[Federal Register Volume 63, Number 113 (Friday, June 12, 1998)]
[Notices]
[Pages 32219-32234]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 98-15696]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. 98D-0307]
Draft Guidance for Industry; Exports and Imports Under the FDA
Export Reform and Enhancement Act of 1996
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice.
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SUMMARY: The Food and Drug Administration (FDA) is announcing the
availability of a draft guidance document entitled, ``FDA Draft
Guidance for Industry on: Exports and Imports Under the FDA Export
Reform and Enhancement Act of 1996.'' The draft guidance document
addresses issues pertaining to the exportation of human drugs, animal
drugs, biologics, food additives, and devices as well as the
importation of components, parts, accessories, or other articles for
incorporation or further processing into articles intended for export.
DATES: Written comments on the draft guidance document may be submitted
by August 26, 1998. General comments on the agency's guidance documents
may be submitted at any time.
ADDRESSES: Submit written comments on the draft guidance document to
the Dockets Management Branch (HFA-305), Food and Drug Administration,
12420 Parklawn Dr., rm. 1-23, Rockville, MD 20857.
FOR FURTHER INFORMATION CONTACT: Philip L. Chao, Office of Policy (HF-
23), Food and Drug Administration, 5600 Fishers Lane, Rockville, MD
20857, 301-827-3380.
SUPPLEMENTARY INFORMATION: FDA is announcing the availability of a
draft guidance document entitled, ``FDA Draft Guidance for Industry on:
Exports and Imports Under the FDA Export Reform and Enhancement Act of
1996.'' Enacted and later amended in 1996, the FDA Export Reform and
Enhancement Act (Pub. L. 104-134, as amended by Pub. L. 104-180)
significantly changed the export requirements for human drugs, animal
drugs, biologics, devices, and, to a limited extent, food additives.
For example, before the law was enacted, most exports of unapproved new
drug products could only be made to 21 countries identified in section
802 of the Federal Food, Drug, and Cosmetic Act (the act), and these
exports were subject to various restrictions. The FDA Export Reform and
Enhancement Act amended section 802 of the act to allow, among other
things, the export of unapproved new drugs to any country in the world
if the drug complies with the laws of the importing country and has
valid marketing authorization from any of the following countries:
Australia, Canada, Israel, Japan, New Zealand, Switzerland, South
Africa, and the countries in the European Union (EU) and the European
Economic Area (EEA). (Currently, the EU countries are Austria, Belgium,
Denmark, Germany, Greece, Finland, France, Ireland, Italy, Luxembourg,
the Netherlands, Portugal, Spain, Sweden, and the United Kingdom. The
EEA countries are the EU countries, Iceland, Liechtenstein, and Norway.
The list of countries will expand automatically if any country accedes
to the EU or becomes a member of the EEA.)
The draft guidance document provides information on the statutory
requirements for exporting human drugs, animal drugs, biologics, and
medical devices, general requirements for products exported under
section 801 of the act (21 U.S.C. 381), labeling requirements for drugs
and biologics exported under section 801(e) of the act, export
requirements for unapproved drugs, biologics, and devices under section
802(b) of the act (21 U.S.C. 382(b)), exports of unapproved drugs and
devices for investigational use, exports of unapproved drugs and
devices in anticipation of foreign approval; exports of drugs and
devices for diagnosing, preventing, or treating a tropical disease or a
disease ``not of significant prevalence in the United States,'' export
notifications to FDA, and ``import for export.''
The draft guidance document represents the agency's current
thinking on exports and imports-for-export under sections 801 and 802
of the act. It does not create or confer any rights for or on any
person and does not operate to bind FDA or the public. An alternative
approach may be used if such approach satisfies the requirements of the
applicable statute, regulations, or both.
Interested persons may submit to the Dockets Management Branch
(address above) written comments on the draft guidance document. Two
copies of any comments are to be submitted, except that individuals may
submit one copy. Comments are to be identified with the docket number
found in brackets in the heading of this document. A copy of the draft
guidance document and received comments may be seen in the office
[[Page 32220]]
above between 9 a.m. and 4 p.m., Monday through Friday. The agency
invites comments on the following issues:
What are the draft guidance document's strengths and
weaknesses? For example, which topics might require more explanation?
Which international standards organization(s), if any,
should FDA recognize for purposes of section 802(f)(1) of the act?
Which international standards should be used and for which products?
Under section 802(f)(1) of the act, all drugs and devices exported
under section 802 of the act must be in substantial conformity with
current good manufacturing practice requirements or meet
``international standards as certified by an international standards
organization recognized'' by FDA.
Section 802(e) of the act requires an application to
export a drug or device intended to treat a tropical disease or a
disease that is not of significant prevalence in the United States. FDA
may approve exportation if it finds that the drug or device will not
expose patients in the foreign country to an unreasonable risk of
illness or injury and that the probable health benefits from using the
drug or device under its labeled conditions of use outweigh the risk of
injury or illness from its use, ``taking into account the probable
risks and benefits of currently available drug or device treatment.''
What should the application contain so that FDA may make these
findings? How many applications might be submitted?
The draft guidance document, with a table of contents and ``quick
locator guide,'' can be accessed electronically at http://www.fda.gov/
opacom/fedregister/frexport.html. The full text of the draft guidance
document, without the table of contents and quick locator guide (due to
reformatting and pagination changes in the Federal Register), follows:
FDA Guidance for Industry on: Exports and Imports Under the FDA
Export Reform and Enhancement Act of 1996
I. Introduction
This guidance document is intended to summarize and to explain the
basic requirements and procedures for exporting and importing human
drugs, animal drugs, biologics, devices, food additives, color
additives, and dietary supplements that may not be sold or distributed
in the United States under the FDA Export Reform and Enhancement Act of
1996 (Pub. L. 104-134, and amended by Pub. L. 104-180). \1\ This law
amended sections 801 and 802 of the Federal Food, Drug, and Cosmetic
Act (the act), as well as section 351(h) of the Public Health Service
Act, simplifying the requirements for exporting unapproved human drugs,
biologics, and devices. \2\ In addition, the FDA Export Reform and
Enhancement Act substantially reduced the requirements for exporting
unapproved new animal drugs, provided a new option for exporting
unapproved devices, and added a new provision, at section 801(d)(3) of
the act that permits the import of certain components, parts, and
accessories of human drugs, biologics, devices, food additives, color
additives, and dietary supplements for further processing or
incorporation into products intended for export.
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\1\ This guidance document may be supplemented by other guidance
documents on specific topics.
\2\ If a product meets the requirements for sale in the United
States, the act has no restrictions on its exportation.
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This guidance document does not address export certificates and
fees. Information on these subjects can be found in Compliance Policy
Guide 7150.01, ``Certification for Exports.''
Please note that a firm or product may be subject to additional
statutory or regulatory requirements beyond those described in this
guidance. For example, depending on the type of products it
manufactures, a firm may be subject to registration requirements under
section 510 of the act (21 U.S.C. 360).
This guidance document represents the agency's current thinking
with respect to the exportation of various products under the FDA
Export Reform and Enhancement Act of 1996 and replaces FDA's previous
guidance on exports entitled, ``A Review of FDA's Implementation of the
Drug Export Amendments of 1986.'' It does not create or confer any
rights for or on any person and does not operate to bind FDA or the
public. An alternative approach may be used if such approach satisfies
the requirements of the applicable statute, regulations, or both.
II. Terms Used in This Guidance
This guidance uses the following terms:
``act'' means the Federal Food, Drug, and Cosmetic Act. Citations
to specific sections of the act will use the numerical sequence
specified in the act rather than the section numbers used in the U.S.
Code.
``cGMP'' means current good manufacturing practice. For drugs and
biologics, cGMP regulations can be found at parts 210 and 211 (21 CFR
parts 210 and 211). For devices, cGMP regulations can be found at part
820 (21 CFR part 820). For blood and blood components, additional
regulations can be found at part 606 (21 CFR part 606).
``FDA'' or ``agency'' means the Food and Drug Administration.
``IDE'' means an investigational device exemption application.
These are applications containing requests to use an unapproved device
in clinical tests using human subjects. The regulations are authorized
under section 520(g) of the act (21 U.S.C. 360(g)), and the
implementing regulations can be found at part 812 (21 CFR part 812).
``IND'' means an investigational new drug application. These
applications are required for persons who intend to conduct clinical
investigations involving products subject to section 505 of the act (21
U.S.C. 355) or to the licensure provisions of the Public Health Service
Act (42 U.S.C. 262). The IND regulations are authorized by section
505(i) of the act and are found at part 312 (21 CFR part 312).
``1986 Amendments'' means the Drug Export Amendments Act of 1986
(Pub. L. 99-960). Most provisions in the 1986 Amendments were revised
or eliminated by the 1996 Amendments.
``1996 Amendments'' means the FDA Export Reform and Enhancement Act
of 1996 (Pub. L. 104-134 and amended by Pub. L. 104-180).
``PHS Act'' means the Public Health Service Act (42 U.S.C. 201 et
seq.). Citations to specific sections of the PHS Act will use the
numbers specified in the PHS Act rather than the section numbers used
in the U.S. Code.
``PMA'' means a premarket approval application. This is a marketing
application for certain devices under section 515 of the act. The
regulation for PMA's can be found at 21 CFR part 814.
``312 Program'' means the regulatory program used by FDA for
permitting the exportation of investigational drugs or biologics for
clinical use in foreign countries. The principal statutory authority
for the 312 Program is section 505(i) of the act, and the regulation
can be found at Sec. 312.110.
III. Statutory Background
Some background information on the statutory requirements that
existed before the enactment of the 1996 Amendments is helpful to
understand why the 1996 Amendments were enacted.
A. Exports of Drugs and Biologics That May Not be Sold in the United
States
The export provision in the act had its origins in 1906 as part of
the Federal Food and Drugs Act (Pub. L. 59-384).
[[Page 32221]]
Section 2 of the 1906 Federal Food and Drugs Act stated that:
* * * no article shall be deemed misbranded or adulterated
within the provisions of this act when intended for export to any
foreign country and prepared or packed according to the
specifications or directions of the foreign purchaser when no
substance is used in the preparation or packing thereof in conflict
with the laws of the foreign country to which said article is
intended to be shipped; but if said article shall be in fact sold or
offered for sale for domestic use or consumption, then this proviso
shall not exempt said article from the operation of any of the other
provisions of this act.
This export provision remained essentially unchanged in the Federal
Food, Drug, and Cosmetic Act of 1938 (Pub. L. 75-717), where it was
codified as section 801(d). Section 801(d) of the 1938 Act stated that:
A food, drug, device, or cosmetic intended for export shall not
be deemed to be adulterated or misbranded under this Act if it (1)
accords to the specifications of the foreign purchaser, (2) is not
in conflict with the laws of the country to which it is intended for
export, (3) is labeled on the outside of the shipping package that
it is intended for export, and (4) is not sold or offered for sale
in domestic commerce * * *.
