FDA Guidance for
Industry on:
Exports and Imports Under the
FDA Export
Reform and Enhancement Act of
1996
Food and Drug Administration
U.S. Department of Health and Human Services
February 1998
II. Terms Used in This Guidance
- A. Exports of Drugs and Biologics That May
Not be Sold in the United States
B. Exports of Animal Drugs That May Not be Sold in the United States
C. Exports of Devices That May Not be Sold in the United States
D. Enactment of the FDA Export Reform and Enhancement Act of 1996
- A. Special Requirements for Certain
Devices
B. Special Requirements for Partially Processed Biologics
1. What Constitutes a Partially Processed Biological Product?
2. cGMP Requirements
3. Additional Requirements Under Section 351(h) of the PHS Act
VII. Exports of Unapproved Drugs,
Biologics, and Devices
Under Section 802(b) of the Act
- A. Drugs and Biologics
B. Devices
C.Basic Requirements for All Products Exported Under Section 802 of the Act
D. Exports of Unapproved New Drugs, Biologics, and Devices to a Listed Country - Section 802(b)(1)(A) of the Act
E.Expanding the List of Countries in Section 802(b)(1)(A) of the Act
F.Exports of Unapproved New Drugs and Biologics to an Unlisted Country - Section 802(b)(2) and (b)(3) of the Act
- A. Background
B. Impact of the 1996 Amendments on Drug Exports for Investigational Use
C.Impact of the 1996 Amendments on Device Exports for Investigational Use
XI. Export Notification Under Section 802(g) of the Act
XII. "Import for Export" - Section 801(d)(3) and (d)(4) of the ActB.Activities Covered Under the Concept of "Incorporation" and "Further Processing"C.Submission of Statements to FDA
D. Records to be Retained and Reports to be Submitted for Exports Under Section 801(d)(3) 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
2. Tissues
3. Requests to Import Blood, Blood Components, Plasma, and Source Leukoctyes for Further Processing or Incorporation into a Product for Export ("Request for Determination")
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). 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. 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 importation 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.
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.
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 312.110.
For information concerning exports of:
* drugs and biologics that are not approved for marketing
in the United States, but are approved for marketing in
Australia, Canada, Israel, Japan, New Zealand,
Switzerland, South Africa, or any member nation of the
European Union or the European Economic Area, see the
discussion of section 802(b)(1) of the act at page 33.
* drugs and biologics that are not approved for marketing
in the United States and are intended for export to a
country that is not listed above, see the discussion of
section 802(b)(2) and (b)(3) of the act at page 35.
* drug components that are not approved for use in
marketed products in the United States, but are
intended for incorporation into a product to be
exported from the United States or intended for further
processing before being exported from the United
States, see the discussion of section 801(d) of the act
at page 50.
* drugs approved for marketing in the United States, but
being exported for an unapproved use, see the
discussion of section 801(e) and (f) of the act at page
27.
* drugs and biologics that are not approved for marketing
in the United States and are being exported for
investigational use in Australia, Canada, Israel,
Japan, New Zealand, Switzerland, South Africa, or any
member nation of the European Union or the European
Economic Area, see the discussion of section 802(c) of
the act at page 39.
* drugs and biologics that are not approved for marketing
in the United States and are being exported for
investigational use in any country other than those
listed in section 802(b)(1)(a) of the act (listed
immediately above), see the discussion of the "312
program" at page 39.
* drugs and biologics that are not approved for marketing
in the United States and are being exported in
anticipation of market authorization in Australia,
Canada, Israel, Japan, New Zealand, Switzerland, South
Africa, or any member nation of the European Union and
the European Economic Area, see the discussion of
section 802(d) of the act at page 43.
* drugs and biologics that are not approved for marketing
in the United States and are intended for use in the
diagnosis, prevention, or treatment of a tropical
disease or a disease that is not of significant
prevalence in the United States, see the discussion of
section 802(e) of the act at page 45.
* partially processed biologics, see the discussion of
section 351(h) of the Public Health Service Act at page
22.
* animal drugs that are not approved for marketing in the
United States, see the discussion of section 801(e)(1)
of the act at page 18.
