2001L0083 — EN — 30.04.2004 — 003.001 — 1
This document is meant purely as a documentation tool and the institutions do not assume any liability for its contents
►B DIRECTIVE 2001/83/EC OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL
of 6 November 2001
on the Community code relating to medicinal products for human use
(OJ L 311, 28.11.2001, p. 67)
Amended by:
Official Journal
No page date
►M1 Directive 2002/98/EC of the European Parliament and of the Council of
27 January 2003L 33 30 8.2.2003
►M2 Commission directive 2003/63/EC of 25 June 2003 L 159 46 27.6.2003
►M3 Directive 2004/24/EC of the European Parliament and of the Council of
31 March 2004L 136 85 30.4.2004
►M4 Directive 2004/27/EC of the European Parliament and of the Council of
31 March 2004L 136 34 30.4.2004
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DIRECTIVE 2001/83/EC OF THE EUROPEAN PARLIAMENT
AND OF THE COUNCIL
of 6 November 2001
on the Community code relating to medicinal products for human
use
THE EUROPEAN PARLIAMENT AND THE COUNCIL OF THE
EUROPEAN UNION,
Having regard to the Treaty establishing the European Community, and
in particular Article 95 thereof,
Having regard to the proposal from the Commission;
Having regard to the opinion of the Economic and Social
Committee (1),
Acting in accordance with the procedure laid down in Article 251 of
the Treaty (2),
Whereas:
(1) Council Directive 65/65/EEC of 26 January 1965 on the approx-
imation of provisions laid down by law, regulation oradministrative action relating to medicinal products (
3), Council
Directive 75/318/EEC of 20 May 1975 on the approximation ofthe laws of Member States relating to analytical, pharmaco-toxi-
cological and clinical standards and protocols in respect of the
testing of proprietary medicinal products (
4), Council Directive
75/319/EEC of 20 May 1975 on the approximation of provisionslaid down by law, regulation or administrative action relating toproprietary medicinal products (
5), Council Directive 89/342/
EEC of 3 May 1989 extending the scope of Directives 65/65/
EEC and 75/319/EEC and laying down additional provisions for
immunological medicinal products consisting of vaccines, toxinsor serums and allergens (
6), Council Directive 89/343/EEC of 3
May 1989 extending the scope of Directives 65/65/EEC and 75/319/EEC and laying down additional provisions for radiophar-
maceuticals (
7), Council Directive 89/381/EEC of 14 June 1989
extending the scope of Directives 65/65/EEC and 75/319/EECon the approximation of provisions laid down by law, regulationor administrative action relating to medicinal products andlaying down special provisions for proprietary medicinalproducts derived from human blood or human plasma (
8),
Council Directive 92/25/EEC of 31 March 1992 on the whole-
sale distribution of medicinal products for human use (9),
Council Directive 92/26/EEC of 31 March 1992 concerning theclassification for the supply of medicinal products for humanuse (
10), Council Directive 92/27/EEC of 31 March 1992 on the
labelling of medicinal products for human use and on package
leaflets (11), Council Directive 92/28/EEC of 31 March 1992 on
the advertising of medicinal products for human use (12), Council
Directive 92/73/EEC of 22 September 1992 widening the scope2001L0083 — EN — 30.04.2004 — 003.001 — 2
(1) OJ C 368, 20.12.1999, p. 3.
(2) Opinion of the European Parliament of 3 July 2001 (not yet published in the
Official Journal) and Council Decision of 27 September 2001.
(3) OJ 22, 9.2.1965, p. 369/65. Directive as last amended by Directive 93/39/
EEC (OJ L 214, 24.8.1993, p. 22).
(4) OJ L 147, 9.6.1975, p. 1. Directive as last amended by Commission Direc-
tive 1999/83/EC (OJ L 243, 15.9.1999, p. 9).
(5) OJ L 147, 9.6.1975, p. 13. Directive as last amended by Commission Direc-
tive 2000/38/EC (OJ L 139, 10.6.2000, p. 28).
(6) OJ L 142, 25.5.1989, p. 14.
(7) OJ L 142, 25.5.1989, p. 16.
(8) OJ L 181, 28.6.1989, p. 44.
(9) OJ L 113, 30.4.1992, p. 1.
(10) OJ L 113, 30.4.1992, p. 5.
(11) OJ L 113, 30.4.1992, p. 8.
(12) OJ L 113, 30.4.1992, p. 13.
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of Directives 65/65/EEC and 75/319/EEC on the approximation
of provisions laid down by law, regulation or administrativeaction relating to medicinal products and laying down additional
provisions on homeopathic medicinal products (
1) have been
frequently and substantially amended. In the interests of clarityand rationality, the said Directives should therefore be codifiedby assembling them in a single text.
(2) The essential aim of any rules governing the production, distri-bution and use of medicinal products must be to safeguardpublic health.
(3) However, this objective must be attained by means which willnot hinder the development of the pharmaceutical industry ortrade in medicinal products within the Community.
(4) Trade in medicinal products within the Community is hinderedby disparities between certain national provisions, in particularbetween provisions relating to medicinal products (excluding
substances or combinations of substances which are foods,
animal feeding-stuffs or toilet preparations), and such disparitiesdirectly affect the functioning of the internal market.
(5) Such hindrances must accordingly be removed; whereas thisentails approximation of the relevant provisions.
(6) In order to reduce the disparities which remain, rules should be
laid down on the control of medicinal products and the duties
incumbent upon the Member States' competent authorities shouldbe specified with a view to ensuring compliance with legalrequirements.
(7) The concepts of harmfulness and therapeutic efficacy can onlybe examined in relation to each other and have only a relativesignificance depending on the progress of scientific knowledgeand the use for which the medicinal product is intended. The
particulars and documents which must accompany an application
for marketing authorization for a medicinal product demonstratethat potential risks are outweighed by the therapeutic efficacy ofthe product.
(8) Standards and protocols for the performance of tests and trialson medicinal products are an effective means of control of theseproducts and hence of protecting public health and can facilitatethe movement of these products by laying down uniform rules
applicable to tests and trials, the compilation of dossiers and
the examination of applications.
(9) Experience has shown that it is advisable to stipulate more
precisely the cases in which the results of toxicological and
pharmacological tests or clinical trials do not have to beprovided with a view to obtaining authorization for a medicinalproduct which is essentially similar to an authorized product,while ensuring that innovative firms are not placed at a disad-
vantage.
(10) However, there are reasons of public policy for not conducting
repetitive tests on humans or animals without over-riding cause.
(11) The adoption of the same standards and protocols by all theMember States will enable the competent authorities to arrive attheir decisions on the basis of uniform tests and by reference to
uniform criteria and will therefore help to avoid differences in
evaluation.
(12) With the exception of those medicinal products which aresubject to the centralized Community authorization procedureestablished by Council Regulation (EEC) No 2309/93 of 22July 1993 laying down Community procedures for the authoriza-tion and supervision of medicinal products for human andveterinary use and establishing a European Agency for the2001L0083 — EN — 30.04.2004 — 003.001 — 3
(1) OJ L 297, 13.10.1992, p. 8.
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Evaluation of Medicinal Products (1) a marketing authorization
for a medicinal product granted by a competent authority in oneMember State ought to be recognized by the competent authori-
ties of the other Member States unless there are serious grounds
for supposing that the authorization of the medicinal productconcerned may present a risk to public health. In the event of adisagreement between Member States about the quality, thesafety or the efficacy of a medicinal product, a scientific evalua-
tion of the matter should be undertaken according to a
Community standard, leading to a single decision on the area ofdisagreement binding on the Member States concerned. Whereasthis decision should be adopted by a rapid procedure ensuringclose cooperation between the Commission and the MemberStates.
(13) For this purpose, a Committee for Proprietary MedicinalProducts should be set up attached to the European Agency forthe Evaluation of Medicinal Products established in the above-mentioned Regulation (EEC) No 2309/93.
(14) This Directive represents an important step towards achievementof the objective of the free movement of medicinal products.Further measures may abolish any remaining barriers to the freemovement of proprietary medicinal products will be necessary in
the light of experience gained, particularly in the abovemen-
tioned Committee for Proprietary Medicinal Products.
(15) In order better to protect public health and avoid any unneces-sary duplication of effort during the examination of application
for a marketing authorization for medicinal products, Member
States should systematically prepare assessment reports inrespect of each medicinal product which is authorized by them,and exchange the reports upon request. Furthermore, a MemberState should be able to suspend the examination of an applica-tion for authorization to place a medicinal product on the
market which is currently under active consideration in another
Member State with a view to recognizing the decision reachedby the latter Member State.
(16) Following the establishment of the internal market, specific
controls to guarantee the quality of medicinal products imported
from third countries can be waived only if appropriate arrange-ments have been made by the Community to ensure that thenecessary controls are carried out in the exporting country.
(17) It is necessary to adopt specific provisions for immunologicalmedicinal products, homeopathic medicinal products, radiophar-maceuticals, and medicinal products based on human blood orhuman plasma.
(18) Any rules governing radiopharmaceuticals must take into
account the provisions of Council Directive 84/466/Euratom of
3 September 1984 laying down basic measures for the radiationprotection of persons undergoing medical examination or treat-ment (
2). Account should also be taken of Council Directive 80/
836/Euratom of 15 July 1980 amending the Directives laying
down the basic safety standards for the health protection of the
general public and workers against the dangers of ionizing radia-tion (
3), the objective of which is to prevent the exposure of
workers or patients to excessive or unnecessarily high levels ofionizing radiation, and in particular of Article 5c thereof, whichrequires prior authorization for the addition of radioactive2001L0083 — EN — 30.04.2004 — 003.001 — 4
(1) OJ L 214, 24.8.1993, p. 1. Regulation as amended by Commission Regula-
tion (EC) No 649/98 (OJ L 88, 24.3.1998, p. 7).
(2) OJ L 265, 5.10.1984, p. 1. Directive repealed with effect from 13 May 2000
by Directive 97/43/Euratom (OJ L 180, 9.7.1997, p. 22).
(3) OJ L 246, 17.9.1980, p. 1. Directive as amended by Directive 84/467/
Euratom (OJ L 265, 5.10.1984, p. 4), repealed with effect from 13 May
2000 by Directive 96/29/Euratom (OJ L 314, 4.12.1996, p. 20).
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substances to medicinal products as well as for the importation
of such medicinal products.
(19) The Community entirely supports the efforts of the Council ofEurope to promote voluntary unpaid blood and plasma donationto attain self-sufficiency throughout the Community in thesupply of blood products, and to ensure respect for ethical prin-
ciples in trade in therapeutic substances of human origin.
(20) The rules designed to guarantee the quality, safety and efficacy
of medicinal products derived from human blood or human
plasma must be applied in the same manner to both public and
private establishments, and to blood and plasma imported fromthird countries.
(21) Having regard to the particular characteristics of these homeo-pathic medicinal products, such as the very low level of activeprinciples they contain and the difficulty of applying to themthe conventional statistical methods relating to clinical trials, itis desirable to provide a special, simplified registration proce-dure for those homeopathic medicinal products which are
placed on the market without therapeutic indications in a phar-
maceutical form and dosage which do not present a risk for thepatient.
(22) The anthroposophic medicinal products described in an officialpharmacopoeia and prepared by a homeopathic method are tobe treated, as regards registration and marketing authorization,in the same way as homeopathic medicinal products.
(23) It is desirable in the first instance to provide users of thesehomeopathic medicinal products with a very clear indication oftheir homeopathic character and with sufficient guarantees oftheir quality and safety.
(24) The rules relating to the manufacture, control and inspection ofhomeopathic medicinal products must be harmonized to permitthe circulation throughout the Community of medicinal productswhich are safe and of good quality.
(25) The usual rules governing the authorization to market medicinalproducts should be applied to homeopathic medicinal productsplaced on the market with therapeutic indications or in a form
which may present risks which must be balanced against the
desired therapeutic effect. In particular, those Member Stateswhich have a homeopathic tradition should be able to applyparticular rules for the evaluation of the results of tests and trialsintended to establish the safety and efficacy of these medicinal
products provided that they notify them to the Commission.
(26) In order to facilitate the movement of medicinal products and to
prevent the controls carried out in one Member State from beingrepeated in another, minimum requirements should be laid down
for manufacture and imports coming from third countries and for
the grant of the authorization relating thereto.
(27) It should be ensured that, in the Member States, the supervision
and control of the manufacture of medicinal products is carried
out by a person who fulfils minimum conditions of qualification.
(28) Before an authorization to market an immunological medicinal
product or derived from human blood or human plasma can be
granted, the manufacturer must demonstrate his ability to attainbatch-to-batch consistency. Before an authorization to market amedicinal product derived from human blood or human plasmacan be granted, the manufacturer must also demonstrate the
absence of specific viral contamination, to the extent that the
state of technology permits.
(29) The conditions governing the supply of medicinal products to thepublic should be harmonized.
(30) In this connection persons moving around within the Communityhave the right to carry a reasonable quantity of medicinalproducts lawfully obtained for their personal use. It must also2001L0083 — EN — 30.04.2004 — 003.001 — 5
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be possible for a person established in one Member State to
receive from another Member State a reasonable quantity ofmedicinal products intended for his personal use.
(31) In addition, by virtue of Regulation (EC) No 2309/93, certainmedicinal products are the subject of a Community marketingauthorization. In this context, the classification for the supply ofmedicinal products covered by a Community marketing authori-zation needs to be established. It is therefore important to set thecriteria on the basis of which Community decisions will be
taken.
(32) It is therefore appropriate, as an initial step, to harmonize the
basic principles applicable to the classification for the supply ofmedicinal products in the Community or in the Member Stateconcerned, while taking as a starting point the principles alreadyestablished on this subject by the Council of Europe as well as
the work of harmonization completed within the framework of
the United Nations, concerning narcotic and psychotropicsubstances.
(33) The provisions dealing with the classification of medicinalproducts for the purpose of supply do not infringe the nationalsocial security arrangements for reimbursement or payment for
medicinal products on prescription.
(34) Many operations involving the wholesale distribution of medic-
inal products for human use may cover several Member Statessimultaneously.
(35) It is necessary to exercise control over the entire chain of distri-bution of medicinal products, from their manufacture or importinto the Community through to supply to the public, so as to
guarantee that such products are stored, transported and handled
in suitable conditions. The requirements which must be adoptedfor this purpose will considerably facilitate the withdrawal ofdefective products from the market and allow more effectiveefforts against counterfeit products.
(36) Any person involved in the wholesale distribution of medicinal
products should be in possession of a special authorization. Phar-
macists and persons authorized to supply medicinal products tothe public, and who confine themselves to this activity, shouldbe exempt from obtaining this authorization. It is however neces-sary, in order to control the complete chain of distribution of
medicinal products, that pharmacists and persons authorized to
supply medicinal products to the public keep records showingtransactions in products received.
(37) Authorization must be subject to certain essential conditions andit is the responsibility of the Member State concerned to ensurethat such conditions are met; whereas each Member State must
recognize authorizations granted by other Member States.
(38) Certain Member States impose on wholesalers who supply
medicinal products to pharmacists and on persons authorized tosupply medicinal products to the public certain public serviceobligations. Those Member States must be able to continue toimpose those obligations on wholesalers established within their
territory. They must also be able to impose them on wholesalers
in other Member States on condition that they do not impose anyobligation more stringent than those which they impose on theirown wholesalers and provided that such obligations may beregarded as warranted on grounds of public health protectionand are proportionate in relation to the objective of such protec-
tion.
(39) Rules should be laid down as to how the labelling and package
leaflets are to be presented.
(40) The provisions governing the information supplied to usersshould provide a high degree of consumer protection, in orderthat medicinal products may be used correctly on the basis offull and comprehensible information.2001L0083 — EN — 30.04.2004 — 003.001 — 6
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(41) The marketing of medicinal products whose labelling and
package leaflets comply with this Directive should not be
prohibited or impeded on grounds connected with the labellingor package leaflet.
(42) This Directive is without prejudice to the application of
measures adopted pursuant to Council Directive 84/450/EEC of
10 September 1984 relating to the approximation of the laws,regulations and administrative provisions of the Member Statesconcerning misleading advertising (
1).
(43) All Member States have adopted further specific measuresconcerning the advertising of medicinal products. There aredisparities between these measures. These disparities are likelyto have an impact on the functioning of the internal market,since advertising disseminated in one Member State is likely to
have effects in other Member States.
(44) Council Directive 89/552/EEC of 3 October 1989 on the coordi-
nation of certain provisions laid down by law, regulation oradministrative action in Member States concerning the pursuit
of television broadcasting activities (
2) prohibits the television
advertising of medicinal products which are available only onmedical prescription in the Member State within whose jurisdic-tion the television broadcaster is located. This principle shouldbe made of general application by extending it to other media.
(45) Advertising to the general public, even of non-prescriptionmedicinal products, could affect public health, were it to beexcessive and ill-considered. Advertising of medicinal productsto the general public, where it is permitted, ought therefore tosatisfy certain essential criteria which ought to be defined.
(46) Furthermore, distribution of samples free of charge to thegeneral public for promotional ends must be prohibited.
(47) The advertising of medicinal products to persons qualified toprescribe or supply them contributes to the information availableto such persons. Nevertheless, this advertising should be subjectto strict conditions and effective monitoring, referring in parti-cular to the work carried out within the framework of the
Council of Europe.
(48) Advertising of medicinal products should be subject to effective,
adequate monitoring. Reference in this regard should be made tothe monitoring mechanisms set up by Directive 84/450/EEC.
(49) Medical sales representatives have an important role in thepromotion of medicinal products. Therefore, certain obligationsshould be imposed upon them, in particular the obligation tosupply the person visited with a summary of product characteris-
tics.
(50) Persons qualified to prescribe medicinal products must be able to
carry out these functions objectively without being influenced by
direct or indirect financial inducements.
(51) It should be possible within certain restrictive conditions to
provide samples of medicinal products free of charge to personsqualified to prescribe or supply them so that they can familiarize
themselves with new products and acquire experience in dealing
with them.
(52) Persons qualified to prescribe or supply medicinal products musthave access to a neutral, objective source of information about
products available on the market. Whereas it is nevertheless for
the Member States to take all measures necessary to this end, inthe light of their own particular situation.2001L0083 — EN — 30.04.2004 — 003.001 — 7
(1) OJ L 250, 19.9.1984, p. 17. Directive as amended by Directive 97/55/EC
(OJ L 290, 23.10.1997, p. 18).
(2) OJ L 298, 17.10.1989, p. 23. Directive as amended by Directive 97/36/EC
(OJ L 202, 30.7.1997, p. 60).
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(53) Each undertaking which manufactures or imports medicinal
products should set up a mechanism to ensure that all informa-
tion supplied about a medicinal product conforms with theapproved conditions of use.
(54) In order to ensure the continued safety of medicinal products inuse, it is necessary to ensure that pharmacovigilance systems inthe Community are continually adapted to take account of scien-tific and technical progress.
(55) It is necessary to take account of changes arising as a result ofinternational harmonisation of definitions, terminology and tech-nological developments in the field of pharmacovigilance.
(56) The increasing use of electronic networks for communication ofinformation on adverse reactions to medicinal products marketedin the Community is intended to allow competent authorities to
share the information at the same time.
(57) It is the interest of the Community to ensure that the pharmacov-
igilance systems for centrally authorised medicinal products and
those authorised by other procedures are consistent.
(58) Holders of marketing authorisations should be proactivelyresponsible for on-going pharmacovigilance of the medicinal
products they place on the market.
(59) The measures necessary for the implementation of this Directive
should be adopted in accordance with Council Decision 1999/
468/EC of 28 June 1999 laying down the procedures for theexercise of implementing powers conferred on the Commis-sion (
1).
(60) The Commission should be empowered to adopt any necessarychanges to Annex I in order to take into account scientific andtechnical progress.
(61) This Directive should be without prejudice to the obligations ofthe Member States concerning the time-limits for transpositionof the Directives set out in Annex II, Part B.
HAVE ADOPTED THIS DIRECTIVE:
TITLE I
DEFINITIONS
Article 1
For the purposes of this Directive, the following terms shall bear the
following meanings:
2. Medicinal product:
(a) Any substance or combination of substances presented as
having properties for treating or preventing disease inhuman beings; or
(b) Any substance or combination of substances which may be
used in or administered to human beings either with a viewto restoring, correcting or modifying physiological functionsby exerting a pharmacological, immunological or metabolicaction, or to making a medical diagnosis.2001L0083 — EN — 30.04.2004 — 003.001 — 8
(1) OJ L 184, 17.7.1999, p. 23.▼M4
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3. Substance:
Any matter irrespective of origin which may be:
— human, e.g.
human blood and human blood products;
— animal, e.g.
micro-organisms, whole animals, parts of organs, animal
secretions, toxins, extracts, blood products;
— vegetable, e.g.
micro-organisms, plants, parts of plants, vegetable secre-
tions, extracts;
— chemical, e.g.
elements, naturally occurring chemical materials and
chemical products obtained by chemical change or synth-esis.
4. Immunological medicinal product:
Any medicinal product consisting of vaccines, toxins, serums or
allergen products:
(a) vaccines, toxins and serums shall cover in particular:
(i) agents used to produce active immunity, such as
cholera vaccine, BCG, polio vaccines, smallpoxvaccine;
(ii) agents used to diagnose the state of immunity,
including in particular tuberculin and tuberculin PPD,toxins for the Schick and Dick Tests, brucellin;
(iii) agents used to produce passive immunity, such as
diphtheria antitoxin, anti-smallpox globulin, antilym-phocytic globulin;
(b) ‘allergen product’ shall mean any medicinal product which
is intended to identify or induce a specific acquired altera-
tion in the immunological response to an allergizing agent.
5. Homeopathic medicinal product:
Any medicinal product prepared from substances called homeo-
pathic stocks in accordance with a homeopathic manufacturingprocedure described by the European Pharmacopoeia or, in theabsence thereof, by the pharmacopoeias currently used offi-
cially in the Member States. A homeopathic medicinal product
may contain a number of principles.
6. Radiopharmaceutical:
Any medicinal product which, when ready for use, contains one
or more radionuclides (radioactive isotopes) included for amedicinal purpose.
7. Radionuclide generator:
Any system incorporating a fixed parent radionuclide from
which is produced a daughter radionuclide which is to be
obtained by elution or by any other method and used in a radio-
pharmaceutical.
8.►
M4 Kit◄:
Any preparation to be reconsitituted or combined with radionu-
clides in the final radiopharmaceutical, usually prior to itsadministration.
9. Radionuclide precursor:
Any other radionuclide produced for the radio-labelling of
another substance prior to administration.2001L0083 — EN — 30.04.2004 — 003.001 — 9
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10. Medicinal products derived from human blood or human
plasma:
Medicinal products based on blood constitutents which are
prepared industrially by public or private establishments, suchmedicinal products including, in particular, albumin, coagu-lating factors and immunoglobulins of human origin.
11. Adverse reaction:
A response to a medicinal product which is noxious and unin-
tended and which occurs at doses normally used in man for theprophylaxis, diagnosis or therapy of disease or for the restora-tion, correction or modification of physiological function.
12. Serious adverse reaction:
An adverse reaction which results in death, is life-threatening,
requires inpatient hospitalisation or prolongation of existinghospitalisation, results in persistent or significant disability orincapacity, or is a congenital anomaly/birth defect.
13. Unexpected adverse reaction:
An adverse reaction, the nature, severity or outcome of which is
not consistent with the summary of product characteristics.
14. Periodic safety update reports:
The periodical reports containing the records referred to in
Article 104.
15. Post-authorisation safety study:
A pharmacoepidemiological study or a clinical trial carried out
in accordance with the terms of the marketing authorisation,
conducted with the aim of identifying or quantifying a safety
hazard relating to an authorised medicinal product.
16. Abuse of medicinal products:
Persistent or sporadic, intentional excessive use of medicinal
products which is accompanied by harmful physical or psycho-
logical effets.
17. Wholesale distribution of medicinal products:
All activities consisting of procuring, holding, supplying or
exporting medicinal products, apart from supplying medicinalproducts to the public. Such activities are carried out with
manufacturers or their depositories, importers, other wholesale
distributors or with pharmacists and persons authorized orentitled to supply medicinal products to the public in theMember State concerned.
18. Public service obligation:
The obligation placed on wholesalers to guarantee permanently
an adequate range of medicinal products to meet the require-ments of a specific geographical area and to deliver thesupplies requested within a very short time over the whole ofthe area in question.