The 1938 act, however, also defined the terms, ``drug,'' and ``new
drug,'' and these definitions led to the conclusion that section
801(d)(1) of the act did not apply to new drugs. (See, e.g., United
States v. An Article of Drug, etc. * * * Ethionamide-INH, No. 67 C 288
(E.D. N.Y., Aug. 19, 1967); United States v. Yaron Laboratories, Inc.,
365 F.Supp. 917, 919 (N.D. Cal. 1972); Compliance Policy Guide 7132c.01
(Oct. 1, 1980).) As a result, the act was interpreted as permitting the
export of approved drugs, but not the export of unapproved new drugs.
This interpretation was viewed as imposing hardships on the
pharmaceutical industry (by impairing its ability to compete in
international markets) without any accompanying public health benefits
(see S. Rept. 99-225, 99th Cong., 2d sess. 5-6 (1985)).
To remedy the situation, Congress enacted the Drug Export
Amendments Act of 1986 (Pub. L. 99-960). Insofar as human drug products
and biologics were concerned, the 1986 Amendments created section 802
of the act and established three separate ``tracks'' for exporting
unapproved drugs and unlicensed biologics. Under ``track 1,'' FDA was
authorized to approve an application for the export of new human and
animal drugs and biologics that were not approved in the United States,
so long as the drug contained the same active ingredient(s) as a
product for which marketing approval in the United States was being
sought or the biological product was one for which licensing was
actively being pursued. Exports under ``track 1'' were confined to 21
specific countries listed in section 802 of the act. Those countries
were: Australia, Austria, Belgium, Canada, Denmark, the Federal
Republic of Germany, Finland, France, Iceland, Ireland, Italy, Japan,
Luxembourg, the Netherlands, New Zealand, Norway, Portugal, Spain,
Sweden, Switzerland, and the United Kingdom.
Under ``track 2,'' FDA was authorized to approve the export of
drugs and biologics intended for the treatment of tropical diseases.
Persons seeking to export a drug under track 2 had to submit an
application to FDA, and FDA had to find, based on ``credible scientific
evidence,'' that the drug would be safe and effective in the country to
which it would be exported in the prevention or treatment of a tropical
disease in that country.
``Track 3'' applied to partially processed biological products and
amended section 351 of the PHS Act. FDA was authorized to approve the
export of partially processed human biological products intended for
further manufacture in any of the 21 listed countries, but the final
product had to be approved or in the process of receiving approval from
the foreign country.
Additionally, the 1986 Amendments added a new section 801(d) of the
act (regarding importation of drugs), and renumbered the existing
section 801(d) as a new section 801(e)(1) of the act. \3\
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\3\ The 1986 Amendments did not alter the export requirements
for insulin and antibiotics. These products remained subject to the
basic export requirements that are now seen in section 801(e)(1) of
the act, and so exports could occur without prior FDA approval.
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The 1986 Amendments, however, presented several problems and
concerns. One significant problem was that the 1986 Amendments limited
exports of unapproved drugs and biologics to 21 countries. Although the
1986 Amendments provided criteria for adding more countries to the
list, it did not provide any administrative mechanism for doing so.
Consequently, exports to countries that were not on the list were not
permitted.
The requirement that the drug contain the same active ingredient as
a drug for which marketing approval in the United States was being
``actively pursued'' also caused some concern in the industry.
Questions arose concerning the degree to which the active ingredient
had to be the ``same'' or how ``actively'' the manufacturer had to be
seeking approval.
The concept in the 1986 Amendments which required FDA approval
before a product could be exported generated criticism and debate as
well. The 1986 Amendments required a person to file an application to
export a drug at least 90 days before the date on which the applicant
proposed to export the drug; required FDA to publish a notice in the
Federal Register identifying the applicant, the drug to be exported,
and the country to which the drug was being exported (for Track 1
exports only); and established requirements for the application as well
as the agency's action on an application. For example, if the agency
decided to disapprove an application, it had to provide a written
statement to the applicant describing deficiencies that the applicant
must correct and give the applicant 60 days to correct those
deficiencies. Some firms charged that this approval process took too
long; others questioned why the United States should have to approve
the export of a product to a foreign country, particularly when the
foreign country had its own public health authorities or had approved
the product for marketing.
B. Exports of Animal Drugs That May Not be Sold in the United States
As stated earlier, section 801(e) of the act was construed as not
applying to the exportation of unapproved new human drugs. This
interpretation also covered unapproved new animal drugs, and was made
explicit in 1968 as part of the Animal Drug Amendments of 1968 (Pub. L.
90-399). Although the initial Congressional bill would have permitted
exportation of unapproved new animal drugs, Congress, at the request of
the then-Department of Health, Education, and Welfare, elected to amend
section 801 of the act to prevent the exportation of unapproved new
animal drugs and animal feed containing unapproved new animal drugs
(see S. Rept. 1308, 90th Cong., 2d sess., 1968 U.S. Code Cong. & Admin.
News 2160). The legislative history explained that the amendment's
purpose was to ``preserve, essentially, the status quo with respect to
the export exemption'' (id.).
The Drug Export Amendments Act of 1986 altered the export
requirements for unapproved new animal drugs in the same manner that it
changed the export requirements for unapproved new human drugs (such as
limiting exports to 21 countries and requiring the exporter to be
pursuing product approval in the United States as a condition for
allowing exportation). Consequently, an unapproved new
[[Page 32222]]
animal drug could be exported under section 802 of the act.
C. Exports of Devices That May Not be Sold in the United States
As stated earlier, then-section 801(d) of the Federal Food, Drug,
and Cosmetic Act of 1938 (now codified at section 801(e)) stated that a
food, drug, device, or cosmetic intended for export would not be
considered adulterated or misbranded if the product: (1) Met the
foreign purchaser's specifications; (2) was not in conflict with the
laws of the country to which it was being exported; (3) was labeled on
the outside of the shipping package that the product was intended for
export; and (4) was not sold or offered for sale in domestic commerce.
This authority remained unchanged until 1976 when, as part of the
Medical Device Amendments Act of 1976 (Pub. L. 94-295), Congress
amended the provision to state that the four criteria did not apply to
any device that did not comply with an applicable requirement under
sections 514 (performance standards) or 515 (premarket approval) of the
act, to devices that were exempt from sections 514 or 515 of the act
under section 520(g) of the act (devices subject to an IDE), and to
banned devices (under section 516 of the act) unless, in addition to
requiring compliance with section 801(e)(1) of the act, the agency
determined that exportation of the device would not be contrary to the
public health and safety and the device had the approval of the foreign
country that would receive the device. In other words, most unapproved
devices could not be exported unless the agency determined that
exportation would not be contrary to the public health or safety and
that the foreign country approved of the device. This provision was,
and remains, codified at section 801(e)(2) of the act (21 U.S.C.
381(e)(2)).
As in the case of FDA drug export approvals, the statutory
requirement that FDA approve device exports began to generate criticism
from the device industry. The device industry criticized the agency for
the time FDA took to determine whether an export request met the
statutory criteria. FDA reduced the average time for processing device
export requests from an average of 91 days in 1992 to 10 days in 1995,
yet, despite this significant reduction in processing time, the
statute's export approval requirements were seen as adversely affecting
the ability of U.S. firms to enter or to compete in foreign markets.
D. Enactment of the FDA Export Reform and Enhancement Act of 1996
The FDA Export Reform and Enhancement Act of 1996 (Pub. L. 104-134,
and amended by Pub. L. 104-180) addressed industry's problems and
concerns. For human drugs and biologics that may not be sold in the
United States, the 1996 Amendments:
Amended section 801(d) of the act to allow import of
components of drugs and biologics into the United States that do not
comply with other provisions in the act where those components are
intended for incorporation or further processing by the initial owner
or consignee into a drug or biologic that will be exported under
section 801(e) or section 802 of the act or section 351(h) of the PHS
Act.
Amended section 801 of the act to allow exports of
approved drugs (except for insulin and antibiotics) to countries that
have different or additional labeling requirements. The new provision,
at section 801(f) of the act, requires such drugs to be labeled in
accordance with the requirements and conditions for use in the foreign
country and to be labeled in accordance with the act. If the drug's
labeling includes conditions of use that are not approved in the United
States, the labeling must state that such conditions for use have not
been approved under the act.
Replaced section 802 of the act in its entirety with a new
section 802 of the act that:
Eliminated the requirement for prior FDA approval of
exports of unapproved drugs (in most cases),
Significantly expanded the list of countries to which
unapproved products can be exported without prior FDA approval (and
also provided administrative mechanisms for the Secretary of Health
and Human Services (the Secretary) to add countries to the list and
for FDA to permit exports of specific products to unlisted
countries),
Authorized exports of unapproved drugs and biologics
intended for use in clinical investigations in any of 25 countries
identified in section 802(b)(1)(A) of the act,
Authorized the export of unapproved products to a
listed country in anticipation of marketing approval in that
country,
Created a simple notification process for most exported
products (as opposed to the application process required under the
1986 Amendments). Notification is not required for drugs exported
for investigational use in a listed country or drugs exported in
anticipation of marketing authorization in a listed country, and
Authorized FDA to permit the export of unapproved
products intended to treat tropical or other diseases that are ``not
of significant prevalence in the United States.''
For animal drugs that may not be sold in the United States, the
1996 Amendments:
Again restricted the authority to export an unapproved new
animal drug to section 801 of the act. \4\ However, unlike the
situation that existed from 1968 to 1986, an unapproved new animal drug
can be exported if it is: Intended for export; accords to the
specifications of the foreign purchaser; is not in conflict with the
laws of the importing country; is labeled on the outside of the
shipping package that it is intended for export; and is not sold or
offered for sale in interstate commerce (see section 801(e)(1) of the
act).
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\4\ Animal drugs cannot be exported under section 802 of the act
because that section pertains to biologics, devices, and human
drugs.
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The only unapproved new animal drugs that cannot be
exported under section 801 of the act are ``banned'' animal drugs (see
section 801(e)(3) of the act). Neither the statute nor the legislative
history explains what a ``banned'' animal drug is, and FDA is working
on an interpretation as to what constitutes a ``banned'' animal drug.
For devices that may not be sold in the United States, the 1996
Amendments:
Amended section 801(d) of the act to permit the import of
component parts, accessories, or other articles of a device that do not
comply with other provisions in the act, if those component parts,
accessories, or other articles are intended for incorporation or
further processing by the initial owner or consignee into a device that
will be exported under section 801(e) or section 802 of the act or
section 351(h) of the PHS Act;
Amended section 801 of the act to permit exportation of
devices under section 801(e) of the act or under section 802 of the
act;
Replaced section 802 of the act in its entirety with a new
section 802 of the act that:
Eliminated the requirement for prior FDA approval for
exports (for devices approved in a listed country or destined for
clinical investigations in a listed country),
Created administrative mechanisms for the Secretary to
add countries to the list and for FDA to approve exports of specific
products to unlisted countries,
Authorized exports of unapproved devices intended for
use in clinical investigations in any of 25 countries identified in
section 802 of the act,
Authorized the export of unapproved devices to a listed
country in anticipation of marketing approval in that country,
Created a simple notification process for exported
devices (as opposed to the application process under section
801(e)(2) of the act). Notification is not required for devices
exported for investigational use to a listed country or devices
exported in
[[Page 32223]]
anticipation of marketing authorization in the listed country, and
Authorized FDA to permit the export of unapproved
devices intended to treat tropical diseases or other diseases that
are ``not of significant prevalence in the United States.''