* devices that are not approved for use in the United
States and are not subject to licensure under section
351 of the Public Health Service Act, but are approved
for marketing in Australia, Canada, Israel, Japan, New
Zealand, Switzerland, South Africa, or any member
nation of the European Union or the European Economic
Area, see the discussion of section 802(b)(1) of the
act at page 33 OR see the discussion of section 801(e)
of the act at page 18. (In some cases, the device may
be exported under either provision.)
* device components, parts, accessories, or other
articles of a device not approved in the United States,
but are intended for incorporation into a product to be
exported from the United States or intended for further
processing before being exported from the United
States, see the discussion of section 801(d) of the act
at page 50.
* devices that are being exported for investigational use
in Australia, Canada, Israel, Japan, New Zealand,
Switzerland, South Africa, or any member nation of the
European Union or the European Economic Area, see the
discussion of section 802(c) of the act at page 41, OR
see the discussion of section 801(e) of the act at page
18.
* devices that are being exported in anticipation of
market authorization in Australia, Canada, Israel,
Japan, New Zealand, Switzerland, South Africa, or any
member nation of the European Union or the European
Economic Area, see the discussion of section 802(d) of
the act at page 43.
* devices intended for use in the diagnosis, prevention,
or treatment of a tropical disease or a disease that is
not of significant prevalence in the United States, see
the discussion of section 802(e) of the act at page 45,
OR see the discussion of section 801(e) of the act at
page 18.
* food additives, color additives, and dietary
supplements that are not approved or listed in the
United States, but are intended for incorporation into
a product to be exported from the United States or
intended for further processing before being exported
from the United States, see the discussion of section
801(d) of the act at page 52.
Additionally, for information on:
* basic requirements applicable to all products exported
under section 801(e) or section 802 of the act or
section 351(h) of the PHS Act, see the discussion of
section 801(e)(1) of the act at page 18.
* labeling requirements applicable to drugs exported
under section 801 of the act, see the discussion of
section 801(f) of the act at page 27.
* requirements that apply to all products exported under
section 802 of the act, see the discussion of section
802 of the act at page 30. Information concerning the
labeling for products exported under section 802 of the
act can also be found in that discussion. (The actual
relevant is section 802(f) of the act.)
* imports of blood, blood components, source plasma,
source leukocytes, or their components, accessories, or
parts into the United States, see the discussion of
section 801(d)(4) at page 57.
* imports of tissues into the United States, see the
discussion of section 801(d)(4) at page 59.
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.
The export provision in the act had its origins in 1906 as
part of the Federal Food and Drugs Act (Pub. L. 59-384). 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.
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.
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 animal drug could be exported under section 802 of
the act.
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 amount of time FDA took to
determine whether an export request met the statutory criteria.
FDA reduced the 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.
The FDA Export Reform and Enhancement Act of 1996 (Pub. L.
104-134, and amended by Pub. L. 104-180) addressed industry's
problems and concerns. For human drugs and biologics that may
not be sold in the United States, the 1996 Amendments:
* Amended section 801(d) of the act to allow import of
components of drugs and biologics into the United
States that do not comply with other provisions in the
act where those components are intended for
incorporation or further processing by the initial
owner or consignee into a drug or biologic that will be
exported under section 801(e) or section 802 of the act
or section 351(h) of the PHS Act.
* Amended section 801 of the act to allow exports of
approved drugs (except for insulin and antibiotics) to
countries that have different or additional labeling
requirements. The new provision, at section 801(f) of
the act, requires such drugs to be labeled in
accordance with the requirements and conditions for use
in the foreign country and to be labeled in accordance
with the act. If the drug's labeling includes
conditions of use that are not approved in the United
States, the labeling must state that such conditions
for use have not been approved under the act.
