Exports and Imports Under the FDA Export Reform and Enhancement Act of 1996
FDA Guidance for Industry on:
Exports and Imports Under the FDA Export
Reform and Enhancement Act of 1996
DRAFT
Food and Drug Administration
U.S. Department of Health and Human Services
February 1998
Table of Contents
I. Introduction
II. Terms Used in This Guidance
III. Quick Locator Guide
IV. Statutory Background
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
V. General Requirements for Products Exported Under Section 801(e)(1) of the Act
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
VI. Labeling Requirements for Drugs and Biologics Exported Under Section
801(e)(1) of the Act - Section 801(f) of the 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
VIII. Exports of Unapproved Drugs and Devices for Investigational Use to Listed
Countries Under Section 802(c) 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
IX. Exports of Unapproved Drugs and Devices in Anticipation of Foreign Approval
- Section 802(d) of the Act
X. 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
XI. Export Notification Under Section 802(g) of the Act
A.The Content of the Simple Notification
B.Where to Send the Simple Notification
C. Recordkeeping
XII. "Import for Export" - Section 801(d)(3) and (d)(4) of the Act
A. Items Covered Under the Import for Export Provision
1.Human Drugs
2.Devices
3. Food Additives, Color Additives, and Dietary Supplements
B.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")
XIII. For Further Information, Contact
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.
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
312.110.
III. Quick Locator Guide
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.
IV. 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). 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.
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 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 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.
D. Enactment of the FDA Export Reform and Enhancement Act of 1996
The FDA Export Reform and Enhancement Act of 1996 (Pub. L.
104-134, and amended by Pub. L. 104-180) addressed industry's
problems and concerns. For human drugs and biologics that may
not be sold in the United States, the 1996 Amendments:
* Amended section 801(d) of the act to allow import of
components of drugs and biologics into the United
States that do not comply with other provisions in the
act where those components are intended for
incorporation or further processing by the initial
owner or consignee into a drug or biologic that will be
exported under section 801(e) or section 802 of the act
or section 351(h) of the PHS Act.
* Amended section 801 of the act to allow exports of
approved drugs (except for insulin and antibiotics) to
countries that have different or additional labeling
requirements. The new provision, at section 801(f) of
the act, requires such drugs to be labeled in
accordance with the requirements and conditions for use
in the foreign country and to be labeled in accordance
with the act. If the drug's labeling includes
conditions of use that are not approved in the United
States, the labeling must state that such conditions
for use have not been approved under the act.
* Replaced section 802 of the act in its entirety with a
new section 802 of the act that:
** Eliminated the requirement for prior FDA approval
of exports of unapproved drugs (in most cases),
** Significantly expanded the list of countries to
which unapproved products can be exported without
prior FDA approval (and also provided
administrative mechanisms for the Secretary of
Health and Human Services (the Secretary) to add
countries to the list and for FDA to permit
exports of specific products to unlisted
countries),
** Authorized exports of unapproved drugs and
biologics intended for use in clinical
investigations in any of 25 countries identified
in section 802(b)(1)(A) of the act,
** Authorized the export of unapproved products to a
listed country in anticipation of marketing
approval in that country,
** Created a simple notification process for most
exported products (as opposed to the application
process required under the 1986 Amendments).
Notification is not required for drugs exported
for investigational use in a listed country or
drugs exported in anticipation of marketing
authorization in a listed country, and
** Authorized FDA to permit the export of unapproved
products intended to treat tropical or other
diseases that are "not of significant prevalence
in the United States."
For animal drugs that may not be sold in the United States,
the 1996 Amendments:
* Again restricted the authority to export an unapproved
new animal drug to section 801 of the act. 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.
V. 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. (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.
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 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.)
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.
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).
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 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.
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 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).
VI. 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) 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
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. 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.
B. Devices
Section 802(b) of the act, like section 801(e)(2) of the
act, applies to devices that:
* Do not comply with an applicable requirement under
section 514 or 515 of the act;
* Are subject to an IDE; or
* Are banned devices.
