Chapter 1 - General
Return to Compliance Guides Table of Contents
CONTENTS
Sub Chapter 100 - General
100.100 Responsibility for Reporting Possible or Potential Violations
of Laws Administered by FDA, Regulations Issued by FDA, Other
Possible or Potential Hazards to the Public Health
100.200 FDA Jurisdiction Over Products Composed of Interstate
Ingredients
100.300 Non-FDA Regulated Products Involving Communicable
Disease Hazards
100.350 FDA Jurisdiction on Indian Reservations
100.500 Common Carrier as a Relabeler, Repacker, Reprocessor, etc.
100.550 Status and Responsibilities of Contract Sterilizers Engaged in
the Sterilization of Drugs and Devices
100.600 Status of Facial Tissues, Paper Napkins, Paper Towel#S and
Similar Paper Products
100.700 GWQAP Pre-Award Evaluation - Inadequate Information to
Evaluate Prospective Supplier
100.800 Guaranties Over Printed Signatures
100.900 International Memoranda of Understanding
Sub Chapter 110 - Exports/Imports
110.100 Certification for Exports
110.200 Export of FDA Regulated Products from U.S. Foreign Trade
Zones
110.500 Food and Drug Guaranty - Imports
110.600 FDA Authority Over Products of Foreign Origin Located in
Foreign Trade Zones, Bonded Warehouses or on Bonded Carriers
110.700 Seizures by the U.S. Customs Service of Prohibited Articles
of Foreign Origin Not Intended for Entry into the United States
110.800 Imports, Post Detention Sampling
110.900 Imported Products - Lack of English Labeling
Sub Chapter 120 - Fraud
120.100 Fraud, Untrue Statements of Material Facts, Bribery, and
Illegal Gratuities
120.500 Health Fraud - Factors in Considering Regulatory Action
Sub Chapter 130 - Inspections
130.100 Inspectional Authority; Refusal to Permit Inspection. CPG 7151.01 Page 15
130.200 Inspection of Firms when Legal Action is Pending
130.300 FDA Access to Results of Quality Assurance Program
Audits and Inspections
130.400 Use of Microfiche and/or Microfilm for Method of Records
Retention
Sub Chapter 140 - Labeling
140.100 Seizure of Books that Constitute Misleading Labeling
140.500 Metric Declarations of Quantity of Contents on Product Label#S
Sub Chapter 150 - Laboratory/Analytic
150.100 Requests for Portions of Intermediate or End Products
Resulting from FDA Sample Analysis
150.500 Analytical Methodology Used by FDA - Drugs
Sub Chapter 160 -Regulatory
160.100 Regulatory Actions and Small Business
160.200 FDA Use of Income Tax Information from IRS in CPG 7153.09
Compliance Activity
160.300 Requests for Records Under Section 703
160.400 Section 305 Meeting - Before Report of Criminal Violation
160.500 Answering Inquiries on Status of Criminal Records
160.600 Payment of Expert Witness
160.700 Reconditioning of Foods Adulterated Under 402(a)(4)
160.750 Drug and Device Products (Including Biologics and
Animal Drugs) Found in Violation of GMPRs - Reconditioning
Sub Chapter 170 - Specific Problems - Non-Food, Drug, or Cosmetic Related
170.100 Turtles - Ban on Interstate and Intrastate Sales and
Distribution
______________________________________________________
Sub Chapter 100 General
Sec. 100.100 Responsibility for Reporting
Possible or Potential Violations of Laws Administered by FDA, Regulations
Issued by FDA, Other Possible or Potential Hazards to the Public Health
(CPG 7150.05)
*POLICY:
It is the responsibility of all FDA employees, whatever their grade
or job designation, to promptly notify their supervisors for appropriate
referral as soon as they become aware of any circumstances that may be
a violation of any of the laws or regulations we enforce or administer,
or pose a potential hazard to the public health. When necessary, each director
and each equivalent official in the Office of the Commissioner shall be
responsible for taking any necessary action within their own authority,
and for notification to their appropriate offices. If any questions exist
after such referral, the matter should be promptly addressed to the Associate
Commissioner for Regulatory Affairs, who will then be responsible for determining
necessary action within the agency. The Associate Commissioner for Regulatory
Affairs will also be responsible for communicating with other Federal agencies
and governments of other nations.
In any instances in which there is joint responsibility and authority,
or any ambiguity of responsibility or authority between FDA and any other
agency, FDA shall assume an obligation to be certain that everyone concerned,
including those in other agencies, are aware of pertinent information in
the possession of this agency.*
*Material between asterisks is new or revised.*
Issued: 4/5/77
Reissued: 10/1/80
Revised: 9/1/87
Sec. 100.200 FDA Jurisdiction Over Products
Composed of Interstate Ingredients (CPG 7153.11)
BACKGROUND:
This policy guide sets forth the position of FDA with respect to products
composed of ingredients which were shipped in interstate commerce and were
then used in the manufacture of a finished product. This policy is applicable
only when the finished product has not itself been shipped in interstate
commerce as defined by Section 20l(b) of the FD&C Act. For oleomargarine
see Sec. 407 of the FD&C Act. For devices see 304(a)(2)(D) and Sec.
709 of the FD&C Act. For counterfeit drugs and materials see 304(a)(2)(A),
(B) and (C) and 301(i)(2) and (3) of the FD&C Act.
Over the years, the courts have reviewed the question of jurisdiction
over products made from interstate components. The defense in these cases
has been that the finished product is a new entity and FDA lacks jurisdiction
until the "new" product is itself shipped in interstate commerce.
The following court cases involving this question establish that FDA
clearly has jurisdiction over finished products made from interstate components.
1. U.S. v. An Article of Drug ... Korleen Tablets
192 F. Supp. 51 (E.D. Mich., 1961), Affirmed at 330 F. 2nd 78 (C. A.
6, 1964) KK 61-64 at 754
2. U.S. v. 40 Cases ... Pinocchio Brand ... Olive Oil
289 F. 2nd 343 (C. A. 2, 1961) KK 58-60 at 106 and 35
3. Palmer v. U. S.
340 F. 2nd 48 (C. A. 5, 1964)
KK 61-64 at 809
4. *U.S. v. Dianovin Pharmaceuticals, Inc.
342 F. Supp. 724(D.P.R. 1972). Affirmed at 475 F. 2nd 100 (C. A. 1,
1973)
KKW 69-74 at 369 and 382*
*
5. U.S. v. 14 Cases ... Naremco Medimatic
374 F. Supp. 922 (W. D. Mo., 1974)
KKW 69-74 at 168*
POLICY:
The Food & Drug Administration has jurisdiction over all products
made from interstate components regardless of the amount present, even
though the finished product has not moved in interstate commerce. Action
may be taken against the product or the responsible firm when violative
finished products are encountered, or when conditions of manufacture result
in nonviolative interstate ingredients becoming adulterated or misbranded.
The importance and the amount of the ingredient in the product, as well
as the seriousness of the violation, will be considered in arriving at
the decision to take action.
*Material between asterisks is new or revised*
Issued: 11/10/78
Revised: 10/1/80, 8/31/89
Sec. 100.300 *Non-FDA Regulated Products
Involving Communicable Disease Hazards* (CPG 7150.08)
BACKGROUND:
*Some time ago, an incident* occurred which involved plasma thawing
during transit and leaking onto other commodities in the truck, including
stepstools and printed material. The *Center for Biologics Evaluation and
Research (CBER)* determined that this situation presented a potential health
hazard to anyone handling the contaminated commodities, since intact and
potentially infectious particles of the hepatitis B virus or other viruses
might be present in the dried plasma on the contaminated articles.
There is no doubt that FDA has jurisdiction over the thawed plasma and
would take whatever action was appropriate against the plasma and responsible
individuals.
This policy guide addresses our authority with regard to the contamination
of non-FDA regulated products.
In the above incident *CBER* recommended, for expediency and ease of
handling, that the consignees be advised through local health authorities
to disinfect or destroy the contaminated articles.
*In other incidents involving Anthrax on drum skins and saddle blankets,
FDA has referred such problems to the Consumer Product Safety Commission
and the Centers for Disease Control.*
POLICY:
*Such problems which are not specifically covered by the laws and/or
regulations administered by FDA should be referred when we can identify
a responsible agency at the federal, state, or local level that can expeditiously
accomplish corrective action.
Sec. 361 of the Public Health Service Act is the source for authority
to control the interstate movement of animals or articles found to be contaminated
so as to be sources of dangerous infections to human beings. Such relevant
regulations, 21 CFR Part 1210, may be utilized whenever necessary to protect
the public health.*
*Material between asterisks is new or revised*
Issued: 2/8/78
Revised: 10/1/80, 8/31/89
Sec. 100.350 FDA Jurisdiction on Indian
Reservations (CPG 7150.06)
BACKGROUND and POLICY:
The FDA considers Indian Reservations to be possessions of the United
States within the meaning of section 20l(a)(2) of the Federal Food, Drug,
and Cosmetic Act. Consequently, FDA has complete jurisdiction over products
within the purview of the Act that are manufactured on an Indian reservation.