18a Representative of the marketing authorisation holder:
The person, commonly known as local representative, desig-
nated by the marketing authorisation holder to represent himin the Member State concerned.2001L0083 — EN — 30.04.2004 — 003.001 — 10
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19. Medicinal Prescription:
Any medicinal prescription issued by a professional person
qualified to do so.
20. Name of the medicinal product:
The name, which may be either an invented name not liable to
confusion with the common name, or a common or scientific
name accompanied by a trade mark or the name of themarketing authorisation holder.
21. Common name:
The international non-proprietary name recommended by the
World Health Organization, or, if one does not exist, the usualcommon name.
22. Strength of the medicinal product:
The content of the active substances expressed quantitatively
per dosage unit, per unit of volume or weight according to thedosage form.
23. Immediate packaging:
The container or other form of packaging immediately in
contact with the medicinal product.
24. Outer packaging:
The packaging into which is placed the immediate packaging.
25. Labelling:
Information on the immediate or outer packaging.
26. Package leaflet:
A leaflet containing information for the user which accompa-
nies the medicinal product.
27. Agency:
The European Medicines Agency established by Regulation
(EC) No 726/2004 (
1).
28. Risks related to use of the medicinal product:
— any risk relating to the quality, safety or efficacy of the
medicinal product as regards patients' health or publichealth;
— any risk of undesirable effects on the environment.
28a. Risk-benefit balance:
An evaluation of the positive therapeutic effects of the medic-
inal product in relation to the risks as defined in point 28, firstindent.
29. Traditional herbal medicinal product:
A herbal medicinal product that fulfils the conditions laid down
in Article 16a(1).2001L0083 — EN — 30.04.2004 — 003.001 — 11
(1) OJ L 136, 30.4.2004, p. 1.▼M4
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30. Herbal medicinal product:
Any medicinal product, exclusively containing as active ingre-
dients one or more herbal substances or one or more herbalpreparations, or one or more such herbal substances in combi-
nation with one or more such herbal preparations.
31. Herbal substances:
All mainly whole, fragmented or cut plants, plant parts, algae,
fungi, lichen in an unprocessed, usually dried, form, but some-times fresh. Certain exudates that have not been subjected to a
specific treatment are also considered to be herbal substances.
Herbal substances are precisely defined by the plant part usedand the botanical name according to the binomial system(genus, species, variety and author).
32. Herbal preparations:
Preparations obtained by subjecting herbal substances to treat-
ments such as extraction, distillation, expression, fractionation,
purification, concentration or fermentation. These includecomminuted or powdered herbal substances, tinctures, extracts,essential oils, expressed juices and processed exudates.
TITLE II
SCOPE
Article 2
1. This Directive shall apply to medicinal products for human use
intended to be placed on the market in Member States and eitherprepared industrially or manufactured by a method involving an indus-trial process.
2. In cases of doubt, where, taking into account all its characteris-
tics, a product may fall within the definition of a ‘medicinal product’and within the definition of a product covered by other Community
legislation the provisions of this Directive shall apply.
3. Notwithstanding paragraph 1 and Article 3(4), Title IV of this
Directive shall apply to medicinal products intended only for export
and to intermediate products.
Article 3
This Directive shall not apply to:
1. Any medicinal product prepared in a pharmacy in accordance with a
medical prescription for an individual patient (commonly known asthe magistral formula).
2. Any medicinal product which is prepared in a pharmacy in accor-
dance with the prescriptions of a pharmacopoeia and is intended tobe supplied directly to the patients served by the pharmacy in ques-tion (commonly known as the officinal formula).
3. Medicinal products intended for research and development trials, but
without prejudice to the provisions of Directive 2001/20/EC of the
European Parliament and of the Council of 4 April 2001 on theapproximation of the laws, regulations and administrative provisionsof the Member States relating to the implementation of good clinicalpractice in the conduct of clinical trials on medicinal products forhuman use (
1).2001L0083 — EN — 30.04.2004 — 003.001 — 12
(1) OJ L 121, 1.5.2001, p. 34.▼B
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4. Intermediate products intended for further processing by an author-
ized manufacturer.
5. Any radionuclides in the form of sealed sources.
6. Whole blood, plasma or blood cells of human origin, except for
plasma which is prepared by a method involving an industrialprocess.
Article 4
1. Nothing in this Directive shall in any way derogate from the
Community rules for the radiation protection of persons undergoingmedical examination or treatment, or from the Community rules laying
down the basic safety standards for the health protection of the general
public and workers against the dangers of ionizing radiation.
2. This Directive shall be without prejudice to Council Decision 86/
346/EEC of 25 June 1986 accepting on behalf of the Community theEuropean Agreement on the Exchange of Therapeutic Substances ofHuman Origin (
1).
3. The provisions of this Directive shall not affect the powers of the
Member States' authorities either as regards the setting of prices formedicinal products or their inclusion in the scope of national health
insurance schemes, on the basis of health, economic and social condi-
tions.
4. This Directive shall not affect the application of national legisla-
tion prohibiting or restricting the sale, supply or use of medicinalproducts as contraceptives or abortifacients. The Member States shallcommunicate the national legislation concerned to the Commission.
Article 5
1. A Member State may, in accordance with legislation in force and
to fulfil special needs, exclude from the provisions of this Directivemedicinal products supplied in response to a bona fide unsolicitedorder, formulated in accordance with the specifications of an authorisedhealth-care professional and for use by an individual patient under hisdirect personal responsibility.
2. Member States may temporarily authorise the distribution of an
unauthorised medicinal product in response to the suspected or
confirmed spread of pathogenic agents, toxins, chemical agents or
nuclear radiation any of which could cause harm.
3. Without prejudice to paragraph 1, Member States shall lay down
provisions in order to ensure that marketing authorisation holders,manufacturers and health professionals are not subject to civil oradministrative liability for any consequences resulting from the use ofa medicinal product otherwise than for the authorised indications or
from the use of an unauthorised medicinal product, when such use is
recommended or required by a competent authority in response to thesuspected or confirmed spread of pathogenic agents, toxins, chemicalagents or nuclear radiation any of which could cause harm. Such provi-sions shall apply whether or not national or Community authorisationhas been granted.
4. Liability for defective products, as provided for by Council Direc-
tive 85/374/EEC of 25 July 1985 on the approximation of the laws,
regulations and administrative provisions of the Member States,
concerning liability for defective products (
2), shall not be affected by
paragraph 3.2001L0083 — EN — 30.04.2004 — 003.001 — 13
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TITLE III
PLACING ON THE MARKET
CHAPTER 1
Marketing authorization
Article 6
1. No medicinal product may be placed on the market of a Member
State unless a marketing authorization has been issued by the compe-
tent authorities of that Member State in accordance with this Directiveor an authorization has been granted in accordance with Regulation(EEC) No 2309/93.
When a medicinal product has been granted an initial marketing
authorisation in accordance with the first subparagraph, any additionalstrengths, pharmaceutical forms, administration routes, presentations, as
well as any variations and extensions shall also be granted an authori-
sation in accordance with the first subparagraph or be included in theinitial marketing authorisation. All these marketing authorisations shallbe considered as belonging to the same global marketing authorisation,in particular for the purpose of the application of Article 10(1).
1a The marketing authorisation holder shall be responsible for
marketing the medicinal product. The designation of a representative
shall not relieve the marketing authorisation holder of his legal respon-
sibility.
2. The authorisation referred to in paragraph 1 shall also be required
for radionuclide generators, ►
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radiopharmaceuticals and industrially prepared radiopharmaceuticals.
Article 7
A marketing authorization shall not be required for a radiopharmaceu-
tical prepared at the time of use by a person or by an establishment
authorized, according to national legislation, to use such medicinalproducts in an approved health care establishment exclusively fromauthorized radionuclide generators, ►
M4 kits◄ or radionuclide
precursors in accordance with the manufacturer's instructions.
Article 8
1. In order to obtain an authorization to place a medicinal product
on the market regardless of the procedure established by Regulation(EEC) No 2309/93, an application shall be made to the competentauthority of the Member State concerned.
2. A marketing authorization may only be granted to an applicant
established in the Community.
3. The application shall be accompanied by the following particulars
and documents, submitted in accordance with Annex I:
(a) Name or corporate name and permanent address of the applicant
and, where applicable, of the manufacturer.
(b) Name of the medicinal product.
(c) Qualitative and quantitative particulars of all the constituents of
the medicinal product, including the reference to its internationalnon-proprietary name (INN) recommended by the WHO, where
an INN for the medicinal product exists, or a reference to the
relevant chemical name.
(ca) Evaluation of the potential environmental risks posed by the
medicinal product. This impact shall be assessed and, on acase-by-case basis, specific arrangements to limit it shall beenvisaged.2001L0083 — EN — 30.04.2004 — 003.001 — 14
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(d) Description of the manufacturing method.
(e) Therapeutic indications, contra-indications and adverse reactions.
(f) Posology, pharmaceutical form, method and route of administra-
tion and expected shelf life.
(g) Reasons for any precautionary and safety measures to be taken
for the storage of the medicinal product, its administration topatients and for the disposal of waste products, together with anindication of potential risks presented by the medicinal product
for the environment.
(h) Description of the control methods employed by the manufac-
turer.
(i) Results of:
— pharmaceutical (physico-chemical, biological or microbiolo-
gical) tests,
— pre-clinical (toxicological and pharmacological) tests,— clinical trials.
(ia) A detailed description of the pharmacovigilance and, where
appropriate, of the risk-management system which the applicant
will introduce.
(ib) A statement to the effect that clinical trials carried out outside
the European Union meet the ethical requirements of Directive
2001/20/EC.
(j) A summary, in accordance with Article 11, of the product char-
acteristics, a mock-up of the outer packaging, containing thedetails provided for in Article 54, and of the immediate packa-
ging of the medicinal product, containing the details provided
for in Article 55, together with a package leaflet in accordancewith Article 59.
(k) A document showing that the manufacturer is authorised in his
own country to produce medicinal products.
(l) Copies of any authorisation obtained in another Member State or
in a third country to place the medicinal product on the market,
together with a list of those Member States in which an applica-
tion for authorisation submitted in accordance with this Directiveis under examination. Copies of the summary of the productcharacteristics proposed by the applicant in accordance withArticle 11 or approved by the competent authorities of theMember State in accordance with Article 21. Copies of the
package leaflet proposed in accordance with Article 59 or
approved by the competent authorities of the Member State inaccordance with Article 61. Details of any decision to refuseauthorization, whether in the Community or in a third country,and the reasons for such a decision.
This information shall be updated on a regular basis.
(m) A copy of any designation of the medicinal product as an orphan
medicinal product under Regulation (EC) No 141/2000 of the
European Parliament and of the Council of 16 December 1999on orphan medicinal products (
1), accompanied by a copy of the
relevant Agency opinion.
(n) Proof that the applicant has the services of a qualified person
responsible for pharmacovigilance and has the necessary meansfor the notification of any adverse reaction suspected of occur-ring either in the Community or in a third country.
The documents and information concerning the results of the pharma-
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(i) of the first subparagraph shall be accompanied by detailed summa-
ries in accordance with Article 12.
Article 9
In addition to the requirements set out in Articles 8 and 10(1), an appli-
cation for authorization to market a radionuclide generator shall alsocontain the following information and particulars:
— a general description of the system together with a detailed
description of the components of the system which may affectthe composition or quality of the daughter nucleid preparation,
— qualitative and quantitative particulars of the eluate or the subli-
mate.
Article 10
1. By way of derogation from Article 8(3)(i), and without prejudice
to the law relating to the protection of industrial and commercial prop-erty, the applicant shall not be required to provide the results of pre-clinical tests and of clinical trials if he can demonstrate that the medic-inal product is a generic of a reference medicinal product which is or
has been authorised under Article 6 for not less than eight years in a
Member State or in the Community.
A generic medicinal product authorised pursuant to this provision shall
not be placed on the market until ten years have elapsed from theinitial authorisation of the reference product.
The first subparagraph shall also apply if the reference medicinal
product was not authorised in the Member State in which the applica-tion for the generic medicinal product is submitted. In this case, theapplicant shall indicate in the application form the name of theMember State in which the reference medicinal product is or has beenauthorised. At the request of the competent authority of the Member
State in which the application is submitted, the competent authority of
the other Member State shall transmit within a period of one month, aconfirmation that the reference medicinal product is or has beenauthorised together with the full composition of the reference productand if necessary other relevant documentation.
The ten-year period referred to in the second subparagraph shall be
extended to a maximum of eleven years if, during the first eight yearsof those ten years, the marketing authorisation holder obtains anauthorisation for one or more new therapeutic indications which, duringthe scientific evaluation prior to their authorisation, are held to bring asignificant clinical benefit in comparison with existing therapies.
2. For the purposes of this Article:
(a) ‘reference medicinal product’ shall mean a medicinal product
authorised under Article 6, in accordance with the provisions ofArticle 8;
(b) ‘generic medicinal product’ shall mean a medicinal product which
has the same qualitative and quantitative composition in activesubstances and the same pharmaceutical form as the referencemedicinal product, and whose bioequivalence with the reference
medicinal product has been demonstrated by appropriate bioavail-
ability studies. The different salts, esters, ethers, isomers, mixturesof isomers, complexes or derivatives of an active substance shall beconsidered to be the same active substance, unless they differsignificantly in properties with regard to safety and/or efficacy. In
such cases, additional information providing proof of the safety
and/or efficacy of the various salts, esters or derivatives of anauthorised active substance must be supplied by the applicant. Thevarious immediate-release oral pharmaceutical forms shall beconsidered to be one and the same pharmaceutical form. Bioavail-ability studies need not be required of the applicant if he can2001L0083 — EN — 30.04.2004 — 003.001 — 16
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demonstrate that the generic medicinal product meets the relevant
criteria as defined in the appropriate detailed guidelines.
3. In cases where the medicinal product does not fall within the
definition of a generic medicinal product as provided in paragraph2(b) or where the bioequivalence cannot be demonstrated through bioa-
vailability studies or in case of changes in the active substance(s),
therapeutic indications, strength, pharmaceutical form or route ofadministration, vis-à-vis the reference medicinal product, the results ofthe appropriate pre-clinical tests or clinical trials shall be provided.
4. Where a biological medicinal product which is similar to a refer-
ence biological product does not meet the conditions in the definitionof generic medicinal products, owing to, in particular, differences
relating to raw materials or differences in manufacturing processes of
the biological medicinal product and the reference biological medicinalproduct, the results of appropriate pre-clinical tests or clinical trialsrelating to these conditions must be provided. The type and quantityof supplementary data to be provided must comply with the relevantcriteria stated in Annex I and the related detailed guidelines. The
results of other tests and trials from the reference medicinal product's
dossier shall not be provided.
5. In addition to the provisions laid down in paragraph 1, where an
application is made for a new indication for a well-establishedsubstance, a non-cumulative period of one year of data exclusivity shallbe granted, provided that significant pre-clinical or clinical studieswere carried out in relation to the new indication.
6. Conducting the necessary studies and trials with a view to the
application of paragraphs 1, 2, 3 and 4 and the consequential practicalrequirements shall not be regarded as contrary to patent rights or to
supplementary protection certificates for medicinal products.
Article 10a
By way of derogation from Article 8(3)(i), and without prejudice to the
law relating to the protection of industrial and commercial property, theapplicant shall not be required to provide the results of pre-clinical
tests or clinical trials if he can demonstrate that the active substances
of the medicinal product have been in well-established medicinal usewithin the Community for at least ten years, with recognised efficacyand an acceptable level of safety in terms of the conditions set out inAnnex I. In that event, the test and trial results shall be replaced byappropriate scientific literature.
Article 10b
In the case of medicinal products containing active substances used in
the composition of authorised medicinal products but not hitherto usedin combination for therapeutic purposes, the results of new pre-clinicaltests or new clinical trials relating to that combination shall be
provided in accordance with Article 8(3)(i), but it shall not be neces-
sary to provide scientific references relating to each individual activesubstance.
Article 10c
Following the granting of a marketing authorisation, the authorisation
holder may allow use to be made of the pharmaceutical, pre-clinical
and clinical documentation contained in the file on the medicinalproduct, with a view to examining subsequent applications relating toother medicinal products possessing the same qualitative and quantita-tive composition in terms of active substances and the samepharmaceutical form.2001L0083 — EN — 30.04.2004 — 003.001 — 17
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Article 11
The summary of the product characteristics shall contain, in the order
indicated below, the following information:
1. name of the medicinal product followed by the strength and the
pharmaceutical form.
2. qualitative and quantitative composition in terms of the active
substances and constituents of the excipient, knowledge of whichis essential for proper administration of the medicinal product.
The usual common name or chemical description shall be used.
3. pharmaceutical form.4. clinical particulars:
4.1. therapeutic indications,
4.2. posology and method of administration for adults and,
where necessary for children,
4.3. contra-indications,4.4. special warnings and precautions for use and, in the case
of immunological medicinal products, any special precau-
tions to be taken by persons handling such products andadministering them to patients, together with any precau-tions to be taken by the patient,
4.5. interaction with other medicinal products and other forms
of interactions,
4.6. use during pregnancy and lactation,4.7. effects on ability to drive and to use machines,
4.8. undesirable effects,
4.9. overdose (symptoms, emergency procedures, antidotes).
5. pharmacological properties:
5.1. pharmacodynamic properties,
5.2. pharmacokinetic properties,
5.3. preclinical safety data.
6. pharmaceutical particulars:
6.1. list of excipients,
6.2. major incompatibilities,
6.3. shelf life, when necessary after reconstitution of the medic-
inal product or when the immediate packaging is openedfor the first time,
6.4. special precautions for storage,
6.5. nature and contents of container,
6.6. special precautions for disposal of a used medicinal
product or waste materials derived from such medicinalproduct, if appropriate.
7. marketing authorisation holder.
8. marketing authorisation number(s).9. date of the first authorisation or renewal of the authorisation.
10. date of revision of the text.
11. for radiopharmaceuticals, full details of internal radiation dosi-
metry.
12. for radiopharmaceuticals, additional detailed instructions for
extemporaneous preparation and quality control of such prepara-tion and, where appropriate, maximum storage time during whichany intermediate preparation such as an eluate or the ready-to-usepharmaceutical will conform with its specifications.
For authorisations under Article 10, those parts of the summary of
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indications or dosage forms which were still covered by patent law at
the time when a generic medicine was marketed need not be included.
Article 12
1. The applicant shall ensure that, before the detailed summaries
referred to in the last subparagraph of Article 8(3) are submitted tothe competent authorities, they have been drawn up and signed byexperts with the necessary technical or professional qualifications,
which shall be set out in a brief curriculum vitae.
2. Persons having the technical and professional qualifications
referred to in paragraph 1 shall justify any use made of scientific litera-
ture under Article 10a in accordance with the conditions set out in
Annex I.
3. The detailed summaries shall form part of the file which the
applicant submits to the competent authorities.
CHAPTER 2
Specific provisions applicable to homeopathic medicinal products
Article 13
1. Member States shall ensure that homeopathic medicinal products
manufactured and placed on the market within the Community areregistered or authorised in accordance with Articles 14, 15 and 16,
except where such medicinal products are covered by a registration or
authorisation granted in accordance with national legislation on orbefore 31 December 1993. In case of registrations, Article 28 andArticle 29(1) to (3) shall apply.
2. Member States shall establish a special simplified registration
procedure for the homeopathic medicinal products referred to in Article14.
Article 14
1. Only homeopathic medicinal products which satisfy all of the
following conditions may be subject to a special, simplified registrationprocedure:
— they are administered orally or externally,
— no specific therapeutic indication appears on the labelling of the
medicinal product or in any information relating thereto,
— there is a sufficient degree of dilution to guarantee the safety of the
medicinal product; in particular, the medicinal product may notcontain either more than one part per 10 000 of the mother tinctureor more than 1/100th of the smallest dose used in allopathy withregard to active substances whose presence in an allopathic medic-
inal product results in the obligation to submit a doctor's
prescription.
If new scientific evidence so warrants, the Commission may amend the
third indent of the first subparagraph by the procedure referred to inArticle 121(2).
At the time of registration, Member States shall determine the classifi-
cation for the dispensing of the medicinal product.
2. The criteria and rules of procedure provided for in Article 4(4),
Article 17(1) and Articles 22 to 26, 112, 116 and 125 shall apply byanalogy to the special, simplified registration procedure for homeo-pathic medicinal products, with the exception of the proof oftherapeutic efficacy.2001L0083 — EN — 30.04.2004 — 003.001 — 19
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Article 15
An application for special, simplified registration may cover a series of
medicinal products derived from the same homeopathic stock or stocks.
The following documents shall be included with the application in
order to demonstrate, in particular, the pharmaceutical quality and thebatch-to-batch homogeneity of the products concerned:
— scientific name or other name given in a pharmacopoeia of the
homeopathic stock or stocks, together with a statement of thevarious routes of administration, pharmaceutical forms and degreeof dilution to be registered,
— dossier describing how the homeopathic stock or stocks is/are
obtained and controlled, and justifying its/their homeopathic use,on the basis of an adequate bibliography,
— manufacturing and control file for each pharmaceutical form and a
description of the method of dilution and potentization,
— manufacturing authorization for the medicinal product concerned,— copies of any registrations or authorizations obtained for the same
medicinal product in other Member States,
— one or more mock-ups of the outer packaging and the immediate
packaging of the medicinal products to be registered,
— data concerning the stability of the medicinal product.
Article 16
1. Homeopathic medicinal products other than those referred to in
Article 14(1) shall be authorized and labelled in accordance with
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2. A Member State may introduce or retain in its territory specific
rules for the ►M4 pre-clinical tests ◄ and clinical trials of homeo-
pathic medicinal products other than those referred to in Article 14(1)
in accordance with the principles and characteristics of homeopathy as
practised in that Member State.
In this case, the Member State concerned shall notify the Commission
of the specific rules in force.
3. Title IX shall apply to homeopathic medicinal products, with the
exception of those referred to in Article 14(1).
CHAPTER 2a
Specific provisions applicable to traditional herbal medicinal
products
Article 16a
1. A simplified registration procedure (hereinafter ‘traditional-use
registration’) is hereby established for herbal medicinal products which
fulfil all of the following criteria:
(a) they have indications exclusively appropriate to traditional herbal
medicinal products which, by virtue of their composition andpurpose, are intended and designed for use without the supervision
of a medical practitioner for diagnostic purposes or for prescrip-
tion or monitoring of treatment;
(b) they are exclusively for administration in accordance with a speci-
fied strength and posology;
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(d) the period of traditional use as laid down in Article 16c(1)(c) has
elapsed;
(e) the data on the traditional use of the medicinal product are suffi-
cient; in particular the product proves not to be harmful in thespecified conditions of use and the pharmacological effects or effi-cacy of the medicinal product are plausible on the basis of long-standing use and experience.
2. Notwithstanding Article 1(30), the presence in the herbal medic-
inal product of vitamins or minerals for the safety of which there is
well-documented evidence shall not prevent the product from beingeligible for registration in accordance with paragraph 1, provided thatthe action of the vitamins or minerals is ancillary to that of the herbalactive ingredients regarding the specified claimed indication(s).
3. However, in cases where the competent authorities judge that a
traditional herbal medicinal product fulfils the criteria for authorisation
in accordance with Article 6 or registration pursuant to Article 14, the
provisions of this chapter shall not apply.
Article 16b
1. The applicant and registration holder shall be established in the
Community.
2. In order to obtain traditional-use registration, the applicant shall
submit an application to the competent authority of the Member Stateconcerned.
Article 16c
1. The application shall be accompanied by:(a) the particulars and documents:
(i) referred to in Article 8(3)(a) to (h), (j) and (k);
(ii) the results of the pharmaceutical tests referred to in the
second indent of Article 8(3)(i);
(iii) the summary of product characteristics, without the data
specified in Article 11(4);
(iv) in case of combinations, as referred to in Article 1(30) or
Article 16a(2), the information referred to in Article16a(1)(e) relating to the combination as such; if the indivi-dual active ingredients are not sufficiently known, the datashall also relate to the individual active ingredients;
(b) any authorisation or registration obtained by the applicant in
another Member State, or in a third country, to place the medic-inal product on the market, and details of any decision to refuseto grant an authorisation or registration, whether in the Commu-nity or a third country, and the reasons for any such decision;
(c) bibliographical or expert evidence to the effect that the medicinal
product in question, or a corresponding product has been inmedicinal use throughout a period of at least 30 years precedingthe date of the application, including at least 15 years within theCommunity. At the request of the Member State where the appli-
cation for traditional-use registration has been submitted, the
Committee for Herbal Medicinal Products shall draw up anopinion on the adequacy of the evidence of the long-standing useof the product, or of the corresponding product. The Member Stateshall submit relevant documentation supporting the referral;
(d) a bibliographic review of safety data together with an expert
report, and where required by the competent authority, upon addi-tional request, data necessary for assessing the safety of themedicinal product.
