EC-U.S.
MRA
SECTORAL
ANNEX
FOR
PHARMACEUTICAL
GOOD MANUFACTURING PRACTICES (GMPs)
PREAMBLE
Recognizing
that this Annex constitutes a Sectoral Annex to the framework Agreement on
Mutual Recognition between the United States and the European Community.
Definitions,
Purpose, Scope and Coverage
Article 1
Definitions
1."Equivalence"
of the
regulatory systems means that the systems are sufficiently comparable
to assure that the process of inspection and the ensuing inspection reports
will provide adequate information to determine whether respective statutory
and regulatory requirements of the authorities have been fulfilled. "Equivalence"
does not require that the respective regulatory systems have identical
procedures.
2."Enforcement"
means action
taken by an authority to protect the public from products
of suspect quality, safety and efficacy or to assure that products are
manufactured
in compliance with appropriate laws, regulations, standards and commitments
made as part of the approval to market a product.
3."Good
Manufacturing Practices" :
(tentative merging of US and EC concepts to
be revisited)
GMPs
mean the requirements found in the respective legislations, regulations, and
administrative provisions for methods to be used in, and the facilities or
controls to be used for, the manufacturing, processing, packing, and/or
holding of a drug to assure that such drug meets the requirements as to
safety, and has the identity and strength, and meets the quality and purity
characteristics that it purports or is represented to process.
GMPs
are that part of quality assurance which ensures that products are
consistently produced and controlled to quality standards. For the purpose
of this Annex, GMPs include therefore the system whereby the manufacturer
receives the specifications of the product and/or process from the Marketing
Authorization/Product Authorization or License holder or applicant and
ensures the product is made in compliance with its specifications (Qualified
Person certification in the EC).
4."Inspection"
means an
on-site evaluation of a manufacturing facility to determine
whether such manufacturing facility is operating in compliance with Good
Manufacturing Practices and/or commitments made as part of the approval to
market a product.
5."Inspection
Report" means
the written observations and Good Manufacturing Practices
compliance assessment completed by an authority listed in Appendix 2.
6."Regulatory
System" means
the body of legal requirements for Good Manufacturing
Practices, inspections, and enforcements that ensure public health
protection and legal authority to assure adherence to these requirements.
Article
2
Purpose
The
provisions of this Annex govern the exchange between the Parties and normal
endorsement
by the receiving authority of official Good Manufacturing Practices (GMP)
inspection reports after a transitional period aimed at determination of the
equivalence of the regulatory systems of the Parties, which is the
cornerstone of this Annex.
Article
3
Scope
The
provisions of this Annex shall apply to pharmaceutical inspections carried
out in the United States and Member States of the European Community before
products are marketed (hereafter referred to as "pre-approval
inspections") as well as during their marketing (hereafter referred to
as "post-approval inspections").
Appendix
1 names the laws, regulations and administrative provisions governing these
inspections and the GMP requirements.
Appendix
2 lists the authorities participating in activities under this Annex.
Articles
6, 7, 8, 9, 10 and 11 of the Agreement do not apply to this Annex.
Article
4
Product
coverage
These
provisions will apply to medicinal products for human or animal use,
intermediates and starting materials (as referred to in the EU) and to drugs
for human or animal use, biological products for human use , and active
pharmaceutical ingredients (as referred to in the United States), only to
the extent they are regulated by the authorities of both Parties as listed
in Appendix 2.
Human
blood, human plasma, human tissues and organs, and veterinary immunologicals
are excluded from the scope of this Annex. Human plasma derivatives (such as
immunoglobulins and albumin), investigational medicinal products/new drugs,
human radiopharmaceuticals and medicinal gases are also excluded during the
transition phase, their situation will be reconsidered at the end of the
transition period. Products regulated by the Center for Biologics Evaluation
and Research as devices are not covered under this Annex.
Appendix
3 contains an indicative list of products covered by this Annex.
Chapter
2
TRANSITION
PERIOD
Article
5
Length
of transition period
A
three-year transition period will start immediately after the effective date
of the Agreement.
Article
6
Equivalence
assessment
1.
The
criteria to be used by the Parties to assess equivalence are listed in
Appendix 4. Information pertaining to the criteria under Community
competence will be provided by the Community.
2.
The
authorities of the parties will establish and communicate to each other
their draft programs for assessing the equivalence of the respective
regulatory systems in terms of quality assurance of the products and
consumer protection. These programs will be carried out, as deemed necessary
by the authorities, for post- and pre-approval inspections and for various
product classes or processes.
