[Federal Register Volume 63, Number 113 (Friday, June 12, 1998)]
[Notices]
[Pages 32219-32234]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 98-15696]


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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Draft Guidance for Industry; Exports and Imports Under the FDA 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availability of a draft guidance document entitled, ``FDA Draft 
Guidance for Industry on: Exports and Imports Under the FDA Export 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 The draft guidance document 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DATES: Written comments on the draft guidance document may be submitted 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ADDRESSES: Submit written comments on the draft guidance document to 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draft guidance document entitled, ``FDA Draft Guidance for Industry on: 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:
    <bullet> What are the draft guidance document's strengths and 
weaknesses? For example, which topics might require more explanation?
    <bullet> 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.
    <bullet> 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 <a href="http://www.fda.gov/
opacom/fedregister/frexport.html">http://www.fda.gov/
opacom/fedregister/frexport.html</a>. 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:
    <bullet> 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.
    <bullet> 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.
    <bullet> Replaced section 802 of the act in its entirety with a new 
section 802 of the act that:
    <bullet> Eliminated the requirement for prior FDA approval of 
exports of unapproved drugs (in most cases),
    <bullet> 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),
    <bullet> 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,
    <bullet> Authorized the export of unapproved products to a 
listed country in anticipation of marketing approval in that 
country,
    <bullet> 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
    <bullet> 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:
    <bullet> 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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    <bullet> 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:
    <bullet> 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;
    <bullet> 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;
    <bullet> Replaced section 802 of the act in its entirety with a new 
section 802 of the act that:
    <bullet> 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),
    <bullet> Created administrative mechanisms for the Secretary to 
add countries to the list and for FDA to approve exports of specific 
products to unlisted countries,
    <bullet> Authorized exports of unapproved devices intended for 
use in clinical investigations in any of 25 countries identified in 
section 802 of the act,
    <bullet> Authorized the export of unapproved devices to a listed 
country in anticipation of marketing approval in that country,
    <bullet> 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
    <bullet> 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.)
---------------------------------------------------------------------------

    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\
---------------------------------------------------------------------------

    \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).
---------------------------------------------------------------------------

    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\
---------------------------------------------------------------------------

    \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.
---------------------------------------------------------------------------

    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.
    <bullet> Evidence that product for export qualifies as a partially 
processed biological product;
    <bullet> 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;
    <bullet> 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;
    <bullet> Distribution records of exported partially processed 
biological products;
    <bullet> 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
    <bullet> 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.
---------------------------------------------------------------------------

    \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.
---------------------------------------------------------------------------

    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.
---------------------------------------------------------------------------

    \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.
---------------------------------------------------------------------------

    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:
    <bullet> 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.
---------------------------------------------------------------------------

    \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.
---------------------------------------------------------------------------

    <bullet> 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;
    <bullet> 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;
    <bullet> The product must have the strength, purity, or quality 
that it is represented to possess;
    <bullet> 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;
    <bullet> 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.)
---------------------------------------------------------------------------

    \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.
---------------------------------------------------------------------------

    <bullet> 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;
    <bullet> The product cannot present an imminent hazard to the 
public health of the country to which it would be exported; and
    <bullet> 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.
---------------------------------------------------------------------------

    \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.
---------------------------------------------------------------------------

    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\
---------------------------------------------------------------------------

    \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.
---------------------------------------------------------------------------

    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\
---------------------------------------------------------------------------

    \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.
---------------------------------------------------------------------------

    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:
    <bullet> The drug complies with the laws of the foreign country and 
has valid marketing authorization by the ``responsible authority'' in 
that country, and
    <bullet> The agency determines that the foreign country has 
statutory or regulatory requirements:
    <bullet> 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);
    <bullet> Pertaining to cGMP's;
    <bullet> For reporting adverse events and for removing unsafe or 
ineffective drugs from the market; and
    <bullet> 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:
    <bullet> 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
    <bullet> 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:
    <bullet> 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
    <bullet> 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
    <bullet> 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:
    <bullet> Will not expose patients in the foreign country to an 
unreasonable risk of illness or injury, and
    <bullet> 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:
    <bullet> The product's name and its generic name (if the product is 
a drug or a device),
    <bullet> The type of device (if the product is a device),
    <bullet> 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),
    <bullet> The consignee's name and address, and
    <bullet> 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:
    <bullet> 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).
    <bullet> 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).
    <bullet> 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:
    <bullet> 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);
    <bullet> The imported article's name or description (including any 
scientific or technical name);
    <bullet> Any product coding, batch, lot, or other identifying 
numbers;
    <bullet> 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
    <bullet> 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:
    <bullet> The name or description of the article (including any 
scientific or technical name);
    <bullet> Any product coding, lot, batch, or other identifying 
numbers;
    <bullet> The name and address of the foreign manufacturer of the 
imported article;
    <bullet> 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;
    <bullet> The signature of the responsible person at the importing 
firm;
    <bullet> 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;
    <bullet> 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;
    <bullet> Any product coding, lot, batch, or other identification 
number for the further-processed article or product incorporating the 
imported article;
    <bullet> 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
    <bullet> The name and address of the foreign purchaser of the 
further-processed article or product incorporating the imported 
article.
    <bullet> 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.
---------------------------------------------------------------------------

    \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.
---------------------------------------------------------------------------

    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:
    <bullet> 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;
    <bullet> 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;
    <bullet> 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);
    <bullet> General donor screening questionnaire or criteria, 
translated into English, that will be used to screen donors;
    <bullet> 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
    <bullet> 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