Annex I shall apply by analogy to the particulars and documents speci-
fied in point (a).
2. A corresponding product, as referred to in paragraph 1(c), is char-
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excipients used, the same or similar intended purpose, equivalent
strength and posology and the same or similar route of administrationas the medicinal product applied for.
3. The requirement to show medicinal use throughout the period of
30 years, referred to in paragraph 1(c), is satisfied even where themarketing of the product has not been based on a specific authorisa-tion. It is likewise satisfied if the number or quantity of ingredients ofthe medicinal product has been reduced during that period.
4. Where the product has been used in the Community for less than
15 years, but is otherwise eligible for simplified registration, theMember State where the application for traditional-use registration hasbeen submitted shall refer the product to the Committee for HerbalMedicinal Products. The Member State shall submit relevant documen-tation supporting the referral.
The Committee shall consider whether the other criteria for a simpli-
fied registration as referred to in Article 16a are fully complied with.If the Committee considers it possible, it shall establish a Communityherbal monograph as referred to in Article 16h(3) which shall be takeninto account by the Member State when taking its final decision.
Article 16d
1. Without prejudice to Article 16h(1), Chapter 4 of Title III shall
apply by analogy to registrations granted in accordance with Article16a, provided that:
(a) a Community herbal monograph has been established in accor-
dance with Article 16h(3), or
(b) the herbal medicinal product consists of herbal substances,
preparations or combinations thereof contained in the list referredto in Article 16f.
2. For other herbal medicinal products as referred to in Article 16a,
each Member State shall, when evaluating an application for tradi-
tional-use registration, take due account of registrations granted byanother Member State in accordance with this chapter.
Article 16e
1. Traditional-use registration shall be refused if the application does
not comply with Articles 16a, 16b or 16c or if at least one of thefollowing conditions is fulfilled:
(a) the qualitative and/or quantitative composition is not as declared;
(b) the indications do not comply with the conditions laid down in
Article 16a;
(c) the product could be harmful under normal conditions of use;
(d) the data on traditional use are insufficient, especially if pharmaco-
logical effects or efficacy are not plausible on the basis of long-
standing use and experience;
(e) the pharmaceutical quality is not satisfactorily demonstrated.
2. The competent authorities of the Member States shall notify the
applicant, the Commission and any competent authority that requestsit, of any decision they take to refuse traditional-use registration andthe reasons for the refusal.
Article 16f
1. A list of herbal substances, preparations and combinations thereof
for use in traditional herbal medicinal products shall be established in
accordance with the procedure referred to in Article 121(2). The listshall contain, with regard to each herbal substance, the indication, thespecified strength and the posology, the route of administration and anyother information necessary for the safe use of the herbal substance asa traditional medicinal product.2001L0083 — EN — 30.04.2004 — 003.001 — 22
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2. If an application for traditional-use registration relates to a herbal
substance, preparation or a combination thereof contained in the listreferred to in paragraph 1, the data specified in Article 16c(1)(b)(c)
and (d) do not need to be provided. Article 16e(1)(c) and (d) shall not
apply.
3. If a herbal substance, preparation or a combination thereof ceases
to be included in the list referred to in paragraph 1, registrations
pursuant to paragraph 2 for herbal medicinal products containing this
substance shall be revoked unless the particulars and documentsreferred to in Article 16c(1) are submitted within three months.
Article 16g
1. Articles 3(1) and (2), 4(4), 6(1), 12, 17(1), 19, 20, 23, 24, 25, 40
to 52, 70 to 85, 101 to 108, 111(1) and (3), 112, 116 to 118, 122, 123,125, 126, second subparagraph, and 127 of this Directive as well asCommission Directive 91/356/EEC (
1) shall apply, by analogy, to tradi-
tional-use registration granted under this chapter.
2. In addition to the requirements of Articles 54 to 65, any labelling
and user package leaflet shall contain a statement to the effect that:
(a) the product is a traditional herbal medicinal product for use in
specified indication(s) exclusively based upon long-standing use;
and
(b) the user should consult a doctor or a qualified health care practi-
tioner if the symptoms persist during the use of the medicinal
product or if adverse effects not mentioned in the package leafletoccur.
A Member State may require that the labelling and the user package
leaflet shall also state the nature of the tradition in question.
3. In addition to the requirements of Articles 86 to 99, any adver-
tisement for a medicinal product registered under this chapter shallcontain the following statement: Traditional herbal medicinal productfor use in specified indication(s) exclusively based upon long-standing
use.
Article 16h
1. A Committee for Herbal Medicinal Products is hereby estab-
lished. That Committee shall be part of the Agency and shall have thefollowing competence:
(a) as regards simplified registrations, to:
— perform the tasks arising from Article 16c(1) and (4),
— perform the tasks arising from Article 16d,— prepare a draft list of herbal substances, preparations and
combinations thereof, as referred to in Article 16f(1), and
— establish Community monographs for traditional herbal medic-
inal products, as referred to in paragraph 3 of this Article;
(b) as regards authorisations of herbal medicinal products, to establish
Community herbal monographs for herbal medicinal products, as
referred to in paragraph 3 of this Article;
(c) as regards referrals to the Agency under Chapter 4 of Title III, in
relation to herbal medicinal products as referred to in Article 16a,
to perform the tasks set out in Article 32;
(d) where other medicinal products containing herbal substances are
referred to the Agency under Chapter 4 of Title III, to give anopinion on the herbal substance where appropriate.
Finally, the Committee for Herbal Medicinal Products shall perform
any other task conferred upon it by Community law.2001L0083 — EN — 30.04.2004 — 003.001 — 23
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The appropriate coordination with the Committee for Human Medicinal
Products shall be ensured by a procedure to be determined by theExecutive Director of the Agency in accordance with Article 57(2) of
Regulation (EEC) No 2309/93.
2. Each Member State shall appoint, for a three-year term which
may be renewed, one member and one alternate to the Committee forHerbal Medicinal Products.
The alternates shall represent and vote for the members in their
absence. Members and alternates shall be chosen for their role andexperience in the evaluation of herbal medicinal products and shallrepresent the competent national authorities.
The said Committee may coopt a maximum of five additional members
chosen on the basis of their specific scientific competence. Thesemembers shall be appointed for a term of three years, which may berenewed, and shall not have alternates.
With a view to the coopting of such members, the said Committee shall
identify the specific complementary scientific competence of the addi-tional member(s). Coopted members shall be chosen among expertsnominated by Member States or the Agency.
The members of the said Committee may be accompanied by experts
in specific scientific or technical fields.
3. The Committee for Herbal Medicinal Products shall establish
Community herbal monographs for herbal medicinal products withregard to the application of Article 10(1)(a)(ii) as well as traditionalherbal medicinal products. The said Committee shall fulfil further
responsibilities conferred upon it by provisions of this chapter and
other Community law.
When Community herbal monographs within the meaning of this para-
graph have been established, they shall be taken into account by the
Member States when examining an application. Where no such
Community herbal monograph has yet been established, other appro-priate monographs, publications or data may be referred to.
When new Community herbal monographs are established, the registra-
tion holder shall consider whether it is necessary to modify the
registration dossier accordingly. The registration holder shall notify
any such modification to the competent authority of the Member Stateconcerned.
The herbal monographs shall be published.
4. The general provisions of Regulation (EEC) No 2309/93 relating
to the Committee for Human Medicinal Products shall apply byanalogy to the Committee for Herbal Medicinal Products.
Article 16i
Before 30 April 2007, the Commission shall submit a report to the
European Parliament and to the Council concerning the application ofthe provisions of this chapter.
The report shall include an assessment on the possible extension of
traditional-use registration to other categories of medicinal products.
CHAPTER 3
Procedures relevant to the marketing authorization
Article 17
1. Member States shall take all appropriate measures to ensure that
the procedure for granting a marketing authorisation for medicinalproducts is completed within a maximum of 210 days after the submis-sion of a valid application.2001L0083 — EN — 30.04.2004 — 003.001 — 24
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Applications for marketing authorisations in two or more Member
States in respect of the same medicinal product shall be submitted inaccordance with Articles 27 to 39.
2. Where a Member State notes that another marketing authorisation
application for the same medicinal product is being examined inanother Member State, the Member State concerned shall decline toassess the application and shall advise the applicant that Articles 27 to39 apply.
Article 18
Where a Member State is informed in accordance with Article 8(3)(1)
that another Member State has authorised a medicinal product which is
the subject of a marketing authorisation application in the MemberState concerned, it shall reject the application unless it was submittedin compliance with Articles 27 to 39.
Article 19
In order to examine the application submitted in accordance with
►
M4 Articles 8, 10, 10a, 10b and 10c ◄, the competent authority
of the Member State:
1. must verify whether the particulars submitted in support of the
application comply with the said ►M4 Articles 8, 10, 10a, 10b
and 10c ◄ and examine whether the conditions for issuing an
authorization to place medicinal products on the market
(marketing authorization) are complied with.
2. may submit the medicinal product, its starting materials and, if
need be, its intermediate products or other constituent materials,
for testing by ►M4 an Official Medicines Control Laboratory
or a laboratory that a Member State has designated for thatpurpose◄in order to ensure that the control methods employed
by the manufacturer and described in the particulars accompa-nying the application in accordance with Article 8(3)(h) are
satisfactory.
3. may, where appropriate, require the applicant to supplement the
particulars accompanying the application in respect of the itemslisted in the ►
M4 Articles 8(3), 10, 10a, 10b and 10c ◄. Where
the competent authority avails itself of this option, the time limits
laid down in Article 17 shall be suspended until such time as thesupplementary information required has been provided. Likewise,these time limits shall be suspended for the time allowed theapplicant, where appropriate, for giving oral or written explana-tion.
Article 20
Member States shall take all appropriate measures to ensure that:
(a) the competent authorities verify that manufacturers and importers
of medicinal products coming from third countries are able tocarry out manufacture in compliance with the particulars suppliedpursuant to Article 8(3)(d), and/or to carry out controls accordingto the methods described in the particulars accompanying the
application in accordance with Article 8(3)(h);
(b) the competent authorities may allow manufacturers and importers
of medicinal products coming from third countries, ►
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justifiable cases ◄, to have certain stages of manufacture and/or
certain of the controls referred to in (a) carried out by third
parties; in such cases, the verifications by the competent authori-ties shall also be made in the establishment designated.
Article 21
1. When the marketing authorization is issued, the holder shall be
informed, by the competent authorities of the Member State concerned,of the summary of the product characteristics as approved by it.2001L0083 — EN — 30.04.2004 — 003.001 — 25
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2. The competent authorities shall take all necessary measures to
ensure that the information given in the summary is in conformitywith that accepted when the marketing authorization is issued or subse-
quently.
3. The competent authorities shall make publicly available without
delay the marketing authorisation together with the summary of theproduct characteristics for each medicinal product which they have
authorised.
4. The competent authorities shall draw up an assessment report and
comments on the file as regards the results of the pharmaceutical andpre-clinical tests and the clinical trials of the medicinal productconcerned. The assessment report shall be updated whenever newinformation becomes available which is of importance for the evalua-
tion of the quality, safety or efficacy of the medicinal product
concerned.
The competent authorities shall make publicly accessible without delay
the assessment report, together with the reasons for their opinion, afterdeletion of any information of a commercially confidential nature. Thejustification shall be provided separately for each indication applied
for.
Article 22
In exceptional circumstances and following consultation with the appli-
cant, the authorisation may be granted subject to a requirement for theapplicant to meet certain conditions, in particular concerning the safetyof the medicinal product, notification to the competent authorities ofany incident relating to its use, and action to be taken. This authorisa-
tion may be granted only for objective, verifiable reasons and must be
based on one of the grounds set out in Annex I. Continuation of theauthorisation shall be linked to the annual reassessment of these condi-tions. The list of these conditions shall be made publicly accessiblewithout delay, together with deadlines and dates of fulfilment.
Article 23
After an authorization has been issued, the authorization holder must,
in respect of the methods of manufacture and control provided for inArticle 8(3)(d) and (h), take account of scientific and technical progressand introduce any changes that may be required to enable the medic-inal product to be manufactured and checked by means of generally
accepted scientific methods.
These changes shall be subject to the approval of the competent
authority of the Member State concerned.
The authorisation holder shall forthwith supply to the competent
authority any new information which might entail the amendment of
the particulars or documents referred to in Articles 8(3), 10, 10a, 10b
and 11, or 32(5), or Annex I.
In particular, he shall forthwith inform the competent authority of any
prohibition or restriction imposed by the competent authorities of anycountry in which the medicinal product for human use is marketedand of any other new information which might influence the evaluation
of the benefits and risks of the medicinal product for human use
concerned.
In order that the risk-benefit balance may be continuously assessed, the
competent authority may at any time ask the holder of the marketingauthorisation to forward data demonstrating that the risk-benefitbalance remains favourable.2001L0083 — EN — 30.04.2004 — 003.001 — 26
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Article 23a
After a marketing authorisation has been granted, the holder of the
authorisation shall inform the competent authority of the authorisingMember State of the date of actual marketing of the medicinal productfor human use in that Member State, taking into account the various
presentations authorised.
The holder shall also notify the competent authority if the product
ceases to be placed on the market of the Member State, either tempora-
rily or permanently. Such notification shall, otherwise than in
exceptional circumstances, be made no less than 2 months before theinterruption in the placing on the market of the product.
Upon request by the competent authority, particularly in the context of
pharmacovigilance, the marketing authorisation holder shall provide thecompetent authority with all data relating to the volume of sales of themedicinal product, and any data in his possession relating to thevolume of prescriptions.
Article 24
1. Without prejudice to paragraphs 4 and 5, a marketing authorisa-
tion shall be valid for five years.
2. The marketing authorisation may be renewed after five years on
the basis of a re-evaluation of the risk-benefit balance by the competentauthority of the authorising Member State.
To this end, the marketing authorisation holder shall provide the
competent authority with a consolidated version of the file in respectof quality, safety and efficacy, including all variations introduced sincethe marketing authorisation was granted, at least six months before themarketing authorisation ceases to be valid in accordance with para-
graph 1.
3. Once renewed, the marketing authorisation shall be valid for an
unlimited period, unless the competent authority decides, on justified
grounds relating to pharmacovigilance, to proceed with one additionalfive-year renewal in accordance with paragraph 2.
4. Any authorisation which within three years of its granting is not
followed by the actual placing on the market of the authorised productin the authorising Member State shall cease to be valid.
5. When an authorised product previously placed on the market in
the authorising Member State is no longer actually present on themarket for a period of three consecutive years, the authorisation forthat product shall cease to be valid.
6. The competent authority may, in exceptional circumstances and
on public health grounds grant exemptions from paragraphs 4 and 5.Such exemptions must be duly justified.
Article 25
Authorization shall not affect the civil and criminal liability of the
manufacturer and, where applicable, of the marketing authorization
holder.
Article 26
1. The marketing authorisation shall be refused if, after verification
of the particulars and documents listed in Articles 8, 10, 10a, 10b and10c, it is clear that:
(a) the risk-benefit balance is not considered to be favourable; or
(b) its therapeutic efficacy is insufficiently substantiated by the appli-
cant; or
(c) its qualitative and quantitative composition is not as declared.2001L0083 — EN — 30.04.2004 — 003.001 — 27
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2. Authorisation shall likewise be refused if any particulars or docu-
ments submitted in support of the application do not comply withArticles 8, 10, 10a, 10b and 10c.
3. The applicant or the holder of a marketing authorisation shall be
responsible for the accuracy of the documents and the data submitted.
CHAPTER 4
Mutual recognition procedure and decentralised procedure
Article 27
1. A coordination group shall be set up for the examination of any
question relating to marketing authorisation of a medicinal product in
two or more Member States in accordance with the procedures laiddown in this Chapter. The Agency shall provide the secretariat of thiscoordination group.
2. The coordination group shall be composed of one representative
per Member State appointed for a renewable period of three years.Members of the coordination group may arrange to be accompaniedby experts.
3. The coordination group shall draw up its own Rules of Procedure,
which shall enter into force after a favourable opinion has been given
by the Commission. These Rules of Procedure shall be made public.
Article 28
1. With a view to the granting of a marketing authorisation for a
medicinal product in more than one Member State, an applicant shallsubmit an application based on an identical dossier in these MemberStates. The dossier shall contain the information and documents
referred to in Articles 8, 10, 10a, 10b, 10c and 11. The documents
submitted shall include a list of Member States concerned by the appli-cation.
The applicant shall request one Member State to act as ‘reference
Member State’ and to prepare an assessment report on the medicinalproduct in accordance with paragraphs 2 or 3.
2. Where the medicinal product has already received a marketing
authorisation at the time of application, the concerned Member Statesshall recognise the marketing authorisation granted by the referenceMember State. To this end, the marketing authorisation holder shall
request the reference Member State either to prepare an assessment
report on the medicinal product or, if necessary, to update any existingassessment report. The reference Member State shall prepare or updatethe assessment report within 90 days of receipt of a valid application.The assessment report together with the approved summary of productcharacteristics, labelling and package leaflet shall be sent to the
concerned Member States and to the applicant.
3. In cases where the medicinal product has not received a
marketing authorisation at the time of application, the applicant shall
request the reference Member State to prepare a draft assessmentreport, a draft summary of product characteristics and a draft of thelabelling and package leaflet. The reference Member State shallprepare these draft documents within 120 days after receipt of a validapplication and shall send them to the concerned Member States and to
the applicant.
4. Within 90 days of receipt of the documents referred to in para-
graphs 2 and 3, the Member States concerned shall approve the
assessment report, the summary of product characteristics and thelabelling and package leaflet and shall inform the reference MemberState accordingly. The reference Member State shall record the agree-ment of all parties, close the procedure and inform the applicant
accordingly.
5. Each Member State in which an application has been submitted in
accordance with paragraph 1 shall adopt a decision in conformity with2001L0083 — EN — 30.04.2004 — 003.001 — 28
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the approved assessment report, the summary of product characteristics
and the labelling and package leaflet as approved, within 30 days afteracknowledgement of the agreement.
Article 29
1. If, within the period laid down in Article 28(4), a Member State
cannot approve the assessment report, the summary of product charac-teristics, the labelling and the package leaflet on the grounds of
potential serious risk to public health, it shall give a detailed exposition
of the reasons for its position to the reference Member State, to theother Member States concerned and to the applicant. The points ofdisagreement shall be forthwith referred to the coordination group.
2. Guidelines to be adopted by the Commission shall define a poten-
tial serious risk to public health.
3. Within the coordination group, all Member States referred to in
paragraph 1 shall use their best endeavours to reach agreement on theaction to be taken. They shall allow the applicant the opportunity to
make his point of view known orally or in writing. If, within 60 days
of the communication of the points of disagreement, the Member Statesreach an agreement, the reference Member State shall record the agree-ment, close the procedure and inform the applicant accordingly. Article28(5) shall apply.
4. If the Member States fail to reach an agreement within the 60-day
period laid down in paragraph 3, the Agency shall be immediatelyinformed, with a view to the application of the procedure under Arti-cles 32, 33 and 34. The Agency shall be provided with a detailedstatement of the matters on which the Member States have been unable
to reach agreement and the reasons for their disagreement. A copy shall
be forwarded to the applicant.
5. As soon as the applicant is informed that the matter has been
referred to the Agency, he shall forthwith forward to the Agency acopy of the information and documents referred to in the first subpara-
graph of Article 28(1).
6. In the circumstances referred to in paragraph 4, Member States
that have approved the assessment report, the draft summary of productcharacteristics and the labelling and package leaflet of the referenceMember State may, at the request of the applicant, authorise the medic-
inal product without waiting for the outcome of the procedure laid
down in Article 32. In that event, the authorisation granted shall bewithout prejudice to the outcome of that procedure.
Article 30
1. If two or more applications submitted in accordance with Articles
8, 10, 10a, 10b, 10c and 11 have been made for marketing authorisa-tion for a particular medicinal product, and if Member States haveadopted divergent decisions concerning the authorisation of the medic-inal product or its suspension or revocation, a Member State, theCommission or the applicant or the marketing authorisation holder
may refer the matter to the Committee for Medicinal Products for
Human Use, hereinafter referred to as ‘the Committee’, for the applica-tion of the procedure laid down in Articles 32, 33 and 34.
2. In order to promote harmonisation of authorisations for medicinal
products authorised in the Community, Member States shall, each year,
forward to the coordination group a list of medicinal products forwhich a harmonised summary of product characteristics should bedrawn up.
The coordination group shall lay down a list taking into account the
proposals from all Member States and shall forward this list to the
Commission.
The Commission or a Member State, in agreement with the Agency
and taking into account the views of interested parties, may refer theseproducts to the Committee in accordance with paragraph 1.2001L0083 — EN — 30.04.2004 — 003.001 — 29
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Article 31
1. The Member States or the Commission or the applicant or the
marketing authorisation holder shall, in specific cases where the inter-
ests of the Community are involved, refer the matter to the Committeefor application of the procedure laid down in Articles 32, 33 and 34before any decision is reached on a request for a marketing authorisa-tion or on the suspension or revocation of an authorisation, or on any
other variation to the terms of a marketing authorisation which appears
necessary, in particular to take account of the information collected inaccordance with Title IX.
The Member State concerned or the Commission shall clearly identify
the question which is referred to the Committee for consideration and
shall inform the applicant or the marketing authorisation holder.
The Member States and the applicant or the marketing authorisation
holder shall supply the Committee with all available informationrelating to the matter in question.
2. Where the referral to the Committee concerns a range of medic-
inal products or a therapeutic class, the Agency may limit theprocedure to certain specific parts of the authorisation.
In that event, Article 35 shall apply to those medicinal products only if
they were covered by the authorisation procedures referred to in this
Chapter.
Article 32
1. When reference is made to the procedure laid down in this
Article, the Committee shall consider the matter concerned and shallissue a reasoned opinion within 60 days of the date on which the
matter was referred to it.
However, in cases submitted to the Committee in accordance with Arti-
cles 30 and 31, this period may be extended by the Committee for afurther period of up to 90 days, taking into account the views of theapplicants or the marketing authorisation holders concerned.
In an emergency, and on a proposal from its Chairman, the Committee
may agree to a shorter deadline.
2. In order to consider the matter, the Committee shall appoint one
of its members to act as rapporteur. The Committee may also appoint
individual experts to advise it on specific questions. When appointing
experts, the Committee shall define their tasks and specify the time-limit for the completion of these tasks.
3. Before issuing its opinion, the Committee shall provide the appli-
cant or the marketing authorisation holder with an opportunity to
present written or oral explanations within a time limit which it shall
specify.
The opinion of the Committee shall be accompanied by a draft
summary of product characteristics for the product and a draft text ofthe labelling and package leaflet.
If necessary, the Committee may call upon any other person to provide
information relating to the matter before it.
The Committee may suspend the time-limits referred to in paragraph 1
in order to allow the applicant or the marketing authorisation holder to
prepare explanations.
4. The Agency shall forthwith inform the applicant or the marketing
authorisation holder where the opinion of the Committee is that:
(a) the application does not satisfy the criteria for authorisation; or
(b) the summary of the product characteristics proposed by the appli-
cant or the marketing authorisation holder in accordance withArticle 11 should be amended; or2001L0083 — EN — 30.04.2004 — 003.001 — 30
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(c) the authorisation should be granted subject to certain conditions,
in view of conditions considered essential for the safe and effec-tive use of the medicinal product including pharmacovigilance; or
(d) a marketing authorisation should be suspended, varied or revoked.
Within 15 days after receipt of the opinion, the applicant or the
marketing authorisation holder may notify the Agency in writing of
his intention to request a re-examination of the opinion. In that case,he shall forward to the Agency the detailed grounds for the requestwithin 60 days after receipt of the opinion.
Within 60 days following receipt of the grounds for the request, the
Committee shall re-examine its opinion in accordance with the fourth
subparagraph of Article 62(1) of Regulation (EC) No 726/2004. Thereasons for the conclusion reached shall be annexed to the assessmentreport referred to in paragraph 5 of this Article.
5. Within 15 days after its adoption, the Agency shall forward the
final opinion of the Committee to the Member States, to the Commis-
sion and to the applicant or the marketing authorisation holder, togetherwith a report describing the assessment of the medicinal product andstating the reasons for its conclusions.