The products are in interstate commerce within the meaning of section 20l(b)
of the Act at all times.
*Under the Food, Drug and Cosmetic Act, the FDA has the same authority
on a reservation as it does anywhere else, to inspect, to take official
samples, and to initiate regulatory actions.*
*Material between asterisks is new or revised*
Issued: 3/15/87
Revised: 10/1/80, 9/1/87
Sec. 100.500 Common Carrier as a Relabeler,
Repacker, Reprocessor, etc. (CPG 7150.03)
BACKGROUND:
A transportation company asked for information concerning the responsibility
of a common carrier in connection with the relabeling of merchandise which,
for one reason or another, had come into its possession.
The proviso in section 703 of the Federal Food, Drug, and Cosmetic Act,
grants immunity from prosecution to carriers by reason of their receipt,
carriage, holding, or delivery of products subject to the Act in their
usual course of business as carriers. The immunity does not extend to operations
or functions which are outside the normal duties of a carrier.
POLICY:
A carrier acting otherwise than as specified in section 703 incurs the
same responsibility as anyone else who labels, repacks, or reprocesses
goods, whether or not the carrier has any ownership interest in the goods.
Issued: 10/26/76
Revised: 10/1/80, 8/31/89
Sec. 100.550 Status and Responsibilities
of Contract Sterilizers Engaged in the Sterilization of Drugs and Devices
(CPG 7150.16)
BACKGROUND:
Questions have been raised as to the responsibilities of a contract
sterilizer under the Food, Drug, and Cosmetic Act. The questions concern
registration requirements under Section 510, Agency inspectional policy,
documentation and validation requirements, and responsibilities of the
parties to the contractual agreements.
DEFINITION:
For the purposes of this guide the following definition will apply:
Contract Sterilizer. An establishment that provides a contractual service
intended to sterilize an FDA regulated product.
POLICY:
1. Responsibility of Contract Sterilizers:
Contract sterilizers are responsible for conformance with the portions
of the current Good Manufacturing Practice (CGMP) regulations that pertain
to the services they provide.
2. Registration:
Each contract sterilizer of a drug or device product must register as
set forth under section 510 of the Act.
3. Documentation:
The finished drug or device manufacturer should maintain, as part of
the master production and control record, or reference, written process
specifications and documentation of the validation of the sterilization
process conducted by the contract sterilizer. The finished drug or device
manufacturer should also maintain, or have readily available, copies of
the contract sterilizer's batch production records.
The contract sterilizer must maintain documentation of validation and
the written process and production specifications and procedures necessary
to assure the process is adequately completed. Contract sterilizers are
also responsible for completing and maintaining batch records of all operations
performed.
4. Inspections:
Contract sterilizers, as drug or device processors, are subject to the
biennial inspection requirements of the Act.
5. Contractual Agreements:
The contractual agreement should specify which establishment will execute
various functions. In general, the establishment which executes a given
function will be primarily responsible for the CGMP's which apply to that
function.
6. Sterilization Process Validation:
Sterilization processes are required by the CGMP's to be validated.
The validation may be conducted by either the finished drug or device manufacturer
or the contractor. The finished drug or device manufacturer has ultimate
responsibility for assuring that the finished drug or device meets sterility
specifications and is processed under adequate CGMP controls. The contractor
who offers a sterilization process has responsibility to assure the process
is effective and that adequate GMP controls are established and implemented.
Therefore both parties are responsible for validation and liable to the
extent that they have contributed to the noncompliance. The absence of
an agreement does not remove this responsibility for either party.
NOTE: For licensed biologicals, the *Center for Biologics Evaluation
and Research* holds the final manufacturer responsible for all production
processes, including validations of sterilization performed under contract,
whether or not the contract so states.
REGULATORY ACTION GUIDANCE:
If adverse findings are encountered during an inspection, the appropriate
Center should be notified. In addition, the districts that have firms using
the services of contractors outside the district should be advised of any
adverse finding.
In considering regulatory, voluntary, or administrative action, the
agency will regard the manufacturer as primarily responsible for assuring
the compliance of the medical product. However, the contract sterilizer
and the manufacturer will be held jointly responsible for those processes
performed by the contractor to the extent that each party contributed to
the violations. Performance of each party will be considered in determining
whether one or both parties are subject to regulatory action for failure
to comply with GMPs. Should regulatory action be generated as a result
of inspection of the contract sterilizer, both parties should receive copies
of all correspondence.
*Material between asterisks is new or revised*
Issued: 3/1/84
Revised: 8/31/89, 3/95
Sec. 100.600 Status of Facial Tissues,
Paper Napkins, Paper Towels, and Similar Paper Products (CPG 7150.02)
BACKGROUND:
Inquiries are occasionally received concerning the status under the
Federal Food, Drug, and Cosmetic Act of facial tissues, paper napkins,
paper towels or similar paper products.
POLICY:
The Food and Drug Administration does not consider facial tissues, paper
napkins, paper towels or similar products subject to the Act when sold
only for conventional wiping purposes. If the labeling of such products
suggests or implies a therapeutic or cosmetic benefit is to be derived
from this use, this may bring them within the definition of a "drug"
within the meaning of section 201(g), a "device" within the meaning
of section 201(h), or a "cosmetic" within the meaning of section
201(i) of the Act.
Issued: 10/6/76
Revised: 10/1/80, 8/31/89
Sec. 100.700 GWQAP Pre-Award Evaluation
- Inadequate Information to Evaluate Prospective Supplier (CPG 7150.07)
BACKGROUND:
One of FDA's responsibilities under the Government-Wide Quality Assurance
Program for medical products is to perform pre-award evaluations to determine
the capability of prospective suppliers to furnish products of acceptable
quality. In performing this assessment, FDA evaluates all information available
to the agency bearing on the quality capability of the firm with respect
to the product(s) involved. When sufficient current, reliable information
is not in the agency's file, an on-site inspection is made to obtain whatever
information is considered necessary to properly evaluate the prospective
supplier. When performing these inspections the FDA investigator is acting
both under the authority of the Federal Food, Drug, and Cosmetic Act (Act),
*and related statutes,* and as an agent of the contracting officer in the
purchasing agency.
There are times when FDA does not have in its files, and is unable to
obtain through inspection, information that is crucial in performing a
proper quality evaluation. Examples of such instances include the following:
A firm is not operating, and FDA is therefore not able to conduct an
adequate inspection to obtain information regarding manufacturing practices
and procedures necessary for determining the acceptability of manufacturing
operations and controls.
A tablet manufacturing firm which has never produced small volume parenterals
seeks to be awarded a contract to sell small volume parenterals to the
Government, and intends to set up a parenteral manufacturing operation
if awarded the contract.
A manufacturer of a medical product such as an in-vitro diagnostic desires
to sell his product on contract to the Government, but declines to allow
inspection of some or all of his manufacturing operation and/or related
records, including complaint files, on the basis that he is not required
under the Act to allow the FDA investigator to have access to this information.
POLICY
When FDA determines it is unable to perform a proper evaluation of a
prospective contractor because the agency does not have, or is not able
to obtain, the information necessary for performing the evaluation, FDA
will report to the purchasing agency that based upon all the available
information, FDA is not able to perform a proper evaluation and therefore
cannot make recommendations on the acceptability of the prospective contractor
as a supplier. This report will include the reasons why information necessary
for proper evaluation is not available.
*Material between asterisks is new or revised*
Issued: 11/29/77
Revised: 10/1/80, 9/1/87
Sec. 100.800 Guaranties Over Printed Signatures
(CPG 7150.12)
BACKGROUND:
There has been no court decision on the question of whether a guaranty
must be manually signed by the guarantor in order to afford the protection
of Section 303(c)(2) and/or subject the provider of the guaranty to the
provisions of Section 301(h).
Many firms use facsimile signature or printed firm names on business
documents bearing guaranties. These names may appear either beneath the
guaranty or somewhere else on the document.
Section 201(e) of the FD&C Act defines "person" to include
individual, partnership, corporation and association. These entities act
through agents who are authorized to and routinely do affix the signature
or print the name of an officer or company to official business records
and specify the statements which appear on these records.
POLICY:
We will regard guaranties on documents which contain a facsimile signature
or printed signature or company name to constitute guaranties within the
meaning of Section 303(c)(2) and will regard such guaranties which are
false to be in violation of Section 301(h) of the Act.
