretion, has not taken

enforcement action against those manufacturers who have not complied

with the export criteria in section 801(e)(2) of the act, provided that

the manufacturers have reasonably concluded that, if a report under

section 510(k) of the act had been submitted to FDA, FDA would have

granted 510(k) marketing clearance. FDA intends to continue exercising

its enforcement discretion in this manner, with respect to the

requirements in section 801(e)(2) of the act. FDA emphasizes, however,

that it does not intend to exercise enforcement discretion with respect

to the requirements in section 801(e)(1) of the act for manufacturers

who reasonably believe that their devices would receive a 510(k)

marketing clearance.

---------------------------------------------------------------------------

\6\ Such devices may be eligible for export under section 802 of

the act. (A discussion of section 802 of the act appears in section

VI.B of this document.)

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To help FDA determine whether exportation of the device is not

contrary to the public health and safety, FDA recommends that

manufacturers provide basic safety data for the device. Such data often

consists of a statement certifying that a search of medical databases

has not identified any adverse safety data for similar devices or the

materials used in the device, or summaries of any adverse safety data,

including a discussion as to why the adverse effects should not be

considered applicable to the device that is to be exported. Brief

summaries of available animal safety studies conducted with the device

and safety data from human clinical studies are also helpful. \7\ FDA

ordinarily does not need safety data if the device is the subject of an

approved IDE or is considered to have an approved IDE and will be

marketed or used in the importing country for the same intended use.

\8\

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\7\ For in vitro diagnostic devices, where the device is to be

the sole determinate of whether a particular course of treatment

will be initiated for a life-threatening disease, the agency

recommends that the manufacturer provide a statement indicating

whether an alternative test will be available to confirm the test

results.

\8\A device may be considered to have an approved IDE if an

institutional review board determines that the device is a

nonsignificant risk device, and provided the device has met the

requirements for nonsignificant risk devices under Sec. 812.2(b).

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To help FDA determine whether exportation of the device has the

approval of the country to which it is intended for export, FDA

recommends that the manufacturer obtain a letter from the foreign

country approving of the device's importation. If the manufacturer is

exporting the device to a country in the European Economic Area and the

device has received a CE mark, documentation of the CE mark will

ordinarily be sufficient.

Additional information regarding device exports under section

801(e)(2) of the act can be found in the guidance document entitled,

``Procedures for Obtaining FDA Approval to Export Unapproved Medical

Devices.'' (See ``For Further Information Contact'' in section XII of

this document.)

B. Special Requirements for Partially Processed Biologics

The 1996 Amendments also changed the export requirements for

partially processed biological products. Under section 351(h) of the

PHS Act, a partially processed biological product may be exported if it

is: ``not in a form applicable to the prevention, treatment, or cure of

diseases or injuries of man;'' not intended for sale in the United

States; and intended for further manufacture into final dosage forms

outside the United States.

Exports of such products must comply with section 801(e)(1) of the

act and with cGMP's or international manufacturing standards as

certified by an international standards organization recognized by the

agency.

1. What Constitutes a Partially Processed Biological Product?

FDA interprets the term ``partially processed biological products''

as meaning biological products requiring purification, inactivation,

fractionation, or significant chemical modification (such as the

formation or breakage of covalent bonds and the incorporation of

peptides into a diagnostic test kit) before being used in the

formulation of a final product. Thus, a finished bulk product that

could be formulated into a finished dosage form through manufacturing

steps other than purification, inactivation, fractionation, or

significant chemical modification would not constitute a partially

processed biological product that could be exported under section

351(h) of the PHS Act. Certain other products, such as source plasma

and source leukocytes, also would not be partially processed biological

products because they are finished products (notwithstanding the

possibility that their intended use may be as a source material for

further manufacturing into another product), and FDA requires such

products to be licensed. \9\

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\9\ Unlicensed biologics that fail to qualify for export under

section 351(h) of the PHS Act may qualify for export under section

802 of the act.

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Products that do qualify as partially processed biological products

include intermediate biological products that a manufacturer has

partially processed and that would be subject to licensure as final

products after the completion of additional manufacturing steps. For

example, synthetic peptides that are a component of an in vitro

diagnostic test kit would be partially processed biological products.

FDA encourages persons who may be uncertain as to whether their

products are partially processed biological products to contact the

Import/Export Team in the Center for Biologics Evaluation and Research

(see the ``For Further Information Contact'' in section XII of this

document for the address and phone number).

2. cGMP Requirements

Section 351(h) of the PHS Act also requires partially processed

biological products to be ``manufactured, processed, packaged, and held

in conformity with current good manufacturing practice requirements''

or international manufacturing standards recognized by the agency. FDA

will inspect manufacturers to ensure that they are in compliance with

cGMP's.

FDA acknowledges that section 351(h) of the PHS Act also refers to

``international manufacturing standards as certified by an

international standards organization'' recognized by FDA. At this time,

FDA has not recognized any such international standards or

organizations for purposes of section 351(h) of the PHS Act, but is

examining this issue closely.

3. Additional Requirements Under Section 351(h) of the PHS Act

All exports of FDA-regulated products that may not be sold or

marketed in the United States, including partially processed biological

products exported under section 351(h) of the PHS Act, must conform to

the standard export requirements of section 801(e)(1) of the act. Thus,

a product intended for export under section 351(h) of the PHS Act must:

Accord with specifications of the foreign purchaser; not be in conflict

with the laws of the country to which it is intended for export; be

labeled on the outside of the shipping package that as intended for

export; and not be sold or offered for sale in domestic commerce.

Consistent with section 801(e)(1) of the act, section 351(h)(2) of the

PHS Act further requires that the product may not be intended for sale

in the United States.

Records are important in FDA's evaluation of compliance with

section

[[Page 32225]]

351(h) of the PHS Act, including the requirements section 801(e)(1) of

the act. FDA recommends that the firm or manufacturer maintain the

following records for possible review during a routine annual or

biennial FDA inspection. Depending on the particular circumstances of

export, different or additional records may also be relevant.

Evidence that product for export qualifies as a partially

processed biological product;

Evidence that the partially processed biological product

complies with the laws of the country to which it is being exported and

accords to the specifications of the foreign purchaser, in accordance

with section 801(e)(1) of the act, and is intended for further

manufacture into final dosage form outside the United States, in

accordance with section 351(h)(3) of the PHS Act. Such evidence may

consist of a valid marketing authorization for the partially processed

biological product or the final product from the foreign ministry of

health, contractual agreement, and purchase orders that may include

foreign specifications;

Records, such as manufacturing records, that trace the

partially processed biological product through the assignment of a

batch or lot numbering system at the U.S. exporting firm. The agency

suggests that these records also include temperature stability data for

product during the conditions of transit (export) and periodic checks

of the capacity of the shipping containers;

Distribution records of exported partially processed

biological products;

Copies of all labeling that accompanies the partially

processed biological product for export (i.e., container label or any

package insert). FDA recommends that the partially processed biological

product's container label state, ``Caution: For Further Manufacturing

Use Only;'' and

Evidence that the product is not intended for sale in the

United States and has not been sold or offered for sale in the United

States. This may consist of purchase orders from the foreign purchaser

and distribution records and records of the product's labeling and

similar products sold in the United States. FDA examines whether the

product itself (as opposed to batches or lots) is sold or offered for

sale in the United States. For example, if a company produces five

batches of a partially processed biological product and intends to

export two batches and sell the remaining three in the United States,

the product is deemed ``sold or offered for sale in the United States''

and ``intended for sale in the United States'' within the meaning of

section 351(h) of the PHS Act.