In the event of an opinion in favour of granting or maintaining an
authorisation to place the medicinal product concerned on the market,
the following documents shall be annexed to the opinion:
(a) a draft summary of the product characteristics, as referred to in
Article 11;
(b) any conditions affecting the authorisation within the meaning of
paragraph 4(c);
(c) details of any recommended conditions or restrictions with regard
to the safe and effective use of the medicinal product;
(d) the proposed text of the labelling and leaflet.
Article 33
Within►
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sion shall prepare a draft of the decision to be taken in respect of theapplication, taking into account Community law.
In the event of a draft decision which envisages the granting of
marketing authorization, the documents referred to in ►
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32(5), second subparagraph ◄shall be annexed.
Where, exceptionally, the draft decision is not in accordance with the
opinion of the Agency, the Commission shall also annex a detailedexplanation of the reasons for the differences.
The draft decision shall be forwarded to the Member States and the
applicant ►
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Article 34
1. The Commission shall take a final decision in accordance with,
and within 15 days after the end of, the procedure referred to in Article121(3).
2. The rules of procedure of the Standing Committee established by
Article 121(1) shall be adjusted to take account of the tasks incumbent
upon it under this Chapter.
Those adjustments shall entail the following provisions:
(a) except in cases referred to in the third paragraph of Article 33, the
opinion of the Standing Committee shall be given in writing;
(b) Member States shall have 22 days to forward their written observa-
tions on the draft decision to the Commission. However, if adecision has to be taken urgently, a shorter time-limit may be setby the Chairman according to the degree of urgency involved.2001L0083 — EN — 30.04.2004 — 003.001 — 31
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This time-limit shall not, otherwise than in exceptional circum-
stances, be shorter than 5 days;
(c) Member States shall have the option of submitting a written request
that the draft Decision be discussed in a plenary meeting of the
Standing Committee.
Where, in the opinion of the Commission, the written observations of a
Member State raise important new questions of a scientific or technical
nature which have not been addressed in the opinion delivered by the
Agency, the Chairman shall suspend the procedure and refer the appli-cation back to the Agency for further consideration.
The provisions necessary for the implementation of this paragraph shall
be adopted by the Commission in accordance with the procedure
referred to in Article 121(2).
3. The decision as referred to in paragraph 1 shall be addressed to
all Member States and reported for information to the marketing
authorisation holder or applicant. The concerned Member States andthe reference Member State shall either grant or revoke the marketingauthorisation, or vary its terms as necessary to comply with the deci-sion within 30 days following its notification, and they shall refer toit. They shall inform the Commission and the Agency accordingly.
Article 35
1. Any application by the marketing authorization holder to vary a
marketing authorization which has been granted in accordance withthe provisions of this Chapter shall be submitted to all the Member
States which have previously authorized the medicinal product
concerned.
The Commission shall, in consultation with the Agency, adopt appro-
priate arrangements for the examination of variations to the terms of a
marketing authorization.
These arrangements shall be adopted by the Commission in the form of
an implementing Regulation in accordance with the procedure referred
to in Article 121(2).
2. In case of arbitration submitted to the Commission, the procedure
laid down in Articles 32, 33 and 34 shall apply by analogy to variations
made to marketing authorizations.
Article 36
1. Where a Member State considers that the variation of a marketing
authorization which has been granted in accordance with the provisionsof this Chapter or its suspension or withdrawal is necessary for theprotection of public health, the Member State concerned shall forthwithrefer the matter to the Agency for the application of the procedures laid
down in Articles 32, 33 and 34.
2. Without prejudice to the provisions of Article 31, in exceptional
cases, where urgent action is essential to protect public health, until adefinitive decision is adopted a Member State may suspend the
marketing and the use of the medicinal product concerned on its terri-
tory. It shall inform the Commission and the other Member States nolater than the following working day of the reasons for its action.
Article 37
Articles 35 and 36 shall apply by analogy to medicinal products author-
ized by Member States following an opinion of the Committee given inaccordance with Article 4 of Directive 87/22/EEC before 1 January1995.2001L0083 — EN — 30.04.2004 — 003.001 — 32
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Article 38
1. The Agency shall publish an annual report on the operation of the
procedures laid down in this Chapter and shall forward that report tothe European Parliament and the Council for information.
2. At least every ten years the Commission shall publish a report on
the experience acquired on the basis of the procedures described in thisChapter and shall propose any amendments which may be necessary toimprove those procedures. The Commission shall submit this report tothe European Parliament and to the Council.
Article 39
Article 29(4), (5) and (6) and Articles 30 to 34 shall not apply to the
homeopathic medicinal products referred to in Article 14.
Articles 28 to 34 shall not apply to the homeopathic medicinal products
referred to in Article 16(2).
TITLE IV
MANUFACTURE AND IMPORTATION
Article 40
1. Member States shall take all appropriate measures to ensure that
the manufacture of the medicinal products within their territory issubject to the holding of an authorization. This manufacturing authori-zation shall be required nothwithstanding that the medicinal productsmanufactured are intended for export.
2. The authorization referred to in paragraph 1 shall be required for
both total and partial manufacture, and for the various processes of
dividing up, packaging or presentation.
However, such authorization shall not be required for preparation,
dividing up, changes in packaging or presentation where theseprocesses are carried out, solely for retail supply, by pharmacists indispensing pharmacies or by persons legally authorized in the MemberStates to carry out such processes.
3. Authorization referred to in paragraph 1 shall also be required for
imports coming from third countries into a Member State; this Title
and Article 118 shall have corresponding application to such imports
as they have to manufacture.
4. The Member States shall forward to the Agency a copy of the
authorisation referred to in paragraph 1. The Agency shall enter thatinformation on the Community database referred to in Article 111(6).
Article 41
In order to obtain the manufacturing authorization, the applicant shall
meet at least the following requirements:
(a) specify the medicinal products and pharmaceutical forms which are
to be manufactured or imported and also the place where they are
to be manufactured and/or controlled;
(b) have at his disposal, for the manufacture or import of the above,
suitable and sufficient premises, technical equipment and controlfacilities complying with the legal requirements which the Member
State concerned lays down as regards both manufacture and control
and the storage of medicinal products, in accordance with Article20;
(c) have at his disposal the services of at least one qualified person
within the meaning of Article 48.2001L0083 — EN — 30.04.2004 — 003.001 — 33
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The applicant shall provide particulars in support of the above in his
application.
Article 42
1. The competent authority of the Member State shall issue the
manufacturing authorization only after having made sure of the accu-racy of the particulars supplied pursuant to Article 41, by means of aninquiry carried out by its agents.
2. In order to ensure that the requirements referred to in Article 41
are complied with, authorization may be made conditional on thecarrying out of certain obligations imposed either when authorizationis granted or at a later date.
3. The authorization shall apply only to the premises specified in the
application and to the medicinal products and pharmaceutical formsspecified in that same application.
Article 43
The Member States shall take all appropriate measures to ensure that
the time taken for the procedure for granting the manufacturing author-
ization does not exceed 90 days from the day on which the competentauthority receives the application.
Article 44
If the holder of the manufacturing authorization requests a change in
any of the particulars referred to in points (a) and (b) of the first para-graph of Article 41, the time taken for the procedure relating to thisrequest shall not exceed 30 days. In exceptional cases this period oftime may be extended to 90 days.
Article 45
The competent authority of the Member State may require from the
applicant further information concerning the particulars suppliedpursuant to Article 41 and concerning the qualified person referred toin Article 48; where the competent authority concerned exercises this
right, application of the time-limits referred to in Article 43 and 44
shall be suspended until the additional data required have beensupplied.
Article 46
The holder of a manufacturing authorization shall at least be obliged:
(a) to have at his disposal the services of staff who comply with the
legal requirements existing in the Member State concerned both asregards manufacture and controls;
(b) to dispose of the authorized medicinal products only in accordance
with the legislation of the Member States concerned;
(c) to give prior notice to the competent authority of any changes he
may wish to make to any of the particulars supplied pursuant toArticle 41; the competent authority shall, in any event, be immedi-ately informed if the qualified person referred to in Article 48 isreplaced unexpectedly;
(d) to allow the agents of the competent authority of the Member State
concerned access to his premises at any time;
(e) to enable the qualified person referred to in Article 48 to carry out
his duties, for example by placing at his disposal all the necessaryfacilities;
(f) to comply with the principles and guidelines of good manufac-
turing practice for medicinal products and to use as startingmaterials only active substances, which have been manufacturedin accordance with the detailed guidelines on good manufacturingpractice for starting materials.2001L0083 — EN — 30.04.2004 — 003.001 — 34
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This point shall also be applicable to certain excipients, the list of
which as well as the specific conditions of application shall beestablished by a Directive adopted by the Commission in accor-
dance with the procedure referred to in Article 121(2).
Article 46a
1. For the purposes of this Directive, manufacture of active
substances used as starting materials shall include both total and partial
manufacture or import of an active substance used as a starting mate-rial as defined in Part I, point 3.2.1.1 (b) Annex I, and the variousprocesses of dividing up, packaging or presentation prior to its incor-poration into a medicinal product, including repackaging or re-labelling, such as are carried out by a distributor of starting materials.
2. Any amendments necessary to adapt paragraph 1 to new scientific
and technical developments shall be laid down in accordance with the
procedure referred to in Article 121(2).
Article 47
The principles and guidelines of good manufacturing practices for
medicinal products referred to in Article 46(f) shall be adopted in theform of a directive, in accordance with the procedure referred to inArticle 121(2).
Detailed guidelines in line with those principles will be published by
the Commission and revised necessary to take account of technicaland scientific progress.
The principles of good manufacturing practice for active substances
used as starting materials referred to in point (f) of Article 46 shall be
adopted in the form of detailed guidelines.
The Commission shall also publish guidelines on the form and content
of the authorisation referred to in Article 40(1), on the reports referredto in Article 111(3) and on the form and content of the certificate ofgood manufacturing practice referred to in Article 111(5).
Article 48
1. Member States shall take all appropriate measures to ensure that
the holder of the manufacturing authorization has permanently andcontinuously at his disposal the services of at least one qualifiedperson, in accordance with the conditions laid down in Article 49,
responsible in particular for carrying out the duties specified in Article
51.
2. If he personally fulfils the conditions laid down in Article 49, the
holder of the authorization may himself assume the responsibilityreferred to in paragraph 1.
Article 49
1. Member States shall ensure that the qualified person referred to in
Article 48 fulfils the ►
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set out in paragraphs 2 and 3.
2. A qualified person shall be in possession of a diploma, certificate
or other evidence of formal qualifications awarded on completion of auniversity course of study, or a course recognized as equivalent by the
Member State concerned, extending over a period of at least four years
of theoretical and practical study in one of the following scientificdisciplines: pharmacy, medicine, veterinary medicine, chemistry, phar-maceutical chemistry and technology, biology.
However, the minimum duration of the university course may be three
and a half years where the course is followed by a period of theoreticaland practical training of a minimum duration of one year and including2001L0083 — EN — 30.04.2004 — 003.001 — 35
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a training period of at least six months in a pharmacy open to the
public, corroborated by an examination at university level.
Where two university courses or two courses recognized by the State as
equivalent co-exist in a Member State and where one of these extends
over four years and the other over three years, the three-year course
leading to a diploma, certificate or other evidence of formal qualifica-tions awarded on completion of a university course or its recognizedequivalent shall be considered to fulfil the condition of durationreferred to in the second subparagraph in so far as the diplomas, certi-
ficates or other evidence of formal qualifications awarded on
completion of both courses are recognized as equivalent by the Statein question.
The course shall include theoretical and practical study bearing upon at
least the following basic subjects:
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— General and inorganic chemistry— Organic chemistry— Analytical chemistry— Pharmaceutical chemistry, including analysis of medicinal products
— General and applied biochemistry (medical)
— Physiology— Microbiology— Pharmacology
— Pharmaceutical technology
— Toxicology— Pharmacognosy (study of the composition and effects of the natural
active substances of plant and animal origin).
Studies in these subjects should be so balanced as to enable the person
concerned to fulfil the obligations specified in Article 51.
In so far as certain diplomas, certificates or other evidence of formal
qualifications mentioned in the first subparagraph do not fulfil the
criteria laid down in this paragraph, the competent authority of the
Member State shall ensure that the person concerned provides evidenceof adequate knowledge of the subjects involved.
3. The qualified person shall have acquired practical experience over
at least two years, in one or more undertakings which are authorized tomanufacture medicinal products, in the activities of qualitative analysisof medicinal products, of quantitative analysis of active substances and
of the testing and checking necessary to ensure the quality of medicinal
products.
The duration of practical experience may be reduced by one year
where a university course lasts for at least five years and by a yearand a half where the course lasts for at least six years.
Article 50
1. A person engaging in the activities of the person referred to in
Article 48 from the time of the application of Directive 75/319/EEC,in a Member State without complying with the provisions of Article49 shall be eligible to continue to engage in those activities
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2. The holder of a diploma, certificate or other evidence of formal
qualifications awarded on completion of a university course — or acourse recognized as equivalent by the Member State concerned — ina scientific discipline allowing him to engage in the activities of theperson referred to in Article 48 in accordance with the laws of that
State may — if he began his course prior to 21 May 1975 — be
considered as qualified to carry out in that State the duties of theperson referred to in Article 48 provided that he has previouslyengaged in the following activities for at least two years before 21May 1985 following notification of this directive in one or more under-takings authorized to manufacture: production supervision and/or2001L0083 — EN — 30.04.2004 — 003.001 — 36
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qualitative and quantitative analysis of active substances, and the
necessary testing and checking under the direct authority of the personreferred to in Article 48 to ensure the quality of the medicinal products.
If the person concerned has acquired the practical experience referred
to in the first subparagraph before 21 May 1965, a further one year's
practical experience in accordance with the conditions referred to in
the first subparagraph will be required to be completed immediatelybefore he engages in such activities.
Article 51
1. Member States shall take all appropriate measures to ensure that
the qualified person referred to in Article 48, without prejudice to his
relationship with the holder of the manufacturing authorization, isresponsible, in the context of the procedures referred to in Article 52,for securing:
(a) in the case of medicinal products manufactured within the Member
States concerned, that each batch of medicinal products has beenmanufactured and checked in compliance with the laws in force in
that Member State and in accordance with the requirements of the
marketing authorization;
(b) in the case of medicinal products coming from third countries, irre-
spective of whether the product has been manufactured in theCommunity, that each production batch has undergone in aMember State a full qualitative analysis, a quantitative analysis of
at least all the active substances and all the other tests or checks
necessary to ensure the quality of medicinal products in accordancewith the requirements of the marketing authorisation.
The batches of medicinal products which have undergone such controls
in a Member State shall be exempt from the controls if they are
marketed in another Member State, accompanied by the control reportssigned by the qualified person.
2. In the case of medicinal products imported from a third country,
where appropriate arrangements have been made by the Communitywith the exporting country to ensure that the manufacturer of themedicinal product applies standards of good manufacturing practice atleast equivalent to those laid down by the Community, and to ensure
that the controls referred to under point (b) of the first subparagraph
of paragraph 1 have been carried out in the exporting country, thequalified person may be relieved of responsibility for carrying outthose controls.
3. In all cases and particularly where the medicinal products are
released for sale, the qualified person must certify in a register orequivalent document provided for that purpose, that each production
batch satisfies the provisions of this Article; the said register or equiva-
lent document must be kept up to date as operations are carried out andmust remain at the disposal of the agents of the competent authority forthe period specified in the provisions of the Member State concernedand in any event for at least five years.
Article 52
Member States shall ensure that the duties of qualified persons referred
to in Article 48 are fulfilled, either by means of appropriate administra-tive measures or by making such persons subject to a professional codeof conduct.
Member States may provide for the temporary suspension of such a
person upon the commencement of administrative or disciplinaryprocedures against him for failure to fulfil his obligations.2001L0083 — EN — 30.04.2004 — 003.001 — 37
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Article 53
The provisions of this Title shall also apply to homeopathic medicinal
products.
TITLE V
LABELLING AND PACKAGE LEAFLET
Article 54
The following particulars shall appear on the outer packaging of medic-
inal products or, where there is no outer packaging, on the immediatepackaging:
(a) the name of the medicinal product followed by its strength and
pharmaceutical form, and, if appropriate, whether it is intended
for babies, children or adults; where the product contains up to
three active substances, the international non-proprietary name(INN) shall be included, or, if one does not exist, the commonname;
(b) a statement of the active substances expressed qualitatively and
quantitatively per dosage unit or according to the form of adminis-tration for a given volume or weight, using their common names;
(c) the pharmaceutical form and the contents by weight, by volume or
by number of doses of the product;
(d) a list of those excipients known to have a recognized action or
effect and included in the ►
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pursuant to Article 65. However, if the product is injectable, or a
topical or eye preparation, all excipients must be stated;
(e) the method of administration and, if necessary, the route of admin-
istration. Space shall be provided for the prescribed dose to be
indicated;
(f) a special warning that the medicinal product must be stored out of
the reach and sight of children;
(g) a special warning, if this is necessary for the medicinal product;
(h) the expiry date in clear terms (month/year);
(i) special storage precautions, if any;
(j) specific precautions relating to the disposal of unused medicinal
products or waste derived from medicinal products, where appro-priate, as well as reference to any appropriate collection system in
place;
(k) the name and address of the marketing authorisation holder and,
where applicable, the name of the representative appointed by theholder to represent him;
(l) the number of the authorization for placing the medicinal product
on the market;
(m) the manufacturer's batch number;
(n) in the case of non-prescription medicinal products, instructions for
use.
Article 55
1. The particulars laid down ►
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immediate packagings other than those referred to in paragraphs 2 and3.2001L0083 — EN — 30.04.2004 — 003.001 — 38
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2. The following particulars at least shall appear on immediate
packagings which take the form of blister packs and are placed in anouter packaging that complies with the requirements laid down in Arti-
cles 54 and 62.
— the name of the medicinal product as laid down in point (a) of
Article 54,
— the name of the holder of the authorization for placing the product
on the market,
— the expiry date,
— the batch number.
3. The following particulars at least shall appear on small immediate
packaging units on which the particulars laid down in Articles 54 and
62 cannot be displayed:
— the name of the medicinal product as laid down in point (a) of
Article 54 and, if necessary, the route of administration,
— the method of administration,
— the expiry date,
— the batch number,
— the contents by weight, by volume or by unit.
Article 56
The particulars referred to in Articles 54, 55 and 62 shall be easily
legible, clearly comprehensible and indelible.
Article 56a
The name of the medicinal product, as referred to in Article 54, point
(a) must also be expressed in Braille format on the packaging. The
marketing authorisation holder shall ensure that the package informa-tion leaflet is made available on request from patients' organisationsin formats appropriate for the blind and partially-sighted.
Article 57
Notwithstanding Article 60, Member States may require the use of
certain forms of labelling of the medicinal product making it possibleto ascertain:
— the price of the medicinal product,
— the reimbursement conditions of social security organizations,
— the legal status for supply to the patient, in accordance with Title
VI,
— identification and authenticity.
For medicinal products authorised under Regulation (EC) No 726/2004,
Member States shall, when applying this Article, observe the detailedguidance referred to in Article 65 of this Directive.
Article 58
The inclusion in the packaging of all medicinal products of a package
leaflet shall be obligatory unless all the information required by Arti-cles 59 and 62 is directly conveyed on the outer packaging or on theimmediate packaging.2001L0083 — EN — 30.04.2004 — 003.001 — 39
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Article 59
1. The package leaflet shall be drawn up in accordance with the
summary of the product characteristics; it shall include, in the
following order:
(a) for the identification of the medicinal product:
(i) the name of the medicinal product followed by its strength and
pharmaceutical form, and, if appropriate, whether it is intended
for babies, children or adults. The common name shall be
included where the product contains only one active substanceand if its name is an invented name;
(ii) the pharmaco-therapeutic group or type of activity in terms
easily comprehensible for the patient;
(b) the therapeutic indications;
(c) a list of information which is necessary before the medicinal
product is taken:
(i) contra-indications;
(ii) appropriate precautions for use;
(iii) forms of interaction with other medicinal products and other
forms of interaction (e.g. alcohol, tobacco, foodstuffs) whichmay affect the action of the medicinal product;
(iv) special warnings;
(d) the necessary and usual instructions for proper use, and in parti-
cular:
(i) the dosage,
(ii) the method and, if necessary, route of administration;
(iii) the frequency of administration, specifying if necessary the
appropriate time at which the medicinal product may or mustbe administered;
and, as appropriate, depending on the nature of the product:
(iv) the duration of treatment, where it should be limited;
(v) the action to be taken in case of an overdose (such as symp-
toms, emergency procedures);
(vi) what to do when one or more doses have not been taken;
(vii) indication, if necessary, of the risk of withdrawal effects;
(viii) a specific recommendation to consult the doctor or the phar-
macist, as appropriate, for any clarification on the use of theproduct;
(e) a description of the adverse reactions which may occur under
normal use of the medicinal product and, if necessary, the actionto be taken in such a case; the patient should be expressly asked
to communicate any adverse reaction which is not mentioned in
the package leaflet to his doctor or pharmacist;
(f) a reference to the expiry date indicated on the label, with:
(i) a warning against using the product after that date;
(ii) where appropriate, special storage precautions;
(iii) if necessary, a warning concerning certain visible signs of
deterioration;
(iv) the full qualitative composition (in active substances and exci-
pients) and the quantitative composition in active substances,using common names, for each presentation of the medicinalproduct;
(v) for each presentation of the product, the pharmaceutical form
and content in weight, volume or units of dosage;
(vi) the name and address of the marketing authorisation holder
and, where applicable, the name of his appointed representa-
tives in the Member States;
(vii) the name and address of the manufacturer;
(g) where the medicinal product is authorised in accordance with Arti-
cles 28 to 39 under different names in the Member Statesconcerned, a list of the names authorised in each Member State;2001L0083 — EN — 30.04.2004 — 003.001 — 40
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(h) the date on which the package leaflet was last revised.
2. The list set out in point (c) of paragraph 1 shall:
(a) take into account the particular condition of certain categories of
users (children, pregnant or breastfeeding women, the elderly,
persons with specific pathological conditions);
(b) mention, if appropriate, possible effects on the ability to drive vehi-
cles or to operate machinery;
(c) list those excipients knowledge of which is important for the safe
and effective use of the medicinal product and which are includedin the detailed guidance published pursuant to Article 65.
3. The package leaflet shall reflect the results of consultations with
target patient groups to ensure that it is legible, clear and easy to use.
Article 60
Member States may not prohibit or impede the placing on the market
of medicinal products within their territory on grounds connected with
labelling or the package leaflet where these comply with the require-
ments of this Title.
Article 61
1. One or more mock-ups of the outer packaging and the immediate
packaging of a medicinal product, together with the draft packageleaflet, shall be submitted to the authorities competent for authorisingmarketing when the marketing authorisation is requested. The results
of assessments carried out in cooperation with target patient groups
shall also be provided to the competent authority.
2. The competent authority shall refuse the marketing authorization
if the labelling or the package leaflet do not comply with the provisionsof this Title or if they are not in accordance with the particulars listed
in the summary of product characteristics.
3. All proposed changes to an aspect of the labelling or the package
leaflet covered by this Title and not connected with the summary ofproduct characteristics shall be submitted to the authorities competentfor authorizing marketing. If the competent authorities have notopposed a proposed change within 90 days following the introductionof the request, the applicant may put the change into effect.
4. The fact that the competent authority do not refuse a marketing
authorization pursuant to paragraph 2 or a change to the labelling or
the package leaflet pursuant to paragraph 3 does not alter the generallegal liability of the manufacturer ►
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ization holder.
Article 62
The outer packaging and the package leaflet may include symbols or
pictograms designed to clarify certain information mentioned in Arti-cles 54 and 59(1) and other information compatible with the summary
of the product characteristics which is useful ►
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to the exclusion of any element of a promotional nature.
Article 63
1. The particulars for labelling listed in Articles 54, 59 and 62 shall
appear in the official language or languages of the Member State wherethe product is placed on the market.
The first subparagraph shall not prevent these particulars from being
indicated in several languages, provided that the same particularsappear in all the languages used.2001L0083 — EN — 30.04.2004 — 003.001 — 41
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In the case of certain orphan medicinal products, the particulars listed
in Article 54 may, on reasoned request, appear in only one of the offi-cial languages of the Community.
2. The package leaflet must be written and designed to be clear and
understandable, enabling the users to act appropriately, when necessarywith the help of health professionals. The package leaflet must be
clearly legible in the official language or languages of the Member
State in which the medicinal product is placed on the market.
The first subparagraph shall not prevent the package leaflet from being
printed in several languages, provided that the same information is
given in all the languages used.