This means that devices that have premarket approval are not
subject to section 802 of the act, nor are devices that are the
subject of a marketing clearance under the premarket notification
provision under section 510(k) of the act.
C. Basic Requirements for All Products Exported Under Section 802 of the Act
Under section 802(f) of the act, the basic requirements for
all drugs, biologics, and devices exported under section 802 of
the act are as follows:
* The product must be manufactured, processed, packaged,
and held in "substantial conformity" with cGMP's or
meet international standards as certified by an
international standards organization recognized by
FDA. 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.
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.
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.
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.
One option is in section 802(b)(2) of the act. This section
permits a firm to export an unapproved drug directly to an
unlisted country if:
* The drug complies with the laws of the foreign country
and has valid marketing authorization by the
"responsible authority" in that country, and
* The agency determines that the foreign country has
statutory or regulatory requirements:
** Which require the review of drugs for safety and
effectiveness by a government entity in that
country and which authorizes marketing approval of
drugs which trained and experienced experts have
determined to be safe and effective. The experts
must be employed by or acting on behalf of the
foreign government entity and base their
determination on adequate and well-controlled
investigations (including clinical
investigations);
** Pertaining to cGMP's;
** For reporting adverse events and for removing
unsafe or ineffective drugs from the market; and
** Which require that the labeling and promotion be
in accordance with the product's approval.
FDA recommends that firms intending to export drugs under
section 802(b)(2) of the act provide documentation showing that
the drug complies with the foreign country's laws and has valid
marketing authorization. (If the country has a regulatory system
that allows marketing without an affirmative decision by the
government, FDA recommends that the firm obtain a document
indicating that the authorities in the listed country do not
object to the product's marketing.) The agency also suggests
that firms provide documentation so FDA can make its
determination on the foreign country's statutory and/or
regulatory requirements. Copies of the foreign country's laws
and regulations (in English) may be helpful, but are not
required; firms may also provide a description of the foreign
country's laws and regulations with citations that identify the
precise law or regulation. If FDA cannot make the necessary
determinations concerning the foreign country's statutory and
regulatory requirements, the firm cannot export the drug under
section 802(b)(2) of the act.
The second option is in section 802(b)(3) of the act. This
section permits a firm to petition the agency to approve
exportation to an unlisted country if the conditions for export
under section 802(b)(1) and 802(b)(2) of the act cannot be met.
Under section 802(b)(3) of the act, FDA must allow exportation of
the drug if:
* The person exporting the drug: (1) Certifies that the
drug would not meet the conditions for approval under
the Act or the conditions for approval in a listed
country; and (2) provides "credible scientific
evidence" that is acceptable to FDA to show that the
drug would be safe and effective under the conditions
of use in the country to which it is being exported.
The statute does not specify what constitutes "credible
scientific evidence," but an adequate and well-controlled
study or studies, animal and in vitro
pharmacology and toxicology studies, microbiology
studies (for biologics), and statistical analyses of
data should be helpful; and
* The appropriate health authority in the foreign country
that is to receive the drug: (1) Requests approval of
the drug's exportation, (2) certifies that the health
authority understands that the drug is not approved
under the Act or by any listed country, and (3) concurs
that the scientific evidence provided to FDA is
credible scientific evidence that the drug would be
reasonably safe and effective in the foreign country.
A letter from the relevant foreign government entity
addressing each item in this paragraph should be
acceptable.
As a reminder, any person who exports a drug under section
802 of the act also must comply with the basic export
requirements set forth in section 802(f) of the act.
Persons who wish to export a drug under sections 802(b)(2)
or 802(b)(3) of the act should send their documentation or
requests to:
(For Biologics)
Division of Case Management (HFM-610),
Center for Biologics Evaluation and Research,
Food and Drug Administration,
1401 Rockville Pike, rm. 200N,
Rockville, MD 20852-1448.
(For Drug Products)
Executive Secretariat Team (HFD-6),
Center for Drug Evaluation and Research,
1451 Rockville Pike,
Rockville, MD 20852-1420.