Additionally, firms that manufacture, prepare, or process partially

processed biologics for export must register with FDA and list their

products under section 510 of the act and parts 207 and 607 (21 CFR

parts 207 and 607).

V. Labeling Requirements for Drugs and Biologics Exported Under

Section 801(e)(1) of the Act--Section 801(f) of the Act

The 1996 Amendments contained a new provision that permits the

export of drugs (other than insulin, antibiotics, animal drugs, or

drugs exported under section 802 of the act) \10\ that may be sold in

the United States. For these drugs, section 801(f) of the act imposes

certain labeling requirements. If the drug that is approved in the

United States is being exported to a country that has different or

additional labeling requirements or conditions for use (compared to

those on the FDA-approved labeling), and the foreign country requires

the drug to be labeled in accordance with those requirements or uses,

section 801(f)(1) of the act specifies that the drug may be labeled in

accordance with the foreign requirements and conditions for use so long

as the drug is also labeled in accordance with the act.

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\10\ Insulin and antibiotics were excluded from section 801(f)

of the act because they have historically been subject only to the

export requirements now seen in section 801(e)(1) of the act. In

1997, the Food and Drug Administration Modernization Act (Pub. L.

105-115) expressly stated that insulin and antibiotics may be

exported without regard to the requirements in section 802 of the

act so long as they meet the requirements in section 801(e)(1) of

the act.

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For those conditions of use that are not approved in the United

States, section 801(f)(2) of the act requires the labeling to state

that those uses are not approved under the act. The act defines

``labeling'' as ``all labels and other written, printed, or graphic

matter (1) upon any article or any of its containers or wrappers, or

(2) accompanying such article.'' Thus, to comply with section 801(f)(2)

of the act, FDA suggests that a firm place a statement on the labeling

regarding the uses that are not approved in the United States wherever

an unapproved use appears. For example, if an unapproved use is on the

immediate label and on the product's container, a statement identifying

the uses that are not approved in the United States would appear on the

immediate label and on the product's container.

FDA has received questions whether the statement identifying the

uses that are not approved in the United States should be in the

language used in the foreign country. Although section 801(f) of the

act is silent on this point, the agency suggests that the statement be

in the foreign language because the requirement would be meaningless if

foreign consumers could not read the statement and would have no value

for U.S. consumers who, because section 801(e)(1)(D) of the act

prohibits the exported product from being sold or offered for sale in

domestic commerce, would not have access to the product when labeled

for the unapproved use(s).

In some instances, products that may be exported in compliance with

the labeling requirements in section 801(f) of the act may also qualify

for export under section 802(b)(1)(A) of the act (discussed later in

section VII.D of this document). In such cases, a firm may elect to

export a product under either section 801(e) or section 802(b) of the

act so long as the product meets the statutory requirements for export.

As discussed in section VII of this document, a drug exported under

section 802 of the act is not subject to the labeling requirements in

section 801(f) of the act.

VI. Exports of Unapproved Drugs, Biologics, and Devices Under

Section 802(b) of the act

A. Drugs and Biologics

As stated earlier, courts and FDA have interpreted section 801(e)

of the act as being inapplicable to unapproved new drugs and biologics.

As a result, the 1986 Amendments amended the act so that the export of

unapproved new drugs and biologics was regulated under section 802 of

the act.

The 1996 Amendments, insofar as human drugs and biologics are

concerned, modified the scope of section 802 of the act to state that

the provision applies to drugs and biologics that: Require approval

under section 505 of the act or, for biologics, require licensing under

section 351 of the PHS Act; do not have such approval or license; and

are not exempt from section 505 of the act or section 351 of the PHS

Act.

Thus, section 802 of the act applies to unapproved new human drugs

and biologics and to approved human drugs and biologics being exported

for unapproved uses. \11\ If FDA declines to approve or license a drug

or biologic or

[[Page 32226]]

decides to withdraw approval or revoke licensure for a drug or biologic

and that product has been exported to one or more foreign countries,

section 802(a) of the act requires FDA to notify the appropriate

foreign public health official in those countries of its decision.

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\11\ While section 802(b) of the act refers to drugs requiring

approval under section 505 of the act, it does not apply to insulin,

antibiotics, or over-the-counter drug products that do not require

approval under section 505 of the act. In 1997, the Food and Drug

Administration Modernization Act amended section 802 of the act so

that exports of insulin and antibiotics are subject to the export

requirements in section 801(e)(1) of the act.

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Section 802 of the act also contains special provisions for drugs

intended for investigational use in a listed country, drugs intended

for further processing or labeling to fill the pipeline in anticipation

of marketing authorization in a listed country, and drugs intended to

treat a tropical disease or disease that is ``not of significant

prevalence in the United States.'' These provisions are discussed in

greater detail in sections VII through IX of this document.

B. Devices

Section 802(b) of the act, like section 801(e)(2) of the act,

applies to devices that: Do not comply with an applicable requirement

under section 514 or 515 of the act; are subject to an IDE; or are

banned devices.

This means that devices that have premarket approval are not

subject to section 802 of the act, nor are devices that are the subject

of a marketing clearance under the premarket notification provision

under section 510(k) of the act.

C. Basic Requirements for All Products Exported Under Section 802 of

the Act

Under section 802(f) of the act, the basic requirements for all

drugs, biologics, and devices exported under section 802 of the act are

as follows:

The product must be manufactured, processed, packaged, and

held in ``substantial conformity'' with cGMP's or meet international

standards as certified by an international standards organization

recognized by FDA. \12\ Neither the 1996 Amendments nor its legislative

history explains what constitutes ``substantial conformity'' with

cGMP's, but the legislative history for the Generic Drug Enforcement

Act of 1992 may be instructive. In discussing the terms ``substantial

compliance'' with cGMP's and good laboratory practices, the House

Committee on Energy and Commerce suggested that ``substantial

compliance'' could not mean full compliance with GMP's because FDA

``lacks the continuing presence that would be necessary to conclude

that a firm is in full compliance with GMPs and GLPs'' (see H. Rept.

102-272, 102d Cong., 2d sess. 20 (1992)). The term does mean that the

firm must have passed its most recent GMP inspection (or that GMP

violations have been rectified, and the firm has credible systems and

personnel in place to prevent a recurrence of the violation(s)). FDA

interprets the term ``substantial conformity'' under section 802(f)(1)

of the act in a similar manner.

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\12\ The agency has not recognized an international standards

organization or standard for any FDA-regulated product for purposes

of section 802(f) of the act, but is examining this issue closely.

---------------------------------------------------------------------------

The product must not consist in whole or in part of any

filthy, putrid, or decomposed substance and must not have been

prepared, packed, or held under insanitary conditions where it may have

been contaminated or made injurious to health;

The container for the product must not be composed, in

whole or in part, of any poisonous or deleterious substance which may

render the contents injurious to health;

The product must have the strength, purity, or quality

that it is represented to possess;

For drugs, no substance may be mixed or packed with the

drug that would reduce the drug's quality or strength or may substitute

in whole or in part for another substance in the drug;

The product must comply with the requirements in section

801(e)(1) of the act. As stated earlier, section 801(e)(1) of the Act

requires that the drug or device to be exported: (1) Accords to the

specifications of the foreign purchaser; (2) not conflict with the laws

of the country to which it is intended for export; (3) be labeled on

the outside of the shipping package that it is intended for export;

\13\ and (4) not be sold or offered for sale in domestic commerce. \14\

(A discussion of the requirements in section 801(e)(1) of the act

appears earlier in this guidance.)

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\13\ A statement on the outside of the shipping package, such

as, ``For export only'' or similar language, may be sufficient.

\14\ As stated in section IV of this document, FDA advises firms

to maintain records concerning the product, its labeling, and

similar products sold in the United States. The product's labeling

can state that the product is ``Not for sale in the U.S.'' or use

similar language.