Issued: 04/9/79
Revised: 10/1/80, 8/31/89
Sec. 100.900 International Memoranda of
Understanding (CPG 7150.19)
SUBJECT:
This guide sets forth policy for initiating, developing, and monitoring
agreements such as memoranda of understanding (MOU's) between the Food
and Drug Administration (FDA) and foreign governments. The general principles
herein may also be applicable to MOU's with international organizations.
BACKGROUND:
The FDA International Harmonization Task Force recommended in December
1992 that guidance be developed that describes the agency's objectives
and promotes uniformity in developing MOU's with foreign government agencies.
MOU's promote harmonization of laws, regulations, and enforcement activities.
Further, MOU's, if negotiated and implemented properly, enhance FDA's ability
to carry out its mission. Attachment A to this Compliance Policy Guide
(CPG) sets forth the agency's criteria for setting priorities for international
MOU's.
The three categories of MOU's described in the following paragraphs
are merely examples. These categories are not mutually exclusive, and the
concepts may be altered or combined as necessary. Because officials of
sovereign nations have different approaches to regulation, FDA needs to
maintain flexibility in its discussions with these officials.
Reciprocal Agreements with Countries Having the Same or Similar
Systems
MOU's may provide for the mutual assessment of the comparability of
specific FDA's programs or activities with those of a foreign regulatory
authority. These MOU's are similar to mutual recognition agreements (MRA's),
referred to in recent trade agreements, and include equivalence agreements.
FDA MOU's that provide for the mutual assessment of the comparability of
a foreign regulatory system or measure are suitable when it can be determined
that FDA's controls and the foreign regulatory authority's controls are
comparable and are designed to provide the same level of protection. Under
one form of such agreements, mutual acceptance of data and information,
such as analytical findings and inspection results, may ordinarily be considered
adequate for regulatory decisions. The MOU's now in place for the exchange
of results of good manufacturing practices and good laboratory practices
inspections are examples. Under another form of such agreements, FDA and
another country may agree that their regulatory systems governing certain
products are the same or similar and are designed to provide the needed
level of protection, enabling each country to consider reducing the rate
of inspection or sampling of imports from the other country that would
otherwise be necessary.
Certification of Import/Exports
MOU's may establish certification criteria for products regulated by
FDA. Historically, these MOU's have concerned products exported to the
United States with inherent or consistent quality or safety problems. However,
they may also involve products with a good compliance history (see Attachment
A of this CPG). They may identify controls to be employed by the exporting
country to assure the validity and reliability of certification. Such agreements
should be designed with the intent of reducing the FDA rate of inspection
or sampling that would otherwise be necessary and with the intent of providing
a basis for assurance that the consumer protection objectives of FDA are
being met. Certification may be shown by marks on the product, container,
or entry documents or by other paper or electronic communication. An MOU
based on the controls to be employed and maintained by the exporting country
to ensure that articles exported comply with FDA laws and regulations may
render such certifying marks, documents, or other communication unnecessary.
Communications
Formalizing communication links facilitates the exchange of technical,
scientific, and regulatory information. Technical cooperation leads to
better understanding of safety and quality standards for products traded
between the United States and other countries and promotes harmonization.
Improved communications with foreign officials may improve FDA decision
making and reduce resource expenditures for monitoring foreign made products.
POLICY:
It is the policy of FDA to pursue the development of MOU's that will
further the agency's public health mission. FDA intends to enter into an
MOU only with an agency of a foreign government or an international organization.
The MOU should be designed to meet the following goals:
1. To enhance FDA's ability to ensure that regulated products are safe,
effective, of good quality, and properly labeled;
2. To allow FDA to utilize its resources more effectively or efficiently,
without compromising its ability to carry out its responsibilities; and
3. To improve communications between FDA and foreign officials concerning
FDA regulated products.
Further, before accepting the procedures and activities, including enforcement
methods, of foreign governments as equivalent to its own, FDA will seek
assurance that such activities provide the same level of product quality,
safety and efficacy that is provided under the Federal Food, Drug, and
Cosmetic Act (the act); the Fair Packaging and Labeling Act; the Public
Health Service Act; and any other relevant law of the United States. FDA
may find it necessary to confirm by on-site review or other appropriate
means that the foreign government agency has the necessary authorities,
product standards, capabilities, and infrastructure to successfully achieve
the proposed terms of the MOU, and, therefore, that a determination of
equivalence can be made. Where appropriate, FDA will publish proposed equivalence
determination for comment.
FDA's criteria for deciding when to initiate consideration of developing
MOU's are set forth in Attachment A of this CPG. FDA intends to review
and update these criteria periodically.
Affected agency units will review the proposal for a new or revised
MOU for consistency with the agency's international policy objectives and
priorities before an FDA component begins substantive discussions with
foreign officials about the MOU.
FDA auditing may be necessary to assure that the circumstances supporting
the basis for an agreement continue to exist, whether or not the foreign
government intends to conduct audits. The liaison office identified in
the MOU is responsible for preparing a written evaluation. Participating
FDA components will be queried by the responsible liaison office as to
the overall effectiveness of the agreement, whether provisions should be
added or deleted, and whether the MOU should be terminated.
Countersigned agreements are commonly referred to by FDA as "Memoranda
of Understanding." However, some foreign governments have requested
that such documents be titled as "Notes Verbal," "Arrangements,"
or "Mutual Recognition Agreements." Regardless of title, such
agreements will be filed in chapter 56 of the Compliance Policy Guides
Manual, and a notice of availability will be published in the FEDERAL REGISTER.
An "exchange of letters" should be used in lieu of a formal
agreement when the actions contemplated require only a limited resource
expenditure and do not rise to the significance of a formal agreement.
For example, an exchange of letters could formalize an understanding that
each agency will provide the other with documents that are available upon
request to any member of the public. Each letter should set out only the
actions to be carried out by the agency signing the letter and not mutual
considerations. Clearance of exchange of letters will be by the same process
as used for MOU's except that, after clearance, the FDA letter may be signed
by the appropriate Center or Office Director. Copies of the letters exchanged
should be placed in the cooperative agreements portion of the Compliance
Policy Guide Manual.
FDA's practice is to enter into MOU's for a period of 5 years. Each
existing MOU should be evaluated at least once during the 5 year period
of the agreement to determine whether the MOU should be modified, continued,
or canceled. As part of the evaluation of an MOU, the agency may conduct
independent or joint inspections or analyze imported products to evaluate
the effectiveness of the MOU.
DEVELOPMENT GUIDANCE:
Developing an MOU with a foreign government requires coordination between
the sponsoring center or office, the Office of Regulatory Affairs (ORA),
the International Affairs Staff/Office of Health Affairs (IAS/OHA), and
the Office of Policy (OP). Generally, there are three phases in the process
as described below:
Stage I--Exploring Feasibility
1. The sponsoring Center or Office makes a preliminary assessment whether
the proposed MOU is in line with FDA policy goals. If the sponsoring Center
or Office believes that the MOU should be pursued, the Center or Office
informs ORA (HFC-10) in writing and explain why it believes that the MOU
should be pursued.
2. The initiating agency component provides a general description of
the agreement it wishes to develop, e.g., mutual recognition of a quality
assurance program, product certification, information exchange, etc.
3. The parties exchange information on laws, standards, and other requirements
for subject products, inspection and sampling abilities, and analytical
methodology, as appropriate.
4. On-site review of facilities, operations, and controls may be arranged.
5. If the foreign government appears not to be, and in FDA's opinion
is not, capable of developing an adequate infrastructure to carry out the
intended program, the sponsoring agency component will explain FDA's position
in writing and suspend further action until FDA's concerns are adequately
addressed. The letter addressing this issue should be reviewed by OP and
IAS/OHA.
Stage II--Determining Effectiveness
1. If discussions are to continue, IAS/OHA should be notified so that
appropriate notification to the Department of State (DOS) can be made.
2. The parties may consider an informal trial to gain confidence in
the planned agreement. A draft MOU may be prepared along with a protocol
that may provide a basis for the trial. Together these documents may include:
A. A complete description of the trial program.
B. Information regarding roles and capabilities of involved government
and private organizations.
C. Certificate issuance and use procedure, if any.
D. Audit frequency and measures to be applied.
E. Description of training or information needs.
3. Whether or not there is a trial, FDA may conduct as appropriate independent
or joint inspections with the foreign government, or analyze imported products
to evaluate the effectiveness of the program.
Stage III--Finalizing an MOU
1. The MOU should be prepared for clearance after the substance of the
MOU has been finalized, including after rulemaking, where appropriate.
2. If appropriate, instructions for auditing the agreement should be
issued to field offices by the sponsoring center or office, through ORA.
ATTACHMENT A
FOOD AND DRUG ADMINISTRATION
CRITERIA FOR MEMORANDA OF
UNDERSTANDING
In deciding whether to begin discussions that could lead to the development
of an MOU, an agency component should consider the factors that are listed
below:
Health Benefits (Including Risk Reduction) Associated With Products
or Programs
FDA should consider the benefits to public health (particularly for
the United States population) when it sets priorities for its international
activities.