Additionally, the 1996 Amendments permit importation of food
additives, color additives, and dietary supplements into the United
States if those articles are intended for incorporation or further
processing by the initial owner or consignee into a drug, biologic,
device, food, food additive, color additive, or dietary supplement that
will be exported.
This document describes the requirements for drugs (both human and
animal), biologics, and devices under sections 801 and 802 of the act
and section 351(h) of the PHS Act, as amended by the 1996 Amendments.
It begins with a discussion of the principal export requirements under
sections 801 and 802 of the act and section 351(h) of the PHS Act,
followed by a discussion of the ``import-for-export'' requirements
under section 801 of the act.
IV. General Requirements for Products Exported Under Section
801(e)(1) of the Act
Section 801(e)(1) of the act contains general requirements for any
food, drug, device, or cosmetic that may not be sold in the United
States and is intended for export. These requirements apply regardless
of whether the product is exported under section 801(e) or section 802
of the act or section 351(h) of the PHS Act. \5\ (Additional
requirements apply to products exported under section 802 of the act
and to devices exported under section 801(e)(2) of the act; those
requirements are described later in this document).
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\5\ The requirements in section 801(e)(1) of the act apply to
all products exported under section 802 of the act due to section
802(f)(3) of the act. That section prohibits exportation of a
product under section 802 of the act if the requirements in section
801(e)(1)(A) through (e)(1)(D) of the act are not met. The
requirements in section 801(e)(1) of the act also apply to partially
processed biologics exported under section 351(h) of the PHS Act.
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Section 801(e)(1) of the act states that a food, drug, device, or
cosmetic intended for export shall not be deemed to be adulterated or
misbranded if the product: Accords to the specifications of the foreign
purchaser; is not in conflict with the laws of the country to which it
is intended for export; is labeled on the outside of the shipping
package that it is intended for export; and is not sold or offered for
sale in domestic commerce.
During routine inspections, FDA will evaluate whether a firm has
complied with section 801(e)(1) of the act. Consequently, records are
very important for demonstrating compliance with each element of
section 801(e)(1) of the act.
To demonstrate that the product meets the foreign purchaser's
specifications, FDA recommends that the firm exporting the product
maintain records describing or listing the product specifications
requested by the foreign purchaser. This would include details about
the product (e.g., dosage strength, dosage form, purity, quality,
operating parameters, composition, etc.) and any details concerning the
product's manufacture (e.g., type of sterilization process to be used,
compliance with a particular manufacturing standard, etc.) as requested
by the foreign purchaser. FDA recommends that the firm have an English-
language translation of the specifications document or be prepared to
translate the document into English at the time of any FDA inspection.
To demonstrate that the product does not conflict with the laws of
the importing country, FDA recommends that the firm obtain a letter
from the foreign government agency, department, or other body stating
that the product has marketing approval from the foreign government or
does not conflict with that country's laws. Letters should not be from
nongovernmental bodies or persons (such as company officials or
attorneys in the foreign country). Additionally, if the letter from the
foreign government is not in English, FDA recommends that the firm have
an English-language translation of that document or be prepared to
translate the document into English at the time of any FDA inspection.
Such translations are essential because they will enable the firm to
show, and for FDA to verify, that the product does not conflict with
the laws of the importing country.
To demonstrate that the product is labeled on the outside of the
shipping package that it is intended for export, FDA recommends that
the firm place a statement on the shipping packages themselves. A
statement such as ``For export only'' may be sufficient.
To demonstrate that the product is not sold or offered for sale in
the United States, FDA recommends that the firm maintain records
concerning the product, its labeling, and similar products sold or
offered for sale in the United States. The labeling can simply state
that the product is ``Not for sale in the United States,'' or bear a
similar statement. As for the product itself, FDA examines whether the
product (as opposed to batches, lots, or production runs of a product)
is sold or offered for sale in the United States. For example, if
company A makes five batches of a particular unapproved drug and
intends to export two batches (and sell the remaining three batches in
the United States), the fact that company A intends to export the two
batches does not mean that the product is ``not sold or offered for
sale in the United States.'' Instead, FDA considers the unapproved drug
to be sold in the United States because other batches of the same
product are sold in the United States.
The requirements in section 801(e)(1) of the act apply to foods,
drugs (both human and animal (except for ``banned'' animal drugs, which
may not be exported)), biologics, devices, and cosmetics intended for
export, whether they are exported under section 801 or section 802 of
the act or section 351(h) of the PHS Act. Furthermore, depending on the
type of product being exported and the legal authority supporting the
product's exportation, additional requirements may apply.
A. Special Requirements for Certain Devices
Some devices face additional statutory requirements before they can
be exported under section 801(e)(1) of the act. Under section 801(e)(2)
of the act, if an unapproved device does not comply with an applicable
requirement under sections 514 (performance standards) or 515
(premarket approval) of the act, is exempt from either such section
under section 520(g) of the act, or is a banned device under section
516 of the act, the device may be deemed to be adulterated or
misbranded unless, in addition to the requirements in section 801(e)(1)
of the act, FDA has determined that exportation of the device is not
contrary to the public health and safety and has the approval of the
country to which it is intended for export.
The act provides that any device introduced into interstate
commerce after May 28, 1976, is automatically considered to be a
``class III'' device requiring premarket approval under section 515 of
the act. Such devices may not be legally marketed, unless and until
FDA: (1) Classifies the device into class I or II; (2) grants marketing
clearance by issuing an order under section 513(i) of the act, in
response to a report submitted by the sponsor under section 510(k) of
the act, determining that the device is substantially equivalent to a
predicate device that does not require premarket approval (hereinafter
referred to as 510(k) marketing clearance); or (3) issues an order
under section 515(d)(1)(A) of the act approving an application for
premarket approval.
Although the act prohibits exportation of class III devices
requiring premarket
[[Page 32224]]
approval unless the criteria under section 801(e)(2) of the act are
met, \6\ FDA, in exercising its enforcement discretion, has not taken
enforcement action against those manufacturers who have not complied
with the export criteria in section 801(e)(2) of the act, provided that
the manufacturers have reasonably concluded that, if a report under
section 510(k) of the act had been submitted to FDA, FDA would have
granted 510(k) marketing clearance. FDA intends to continue exercising
its enforcement discretion in this manner, with respect to the
requirements in section 801(e)(2) of the act. FDA emphasizes, however,
that it does not intend to exercise enforcement discretion with respect
to the requirements in section 801(e)(1) of the act for manufacturers
who reasonably believe that their devices would receive a 510(k)
marketing clearance.
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\6\ Such devices may be eligible for export under section 802 of
the act. (A discussion of section 802 of the act appears in section
VI.B of this document.)
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To help FDA determine whether exportation of the device is not
contrary to the public health and safety, FDA recommends that
manufacturers provide basic safety data for the device. Such data often
consists of a statement certifying that a search of medical databases
has not identified any adverse safety data for similar devices or the
materials used in the device, or summaries of any adverse safety data,
including a discussion as to why the adverse effects should not be
considered applicable to the device that is to be exported. Brief
summaries of available animal safety studies conducted with the device
and safety data from human clinical studies are also helpful. \7\ FDA
ordinarily does not need safety data if the device is the subject of an
approved IDE or is considered to have an approved IDE and will be
marketed or used in the importing country for the same intended use.
\8\
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\7\ For in vitro diagnostic devices, where the device is to be
the sole determinate of whether a particular course of treatment
will be initiated for a life-threatening disease, the agency
recommends that the manufacturer provide a statement indicating
whether an alternative test will be available to confirm the test
results.
\8\A device may be considered to have an approved IDE if an
institutional review board determines that the device is a
nonsignificant risk device, and provided the device has met the
requirements for nonsignificant risk devices under Sec. 812.2(b).
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To help FDA determine whether exportation of the device has the
approval of the country to which it is intended for export, FDA
recommends that the manufacturer obtain a letter from the foreign
country approving of the device's importation. If the manufacturer is
exporting the device to a country in the European Economic Area and the
device has received a CE mark, documentation of the CE mark will
ordinarily be sufficient.
Additional information regarding device exports under section
801(e)(2) of the act can be found in the guidance document entitled,
``Procedures for Obtaining FDA Approval to Export Unapproved Medical
Devices.'' (See ``For Further Information Contact'' in section XII of
this document.)
B. Special Requirements for Partially Processed Biologics
The 1996 Amendments also changed the export requirements for
partially processed biological products. Under section 351(h) of the
PHS Act, a partially processed biological product may be exported if it
is: ``not in a form applicable to the prevention, treatment, or cure of
diseases or injuries of man;'' not intended for sale in the United
States; and intended for further manufacture into final dosage forms
outside the United States.
Exports of such products must comply with section 801(e)(1) of the
act and with cGMP's or international manufacturing standards as
certified by an international standards organization recognized by the
agency.
1. What Constitutes a Partially Processed Biological Product?
FDA interprets the term ``partially processed biological products''
as meaning biological products requiring purification, inactivation,
fractionation, or significant chemical modification (such as the
formation or breakage of covalent bonds and the incorporation of
peptides into a diagnostic test kit) before being used in the
formulation of a final product. Thus, a finished bulk product that
could be formulated into a finished dosage form through manufacturing
steps other than purification, inactivation, fractionation, or
significant chemical modification would not constitute a partially
processed biological product that could be exported under section
351(h) of the PHS Act. Certain other products, such as source plasma
and source leukocytes, also would not be partially processed biological
products because they are finished products (notwithstanding the
possibility that their intended use may be as a source material for
further manufacturing into another product), and FDA requires such
products to be licensed. \9\
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\9\ Unlicensed biologics that fail to qualify for export under
section 351(h) of the PHS Act may qualify for export under section
802 of the act.
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Products that do qualify as partially processed biological products
include intermediate biological products that a manufacturer has
partially processed and that would be subject to licensure as final
products after the completion of additional manufacturing steps. For
example, synthetic peptides that are a component of an in vitro
diagnostic test kit would be partially processed biological products.
FDA encourages persons who may be uncertain as to whether their
products are partially processed biological products to contact the
Import/Export Team in the Center for Biologics Evaluation and Research
(see the ``For Further Information Contact'' in section XII of this
document for the address and phone number).
2. cGMP Requirements
Section 351(h) of the PHS Act also requires partially processed
biological products to be ``manufactured, processed, packaged, and held
in conformity with current good manufacturing practice requirements''
or international manufacturing standards recognized by the agency. FDA
will inspect manufacturers to ensure that they are in compliance with
cGMP's.
FDA acknowledges that section 351(h) of the PHS Act also refers to
``international manufacturing standards as certified by an
international standards organization'' recognized by FDA. At this time,
FDA has not recognized any such international standards or
organizations for purposes of section 351(h) of the PHS Act, but is
examining this issue closely.