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The product cannot be the subject of a notice by FDA or

the U.S. Department of Agriculture determining that the probability of

reimportation of the exported product would present an imminent hazard

to the public health and safety of the United States, such that

exportation must be prohibited;

The product cannot present an imminent hazard to the

public health of the country to which it would be exported; and

The product must be labeled in accordance with the

requirements and conditions of use in the listed country \15\ which

authorized it for marketing and the country to which it is being

exported, and must be labeled in the language and units of measurement

used in or designated by the country to which the drug or device is

being exported. Additionally, a drug or device may not be exported if

the drug or device is not promoted in accordance with these labeling

requirements.

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\15\ The listed countries, under section 802(b) of the act, are:

Australia, Canada, Israel, Japan, New Zealand, Switzerland, South

Africa, and the member nations of the European Union and the

European Economic Area. As of January 1, 1998, the EU countries are

Austria, Belgium, Denmark, Germany, Greece, Finland, France,

Ireland, Italy, Luxembourg, the Netherlands, Portugal, Spain,

Sweden, and the United Kingdom. The EEA countries are the EU

countries, Iceland, Liechtenstein, and Norway. The number of listed

countries expands automatically as countries become members of the

EU or the EEA.

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If the above requirements are not met, section 802(f) of the act

states that a drug or device may not be exported. Furthermore, in

determining whether a drug or device may present an imminent hazard to

the public health of the foreign country or is improperly labeled or

promoted, section 802(f) of the act requires FDA to consult with the

``appropriate public health official in the affected country.''

Exporters are primarily responsible for determining whether export

is permitted under the act and whether their exports meet the

requirements in section 802(f) of the act. During an inspection, FDA

will evaluate compliance with the relevant export provisions as

appropriate. As discussed below, section 802(g) of the act requires

persons exporting drugs and devices under section 802(b)(1) of the act

to maintain records of such exported products and the countries to

which they were exported and to provide a simple notification to the

agency regarding such exports.

D. Exports of Unapproved New Drugs, Biologics, and Devices to a Listed

Country--Section 802(b)(1)(A) of the Act

The principal provision authorizing the exportation of unapproved

new drugs, biologics, and devices is section 802(b)(1)(A) of the act.

Section 802(b)(1)(A) of the act states that a drug or device ``may be

exported to any country, if the drug or device complies with the laws

of that country and has valid marketing authorization by the

appropriate authority'' in Australia, Canada, Israel, Japan, New

Zealand, Switzerland, South Africa, or any member nation in the

European Union or the European Economic Area.

[[Page 32227]]

This means that a firm whose drug or device has received marketing

authorization in any of the countries listed above can export that drug

or device to any country in the world as long as the drug or device

meets applicable requirements of the act, without submitting an export

request to FDA or receiving FDA approval to export the drug or device.

Moreover, in a change from the 1986 Amendments, firms do not have to

seek U.S. approval of the product as a condition of exportation.

FDA interprets the terms ``marketing authorization'' as meaning an

affirmative decision by the appropriate public health authority in a

foreign country to permit the drug, biologic, or device to be sold in

that country. For example, if country D approves a drug for

investigational use, the approval would not constitute ``marketing

authorization'' because country D's decision did not extend to

commercial marketing. Likewise, a decision by country D to permit sales

to another country would not represent ``marketing authorization''

because it does not permit sales within country D.

Some countries, however, have regulatory systems that permit

marketing without an affirmative act or decision by the government. In

such cases, FDA would consider a drug, biologic, or device to have

``marketing authorization'' if the listed country does not object to

the product's marketing, and FDA recommends that the firm obtain a

document from the relevant authority in the listed country indicating

that it does not object to the product's marketing.

As for the word ``drug,'' the drug to be exported under section

802(b)(1)(A) of the act should be the same product as the drug that

received marketing authorization in the listed foreign country. Thus,

the issue of whether the drug to be exported must be exactly identical

to the drug authorized in the listed country may depend on the

conditions surrounding market authorization in the foreign country. For

example, if country E's marketing authorization applies only to a drug

product with a specific composition, rather than to drugs that have a

particular active ingredient or general composition, then the drug that

is to be exported from the United States must have the same composition

as the drug that received marketing authorization in country E. If,

however, country E approves a drug product and, as a result of that

approval, permits marketing of other drugs using the same active

ingredient, then the ``drug'' that could be exported under section

802(b)(1)(A) of the act could be any drug that has the same active

ingredient. \16\

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\16\ Additionally, under the 1986 Amendments, FDA approved

exports of drugs that varied, in limited respects, from drugs that

were the subject of an IND or a marketing application. The 1986

Amendments required firms to be actively pursuing market approval of

the drug in the United States as a condition for exportation; this

condition no longer exists in the act.

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A similar concept applies to devices. Devices that are exported

under section 802(b)(1)(A) of the act should be similar (to the degree

that any variation could not affect the safety or effectiveness of the

product) or identical to the devices that receive marketing

authorization in a listed country, depending on the requirements of

that listed country.

E. Expanding the List of Countries in Section 802(b)(1)(A) of the Act

The list of countries in section 802(b)(1)(A) of the act is not

closed. The 1996 Amendments contain a mechanism whereby the Secretary

may add other countries to the list, provided that the country meets

certain criteria. These criteria include: (1) Statutory or regulatory

requirements which require the review of drugs and devices for safety

and effectiveness by a government entity in that country and which

authorizes marketing approval of drugs and devices that trained and

qualified experts acting on behalf of the government have determined to

be safe and effective, (2) statutory or regulatory requirements

pertaining to cGMP's, (3) statutory or regulatory requirements for

reporting adverse events and for removing unsafe or ineffective drugs

and devices from the market, (4) statutory or regulatory requirements

that a product's labeling and promotion be in accordance with the

product's approval, and (5) equivalence of the country's marketing

authorization system with that in the listed countries.

The authority to add countries to the list, by law, cannot be

delegated below the Office of the Secretary. Thus, FDA has no authority

to add countries to the list.

F. Exports of Unapproved New Drugs and Biologics to an Unlisted

Country--Section 802(b)(2) and (b)(3) of the Act

If a firm intends to export an unapproved new drug (including

biologics) to a foreign country, but none of the listed countries has

approved the drug for marketing, it has two other options for exporting

the product. \17\

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\17\ The requirements in sections 802(b)(2) and (b)(3) of the

act do not apply to devices. Congress omitted devices from these

provisions to the act because it found FDA's practice of permitting

(under section 801(e)(2) of the act) exports of devices that had

approved IDE's to provide an acceptable alternative.

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One option is in section 802(b)(2) of the act. This section permits

a firm to export an unapproved drug directly to an unlisted country if:

The drug complies with the laws of the foreign country and

has valid marketing authorization by the ``responsible authority'' in

that country, and

The agency determines that the foreign country has

statutory or regulatory requirements:

Which require the review of drugs for safety and

effectiveness by a government entity in that country and which

authorizes marketing approval of drugs which trained and experienced

experts have determined to be safe and effective. The experts must

be employed by or acting on behalf of the foreign government entity

and base their determination on adequate and well-controlled

investigations (including clinical investigations);

Pertaining to cGMP's;

For reporting adverse events and for removing unsafe or

ineffective drugs from the market; and

Which require that the labeling and promotion be in

accordance with the product's approval.