Products Imported into the United States
FDA should place a higher priority on international activities that
are directed toward improving the quality, safety, or efficacy of products
offered to consumers in the United States For example, FDA should give
a low priority to investing resources in developing a memorandum of understanding
with a foreign country that covers a product where there is little likelihood
of significant exports to the United States or significant risk to the
public.
History of Compliance Problems
FDA should place a higher priority on international activities directed
toward remedying product defects that have been demonstrated to be previous
compliance problems or where there is a demonstrated scientific basis for
increased surveillance.
Comparative Costs of Alternative Programs
FDA should pursue international programs and activities that provide
the greatest benefit in relation to the resources required to administer
them. For example, the costs of developing, implementing, and monitoring
an agreement should be weighed against the costs of higher sampling levels
to obtain the same degree of confidence in rates of compliance in the absence
of an agreement.
Regulatory Burden on Industry
FDA should consider the regulatory burden on industry that could be
diminished by harmonization efforts. However, these activities need to
be compatible with FDA's primary public health mission, the act, and other
laws and regulations that FDA enforces.
U.S. Foreign Policy Objectives and Priorities of Other U.S. Government
Agencies
FDA should be knowledgeable of U.S. foreign policy objectives and international
programs and policies of other U.S. Government agencies and appropriately
balance these interests with those of FDA's primary mission.
Issued: 6/7/95
Sub Chapter 110
Exports/Imports
Sec. 110.100 Certification for Exports
(CPG 7150.01)
BACKGROUND:
Firms exporting products from the U.S. are often asked by foreign customers
or foreign governments to supply a certification relating to products subject
to the Federal Food, Drug, and Cosmetic Act (the Act) and other acts FDA
administers. Certification is the process by which a formal or official
attestation is made concerning the regulatory status of a product, or the
system by which a commodity is manufactured. Requests for certification
have variously asked for verification that the products being exported:
(1) are freely marketed in the U.S.; (2) are in compliance with U.S. laws
and regulations; (3) are in compliance with the importing country's requirements;
(4) meet certain national or international standards, such as quality standards;
or (5) do not contain specific contaminants. This certification process
may include issuance of a certificate to accompany the exported product.
FDA has historically issued a number of different types of certificates,
e.g., Certificates of Free Sale, Certificates for Export, Certificates
to Foreign Governments, and the European Union (EU) Health Certificate
for Fishery Products. With expanding world trade, ongoing international
harmonization initiatives (such as the Codex Committee on Food Import and
Export Inspection and Certification Systems, and WHO Certification Scheme
on the Quality of Pharmaceutical Products), and developing international
agreements, pressures on FDA to issue more certificates for U.S. products
are escalating.
POLICY:
FDA's long term goal is to reduce or eliminate export certificates by
finding other means to assure other countries of the acceptability of FDA
regulated products. However, the agency recognizes the current importance
of providing export certificates. For commodities regulated by FDA under
authority of the Federal Food, Drug, and Cosmetic Act, or other acts FDA
administers, FDA is the U.S. agency with regulatory oversight of the certification
process. Under the FDA Export Reform and Enhancement Act of 1996, FDA is
required to issue certificates for drugs and biologics, animal drugs, and
devices that meet the applicable requirements of the Act within 20 days
of receipt of a request for such a certificate. A fee of up to $175 may
be charged for each certificate issued. While FDA is not required to issue
certificates for foods and cosmetics, the agency intends to continue to
provide this service with the anticipation of achieving full cost recovery
by charging the requestor a fee based on the actual expense incurred. In
addition to issuing export certificates for products that are approved,
licensed, or otherwise in compliance with the applicable requirements of
the Act, the FDA will also issue export certificates for products that
meet the requirements of Sections 801(e) or 802 of the Act but that may
not otherwise be marketed, sold, offered for sale, or distributed in interstate
commerce.
GUIDANCE:
Procedures implemented for responding to requests for a certificate
or similar requests should place the burden and responsibility on the certificate
requestor to provide information that will assist FDA in determining whether
a certificate may be issued.
The following guidance has been developed to improve agency uniformity
and consistency in providing export certificates for FDA regulated product(s):
1. Certificates for products that may be legally marketed, sold, offered
for sale, or distributed in the United States should be entitled, "Certificate
to Foreign Government," unless it is required to bear a different
name. Certificates for products not authorized for distribution or sale
in the United States, but which may be legally exported should be entitled,
"Certificate of Exportability." 2. Certificates should be issued
by the appropriate district director, center compliance director, or his/her
designee.
3. If authentication of the certificate is required, the certificate
may be notarized, or certified under seal of the Department of Health and
Human Services in accordance with 21 CFR 5.22, or both.
4. Each center may establish its own internal procedure and requirements
for an exporter to request a certificate. However, the individual representing
the exporting company and submitting a request for certification pursuant
to Section 801(e)(4) of the Act should at a minimum:
a. Provide a written statement that:
(1) identifies the product(s) to be exported; and
(2) demonstrates that the product(s) to be exported--
(ii) meets the requirements of Section 801(e) or Section 802 of the
Act; or
(ii) may be legally marketed, sold, offered for sale, or distributed in
interstate commerce.
b. Provide a written statement acknowledging that he or she is subject
to the provisions of Title 18, Section 1001 of the United States Code (U.S.C.).
This statutory provision makes it a criminal offense to knowingly and willfully
make a false or fraudulent statement, or make or use a false document,
in any matter within the jurisdiction of a department or agency of the
U.S. The provision also makes it a criminal offense to knowingly and willfully
falsify, conceal, or cover up by any trick, scheme, or device a material
fact in any matter within the jurisdiction of a department or agency of
the United States.
5. A certification issued pursuant to Section 801(e)(4) of the Act should
contain:
a. A statement that each specific product identified is subject to FDA
jurisdiction;
b. A statement indicating the compliance status of the system by which
the product is required to be manufactured (may also indicate that the
agency does not certify compliance with our laws for specific lots of product)
for approved or licensed products, or products exported under Section 802
of the Act;
c. A statement indicating the premarket clearance status for a product
requiring pre-market approval (e.g., new drugs, new animal drugs, licensed
biologics), or for a product subject to certification (e.g., insulin, colors);
d. A statement that the named product(s):
(i) may be exported under Section 801(e) or Section 802 of the Act;
or
(ii) may be legally marketed, sold, offered for sale, or distributed in
interstate commerce.
e. A statement that the certificate is valid for a period of thirty
six (36) months from the date authorized.
The requestor should be notified that the issuance of a certificate
by FDA will not preclude regulatory action by FDA against any product that
is covered by such a certificate, if warranted. Additionally, the requestor
should be informed that a certificate or similar statement issued by FDA
is for export purposes only and may not be used for domestic advertising.
REGULATORY GUIDANCE:
FDA intends to pursue regulatory action, including criminal prosecution,
against anyone responsible for causing the submission of false or misleading
information, substitution of a product under a certificate, counterfeiting
or altering a certificate, or the misuse of a certificate.
Attachments:
Model Certificate to Foreign Government
Model Certificate of Exportability - Section 802
Model Certificate of Exportability - Section 801(e)
Sample EU Export Health Certificate for Fishery Products
Sample WHO Certificate for Quality of a Pharmaceutical Product
(Graphic) WHO Certificate for
Quality of a Pharmaceutical Product [8 1/2 x 11 Form]
Issued: 10/1/80
Revised: 6/1/89, 8/15/94, 10/29/96
Attachments:
CERTIFICATE TO FOREIGN GOVERNMENT
In order to allow the importation of United States products into foreign countries, the U.S.
Food and Drug Administration (FDA) certifies the following information concerning the
product(s) to be exported listed below:
NAME OF MANUFACTURER OR DISTRIBUTER, ADDRESS
NAME OF PRODUCT(S) (GENERIC NAME IF APPLICABLE)
COUNTRY OF DESTINATION (OPTIONAL)
PREMARKET APPROVAL IDENTIFIER (IF APPLICABLE, I.E., NDA, NADA, PMA
NUMBER, 510(k) NUMBER, LICENSE NUMBER)
The product(s) described above and the plant(s) where it is produced are subject to the
jurisdiction of the FDA under the Federal Food, Drug, and Cosmetic Act.
It is certified that the above listed product(s) may be marketed in, and legally exported from,
the United States of America at this time. The manufacturing plant(s) in which the product(s)
is produced is subject to periodic inspections. The last such inspection showed that the
plant(s), at that time, appeared to be in substantial compliance with current good
manufacturing practice requirements for the product(s) listed above.
____________________________
Signature
____________________________
Title
Food and Drug Administration
_____________________________
Date
This certificate expires on (insert - date 36 months from date notarized).