3. When the product is not intended to be delivered directly to the
patient, the competent authorities may grant an exemption to the obli-gation that certain particulars should appear on the labelling and in the
package leaflet and that the leaflet must be in the official language or
languages of the Member State in which the product is placed on themarket.
Article 64
Where the provisions of this Title are not complied with, and a notice
served on the person concerned has remained without effect, thecompetent authorities of the Member States may suspend the marketingauthorization, until the labelling and the package leaflet of the medic-inal product in question have been made to comply with therequirements of this Title.
Article 65
In consultation with the Member States and the parties concerned, the
Commission shall draw up and publish detailed guidance concerning inparticular:
(a) the wording of certain special warnings for certain categories of
medicinal products;
(b) the particular information needs relating to non-prescription medic-
inal products;
(c) the legibility of particulars on the labelling and package leaflet;
(d) the methods for the identification and authentication of medicinal
products;
(e) the list of excipients which must feature on the labelling of medic-
inal products and the way in which these excipients must beindicated;
(f) harmonised provisions for the implementation of Article 57.
Article 66
1. The outer carton and the container of medicinal products
containing radionuclides shall be labelled in accordance with the regu-lations for the safe transport of radioactive materials laid down by theInternational Atomic Energy Agency. Moreover, the labelling shallcomply with the provisions set out in paragraphs 2 and 3.
2. The label on the shielding shall include the particulars mentioned
in Article 54. In addition, the labelling on the shielding shall explain infull, the codings used on the vial and shall indicate, where necessary,for a given time and date, the amount of radioactivity per dose or per
vial and the number of capsules, or, for liquids, the number of millili-
tres in the container.
3. The vial shall be labelled with the following information:
— the name or code of the medicinal product, including the name or
chemical symbol of the radionuclide,2001L0083 — EN — 30.04.2004 — 003.001 — 42
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— the batch identification and expiry date,
— the international symbol for radioactivity,
— the name and address of the manufacturer,— the amount of radioactivity as specified in paragraph 2.
Article 67
The competent authority shall ensure that a detailed instruction leaflet
is enclosed with the packaging of radiopharmaceuticals, radionuclide
generators, radionuclide kits or radionuclide precursors. The text of
this leaflet shall be established in accordance with the provisions ofArticle 59. In addition, the leaflet shall include any precautions to betaken by the user and the patient during the preparation and administra-tion of the medicinal product and special precautions for the disposal
of the packaging and its unused contents.
Article 68
Without prejudice to the provisions of Article 69, homeopathic medic-
inal products shall be labelled in accordance with the provisions of this
title and shall be identified by a reference on their labels, in clear andlegible form, to their homeopathic nature.
Article 69
1. In addition to the clear mention of the words ‘homeopathic
medicinal product’, the labelling and, where appropriate, the packageinsert for the medicinal products referred to in Article 14(1) shall bearthe following, and no other, information:
— the scientific name of the stock or stocks followed by the degree of
dilution, making use of the symbols of the pharmacopoeia used inaccordance with Article 1(5); if the homeopathic medicinal product
is composed of two or more stocks, the scientific names of the
stocks on the labelling may be supplemented by an invented name,
— name and address of the registration holder and, where appropriate,
of the manufacturer,
— method of administration and, if necessary, route,
— expiry date, in clear terms (month, year),
— pharmaceutical form,— contents of the sales presentation,— special storage precautions, if any,
— a special warning if necessary for the medicinal product,
— manufacturer's batch number,— registration number,
— ‘homeopathic medicinal product without approved therapeutic indi-
cations’,
— a warning advising the user to consult a doctor if the symptoms
persist.
2. Notwithstanding paragraph 1, Member States may require the use
of certain types of labelling in order to show:
— the price of the medicinal product,
— the conditions for refunds by social security bodies.2001L0083 — EN — 30.04.2004 — 003.001 — 43
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TITLE VI
CLASSIFICATION OF MEDICINAL PRODUCTS
Article 70
1. When a marketing authorization is granted, the competent autho-
rities shall specify the classification of the medicinal product into:
— a medicinal product subject to medical prescription,
— a medicinal product not subject to medical prescription.
To this end, the criteria laid down in Article 71(1) shall apply.2. The competent authorities may fix sub-categories for medicinal
products which are available on medical prescription only. In that
case, they shall refer to the following classification:
(a) medicinal products on medical prescription for renewable or non-
renewable delivery;
(b) medicinal products subject to special medical prescription;
(c) medicinal products on ‘restricted’ medical prescription, reserved for
use in certain specialised areas.
Article 71
1. Medicinal products shall be subject to medical prescription where
they:
— are likely to present a danger either directly or indirectly, even
when used correctly, if utilized without medical supervision, or
— are frequently and to a very wide extent used incorrectly, and as a
result are likely to present a direct or indirect danger to humanhealth, or
— contain substances or preparations thereof, the activity and/or
adverse reactions of which require further investigation, or
— are normally prescribed by a doctor to be administered parenterally.
2. Where Member States provide for the sub-category of medicinal
products subject to special medical prescription, they shall take account
of the following factors:
— the medicinal product contains, in a non-exempt quantity, a
substance classified as a narcotic or a psychotropic substance within
the meaning of the international conventions in force, such as the
United Nations Conventions of 1961 and 1971, or
— the medicinal product is likely, if incorrectly used, to present a
substantial risk of medicinal abuse, to lead to addiction or bemisused for illegal purposes, or
— the medicinal product contains a substance which, by reason of its
novelty or properties, could be considered as belonging to the groupenvisaged in the second indent as a precautionary measure.
3. Where Member States provide for the sub-category of medicinal
products subject to restricted prescription, they shall take account of
the following factors:
— the medicinal product, because of its pharmaceutical characteristics
or novelty or in the interests of public health, is reserved for treat-
ments which can only be followed in a hospital environment,
— the medicinal product is used in the treatment of conditions which
must be diagnosed in a hospital environment or in institutions with
adequate diagnostic facilities, although administration and follow-up may be carried out elsewhere, or
— the medicinal product is intended for outpatients but its use may
produce very serious adverse reactions requiring a prescriptiondrawn up as required by a specialist and special supervisionthroughout the treatment.2001L0083 — EN — 30.04.2004 — 003.001 — 44
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4. A competent authority may waive application of paragraphs 1, 2
and 3 having regard to:
(a) the maximum single dose, the maximum daily dose, the strength,
the pharmaceutical form, certain types of packaging; and/or
(b) other circumstances of use which it has specified.
5. If a competent authority does not designate medicinal products
into sub-categories referred to in Article 70(2), it shall nevertheless
take into account the criteria referred to in paragraphs 2 and 3 of thisArticle in determining whether any medicinal product shall be classi-fied as a prescription-only medicine.
Article 72
Medicinal products not subject to prescription shall be those which do
not meet the criteria listed in Article 71.
Article 73
The competent authorities shall draw up a list of the medicinal
products subject, on their territory, to medical prescription, specifying,if necessary, the category of classification. They shall update this listannually.
Article 74
When new facts are brought to their attention, the competent authori-
ties shall examine and, as appropriate, amend the classification of amedicinal product by applying the criteria listed in Article 71.
Article 74a
Where a change of classification of a medicinal product has been
authorised on the basis of significant pre-clinical tests or clinical trials,the competent authority shall not refer to the results of those tests ortrials when examining an application by another applicant for or holderof marketing authorisation for a change of classification of the samesubstance for one year after the initial change was authorised.
Article 75
Each year, Member States shall communicate to the Commission and
to the other Member States, the changes that have been made to thelist referred to in Article 73.
TITLE VII
WHOLESALE DISTRIBUTION OF MEDICINAL PRODUCTS
Article 76
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take all appropriate action to ensure that only medicinal products inrespect of which a marketing authorization has been granted in accor-dance with Community law are distributed on their territory.
2. In the case of wholesale distribution and storage, medicinal
products shall be covered by a marketing authorisation grantedpursuant to Regulation (EC) No 726/2004 or by the competent authori-ties of a Member State in accordance with this Directive.
3. Any distributor, not being the marketing authorisation holder,
who imports a product from another Member State shall notify the
marketing authorisation holder and the competent authority in theMember State to which the product will be imported of his intentionto import it. In the case of products which have not been granted anauthorisation pursuant to Regulation (EC) No 726/2004, the notifica-tion to the competent authority shall be without prejudice to2001L0083 — EN — 30.04.2004 — 003.001 — 45
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additional procedures provided for in the legislation of that Member
State.
Article 77
1. Member States shall take all appropriate measures to ensure that
the wholesale distribution of medicinal products is subject to the
possession of an authorization to engage in activity as a wholesaler in
medicinal products, stating the place for which it is valid.
2. Where persons authorized or entitled to supply medicinal
products to the public may also, under national law, engage in whole-sale business, such persons shall be subject to the authorizationprovided for in paragraph 1.
3. Possession of a manufacturing authorization shall include author-
ization to distribute by wholesale the medicinal products covered by
that authorization. Possession of an authorization to engage in activity
as a wholesaler in medicinal products shall not give dispensation fromthe obligation to possess a manufacturing authorization and to complywith the conditions set out in that respect, even where the manufac-turing or import business is secondary.
4. At the request of the Commission or any Member State, Member
States shall supply all appropriate information concerning the indivi-
dual authorizations which they have granted under paragraph 1.
5. Checks on the persons authorized to engage in the activity of
wholesaler in medicinal products and the inspection of their premises,shall be carried out under the responsibility of the Member State whichgranted the authorization.
6. The Member State which granted the authorization referred to in
paragraph 1 shall suspend or revoke that authorization if the conditions
of authorization cease to be met. It shall forthwith inform the other
Member States and the Commission thereof.
7. Should a Member State consider that, in respect of a person
holding an authorization granted by another Member State under theterms of paragraph 1, the conditions of authorization are not, or areno longer met, it shall forthwith inform the Commission and the otherMember State involved. The latter shall take the measures necessary
and shall inform the Commission and the first Member State of the
decisions taken and the reasons for those decisions.
Article 78
Member States shall ensure that the time taken for the procedure for
examining the application for the distribution authorization does notexceed 90 days from the day on which the competent authority of theMember State concerned receives the application.
The competent authority may, if need be, require the applicant to
supply all necessary information concerning the conditions of authori-zation. Where the authority exercises this option, the period laid down
in the first paragraph shall be suspended until the requisite additional
data have been supplied.
Article 79
In order to obtain the distribution authorization, applicants must fulfil
the following minimum requirements:
(a) they must have suitable and adequate premises, installations and
equipment, so as to ensure proper conservation and distribution ofthe medicinal products;
(b) they must have staff, and in particular, a qualified person desig-
nated as responsible, meeting the conditions provided for by thelegislation of the Member State concerned;
(c) they must undertake to fulfil the obligations incumbent on them
under the terms of Article 80.2001L0083 — EN — 30.04.2004 — 003.001 — 46
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Article 80
Holders of the distribution authorization must fulfil the following
minimum requirements:
(a) they must make the premises, installations and equipment referred
to in Article 79(a) accessible at all times to the persons responsiblefor inspecting them;
(b) they must obtain their supplies of medicinal products only from
persons who are themselves in possession of the distributionauthorization or who are exempt from obtaining such authorizationunder the terms of Article 77(3);
(c) they must supply medicinal products only to persons who are them-
selves in possession of the distribution authorization or who are
authorized or entitled to supply medicinal products to the public
in the Member State concerned;
(d) they must have an emergency plan which ensures effective imple-
mentation of any recall from the market ordered by the competent
authorities or carried out in cooperation with the manufacturer ormarketing authorization holder for the medicinal productconcerned;
(e) they must keep records either in the form of purchase/sales
invoices, or on computer, or in any other form, giving for anytransaction in medicinal products received or dispatched at leastthe following information:
— date,
— name of the medicinal product,
— quantity received or supplied,
— name and address of the supplier or consignee, as appropriate;
(f) they must keep the records referred to under (e) available to the
competent authorities, for inspection purposes, for a period of fiveyears;
(g) they must comply with the principles and guidelines of good distri-
bution practice for medicinal products as laid down in Article 84.
Article 81
With regard to the supply of medicinal products to pharmacists and
persons authorised or entitled to supply medicinal products to thepublic, Member States shall not impose upon the holder of a distribu-tion authorisation which has been granted by another Member State
any obligation, in particular public service obligations, more stringent
than those they impose on persons whom they have themselvesauthorised to engage in equivalent activities.
The holder of a marketing authorisation for a medicinal product and
the distributors of the said medicinal product actually placed on the
market in a Member State shall, within the limits of their responsibil-
ities, ensure appropriate and continued supplies of that medicinalproduct to pharmacies and persons authorised to supply medicinalproducts so that the needs of patients in the Member State in questionare covered.
The arrangements for implementing this Article should, moreover, be
justified on grounds of public health protection and be proportionatein relation to the objective of such protection, in compliance with theTreaty rules, particularly those concerning the free movement of goodsand competition.
Article 82
For all supplies of medicinal products to a person authorized or entitled
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concerned, the authorized wholesaler must enclose a document that
makes it possible to ascertain:
— the date,
— the name and pharmaceutical form of the medicinal product,
— the quantity supplied,
— the name and address of the supplier and consignor.
Member States shall take all appropriate measures to ensure that
persons authorized or entitled to supply medicinal products to thepublic are able to provide information that makes it possible to tracethe distribution path of every medicinal product.
Article 83
The provisions of this Title shall not prevent the application of more
stringent requirements laid down by Member States in respect of the
wholesale distribution of:
— narcotic or psychotropic substances within their territory,
— medicinal products derived from blood,— immunological medicinal products,
— radiopharmaceuticals.
Article 84
The Commission shall publish guidelines on good distribution practice.
To this end, it shall consult the Committee for Medicinal Products forHuman Use and the Pharmaceutical Committee established by CouncilDecision 75/320/EEC (
1).
Article 85
This Title shall apply to homeopathic medicinal products.
TITLE VIII
ADVERTISING
Article 86
1. For the purposes of this Title, ‘advertising of medicinal products’
shall include any form of door-to-door information, canvassing activityor inducement designed to promote the prescription, supply, sale orconsumption of medicinal products; it shall include in particular:
— the advertising of medicinal products to the general public,
— advertising of medicinal products to persons qualified to prescribe
or supply them,
— visits by medical sales representatives to persons qualified to
prescribe medicinal products,
— the supply of samples,— the provision of inducements to prescribe or supply medicinal
products by the gift, offer or promise of any benefit or bonus,
whether in money or in kind, except when their intrinsic value isminimal,
— sponsorship of promotional meetings attended by persons qualified
to prescribe or supply medicinal products,
— sponsorship of scientific congresses attended by persons qualified to
prescribe or supply medicinal products and in particular payment oftheir travelling and accommodation expenses in connection there-with.2001L0083 — EN — 30.04.2004 — 003.001 — 48
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2. The following are not covered by this Title:
— the labelling and the accompanying package leaflets, which are
subject to the provisions of Title V,
— correspondence, possibly accompanied by material of a non-promo-
tional nature, needed to answer a specific question about aparticular medicinal product,
— factual, informative announcements and reference material relating,
for example, to pack changes, adverse-reaction warnings as part of
general drug precautions, trade catalogues and price lists, provided
they include no product claims,
— information relating to human health or diseases, provided that
there is no reference, even indirect, to medicinal products.
Article 87
1. Member States shall prohibit any advertising of a medicinal
product in respect of which a marketing authorization has not been
granted in accordance with Community law.
2. All parts of the advertising of a medicinal product must comply
with the particulars listed in the summary of product characteristics.
3. The advertising of a medicinal product:
— shall encourage the rational use of the medicinal product, by
presenting it objectively and without exaggerating its properties,
— shall not be misleading.
Article 88
1. Member States shall prohibit the advertising to the general public
of medicinal products which:
(a) are available on medical prescription only, in accordance with Title
VI;
(b) contain substances defined as psychotropic or narcotic by interna-
tional convention, such as the United Nations Conventions of1961 and 1971.
2. Medicinal products may be advertised to the general public
which, by virtue of their composition and purpose, are intended anddesigned for use without the intervention of a medical practitioner fordiagnostic purposes or for the prescription or monitoring of treatment,with the advice of the pharmacist, if necessary.
3. Member States shall be entitled to ban, on their territory, adver-
tising to the general public of medicinal products the cost of whichmay be reimbursed.
4. The prohibition contained in paragraph 1 shall not apply to vacci-
nation campaigns carried out by the industry and approved by thecompetent authorities of the Member States.
5. The prohibition referred to in paragraph 1 shall apply without
prejudice to Article 14 of Directive 89/552/EEC.
6. Member States shall prohibit the direct distribution of medicinal
products to the public by the industry for promotional purposes.
TITLE VIIIa
INFORMATION AND ADVERTISING
Article 88a
Within three years of the entry into force of Directive 2004/726/EC,
the Commission shall, following consultations with patients' and consu-mers' organisations, doctors' and pharmacists' organisations, MemberStates and other interested parties, present to the European Parliament2001L0083 — EN — 30.04.2004 — 003.001 — 49
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and the Council a report on current practice with regard to information
provision — particularly on the Internet — and its risks and benefitsfor patients.
Following analysis of the above data, the Commission shall, if appro-
priate, put forward proposals setting out an information strategy toensure good-quality, objective, reliable and non-promotional informa-tion on medicinal products and other treatments and shall address thequestion of the information source's liability.
Article 89
1. Without prejudice to Article 88, all advertising to the general
public of a medicinal product shall:
(a) be set out in such a way that it is clear that the message is an
advertisement and that the product is clearly identified as a medic-inal product;
(b) include the following minimum information:
— the name of the medicinal product, as well as the common
name if the medicinal product contains only one activesubstance,
— the information necessary for correct use of the medicinal
product,
— an express, legible invitation to read carefully the instructions
on the package leaflet or on the outer packaging, as the casemay be.
2. Member States may decide that the advertising of a medicinal
product to the general public may, notwithstanding paragraph 1,include only the name of the medicinal product or its internationalnon-proprietary name, where this exists, or the trademark if it isintended solely as a reminder.
Article 90
The advertising of a medicinal product to the general public shall not
contain any material which:
(a) gives the impression that a medical consultation or surgical opera-
tion is unnecessary, in particular by offering a diagnosis or by
suggesting treatment by mail;
(b) suggests that the effects of taking the medicine are guaranteed, are
unaccompanied by adverse reactions or are better than, or equiva-lent to, those of another treatment or medicinal product;
(c) suggests that the health of the subject can be enhanced by taking
the medicine;
(d) suggests that the health of the subject could be affected by not
taking the medicine; this prohibition shall not apply to the vaccina-tion campaigns referred to in Article 88(4);
(e) is directed exclusively or principally at children;
(f) refers to a recommendation by scientists, health professionals or
persons who are neither of the foregoing but who, because of their
celebrity, could encourage the consumption of medicinal products;
(g) suggests that the medicinal product is a foodstuff, cosmetic or other
consumer product;
(h) suggests that the safety or efficacy of the medicinal product is due
to the fact that it is natural;
(i) could, by a description or detailed representation of a case history,
lead to erroneous self-diagnosis;
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(k) uses, in improper, alarming or misleading terms, pictorial represen-
tations of changes in the human body caused by disease or injury,or of the action of a medicinal product on the human body or parts
thereof.
Article 91
1. Any advertising of a medicinal product to persons qualified to
prescribe or supply such products shall include:
— essential information compatible with the summary of product char-
acteristics;
— the supply classification of the medicinal product.
Member States may also require such advertising to include the selling
price or indicative price of the various presentations and the conditions
for reimbursement by social security bodies.
2. Member States may decide that the advertising of a medicinal
product to persons qualified to prescribe or supply such products may,
notwithstanding paragraph 1, include only the name of the medicinal
product, or its international non-proprietary name, where this exists, orthe trademark, if it is intended solely as a reminder.
Article 92
1. Any documentation relating to a medicinal product which is
transmitted as part of the promotion of that product to persons qualified
to prescribe or supply it shall include, as a minimum, the particularslisted in Article 91(1) and shall state the date on which it was drawnup or last revised.
2. All the information contained in the documentation referred to in
paragraph 1 shall be accurate, up-to-date, verifiable and sufficiently
complete to enable the recipient to form his or her own opinion of the
therapeutic value of the medicinal product concerned.
3. Quotations as well as tables and other illustrative matter taken
from medical journals or other scientific works for use in the documen-tation referred to in paragraph 1 shall be faithfully reproduced and theprecise sources indicated.
Article 93
1. Medical sales representatives shall be given adequate training by
the firm which employs them and shall have sufficient scientificknowledge to be able to provide information which is precise and ascomplete as possible about the medicinal products which they promote.
2. During each visit, medical sales representatives shall give the
persons visited, or have available for them, summaries of the product
characteristics of each medicinal product they present together, if the
legislation of the Member State so permits, with details of the priceand conditions for reimbursement referred to in Article 91(1).
3. Medical sales representatives shall transmit to the scientific
service referred to in Article 98(1) any information about the use ofthe medicinal products they advertise, with particular reference to any
adverse reactions reported to them by the persons they visit.
Article 94
1. Where medicinal products are being promoted to persons quali-
fied to prescribe or supply them, no gifts, pecuniary advantages orbenefits in kind may be supplied, offered or promised to such personsunless they are inexpensive and relevant to the practice of medicine orpharmacy.2001L0083 — EN — 30.04.2004 — 003.001 — 51
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2. Hospitality at sales promotion events shall always be strictly
limited to their main purpose and must not be extended to personsother than health-care professionals.
3. Persons qualified to prescribe or supply medicinal products shall
not solicit or accept any inducement prohibited under paragraph 1 or
contrary to paragraph 2.
4. Existing measures or trade practices in Member States relating to
prices, margins and discounts shall not be affected by paragraphs 1, 2and 3.
Article 95
The provisions of Article 94(1) shall not prevent hospitality being
offered, directly or indirectly, at events for purely professional and
scientific purposes; such hospitality shall always be strictly limited to
the main scientific objective of the event; it must not be extended topersons other than health-care professionals.
Article 96
1. Free samples shall be provided on an exceptional basis only to
persons qualified to prescribe them and on the following conditions:
(a) the number of samples for each medicinal product each year on
prescription shall be limited;
(b) any supply of samples shall be in response to a written request,
signed and dated, from the prescribing agent;
(c) those supplying samples shall maintain an adequate system of
control and accountability;
(d) each sample shall be no larger than the smallest presentation on the
market;
(e) each sample shall be marked ‘free medical sample — not for sale’
or shall show some other wording having the same meaning;
(f) each sample shall be accompanied by a copy of the summary of
product characteristics;
(g) no samples of medicinal products containing psychotropic or
narcotic substances within the meaning of international conven-tions, such as the United Nations Conventions of 1961 and 1971,may be supplied.
2. Member States may also place further restrictions on the distribu-
tion of samples of certain medicinal products.
Article 97
1. Member States shall ensure that there are adequate and effective
methods to monitor the advertising of medicinal products. Suchmethods, which may be based on a system of prior vetting, shall in
any event include legal provisions under which persons or organiza-
tions regarded under national law as having a legitimate interest inprohibiting any advertisement inconsistent with this Title, may takelegal action against such advertisement, or bring such advertisementbefore an administrative authority competent either to decide on
complaints or to initiate appropriate legal proceedings.
2. Under the legal provisions referred to in paragraph 1, Member
States shall confer upon the courts or administrative authorities powersenabling them, in cases where they deem such measures to be neces-sary, taking into account all the interests involved, and in particular
the public interest:
— to order the cessation of, or to institute appropriate legal proceed-
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— if misleading advertising has not yet been published but publication
is imminent, to order the prohibition of, or to institute appropriatelegal proceedings for an order for the prohibition of, such publica-
tion,
even without proof of actual loss or damage or of intention or negli-
gence on the part of the advertiser.
3. Member States shall make provision for the measures referred to
in the second subparagraph to be taken under an accelerated procedure,either with interim effect or with definitive effect.
It shall be for each Member State to decide which of the two options
set out in the first subparagraph to select.
4. Member States may confer upon the courts or administrative
authorities powers enabling them, with a view to eliminating the conti-
nuing effects of misleading advertising the cessation of which has been
ordered by a final decision:
— to require publication of that decision in full or in part and in such
form as they deem adequate,
— to require in addition the publication of a corrective statement.
5. Paragraphs 1 to 4 shall not exclude the voluntary control of
advertising of medicinal products by self-regulatory bodies andrecourse to such bodies, if proceedings before such bodies are possiblein addition to the judicial or administrative proceedings referred to inparagraph 1.