FDA recommends that firms intending to export drugs under section

802(b)(2) of the act provide documentation showing that the drug

complies with the foreign country's laws and has valid marketing

authorization. (If the country has a regulatory system that allows

marketing without an affirmative decision by the government, FDA

recommends that the firm obtain a document indicating that the

authorities in the listed country do not object to the product's

marketing.) The agency also suggests that firms provide documentation

so FDA can make its determination on the foreign country's statutory

and/or regulatory requirements. Copies of the foreign country's laws

and regulations (in English) may be helpful, but are not required;

firms may also provide a description of the foreign country's laws and

regulations with citations that identify the precise law or regulation.

If FDA cannot make the necessary determinations concerning the foreign

country's statutory and regulatory requirements, the firm cannot export

the drug under section 802(b)(2) of the act.

The second option is in section 802(b)(3) of the act. This section

permits a firm to petition the agency to approve exportation to an

unlisted country if the conditions for export under section 802(b)(1)

and 802(b)(2) of the act cannot be met. Under section 802(b)(3) of the

act, FDA must allow exportation of the drug if:

The person exporting the drug: (1) Certifies that the drug

would not meet

[[Page 32228]]

the conditions for approval under the act or the conditions for

approval in a listed country; and (2) provides ``credible scientific

evidence'' that is acceptable to FDA to show that the drug would be

safe and effective under the conditions of use in the country to which

it is being exported. The statute does not specify what constitutes

``credible scientific evidence,'' but an adequate and well-controlled

study or studies, animal and in vitro pharmacology and toxicology

studies, microbiology studies (for biologics), and statistical analyses

of data should be helpful; and

The appropriate health authority in the foreign country

that is to receive the drug: (1) Requests approval of the drug's

exportation, (2) certifies that the health authority understands that

the drug is not approved under the act or by any listed country, and

(3) concurs that the scientific evidence provided to FDA is credible

scientific evidence that the drug would be reasonably safe and

effective in the foreign country. A letter from the relevant foreign

government entity addressing each item in this paragraph should be

acceptable.

As a reminder, any person who exports a drug under section 802 of

the act also must comply with the basic export requirements set forth

in section 802(f) of the act.

Persons who wish to export a drug under sections 802(b)(2) or

802(b)(3) of the act should send their documentation or requests to:

(For Biologics), Division of Case Management (HFM-610), Center for

Biologics Evaluation and Research, Food and Drug Administration, 1401

Rockville Pike, rm. 200N, Rockville, MD 20852-1448.

(For Drug Products), Executive Secretariat Team (HFD-6), Center for

Drug Evaluation and Research, 1451 Rockville Pike, Rockville, MD 20852-

1420.

FDA has 60 days to act on a request to export a drug under section

802(b)(3) of the act. The agency will begin the 60 day period on the

date that it receives a complete petition containing the certification

and evidence required by the act.

VII. Exports of Unapproved Drugs and Devices for Investigational

Use to Listed Countries Under Section 802(c) of the Act

A. Background

The 1986 Amendments did not impose any special requirements for

drugs or devices exported for investigational use. Moreover, FDA did

not apply section 801(e) of the act to investigational drugs because

section 801 of the act was interpreted as not applying to ``new

drugs.'' Instead, FDA regulated the exportation of unapproved new drugs

(including biologics) for investigational use under its authority over

investigational drugs at section 505(i) of the act.

FDA issued regulations governing the exportation of unapproved new

drugs for investigational use on January 18, 1984 (49 FR 2095), with

minor modifications since then. These regulations were codified at

Sec. 312.110 (the part of the Code of Federal Regulations pertaining to

investigational drugs), and so the program became known as the ``312

program.'' The regulations required any person who intends to export an

unapproved new drug product for use in a clinical investigation either

to have an IND or to submit a written request to FDA. The regulations

required the written request to provide sufficient information about

the drug to satisfy FDA that the drug is appropriate for

investigational use in humans, that the drug will be used for

investigational purposes only, and that the drug may be legally used by

the consignee in the importing country for the proposed investigational

use. The regulations further stated that the request must specify the

quantity of the drug to be shipped and the frequency of expected

shipments. If FDA authorized exportation of the drug, it would notify

the government of the importing country. The regulations, however, did

not apply to drugs approved for export under section 802 of the act or

section 351(h)(1)(A) of the PHS Act.

In contrast, the agency did apply section 801(e) of the act to

investigational devices. This was partly because, unlike the situation

for drugs, the act contains only one definition for ``device.'' The

agency issued a regulation on device exports on January 18, 1980 (45 FR

3732 at 3751). The provision, codified at Sec. 812.18(b), simply stated

that a person who intends to export an unapproved device must obtain

FDA approval (under what is now part of section 801(e)(2) of the act)

before exporting the device.

B. Impact of the 1996 Amendments on Drug Exports for Investigational

Use

The 1996 Amendments changed the 312 program significantly by

creating a new section 802(c) of the act. In brief, section 802(c) of

the act permits a firm to export an unapproved drug for investigational

use in any of the listed countries, without prior FDA approval or even

an IND. The only requirements are that the drug be exported in

accordance with the laws of the foreign country, and comply with the

basic export requirements in section 802(f) of the act. The exporter,

under section 802(g) of the act, must also maintain records of all

drugs exported and the countries to which they were exported.

It is important to note that FDA interprets section 802(c) of the

act as applying only to investigational drugs and devices exported to

the listed countries. The agency is aware that some firms have

interpreted this provision as permitting transshipment to unlisted

countries, but section 802(c) of the act is silent with respect to

transshipment, and a more reasonable interpretation would be that

transshipments are not allowed under section 802(c) of the act.

Interpreting section 802(c) of the act to allow transshipment would

presume that the listed countries may serve as mere transfer points or

conduits for investigational drugs and devices destined for unlisted

countries (when neither the statute nor its legislative history support

such a presumption) and would make the limitation to the listed

countries in section 802(c) of the act virtually meaningless.

Additionally, one should note that section 802(b)(1) of the act

authorizes exportation to unlisted countries if the drug complies with

the foreign country's laws and has valid marketing authorization in a

listed country. Exports under section 802(b)(1) of the act may be made

for investigational uses or for marketing purposes.

For exports of drugs for investigational use in unlisted countries

where the drug product has not received valid marketing authorization

in a listed country, the ``312 program'' requirements at Sec. 312.110

remain applicable. However, FDA is considering possible revisions to

the regulations for the ``312 program'' due to sections 802(b) and (c)

of the act as well as additional changes to the program.

C. Impact of the 1996 Amendments on Device Exports for Investigational

Use

The 1996 Amendments also affected device exports significantly.

Section 802(c) of the act permits a firm to export an unapproved device

for investigational use in any of the listed countries, without prior

FDA approval or an IDE. However, as in the case for drugs, the device

must be exported in accordance with the laws of the foreign country.

Yet, unlike the situation for drug exports, the 1996 Amendments

give device manufacturers the option whether to export a device under

section 801(e)(2) of the act or under

[[Page 32229]]

section 802 of the act. The selected authority is important because

each section of the act carries its own statutory requirements.

For example, if company F wants to export an unapproved device for

investigational use to a listed country, it could:

Export the device under section 801(e)(2) of the act.

Under this provision, the exporter would need to comply with section

801(e)(1) of the act and, depending on the device, might have to submit

information that would enable FDA to determine that exportation is not

contrary to the public health or safety and that the foreign country

approves of the exportation, or

Export the device under section 802(b)(1)(A) of the act if

the device has received valid marketing authorization in any listed

country. Section 802(b)(1)(A) of the act permits exportation of an

unapproved device, for any purpose, if the device complies with the

laws of the foreign country and has received valid marketing

authorization in a listed country. (Exports under section 802(b)(1) of

the act may also occur to unlisted countries so long as the device

complies with the foreign country's laws and has valid marketing

authorization in a listed country.) Exports under this option must

comply with the basic export requirements at section 802(f) of the act

(such as being in ``substantial conformity'' with cGMP's or meeting

international standards as certified by a recognized international

standards organization and complying with section 801(e)(1) of the act)

and the notification and recordkeeping requirements in section 802(g)

of the act; or

Export the device to a listed country under section 802(c)

of the act, without prior FDA approval or the submission of any

information to FDA. However, under this option, compliance with the

basic export requirements in section 802(f) of the act and the

recordkeeping requirement in section 802(g) of the act is necessary.