______________________________________________________________________________
County of ________________
State of _________________
Subscribed and sworn to before me this _____ day of _________.
Notary Public ________________________
My Commission Expires __________________________________
Certificate No.
Certificate of Exportability (Section 802)
The Food and Drug Administration certifies that the product(s) described below is subject to
its jurisdiction under the Federal Food, Drug, and Cosmetic Act (the Act). Such product(s),
which is not approved for marketing in the United States, may be legally exported provided it
meets the requirements of Section 802 of the Act.
Under Section 802 of the Act, a drug or device not approved for marketing in the United
States may be exported if it is manufactured, processed, packaged, and held in substantial
conformity with current good manufacturing practice requirements. The manufacturing
plant(s) in which the product(s) is produced is subject to periodic inspections. The last such
inspection showed that the plant(s), at that time, appeared to be in substantial compliance with
current good manufacturing practice requirements for the product(s) listed below. The
company has certified to the Food and Drug Administration that:
* the product(s) accords to the specifications of the foreign purchaser;
* the product(s) is not in conflict with the laws of the country to which it is
intended for export;
* the shipping package for the product(s) is labeled on the outside that it is
intended for export; and
* the product(s) is not sold or offered for sale in the United States.
Based on the information above, the product(s) listed below may be exported pursuant to
Section 802 of the Act.
NAME OF PRODUCT [NAME OF COMPANY], [ADDRESS]
(GENERIC NAME IF APPLICABLE)
COUNTRY OF DESTINATION (OPTIONAL)
______________________________
Signature
_______________________________
Title
Food and Drug Administration
________________________________
Date
This certificate expires on (insert - date 36 months from date notarized).
____________________________________________________________________________
Couty of ___________________
State of ___________________
Subscribed and sworn to before me this ______ day of __________.
Notary Public ________________________
My Commission Expires _________________________
Certificate No.
Certificate of Exportability (Section 801(e))
The Food and Drug Administration certifies that the product(s) described below is subject to
its jurisdiction under the Federal Food, Drug, and Cosmetic Act (the Act). The product(s)
described below may not be sold or offered for sale in the United States. The company has
certified to the Food and Drug Administration that:
* the product(s) accords to the specifications of the foreign purchaser;
* the product(s) is not in conflict with the laws of the country to which it is
intended for export;
* the shipping package for the product(s) is labeled on the outside that it is
intended for export; and
* the product(s) is not sold or offered for sale in the United States.
Based on the information above, the product(s) listed below may be exported pursuant to
Section 801(e) of the Act.
NAME OF PRODUCT [NAME OF COMPANY], [ADDRESS]
(GENERIC NAME IF APPLICABLE)
COUNTRY OF DESTINATION (OPTIONAL)
___________________________
Signature
_____________________________
Title
Food and Drug Administration
_____________________________
Date
This certificate expires on (insert - date 36 months from date notarized).
______________________________________________________________________________
County of __________________________
State of ____________________________
Subscribed and sworn to before me this ______ day of _________.
Notary Public ______________________________
My Commission Expires ___________________________________
Sample- EU EXPORT HEALTH CERTIFICATE
CERTIFICATE NO. ___________________
HEALTH CERTIFICATE
Covering fishery products for import into the European Economic Community.
Country of dispatch: _____________________________________________
Competent authority (1): __________________________________________
Inspection body (1): ________________________________________________
Reference number of health certificate: ________________________________
1. Details identifying the fishery products
Description:
- Species (scientific name) _____________________________________________
- State (2) or type of processing _____________________________________________
Type of packaging: _____________________________________________
Number of packaging: _____________________________________________
Net Weight: _____________________________________________
Temperature required during storage and transport:
_______________________________________________________________________
2. Provenance of the fishery products
Address(es) and number(s) of preparation or processing establishment(s) authorized for
exports by the competent authority: ________________________________________
3. Destination of the fishery products
The fishery products are to be dispatched from: ________________________________
(Place of dispatch)
to: _____________________________________________
(Country and place of destination)
by the following means of transport: _______________________________________
Name and address of consignor: ___________________________________________________
Name of consignee and address at place of destination: ________________________________
Signature: _____________________ Date: ______________________________
4. Health attestation
The undersigned official inspector hereby certifies that:
1. The fishery products above have been handled, prepared or processed,
identified, stored and transported under conditions at least equivalent to those
laid down in Council Directives 91/493/EEC of 22 July 1991 laying down the
health conditions for the production and the placing on the market of fishery
products.
2. In addition, in the case of frozen or processed bivalve mollusks, the latter have
been gathered in production areas subject to conditions at least equivalent to
those laid down in Council Directive 91/492/EEC of 15 July 1991 laying down
the health conditions for the production and the placing on the market of live
bivalve mollusks.
Done at _________________________ on _________________________
(Place) (Date)
______________________________
Signature of Official Inspector
______________________________
(Name in capitals, capacity and
qualifications)
Sec. 110.200 Export of FDA Regulated Products
from U. S. Foreign Trade Zones (CPG 7150.11)
BACKGROUND:
From time to time industry inquires whether regulated products can be
manufactured in a Foreign Trade Zone (Free Trade Zone) and exported without
meeting the requirements of the laws and regulations administered by the
Food and Drug Administration.
Foreign Trade Zones are provided in the United States by the U. S. Customs
Service for the trade to hold or otherwise manipulate goods for an unlimited
period of time awaiting a favorable market in the U. S. or nearby countries
without being subject to customs entry, payment of duty, tax, or bond.
The location of an establishment in a Foreign Trade Zone has absolutely
no bearing on the jurisdiction of the Food and Drug Administration or the
applicability of the laws it administers.
POLICY:
For the purposes of the laws enforced by the FDA, Foreign Trade Zones
are part of the United States and the movement of regulated products into
or out of such zones, including export, constitutes interstate commerce.
Therefore, regulated products in Foreign Trade Zones must comply with those
laws that come within the purview of FDA.
*Reference: See United States v. Yaron Laboratories, Inc., 365
F. Supp. 917 (N.D Calif., 1972.)*
*Material between asterisks is new or revised*
Issued: 1/5/79
Revised: 10/1/80, 8/31/89
Sec. 110.500 Food and Drug Guaranty -
Imports (CPG 7153.10)
BACKGROUND:
A district compliance officer has inquired if a domestic distributor
can take advantage of the immunity offered by 21 USC 333(c)(2) by obtaining
from a foreign manufacturer, or his resident agent, a continuing guaranty.
POLICY:
21 USC 333(c)(2) provides immunity only if the person against whom action
is contemplated establishes "a guaranty or undertaking signed by and
containing the name and address of the persons residing in the U.S. from
whom he received in good faith the article...". It is thus apparent
from the law itself that the guarantor must be a U.S. resident to comply
with the act.
There seems to be no reason, however, that the domestic agent of the
foreign manufacturer, if he resides in the U.S., could not provide such
a guaranty to the distributor. The law does not require that the guaranty
be given by the manufacturer, wholesaler, packer or any other person in
the direct line of distribution. All that is required is that the signer
of the guaranty be a resident of the U.S. and be the person from whom the
distributor received the article.
21 USC 333(c)(3) also provides immunity in case of adulteration caused
by the presence of an guaranty so specifies.
Issued: 10/1/80
Sec. 110.600 FDA Authority Over Products
of Foreign Origin Located in Foreign Trade Zones, Bonded Warehouses or
on Bonded Carriers (CPG 7150.14)
BACKGROUND:
On occasion, questions have been raised concerning FDA's authority over
foreign origin products brought into the U.S. for which no entry has been
filed or importation has not been made. These products are usually located
in U.S. Foreign (Free) Trade Zones. However, they may also be found in
bonded warehouses or in bonded vehicles.
As stated in CPG 7150.11 (See Sec. 110.200) "Export of FDA Regulated
Products from U.S. Foreign Trade Zones", such zones are provided by
the U.S. Customs Service as a means of avoiding payment of duty, tax, and
bond if the goods are not intended for entry for consumption, to delay
such payment until actual entry for consumption is made.
Products of foreign origin located in Foreign Trade Zones or in bonded
warehouses are in the United States, are in interstate commerce and are
therefore subject to the laws administered by FDA.
Products entered for transportation and exportation (in bond for transportation
through the United States by a bonded carrier without appraisement or the
payment of duties) are also subject to the laws administered by FDA.
POLICY:
FDA has the authority to regulate products of foreign origin brought
into the U.S. whether or not entry has been filed. The location of goods
(truck, bonded warehouse, Foreign Trade Zones, etc.) does not affect FDA's
authority over the goods.
Products not imported or offered for import:
Those products of foreign origin not offered for import but located
within the legal boundaries of the U.S. are to be regulated under the domestic
provisions of statutes.