Article 98
1. The marketing authorization holder shall establish, within his
undertaking, a scientific service in charge of information about themedicinal products which he places on the market.
2. The marketing authorization holder shall:
— keep available for, or communicate to, the authorities or bodies
responsible for monitoring advertising of medicinal products, asample of all advertisements emanating from his undertakingtogether with a statement indicating the persons to whom it is
addressed, the method of dissemination and the date of first disse-
mination,
— ensure that advertising of medicinal products by his undertaking
conforms to the requirements of this Title,
— verify that medical sales representatives employed by his under-
taking have been adequately trained and fulfill the obligations
imposed upon them by Article 93(2) and (3),
— supply the authorities or bodies responsible for monitoring adver-
tising of medicinal products with the information and assistancethey require to carry out their responsibilities,
— ensure that the decisions taken by the authorities or bodies respon-
sible for monitoring advertising of medicinal products areimmediately and fully complied with.
3. The Member States shall not prohibit the co-promotion of a
medicinal product by the holder of the marketing authorisation andone or more companies nominated by him.
Article 99
Member States shall take the appropriate measures to ensure that the
provisions of this Title are applied and shall determine in particularwhat penalties shall be imposed should the provisions adopted in theexecution of Title be infringed.2001L0083 — EN — 30.04.2004 — 003.001 — 53
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Article 100
Advertising of the homeopathic medicinal products referred to in
Article 14(1) shall be subject to the provisions of this Title with the
exception of Article 87(1).
However, only the information specified in Article 69(1) may be used
in the advertising of such medicinal products.
TITLE IX
PHARMACOVIGILANCE
Article 101
The Member States shall take all appropriate measures to encourage
doctors and other health care professionals to report suspected adverse
reactions to the competent authorities.
The Member States may impose specific requirements on doctors and
other health-care professionals in respect of the reporting of suspectedserious or unexpected adverse reactions.
Article 102
In order to ensure the adoption of appropriate and harmonised regula-
tory decisions concerning the medicinal products authorised within theCommunity, having regard to information obtained about adverse reac-tions to medicinal products under normal conditions of use, the
Member States shall operate a pharmacovigilance system. This system
shall be used to collect information useful in the surveillance of medic-inal products, with particular reference to adverse reactions in humanbeings, and to evaluate such information scientifically.
Member States shall ensure that suitable information collected within
this system is communicated to the other Member States and the
Agency. The information shall be recorded in the database referred to
in point (l) of the second subparagraph of Article 57(1) of Regulation(EC) No 726/2004 and shall be permanently accessible to all MemberStates and without delay to the public.
This system shall also take into account any available information on
misuse and abuse of medicinal products which may have an impacton the evaluation of their benefits and risks.
Article 102a
The management of funds intended for activities connected with phar-
macovigilance, the operation of communication networks and market
surveillance shall be under the permanent control of the competent
authorities in order to guarantee their independence.
Article 103
The marketing authorization holder shall have permanently and
continuously at his disposal an appropriately qualified person respon-sible for pharmacovigilance.
That qualified person shall reside in the Community and shall be
responsible for the following:
(a) the establishment and maintenance of a system which ensures that
information about all suspected adverse reactions which arereported to the personnel of the company, and to medical represen-tatives, is collected and collated in order to be accessible at least atone point within the Community;2001L0083 — EN — 30.04.2004 — 003.001 — 54
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(b) the preparation for the competent authorities of the reports referred
to in Article 104, in such form as may be laid down by thoseauthorities, in accordance with the guidance referred to in Article
106(1);
(c) ensuring that any request from the competent authorities for the
provision of additional information necessary for the evaluation ofthe benefits and risks afforded by a medicinal product is answeredfully and promptly, including the provision of information aboutthe volume of sales or prescriptions of the medicinal product
concerned;
(d) the provision to the competent authorities, of any other information
relevant to the evaluation of the benefits and risks afforded by amedicinal product, including appropriate information on post-authorization safety studies.
Article 104
1. The marketing authorisation holder shall be required to maintain
detailed records of all suspected adverse reactions occurring either inthe Community or in a third country.
Save in exceptional circumstances, these reactions shall be communi-
cated electronically in the form of a report in accordance with theguidelines referred to in Article 106(1).
2. The marketing authorisation holder shall be required to record all
suspected serious adverse reactions which are brought to his attentionby a health-care professional and to report them promptly to thecompetent authority of the Member State on whose territory the inci-dent occurred, and no later than 15 days following the receipt of the
information.
3. The marketing authorisation holder shall be required to record
and report all other suspected serious adverse reactions which meet
the notification criteria in accordance with the guidelines referred to
in Article 106(1), of which he can reasonably be expected to haveknowledge, promptly to the competent authority of the Member Statein whose territory the incident occurred, and no later than 15 daysfollowing the receipt of the information.
4. The marketing authorisation holder shall ensure that all suspected
serious unexpected adverse reactions and any suspected transmissionvia a medicinal product of any infectious agent occurring in the terri-tory of a third country are reported promptly in accordance with the
guidelines referred to in Article 106(1), so that the Agency and the
competent authorities of the Member States in which the medicinalproduct is authorised are informed of them, and no later than 15 daysfollowing the receipt of the information.
5. By way of derogation from paragraphs 2, 3 and 4, in the case of
medicinal products which are covered by Directive 87/22/EEC orwhich have qualified for the procedures laid down in Articles 28 and29 of this Directive or which have been the subject of the proceduresunder Articles 32, 33 and 34 of this Directive, the marketing authorisa-
tion holder shall also ensure that all suspected serious adverse reactions
occurring in the Community are reported in such a way as to be acces-sible to the reference Member State or to any competent authorityacting as reference Member State. The reference Member State shallassume the responsibility of analysing and monitoring such adversereactions.
6. Unless other requirements have been laid down as a condition for
the granting of the marketing authorisation, or subsequently as indi-cated in the guidelines referred to in Article 106(1), reports of all
adverse reactions shall be submitted to the competent authorities in
the form of a periodic safety update report, immediately upon requestor at least every six months after authorisation and until the placing onthe market. Periodic safety update reports shall also be submittedimmediately upon request or at least every six months during the firsttwo years following the initial placing on the market and once a year2001L0083 — EN — 30.04.2004 — 003.001 — 55
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for the following two years. Thereafter, the reports shall be submitted
at three-yearly intervals, or immediately upon request.
The periodic safety update reports shall include a scientific evaluation
of the risk-benefit balance of the medicinal product.
7. The Commission may lay down provisions to amend paragraph 6
in view of experience gained through its operation. The Commissionshall adopt the provisions in accordance with the procedure referred to
in Article 121(2).
8. Following the granting of a marketing authorisation, the
marketing authorisation holder may request the amendment of theperiods referred to in paragraph 6 in accordance with the procedurelaid down by Commission Regulation (EC) No 1084/2003 (
1).
9. The holder of a marketing authorisation may not communicate
information relating to pharmacovigilance concerns to the generalpublic in relation to its authorised medicinal product without givingprior or simultaneous notification to the competent authority.
In any case, the marketing authorisation holder shall ensure that such
information is presented objectively and is not misleading.
Member States shall take the necessary measures to ensure that a
marketing authorisation holder who fails to discharge these obligationsis subject to effective, proportionate and dissuasive penalties.
Article 105
1. The Agency, in collaboration with the Member States and the
Commission, shall set up a data-processing network to facilitate the
exchange of pharmacovigilance information regarding medicinalproducts marketed in the Community in order to allow all competentauthorities to share the information at the same time.
2. Making use of the network referred to in paragraph 1, Member
States shall ensure that reports of suspected serious adverse reactions
that have taken place on their territory are promptly made available tothe Agency and the other Member States, and in any case within 15days after their notification at the latest.
3. The Member States shall ensure that reports of suspected serious
adverse reactions that have taken place on their territory are promptly
made available to the marketing authorisation holder, and in any casewithin 15 days after their notification at the latest.
Article 106
1. In order to facilitate the exchange of information on pharmacov-
igilance within the Community, the Commission, after consulting the
Agency, the Member States and interested parties, shall draw up guide-
lines on the collection, verification and presentation of adverse reactionreports, including technical requirements for electronic exchange ofpharmacovigilance information in accordance with internationallyagreed formats, and shall publish a reference to an internationally
agreed medical terminology.
Acting in accordance with the guidelines, marketing authorisation
holders shall use internationally agreed medical terminology for thereporting of adverse reactions.
These guidelines shall be published in Volume 9 of The Rules
governing Medicinal Products in the European Community and shall
take account of international harmonisation work carried out in thefield of pharmacovigilance.
2. For the interpretation of the definitions referred to in points (11)
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marketing authorisation holder and the competent authorities shall
follow the guidelines referred to in paragraph 1.
Article 107
1. Where, as a result of the evaluation of pharmacovigilance data, a
Member State considers that a marketing authorisation should besuspended, revoked or varied in accordance with the guidelines referredto in Article 106(1), it shall forthwith inform the Agency, the otherMember States and the marketing authorisation holder.
2. Where urgent action to protect public health is necessary, the
Member State concerned may suspend the marketing authorisation ofa medicinal product, provided that the Agency, the Commission and
the other Member States are informed no later than the following
working day.
When the Agency is informed in accordance with paragraph 1 in rela-
tion to suspensions and revocation, or the first subparagraph of this
paragraph, the Committee shall prepare an opinion within a time-frameto be determined depending on the urgency of the matter. In relation tovariations, the Committee may upon request from a Member Stateprepare an opinion.
Acting on the basis of this opinion, the Commission may request all
Member States in which the product is being marketed to taketemporary measures immediately.
The final measures shall be adopted in accordance with the procedure
referred to in Article 121(3).
Article 108
Any amendments which may be necessary to update provisions of Arti-
cles 101 to 107 to take account of scientific and technical progress
shall be adopted in accordance with the procedure referred to in Article121(2).
TITLE X
SPECIAL PROVISIONS ON MEDICINAL PRODUCTS DERIVED FROM
HUMAN BLOOD AND PLASMA
Article 109
For the collection and testing of human blood and human plasma,
Directive 2002/98/EC of the European Parliament and of the Council
of 27 January 2003 setting standards of quality and safety for thecollection, testing, processing, storage and distribution of human bloodand blood components and amending Directive 2001/83/EC (
1) shall
apply.
Article 110
Member States shall take the necessary measures to promote Commu-
nity self-sufficiency in human blood or human plasma. For this
purpose, they shall encourage the voluntary unpaid donation of bloodand plasma and shall take the necessary measures to develop theproduction and use of products derived from human blood or humanplasma coming from voluntary unpaid donations. They shall notify theCommission of such measures.2001L0083 — EN — 30.04.2004 — 003.001 — 57
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TITLE XI
SUPERVISION AND SANCTIONS
Article 111
1. The competent authority of the Member State concerned shall
ensure, by means of repeated inspections, and if necessary unan-nounced inspections, and, where appropriate, by asking an Official
Medicines Control Laboratory or a laboratory designated for that
purpose to carry out tests on samples, that the legal requirementsgoverning medicinal products are complied with.
The competent authority may also carry out unannounced inspections
at the premises of manufacturers of active substances used as startingmaterials, or at the premises of marketing authorisation holders when-ever it considers that there are grounds for suspecting non-compliance
with the principles and guidelines of good manufacturing practice
referred to in Article 47. These inspections may also be carried out atthe request of a Member State, the Commission or the Agency.
In order to verify whether the data submitted in order to obtain a
conformity certificate comply with the monographs of the EuropeanPharmacopoeia, the standardisation body of the nomenclatures and thequality norms within the meaning of the Convention relating to theelaboration of the European Pharmacopoeia (
1) (European Directorate
for the quality of Medicinal Products) may ask the Commission or the
Agency to request such an inspection when the starting materialconcerned is the subject of a European Pharmacopoeia monograph.
The competent authority of the Member State concerned may carry out
inspections of starting material manufacturers at the specific request ofthe manufacturer himself.
Such inspections shall be carried out by officials representing the
competent authority who shall be empowered to:
(a) inspect the manufacturing or commercial establishments of manu-
facturers of medicinal products or of active substances used as
starting materials, and any laboratories employed by the holder of
the manufacturing authorisation to carry out checks pursuant toArticle 20;
(b) take samples including with a view to independent tests being
carried out by an Official Medicines Control Laboratory or a
laboratory designated for that purpose by a Member State;
(c) examine any documents relating to the object of the inspection,
subject to the provisions in force in the Member States on 21 May1975 placing restrictions on these powers with regard to thedescription of the manufacturing method;
(d) inspect the premises, records and documents of marketing authori-
sation holders or any firms employed by the marketingauthorisation holder to perform the activities described in Title IX,and in particular Articles 103 and 104.
2. Member States shall take all appropriate steps to ensure that the
manufacturing processes used in the manufacture of immunologicalproducts are properly validated and attain batch-to-batch consistency.
3. After every inspection as referred to in paragraph 1, the officials
representing the competent authority shall report on whether the manu-
facturer complies with the principles and guidelines of goodmanufacturing practice laid down in Article 47 or, where appropriate,with the requirements laid down in Articles 101 to 108. The contentof such reports shall be communicated to the manufacturer ormarketing authorisation holder who has undergone the inspection.2001L0083 — EN — 30.04.2004 — 003.001 — 58
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4. Without prejudice to any arrangements which may have been
concluded between the Community and third countries, a MemberState, the Commission or the Agency may require a manufacturer
established in a third country to submit to an inspection as referred to
in paragraph 1.
5. Within 90 days of an inspection as referred to in paragraph 1, a
certificate of good manufacturing practice shall be issued to a manufac-turer if the outcome of the inspection shows that the manufacturercomplies with the principles and guidelines of good manufacturing
practice as provided for by Community legislation.
If inspections are performed as part of the certification procedure for
the monographs of the European Pharmacopoeia, a certificate shall bedrawn up.
6. Member States shall enter the certificates of good manufacturing
practice which they issue in a Community database managed by the
Agency on behalf of the Community.
7. If the outcome of the inspection as referred to in paragraph 1 is
that the manufacturer does not comply with the principles and guide-lines of good manufacturing practice as provided for by Communitylegislation, the information shall be entered in the Community databaseas referred to in paragraph 6.
Article 112
Member States shall take all appropriate measures to ensure that the
holder of the marketing authorization for a medicinal product and,where appropriate, the holder of the manufacturing authorization,furnish proof of the controls carried out on the medicinal product and/or the ingredients and of the controls carried out at an intermediate
stage of the manufacturing process, in accordance with the methods
laid down in Article 8(3)(h).
Article 113
For the purpose of implementing Article 112, Member States may
require manufacturers of immunological products to submit to acompetent authority copies of all the control reports signed by thequalified person in accordance with Article 51.
Article 114
1. Where it considers it necessary in the interests of public health, a
Member State may require the holder of an authorization for
marketing:
— live vaccines,
— immunological medicinal products used in the primary immuniza-
tion of infants or of other groups at risk,
— immunological medicinal products used in public health immuniza-
tion programmes,
— new immunological medicinal products or immunological medicinal
products manufactured using new or altered kinds of technology ornew for a particular manufacturer, during a transitional period
normally specified in the marketing authorization,
to submit samples from each batch of the bulk and/or the medicinal
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Laboratory or a laboratory that a Member State has designated forthat purpose ◄before release on to the market unless, in the case of
a batch manufactured in another Member State, the competent
authority of that Member State has previously examined the batch in
question and declared it to be in conformity with the approved specifi-cations. Member States shall ensure that any such examination iscompleted within 60 days of the receipt of the samples.
2. Where, in the interests of public health, the laws of a Member
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authorization holder for medicinal products derived from human blood
or human plasma to submit samples from each batch of the bulk and/orthe medicinal product for testing ►
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Control Laboratory or a laboratory that a Member State has designated
for that purpose ◄before being released into free circulation, unless
the competent authorities of another Member State have previouslyexamined the batch in question and declared it to be in conformitywith the approved specifications. Member States shall ensure that any
such examination is completed within 60 days of the receipt of the
samples.
Article 115
Member States shall take all necessary measures to ensure that the
manufacturing and purifying processes used in the preparation of
medicinal products derived from human blood or human plasma areproperly validated, attain batch-to-batch consistency and guarantee,insofar as the state of technology permits, the absence of specific viralcontamination. To this end manufacturers shall notify the competentauthorities of the method used to reduce or eliminate pathogenic
viruses liable to be transmitted by medicinal products derived from
human blood or human plasma. The competent authority may submitsamples of the bulk and/or the medicinal product for testing by a Statelaboratory or a laboratory designated for that purpose, either during theexamination of the application pursuant to Article 19, or after amarketing authorization has been granted.
Article 116
The competent authorities shall suspend, revoke, withdraw or vary a
marketing authorisation if the view is taken that the product is harmfulunder normal conditions of use, or that it lacks therapeutic efficacy, orthat the risk-benefit balance is not positive under the normal conditionsof use, or that its qualitative and quantitative composition is not asdeclared. Therapeutic efficacy is lacking when it is concluded that ther-
apeutic results cannot be obtained from the medicinal product.
An authorisation shall also be suspended, revoked, withdrawn or varied
where the particulars supporting the application as provided for inArticle 8 or Articles 10, 10a, 10b, 10c and 11 are incorrect or have
not been amended in accordance with Article 23, or where the controls
referred to in Article 112 have not been carried out.
Article 117
1. Without prejudice to the measures provided for in Article 116,
Member States shall take all appropriate steps to ensure that the supply
of the medicinal product is prohibited and the medicinal product with-drawn from the market, if the view is taken that:
(a) the medicinal product is harmful under normal conditions of use; or
(b) it lacks therapeutic efficacy; or
(c) the risk-benefit balance is not favourable under the authorised
conditions of use; or
(d) its qualitative and quantitative composition is not as declared; or
(e) the controls on the medicinal product and/or on the ingredients and
the controls at an intermediate stage of the manufacturing process
have not been carried out or if some other requirement or obliga-tion relating to the grant of the manufacturing authorisation hasnot been fulfilled.
2. The competent authority may limit the prohibition to supply the
product, or its withdrawal from the market, to those batches which arethe subject of dispute.2001L0083 — EN — 30.04.2004 — 003.001 — 60
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Article 118
1. The competent authority shall suspend or revoke the marketing
authorization for a category of preparations or all preparations whereany one of the requirements laid down in Article 41 is no longer met.
2. In addition to the measures specified in Article 117, the compe-
tent authority may suspend manufacture or imports of medicinalproducts coming from third countries, or suspend or revoke the manu-facturing authorization for a category of preparations or all preparations
where Articles 42, 46, 51 and 112 are not complied with.
Article 119
The provisions of this Title shall apply to homeopathic medicinal
products.
TITLE XII
STANDING COMMITTEE
Article 120
Any changes which are necessary in order to adapt Annex I to take
account of scientific and technical progress shall be adopted in accor-
dance with the procedure referred to in Article 121(2).
Article 121
1. The Commission shall be assisted by the Standing Committee on
Medicinal Products for Human Use, hereinafter called ‘the StandingCommittee’, in the task of adapting to technical progress the directiveson the removal of technical barriers to trade in the medicinal productssector.
2. Where reference is made to this paragraph, Articles 5 and 7 of
Decision 1999/468/EC shall apply, having regard to the provisions ofArticle 8 thereof.
The period laid down in Article 5(6) of Decision 1999/468/EC shall be
set at three months.
3. Where reference is made to this paragraph, Articles 4 and 7 of
Decision 1999/468/EC shall apply, having regard to the provisions ofArticle 8 thereof.
The period laid down in Article 4(3) of Decision 1999/468/EC shall be
set at one month.
4. The Standing Committee shall adopt its own rules of procedure
which shall be made public.
TITLE XIII
GENERAL PROVISIONS
Article 122
1. Member States shall take all appropriate measures to ensure that
the competent authorities concerned communicate to each other suchinformation as is appropriate to guarantee that the requirements placedon the authorisations referred to in Articles 40 and 77, on the certifi-cates referred to in Article 111(5) or on the marketing authorisationsare fulfilled.
2. Upon reasoned request, Member States shall forthwith communi-
cate the reports referred to in Article 111(3) to the competentauthorities of another Member State.2001L0083 — EN — 30.04.2004 — 003.001 — 61
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3. The conclusions reached in accordance with Article 111(1) shall
be valid throughout the Community.
However, in exceptional cases, if a Member State is unable, for reasons
relating to public health, to accept the conclusions reached followingan inspection under Article 111(1), that Member State shall forthwithinform the Commission and the Agency. The Agency shall inform the
Member States concerned.
When the Commission is informed of these divergences of opinion, it
may, after consulting the Member States concerned, ask the inspectorwho performed the original inspection to perform a new inspection;
the inspector may be accompanied by two other inspectors from
Member States which are not parties to the disagreement.
Article 123
1. Each Member State shall take all the appropriate measures to
ensure that decisions authorizing marketing, refusing or revoking amarketing authorization, cancelling a decision refusing or revoking a
marketing authorization, prohibiting supply, or withdrawing a product
from the market, together with the reasons on which such decisionsare based, are brought to the attention of the Agency forthwith.
2. The marketing authorization holder shall be obliged to notify the
Member States concerned forthwith of any action taken by him to
suspend the marketing of a medicinal product or to withdraw a medic-inal product from the market, together with the reasons for such actionif the latter concerns the efficacy of the medicinal product or theprotection of public health. Member States shall ensure that this infor-
mation is brought to the attention of the Agency.
3. Member States shall ensure that appropriate information about
action taken pursuant to paragraphs 1 and 2 which may affect theprotection of public health in third countries is forthwith brought to
the attention of the World Health Organization, with a copy to the
Agency.
4. The Commission shall publish annually a list of the medicinal
products which are prohibited in the Community.
Article 124
Member States shall communicate to each other all the information
necessary to guarantee the quality and safety of homeopathic medicinalproducts manufactured and marketed within the Community, and in
particular the information referred to in Articles 122 and 123.
Article 125
Every decision referred to in this Directive which is taken by the
competent authority of a Member State shall state in detail the reasons
on which it is based.
Such decision shall be notified to the party concerned, together with
information as to the redress available to him under the laws in force
and of the time-limit allowed for access to such redress.
Decisions to grant or revoke a marketing authorisation shall be made
publicly available.
Article 126
An authorization to market a medicinal product shall not be refused,
suspended or revoked except on the grounds set out in this Directive.
No decision concerning suspension of manufacture or of importation of
medicinal products coming from third countries, prohibition of supplyor withdrawal from the market of a medicinal product may be takenexcept on the grounds set out in Articles 117 and 118.2001L0083 — EN — 30.04.2004 — 003.001 — 62
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Article 126a
1. In the absence of a marketing authorisation or of a pending appli-
cation for a medicinal product authorised in another Member State inaccordance with this Directive, a Member State may for justified publichealth reasons authorise the placing on the market of the said medicinal
product.
2. When a Member State avails itself of this possibility, it shall
adopt the necessary measures in order to ensure that the requirements
of this Directive are complied with, in particular those referred to in
Titles V, VI, VIII, IX and XI.
3. Before granting such an authorisation a Member State shall:
(a) notify the marketing authorisation holder, in the Member State in
which the medicinal product concerned is authorised, of the
proposal to grant an authorisation under this Article in respect of
the product concerned; and
(b) request the competent authority in that State to furnish a copy of
the assessment report referred to in Article 21(4) and of themarketing authorisation in force in respect of the said medicinalproduct.
4. The Commission shall set up a publicly accessible register of
medicinal products authorised under paragraph 1. Member States shallnotify the Commission if any medicinal product is authorised, or ceases
to be authorised, under paragraph 1, including the name or corporate
name and permanent address of the authorisation holder. The Commis-sion shall amend the register of medicinal products accordingly andmake this register available on their website.
5. No later than 30 April 2008, the Commission shall present a
report to the European Parliament and the Council concerning theapplication of this provision with a view to proposing any necessaryamendments.
Article 126b
In order to guarantee independence and transparency, the Member
States shall ensure that members of staff of the competent authorityresponsible for granting authorisations, rapporteurs and expertsconcerned with the authorisation and surveillance of medicinal productshave no financial or other interests in the pharmaceutical industrywhich could affect their impartiality. These persons shall make an
annual declaration of their financial interests.
In addition, the Member States shall ensure that the competent
authority makes publicly accessible its rules of procedure and those of
its committees, agendas for its meetings and records of its meetings,accompanied by decisions taken, details of votes and explanations ofvotes, including minority opinions.