3. Additional Requirements Under Section 351(h) of the PHS Act
All exports of FDA-regulated products that may not be sold or
marketed in the United States, including partially processed biological
products exported under section 351(h) of the PHS Act, must conform to
the standard export requirements of section 801(e)(1) of the act. Thus,
a product intended for export under section 351(h) of the PHS Act must:
Accord with specifications of the foreign purchaser; not be in conflict
with the laws of the country to which it is intended for export; be
labeled on the outside of the shipping package that as intended for
export; and not be sold or offered for sale in domestic commerce.
Consistent with section 801(e)(1) of the act, section 351(h)(2) of the
PHS Act further requires that the product may not be intended for sale
in the United States.
Records are important in FDA's evaluation of compliance with
section
[[Page 32225]]
351(h) of the PHS Act, including the requirements section 801(e)(1) of
the act. FDA recommends that the firm or manufacturer maintain the
following records for possible review during a routine annual or
biennial FDA inspection. Depending on the particular circumstances of
export, different or additional records may also be relevant.
Evidence that product for export qualifies as a partially
processed biological product;
Evidence that the partially processed biological product
complies with the laws of the country to which it is being exported and
accords to the specifications of the foreign purchaser, in accordance
with section 801(e)(1) of the act, and is intended for further
manufacture into final dosage form outside the United States, in
accordance with section 351(h)(3) of the PHS Act. Such evidence may
consist of a valid marketing authorization for the partially processed
biological product or the final product from the foreign ministry of
health, contractual agreement, and purchase orders that may include
foreign specifications;
Records, such as manufacturing records, that trace the
partially processed biological product through the assignment of a
batch or lot numbering system at the U.S. exporting firm. The agency
suggests that these records also include temperature stability data for
product during the conditions of transit (export) and periodic checks
of the capacity of the shipping containers;
Distribution records of exported partially processed
biological products;
Copies of all labeling that accompanies the partially
processed biological product for export (i.e., container label or any
package insert). FDA recommends that the partially processed biological
product's container label state, ``Caution: For Further Manufacturing
Use Only;'' and
Evidence that the product is not intended for sale in the
United States and has not been sold or offered for sale in the United
States. This may consist of purchase orders from the foreign purchaser
and distribution records and records of the product's labeling and
similar products sold in the United States. FDA examines whether the
product itself (as opposed to batches or lots) is sold or offered for
sale in the United States. For example, if a company produces five
batches of a partially processed biological product and intends to
export two batches and sell the remaining three in the United States,
the product is deemed ``sold or offered for sale in the United States''
and ``intended for sale in the United States'' within the meaning of
section 351(h) of the PHS Act.
Additionally, firms that manufacture, prepare, or process partially
processed biologics for export must register with FDA and list their
products under section 510 of the act and parts 207 and 607 (21 CFR
parts 207 and 607).
V. Labeling Requirements for Drugs and Biologics Exported Under
Section 801(e)(1) of the Act--Section 801(f) of the Act
The 1996 Amendments contained a new provision that permits the
export of drugs (other than insulin, antibiotics, animal drugs, or
drugs exported under section 802 of the act) \10\ that may be sold in
the United States. For these drugs, section 801(f) of the act imposes
certain labeling requirements. If the drug that is approved in the
United States is being exported to a country that has different or
additional labeling requirements or conditions for use (compared to
those on the FDA-approved labeling), and the foreign country requires
the drug to be labeled in accordance with those requirements or uses,
section 801(f)(1) of the act specifies that the drug may be labeled in
accordance with the foreign requirements and conditions for use so long
as the drug is also labeled in accordance with the act.
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\10\ Insulin and antibiotics were excluded from section 801(f)
of the act because they have historically been subject only to the
export requirements now seen in section 801(e)(1) of the act. In
1997, the Food and Drug Administration Modernization Act (Pub. L.
105-115) expressly stated that insulin and antibiotics may be
exported without regard to the requirements in section 802 of the
act so long as they meet the requirements in section 801(e)(1) of
the act.
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For those conditions of use that are not approved in the United
States, section 801(f)(2) of the act requires the labeling to state
that those uses are not approved under the act. The act defines
``labeling'' as ``all labels and other written, printed, or graphic
matter (1) upon any article or any of its containers or wrappers, or
(2) accompanying such article.'' Thus, to comply with section 801(f)(2)
of the act, FDA suggests that a firm place a statement on the labeling
regarding the uses that are not approved in the United States wherever
an unapproved use appears. For example, if an unapproved use is on the
immediate label and on the product's container, a statement identifying
the uses that are not approved in the United States would appear on the
immediate label and on the product's container.
FDA has received questions whether the statement identifying the
uses that are not approved in the United States should be in the
language used in the foreign country. Although section 801(f) of the
act is silent on this point, the agency suggests that the statement be
in the foreign language because the requirement would be meaningless if
foreign consumers could not read the statement and would have no value
for U.S. consumers who, because section 801(e)(1)(D) of the act
prohibits the exported product from being sold or offered for sale in
domestic commerce, would not have access to the product when labeled
for the unapproved use(s).
In some instances, products that may be exported in compliance with
the labeling requirements in section 801(f) of the act may also qualify
for export under section 802(b)(1)(A) of the act (discussed later in
section VII.D of this document). In such cases, a firm may elect to
export a product under either section 801(e) or section 802(b) of the
act so long as the product meets the statutory requirements for export.
As discussed in section VII of this document, a drug exported under
section 802 of the act is not subject to the labeling requirements in
section 801(f) of the act.
VI. Exports of Unapproved Drugs, Biologics, and Devices Under
Section 802(b) of the act
A. Drugs and Biologics
As stated earlier, courts and FDA have interpreted section 801(e)
of the act as being inapplicable to unapproved new drugs and biologics.
As a result, the 1986 Amendments amended the act so that the export of
unapproved new drugs and biologics was regulated under section 802 of
the act.
The 1996 Amendments, insofar as human drugs and biologics are
concerned, modified the scope of section 802 of the act to state that
the provision applies to drugs and biologics that: Require approval
under section 505 of the act or, for biologics, require licensing under
section 351 of the PHS Act; do not have such approval or license; and
are not exempt from section 505 of the act or section 351 of the PHS
Act.
Thus, section 802 of the act applies to unapproved new human drugs
and biologics and to approved human drugs and biologics being exported
for unapproved uses. \11\ If FDA declines to approve or license a drug
or biologic or
[[Page 32226]]
decides to withdraw approval or revoke licensure for a drug or biologic
and that product has been exported to one or more foreign countries,
section 802(a) of the act requires FDA to notify the appropriate
foreign public health official in those countries of its decision.
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\11\ While section 802(b) of the act refers to drugs requiring
approval under section 505 of the act, it does not apply to insulin,
antibiotics, or over-the-counter drug products that do not require
approval under section 505 of the act. In 1997, the Food and Drug
Administration Modernization Act amended section 802 of the act so
that exports of insulin and antibiotics are subject to the export
requirements in section 801(e)(1) of the act.
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Section 802 of the act also contains special provisions for drugs
intended for investigational use in a listed country, drugs intended
for further processing or labeling to fill the pipeline in anticipation
of marketing authorization in a listed country, and drugs intended to
treat a tropical disease or disease that is ``not of significant
prevalence in the United States.'' These provisions are discussed in
greater detail in sections VII through IX of this document.
B. Devices
Section 802(b) of the act, like section 801(e)(2) of the act,
applies to devices that: Do not comply with an applicable requirement
under section 514 or 515 of the act; are subject to an IDE; or are
banned devices.
This means that devices that have premarket approval are not
subject to section 802 of the act, nor are devices that are the subject
of a marketing clearance under the premarket notification provision
under section 510(k) of the act.
C. Basic Requirements for All Products Exported Under Section 802 of
the Act
Under section 802(f) of the act, the basic requirements for all
drugs, biologics, and devices exported under section 802 of the act are
as follows:
The product must be manufactured, processed, packaged, and
held in ``substantial conformity'' with cGMP's or meet international
standards as certified by an international standards organization
recognized by FDA. \12\ Neither the 1996 Amendments nor its legislative
history explains what constitutes ``substantial conformity'' with
cGMP's, but the legislative history for the Generic Drug Enforcement
Act of 1992 may be instructive. In discussing the terms ``substantial
compliance'' with cGMP's and good laboratory practices, the House
Committee on Energy and Commerce suggested that ``substantial
compliance'' could not mean full compliance with GMP's because FDA
``lacks the continuing presence that would be necessary to conclude
that a firm is in full compliance with GMPs and GLPs'' (see H. Rept.
102-272, 102d Cong., 2d sess. 20 (1992)). The term does mean that the
firm must have passed its most recent GMP inspection (or that GMP
violations have been rectified, and the firm has credible systems and
personnel in place to prevent a recurrence of the violation(s)). FDA
interprets the term ``substantial conformity'' under section 802(f)(1)
of the act in a similar manner.
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\12\ The agency has not recognized an international standards
organization or standard for any FDA-regulated product for purposes
of section 802(f) of the act, but is examining this issue closely.
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The product must not consist in whole or in part of any
filthy, putrid, or decomposed substance and must not have been
prepared, packed, or held under insanitary conditions where it may have
been contaminated or made injurious to health;
The container for the product must not be composed, in
whole or in part, of any poisonous or deleterious substance which may
render the contents injurious to health;
The product must have the strength, purity, or quality
that it is represented to possess;
For drugs, no substance may be mixed or packed with the
drug that would reduce the drug's quality or strength or may substitute
in whole or in part for another substance in the drug;
The product must comply with the requirements in section
801(e)(1) of the act. As stated earlier, section 801(e)(1) of the Act
requires that the drug or device to be exported: (1) Accords to the
specifications of the foreign purchaser; (2) not conflict with the laws
of the country to which it is intended for export; (3) be labeled on
the outside of the shipping package that it is intended for export;
\13\ and (4) not be sold or offered for sale in domestic commerce. \14\
(A discussion of the requirements in section 801(e)(1) of the act
appears earlier in this guidance.)
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\13\ A statement on the outside of the shipping package, such
as, ``For export only'' or similar language, may be sufficient.
\14\ As stated in section IV of this document, FDA advises firms
to maintain records concerning the product, its labeling, and
similar products sold in the United States. The product's labeling
can state that the product is ``Not for sale in the U.S.'' or use
similar language.
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The product cannot be the subject of a notice by FDA or
the U.S. Department of Agriculture determining that the probability of
reimportation of the exported product would present an imminent hazard
to the public health and safety of the United States, such that
exportation must be prohibited;
The product cannot present an imminent hazard to the
public health of the country to which it would be exported; and
The product must be labeled in accordance with the
requirements and conditions of use in the listed country \15\ which
authorized it for marketing and the country to which it is being
exported, and must be labeled in the language and units of measurement
used in or designated by the country to which the drug or device is
being exported. Additionally, a drug or device may not be exported if
the drug or device is not promoted in accordance with these labeling
requirements.
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\15\ The listed countries, under section 802(b) of the act, are:
Australia, Canada, Israel, Japan, New Zealand, Switzerland, South
Africa, and the member nations of the European Union and the
European Economic Area. As of January 1, 1998, the EU countries are
Austria, Belgium, Denmark, Germany, Greece, Finland, France,
Ireland, Italy, Luxembourg, the Netherlands, Portugal, Spain,
Sweden, and the United Kingdom. The EEA countries are the EU
countries, Iceland, Liechtenstein, and Norway. The number of listed
countries expands automatically as countries become members of the
EU or the EEA.