FDA has 60 days to act on a request to export a drug under
section 802(b)(3) of the act. The agency will begin the 60 day
period on the date that it receives a complete petition
containing the certification and evidence required by the act.
VIII. 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
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
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
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 section 802
of the act. The selected authority is important because each
section of the act carries its own statutory requirements.
For example, if company F wants to export an unapproved
device for investigational use to a listed country, it could:
* Export the device under section 801(e)(2) of the act.
Under this provision, the exporter would need to comply
with section 801(e)(1) of the act and, depending on the
device, might have to submit information that would
enable FDA to determine that exportation is not
contrary to the public health or safety and that the
foreign country approves of the exportation, or
* Export the device under section 802(b)(1)(A) of the act
if the device has received valid marketing
authorization in any listed country. Section
802(b)(1)(A) of the act permits exportation of an
unapproved device, for any purpose, if the device
complies with the laws of the foreign country and has
received valid marketing authorization in a listed
country. (Exports under section 802(b)(1) of the act
may also occur to unlisted countries so long as the
device complies with the foreign country's laws and has
valid marketing authorization in a listed country.)
Exports under this option must comply with the basic
export requirements at section 802(f) of the act (such
as being in "substantial conformity" with cGMP's or
meeting international standards as certified by a
recognized international standards organization and
complying with section 801(e)(1) of the act) and the
notification and recordkeeping requirements in section
802(g) of the act; or
* Export the device to a listed country under section
802(c) of the act, without prior FDA approval or the
submission of any information to FDA. However, under
this option, compliance with the basic export
requirements in section 802(f) of the act and the
recordkeeping requirement in section 802(g) of the act
is necessary.
Consequently, in the Federal Register of May 13, 1997 (62 FR
26228), FDA amended
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.
IX. 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.
X. 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 considered to be a
disease that is not of significant prevalence in the United
States because most children are immunized against measles.
However, like the 1986 Amendments, the revised provision
(which is now codified as section 802(e) of the act) requires FDA
to approve an export application before the product can be
exported. The export application should contain information
showing that the drug or device is intended for use in a tropical
disease or a disease that is not of significant prevalence in the
United States. Additionally, the application should contain
information that will enable FDA to determine whether the drug,
biologic, or device:
* Will not expose patients in the foreign country to an
unreasonable risk of illness or injury, and
* When used under conditions prescribed, recommended, or
suggested in the labeling or proposed labeling has a
probable benefit to health that outweighs the risk of
injury or illness from its use, taking into account the
probable risks and benefits of currently available drug
or device treatment. By "currently available drug or
device treatment," the applicant should consider the
availability of products that are approved for the
particular disease as well as those that are commonly
used to treat the disease, even if the product is not
approved for that indication.
XI. 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
require FDA to consult with the "appropriate public health
official" in the affected country.
B. Where to Send the Simple Notification
Notifications may be sent to the following addresses:
For biological drug products and biological devices:
Division of Case Management (HFM-610),
Office of Compliance,
Center for Biologics Evaluation and Research,
Food and Drug Administration,
1401 Rockville Pike, rm. 200N,
Rockville, MD 20852-1448.
For human drug products:
Division of Labeling and Nonprescription Drug Compliance
(HFD-310),
Center for Drug Evaluation and Research,
Food and Drug Administration,
7520 Standish Pl.,
Rockville, MD 20855-2737.
For devices:
Division of Program Operations (HFZ-305),
Center for Devices and Radiological Health,
Food and Drug Administration,
2094 Gaither Rd.,
Rockville, MD 20850.
C. Recordkeeping
As stated earlier, section 802(g) of the act requires
exporters to maintain records of all drugs and devices exported
and the countries to which the products were exported. FDA
recommends that exporters maintain records showing:
* The product's name and its generic name (if the product
is a drug or a device),
* The type of device (if the product is a device),
* A description of its strength and dosage form and the
product's lot or control number (if the product is a
drug) or the product's model number (if the product is
a device),
* The consignee's name and address, and
* The date and quantity of product exported.