3.
The
equivalence assessment shall include information exchanges (including
inspection
reports), joint training, and joint inspections for the purpose of assessing
regulatory systems and the authorities' capabilities. In conducting the equivalence assessment,
the Parties will ensure that efforts are made to save resources.
4.
Equivalence
assessment for authorities added to Appendix 2 after the effective date of
this agreement will be conducted as described in this Annex, as soon as
practicable.
Article
7
Participation
in the equivalence assessment and determination
The
authorities listed in Appendix 2 will actively participate in these programs
to build a sufficient body of evidence for their equivalence determination.
Both parties will exercise good faith efforts to complete equivalence
assessment as expeditiously as possible to the extent the resources of the
authorities allow.
Article
8
Other
transition activities
As
soon as possible, the authorities will jointly determine the essential
information which must be present in inspection reports and will cooperate
to develop mutually agreed inspection report format(s).
Chapter
3
END
OF TRANSITION PERIOD
Article
9
Equivalence
determination
Equivalence
is established by having in place regulatory systems covering the criteria
referred to in Appendix 4, and a demonstrated pattern of consistent
performance in accordance with these criteria. A list of authorities
determined as equivalent shall beagreed to by the Joint Sectoral Committee
at the end of the transition period, with reference to any limitation in
terms of inspection type (e.g. post-approval or pre-approval) or product
classes or processes.
The
Parties will document insufficient evidence of equivalence, lack of
opportunity to assess equivalence or a determination of non-equivalence, in
sufficient detail to allow the authority being assessed to know how to
attain equivalence.
Article
10
Authorities
not listed as currently equivalent
Authorities
not currently listed as equivalent, or not equivalent for certain types of
inspections,
product classes or processes may apply for reconsideration of their status
once the necessary corrective measures have been taken or additional
experience is gained.
Chapter
4
OPERATIONAL
PERIOD
Article
11
Start of the operational period
The
operational period shall start at the end of the transition period and its
provisions apply to inspection reports generated by authorities listed as
equivalent for the inspections performed in their territory.
In
addition, when an authority is not listed as equivalent based on adequate
experience gained during the transition period, the FDA will accept for
normal endorsement (as provided in Article 12) inspection reports generated
as a result of inspections conducted jointly by that authority on its
territory and another authority listed as equivalent, provided that the
authority of the Member State in which the inspection is performed can
guarantee enforcement of the findings of the inspection report and require
that corrective measures be taken when necessary. FDA has the option to
participate in these inspections, and based on experience gained during the
transition period, the Parties will agree on procedures for exercising this
option.
In
the EC, the qualified person will be relieved of responsibility for carrying
the controls laid down in Article 22 paragraph 1(b) of Council Directive
75/319/EEC provided that these controls have been carried out in the United
States and that each batch/lot is accompanied by a batch certificate (in
accordance with the WHO certification scheme on the quality of medicinal
products) issued by the manufacturer certifying that the product complies
with requirements of the marketing authorization and signed by the person
responsible for releasing the batch/lot.
Article
12
Nature
of recognition of inspection reports
Inspection
reports (containing information as established under Article 8), including a
GMP compliance assessment, prepared by authorities listed as equivalent,
will be provided to the authority of the importing Party. Based on the
determination of equivalence in light of the experience gained, these
inspection reports will normally be endorsed by the authority of the
importing Party, except under specific and delineated circumstances.
Examples of such circumstances include indications of material
inconsistencies or inadequacies in an inspection report, quality defects
identified in the post-market surveillance or other specific evidence of
serious concern in relation to product quality or consumer safety. In such
cases,
the authority of the importing Party may request clarification from the
authority of the exporting Party which may lead to a request for
re-inspection. The authorities will endeavor to respond to requests for
clarification in a timely manner.
Where
divergence is not clarified in this process, an authority of the importing
country maycarry out an inspection of the production facility.
Article
13
Transmission
of post-approval inspection reports
Post-approval
GMP inspection reports concerning products covered by this Annex will be
transmitted to the authority of the importing country within 60 calendar
days of the request. Should a new inspection be needed, the inspection
report will be transmitted 90 calendar days of the request.
Article
14
Transmission
of pre-approval inspection reports
A
preliminary notification that an inspection may have to take place will be
made as soon as possible.