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If the above requirements are not met, section 802(f) of the act
states that a drug or device may not be exported. Furthermore, in
determining whether a drug or device may present an imminent hazard to
the public health of the foreign country or is improperly labeled or
promoted, section 802(f) of the act requires FDA to consult with the
``appropriate public health official in the affected country.''
Exporters are primarily responsible for determining whether export
is permitted under the act and whether their exports meet the
requirements in section 802(f) of the act. During an inspection, FDA
will evaluate compliance with the relevant export provisions as
appropriate. As discussed below, section 802(g) of the act requires
persons exporting drugs and devices under section 802(b)(1) of the act
to maintain records of such exported products and the countries to
which they were exported and to provide a simple notification to the
agency regarding such exports.
D. Exports of Unapproved New Drugs, Biologics, and Devices to a Listed
Country--Section 802(b)(1)(A) of the Act
The principal provision authorizing the exportation of unapproved
new drugs, biologics, and devices is section 802(b)(1)(A) of the act.
Section 802(b)(1)(A) of the act states that a drug or device ``may be
exported to any country, if the drug or device complies with the laws
of that country and has valid marketing authorization by the
appropriate authority'' in Australia, Canada, Israel, Japan, New
Zealand, Switzerland, South Africa, or any member nation in the
European Union or the European Economic Area.
[[Page 32227]]
This means that a firm whose drug or device has received marketing
authorization in any of the countries listed above can export that drug
or device to any country in the world as long as the drug or device
meets applicable requirements of the act, without submitting an export
request to FDA or receiving FDA approval to export the drug or device.
Moreover, in a change from the 1986 Amendments, firms do not have to
seek U.S. approval of the product as a condition of exportation.
FDA interprets the terms ``marketing authorization'' as meaning an
affirmative decision by the appropriate public health authority in a
foreign country to permit the drug, biologic, or device to be sold in
that country. For example, if country D approves a drug for
investigational use, the approval would not constitute ``marketing
authorization'' because country D's decision did not extend to
commercial marketing. Likewise, a decision by country D to permit sales
to another country would not represent ``marketing authorization''
because it does not permit sales within country D.
Some countries, however, have regulatory systems that permit
marketing without an affirmative act or decision by the government. In
such cases, FDA would consider a drug, biologic, or device to have
``marketing authorization'' if the listed country does not object to
the product's marketing, and FDA recommends that the firm obtain a
document from the relevant authority in the listed country indicating
that it does not object to the product's marketing.
As for the word ``drug,'' the drug to be exported under section
802(b)(1)(A) of the act should be the same product as the drug that
received marketing authorization in the listed foreign country. Thus,
the issue of whether the drug to be exported must be exactly identical
to the drug authorized in the listed country may depend on the
conditions surrounding market authorization in the foreign country. For
example, if country E's marketing authorization applies only to a drug
product with a specific composition, rather than to drugs that have a
particular active ingredient or general composition, then the drug that
is to be exported from the United States must have the same composition
as the drug that received marketing authorization in country E. If,
however, country E approves a drug product and, as a result of that
approval, permits marketing of other drugs using the same active
ingredient, then the ``drug'' that could be exported under section
802(b)(1)(A) of the act could be any drug that has the same active
ingredient. \16\
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\16\ Additionally, under the 1986 Amendments, FDA approved
exports of drugs that varied, in limited respects, from drugs that
were the subject of an IND or a marketing application. The 1986
Amendments required firms to be actively pursuing market approval of
the drug in the United States as a condition for exportation; this
condition no longer exists in the act.
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A similar concept applies to devices. Devices that are exported
under section 802(b)(1)(A) of the act should be similar (to the degree
that any variation could not affect the safety or effectiveness of the
product) or identical to the devices that receive marketing
authorization in a listed country, depending on the requirements of
that listed country.
E. Expanding the List of Countries in Section 802(b)(1)(A) of the Act
The list of countries in section 802(b)(1)(A) of the act is not
closed. The 1996 Amendments contain a mechanism whereby the Secretary
may add other countries to the list, provided that the country meets
certain criteria. These criteria include: (1) Statutory or regulatory
requirements which require the review of drugs and devices for safety
and effectiveness by a government entity in that country and which
authorizes marketing approval of drugs and devices that trained and
qualified experts acting on behalf of the government have determined to
be safe and effective, (2) statutory or regulatory requirements
pertaining to cGMP's, (3) statutory or regulatory requirements for
reporting adverse events and for removing unsafe or ineffective drugs
and devices from the market, (4) statutory or regulatory requirements
that a product's labeling and promotion be in accordance with the
product's approval, and (5) equivalence of the country's marketing
authorization system with that in the listed countries.
The authority to add countries to the list, by law, cannot be
delegated below the Office of the Secretary. Thus, FDA has no authority
to add countries to the list.
F. Exports of Unapproved New Drugs and Biologics to an Unlisted
Country--Section 802(b)(2) and (b)(3) of the Act
If a firm intends to export an unapproved new drug (including
biologics) to a foreign country, but none of the listed countries has
approved the drug for marketing, it has two other options for exporting
the product. \17\
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\17\ The requirements in sections 802(b)(2) and (b)(3) of the
act do not apply to devices. Congress omitted devices from these
provisions to the act because it found FDA's practice of permitting
(under section 801(e)(2) of the act) exports of devices that had
approved IDE's to provide an acceptable alternative.
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One option is in section 802(b)(2) of the act. This section permits
a firm to export an unapproved drug directly to an unlisted country if:
The drug complies with the laws of the foreign country and
has valid marketing authorization by the ``responsible authority'' in
that country, and
The agency determines that the foreign country has
statutory or regulatory requirements:
Which require the review of drugs for safety and
effectiveness by a government entity in that country and which
authorizes marketing approval of drugs which trained and experienced
experts have determined to be safe and effective. The experts must
be employed by or acting on behalf of the foreign government entity
and base their determination on adequate and well-controlled
investigations (including clinical investigations);
Pertaining to cGMP's;
For reporting adverse events and for removing unsafe or
ineffective drugs from the market; and
Which require that the labeling and promotion be in
accordance with the product's approval.
FDA recommends that firms intending to export drugs under section
802(b)(2) of the act provide documentation showing that the drug
complies with the foreign country's laws and has valid marketing
authorization. (If the country has a regulatory system that allows
marketing without an affirmative decision by the government, FDA
recommends that the firm obtain a document indicating that the
authorities in the listed country do not object to the product's
marketing.) The agency also suggests that firms provide documentation
so FDA can make its determination on the foreign country's statutory
and/or regulatory requirements. Copies of the foreign country's laws
and regulations (in English) may be helpful, but are not required;
firms may also provide a description of the foreign country's laws and
regulations with citations that identify the precise law or regulation.
If FDA cannot make the necessary determinations concerning the foreign
country's statutory and regulatory requirements, the firm cannot export
the drug under section 802(b)(2) of the act.
The second option is in section 802(b)(3) of the act. This section
permits a firm to petition the agency to approve exportation to an
unlisted country if the conditions for export under section 802(b)(1)
and 802(b)(2) of the act cannot be met. Under section 802(b)(3) of the
act, FDA must allow exportation of the drug if:
The person exporting the drug: (1) Certifies that the drug
would not meet
[[Page 32228]]
the conditions for approval under the act or the conditions for
approval in a listed country; and (2) provides ``credible scientific
evidence'' that is acceptable to FDA to show that the drug would be
safe and effective under the conditions of use in the country to which
it is being exported. The statute does not specify what constitutes
``credible scientific evidence,'' but an adequate and well-controlled
study or studies, animal and in vitro pharmacology and toxicology
studies, microbiology studies (for biologics), and statistical analyses
of data should be helpful; and
The appropriate health authority in the foreign country
that is to receive the drug: (1) Requests approval of the drug's
exportation, (2) certifies that the health authority understands that
the drug is not approved under the act or by any listed country, and
(3) concurs that the scientific evidence provided to FDA is credible
scientific evidence that the drug would be reasonably safe and
effective in the foreign country. A letter from the relevant foreign
government entity addressing each item in this paragraph should be
acceptable.
As a reminder, any person who exports a drug under section 802 of
the act also must comply with the basic export requirements set forth
in section 802(f) of the act.
Persons who wish to export a drug under sections 802(b)(2) or
802(b)(3) of the act should send their documentation or requests to:
(For Biologics), Division of Case Management (HFM-610), Center for
Biologics Evaluation and Research, Food and Drug Administration, 1401
Rockville Pike, rm. 200N, Rockville, MD 20852-1448.
(For Drug Products), Executive Secretariat Team (HFD-6), Center for
Drug Evaluation and Research, 1451 Rockville Pike, Rockville, MD 20852-
1420.
FDA has 60 days to act on a request to export a drug under section
802(b)(3) of the act. The agency will begin the 60 day period on the
date that it receives a complete petition containing the certification
and evidence required by the act.
VII. Exports of Unapproved Drugs and Devices for Investigational
Use to Listed Countries Under Section 802(c) of the Act
A. Background
The 1986 Amendments did not impose any special requirements for
drugs or devices exported for investigational use. Moreover, FDA did
not apply section 801(e) of the act to investigational drugs because
section 801 of the act was interpreted as not applying to ``new
drugs.'' Instead, FDA regulated the exportation of unapproved new drugs
(including biologics) for investigational use under its authority over
investigational drugs at section 505(i) of the act.
FDA issued regulations governing the exportation of unapproved new
drugs for investigational use on January 18, 1984 (49 FR 2095), with
minor modifications since then. These regulations were codified at
Sec. 312.110 (the part of the Code of Federal Regulations pertaining to
investigational drugs), and so the program became known as the ``312
program.'' The regulations required any person who intends to export an
unapproved new drug product for use in a clinical investigation either
to have an IND or to submit a written request to FDA. The regulations
required the written request to provide sufficient information about
the drug to satisfy FDA that the drug is appropriate for
investigational use in humans, that the drug will be used for
investigational purposes only, and that the drug may be legally used by
the consignee in the importing country for the proposed investigational
use. The regulations further stated that the request must specify the
quantity of the drug to be shipped and the frequency of expected
shipments. If FDA authorized exportation of the drug, it would notify
the government of the importing country. The regulations, however, did
not apply to drugs approved for export under section 802 of the act or
section 351(h)(1)(A) of the PHS Act.
In contrast, the agency did apply section 801(e) of the act to
investigational devices. This was partly because, unlike the situation
for drugs, the act contains only one definition for ``device.'' The
agency issued a regulation on device exports on January 18, 1980 (45 FR
3732 at 3751). The provision, codified at Sec. 812.18(b), simply stated
that a person who intends to export an unapproved device must obtain
FDA approval (under what is now part of section 801(e)(2) of the act)
before exporting the device.