Article 127
1. At the request of the manufacturer, the exporter or the authorities
of an importing third country, Member States shall certify that a manu-
facturer of medicinal products is in possession of the manufacturing
authorization. When issuing such certificates Member States shallcomply with the following conditions:
(a) they shall have regard to the prevailing administrative arrange-
ments of the World Health Organization;
(b) for medicinal products intended for export which are already
authorized on their territory, they shall supply the summary of theproduct characteristics as approved in accordance with Article 21.
2. When the manufacturer is not in possession of a marketing
authorization he shall provide the authorities responsible for estab-lishing the certificate referred to in paragraph 1, with a declarationexplaining why no marketing authorization is available.2001L0083 — EN — 30.04.2004 — 003.001 — 63
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Article 127a
When a medicinal product is to be authorised in accordance with Regu-
lation (EC) No 726/2004 and the Scientific Committee in its opinion
refers to recommended conditions or restrictions with regard to the
safe and effective use of the medicinal product as provided for inArticle 9(4)(c) of that Regulation, a decision addressed to the MemberStates shall be adopted in accordance with the procedure provided forin Articles 33 and 34 of this Directive, for the implementation of thoseconditions or restrictions.
Article 127b
Member States shall ensure that appropriate collection systems are in
place for medicinal products that are unused or have expired.
TITLE XIV
FINAL PROVISIONS
Article 128
Directives 65/65/EEC, 75/318/EEC, 75/319/EEC, 89/342/EEC, 89/343/
EEC, 89/381/EEC, 92/25/EEC, 92/26/EEC, 92/27/EEC, 92/28/EEC and92/73/EEC, amended by the Directives referred to in Annex II, Part A,
are repealed, without prejudice to the obligations of the Member States
concerning the time-limits for implementation set out in Annex II, PartB.
References to the repealed Directives shall be construed as references
to this Directive and shall be read in accordance with the correlationtable in Annex III.
Article 129
This Directive shall enter into force on the twentieth day following that
of its publication in the Official Journal of the European Communities .
Article 130
This Directive is addressed to the Member States.2001L0083 — EN — 30.04.2004 — 003.001 — 64
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ANNEX I
ANALYTICAL, PHARMACOTOXICOLOGICAL AND CLINICAL STANDARDS AND
PROTOCOLS IN RESPECT OF THE TESTING OF MEDICINAL PRODUCTS
TABLE OF CONTENTS
Introduction and general principles . . . ..................................................
Part I: Standardised marketing authorisation dossier requirements ............................
1. Module 1: Administrative information . . ......................................
1.1. Table of contents . . .......................................................
1.2. Application form . . .......................................................
1.3. Summary of product characteristics, labelling and package leaflet . ................
1.3.1. Summary of product characteristics ..........................................
1.3.2. Labelling and package leaflet . . . ............................................
1.3.3. Mock-ups and specimens . . .................................................
1.3.4. Summaries of product characteristics already approved in the Member States . . . .....
1.4. Information about the experts . . . ............................................
1.5. Specific requirements for different types of applications . . . ......................
1.6. Environmental risk assessment . . ............................................
2. Module 2: Summaries .....................................................
2.1. Overall table of contents . . .................................................
2.2. Introduction . . ............................................................
2.3. Quality overall summary . . .................................................
2.4. Non-clinical overview .....................................................
2.5. Clinical overview . . .......................................................
2.6. Non-clinical summary .....................................................
2.7. Clinical Summary . . .......................................................
3. Module 3: Chemical, pharmaceutical and biological information for medicinal products
containing chemical and/or biological active substances ..........................
3.1. Format and presentation . . . .................................................
3.2. Content: basic principles and requirements . . . .................................
3.2.1. Active substance(s) . .......................................................
3.2.1.1. General information and information related to the starting and raw materials . . .....
3.2.1.2. Manufacturing process of the active substance(s) ...............................
3.2.1.3. Characterisation of the active substance(s) .....................................
3.2.1.4. Control of active substance(s) . . . ............................................
3.2.1.5. Reference standards or materials . ............................................
3.2.1.6. Container and closure system of the active substance . ...........................
3.2.1.7. Stability of the active substance(s) ...........................................
3.2.2. Finished medicinal product .................................................
3.2.2.1. Description and composition of the finished medicinal product ....................
3.2.2.2. Pharmaceutical development ................................................
3.2.2.3. Manufacturing process of the finished medicinal product . . . ......................
3.2.2.4. Control of excipients ......................................................
3.2.2.5. Control of the finished medicinal product .....................................
3.2.2.6. Reference standards or materials . ............................................
3.2.2.7. Container and closure of the finished medicinal product . . . ......................
3.2.2.8. Stability of the finished medicinal product .....................................
4. Module 4: Non-clinical reports . . ............................................
4.1. Format and Presentation . . .................................................2001L0083 — EN — 30.04.2004 — 003.001 — 65
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4.2. Content: basic principles and requirements . . . .................................
4.2.1. Pharmacology ............................................................
4.2.2. Pharmaco-kinetics . . .......................................................
4.2.3. Toxicology . . ............................................................
5. Module 5: Clinical study reports . ............................................
5.1. Format and Presentation . . .................................................
5.2. Content: basic principles and requirements . . . .................................
5.2.1. Reports of bio-pharmaceutics studies . . . ......................................
5.2.2. Reports of studies pertinent to pharmaco-kinetics using human bio-materials . . . .....
5.2.3. Reports of human pharmaco-kinetic studies . . . .................................
5.2.4. Reports of human pharmaco-dynamic studies . .................................
5.2.5. Reports of efficacy and safety studies . . ......................................
5.2.5.1. Study Reports of Controlled Clinical Studies Pertinent to the Claimed Indication .....
5.2.5.2. Study reports of uncontrolled clinical studies reports of analyses of data from more than
one study and other clinical study reports .....................................
5.2.6. Reports of post-marketing experience . . . ......................................
5.2.7. Case reports forms and individual patient listings ...............................
Part II: Specific marketing authorisation dossiers and requirements ..........................
1. Well-established medicinal use . . ............................................
2. Essentially similar medicinal products . . ......................................
3. Additional data required in specific situations . .................................
4. Similar biological medicinal products . . . ......................................
5. Fixed combination medicinal products . . ......................................
6. Documentation for applications in exceptional circumstances .....................
7. Mixed marketing authorisation applications . . . .................................
Part III: Particular medicinal products ..................................................
1. Biological medicinal products . . . ............................................
1.1. Plasma-derived medicinal product ............................................
1.2. Vaccines ................................................................
2. Radio-pharmaceuticals and precursors . . ......................................
2.1. Radio-pharmaceuticals .....................................................
2.2. Radio-pharmaceutical precursors for radio-labelling purposes .....................
3. Homeopathic medicinal products ............................................
4. Herbal medicinal products . .................................................
5. Orphan Medicinal Products .................................................
Part IV: Advanced therapy medicinal products ...........................................
1. Gene therapy medicinal products (human and xenogeneic) . ......................
1.1. Diversity of gene therapy medicinal products . .................................
1.2. Specific requirements regarding Module 3 .....................................
2. Somatic cell therapy medicinal products (human and xenogeneic) . ................
3. Specific requirements for gene therapy and somatic cell therapy (human and xeno-
geneic) medicinal products regarding Modules 4 and 5 ..........................
3.1. Module 4 ................................................................
3.2. Module 5 ................................................................2001L0083 — EN — 30.04.2004 — 003.001 — 66
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3.2.1. Human pharmacology and efficacy studies . . . .................................
3.2.2. Safety ..................................................................
4. Specific Statement on Xeno-transplantation Medicinal Products . . . ................2001L0083 — EN — 30.04.2004 — 003.001 — 67
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Introduction and general principles
(1) The particulars and documents accompanying an application for
marketing authorisation pursuant to Articles 8 and 10 (1) shall be
presented in accordance with the requirements set out in this Annex
and shall follow the guidance published by the Commission in The
rules governing medicinal products in the European Community,
Volume 2 B, Notice to applicants, Medicinal products for human use,
Presentation and content of the dossier, Common Technical Document
(CTD).
(2) The particulars and documents shall be presented as five modules:
Module 1 provides European Community specific administrative data;
Module 2 provides quality, non-clinical and clinical summaries,
Module 3 provides chemical, pharmaceutical and biological informa-
tion, Module 4 provides non-clinical reports and Module 5 provides
clinical study reports. This presentation implements a common format
for all ICH (1) regions (European Community, United States of
America, Japan). These five Modules shall be presented in strict accor-
dance with the format, content and numbering system delineated in
details in Volume 2 B of the Notice to Applicants referred to above.
(3) The European Community-CTD-presentation is applicable for all types
of marketing authorisation applications irrespective of the procedure to
be applied (i.e. centralised, mutual recognition or national) and of
whether they are based on a full or abridged application. It is also
applicable for all types of products including new chemical entities
(NCE), radio-pharmaceuticals, plasma derivatives, vaccines, herbal
medicinal products, etc.
(4) In assembling the dossier for application for marketing authorisation,
applicants shall also take into account the scientific guidelines relating
to the quality, safety and efficacy of medicinal products for human use
as adopted by the Committee for Proprietary Medicinal Products
(CPMP) and published by the European Medicine Evaluation Agency
(EMEA) and the other pharmaceutical Community guidelines published
by the Commission in the different volumes of The rules governing
medicinal products in the European Community.
(5) With respect to the quality part (chemical, pharmaceutical and biolo-
gical) of the dossier, all monographs including general monographs
and general chapters of the European Pharmacopoeia are applicable.
(6) The manufacturing process shall comply with the requirements of
Commission Directive 91/356/EEC laying down the principles and
guidelines of Good Manufacturing Practice (GMP) for medicinal
products for human use (2) and with the principles and guidelines on
GMP, published by the Commission in The rules governing medicinal
products in the European Community, Volume 4.
(7) All information, which is relevant to the evaluation of the medicinal
product concerned, shall be included in the application, whether favour-able or unfavourable to the product. In particular, all relevant details
shall be given of any incomplete or abandoned pharmaco-toxicological
or clinical test or trial relating to the medicinal product and/or
completed trials concerning therapeutic indications not covered by the
application.
(8) All clinical trials, conducted within the European Community, must
comply with the requirements of Directive 2001/20/EC of the European
Parliament and of the Council on the approximation of the laws, regula-
tions and administrative provisions of the Member States relating to the
implementation of good clinical practice in the conduct of clinical trials
on medicinal products for human use (
3). To be taken into account
during the assessment of an application, clinical trials, conducted
outside the European Community, which relate to medicinal products
intended to be used in the European Community, shall be designed,
implemented and reported on what good clinical practice and ethical
principles are concerned, on the basis of principles, which are equiva-
lent to the provisions of Directive 2001/20/EC. They shall be carried
out in accordance with the ethical principles that are reflected, for
example, in the Declaration of Helsinki.2001L0083 — EN — 30.04.2004 — 003.001 — 68
(1) International Conference on Harmonisation of Technical Requirements for Registration
of Pharmaceuticals for Human Use.
(2) OJ L 193, 17.7.1991, p. 30.
(3) OJ L 121, 1.5.2001, p. 34.
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(9) Non-clinical (pharmaco-toxicological) studies shall be carried out in
conformity with the provisions related to Good Laboratory Practice
laid down in Council Directives 87/18/EEC on the harmonisation of
regulations and administrative provisions relating to the application of
the principles of good laboratory practice and the verification of their
application for tests in chemical substances (1) and 88/320/EEC on the
inspection and verification of good laboratory practice (GLP) (2).
(10) Member States shall also ensure that all tests on animals are conducted
in accordance with Council Directive 86/609/EEC of 24 November
1986 on the approximation of laws, regulation and administrative provi-
sions of the Member States regarding the protection of animals for
experimental and other scientific purposes.
(11) In order to monitor the benefit/risk assessment, any new information
not in the original application and all pharmaco-vigilance information
shall be submitted to the competent authority. After marketing authori-
sation has been granted, any change to the data in the dossier shall be
submitted to the competent authorities in accordance with the require-
ments of Commission Regulations (EC) No 1084/2003 (3) and (EC) No
1085/2003 (4) of the Commission or, if relevant, in accordance with
national provisions, as well as the requirements in Volume 9 of
Commission publication The rules governing medicinal products in the
European Community.
This Annex is divided in four different parts:
— Part I describes the application format, the summary of product
characteristics, the labelling, the leaflet and presentation require-
ments for standard applications (Modules 1 to 5).
— Part II provides derogation for ‘Specific applications’, i.e. well-
established medicinal use, essentially similar products, fixed combi-
nations, similar biological products, exceptional circumstances and
mixed applications (part bibliographic and part own studies).
— Part III deals with ‘Particular application requirements’ for biolo-
gical medicinal products (Plasma Master File; Vaccine Antigen
Master File), radio-pharmaceuticals, homeopathic medicinal
products, herbal medicinal products and orphan medicinal products.
— Part IV deals with ‘Advanced therapy medicinal products’ and
concerns specific requirements for gene therapy medicinal products
(using human autologous or allogeneic system, or xenogeneic
system) and cell therapy medicinal products both of human or
animal origin and xenogeneic transplantation medicinal products.
PART I
STANDARDISED MARKETING AUTHORISATION DOSSIER
REQUIREMENTS
1. MODULE 1: ADMINISTRATIVE INFORMATION
1.1. Table of contents
A comprehensive table of contents of Modules 1 to 5 of the dossier
submitted for marketing authorisation application shall be presented.
1.2. Application form
The medicinal product, which is the subject of the application, shall be
identified by name and name of the active substance(s), together with
the pharmaceutical form, the route of administration, the strength and
the final presentation, including packaging.
The name and address of the applicant shall be given, together with the
name and address of the manufacturers and the sites involved in the
different stages of the manufacture (including the manufacturer of the
finished product and the manufacturer(s) of the active substance(s)),
and where relevant the name and address of the importer.
The applicant shall identify the type of application and indicate what
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(1) OJ L 15, 17.1.1987, p. 29.
(2) OJ L 145, 11.6.1988, p. 35.
(3) See p. 1 of this Official Journal.
(4) See p. 24 of this Official Journal.
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Annexed to the administrative data shall be copies of the manufacturing
authorisation as defined in Article 40, together with a list of countries
in which authorisation has been granted, copies of all the summaries of
product characteristics in accordance with Article 11 as approved by
Member States and a list of countries in which an application has been
submitted.
As outlined in the application form, the applicants shall provide, inter
alia, details of the medicinal product subject of the application, the
legal basis of the application, the proposed marketing authorisation
holder and manufacture(s), information on orphan medicinal product
status, scientific advice and paediatric development program.
1.3. Summary of product characteristics, labelling and package leaflet
1.3.1. Summary of product characteristics
The applicant shall propose a summary of the product characteristics, in
accordance with Article 11.
1.3.2. Labelling and package leaflet
A proposed labelling text for immediate and outer packaging as well as
for the package leaflet shall be provided. These shall be in accordance
with all mandatory items listed in Title V on the labelling of medicinal
products for human use (Article 63) and on package leaflet (Article 59).
1.3.3. Mock-ups and specimens
The applicant shall provide specimen and/or mock-ups of the
immediate and outer packaging, labels and package leaflets for themedicinal product concerned.
1.3.4. Summaries of product characteristics already approved in the Member
States
Annexed to the administrative data of the application form shall be
copies of all the summaries of product characteristics in accordance
with Articles 11 and 21 as approved by Member States, where applic-
able and a list of countries in which an application has been submitted.
1.4. Information about the experts
In accordance with Article 12 (2) experts must provide detailed reports
of their observations on the documents and particulars which constitute
the marketing authorisation dossier and in particular on Modules 3, 4
and 5 (chemical, pharmaceutical and biological documentation, non-
clinical documentation and clinical documentation, respectively). The
experts are required to address the critical points related to the quality
of the medicinal product and of the investigations carried out on
animals and human beings and bring out all the data relevant for
evaluation.
These requirements shall be met by providing a quality overall
summary, a non-clinical overview (data from studies carried out in
animals) and a clinical overview that shall be located in Module 2 of
the marketing authorisation application dossier. A declaration signed
by the experts together with brief information on their educational
background, training and occupational experience shall be presented in
Module 1. The experts shall have suitable technical or professional
qualifications. The professional relationship of the expert to the appli-
cant shall be declared.
1.5. Specific requirements for different types of applications
Specific requirements for different types of applications are addressed
in Part II of the present Annex.
1.6. Environmental risk assessment
Where applicable, applications for marketing authorisations shall
include a risk assessment overview evaluating possible risks to theenvironment due to the use and/or disposal of the medicinal product
and make proposals for appropriate labelling provisions. Environmental
risk connected with the release of medicinal products containing or
consisting of GMOs (Genetically Modified Organisms) within the
meaning of Article 2 of Directive 2001/18/EC of the European2001L0083 — EN — 30.04.2004 — 003.001 — 70
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Parliament and of the Council of 12 March 2001 on the deliberate
release into the environment of modified organisms and repealing
Council Directive 90/220/EEC (1) shall be addressed.
Information pertaining to the environmental risk shall appear as an
appendix to Module 1.
The information shall be presented in accordance with the provisions of
Directive 2001/18/EC, taking into account any guidance documents
published by the Commission in connection with the implementation
of the said Directive.
The information shall consist of:
— an introduction;
— a copy of any written consent or consents to the deliberate release
into the environment of the GMO(s) for research and development
purposes according to Part B of Directive 2001/18/EC;
— the information requested in Annexes II to IV of the Directive 2001/
18/EC, including detection and identification methods as well as
unique code of the GMO, plus any additional information on the
GMO or the product of relevance to evaluating the environmental
risk;
— an environment risk assessment (ERA) report prepared on basis of
the information specified in Annexes III and IV of Directive 2001/
18/EC and in accordance with Annex II of Directive 2001/18/EC;
— taking into account the above information and the ERA, a conclu-
sion which proposes an appropriate risk management strategy
which includes, as relevant to the GMO and product in question, a
post-market monitoring plan and the identification of any special
particulars which need to appear in the Summary of Product Char-
acteristics, labelling and package leaflet;
— appropriate measures in order to inform the public.
A dated signature of the author, information on the author's educational,
training and occupational experience, and a statement of the author's
relationship with the applicant, shall be included.
2. MODULE 2: SUMMARIES
This Module aims to summarise the chemical, pharmaceutical and
biological data, the non-clinical data and the clinical data presented in
Modules 3, 4 and 5 of the dossier for marketing authorisation, and to
provide the reports/overviews described in Article 12 of this Directive.
Critical points shall be addressed and analysed. Factual summaries
including tabular formats shall be provided. Those reports shall provide
cross-references to tabular formats or to the information contained in
the main documentation presented in Module 3 (chemical, pharmaceu-
tical and biological documentation), Module 4 (non-clinical
documentation) and Module 5 (clinical documentation).
Information contained in Module 2 shall be presented in accordance
with the format, content and numbering system delineated in the
Volume 2 of the Notice to Applicants. The overviews and summaries
shall comply with the basic principles and requirements as laid down
herewith:
2.1. Overall table of contents
Module 2 shall contain a table of contents for the scientific documenta-
tion submitted in Modules 2 to 5.
2.2. Introduction
Information on the pharmacological class, mode of action and proposed
clinical use of the medicinal product for which a marketing authorisa-
tion is requested shall be supplied.
2.3. Quality overall summary
A review of the information related to the chemical, pharmaceutical and
biological data shall be provided in a quality overall summary.2001L0083 — EN — 30.04.2004 — 003.001 — 71
(1) OJ L 106, 17.4.2001, p. 1.
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Key critical parameters and issues related to quality aspects shall be
emphasised as well as justification in cases where the relevant guide-
lines are not followed. This document shall follow the scope and
outline of the corresponding detailed data presented in Module 3.
2.4. Non-clinical overview
An integrated and critical assessment of the non-clinical evaluation of
the medicinal product in animals/in vitro shall be required. Discussion
and justification of the testing strategy and of deviation from the rele-
vant guidelines shall be included.
Except for biological medicinal products, an assessment of the impuri-
ties and degradation products shall be included along with their
potential pharmacological and toxicological effects. The implications
of any differences in the chirality, chemical form, and impurity profile
between the compound used in the non-clinical studies and the product
to be marketed shall be discussed.
For biological medicinal products, comparability of material used in
non-clinical studies, clinical studies, and the medicinal product for
marketing shall be assessed.
Any novel excipient shall be the subject of a specific safety assessment.The characteristics of the medicinal product, as demonstrated by the
non-clinical studies shall be defined and the implications of the findings
for the safety of the medicinal product for the intended clinical use in
human shall be discussed.
2.5. Clinical overview
The clinical overview is intended to provide a critical analysis of the
clinical data included in the clinical summary and Module 5. The
approach to the clinical development of the medicinal product,
including critical study design, decisions related to and performance of
the studies shall be provided.
A brief overview of the clinical findings, including important limita-
tions as well as an evaluation of benefits and risks based on the
conclusions of the clinical studies shall be provided. An interpretation
of the way the efficacy and safety findings support the proposed dose
and target indications and an evaluation of how the summary of product
characteristics and other approaches will optimise the benefits and
manage the risks is required.
Efficacy or safety issues encountered in development and unresolved
issues shall be explained.
2.6. Non-clinical summary
The results of pharmacology, pharmaco-kinetics and toxicology studies
carried out in animals/in vitro shall be provided as factual written and
tabulated summaries which shall be presented in the following order:
— Introduction
— Pharmacology Written Summary— Pharmacology Tabulated Summary
— Pharmaco-kinetics Written Summary
— Pharmaco-kinetics Tabulated Summary— Toxicology Written Summary— Toxicology Tabulated Summary.
2.7. Clinical Summary
A detailed, factual summary of the clinical information on the medic-
inal product included in Module 5 shall be provided. This shall
include the results of all bio-pharmaceutics studies, of clinical pharma-
cology studies, and of clinical efficacy and safety studies. A synopsis of
the individual studies is required.
Summarised clinical information shall be presented in the following
order:
— Summary of Bio-pharmaceutics and Associated Analytical Methods
— Summary of Clinical Pharmacology Studies— Summary of Clinical Efficacy
— Summary of Clinical Safety2001L0083 — EN — 30.04.2004 — 003.001 — 72
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— Synopses of Individual Studies
3. MODULE 3: CHEMICAL, PHARMACEUTICAL AND BIOLOGICAL
INFORMATION FOR MEDICINAL PRODUCTS CONTAINING
CHEMICAL AND/OR BIOLOGICAL ACTIVE SUBSTANCES
3.1. Format and presentation
The general outline of Module 3 is as follows:
— Table of contents
— Body of data
—Active substance
General Information
— Nomenclature
— Structure
— General Properties
Manufacture— Manufacturer(s)
— Description of Manufacturing Process and Process Controls— Control of Materials
— Controls of Critical Steps and Intermediates
— Process Validation and/or Evaluation
— Manufacturing Process Development
Characterisation— Elucidation of Structure and other Characteristics
— Impurities
Control of Active Substance— Specification
— Analytical Procedures
— Validation of Analytical Procedures
— Batch Analyses
— Justification of Specification
Reference Standards or Materials
Container Closure SystemStability— Stability Summary and Conclusions
— Post-approval Stability Protocol and Stability Commitment
— Stability Data
—Finished Medicinal Product
Description and Composition of the Medicinal
Product
Pharmaceutical Development— Components of the Medicinal Product
— Active Substance
— Excipients
— Medicinal Product
— Formulation Development
— Overages
— Physicochemical and Biological Properties
— Manufacturing Process Development
— Container Closure System
— Microbiological Attributes
— Compatibility
Manufacture— Manufacturer(s)
— Batch Formula
— Description of Manufacturing Process and Process Controls
— Controls of Critical Steps and Intermediates
— Process Validation and/or Evaluation2001L0083 — EN — 30.04.2004 — 003.001 — 73
▼M2
Control of Excipients
— Specifications
— Analytical Procedures
— Validation of Analytical Procedures
— Justification of Specifications— Excipients of Human or Animal Origin— Novel Excipients
Control of Finished Medicinal Product— Specification(s)
— Analytical Procedures— Validation of Analytical Procedures— Batch Analyses— Characterisation of Impurities
— Justification of Specification(s)
Reference Standards or Materials
Container Closure SystemStability— Stability Summary and Conclusion
— Post-approval Stability Protocol and Stability Commitment— Stability Data
—Appendices
— Facilities and Equipment (Biological Medicinal Products
only)
— Adventitious Agents Safety Evaluation— Excipients
—European Community Additional Information
— Process Validation Scheme for the Medicinal Product
— Medical Device— Certificate(s) of Suitability
— Medicinal products containing or using in the manufacturing
process materials of animal and/or human origin (TSE
procedure)
— Literature References
3.2. Content: basic principles and requirements
(1) The chemical, pharmaceutical and biological data that shall be
provided shall include for the active substance(s) and for the
finished medicinal product all of relevant information on: the
development, the manufacturing process, the characterisation and
properties, the quality control operations and requirements, the
stability as well as a description of the composition and presenta-
tion of the finished medicinal product.