Within
15 calendar days, the relevant authority will acknowledge receipt of the
request and confirm its ability to carry out the inspection. In the EC,
requests will be sent directly to the relevant authority, with a copy to the
European Agency for the Evaluation of Medicinal Products (EMEA). If the
authority receiving the request cannot carry out the inspection as
requested, the requesting authority shall have the right to conduct the
inspection.
Reports
of pre-approval inspections will be sent within 45 calendar days of the
request that transmitted the appropriate information and detailed the
precise issues to be addressed during the inspection. A shorter time may be
necessary in exceptional cases and these will be described in the request.
Article
15
Monitoring
continued equivalence
Monitoring
activities for the purpose of maintaining equivalence shall include review
of the exchange of inspection reports and their quality and timeliness;
performance of a limited number of joint inspections; and the conduct of
common training sessions.
Article
16
Suspension
Each
Party has the right to contest the equivalence of an authority. This right
will be exercised in an objective and reasoned manner in writing to the
other Party.
The
issue shall be discussed in the Joint Sectoral Committee promptly upon such
notification.
Where the JSC determines that verification of equivalence is required, it
may be carried out jointly by the Parties in a timely manner, pursuant to
Article 6.
Efforts
will be made by the Joint Sectoral Committee to reach unanimous consent on
the appropriate action. If agreement to suspend is reached in the Joint
Sectoral Committee, an authority may be suspended immediately thereafter. If
no agreement is reached in the Joint Sectoral Committee, the matter is
referred to the Joint Committee. If no unanimous consent is reached within
30 days after such notification, the contested authority will be suspended.
Upon
the suspension of an authority previously listed as equivalent, a Party is
no longer obligated to normally endorse the inspection reports of the
suspended authority. A Party shall continue to normally endorse the
inspection reports of that authority prior to suspension, unless the
authority of the receiving party decides otherwise based on health or safety
considerations. The suspension will remain in effect until unanimous consent
has been reached by the Parties on the future status of that authority.
Chapter
5
Joint
Sectoral Committee
Article
17
Role
and composition of the Joint Sectoral Committee
A
Joint
Sectoral Committee is set up to monitor the activities under both the
transitional and operational phases of this Annex.
The
Committee will be co-chaired by a representative of FDA for the US and a
representative of the EC who each will have one vote. Decisions will be
taken by unanimous consent.
The
Joint Sectoral Committee's functions will include:
1.
making
a joint assessment, which must be agreed by both Parties, of the equivalence
of the respective authorities,
2.
developing
and maintaining the list of equivalent authorities, including any limitatio
in
terms of inspecting type or products, and communicating the list to all
authorities and the
Joint Committee,
3.
providing
a forum to discuss issues relating to this Annex, including concerns that an
authority
may be no longer equivalent and opportunity to review product coverage,
4.
consideration
of the issue of suspension.
The
Joint Sectoral Committee shall meet at the request of either Party and,
unless the co-chairs
otherwise agree, at least once each year. The Joint Committee will be kept
informed
of the agenda and conclusions of meetings of the Joint Sectoral Committee.
Chapter
6
Information
exchange
Article
18
Regulatory
collaboration
The
Parties and authorities shall inform and consult one another, as permitted
by law, on proposals to introduce new controls or to change existing
technical regulations or inspection procedures and to provide the
opportunity to comment on such proposals.
The
Parties shall notify each other in writing of any changes to Appendix 2.
Article
19
Information
relating to quality aspects
The
authorities will establish an appropriate means of exchanging information on
any confirmed problem reports, corrective actions, recalls, rejected import
consignments and other regulatory and enforcement problems for products
subject to this Annex.
Article
20
Alert
System
The
details of an alert system will be developed during the transitional period.
The system will be maintained in place at all times. Elements to be
considered in developing such a system are described in Appendix 5.
Contact
points will be agreed between both Parties to permit authorities to be made
aware with the appropriate speed in case of quality defect, recalls,
counterfeiting and other problems concerning quality, which could
necessitate additional controls or suspension of the distribution of the
product.
Chapter
7
Safeguard
clause
Article
21
Each
Party recognizes that the importing country has a right to fulfill its legal
responsibilities by taking actions necessary to ensure the protection of
human and animal health at the level of protection it deems appropriate.
This includes the suspension of the distribution, product detention at the
border of the importing country, withdrawal of the batches and any request
for additional information or inspection as provided in Article 12.
APPENDIX
1
List
of applicable laws, regulations and administrative provisions
For
the European Community:
Council
Directive 65/65/EEC of 26 January 1965 on the approximation of provisions
laid down
by law, regulation or administrative action relating to proprietary
medicinal products as extended, widened and amended.