B. Impact of the 1996 Amendments on Drug Exports for Investigational
Use
The 1996 Amendments changed the 312 program significantly by
creating a new section 802(c) of the act. In brief, section 802(c) of
the act permits a firm to export an unapproved drug for investigational
use in any of the listed countries, without prior FDA approval or even
an IND. The only requirements are that the drug be exported in
accordance with the laws of the foreign country, and comply with the
basic export requirements in section 802(f) of the act. The exporter,
under section 802(g) of the act, must also maintain records of all
drugs exported and the countries to which they were exported.
It is important to note that FDA interprets section 802(c) of the
act as applying only to investigational drugs and devices exported to
the listed countries. The agency is aware that some firms have
interpreted this provision as permitting transshipment to unlisted
countries, but section 802(c) of the act is silent with respect to
transshipment, and a more reasonable interpretation would be that
transshipments are not allowed under section 802(c) of the act.
Interpreting section 802(c) of the act to allow transshipment would
presume that the listed countries may serve as mere transfer points or
conduits for investigational drugs and devices destined for unlisted
countries (when neither the statute nor its legislative history support
such a presumption) and would make the limitation to the listed
countries in section 802(c) of the act virtually meaningless.
Additionally, one should note that section 802(b)(1) of the act
authorizes exportation to unlisted countries if the drug complies with
the foreign country's laws and has valid marketing authorization in a
listed country. Exports under section 802(b)(1) of the act may be made
for investigational uses or for marketing purposes.
For exports of drugs for investigational use in unlisted countries
where the drug product has not received valid marketing authorization
in a listed country, the ``312 program'' requirements at Sec. 312.110
remain applicable. However, FDA is considering possible revisions to
the regulations for the ``312 program'' due to sections 802(b) and (c)
of the act as well as additional changes to the program.
C. Impact of the 1996 Amendments on Device Exports for Investigational
Use
The 1996 Amendments also affected device exports significantly.
Section 802(c) of the act permits a firm to export an unapproved device
for investigational use in any of the listed countries, without prior
FDA approval or an IDE. However, as in the case for drugs, the device
must be exported in accordance with the laws of the foreign country.
Yet, unlike the situation for drug exports, the 1996 Amendments
give device manufacturers the option whether to export a device under
section 801(e)(2) of the act or under
[[Page 32229]]
section 802 of the act. The selected authority is important because
each section of the act carries its own statutory requirements.
For example, if company F wants to export an unapproved device for
investigational use to a listed country, it could:
Export the device under section 801(e)(2) of the act.
Under this provision, the exporter would need to comply with section
801(e)(1) of the act and, depending on the device, might have to submit
information that would enable FDA to determine that exportation is not
contrary to the public health or safety and that the foreign country
approves of the exportation, or
Export the device under section 802(b)(1)(A) of the act if
the device has received valid marketing authorization in any listed
country. Section 802(b)(1)(A) of the act permits exportation of an
unapproved device, for any purpose, if the device complies with the
laws of the foreign country and has received valid marketing
authorization in a listed country. (Exports under section 802(b)(1) of
the act may also occur to unlisted countries so long as the device
complies with the foreign country's laws and has valid marketing
authorization in a listed country.) Exports under this option must
comply with the basic export requirements at section 802(f) of the act
(such as being in ``substantial conformity'' with cGMP's or meeting
international standards as certified by a recognized international
standards organization and complying with section 801(e)(1) of the act)
and the notification and recordkeeping requirements in section 802(g)
of the act; or
Export the device to a listed country under section 802(c)
of the act, without prior FDA approval or the submission of any
information to FDA. However, under this option, compliance with the
basic export requirements in section 802(f) of the act and the
recordkeeping requirement in section 802(g) of the act is necessary.
Consequently in the Federal Register of May 13, 1997 (62 FR 26228),
FDA amended Sec. 812.18 to state that a person exporting an
investigational device subject to part 812 must obtain FDA's prior
approval under section 801(e)(2) of the act or comply with section 802
of the act.
Of course, a firm always has the additional option of conducting
the investigation under an IDE, in which case the IDE requirements in
part 812 would apply.
VIII. Exports of Unapproved Drugs and Devices in Anticipation of
Foreign Approval--Section 802(d) of the Act
Section 802(d) of the act permits the exportation of an unapproved
drug, biologic, or device ``intended for formulation, filling,
packaging, labeling, or further processing in anticipation of market
authorization'' in any of the listed countries. The only express
requirements for such exports are that the product comply with the laws
of the foreign country and the requirements in section 802(f) of the
act. Records for such exports must be kept in accordance with section
802(g) of the act.
The range of activities covered under section 802(d) of the act is
very broad, although mere storage of an unapproved drug, biologic, or
device would not constitute ``formulation, filling, packaging,
labeling, or further processing.'' Additionally, FDA interprets the
phrase ``in anticipation of market authorization'' as meaning that the
manufacturer exporting the product has filed an application or
submission to obtain final marketing authorization in the foreign
country. FDA does not consider an intent to seek market authorization
or to file a marketing application at some future time to constitute
``anticipation of market authorization.''
FDA advises firms that export a product in anticipation of market
authorization, under section 802(d) of the act, to notify FDA when they
export the product. The notification should identify the drug,
biologic, or device being exported and the country receiving the
product. Notification when a product is exported under section 802(d)
of the act is consistent with section 802(f) of the act. As stated
earlier, section 802(f) of the act establishes conditions for all
products exported under section 802 of the act. For example, a product
cannot be exported under section 802 of the act if it is not in
substantial conformity with cGMP's. Yet, if firms do not notify FDA
about the products that have been exported, FDA cannot determine
whether products exported under section 802(d) of the act comply with
cGMP's.
Additionally, notification is consistent with a practical
interpretation of section 802(g) of the act which requires exporters of
drugs, biologics, and devices to provide a simple notification to the
agency when they export a product to a listed country or to an unlisted
country under section 802(b)(1) of the act. Section 802(b)(1) of the
act permits exports when the drug, biologic, or device has received
market authorization in a listed country, whereas section 802(d) of the
act permits exports to a listed country in anticipation of market
authorization. A literal interpretation of section 802(g) of the act
would not require an exporter to notify FDA when it shipped a product
to a listed country in anticipation of market authorization, but would
instead require the exporter to notify FDA when the exporter shipped
the same product to the same country once it received market
authorization. It would be more practical, simple, and efficient-both
for exporters and FDA- if exporters notify FDA when they export a
product in anticipation of market authorization, under section 802(d)
of the act, rather than wait for market authorization in the listed
country and then notify FDA.
Details on notification under section 802(g) of the act appear
later in this guidance.
IX. Exports of Drugs and Devices for Diagnosing, Preventing, or
Treating a Tropical Disease or a Disease ``Not of Significant
Prevalence in the United States''--Section 802(e) of the Act
The 1986 Amendments authorized exports of unapproved new drugs and
biologics intended to prevent or to treat a tropical disease. Under the
1986 Amendments, the exporter had to submit an export application to
FDA. The export application had to: (1) Describe the drug being
exported, (2) list each country to which the drug would be exported,
(3) contain a certification that the drug would not be exported to a
country if the agency could not find that the drug would be safe and
effective in that country, (4) identify the establishments where the
drug is made, and (5) show that other statutory requirements (such as
compliance with cGMP's) are met. FDA had to approve the export
application before exportation could proceed.
The 1996 Amendments amended the tropical disease provision in
several ways. The provision now covers drugs intended to diagnose,
prevent, or treat tropical diseases, includes devices among the
products eligible for exportation, and includes drugs, biologics, and
devices that are intended to treat diseases that are ``not of
significant prevalence'' in the United States. A disease that is ``not
of significant prevalence'' in the United States can be one that is not
manifested in many Americans (either because the pathogen is not common
or because available treatments have made the disease rare in the
United States) or is indigenous to a particular foreign country or to
an area in another country. For example, measles may be
[[Page 32230]]
considered to be a disease that is not of significant prevalence in the
United States because most children are immunized against measles.
However, like the 1986 Amendments, the revised provision (which is
now codified as section 802(e) of the act) requires FDA to approve an
export application before the product can be exported. The export
application should contain information showing that the drug or device
is intended for use in a tropical disease or a disease that is not of
significant prevalence in the United States. Additionally, the
application should contain information that will enable FDA to
determine whether the drug, biologic, or device:
Will not expose patients in the foreign country to an
unreasonable risk of illness or injury, and
When used under conditions prescribed, recommended, or
suggested in the labeling or proposed labeling has a probable benefit
to health that outweighs the risk of injury or illness from its use,
taking into account the probable risks and benefits of currently
available drug or device treatment. By ``currently available drug or
device treatment,'' the applicant should consider the availability of
products that are approved for the particular disease as well as those
that are commonly used to treat the disease, even if the product is not
approved for that indication.
X. Export Notification Under Section 802(g) of the Act
Section 802(g) of the act requires persons exporting a drug or
device under section 802(b)(1) of the act to provide a ``simple
notification * * * identifying the drug or device when the exporter
first begins to export such drug or device'' to any country listed in
section 802(b)(1) of the act. If the product is to be exported to an
unlisted country, section 802(g) of the act requires the exporter to
provide a simple notification ``identifying the drug or device and the
country to which such drug or device is being exported.''
In all cases, section 802(g) of the act requires the exporter to
maintain records of all drugs or devices exported and the countries to
which they were exported.
A. The Content of the Simple Notification
FDA suggests that, to identify a drug or device, the exporter
describe in the notification the product's name or type of device, its
generic name, and a description of its strength and dosage form (if the
product is a drug) or the product's model number (if the product is a
device).
As for identifying the country that is to receive the exported
product, FDA acknowledges that section 802(g) of the act requires
exporters to identify the country that is to receive the exported
product only if the country is not a listed country. However, FDA
encourages exporters to identify the country that is to receive the
exported product in all cases, regardless of whether the country is
among those listed in section 802(b)(1) of the act. Identification of
the foreign country, regardless of whether it is listed or not, helps
FDA meet its obligations under sections 802(a) and 802(f)(4), (f)(5),
and (f)(6) of the act which prohibit exports under certain conditions
(such as a finding of an imminent hazard to the public health) and/or
requires FDA to consult with the ``appropriate public health official''
in the affected country.
B. Where to Send the Simple Notification
Notifications may be sent to the following addresses:
For biological drug products and biological devices: Division of
Case Management (HFM-610), Office of Compliance, Center for Biologics
Evaluation and Research, Food and Drug Administration, 1401 Rockville
Pike, rm. 200N, Rockville, MD 20852-1448.
For human drug products: Division of Labeling and Nonprescription
Drug Compliance (HFD-310), Center for Drug Evaluation and Research,
Food and Drug Administration, 7520 Standish Pl., Rockville, MD 20855-
2737.
For devices: Division of Program Operations (HFZ-305), Center for
Devices and Radiological Health, Food and Drug Administration, 2094
Gaither Rd., Rockville, MD 20850.
C. Recordkeeping
As stated earlier, section 802(g) of the act requires exporters to
maintain records of all drugs and devices exported and the countries to
which the products were exported. FDA recommends that exporters
maintain records showing:
The product's name and its generic name (if the product is
a drug or a device),
The type of device (if the product is a device),
A description of its strength and dosage form and the
product's lot or control number (if the product is a drug) or the
product's model number (if the product is a device),
The consignee's name and address, and
The date and quantity of product exported.