Consequently in the Federal Register of May 13, 1997 (62 FR 26228),

FDA amended Sec. 812.18 to state that a person exporting an

investigational device subject to part 812 must obtain FDA's prior

approval under section 801(e)(2) of the act or comply with section 802

of the act.

Of course, a firm always has the additional option of conducting

the investigation under an IDE, in which case the IDE requirements in

part 812 would apply.

VIII. Exports of Unapproved Drugs and Devices in Anticipation of

Foreign Approval--Section 802(d) of the Act

Section 802(d) of the act permits the exportation of an unapproved

drug, biologic, or device ``intended for formulation, filling,

packaging, labeling, or further processing in anticipation of market

authorization'' in any of the listed countries. The only express

requirements for such exports are that the product comply with the laws

of the foreign country and the requirements in section 802(f) of the

act. Records for such exports must be kept in accordance with section

802(g) of the act.

The range of activities covered under section 802(d) of the act is

very broad, although mere storage of an unapproved drug, biologic, or

device would not constitute ``formulation, filling, packaging,

labeling, or further processing.'' Additionally, FDA interprets the

phrase ``in anticipation of market authorization'' as meaning that the

manufacturer exporting the product has filed an application or

submission to obtain final marketing authorization in the foreign

country. FDA does not consider an intent to seek market authorization

or to file a marketing application at some future time to constitute

``anticipation of market authorization.''

FDA advises firms that export a product in anticipation of market

authorization, under section 802(d) of the act, to notify FDA when they

export the product. The notification should identify the drug,

biologic, or device being exported and the country receiving the

product. Notification when a product is exported under section 802(d)

of the act is consistent with section 802(f) of the act. As stated

earlier, section 802(f) of the act establishes conditions for all

products exported under section 802 of the act. For example, a product

cannot be exported under section 802 of the act if it is not in

substantial conformity with cGMP's. Yet, if firms do not notify FDA

about the products that have been exported, FDA cannot determine

whether products exported under section 802(d) of the act comply with

cGMP's.

Additionally, notification is consistent with a practical

interpretation of section 802(g) of the act which requires exporters of

drugs, biologics, and devices to provide a simple notification to the

agency when they export a product to a listed country or to an unlisted

country under section 802(b)(1) of the act. Section 802(b)(1) of the

act permits exports when the drug, biologic, or device has received

market authorization in a listed country, whereas section 802(d) of the

act permits exports to a listed country in anticipation of market

authorization. A literal interpretation of section 802(g) of the act

would not require an exporter to notify FDA when it shipped a product

to a listed country in anticipation of market authorization, but would

instead require the exporter to notify FDA when the exporter shipped

the same product to the same country once it received market

authorization. It would be more practical, simple, and efficient-both

for exporters and FDA- if exporters notify FDA when they export a

product in anticipation of market authorization, under section 802(d)

of the act, rather than wait for market authorization in the listed

country and then notify FDA.

Details on notification under section 802(g) of the act appear

later in this guidance.

IX. Exports of Drugs and Devices for Diagnosing, Preventing, or

Treating a Tropical Disease or a Disease ``Not of Significant

Prevalence in the United States''--Section 802(e) of the Act

The 1986 Amendments authorized exports of unapproved new drugs and

biologics intended to prevent or to treat a tropical disease. Under the

1986 Amendments, the exporter had to submit an export application to

FDA. The export application had to: (1) Describe the drug being

exported, (2) list each country to which the drug would be exported,

(3) contain a certification that the drug would not be exported to a

country if the agency could not find that the drug would be safe and

effective in that country, (4) identify the establishments where the

drug is made, and (5) show that other statutory requirements (such as

compliance with cGMP's) are met. FDA had to approve the export

application before exportation could proceed.

The 1996 Amendments amended the tropical disease provision in

several ways. The provision now covers drugs intended to diagnose,

prevent, or treat tropical diseases, includes devices among the

products eligible for exportation, and includes drugs, biologics, and

devices that are intended to treat diseases that are ``not of

significant prevalence'' in the United States. A disease that is ``not

of significant prevalence'' in the United States can be one that is not

manifested in many Americans (either because the pathogen is not common

or because available treatments have made the disease rare in the

United States) or is indigenous to a particular foreign country or to

an area in another country. For example, measles may be

[[Page 32230]]

considered to be a disease that is not of significant prevalence in the

United States because most children are immunized against measles.

However, like the 1986 Amendments, the revised provision (which is

now codified as section 802(e) of the act) requires FDA to approve an

export application before the product can be exported. The export

application should contain information showing that the drug or device

is intended for use in a tropical disease or a disease that is not of

significant prevalence in the United States. Additionally, the

application should contain information that will enable FDA to

determine whether the drug, biologic, or device:

Will not expose patients in the foreign country to an

unreasonable risk of illness or injury, and

When used under conditions prescribed, recommended, or

suggested in the labeling or proposed labeling has a probable benefit

to health that outweighs the risk of injury or illness from its use,

taking into account the probable risks and benefits of currently

available drug or device treatment. By ``currently available drug or

device treatment,'' the applicant should consider the availability of

products that are approved for the particular disease as well as those

that are commonly used to treat the disease, even if the product is not

approved for that indication.

X. Export Notification Under Section 802(g) of the Act

Section 802(g) of the act requires persons exporting a drug or

device under section 802(b)(1) of the act to provide a ``simple

notification * * * identifying the drug or device when the exporter

first begins to export such drug or device'' to any country listed in

section 802(b)(1) of the act. If the product is to be exported to an

unlisted country, section 802(g) of the act requires the exporter to

provide a simple notification ``identifying the drug or device and the

country to which such drug or device is being exported.''

In all cases, section 802(g) of the act requires the exporter to

maintain records of all drugs or devices exported and the countries to

which they were exported.

A. The Content of the Simple Notification

FDA suggests that, to identify a drug or device, the exporter

describe in the notification the product's name or type of device, its

generic name, and a description of its strength and dosage form (if the

product is a drug) or the product's model number (if the product is a

device).

As for identifying the country that is to receive the exported

product, FDA acknowledges that section 802(g) of the act requires

exporters to identify the country that is to receive the exported

product only if the country is not a listed country. However, FDA

encourages exporters to identify the country that is to receive the

exported product in all cases, regardless of whether the country is

among those listed in section 802(b)(1) of the act. Identification of

the foreign country, regardless of whether it is listed or not, helps

FDA meet its obligations under sections 802(a) and 802(f)(4), (f)(5),

and (f)(6) of the act which prohibit exports under certain conditions

(such as a finding of an imminent hazard to the public health) and/or

requires FDA to consult with the ``appropriate public health official''

in the affected country.

B. Where to Send the Simple Notification

Notifications may be sent to the following addresses:

For biological drug products and biological devices: Division of

Case Management (HFM-610), Office of Compliance, Center for Biologics

Evaluation and Research, Food and Drug Administration, 1401 Rockville

Pike, rm. 200N, Rockville, MD 20852-1448.

For human drug products: Division of Labeling and Nonprescription

Drug Compliance (HFD-310), Center for Drug Evaluation and Research,

Food and Drug Administration, 7520 Standish Pl., Rockville, MD 20855-

2737.