FDA recommends that these records be kept at the site from
which the products were exported and be maintained at least 5
years after the date of exportation. The agency may request that
the records be made readily available for review and copying
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.
XII. "Import for Export" - Section 801(d)(3) and (d)(4) of the Act
Before the 1996 Amendments, all imported components of
drugs, biologics, devices, and other FDA-regulated products had
to comply with the requirements of the act, even if they were to
be incorporated into products destined solely for export.
The 1996 Amendments changed the law by creating two
subsections at 801(d)(3) and (d)(4) of the act. Under section
801(d)(3) of the act, a component of a drug or a biologic, a
component part, accessory, or other article of a device, or a
food additive, color additive, or dietary supplement that would
otherwise be refused entry into the United States, can be
imported into the United States if:
* The importer submits a statement to the agency at the
time of initial importation declaring that the
component, part, accessory, or article is intended to
be "incorporated" or "further processed" by the initial
owner or consignee into a drug, biological product,
device, food, food additive, color additive, or dietary
supplement that will be exported from the United States
by the initial owner or consignee in accordance with
section 801(e) or section 802 of the act or section
351(h) of the PHS Act (see section 801(d)(3)(A) of the
act).
* The initial owner or consignee responsible for the
imported article maintains records that identify the
use of the imported component, part, accessory, or
article. Upon request from the agency, the initial
owner or consignee must submit a report that accounts
for the exportation or the disposition of the imported
component, part, accessory, or article (including
quantities that were destroyed), including the manner
in which the initial owner or consignee complied with
the requirements in section 801(d) of the act (see
section 801(d)(3)(B) of the act).
* Any imported component, part, accessory, or article
that is not incorporated into a product must be
destroyed or exported by the owner or consignee (see
section 801(d)(3)(C) of the Act).
This provision is commonly referred to as the "import for export"
provision.
A. Items Covered Under the Import for Export Provision
1. Human Drugs
One issue under section 801(d)(3) of the act is what
constitutes a "component" of a drug. FDA regulations define
"component" as meaning "any ingredient intended for use in the
manufacture of a drug product, including those that may not
appear in such drug product." (See
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
820.3(c).)
As in the case of drugs and biologics, FDA interprets the term
"component" in section 801(d) of the act broadly to encompass a
range of items.
Yet, regardless of whether the imported item is a drug or
device component, the key issue under section 801(d)(3) of the
act is how the component will be "incorporated" or "further
processed."
3. Food Additives, Color Additives, and Dietary Supplements
Section 801(d)(3) of the act refers to food additives, color
additives, and dietary supplements. The act defines "food
additive" at section 201(s) of the act, "color additive" at
section 201(t) of the act, and "dietary supplement" at section
201(ff) of the act.
B. Activities Covered Under the Concept of "Incorporation" and "Further
Processing"
Section 801(d)(3) of the act only permits a component, part,
accessory, or article to enter the United States if it is
intended to be "incorporated" into a product for export or is to
be "further processed" into a product that will be exported.
In the context of section 801(d)(3) of the act, FDA
interprets the terms "incorporated" and "further processing" to
encompass a wide range of activities. Thus, "incorporation" and
"further processing" are not confined to product manufacture.
Instead, they include related activities such as packaging and
labeling of finished products and specialized processing (such as
sterilization) of a product.
However, FDA does not consider a component, part, accessory,
or article to be "incorporated" or "further processed" if it is
merely stored in the United States before being exported
elsewhere. Although FDA has exercised enforcement discretion
regarding specific entries of violative products that are stored
in the United States, the agency does not consider the
importation of an unapproved product for storage purposes to fall
within the meaning of "incorporated" or "further processed" under
section 801(d)(3) of the act.
C. Submission of Statements to FDA
Section 801(d)(3)(A) of the act requires the importer to
submit, "at the time of initial importation," a statement to the
agency indicating that the imported component, part, accessory,
or other article is intended to be incorporated or further
processed by the initial owner or consignee into a product that
will be exported in compliance with section 801(e) or section 802
of the act or section 351(h) of the PHS Act. Firms should submit
this statement to FDA each time they import an article under the
"import for export" provision in the Act. The statement (along
with other import documents) should be provided to the FDA field
office that has responsibility over the port or site of entry
into the United States.