Products imported or offered for import:
Those products (whether in Foreign Trade Zones, bonded warehouses, etc.)
which have been offered for entry and those already imported but still
in import status are regulated under the provisions of section 801 of the
FD&C Act or 360(a) of the RCHS Act.
Issued: 4/1/82
Revised: 8/31/89
Sec. 110.700 Seizures by the U. S. Customs
Service of Prohibited Articles of Foreign Origin Not Intended for Entry
into the United States (CPG 7153.08)
BACKGROUND:
19 CFR 18.21(b) states: "Narcotics and other articles prohibited
admission into commerce of the United States shall not be entered for transportation
and exportation and any such merchandise offered for entry for that purpose
shall be seized, except that exportation or transportation and exportation
may be permitted upon written authority from the proper governmental agency
and on compliance with the regulations of such agency."
*For example,* a shipment of amygdalin was entered for transportation
and exportation and was seized by the U. S. Customs Service as a prohibited
article. The importer was notified that consideration for release for export
of the article must be obtained from the Food and Drug Administration.
The importer wrote us requesting such release for export. In response,
we informed the importer that we fully supported the U. S. Customs Service
in their action and that we would not authorize the exportation of the
article, since the importation, exportation, or other shipment in interstate
commerce of amygdalin is prohibited by the Federal Food, Drug, and Cosmetic
Act.
POLICY:
FDA supports the use of seizure by the U.S. Customs Service under authority
of 19 CFR 18.21(b) of articles regulated by FDA, which are offered under
a Transportation and Exportation Entry (T & E), if certain conditions
are met. Such conditions may be: the article poses a hazard to health,
consists of gross filth, or represents a gross consumer fraud *or we have
reason to believe the article may be offered for entry into the U.S. at
a later date or that its routing might be deviated during transit.*
If Customs has seized and the importer requests release of the article
for export; if Customs inquires whether they should seize; or if we believe
Customs should seize under the authority of 19 CFR 18.21(b) articles regulated
by FDA offered under a Transportation and Exportation Entry (T & E),
the facts should be sent to the appropriate *Center* for action and/or
consideration.
*Material between asterisks is new or revised*
Issued: 11/26/76
Revised: 10/1/80, 8/31/89
Sec. 110.800 Imports, Post Detention Sampling
(CPG 7150.04)
BACKGROUND:
*Importers sometimes request from FDA, rather than Customs, permission
to take samples from detained lots for the purpose of analysis, or other
examination, usually to explore the possibility of reconditioning or contest.
Frequently the imported lot may be physically in possession of the importer
and held under redelivery bond or in Customs custody pending final disposition.*
POLICY:
*The Food and Drug Administration has no objection to an importer taking
reasonable samples for appropriate analysis or other examination from detained
shipments. Whether the goods are in Customs custody or in physical possession
of the importer under redelivery bond, the importer must assume responsibility
for obtaining permission from Customs and complying with any instructions
from that agency. The importer must take such steps as may be necessary
to account to Customs for whatever amount is missing if he is called upon
to redeliver the detained lot to Customs custody for destruction or exportation.*
*Material between asterisks is new or revised*
Issued: 3/15/77
Revised: 10/1/80, 8/31/89
Sec. 110.900 Imported Products - Lack
of English Labeling (CPG 7150.15)
BACKGROUND:
Violative imported products should preferably be handled at the port
of entry. However, all imported products entered into the United States
are not sampled or examined. In fact, most imported articles subject to
the agency's jurisdiction are given a "May Proceed Notice" upon
entry and are not examined prior to entering domestic commerce. Although
the agency attempts to sample or examine as many potentially violative
products as possible, it is inevitable that some violative foreign products
enter into United States commerce.
On occasion, violative imported products that are labeled solely in
a foreign language [violation of 21 CFR 101.15(c)(1) for foods, 21 CFR
201.15(c)(1) for drugs, 21 CFR 501.15(c)(1) for animal drugs, 21 CFR 701.2(b)(1)
for cosmetics, and 21 CFR 801.15(c)(1) for medical devices] are able to
enter into United States commerce without being detained when they are
in import status. At some point later, these foreign labeled products may
be brought to the agency's attention by a complaint. When this occurs,
the most desirable solution is voluntary correction (e.g., relabeling or
destruction). Failing voluntary correction, the action of choice is seizure
of the misbranded lot.
NOTE: These sections contain an exemption which allows for labeling
in the predominant language other than English, in the Commonwealth of
Puerto Rico or in a U.S. territory.
REGULATORY ACTION GUIDANCE:
Violative imported products should be dealt with at the port of entry
whenever possible. In the few instances where products labeled solely in
a foreign language gain entry without examination, district offices are
authorized to refer for direct reference seizure to the *Office of Chief
Counsel (GCF-1)* through the Division of Compliance Management and Operations
(HFC-210), seizable size lots ($1,000 or more) of foods, drugs, animal
feeds or drugs, cosmetics and medical devices, which are labeled solely
in a foreign language when the owner or other party controlling the lot
refuses to voluntarily correct the violation. In instances where this occurs,
the district should take appropriate steps to assure that future import
shipments either comply with our laws or are detained at the port of entry.
This may entail intensive coverage of FDA regulated commodities imported
by that firm.
For lots valued under $1,000 attempt to obtain state or local condemnation.
*Material between asterisks is new or revised*
Issued: 3/1/84
Revised: 8/31/89, 3/95, 8/96
Sub Chapter 120 Fraud
Sec. 120.100 Fraud, Untrue Statements
of Material Facts, Bribery, and Illegal Gratuities (CPG 7150.09)
BACKGROUND:
The House Subcommittee on Oversight and Investigations began an investigation
of wrongful acts involving some manufacturers of generic drugs and some
employees of the Food and Drug Administration (FDA) during July 1988. As
a result of those investigations and investigations conducted by FDA, four
FDA employees were found to have accepted illegal gratuities from generic
drug companies, and to date, eleven generic drug companies were found to
have falsified data submitted in premarket applications to FDA.
In FDA's investigations, which began as inquiries into illegal gratuities
and questionable data submissions, the agency discovered broad patterns
and practices of fraud in the applicants' abbreviated new drug applications.
The discovery of this extensive pattern of fraudulent data submissions
prompted FDA to develop a program (1) to ensure validity of data submissions
called into question by the agency's discovery of wrongful acts such as
fraud, untrue statements of material fact, bribery, and illegal gratuities
and (2) to withdraw approval of, or refuse to approve, applications containing
fraudulent data. This guide sets forth the agency's general approach to
applications that have been called into question by such wrongful acts
and applications found to contain fraudulent data.
TERMINOLOGY:
The terms "applicant" and "application" are used
broadly in this policy statement. References to the "applicant"
include any person within the meaning of section 201(e) of the Federal
Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 321 (e)) who submits
to FDA data or other information to influence or support an agency decision
regarding approval to market an FDA-regulated product. Actions by an applicant's
employees or agents are considered actions by the applicant.
References to the "application" include any application, petition,
amendment, supplement, or other submission made by an applicant to an agency
review process in support of the approval or marketing of a regulated product.
These review processes include, but are not limited to, new drug and new
animal drug approvals, biological product and establishment licensing,
premarket notification, classification, and premarket approval of medical
devices, food additive petitions, and color additive petitions. References
to data in an application include all data and other information submitted
in or in relation to, or incorporated by reference in, the application.
POLICY:
Validity Assessment
Actions on the part of an applicant to subvert the integrity of an FDA
review process through acts such as submitting fraudulent applications,
making untrue statements of material facts, or giving or promising bribes
or illegal gratuities may call into question the integrity of some or all
of the applicant's submissions to the agency. In such cases, FDA will conduct
an investigation to identify all instances of wrongful acts and to determine
the extent to which the wrongful acts may have affected approved or pending
applications. The scope of FDA's investigation will be determined based
on the nature of the offense and will focus on the reliability of the applicant's
research and manufacturing data. If the wrongful acts have raised a significant
question regarding reliability of data in some or all of the applicant's
pending applications, FDA ordinarily will conduct validity assessments
of those applications.
FDA generally intends to defer substantive scientific review of the
data in a pending application undergoing a validity assessment until the
assessment is complete and questions regarding reliability of the data
are resolved. To approve an application, FDA generally must determine that
the applicant is capable of producing a safe and, for some types of applications,
an effective or functional product based on, among other things, testing
and other data provided by the applicant and the adequacy of the applicant's
manufacturing processes and controls. The principle basis for this determination
is the data in the application; therefore, the reliability of data is of
critical importance.
If the agency determines that the criteria for approval cannot be met
because of unresolved questions regarding reliability of data, the agency
will not approve the application.