For devices: Division of Program Operations (HFZ-305), Center for

Devices and Radiological Health, Food and Drug Administration, 2094

Gaither Rd., Rockville, MD 20850.

C. Recordkeeping

As stated earlier, section 802(g) of the act requires exporters to

maintain records of all drugs and devices exported and the countries to

which the products were exported. FDA recommends that exporters

maintain records showing:

The product's name and its generic name (if the product is

a drug or a device),

The type of device (if the product is a device),

A description of its strength and dosage form and the

product's lot or control number (if the product is a drug) or the

product's model number (if the product is a device),

The consignee's name and address, and

The date and quantity of product exported.

FDA recommends that these records be kept at the site from which

the products were exported and be maintained at least 5 years after the

date of exportation. The agency may request that the records be made

readily available for review and during an agency inspection.

Additionally, FDA reminds parties that they may need to maintain

other records beyond those specified in section 802(g) of the act. For

example, firms whose products must be in substantial conformity with

cGMP's under section 802(f)(1) of the act may be subject to cGMP

recordkeeping requirements under the regulations that apply to their

products.

XI. ``Import for Export''--Section 801(d)(3) and (d)(4) of the Act

Before the 1996 Amendments, all imported components of drugs,

biologics, devices, and other FDA-regulated products had to comply with

the requirements of the act, even if they were to be incorporated into

products destined solely for export.

The 1996 Amendments changed the law by creating two subsections at

801(d)(3) and (d)(4) of the act. Under section 801(d)(3) of the act, a

component of a drug or a biologic, a component part, accessory, or

other article of a device, or a food additive, color additive, or

dietary supplement that would otherwise be refused entry into the

United States, can be imported into the United States if:

The importer submits a statement to the agency at the time

of initial importation declaring that the component, part, accessory,

or article is intended to be ``incorporated'' or ``further processed''

by the initial owner or consignee into a drug, biological product,

device, food, food additive, color additive, or dietary supplement that

will be exported from the United States by the initial owner or

consignee in accordance with section 801(e) or section 802 of the act

or section 351(h) of the PHS Act (see section 801(d)(3)(A) of the act).

The initial owner or consignee responsible for the

imported article maintains records that identify the use of the

imported component, part, accessory, or article. Upon request from the

agency, the initial owner or consignee must submit a report that

accounts for the exportation or the disposition of the imported

component, part, accessory, or article (including quantities that were

destroyed), including the manner in which the initial owner or

consignee complied

[[Page 32231]]

with the requirements in section 801(d) of the act (see section

801(d)(3)(B) of the act).

Any imported component, part, accessory, or article that

is not incorporated into a product must be destroyed or exported by the

owner or consignee (see section 801(d)(3)(C) of the act).

This provision is commonly referred to as the ``import for export''

provision.

A. Items Covered Under the Import for Export Provision

1. Human Drugs

One issue under section 801(d)(3) of the act is what constitutes a

``component'' of a drug. FDA regulations define ``component'' as

meaning ``any ingredient intended for use in the manufacture of a drug

product, including those that may not appear in such drug product.''

(See Sec. 210.3(b)(3).) Additionally, for purposes of section 801(d) of

the act, FDA interprets the term ``component'' broadly to include a

range of items, such as the active and inactive ingredients for a drug

or biologic, bulk drugs, and even unapproved foreign versions of drugs

that are approved for use in the United States. So, for example, if

company X wants to import a bulk drug from a source that differs from

the bulk drug source it uses for products sold in the United States,

company X may import the bulk drug from the different source provided

that company X incorporates the bulk drug into a product for export or

further processes the bulk drug before exporting it (or otherwise

destroys the bulk drug). The imported bulk drug from the different

source cannot be used in the product to be sold in the United States.

Additionally, an item can be a ``component'' if it is intended for

``further processing'' in the United States before being exported to

another country. For example, a finished dosage form that is sterilized

in the United States would be a ``component'' within section 801(d)(3)

of the act (because the drug is ``further processed'' during the

sterilization process).

2. Devices

For devices, FDA regulations define a ``component'' as ``any raw

material, substance, piece, part, software, firmware, labeling, or

assembly which is intended to be included as part of the finished,

packaged, and labeled device.'' (See Sec. 820.3(c).) As in the case of

drugs and biologics, FDA interprets the term ``component'' in section

801(d) of the act broadly to encompass a range of items.

Yet, regardless of whether the imported item is a drug or device

component, the key issue under section 801(d)(3) of the act is how the

component will be ``incorporated'' or ``further processed.''

3. Food Additives, Color Additives, and Dietary Supplements

Section 801(d)(3) of the act refers to food additives, color

additives, and dietary supplements. The act defines ``food additive''

at section 201(s) of the act, ``color additive'' at section 201(t) of

the act, and ``dietary supplement'' at section 201(ff) of the act.

B. Activities Covered Under the Concept of ``Incorporation'' and

``Further Processing''

Section 801(d)(3) of the act only permits a component, part,

accessory, or article to enter the United States if it is intended to

be ``incorporated'' into a product for export or is to be ``further

processed'' into a product that will be exported.

In the context of section 801(d)(3) of the act, FDA interprets the

terms ``incorporated'' and ``further processing'' to encompass a wide

range of activities. Thus, ``incorporation'' and ``further processing''

are not confined to product manufacture. Instead, they include related

activities such as packaging and labeling of finished products and

specialized processing (such as sterilization) of a product.

However, FDA does not consider a component, part, accessory, or

article to be ``incorporated'' or ``further processed'' if it is merely

stored in the United States before being exported elsewhere. Although

FDA has exercised enforcement discretion regarding specific entries of

violative products that are stored in the United States, the agency

does not consider the importation of an unapproved product for storage

purposes to fall within the meaning of ``incorporated'' or ``further

processed'' under section 801(d)(3) of the act.

C. Submission of Statements to FDA

Section 801(d)(3)(A) of the act requires the importer to submit,

``at the time of initial importation,'' a statement to the agency

indicating that the imported component, part, accessory, or other

article is intended to be incorporated or further processed by the

initial owner or consignee into a product that will be exported in

compliance with section 801(e) or section 802 of the act or section

351(h) of the PHS Act. Firms should submit this statement to FDA each

time they import an article under the ``import for export'' provision

in the act. The statement (along with other import documents) should be

provided to the FDA field office that has responsibility over the port

or site of entry into the United States.

FDA recommends that the statement contain the following

information:

The purpose for which the article is being imported prior

to export (how it will be further processed or the name or description

of the product into which it will be incorporated);

The imported article's name or description (including any

scientific or technical name);

Any product coding, batch, lot, or other identifying

numbers;

The name and address of the imported article's foreign

manufacturer (if different from the name of the foreign shipper

identified in the import records at the U.S. Customs Service); and

The name and address of the initial owner or consignee in

the United States and, if different, the address in the United States

where the imported article will be further processed or incorporated

into a product for export.

For blood, blood components, source plasma, source leukocytes, or a

component, accessory, or part that is not licensed under section 351(a)

of the PHS Act and is to be imported under section 801(d)(4) of the

act, FDA suggests that the statement include a copy of the

determination by FDA granting permission to import the product or

article. (The request for determination is described in more detail

later in section XI.E.3 of this document.)

FDA emphasizes that, under section 801(d) of the act, the imported

article must ultimately be further processed or incorporated into a

product that is exported in accordance with the act's export provisions

from the United States or the imported article must be destroyed. The

imported article cannot be used in any product which is to be

introduced into U.S. commerce.

The agency intends to issue regulations covering statements under

section 801(d) of the act.