Council
Directive 75/319/EEC of 20 May 1975 on the approximation of provisions laid
down
by law, regulation or administrative action relating to proprietary
medicinal products as extended, widened and amended.
Council
Directive 81/851/EEC of 6 November 1981 on the approximation of the laws of
the Member States relating to veterinary medicinal products as widened and
amended.
Commission
Directive 91/356/EEC of 13 June 1991 laying down the principles and guidelines
of good manufacturing practice for medicinal products for human use
Commission
Directive 91/412/EEC of 23 July 1991 laying down the principles and guidelines
of good manufacturing practice for veterinary medicinal products
Council
Regulation No (EEC) 2309/93 of 23 July 1993 laying down Community procedures
for the authorization and supervision of medicinal products for human and
veterinary use and establishing a European Agency for the Evaluation of
Medicinal Products
Council
Directive 25/92/EEC of 31 March 1992 on the wholesale distribution of
medicinal products for human use & Guide to Good Distribution Practice
Current
version of the Guide to Good Manufacturing Practice, Rules Governing
Medicinal Products
in the European Community, Volume IV.
For
the United States :
Relevant
sections of the United States Federal Food, Drug, and Cosmetic Act and the
United
States Public Health Service Act
Relevant
sections of Title 21, United States Code of Federal Regulations (CFR) Parts
1-99,
Parts 200-299, Parts 500-599, and Parts 600-799
Relevant
sections of the FDA Investigations Operations Manual, the FDA Regulatory
Procedures
Manual, the FDA Compliance Policy Guidance Manual, the FDA Compliance
Program
Guidance Manual, and other FDA guidances.
APPENDIX
2
List
of Authorities
United
States
In
the United States, the regulatory authority is the Food and Drug
Administration.
European
Community
In
the European Community, the regulatory authorities are the following :
Austria:
Bundesministerium
Fur Arbeit, Gesundheit, und Soziales, Wien
Belgium:
Ministèrie
van Sociale Zakem, Volksgezondheid en Leefmilieu /Ministere des Affaires
Sociales, Sante Publique et Environment/ Algemeine Farmaceutische Inspectie,
Inspection Generale de la Pharmacie, Bruxelles,Brussel.
Denmark:
Laegemiddelstryelsen,
(Danish Medicines Agency), Brønshøj
Finland:
Laakelaittos/Lakemedelsverket
(National Agency for Medicines), Helsinki.
France:
Agence
du Médicament, Direction de l'inspection et des établissements, Saint Denis. (Human)
Agence
Nationale du Médicament Vétérinaire, Fougères
(Veterinary)
Germany:
Bundesgesundheitsministerium,
Bonn.
Paul-Ehrlich
Institut, Langen (biologicals only)
Zustandige
Behorden der 16 Bundeslander: Bayern, Berlin, Brandenberg,
Bremen, Hamburg, Hessen, Niedersachsen, Nordrhein- Westfalen, Rheinland-Pfalz,
Mecklenberg-Vorpommern, Saarland, Sachsen, Sachsenanhalt, Schleswog-Holstein,
Thuringen.
Greece:
Ministry of
Health and Welfare, National Drug Organisation (E.O.F.), Athens.
Ireland:
Irish
Medicines Board, Dublin.
Italy:
Ministero
della Sanità, Dipartimento Farmaci e Farmacovigilanza, Roma.
(Human)
Ministero
della Sanità, Dipartimento alimenti e nutrizione e sanità
pubblica veterinaria - Div. IX, Roma (Veterinary)
Luxembourg:
Direction
de la Santé, Division de la Pharmacie et des Médicaments,
Luxembourg
The
Netherlands: Staatstoezicht
op de Volksgezondheid, Inspectie voor de Gezondheidszorg,
Rijswijk
Portugal:
Instituto
da Farmácia e do Medicamento (INFARMED), Lisboa
Spain:
Ministerio
Sanidad y Consumo, Subdirección. General de Control Farmacéutico, Madrid.
(Human)
Ministerio
de Agricultura Pesca y Alimentación, Madrid, (Veterinary)
Sweden:
Läkemedelsverket
( Medical Products Agency), Uppsala.
United
Kingdom: Medicines
Control Agency, London.
Veterinary
Medicines Directorate, Addlestone.
European
Union: European
Commission, Brussels.
European
Agency for the Evaluation of Medicinal Products (EMEA), London.