FDA recommends that the statement contain the following
information:
* The purpose for which the article is being imported
prior to export (how it will be further processed or
the name or description of the product into which it
will be incorporated);
* The imported article's name or description (including
any scientific or technical name);
* Any product coding, batch, lot, or other identifying
numbers;
* The name and address of the imported article's foreign
manufacturer (if different from the name of the foreign
shipper identified in the import records at the U.S.
Customs Service); and
* The name and address of the initial owner or consignee
in the United States and, if different, the address in
the United States where the imported article will be
further processed or incorporated into a product for
export.
For blood, blood components, source plasma, source
leukocytes, or a component, accessory, or part that is not
licensed under section 351(a) of the PHS Act and is to be
imported under section 801(d)(4) of the act, FDA suggests that
the statement include a copy of the determination by FDA granting
permission to import the product or article. (The request for
determination is described in more detail later in section
XII.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 United
States 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
which such person complied with the requirements of this
paragraph * * *."
The statutory reference to the initial owner or consignee
indicates that, under section 801(d)(3) of the act, the person
who imports the article for incorporation or further processing
may, in turn, have other persons perform the actions that lead to
the incorporation or further processing of the imported article.
For example, if company C imports a drug into the United States
for sterilization purposes, but does not have the technological
capability to sterilize the drug itself, company C could send the
drug to company D for sterilization and, after receiving the
sterilized drug back from company D, export the drug from the
United States. However, under this scenario, company C would
remain the owner of the product and would be responsible for
maintaining records and for submitting, upon FDA's request, a
report accounting for the exportation or disposition of the
imported article.
The agency suggests that firms importing an article into the
United States under section 801(d)(3) of the act retain records
showing:
* The name or description of the article (including any
scientific or technical name);
* Any product coding, batch, lot, or other identifying
numbers;
* The name and address of the foreign manufacturer of the
imported article;
* How the article will be or was further processed, and
the name or description of any product into which it
will be or was incorporated in the United States;
* The signature of the responsible individual at the
importing firm;
* The name and address of the firm in the United States
where the article will be or was further processed or
incorporated into another product;
* The disposition of the imported article, i.e.,
manufacturing records showing how specific articles
were used or destroyed and the dates of receipt, use,
destruction, and/or reexportation, as that information
becomes available;
* Any product coding, lot, batch, or other identification
number for the further-processed article or product
incorporating the imported article;
* A copy of the label to be applied to the shipping
package, container, or crate used to export the
further-processed article or product incorporating the
imported article (indicating that it contains articles
that may not to be sold or offered for sale in the
United States and are intended for export only); and
* The name and address of the foreign purchaser of the
further-processed article or product incorporating the
imported article.
* Additionally, for blood, blood components, source
plasma, source leukocytes, or a component, accessory,
or part thereof (including blood or plasma derivatives
or intermediates) that is not licensed under section
351(a) of the PHS Act and is to be imported under
section 801(d)(4) of the act, the agency recommends
that the records also include documentation of the
agreement between the foreign material supplier and the
U.S. manufacturer. The documentation should outline
the specific contractual relationship, the foreign
manufacturing specifications, and the U.S.
manufacturer's plan for auditing the foreign supplier
to ensure compliance with the terms of the contract.
FDA suggests that the initial owner or consignee have
written standard operating procedures to ensure that
such products are not diverted to domestic use in the
United States and are kept segregated from and not
co-mingled with products or components intended for use in
the United States (e.g., quarantine procedures used for
segregating imported blood, blood components, or final
products from products intended for use in the United
States, including validation data for procedures to
clean equipment and facilities used for manufacturing
products for use in the United States and exported
products).
FDA also encourages firms to maintain any other records that
would assist FDA in determining whether they comply with section
801(d)(3) or (d)(4) of the act. 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.
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, blood
components, plasma, and source leukocytes 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.)
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.
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
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 21 CFR 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
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
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
1270.31).