D. Records to be Retained and Reports to be Submitted for Exports Under

Section 801(d)(3) of the Act

Section 801(d)(3)(B) of the act requires the initial owner or

consignee responsible for an imported article to ``maintain records

that identify the use of such imported article and upon request * * *

[to] submit[ ] a report that provides an accounting of the exportation

or disposition of the imported article, including portions that have

been destroyed, and the manner in

[[Page 32232]]

which such person complied with the requirements of this paragraph * *

*.''

The statutory reference to the initial owner or consignee indicates

that, under section 801(d)(3) of the act, the person who imports the

article for incorporation or further processing may, in turn, have

other persons perform the actions that lead to the incorporation or

further processing of the imported article. For example, if company C

imports a drug into the United States for sterilization purposes, but

does not have the technological capability to sterilize the drug

itself, company C could send the drug to company D for sterilization

and, after receiving the sterilized drug back from company D, export

the drug from the United States. However, under this scenario, company

C would remain the owner of the product and would be responsible for

maintaining records and for submitting, upon FDA's request, a report

accounting for the exportation or disposition of the imported article.

The agency suggests that firms importing an article into the United

States under section 801(d)(3) of the act retain records showing:

The name or description of the article (including any

scientific or technical name);

Any product coding, lot, batch, or other identifying

numbers;

The name and address of the foreign manufacturer of the

imported article;

How the article will be or was further processed, and the

name and description of any product into which it will be or was

incorporated in the United States;

The signature of the responsible person at the importing

firm;

The name and address of the firm in the United States

where the article will be or was further processed or incorporated into

another product;

The disposition of the imported article, i.e.,

manufacturing records showing how specific articles were used or

destroyed and the dates of receipt, use, destruction, and/or

reexportation, as that information becomes available;

Any product coding, lot, batch, or other identification

number for the further-processed article or product incorporating the

imported article;

A copy of the label to be applied to the shipping package,

container, or crate used to export the further-processed article or

product incorporating the imported article (indicating that it contains

articles that may not be sold or offered for sale in the United States

and are intended for export only); and

The name and address of the foreign purchaser of the

further-processed article or product incorporating the imported

article.

Additionally, for blood, blood components, source plasma,

source leukocytes, or a component, accessory, or part thereof

(including blood or plasma derivatives or intermediates) that is not

licensed under section 351(a) of the PHS Act and is to be imported

under section 801(d)(4) of the act, the agency recommends that the

records also include documentation of the agreement between the foreign

material supplier and the U.S. manufacturer. The documentation should

outline the specific contractual relationship, the foreign

manufacturing specifications, and the U.S. manufacturer's plan for

auditing the foreign supplier to ensure compliance with the terms of

the contract. FDA suggests that the initial owner or consignee have

written standard operating procedures to ensure that such products are

not diverted to domestic use in the United States and are kept

segregated from and not co-mingled with products or components intended

for use in the United States (e.g., quarantine procedures used for

segregating imported blood, blood components, or final products from

products intended for use in the United States, including validation

data for procedures to clean equipment and facilities used for

manufacturing products for use in the United States and exported

products).

FDA also encourages firms to maintain any other records that would

assist FDA in determining whether they comply with section 801(d)(3) or

(d)(4) of the act. \18\ FDA suggests that firms retain records relating

to the importation of an article for incorporation or further

processing in the United States for 5 years after the destruction or

exportation of the last imported component, part, accessory, or article

for a particular lot or batch. The records may be maintained at the

importing firm's site and may be subject to inspection by FDA.

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\18\ A firm may also be subject to certain recordkeeping

requirements outside those described in section 802(g) of the act.

For example, because all drugs and devices exported under section

802 of the act must be in substantial conformity with cGMP's or

international standards recognized by FDA, there may be cGMP

recordkeeping requirements that apply to the exported drug or

device.

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FDA intends to issue regulations to establish recordkeeping

requirements, and persons subject to this provision should note that

the act specifically prohibits the making of a knowingly false

statement in any record or report required under section 801(d)(3)(A)

or (d)(3)(B) of the act as well as the failure to submit or maintain

records under these sections of the act (see section 301(w) of the

act).

E. Special Requirements for Blood, Blood Components, Plasma, Source

Leukocytes, and Tissues--Section 801(d)(4) of the Act

1. Blood, Blood Components, Plasma, and Source Leukocytes

The ``import for export'' requirements for blood, \19\ blood

components, \20\ plasma, \21\ and source leukocytes \22\ differ from

those for drugs and other biologics. Under section 801(d)(4) of the

act, the importation of these products, components, accessories, or

parts is not permitted under section 801(d)(3) of the act unless the

importation complies with section 351(a) of the PHS Act or the agency

permits the importation ``under appropriate circumstances and

conditions.'' (FDA intends to issue regulations specifying the

``appropriate circumstances and conditions'' that would allow

importation of unlicensed products under the import for export

authority.)

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\19\ FDA interprets ``blood'' as whole blood collected from a

single donor and processed either for transfusion or further

manufacturing (see Sec. 606.3(a) and the regulation for whole blood

at 21 CFR 640.1).

\20\ Under FDA regulations, a ``blood component'' is that part

of a single-donor unit of blood separated by physical or mechanical

means (see Sec. 606.3(c) and part 640 (21 CFR part 640)).

\21\ Under Sec. 640.60, ``source plasma'' is the fluid portion

of human blood collected by plasmapheresis and intended as source

material for further manufacturing use. The term does not extend to

single donor plasma products intended for intravenous use.

\22\ FDA interprets ``source leukocytes'' as leukocytes

collected for further manufacturing by leukapheresis (as defined in

Sec. 606.3(g)). This is a procedure in which blood is removed from

the donor, the leukocyte concentrate is separated, and the remaining

formed elements and residual plasma are returned to the donor.

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Under section 801(d)(4) of the act, FDA may permit the import for

export of blood and blood components, source plasma, source leukocytes,

or a component, accessory, or part thereof, which may not be licensed

or meet cGMP requirements. Products imported under section 801(d)(4) of

the act must also comply with section 801(d)(3) of the act. \23\

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\23\ A U.S. manufacturer that intends to incorporate or further

process certain imported blood products for export, or the foreign

supplier of such material, may submit an import for export request

under section 801(d)(4) of the act. Section 801(d)(3) of the act

specifies that the importer must submit the statement of intent to

export to the Secretary, and that the initial owner or consignee

responsible for the imported article must maintain certain records

and submit a report upon request. A U.S. firm that intends to

perform processing or manufacturing steps involving an imported

blood product under section 801(d)(4) and (d)(3) of the act should

have sufficient information, to submit to FDA in support of an

import for export request, that allows FDA to make the determination

whether appropriate circumstances and conditions exist to permit

such importation.

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[[Page 32233]]

Licensed blood products, such as licensed source plasma, may be

imported if such importation complies with section 351(a) of the PHS

Act. Other licensed blood products, such as those having cGMP

deficiencies, are not considered to be in compliance with section

351(a) of the PHS Act. If a product does not have a license or is

considered to be in noncompliance with section 351(a) of the PHS Act,

the manufacturer that wishes to import such a blood product for

incorporation or further processing into a product for export may seek

FDA's permission to import the product. CBER will evaluate such import

for export requests on a case-by-case basis.

Recovered plasma and serum are blood products currently not subject

to licensure. Recovered plasma and serum that are intended for further

manufacture or incorporation into products for export must be imported

in accordance with the short supply provisions at 21 CFR 601.22.

Recovered plasma and serum intended for further manufacturing or

incorporation into noninjectable products not subject to licensure may

be imported without an import for export submission if they are

manufactured in accordance with cGMP's and are labeled appropriately.