FDA recommends that these records be kept at the site from which
the products were exported and be maintained at least 5 years after the
date of exportation. The agency may request that the records be made
readily available for review and during an agency inspection.
Additionally, FDA reminds parties that they may need to maintain
other records beyond those specified in section 802(g) of the act. For
example, firms whose products must be in substantial conformity with
cGMP's under section 802(f)(1) of the act may be subject to cGMP
recordkeeping requirements under the regulations that apply to their
products.
XI. ``Import for Export''--Section 801(d)(3) and (d)(4) of the Act
Before the 1996 Amendments, all imported components of drugs,
biologics, devices, and other FDA-regulated products had to comply with
the requirements of the act, even if they were to be incorporated into
products destined solely for export.
The 1996 Amendments changed the law by creating two subsections at
801(d)(3) and (d)(4) of the act. Under section 801(d)(3) of the act, a
component of a drug or a biologic, a component part, accessory, or
other article of a device, or a food additive, color additive, or
dietary supplement that would otherwise be refused entry into the
United States, can be imported into the United States if:
The importer submits a statement to the agency at the time
of initial importation declaring that the component, part, accessory,
or article is intended to be ``incorporated'' or ``further processed''
by the initial owner or consignee into a drug, biological product,
device, food, food additive, color additive, or dietary supplement that
will be exported from the United States by the initial owner or
consignee in accordance with section 801(e) or section 802 of the act
or section 351(h) of the PHS Act (see section 801(d)(3)(A) of the act).
The initial owner or consignee responsible for the
imported article maintains records that identify the use of the
imported component, part, accessory, or article. Upon request from the
agency, the initial owner or consignee must submit a report that
accounts for the exportation or the disposition of the imported
component, part, accessory, or article (including quantities that were
destroyed), including the manner in which the initial owner or
consignee complied
[[Page 32231]]
with the requirements in section 801(d) of the act (see section
801(d)(3)(B) of the act).
Any imported component, part, accessory, or article that
is not incorporated into a product must be destroyed or exported by the
owner or consignee (see section 801(d)(3)(C) of the act).
This provision is commonly referred to as the ``import for export''
provision.
A. Items Covered Under the Import for Export Provision
1. Human Drugs
One issue under section 801(d)(3) of the act is what constitutes a
``component'' of a drug. FDA regulations define ``component'' as
meaning ``any ingredient intended for use in the manufacture of a drug
product, including those that may not appear in such drug product.''
(See Sec. 210.3(b)(3).) Additionally, for purposes of section 801(d) of
the act, FDA interprets the term ``component'' broadly to include a
range of items, such as the active and inactive ingredients for a drug
or biologic, bulk drugs, and even unapproved foreign versions of drugs
that are approved for use in the United States. So, for example, if
company X wants to import a bulk drug from a source that differs from
the bulk drug source it uses for products sold in the United States,
company X may import the bulk drug from the different source provided
that company X incorporates the bulk drug into a product for export or
further processes the bulk drug before exporting it (or otherwise
destroys the bulk drug). The imported bulk drug from the different
source cannot be used in the product to be sold in the United States.
Additionally, an item can be a ``component'' if it is intended for
``further processing'' in the United States before being exported to
another country. For example, a finished dosage form that is sterilized
in the United States would be a ``component'' within section 801(d)(3)
of the act (because the drug is ``further processed'' during the
sterilization process).
2. Devices
For devices, FDA regulations define a ``component'' as ``any raw
material, substance, piece, part, software, firmware, labeling, or
assembly which is intended to be included as part of the finished,
packaged, and labeled device.'' (See Sec. 820.3(c).) As in the case of
drugs and biologics, FDA interprets the term ``component'' in section
801(d) of the act broadly to encompass a range of items.
Yet, regardless of whether the imported item is a drug or device
component, the key issue under section 801(d)(3) of the act is how the
component will be ``incorporated'' or ``further processed.''
3. Food Additives, Color Additives, and Dietary Supplements
Section 801(d)(3) of the act refers to food additives, color
additives, and dietary supplements. The act defines ``food additive''
at section 201(s) of the act, ``color additive'' at section 201(t) of
the act, and ``dietary supplement'' at section 201(ff) of the act.
B. Activities Covered Under the Concept of ``Incorporation'' and
``Further Processing''
Section 801(d)(3) of the act only permits a component, part,
accessory, or article to enter the United States if it is intended to
be ``incorporated'' into a product for export or is to be ``further
processed'' into a product that will be exported.
In the context of section 801(d)(3) of the act, FDA interprets the
terms ``incorporated'' and ``further processing'' to encompass a wide
range of activities. Thus, ``incorporation'' and ``further processing''
are not confined to product manufacture. Instead, they include related
activities such as packaging and labeling of finished products and
specialized processing (such as sterilization) of a product.
However, FDA does not consider a component, part, accessory, or
article to be ``incorporated'' or ``further processed'' if it is merely
stored in the United States before being exported elsewhere. Although
FDA has exercised enforcement discretion regarding specific entries of
violative products that are stored in the United States, the agency
does not consider the importation of an unapproved product for storage
purposes to fall within the meaning of ``incorporated'' or ``further
processed'' under section 801(d)(3) of the act.
C. Submission of Statements to FDA
Section 801(d)(3)(A) of the act requires the importer to submit,
``at the time of initial importation,'' a statement to the agency
indicating that the imported component, part, accessory, or other
article is intended to be incorporated or further processed by the
initial owner or consignee into a product that will be exported in
compliance with section 801(e) or section 802 of the act or section
351(h) of the PHS Act. Firms should submit this statement to FDA each
time they import an article under the ``import for export'' provision
in the act. The statement (along with other import documents) should be
provided to the FDA field office that has responsibility over the port
or site of entry into the United States.
FDA recommends that the statement contain the following
information:
The purpose for which the article is being imported prior
to export (how it will be further processed or the name or description
of the product into which it will be incorporated);
The imported article's name or description (including any
scientific or technical name);
Any product coding, batch, lot, or other identifying
numbers;
The name and address of the imported article's foreign
manufacturer (if different from the name of the foreign shipper
identified in the import records at the U.S. Customs Service); and
The name and address of the initial owner or consignee in
the United States and, if different, the address in the United States
where the imported article will be further processed or incorporated
into a product for export.
For blood, blood components, source plasma, source leukocytes, or a
component, accessory, or part that is not licensed under section 351(a)
of the PHS Act and is to be imported under section 801(d)(4) of the
act, FDA suggests that the statement include a copy of the
determination by FDA granting permission to import the product or
article. (The request for determination is described in more detail
later in section XI.E.3 of this document.)
FDA emphasizes that, under section 801(d) of the act, the imported
article must ultimately be further processed or incorporated into a
product that is exported in accordance with the act's export provisions
from the United States or the imported article must be destroyed. The
imported article cannot be used in any product which is to be
introduced into U.S. commerce.
The agency intends to issue regulations covering statements under
section 801(d) of the act.
D. Records to be Retained and Reports to be Submitted for Exports Under
Section 801(d)(3) of the Act
Section 801(d)(3)(B) of the act requires the initial owner or
consignee responsible for an imported article to ``maintain records
that identify the use of such imported article and upon request * * *
[to] submit[ ] a report that provides an accounting of the exportation
or disposition of the imported article, including portions that have
been destroyed, and the manner in
[[Page 32232]]
which such person complied with the requirements of this paragraph * *
*.''
The statutory reference to the initial owner or consignee indicates
that, under section 801(d)(3) of the act, the person who imports the
article for incorporation or further processing may, in turn, have
other persons perform the actions that lead to the incorporation or
further processing of the imported article. For example, if company C
imports a drug into the United States for sterilization purposes, but
does not have the technological capability to sterilize the drug
itself, company C could send the drug to company D for sterilization
and, after receiving the sterilized drug back from company D, export
the drug from the United States. However, under this scenario, company
C would remain the owner of the product and would be responsible for
maintaining records and for submitting, upon FDA's request, a report
accounting for the exportation or disposition of the imported article.
The agency suggests that firms importing an article into the United
States under section 801(d)(3) of the act retain records showing:
The name or description of the article (including any
scientific or technical name);
Any product coding, lot, batch, or other identifying
numbers;
The name and address of the foreign manufacturer of the
imported article;
How the article will be or was further processed, and the
name and description of any product into which it will be or was
incorporated in the United States;
The signature of the responsible person at the importing
firm;
The name and address of the firm in the United States
where the article will be or was further processed or incorporated into
another product;
The disposition of the imported article, i.e.,
manufacturing records showing how specific articles were used or
destroyed and the dates of receipt, use, destruction, and/or
reexportation, as that information becomes available;
Any product coding, lot, batch, or other identification
number for the further-processed article or product incorporating the
imported article;
A copy of the label to be applied to the shipping package,
container, or crate used to export the further-processed article or
product incorporating the imported article (indicating that it contains
articles that may not be sold or offered for sale in the United States
and are intended for export only); and
The name and address of the foreign purchaser of the
further-processed article or product incorporating the imported
article.
Additionally, for blood, blood components, source plasma,
source leukocytes, or a component, accessory, or part thereof
(including blood or plasma derivatives or intermediates) that is not
licensed under section 351(a) of the PHS Act and is to be imported
under section 801(d)(4) of the act, the agency recommends that the
records also include documentation of the agreement between the foreign
material supplier and the U.S. manufacturer. The documentation should
outline the specific contractual relationship, the foreign
manufacturing specifications, and the U.S. manufacturer's plan for
auditing the foreign supplier to ensure compliance with the terms of
the contract. FDA suggests that the initial owner or consignee have
written standard operating procedures to ensure that such products are
not diverted to domestic use in the United States and are kept
segregated from and not co-mingled with products or components intended
for use in the United States (e.g., quarantine procedures used for
segregating imported blood, blood components, or final products from
products intended for use in the United States, including validation
data for procedures to clean equipment and facilities used for
manufacturing products for use in the United States and exported
products).
FDA also encourages firms to maintain any other records that would
assist FDA in determining whether they comply with section 801(d)(3) or
(d)(4) of the act. \18\ FDA suggests that firms retain records relating
to the importation of an article for incorporation or further
processing in the United States for 5 years after the destruction or
exportation of the last imported component, part, accessory, or article
for a particular lot or batch. The records may be maintained at the
importing firm's site and may be subject to inspection by FDA.
---------------------------------------------------------------------------
\18\ A firm may also be subject to certain recordkeeping
requirements outside those described in section 802(g) of the act.
For example, because all drugs and devices exported under section
802 of the act must be in substantial conformity with cGMP's or
international standards recognized by FDA, there may be cGMP
recordkeeping requirements that apply to the exported drug or
device.
---------------------------------------------------------------------------
FDA intends to issue regulations to establish recordkeeping
requirements, and persons subject to this provision should note that
the act specifically prohibits the making of a knowingly false
statement in any record or report required under section 801(d)(3)(A)
or (d)(3)(B) of the act as well as the failure to submit or maintain
records under these sections of the act (see section 301(w) of the
act).