When FDA finds, based on fraudulent data in an application, that the
data in the application are unreliable, the agency intends ordinarily to
exercise its authority, under applicable statutes and regulations, to refuse
to approve the application (in the case of a pending application) or to
proceed to withdraw approval (in the case of an approved application),
regardless of whether the applicant attempts to replace the unreliable
data with a new submission in the form of an amendment or supplement. Thus,
if the applicant wishes to replace the false data with a new submission,
the new submission should be in the form of a new application. The new
application should identify the parts of the original application that
were found to be false. The truthfulness and accuracy of the new application
should be certified by the president, chief executive officer, or other
official most responsible for the applicant's operations.
FDA also may seek recalls of marketed products and may request new testing
of critical products. For drugs, for example, retesting may be requested
for products that are difficult to manufacture or that have narrow therapeutic
ranges. FDA may pursue other actions, including seizure, injunction, civil
penalties, and criminal prosecution, under the act or other applicable
laws, as necessary and appropriate.
Corrective Actions
The corrective actions an applicant will be expected to take will depend
upon the facts and circumstances of each case, the nature of the wrongful
acts, the nature of the data under consideration, and the requirements
of the particular review process.
Applicants who engage in wrongful acts ordinarily will need to take
the following corrective actions to establish the reliability of data submitted
to FDA in support of pending applications and to support the integrity
of products on the market:
1. Cooperate fully with FDA and other Federal investigations to determine
the cause and scope of any wrongful acts and to assess the effects of the
acts on the safety, effectiveness, or quality of products;
2. Identify all individuals who were or may have been associated with
or involved in the wrongful acts and ensure that they are removed from
any substantive authority on matters under the jurisdiction of FDA;
3. Conduct a credible internal review designed to identify all instances
of wrongful acts associated with applications submitted to FDA, including
any discrepancies between manufacturing conditions identified in approved
applications and manufacturing conditions during actual production. The
internal review is intended to supplement FDA's ongoing, comprehensive
investigation to identify all instances of wrongful acts. The internal
review should involve an outside consultant or a team of consultants who
are qualified by training and experience to conduct such a review. All
oral or written reports related to the review that are provided by the
consultant to the applicant should be made available simultaneously to
FDA for independent verification;
4. Commit, in writing, to developing and implementing a corrective action
operating plan to assure the safety, effectiveness, and quality of their
products. This commitment ordinarily will be in the form of a consent decree
or agreement, signed by the president, chief executive officer, or other
official most responsible for the applicant's operations, and submitted
to FDA. The corrective action operating plan will, as appropriate, address
procedures and controls to preclude future instances of wrongful acts and
noncompliance with regulatory requirements for approved applications, as
well as procedures and controls to preclude any recurrences of other violations
which may have been found (e.g., a comprehensive ethics program).
FDA intends to reinspect the applicant to determine that the internal
review has been satisfactorily completed and that the applicant's written
corrective action operating plan has been satisfactorily implemented. Such
inspections should disclose positive evidence (e.g., effective management
controls, standard operating procedures, and corroborating documentation)
that the applicant's data are reliable and that the applicant can be expected
to manufacture products in compliance with current good manufacturing practices
and application requirements. In addition, FDA may request an applicant
to commit in writing to retest any product (including, in the case of drugs,
bioequivalence and bioavailability retesting), as FDA deems appropriate.
An applicant also may be requested under existing regulatory procedures
to recall products affected by the wrongful acts, or otherwise lacking
adequate assurance of safety, effectiveness, or quality.
Issued: 7/1/91
Sec. 120.500 Health Fraud - Factors in
Considering Regulatory Action (CPG 7150.10)
BACKGROUND:
Health Fraud products are articles of unproven effectiveness that are
promoted to improve health, well being, or appearance. They can be drugs,
devices, foods or cosmetics for human or animal use.
The previous CPG 7150.10 (See Sec. 120.500), Quackery - Priorities for
Initiating Legal Action, established agency priorities based on categorizing
the violative articles as a "direct health hazard", "indirect
health hazard", or "major economic cheat". While such descriptions
served the purpose of communicating the general impact of different types
of health fraud products on the public, they did not take into account
a number of factors which influence the initiation of a regulatory action.
This revision of the CPG establishes practical definitions for "direct
health hazard", and "indirect health hazard". Because all
health fraud products are in fact economic cheats, a separate definition
for major economic cheat has been eliminated. The revised CPG also describes
factors the agency will consider prior to initiating regulatory actions
against health fraud products.
DEFINITIONS:
*HEALTH FRAUD: The deceptive promotion, advertisement, distribution
or sale of articles, intended for human or animal use, that are represented
as being effective to diagnose, prevent, cure, treat, or mitigate disease
(or other conditions), or provide a beneficial effect on health, but which
have not been scientifically proven safe and effective for such purposes.
Such practices may be deliberate, or done without adequate knowledge or
understanding of the article.*
A health fraud product presents a direct health hazard if it is likely
to cause injury, death or other serious adverse effect when used as directed
or in a customary manner.
A health fraud product presents an indirect health hazard if, as a result
of reliance on the product, the consumer is likely to delay or discontinue
appropriate medical treatment. The health hazard is indirect when it does
no direct harm to the person as a result of its use, but rather denies,
delays, or interferes with effective treatment. Consumers who purchase
these products are misled by exaggerated or false claims that are made
for the products.
POLICY:
Products that pose a direct health hazard to the user shall receive
the agency's highest priority attention, regardless of whether they are
health fraud products. Documented cases of such products should be expedited
and referred to the appropriate center for regulatory follow-up. Health
fraud products for which there is not a documented direct health hazard
(i.e. indirect health hazard products) will still be considered for regulatory
action but on a lower priority.
In evaluating regulatory actions against indirect health hazard products,
the following factors should be considered by districts and the centers:
1. Whether the therapeutic claims or conditions to be treated are significant
as interpreted by the appropriate center;
2. Whether there are scientific data or specific information to support
the safety or effectiveness of the product for its intended or customary
use;
3. The degree of vulnerability of the prospective user group, e.g.,
the elderly, persons with illnesses for which there is no recognized effective
treatment;
4. The availability of other administrative or regulatory alternatives
to bring the product or firm into compliance, e.g., education, referral
or cooperation with local, state or other federal agencies;
5. The amount of agency resources required and whether they are sufficient
to pursue the action to its conclusion;
6. The source of the product, size of the industry distributing the
same or similar products, and the impact of the action on that source and
industry;
7. The cost of the product, the economic impact of this case on the
target user group, as well as the profit (per sale) realized from the sale
of the product;
8. The amount (dollar and volume) of product sold, and the geographical
scope of its distribution;
In most cases, the seriousness of the therapeutic claims and the nature
of the indirect hazard will be obvious. We recognize that when a product
with unproven therapeutic claims is first introduced, it is difficult to
predict its economic impact because, whether or not a regulatory action
is taken, the product may not be accepted in the marketplace. Generally,
new health fraud products with undetermined economic impact and limited
health significance should result in a *Warning* Letter to the promoter.
*Further* regulatory action should be considered for products ** when it
appears there is a growing national or substantial regional market for
them. The office of compliance in each center will designate a contact
and a back-up person for primary consultation on health fraud action.
Foods for human use, nutritional supplements and cosmetics with therapeutic
claims will generally be treated as drugs and should be referred to the
*CBER or CDER*, Health Fraud Staff, which will coordinate these issues
with the Center for Food Safety and Applied Nutrition.
Health fraud products that are the statutory responsibility of another
agency should generally be referred to that agency for follow-up. For example,
a strictly mail order operation, or one which principally uses media advertising
should be referred to the U.S. Postal Service or the Federal Trade Commission
and assistance provided, as needed. Local and state health departments
and other federal agencies should be consulted because they may be sources
of possible corrective action. If the health fraud practice or operation
has been legalized (or its practical equivalent) in a certain locality,
it is unlikely that a referral for a regulatory action against that practice
or operation would be approved in that locality unless there are compelling
reasons to do so. This does not preclude action in other jurisdictions.
Referral of information on fraudulent products to the appropriate home
district and headquarters units should be done as a matter of course.
In general, regulatory action will continue to be deferred on products
that are covered by the OTC Review, pending the publication of final monographs.
*Material between asterisks is new or revised*
Revised: 6/5/87, 3/95
Sub Chapter 130 Inspections
Sec. 130.100 Inspectional Authority; Refusal
to Permit Inspection. (CPG 7151.01)
BACKGROUND:
The authority for duly appointed officers or employees of the Food and
Drug Administration to enter and inspect establishments under the jurisdiction
of the Federal Food, Drug, and Cosmetic Act is in Section 704 of the Act
(21 U.S.C. 374).
Questions concerning the right to inspect such establishments have often
been raised and litigated. The courts have upheld the legality of an FDA
inspection if it is conducted at a reasonable time, within reasonable limits
and in a reasonable manner*. Consent is not the basis upon which a Food
and Drug inspection is conducted, and permission or authorization to inspect
is not required from the firm to be inspected.