Labeling for such products should include the applicable container

label requirements listed in Sec. 606.121. A firm may apply to import

recovered plasma and serum that do not meet cGMP's by submitting an

import for export request. CBER will evaluate these requests on a case-

by-case basis.

Thus, under section 801(d)(4) of the act, no person may import

blood products that are: (1) Subject to licensure and do not comply

with section 351(a) of the PHS Act; or (2) are not subject to licensure

and do not comply with cGMP's, without FDA's prior permission. For the

latter, failure to seek and obtain FDA's permission, under section

801(d)(4) of the act, prior to importation may be a criminal violation.

FDA further recommends that persons who intend to import blood

products under section 801(d)(4) of the act register and list or update

their registration and listing to include a description of the imported

material and the final product for export that will be manufactured

from or incorporate the imported biological material. Registration and

listing information should not be contained in the import for export

request, but may instead be sent to the appropriate registration office

listed in parts 207 or 607. Additionally, the agency requests that

U.S.-licensed facilities receiving any foreign biological components or

products, other than blood, under section 801(d)(3) of the act which

will be used for manufacture into a product for export report such

changes in accordance with 21 CFR 601.12.

2. Tissues

For tissues and tissue parts or components, section 801(d)(4) of

the act prohibits importation unless the importation complies with

section 361 of the PHS Act. (Section 361 of the PHS Act authorizes the

issuance of regulations to control communicable diseases.) Thus,

tissues and their parts or components must comply with the PHS Act and

regulations issued under the PHS Act in order to enter the United

States, even if the product is ultimately destined for exportation.

Persons who intend to import tissues and tissue parts or components

(intended for transplantation) under section 801(d)(4) of the act

should comply with the regulations at part 1270 (21 CFR part 1270) and

also comply with the notification requirement in section 801(d)(3)(A)

of the act. Under Sec. 1270.42, the importer of record must notify the

director (or his or her designee) of the FDA district having

jurisdiction over the port of entry, and the tissue must be held until

FDA releases it. If the human tissue that is imported for further

processing or incorporation into a product for export is kept in

quarantine at all times, it does not have to meet all the screening and

testing requirements in part 1270. If the tissue is declared and

identified as being in quarantine, it must be accompanied by records

assuring identification of the donor and indicating that the tissue has

not been determined to be suitable for transplantation (see

Sec. 1270.33(c)). The owner or consignee in the United States must

prepare and follow written procedures for designating and identifying

quarantined human tissue and preventing infectious disease

contamination or cross-contamination during processing (as stated in

Sec. 1270.31).

If an importer, consignee, or U.S. manufacturer delivers or ships

human tissue or a component thereof before FDA releases it or fails to

quarantine tissue that has not been determined to be suitable for human

transplantation, such action may constitute a criminal violation.

3. Requests to Import Blood, Blood Components, Plasma, and Source

Leukocytes for Further Processing or Incorporation into a Product for

Export (``Requests for Determination'')

Section 801(d)(4) of the act does not specify how persons who wish

to import blood, blood components, source plasma, source leukocytes, or

their components, accessories, or parts obtain permission to import

those products. Nevertheless, to facilitate imports under section

801(d)(4) of the act, FDA recommends that manufacturers provide an

import for export request which demonstrates that appropriate

circumstances or conditions warrant CBER's approval of importation

under section 801(d)(4) of the act. The agency recommends that these

requests, known as a ``request for determination,'' contain the

following information:

The names and addresses of the foreign manufacturer of the

article to be imported and the initial owner or consignee in the United

States that would be responsible for the further processing or

incorporation of the article into another product;

The specific identity of the article to be imported and

details as to how the imported article will be further processed or

incorporated into a product for export;

A description of the standard operating procedures and

safeguards that the initial owner or consignee in the United States

will use or implement to ensure that the imported articles or products

incorporating such articles are segregated from and not comingled with

products, components, accessories, or parts intended for use in the

United States (e.g., quarantine procedures used for segregating

imported blood, blood components, or final products from products

intended for use in the United States, including validation data for

procedures to clean equipment and facilities used in manufacturing

products for use in the United States and products for export);

General donor screening questionnaire or criteria,

translated into English, that will be used to screen donors;

A certification that the foreign supplier will perform

tests for infectious disease on the blood, blood components, source

plasma, or source leukocytes, or their components, accessories, or

parts (including blood or plasma derivatives or intermediates) at the

time of donation and before importation to the United States, and the

expected results of such tests. The infectious disease agents that

should be tested for include, but are not limited to:

[[Page 32234]]

HIV-1, HIV-2, hepatitis B virus, hepatitis C virus, HTLV-I, HTLV-II,

and Treponema palladum. A request for determination may be based upon

infectious agent tests performed using test kits other than those

licensed or approved by FDA. In such cases, FDA suggests that the

request contain a copy of the labeling for the test kit used,

translated into English, as part of the submission; and

A copy of the product's label. FDA recommends that the

label include information such as the product's descriptive name; the

name(s) and address(es) of establishments collecting, preparing,

labeling, or pooling the source material; donor, lot, or pool numbers

relating the unit to the donor; the recommended storage temperature (in

degrees Celsius); the product's quantity; statements such as ``Import

for Export,'' ``Not for Use in Products Subject to Licensure Under

Section 351 of the Public Health Service Act,'' and ``For Manufacturing

Use Only'' or ``For Manufacturing into Noninjectable Products Only;''

statements indicating that the product has been tested for infectious

disease agents and, if the product has tested positive for an

infectious disease agent, the term ``BIOHAZARD'' as well as any other

appropriate warnings or special handling instructions.

A request for determination may be sent to the Center for Biologics

Evaluation and Research, Office of Compliance, Division of Case

Management (HFM-610), 1401 Rockville Pike, Rockville, MD 20852-1448. If

FDA determines that the blood, blood component, source plasma, or

source leukocyte, or a component, accessory, or part meets the

appropriate circumstances and conditions to permit its importation into

the United States, FDA will notify the person requesting the

determination that it has granted permission to import the article.

XII. For Further Information Contact:

For animal drugs: Drugs Team, Division of Compliance, Center for

Veterinary Medicine, Food and Drug Administration, 7500 Standish Pl.,

Rockville, MD 20855, 301-594-1785.

For biologics: Division of Case Management (HFM-610), Office of

Compliance, Center for Biologics Evaluation and Research, Food and Drug

Administration, 1401 Rockville Pike, rm. 200N, Rockville, MD 20852-

1448, 301-827-6201.

For devices: Division of Program Operations (HFZ-305), Center for

Devices and Radiological Health, Food and Drug Administration, 2094

Gaither Rd., Rockville, MD 20850, 301-594-4699.

For drugs: Division of Labeling and Nonprescription Drug Compliance

(HFD-310), Center for Drug Evaluation and Research, Food and Drug

Administration, 7520 Standish Pl., Rockville, MD 20855-2737, 301-594-

0063.

For drugs exported for investigational use under Sec. 312.110:

Office of International Affairs (HFG-1), Food and Drug Administration,

5600 Fishers Lane, Rockville, MD 20857, 301-443-4480.

For food additives, color additives, and dietary supplements:

Office of Field Programs (HFS-602), Center for Food Safety and Applied

Nutrition, Food and Drug Administration, 200 C St. SW., Washington, DC

20204, 202-205-4187.

These offices may have additional guidance documents and

information on specific export topics or products.

For general policy questions: Office of Policy (HF-23), Food and

Drug Administration, 5600 Fishers Lane, Rockville, MD 20857, 301-827-

3344.

Dated: June 2, 1998.

William K. Hubbard,

Associate Commissioner for Policy Coordination.

[FR Doc. 98-15696 Filed 6-11-98; 8:45 am]

BILLING CODE 4160-01-F