If an importer, consignee, or U.S. manufacturer delivers or
ships human tissue or a component thereof before FDA releases it
or fails to quarantine tissue that has not been determined to be
suitable for human transplantation, such action may constitute a
criminal violation.
3. Requests to Import Blood, Blood Components, Plasma, and Source Leukocytes for
Further Processing or Incorporation into a Product for Export ("Requests for
Determination")
Section 801(d)(4) of the act does not specify how persons
who wish to import blood, blood components, source plasma, source
leukocytes, or their components, accessories, or parts obtain
permission to import those products. Nevertheless, to facilitate
imports under section 801(d)(4) of the act, FDA recommends that
manufacturers provide an import for export request which
demonstrates that appropriate circumstances or conditions warrant
CBER's approval of importation under section 801(d)(4) of the
act. The agency recommends that these requests, known as a
"request for determination," contain the following information:
* The names and addresses of the foreign manufacturer of
the article to be imported and the initial owner or
consignee in the United States that would be
responsible for the further processing or incorporation
of the article into another product;
* The specific identity of the article to be imported and
details as to how the imported article will be further
processed or incorporated into a product for export;
* A description of the standard operating procedures and
safeguards that the initial owner or consignee in the
United States will use or implement to ensure that the
imported articles or products incorporating such
articles are segregated from and not comingled with
products, components, accessories, or parts intended
for use in the United States (e.g., quarantine
procedures used for segregating imported blood, blood
components, or final products from products intended
for use in the United States, including validation data
for procedures to clean equipment and facilities used
in manufacturing products for use in the United States
and products for export);
* General donor screening questionnaire or criteria,
translated into English, that will be used to screen
donors;
* A certification that the foreign supplier will perform
tests for infectious disease on the blood, blood
components, source plasma, or source leukocytes, or
their components, accessories, or parts (including
blood or plasma derivatives or intermediates) at the
time of donation and before importation to the United
States, and the expected results of such tests. The
infectious disease agents that should be tested for
include, but are not limited to: HIV-1, HIV-2,
hepatitis B virus, hepatitis C virus, HTLV-I, HTLV-II,
and Treponema palladum. A request for determination
may be based upon infectious agent tests performed
using test kits other than those licensed or approved
by FDA. In such cases, FDA suggests that the request
contain a copy of the labeling for the test kit used,
translated into English, as part of the submission; and
* A copy of the product's label. FDA recommends that the
label include information such as the product's
descriptive name; the name(s) and address(es) of
establishments collecting, preparing, labeling, or
pooling the source material; donor, lot, or pool
numbers relating the unit to the donor; the recommended
storage temperature (in degrees Celsius); the product's
quantity; statements such as "Import for Export," "Not
for Use in Products Subject to Licensure Under Section
351 of the Public Health Service Act," and "For
Manufacturing Use Only" or "For Manufacturing into
Noninjectable Products Only;" statements indicating
that the product has been tested for infectious disease
agents and, if the product has tested positive for an
infectious disease agent, the term "BIOHAZARD" as well
as any other appropriate warnings or special handling
instructions.
A request for determination may be sent to the Center for
Biologics Evaluation and Research, Office of Compliance, Division
of Case Management (HFM-610), 1401 Rockville Pike, Suite 200N,
Rockville, MD 20852-1448. If FDA determines that the blood,
blood component, source plasma, or source leukocyte, or
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.
XIII. 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
312.110:
Office of International Affairs (HFG-1),
Food and Drug Administration,
5600 Fishers Lane,
Rockville, MD 20857,
301-827-4480.
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.
Additional Federal Register documents with FDA-related material are located on
FDA's Dockets Website.
FDA Home Page | Search | A-Z Index | Site Map | Contact FDA
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Web page updated by jch 1998-JUN-12.
| File Type | application/msword |
| File Title | Exports and Imports Under the FDA Export Reform and Enhancement Act of 1996 |
| Author | DPresley |
| Last Modified By | DPresley |
| File Modified | 2007-02-13 |
| File Created | 2007-02-13 |