* Replaced section 802 of the act in its entirety with a
new section 802 of the act that:
** Eliminated the requirement for prior FDA approval
of exports of unapproved drugs (in most cases),
** Significantly expanded the list of countries to
which unapproved products can be exported without
prior FDA approval (and also provided
administrative mechanisms for the Secretary of
Health and Human Services (the Secretary) to add
countries to the list and for FDA to permit
exports of specific products to unlisted
countries),
** Authorized exports of unapproved drugs and
biologics intended for use in clinical
investigations in any of 25 countries identified
in section 802(b)(1)(A) of the act,
** Authorized the export of unapproved products to a
listed country in anticipation of marketing
approval in that country,
** Created a simple notification process for most
exported products (as opposed to the application
process required under the 1986 Amendments).
Notification is not required for drugs exported
for investigational use in a listed country or
drugs exported in anticipation of marketing
authorization in a listed country, and
** Authorized FDA to permit the export of unapproved
products intended to treat tropical or other
diseases that are "not of significant prevalence
in the United States."
For animal drugs that may not be sold in the United States,
the 1996 Amendments:
* Again restricted the authority to export an unapproved
new animal drug to section 801 of the act. 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).
* The only unapproved new animal drugs that cannot be
exported under section 801 of the act are "banned"
animal drugs (see section 801(e)(3) of the act).
Neither the statute nor the legislative history
explains what a "banned" animal drug is, and FDA is
working on an interpretation as to what constitutes a
"banned" animal drug.
For devices that may not be sold in the United States, the
1996 Amendments:
* Amended section 801(d) of the act to permit the import
of component parts, accessories, or other articles of a
device that do not comply with other provisions in the
act, if those component parts, accessories, or other
articles are intended for incorporation or further
processing by the initial owner or consignee into a
device that will be exported under section 801(e) or
section 802 of the act or section 351(h) of the PHS
Act;
* Amended section 801 of the act to permit exportation of
devices under section 801(e) of the act or under
section 802 of the act;
* Replaced section 802 of the act in its entirety with a
new section 802 of the act that:
** Eliminated the requirement for prior FDA approval
for exports (for devices approved in a listed
country or destined for clinical investigations in
a listed country),
** Created administrative mechanisms for the
Secretary to add countries to the list and for FDA
to approve exports of specific products to
unlisted countries,
** Authorized exports of unapproved devices intended
for use in clinical investigations in any of 25
countries identified in section 802 of the act,
** Authorized the export of unapproved devices to a
listed country in anticipation of marketing
approval in that country,
** Created a simple notification process for exported
devices (as opposed to the application process
under section 801(e)(2) of the act). Notification
is not required for devices exported for
investigational use to a listed country or devices
exported in anticipation of marketing
authorization in the listed country; and
** Authorized FDA to permit the export of unapproved
devices intended to treat tropical diseases or
other diseases that are "not of significant
prevalence in the United States."
Additionally, the 1996 Amendments permit importation of food
additives, color additives, and dietary supplements into the
United States if those articles are intended for incorporation or
further processing by the initial owner or consignee into a drug,
biologic, device, food, food additive, color additive, or dietary
supplement that will be exported.
This document describes the requirements for drugs (both
human and animal), biologics, and devices under sections 801 and
802 of the act and section 351(h) of the PHS Act, as amended by
the 1996 Amendments. It begins with a discussion of the
principal export requirements under sections 801 and 802 of the
act and section 351(h) of the PHS Act, followed by a discussion
of the "import-for-export" requirements under section 801 of the
act.
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. (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).
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 would consider 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.
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 or the device is eligible for
export under section 802 of the act.
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 approval unless the criteria under section
801(e)(2) of the act are met, 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.
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. 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.
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 XIII of this document.)
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.
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.
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 XIII of this document for the address and
phone number).
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 meet 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 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.
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 351(h) of the PHS Act, including the requirements section
801(e)(1) of the act. FDA recommends that the firm or
manufacturer maintain the following records for possible review
during a routine annual or biennial FDA inspection. Depending on
the particular circumstances of export, different or additional
records may also be relevant.