APPENDIX
3
Indicative
list of Products covered by the Sectoral Annex
Recognizing
that precise definition of medicinal products and drugs are to be found in
the legislations
referred to above, an indicative list of products covered by the agreement
is given below:
-human
medicinal products including prescription and non-prescription drugs;
-human
biologicals including vaccines, and immunologicals;
-veterinary
pharmaceuticals, including prescription and non-prescription drugs, with
-the
exclusion of veterinary immunologicals;
-pre-mixes
for the preparation of veterinary medicated feeds (EC), Type A medicated
-articles
for the preparation of veterinary medicated feeds (US);
-intermediate
products and active pharmaceutical ingredients or bulk
pharmaceuticals(US)/starting materials (EC).
APPENDIX
4
Criteria
for Assessing Equivalence for Post- and Pre-Approval
I.Legal/Regulatory
authority and structures and procedures providing for post- and pre- approval:
A.Appropriate
statutory mandate and jurisdiction.
B.Ability
to issue and update binding requirements on GMPs and guidance documents.
C.Authority
to make inspections, review and copy documents, and to take samples and
collect other evidence.
D.Ability
to enforce requirements and to remove products found in violation of such
requirements from the market.
E.Substantive
current good manufacturing requirements.
F.Accountability
of the regulatory authority.
G.Inventory
of current products and manufacturers.
H.
System
for maintaining or accessing inspection reports, samples and other analytical
data, and other firm/product information relating to matters covered by this
Sectoral Annex.
II.Mechanisms
in place to assure appropriate professional standards and avoidance of
conflicts of interest.
III.Administration of the regulatory authority:
A.Standards
of education/qualification and training.
B.Effective
quality assurance systems measures to ensure adequate job performance.
C.Appropriate
staffing and resources to enforce laws and regulations.
IV.Conduct
of Inspections:
A. Adequate
pre-inspection preparation, including appropriate expertise of investigator/team,
review of firm/product and databases, and availability of appropriate
inspection equipment.
B.Adequate
conduct of inspection, including statutory access to facilities, effective
response
to refusals, depth and competence of evaluation of operations, systems, and
documentation; collection of evidence; appropriate duration of inspection
and completeness of written report of observations to firm management.
C.Adequate
post-inspection activities, including completeness of inspectors' report,
inspection
report review where appropriate, and conduct of follow-up inspections and
other activities where appropriate, assurance of preservation and retrieval
of records.
V.Execution
of regulatory enforcement actions to achieve corrections, designed to
prevent
future violations, and to remove products found in violation of requirements
from the market.
VI.Effective
Use of Surveillance Systems:
A.Sampling
and analysis
B.Recall
monitoring
C.Product
defect reporting system
D.Routine
surveillance inspections
E.Verification
of approved manufacturing process changes to marketing authorizations/approved applications
VII.Additional
specific criteria for pre-approval inspections
A.
Satisfactory
demonstration through a jointly developed and administered training program
and joint inspections to assess the authorities' capabilities.
B.Pre-inspection
preparation includes the review of appropriate records, including site
plans and drug master file or similar documentation to enable adequate
inspections.
C.Ability
to verify chemistry, manufacturing and control data supporting an application is authentic and complete.
D.Ability
to assess and evaluate research and development data as scientifically
sound,
especially transfer technology of pilot, scale up and full scale production
batches.
E.Ability
to verify conformity of the on site processes and procedures with those
described
in the application.
F.Review
and evaluate equipment installation, operational and performance qualification data, and evaluate test method validation.
APPENDIX
5
Elements
to be Considered in Developing a Two-way Alert System
1.Documentation
-
Definition
of a crisis/emergency and under what circumstances an alert is required
-
Standard
Operating Procedures (SOPs)
-Mechanism
of health hazards evaluation and classification
-Language
of communication and transmission of information
2.Crisis
Management System
-Crisis
analysis and communication mechanisms
-Establishment
of contact points
-Reporting
mechanisms
3.
Enforcement Procedures
-Follow-up
mechanisms
-Corrective
action procedures
4.Quality
Assurance System
-Pharmacovigilance
programme
-Surveillance/monitoring
of implementation of corrective action
5.
Contact points
For
the purpose of this agreement, the contact points for the alert system will
be:
for
the European Community,
the
Executive Director of the European Agency for the Evaluation of Medicinal
Products, 7, Westferry Circus, Canary Wharf, UK - London E14 4HB, England.
Telephone +44-171-418 8400, Fax 418 8416.
for
the United States :