The Federal Food, Drug, and Cosmetic Act provides criminal penalties
for refusal to permit a lawful inspection.
POLICY:
The legality of an FDA inspection, conducted at a reasonable time, and
within reasonable limits, and in a reasonable manner, depends not on consent
but on the validity of statutory authority. An inspection warrant is not
a prerequisite to lawful inspection pursuant to such authority. Refusal
to permit inspection, upon presentation of official notice by appropriately
identified Food and Drug Administration officers or employees pursuant
to 21 U.S.C. 374, exposes any person responsible for such refusal to criminal
penalties under 21 U.S.C. 331(f) and 333.
*United States v. Biswell, 92 S. Ct. 1593 (1972)
United States v. Del Campo Baking Mfg. Company, 345 F.
Supp. 1371 (D., Del., 1972)
United States v. Business Builders, Inc., 353 F. Supp.
1333 (N.D. Okla., 1973)
Issued: 10/1/80
Sec. 130.200 Inspection of Firms when
Legal Action is Pending (CPG 7153.01)
BACKGROUND:
Inquiries from the field have indicated there is some confusion on whether
or not to reinspect a firm while legal action is pending against that firm.
POLICY:
Reinspection of a firm should be based upon public health considerations.
FDA has an obligation to determine compliance with the law even if a case
is pending, and if on reinspection further violations are found, to take
additional steps as necessary to bring about correction.
It must be clearly understood that cessation of a violation is not grounds
for dismissal of a case. Prosecution actions particularly are based on
violations that have already occurred, and nothing that takes place after
the violation changes that fact.
Where a court requests, reinspection is also appropriate. A district
should always be in a position to furnish the court with current information
covering the defendant's operations. This does not mean, however, that
FDA should perform an inspection of each firm just prior to arraignment
or trial. As already indicated, unless a court requests an inspection,
reinspection at that time is based upon public health considerations in
light of priorities and available manpower.
Issued: 12/3/73
Revised: 10/1/80, 8/31/89
Sec. 130.300 *FDA Access to Results of
Quality Assurance Program Audits and Inspections* (CPG 7151.02)
BACKGROUND:
*Within all FDA regulated industries, some firms establish quality assurance
units (QAU) to perform functions independently from the manufacturing or
quality control organization. The QAU may periodically audit and critically
review processes and procedures (for example, data collection, manufacturing
practices, and quality control processes) to determine whether established
protocols and procedures have been followed.
In the preambles to the final regulations on Good Manufacturing Practice
for Medical Devices (43 FR 31508; July 21, 1978) (21 CFR 820) and on Good
Laboratory Practice for Nonclinical Laboratory Studies (43 FR 59986; December
22, 1978) (21 CFR 58), FDA announced its policy not to review or copy a
firm's records and reports that result from audits of a quality assurance
program when such audits are conducted according to a firm's written quality
assurance program at any regulated entity. The intent of the policy is
to encourage firms to conduct quality assurance program audits and inspections
that are candid and meaningful.*
POLICY:
*During routine inspections and investigations conducted at any regulated
entity that has a written quality assurance program, FDA will not review
or copy reports and records that result from audits and inspections of
the written quality assurance program, including audits conducted under
21 CFR 820.20(b) and written status reports required by 21 CFR 58.35(b)(4).*
FDA may seek written certification that such audits and inspections
have been implemented, performed, and documented and that any required
corrective action has been taken. District personnel should consult with
the appropriate headquarters office prior to seeking written certification.
*FDA will continue to review and copy records and reports of such audits
and inspections:
1. In "directed" or "for-cause" inspection and investigations
of a sponsor or monitor of a clinical investigation;
2. In litigation (for example, and not limited to: grand jury subpoenas,
discovery, or other agency or Department of Justice law enforcement activity
(including administrative regulatory actions));
3. During inspections made by inspection warrant where access to records
is authorized by statute; and
4. When executing any judicial search warrant.
FDA will continue to have access to, review, and copy records and reports
required by regulation, relating to quality control investigations of product
failures and manufacturing errors.*
*Material between asterisks is new or revised.*
Issued: 03/01/83
Revised: 03/16/89
Revised: 06/03/89
Revised: 01/03/96
Sec. 130.400 Use of Microfiche and/or
Microfilm for Method of Records Retention (CPG 7150.13)
BACKGROUND:
The agency has received many questions concerning the use of microfiche
and/or microfilm systems in lieu of the retention of original records.
This Compliance Policy Guide is based on a May 11, 1979 response to a request
for an Advisory Opinion on this subject. (Docket Number 77A-0270).
POLICY:
The Food and Drug Administration has ** published several regulations
that permit the maintenance of certain recordkeeping systems in lieu of
the retention of original records: good manufacturing practices for medical
devices (43 FR 31508, July 21, 1978); good manufacturing practices for
human and veterinary drugs (43 FR 45014, September 29, 1978); nonclinical
laboratory studies (43 FR 59986, December 22, 1978). These regulations
include the use of microfiche and/or microfilm. We therefore conclude that
the utilization of a microfiche and/or microfilm reduction system in lieu
of the retention of original pre-clinical, clinical, and related drug and
medical device research records, and drug and medical device quality control
and manufacturing records, is acceptable.
The preambles to these regulations, and the regulations, discuss the
conditions applicable to the maintenance of reduction systems. These include
the following:
1. All records must be readily available for review and copying by FDA
investigators at any reasonable time.
2. All necessary equipment must be provided to facilitate viewing and
copying of the records.
3. A reproduction must be a true and accurate copy of the original record.
Thus, where the reproduction process results in a copy that does not reveal
changes or additions to the original record, the original must be retained.
Also, the reproduced copy and any image shown on a viewing screen must
note, in a suitable manner, that an alteration has been made and that the
original record is available.
*Material between asterisks is new or revised*
Issued: 6/19/79
Revised: 10/1/80, 8/31/89
Model Certificate
for Export
The U.S. Food and Drug Administration certifies for [COUNTRY] the
following information concerning the product listed below manufactured
or distributed by [NAME OF COMPANY], [ADDRESS]:
NAME OF PRODUCT (GENERIC NAME IF APPLICABLE)
CENTRAL FILE NUMBER (CFN) (IF UNIQUE IDENTIFIER IS REQUIRED)
PREMARKET APPROVAL IDENTIFIER (IF APPLICABLE, I.E., NDA, NADA, PMA
NUMBER, 510(k) Number)
The product (and the plant which produces it) described above are subject
to the jurisdiction of the Food and Drug Administration.
It is certified that the above listed product may be freely marketed
in, or may otherwise be exported, from the United States of America at
this time.
The manufacturing plant in which the products are produced is subject
to periodic inspections, and the last such inspection showed that the plant,
at that time, appeared to be in compliance with current Good Manufacturing
Practice (GMP) required by the Federal Food, Drug, and Cosmetic Act.
Signature
Title
Food an Drug Administration
________________________________________________________________________
__ ___________________
Country of _________________
State of _________________
Subscribed and sworn to before me this _________________ day of _________________.
APPENDIX 2 - EC EXPORT
HEALTH CERTIFICATE
CERTIFICATE NO. _________________
HEALTH CERTIFICATE
Covering fishery products for import into the European Community.
Country of dispatch: __________________________________
Competent authority (1): __________________________________
Inspection body (1): ____________________________________________________
Reference number of health certificate: __________________________________
1. Details identifying the fishery products
Description
- Species (scientific name) __________________________________
- State (2) or type of processing __________________________________
Type of packaging: __________________________________
Number of packaging: __________________________________
Net Weight: __________________________________
Temperature required during storage and transport:_____________________________
2. Provenance of the fishery products
Address(es) and number(s) of preparation or processing establishment(s)
authorized for exports by the competent authority: _______________________________________________________________________
3. Destination of the fishery products
The fishery products are to be dispatched from :__________________________________________________
(Place of dispatch)
to:______________________________________________________________________
__ __________
(Country and place of destination)
by the following means of transport:__________________________________________________________
Name and address of consignor:_______________________________________________________________
Name of consignee and address at place of destination: __________________________________________
Signature:__________________________________ Date:__________________________________
4. Health Attestation
The undersigned official inspector hereby certifies that:
1. The fishery products above have been handled, prepared or processed,
identified, stored and transported under conditions at least equivalent
to those laid down in Council Directives 91/493/EC of 22 July 1991 laying
down the health conditions for the production and the placing on the market
of fishery products.
2. In addition, in the case of frozen or processed bivalve mollusks,
the latter have been gathered in production areas subject to conditions
at least equivalent to those laid down in Council Directive 91/492/EC of
15 July 1991 laying down the health conditions for the production and the
placing on the market of live bivalve mollusks.
Done at __________________________________ on __________________________________
(Place) (Date)
__________________________________
Signature of Official Inspector
__________________________________
Name in capitals, capacity and qualifications
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