* Evidence that the product for export qualifies as a
partially processed biological product;
* Evidence that the partially processed biological
product complies with the laws of the country to which
it is being exported and accords to the specifications
of the foreign purchaser, in accordance with section
801(e)(1) of the act, and is intended for further
manufacture into final dosage form outside the United
States, in accordance with section 351(h)(3) of the PHS
Act. Such evidence may consist of a valid marketing
authorization for the partially processed biological
product or the final product from the foreign ministry
of health, contractual agreement, and purchase orders
that may include foreign specifications;
* Records, such as manufacturing records, that trace the
partially processed biological product through the
assignment of a batch or lot numbering system at the
U.S. exporting firm. The agency suggests that these
records also include temperature stability data for the
product during the conditions of transit (export) and
periodic checks of the capacity of the shipping
containers;
* Distribution records of exported partially processed
biological products;
* Copies of all labeling that accompanies the partially
processed biological product for export (i.e.,
container label or any package insert). FDA recommends
that the partially processed biological product's
container label state, "Caution: For Further
Manufacturing Use Only;" and
* Evidence that the product is not intended for sale in
the United States and has not been sold or offered for
sale in the United States. This may consist of
purchase orders from the foreign purchaser and
distribution records and records of the product's
labeling and similar products sold in the United
States. FDA examines whether the product itself (as
opposed to batches or lots) is sold or offered for sale
in the United States. For example, if a company
produces five batches of a partially processed
biological product and intends to export two batches
and sell the remaining three in the United States, the
product is deemed "sold or offered for sale in the
United States" and "intended for sale in the United
States" within the meaning of section 351(h) of the PHS
Act.
Additionally, firms that manufacture, prepare, or process
partially processed biologics for export must register with FDA
and list their products under section 510 of the act and parts
207 and 607 (21 CFR parts 207 and 607).
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) 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.
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 in section VIII.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
VIII 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.
VII. Exports of Unapproved
Drugs, Biologics, and Devices
Under Section 802(b) of the Act
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. If FDA declines to approve
or license a drug or biologic or devices 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.
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 sections VIII through X of this
document.
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.
Under section 802(f) of the act, the basic requirements for
all drugs, biologics, and devices exported under section 802 of
the act are as follows:
* The product must be manufactured, processed, packaged,
and held in "substantial conformity" with cGMP's or
meet international standards as certified by an
international standards organization recognized by
FDA. 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 should 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.
* The product must not consist in whole or in part of any
filthy, putrid, or decomposed substance and must not
have been prepared, packed or held under insanitary
conditions where it may have been contaminated or made
injurious to health;
* The container for the product must not be composed, in
whole or in part, of any poisonous or deleterious
substance which may render the contents injurious to
health;
* The product must have the strength, purity, or quality
that it is represented to possess;
* For drugs, no substance may be mixed or packed with the
drug that would reduce the drug's quality or strength
or may substitute in whole or in part for another
substance in the drug;
* The product must comply with the requirements in
section 801(e)(1) of the act. As stated earlier,
section 801(e)(1) of the act requires that the drug or
device to be exported: (1) Accords to the
specifications of the foreign purchaser; (2) not
conflict with the laws of the country to which it is
intended for export; (3) be labeled on the outside of
the shipping package that it is intended for export;
and (4) not be sold or offered for sale in domestic
commerce. (A discussion of the requirements in
section 801(e)(1) of the act appears earlier in this
guidance.)
* The product cannot be the subject of a notice by FDA or
the U.S. Department of Agriculture determining that the
probability of reimportation of the exported product
would present an imminent hazard to the public health
and safety of the United States, such that exportation
must be prohibited;
* The product cannot present an imminent hazard to the
public health of the country to which it would be
exported; and
* The product must be labeled in accordance with the
requirements and conditions of use in the listed
country 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.
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.
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.
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.
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.
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.
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.
One option is in section 802(b)(2) of the act. This section
permits a firm to export an unapproved drug directly to an
unlisted country if:
* The drug complies with the laws of the foreign country
and has valid marketing authorization by the
"responsible authority" in that country, and
* The agency determines that the foreign country has
statutory or regulatory requirements:
** Which require the review of drugs for safety and
effectiveness by a government entity in that
country and which authorizes marketing approval of
drugs which trained and experienced experts have
determined to be safe and effective. The experts
must be employed by or acting on behalf of the
foreign government entity and base their
determination on adequate and well-controlled
investigations (including clinical