E. Special Requirements for Blood, Blood Components, Plasma, Source
Leukocytes, and Tissues--Section 801(d)(4) of the Act
1. Blood, Blood Components, Plasma, and Source Leukocytes
The ``import for export'' requirements for blood, \19\ blood
components, \20\ plasma, \21\ and source leukocytes \22\ differ from
those for drugs and other biologics. Under section 801(d)(4) of the
act, the importation of these products, components, accessories, or
parts is not permitted under section 801(d)(3) of the act unless the
importation complies with section 351(a) of the PHS Act or the agency
permits the importation ``under appropriate circumstances and
conditions.'' (FDA intends to issue regulations specifying the
``appropriate circumstances and conditions'' that would allow
importation of unlicensed products under the import for export
authority.)
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\19\ FDA interprets ``blood'' as whole blood collected from a
single donor and processed either for transfusion or further
manufacturing (see Sec. 606.3(a) and the regulation for whole blood
at 21 CFR 640.1).
\20\ Under FDA regulations, a ``blood component'' is that part
of a single-donor unit of blood separated by physical or mechanical
means (see Sec. 606.3(c) and part 640 (21 CFR part 640)).
\21\ Under Sec. 640.60, ``source plasma'' is the fluid portion
of human blood collected by plasmapheresis and intended as source
material for further manufacturing use. The term does not extend to
single donor plasma products intended for intravenous use.
\22\ FDA interprets ``source leukocytes'' as leukocytes
collected for further manufacturing by leukapheresis (as defined in
Sec. 606.3(g)). This is a procedure in which blood is removed from
the donor, the leukocyte concentrate is separated, and the remaining
formed elements and residual plasma are returned to the donor.
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Under section 801(d)(4) of the act, FDA may permit the import for
export of blood and blood components, source plasma, source leukocytes,
or a component, accessory, or part thereof, which may not be licensed
or meet cGMP requirements. Products imported under section 801(d)(4) of
the act must also comply with section 801(d)(3) of the act. \23\
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\23\ A U.S. manufacturer that intends to incorporate or further
process certain imported blood products for export, or the foreign
supplier of such material, may submit an import for export request
under section 801(d)(4) of the act. Section 801(d)(3) of the act
specifies that the importer must submit the statement of intent to
export to the Secretary, and that the initial owner or consignee
responsible for the imported article must maintain certain records
and submit a report upon request. A U.S. firm that intends to
perform processing or manufacturing steps involving an imported
blood product under section 801(d)(4) and (d)(3) of the act should
have sufficient information, to submit to FDA in support of an
import for export request, that allows FDA to make the determination
whether appropriate circumstances and conditions exist to permit
such importation.
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[[Page 32233]]
Licensed blood products, such as licensed source plasma, may be
imported if such importation complies with section 351(a) of the PHS
Act. Other licensed blood products, such as those having cGMP
deficiencies, are not considered to be in compliance with section
351(a) of the PHS Act. If a product does not have a license or is
considered to be in noncompliance with section 351(a) of the PHS Act,
the manufacturer that wishes to import such a blood product for
incorporation or further processing into a product for export may seek
FDA's permission to import the product. CBER will evaluate such import
for export requests on a case-by-case basis.
Recovered plasma and serum are blood products currently not subject
to licensure. Recovered plasma and serum that are intended for further
manufacture or incorporation into products for export must be imported
in accordance with the short supply provisions at 21 CFR 601.22.
Recovered plasma and serum intended for further manufacturing or
incorporation into noninjectable products not subject to licensure may
be imported without an import for export submission if they are
manufactured in accordance with cGMP's and are labeled appropriately.
Labeling for such products should include the applicable container
label requirements listed in Sec. 606.121. A firm may apply to import
recovered plasma and serum that do not meet cGMP's by submitting an
import for export request. CBER will evaluate these requests on a case-
by-case basis.
Thus, under section 801(d)(4) of the act, no person may import
blood products that are: (1) Subject to licensure and do not comply
with section 351(a) of the PHS Act; or (2) are not subject to licensure
and do not comply with cGMP's, without FDA's prior permission. For the
latter, failure to seek and obtain FDA's permission, under section
801(d)(4) of the act, prior to importation may be a criminal violation.
FDA further recommends that persons who intend to import blood
products under section 801(d)(4) of the act register and list or update
their registration and listing to include a description of the imported
material and the final product for export that will be manufactured
from or incorporate the imported biological material. Registration and
listing information should not be contained in the import for export
request, but may instead be sent to the appropriate registration office
listed in parts 207 or 607. Additionally, the agency requests that
U.S.-licensed facilities receiving any foreign biological components or
products, other than blood, under section 801(d)(3) of the act which
will be used for manufacture into a product for export report such
changes in accordance with 21 CFR 601.12.
2. Tissues
For tissues and tissue parts or components, section 801(d)(4) of
the act prohibits importation unless the importation complies with
section 361 of the PHS Act. (Section 361 of the PHS Act authorizes the
issuance of regulations to control communicable diseases.) Thus,
tissues and their parts or components must comply with the PHS Act and
regulations issued under the PHS Act in order to enter the United
States, even if the product is ultimately destined for exportation.
Persons who intend to import tissues and tissue parts or components
(intended for transplantation) under section 801(d)(4) of the act
should comply with the regulations at part 1270 (21 CFR part 1270) and
also comply with the notification requirement in section 801(d)(3)(A)
of the act. Under Sec. 1270.42, the importer of record must notify the
director (or his or her designee) of the FDA district having
jurisdiction over the port of entry, and the tissue must be held until
FDA releases it. If the human tissue that is imported for further
processing or incorporation into a product for export is kept in
quarantine at all times, it does not have to meet all the screening and
testing requirements in part 1270. If the tissue is declared and
identified as being in quarantine, it must be accompanied by records
assuring identification of the donor and indicating that the tissue has
not been determined to be suitable for transplantation (see
Sec. 1270.33(c)). The owner or consignee in the United States must
prepare and follow written procedures for designating and identifying
quarantined human tissue and preventing infectious disease
contamination or cross-contamination during processing (as stated in
Sec. 1270.31).
If an importer, consignee, or U.S. manufacturer delivers or ships
human tissue or a component thereof before FDA releases it or fails to
quarantine tissue that has not been determined to be suitable for human
transplantation, such action may constitute a criminal violation.
3. Requests to Import Blood, Blood Components, Plasma, and Source
Leukocytes for Further Processing or Incorporation into a Product for
Export (``Requests for Determination'')
Section 801(d)(4) of the act does not specify how persons who wish
to import blood, blood components, source plasma, source leukocytes, or
their components, accessories, or parts obtain permission to import
those products. Nevertheless, to facilitate imports under section
801(d)(4) of the act, FDA recommends that manufacturers provide an
import for export request which demonstrates that appropriate
circumstances or conditions warrant CBER's approval of importation
under section 801(d)(4) of the act. The agency recommends that these
requests, known as a ``request for determination,'' contain the
following information:
The names and addresses of the foreign manufacturer of the
article to be imported and the initial owner or consignee in the United
States that would be responsible for the further processing or
incorporation of the article into another product;
The specific identity of the article to be imported and
details as to how the imported article will be further processed or
incorporated into a product for export;
A description of the standard operating procedures and
safeguards that the initial owner or consignee in the United States
will use or implement to ensure that the imported articles or products
incorporating such articles are segregated from and not comingled with
products, components, accessories, or parts intended for use in the
United States (e.g., quarantine procedures used for segregating
imported blood, blood components, or final products from products
intended for use in the United States, including validation data for
procedures to clean equipment and facilities used in manufacturing
products for use in the United States and products for export);
General donor screening questionnaire or criteria,
translated into English, that will be used to screen donors;
A certification that the foreign supplier will perform
tests for infectious disease on the blood, blood components, source
plasma, or source leukocytes, or their components, accessories, or
parts (including blood or plasma derivatives or intermediates) at the
time of donation and before importation to the United States, and the
expected results of such tests. The infectious disease agents that
should be tested for include, but are not limited to:
[[Page 32234]]
HIV-1, HIV-2, hepatitis B virus, hepatitis C virus, HTLV-I, HTLV-II,
and Treponema palladum. A request for determination may be based upon
infectious agent tests performed using test kits other than those
licensed or approved by FDA. In such cases, FDA suggests that the
request contain a copy of the labeling for the test kit used,
translated into English, as part of the submission; and
A copy of the product's label. FDA recommends that the
label include information such as the product's descriptive name; the
name(s) and address(es) of establishments collecting, preparing,
labeling, or pooling the source material; donor, lot, or pool numbers
relating the unit to the donor; the recommended storage temperature (in
degrees Celsius); the product's quantity; statements such as ``Import
for Export,'' ``Not for Use in Products Subject to Licensure Under
Section 351 of the Public Health Service Act,'' and ``For Manufacturing
Use Only'' or ``For Manufacturing into Noninjectable Products Only;''
statements indicating that the product has been tested for infectious
disease agents and, if the product has tested positive for an
infectious disease agent, the term ``BIOHAZARD'' as well as any other
appropriate warnings or special handling instructions.
A request for determination may be sent to the Center for Biologics
Evaluation and Research, Office of Compliance, Division of Case
Management (HFM-610), 1401 Rockville Pike, Rockville, MD 20852-1448. If
FDA determines that the blood, blood component, source plasma, or
source leukocyte, or a component, accessory, or part meets the
appropriate circumstances and conditions to permit its importation into
the United States, FDA will notify the person requesting the
determination that it has granted permission to import the article.
XII. For Further Information Contact:
For animal drugs: Drugs Team, Division of Compliance, Center for
Veterinary Medicine, Food and Drug Administration, 7500 Standish Pl.,
Rockville, MD 20855, 301-594-1785.
For biologics: Division of Case Management (HFM-610), Office of
Compliance, Center for Biologics Evaluation and Research, Food and Drug
Administration, 1401 Rockville Pike, rm. 200N, Rockville, MD 20852-
1448, 301-827-6201.
For devices: Division of Program Operations (HFZ-305), Center for
Devices and Radiological Health, Food and Drug Administration, 2094
Gaither Rd., Rockville, MD 20850, 301-594-4699.
For drugs: Division of Labeling and Nonprescription Drug Compliance
(HFD-310), Center for Drug Evaluation and Research, Food and Drug
Administration, 7520 Standish Pl., Rockville, MD 20855-2737, 301-594-
0063.
For drugs exported for investigational use under Sec. 312.110:
Office of International Affairs (HFG-1), Food and Drug Administration,
5600 Fishers Lane, Rockville, MD 20857, 301-443-4480.
For food additives, color additives, and dietary supplements:
Office of Field Programs (HFS-602), Center for Food Safety and Applied
Nutrition, Food and Drug Administration, 200 C St. SW., Washington, DC
20204, 202-205-4187.
These offices may have additional guidance documents and
information on specific export topics or products.
For general policy questions: Office of Policy (HF-23), Food and
Drug Administration, 5600 Fishers Lane, Rockville, MD 20857, 301-827-
3344.
Dated: June 2, 1998.
William K. Hubbard,
Associate Commissioner for Policy Coordination.
[FR Doc. 98-15696 Filed 6-11-98; 8:45 am]
BILLING CODE 4160-01-F