(2) Two main sets of information shall be provided, dealing with the
active substance(s) and with the finished medicinal product,
respectively.
(3) This Module shall in addition supply detailed information on the
starting and raw materials used during the manufacturing opera-
tions of the active substance(s) and on the excipients incorporated
in the formulation of the finished medicinal product.
(4) All the procedures and methods used for manufacturing and
controlling the active substance and the finished medicinal product
shall be described in sufficient details to enable them to be
repeated in control tests, carried out at the request of the compe-
tent authority. All test procedures shall correspond to the state of
scientific progress at the time and shall be validated. Results of
the validation studies shall be provided. In the case of test proce-
dures included in the European Pharmacopoeia, this description
shall be replaced by the appropriate detailed reference to the
monograph(s) and general chapter(s).
(5) The monographs of the European Pharmacopoeia shall be applic-
able to all substances, preparations and pharmaceutical forms
appearing in it. In respect of other substances, each Member State
may require observance of its own national pharmacopoeia.
However, where a material in the European Pharmacopoeia or in
the pharmacopoeia of a Member State has been prepared by a2001L0083 — EN — 30.04.2004 — 003.001 — 74
▼M2
method liable to leave impurities not controlled in the pharmaco-
poeia monograph, these impurities and their maximum tolerance
limits must be declared and a suitable test procedure must be
described. In cases where a specification contained in a mono-
graph of the European Pharmacopoeia or in the national
pharmacopoeia of a Member State might be insufficient to ensure
the quality of the substance, the competent authorities may request
more appropriate specifications from the marketing authorisation
holder. The competent authorities shall inform the authorities
responsible for the pharmacopoeia in question. The marketing
authorisation holder shall provide the authorities of that pharmaco-
poeia with the details of the alleged insufficiency and the
additional specifications applied.
In the case of analytical procedures included in the European
Pharmacopoeia, this description shall be replaced in each relevant
section by the appropriate detailed reference to the monograph(s)
and general chapter(s).
(6) In case where starting and raw materials, active substance(s) or
excipient(s) are described neither in the European Pharmacopoeia
nor in the pharmacopoeia of a Member State, compliance with the
monograph of a third country pharmacopoeia can be accepted. In
such cases, the applicant shall submit a copy of the monograph
accompanied by the validation of the analytical procedures
contained in the monograph and by a translation where appro-
priate.
(7) Where the active substance and/or a raw and starting material or
excipient(s) are the subject of a monograph of the European Phar-
macopoeia, the applicant can apply for a certificate of suitability
that, where granted by the European Directorate for the Quality
of Medicines, shall be presented in the relevant section of this
Module. Those certificates of suitability of the monograph of the
European Pharmacopoeia are deemed to replace the relevant data
of the corresponding sections described in this Module. The manu-
facturer shall give the assurance in writing to the applicant that the
manufacturing process has not been modified since the granting of
the certificate of suitability by the European Directorate for the
Quality of Medicines.
(8) For a well-defined active substance, the active substance manufac-
turer or the applicant may arrange for the
(i) detailed description of the manufacturing process,
(ii) quality control during manufacture, and
(iii) process validation
to be supplied in a separate document directly to the competent
authorities by the manufacturer of the active substance as an
Active Substance Master File.
In this case, the manufacturer shall, however, provide the appli-
cant with all of the data, which may be necessary for the latter to
take responsibility for the medicinal product. The manufacturer
shall confirm in writing to the applicant that he shall ensure batch
to batch consistency and not modify the manufacturing process or
specifications without informing the applicant. Documents and
particulars supporting the application for such a change shall be
supplied to the competent authorities; these documents and parti-
culars will be also supplied to the applicant when they concern
the open part of the active substance master file.
(9) Specific measures concerning the prevention of the transmission
of animal spongiform encephalopathies (materials from ruminant
origin): at each step of the manufacturing process, the applicant
must demonstrate the compliance of the materials used with the
Note for Guidance on Minimising the Risk of Transmitting
Animal Spongiform Encephalopathy Agents via Medicinal
Products and its updates, published by the Commission in the
Official Journal of the European Union. Demonstration of compli-
ance with the said Note for Guidance can be done by submitting
either, preferably a certificate of suitability to the relevant mono-
graph of the European Pharmacopoeia that has been granted by
the European Directorate for the Quality of Medicines or by the
supply of scientific data to substantiate this compliance.
(10) For adventitious agents, information assessing the risk with respect
to potential contamination with adventitious agents, whether they
are non-viral or viral, as laid down in relevant guidelines as well2001L0083 — EN — 30.04.2004 — 003.001 — 75
▼M2
as in relevant general monograph and general chapter of the
European Pharmacopoeia, shall be provided.
(11) Any special apparatus and equipment, which may be used at any
stage of the manufacturing process and control operations of the
medicinal product, shall be described in adequate details.
(12) Where applicable and if needed, a CE marking which is required
by Community legislation on medical devices shall be provided.
Special attention shall be paid to the following selected elements.
3.2.1. Active substance(s)
3.2.1.1. G e n e r a l i n f o r m a t i o n a n d i n f o r m a t i o n r e l a t e d t o t h e s t a r t i n g
and raw materials
a) Information on the nomenclature of the active substance shall be
provided, including recommended International Non-proprietary
Name (INN), European Pharmacopoeia name if relevant, chemical
name(s).
The structural formula, including relative and absolute stereo-chem-
istry, the molecular formula, and the relative molecular mass shall
be provided. For biotechnological medicinal products if appropriate,
the schematic amino acid sequence and relative molecular mass
shall be provided.
A list shall be provided of physicochemical and other relevant prop-
erties of the active substance, including biological activity for
biological medicinal products.
b) For the purposes of this Annex, starting materials shall mean all the
materials from which the active substance is manufactured or
extracted.
For biological medicinal products, starting materials shall mean any
substance of biological origin such as micro-organisms, organs and
tissues of either plant or animal origin, cells or fluids (including
blood or plasma) of human or animal origin, and biotechnological
cell constructs (cell substrates, whether they are recombinant or
not, including primary cells).
A biological medicinal product is a product, the active substance of
which is a biological substance. A biological substance is a
substance that is produced by or extracted from a biological source
and that needs for its characterisation and the determination of its
quality a combination of physico-chemical-biological testing,
together with the production process and its control. The following
shall be considered as biological medicinal products: immunological
medicinal products and medicinal products derived from human
blood and human plasma as defined, respectively in paragraphs (4)
and (10) of Article 1; medicinal products falling within the scope of
Part A of the Annex to Regulation (EEC) No 2309/93; advanced
therapy medicinal products as defined in Part IV of this Annex.
Any other substances used for manufacturing or extracting the active
substance(s) but from which this active substance is not directly
derived, such as reagents, culture media, foetal calf serum, additives,
and buffers involved in chromatography, etc. are known as raw
materials.
3.2.1.2. M a n u f a c t u r i n g p r o c e s s o f t h e a c t i v e s u b s t a n c e ( s )
a) The description of the active substance manufacturing process repre-
sents the applicant's commitment for the manufacture of the active
substance. To adequately describe the manufacturing process and
process controls, appropriate information as laid down in guidelines
published by the Agency shall be provided.
b) All materials needed in order to manufacture the active substance(s)
shall be listed, identifying where each material is used in the
process. Information on the quality and control of these materials
shall be provided. Information demonstrating that materials meet
standards appropriate for their intended use shall be provided.
Raw materials shall be listed and their quality and controls shall also
be documented.
The name, address, and responsibility of each manufacturer,
including contractors, and each proposed production site or facility
involved in manufacturing and testing shall be provided.
c) For biological medicinal products, the following additional require-
ments shall apply.2001L0083 — EN — 30.04.2004 — 003.001 — 76
▼M2
The origin and history of starting materials shall be described and
documented.
Regarding the specific measures for the prevention of the Transmis-
sion of animal Spongiform Encephalopathies, the applicant must
demonstrate that the active substance complies with the Note for
Guidance on Minimising the Risk of Transmitting Animal Spongi-
form Encephalopathy Agents via Medicinal Products and its
updates, published by the Commission in the Official Journal of the
European Union.
When cell banks are used, the cell characteristics shall be shown to
have remained unchanged at the passage level used for the produc-
tion and beyond.
Seed materials, cell banks, pools of serum or plasma and other mate-
rials of biological origin and, whenever possible, the materials from
which they are derived shall be tested for adventitious agents.
If the presence of potentially pathogenic adventitious agents is inevi-
table, the corresponding material shall be used only when further
processing ensures their elimination and/or inactivation, and this
shall be validated.
Whenever possible, vaccine production shall be based on a seed lot
system and on established cell banks. For bacterial and viral
vaccines, the characteristics of the infectious agent shall be demon-
strated on the seed. In addition, for live vaccines, the stability of the
attenuation characteristics shall be demonstrated on the seed; if this
proof is not sufficient, the attenuation characteristics shall also be
demonstrated at the production stage.
For medicinal products derived from human blood or plasma, the
origin and the criteria and procedures for collection, transportation
and storage of the starting material shall be described and docu-
mented in accordance with provisions laid down in Part III of this
Annex.
The manufacturing facilities and equipment shall be described.
d) Tests and acceptance criteria carried out at every critical step, infor-
mation on the quality and control of intermediates and process
validation and/or evaluation studies shall be provided as appropriate.
e) If the presence of potentially pathogenic adventitious agents is inevi-
table, the correspondent material shall be used only when further
processing ensures their elimination and/or inactivation and this
shall be validated in the section dealing with viral safety evaluation.
f) A description and discussion of the significant changes made to the
manufacturing process during development and/or manufacturing
site of the active substance shall be provided.
3.2.1.3. C h a r a c t e r i s a t i o n o f t h e a c t i v e s u b s t a n c e ( s )
Data highlighting the structure and other characteristics of the active
substance(s) shall be provided.
Confirmation of the structure of the active substance(s) based on any
physico-chemical and/or immuno-chemical and/or biological methods,
as well as information on impurities shall be provided.
3.2.1.4. C o n t r o l o f a c t i v e s u b s t a n c e ( s )
Detailed information on the specifications used for routine control of
active substance(s), justification for the choice of these specifications,
methods of analysis and their validation shall be provided.
The results of control carried out on individual batches manufactured
during development shall be presented.
3.2.1.5. R e f e r e n c e s t a n d a r d s o r m a t e r i a l s
Reference preparations and standards shall be identified and described
in detail. Where relevant, chemical and biological reference material
of the European Pharmacopoeia shall be used.
3.2.1.6. C o n t a i n e r a n d c l o s u r e s y s t e m o f t h e a c t i v e s u b s t a n c e
A description of the container and the closure system(s) and their speci-
fications shall be provided.
3.2.1.7. S t a b i l i t y o f t h e a c t i v e s u b s t a n c e ( s )
a) The types of studies conducted, protocols used, and the results of the
studies shall be summarised2001L0083 — EN — 30.04.2004 — 003.001 — 77
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b) Detailed results of the stability studies, including information on the
analytical procedures used to generate the data and validation of
these procedures shall be presented in an appropriate format
c) The post authorisation stability protocol and stability commitment
shall be provided
3.2.2. Finished medicinal product
3.2.2.1. D e s c r i p t i o n a n d c o m p o s i t i o n o f t h e f i n i s h e d m e d i c i n a l
product
A description of the finished medicinal product and its composition
shall be provided. The information shall include the description of the
pharmaceutical form and composition with all the constituents of the
finished medicinal product, their amount on a per-unit basis, the func-
tion of the constituents of:
— the active substance(s),
— the constituent(s) of the excipients, whatever their nature or the
quantity used, including colouring matter, preservatives, adjuvants,
stabilisers, thickeners, emulsifiers, flavouring and aromatic
substances, etc.,
— the constituents, intended to be ingested or otherwise administered
to the patient, of the outer covering of the medicinal products
(hard capsules, soft capsules, rectal capsules, coated tablets, films-
coated tablets, etc.),
— these particulars shall be supplemented by any relevant data
concerning the type of container and, where appropriate, its mannerof closure, together with details of devices with which the medicinal
product will be used or administered and which will be delivered
with the medicinal product.
The ‘usual terminology’, to be used in describing the constituents of
medicinal products, shall mean, notwithstanding the application of theother provisions in Article 8 (3) (c):
— in respect of substances which appear in the European Pharmaco-
poeia or, failing this, in the national pharmacopoeia of one of the
Member States, the main title at the head of the monograph in ques-
tion, with reference to the pharmacopoeia concerned,
— in respect of other substances, the international non-proprietary
name (INN) recommended by the World Health Organisation, or,
failing this, the exact scientific designation; substances not having
an international non-proprietary name or an exact scientific designa-
tion shall be described by a statement of how and from what they
were prepared, supplemented, where appropriate, by any other rele-
vant details,
— in respect of colouring matter, designation by the ‘E’ code assigned
to them in Council Directive 78/25/EEC of 12 December 1977 on
the approximation of the rules of the Member States concerning
the colouring matters authorised for use in medicinal products (
1)
and/or European Parliament and Council Directive 94/36/EC of
30 June 1994 on colours for use in foodstuffs (2).
In order to give the ‘quantitative composition’ of the active substance(s)
of the finished medicinal products, it is necessary, depending on the
pharmaceutical form concerned, to specify the mass, or the number of
units of biological activity, either per dosage-unit or per unit of mass or
volume, of each active substance.
Active substances present in the form of compounds or derivatives shall
be designated quantitatively by their total mass, and if necessary or
relevant, by the mass of active entity or entities of the molecule.
For medicinal products containing an active substance, which is the
subject of an application for marketing authorisation in any Member
State for the first time, the quantitative statement of an active
substance, which is a salt or hydrate shall be systematically expressed
in terms of the mass of the active entity or entities in the molecule.
All subsequently authorised medicinal products in the Member States
shall have their quantitative composition stated in the same way for
the same active substance.
Units of biological activity shall be used for substances, which cannot
be defined molecularly. Where an International Unit of biological2001L0083 — EN — 30.04.2004 — 003.001 — 78
(1) OJ L 11, 14.1.1978, p. 18.
(2) OJ L 237, 10.9.1994, p. 13.
▼M2
activity has been defined by the World Health Organisation, this shall
be used. Where no International Unit has been defined, the units of
biological activity shall be expressed in such a way as to provide unam-
biguous information on the activity of the substances by using where
applicable the European Pharmacopoeia Units.
3.2.2.2. P h a r m a c e u t i c a l d e v e l o p m e n t
This chapter shall be devoted to information on the development studies
conducted to establish that the dosage form, the formulation, manufac-
turing process, container closure system, microbiological attributes and
usage instructions are appropriate for the intended use specified in the
marketing authorisation application dossier.
The studies described in this chapter are distinct from routine control
tests conducted according to specifications. Critical parameters of the
formulation and process attributes that can influence batch reproduci-
bility, medicinal product performance and medicinal product quality
shall be identified and described. Additional supportive data, where
appropriate, shall be referenced to the relevant chapters of Module 4
(Non Clinical Study Reports) and Module 5 (Clinical Study Reports)
of the marketing authorisation application dossier.
a) The compatibility of the active substance with excipients as well as
key physicochemical characteristics of the active substance that can
influence the performance of the finished product or the compat-
ibility of different active substances with each other in the case of
combination products, shall be documented.
b) The choice of excipients, in particular relative to their respective
functions and concentration shall be documented.
c) A description of the development of the finished product shall be
provided, taking into consideration the proposed route of administra-
tion and usage.
d) Any overages in the formulation(s) shall be warranted.
e) As far as the physiochemical and biological properties are
concerned, any parameter relevant to the performance of finished
product shall be addressed and documented.
f) The selection and optimisation of the manufacturing process as well
as differences between the manufacturing process(es) used to
produce pivotal clinical batches and the process used for manufac-
turing the proposed finished medicinal product shall be provided.
g) The suitability of the container and closure system used for the
storage, shipping and use of the finished product shall be docu-
mented. A possible interaction between medicinal product and
container may need to be considered.
h) The microbiological attributes of the dosage form in relation with
non-sterile and sterile products shall be in accordance with and
documented as prescribed in the European Pharmacopoeia.
i) In order to provide appropriate and supportive information for the
labelling the compatibility of the finished product with reconstitution
diluent(s) or dosage devices shall be documented.
3.2.2.3. M a n u f a c t u r i n g p r o c e s s o f t h e f i n i s h e d m e d i c i n a l p r oduct
a) The description of the manufacturing method accompanying the
application for Marketing Authorisation pursuant to Article 8 (3) (d),
shall be drafted in such a way as to give an adequate synopsis of thenature of the operations employed.
For this purpose it shall include at least:— mention of the various stages of manufacture including process
controls and corresponding acceptance criteria, so that an assess-
ment can be made of whether the processes employed in
producing the pharmaceutical form might have produced an
adverse change in the constituents,
— in the case of continuous manufacture, full details concerning
precautions taken to ensure the homogeneity of the finished
product,
— experimental studies validating the manufacturing process, where
a non-standard method of manufacture is used or where it is
critical for the product,
— for sterile medicinal products, details of the sterilisation
processes and/or aseptic procedures used,
— a detailed batch formula.2001L0083 — EN — 30.04.2004 — 003.001 — 79
▼M2
The name, address, and responsibility of each manufacturer,
including contractors, and each proposed production site or facility
involved in manufacturing and testing shall be provided.
b) Particulars relating to the product control tests that may be carried
out at an intermediate stage of the manufacturing process, with a
view to ensuring the consistency of the production process shall be
included.
These tests are essential for checking the conformity of the medic-
inal product with the formula when, exceptionally, an applicant
proposes an analytical method for testing the finished product which
does not include the assay of all the active substances (or of all the
excipient constituents subject to the same requirements as the active
substances).
The same applies where the quality control of the finished product
depends on in-process control tests, particularly if the medicinal
product is essentially defined by its method of preparation.
c) Description, documentation, and results of the validation studies for
critical steps or critical assays used in the manufacturing process
shall be provided.
3.2.2.4. C o n t r o l o f e x c i p i e n t s
a) All the materials needed in order to manufacture the excipient(s)
shall be listed identifying where each material is used in the process.
Information on the quality and control of these materials shall be
provided. Information demonstrating that materials meet standards
appropriate for their intended use shall be provided.
Colouring matter shall, in all cases, satisfy the requirements of
Directives 78/25/EEC and/or 94/36/EC. In addition, colouring matter
shall meet purity criteria as laid down in Directive 95/45/EC, as
amended.
b) For each excipient, the specifications and their justifications shall be
detailed. The analytical procedures shall be described and duly vali-
dated.
c) Specific attention shall be paid to excipients of human or animal
origin.
Regarding the specific measures for the prevention of the Transmis-
sion of animal Spongiform Encephalopathies, the applicant must
demonstrate also for excipients that the medicinal product is manu-
factured in accordance with the Note for Guidance on Minimising
the Risk of Transmitting Animal Spongiform Encephalopathy
Agents via Medicinal Products and its updates, published by the
Commission in the Official Journal of the European Union.
Demonstration of compliance with the aforementioned Note for
Guidance can be done by submitting either preferably a certificate
of suitability to the relevant monograph on Transmissible Spongi-
form Encephalopathies of the European Pharmacopoeia, or by thesupply of scientific data to substantiate this compliance.
d) Novel excipients:
For excipient(s) used for the first time in a medicinal product or by
a new route of administration, full details of manufacture, character-
isation, and controls, with cross references to supporting safety data,
both non-clinical and clinical, shall be provided according to the
active substance format previously described.
A document containing the detailed chemical, pharmaceutical and
biological information shall be presented. This information shall be
formatted in the same order as the chapter devoted to Active
Substance(s) of Module 3.
Information on novel excipient(s) may be presented as a stand-alone
document following the format described in the former paragraphs.
Where the applicant differs from the novel excipient manufacturer
the said stand-alone document shall be made available to the appli-
cant for submission to the competent authority.
Additional information on toxicity studies with the novel excipient
shall be provided in Module 4 of the dossier.
Clinical studies shall be provided in Module 5.
3.2.2.5. C o n t r o l o f t h e f i n i s h e d m e d i c i n a l p r oduct
For the control of the finished medicinal product, a batch of a medicinal
product is an entity which comprises all the units of a pharmaceutical
form which are made from the same initial quantity of material and2001L0083 — EN — 30.04.2004 — 003.001 — 80
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have undergone the same series of manufacturing and/or sterilisation
operations or, in the case of a continuous production process, all the
units manufactured in a given period of time.
Unless there is appropriate justification, the maximum acceptable devia-
tion in the active substance content of the finished product shall not
exceed ± 5 % at the time of manufacture.
Detailed information on the specifications, (release and shelf life) justi-
fication for their choice, methods of analysis and their validation shall
be provided.
3.2.2.6. R e f e r e n c e s t a n d a r d s o r m a t e r i a l s
Reference preparations and standards used for testing of the finished
medicinal product shall be identified and described in detail, if not
previously provided in the section related to the active substance.
3.2.2.7. C o n t a i n e r a n d c l o s u r e o f t h e f i n i s h e d m e d i c i n a l p r o d u c t
A description of the container and the closure system(s) including the
identity of each immediate packaging material and their specifications
shall be provided. The specifications shall include description and iden-tification. Non-pharmacopoeial methods (with validation) shall be
included where appropriate.
For non-functional outer packaging materials only a brief description
shall be provided. For functional outer packaging materials additional
information shall be provided.
3.2.2.8. S t a b i l i t y o f t h e f i n i s h e d m e d i c i n a l p r oduct
a) The types of studies conducted, protocols used, and the results of the
studies shall be summarised;
b) Detailed results of the stability studies, including information on the
analytical procedures used to generate the data and validation of
these procedures shall be presented in an appropriate format; in
case of vaccines, information on cumulative stability shall be
provided where appropriate;
c) The post authorisation stability protocol and stability commitment
shall be provided.
4. MODULE 4: NON-CLINICAL REPORTS4.1. Format and Presentation
The general outline of Module 4 is as follows:
— Table of contents
— Study reports
—Pharmacology
— Primary Pharmaco-dynamics
— Secondary Pharmaco-dynamics
— Safety Pharmacology— Pharmaco-dynamic Interactions
—Pharmaco-kinetics
— Analytical Methods and Validation Reports
— Absorption
— Distribution
— Metabolism— Excretion— Pharmaco-kinetic Interactions (non-clinical)
— Other Pharmaco-kinetic Studies
—Toxicology
— Single-Dose Toxicity
— Repeat-Dose Toxicity— Genotoxicity
— In vitro
— In vivo (including supportive toxico-kinetics evaluations)
— Carcinogenicity
— Long-term studies
— Short- or medium-term studies
— Other studies2001L0083 — EN — 30.04.2004 — 003.001 — 81
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— Reproductive and Developmental Toxicity
— Fertility and early embryonic development
— Embryo-fetal development
— Prenatal and postnatal development
— Studies in which the offspring (juvenile animals) are
dosed and/or further evaluated
— Local Tolerance
—Other Toxicity Studies
— Antigenicity
— Immuno-toxicity— Mechanistic studies— Dependence— Metabolites
— Impurities
— Other
— Literature references
4.2. Content: basic principles and requirements
Special attention shall be paid to the following selected elements.
(1) The pharmacological and toxicological tests must show:
a) the potential toxicity of the product and any dangerous or unde-
sirable toxic effects that may occur under the proposed
conditions of use in human beings; these should be evaluated
in relation to the pathological condition concerned;
b) the pharmacological properties of the product, in both qualita-
tive and quantitative relationship to the proposed use in human
beings. All results must be reliable and of general applicability.
Whenever appropriate, mathematical and statistical procedures
shall be used in designing the experimental methods and in eval-
uating the results.
Additionally, it is necessary for clinicians to be given informa-
tion about the therapeutic and toxicological potential of the
product.
(2) For biological medicinal products such as immunological medicinal
products and medicinal products derived from human blood or
plasma, the requirements of this Module may have to be adapted
for individual products; therefore the testing program carried out
shall be justified by the applicant.
In establishing the testing program, the following shall be taken
into consideration:
all tests requiring repeated administration of the product shall be
designed to take account of the possible induction of, and interfer-
ence by, antibodies;
examination of reproductive function, of embryo/foetal and peri-
natal toxicity, of mutagenic potential and of carcinogenic potential
shall be considered. Where constituents other than the active
substance(s) are incriminated, validation of their removal may
replace the study.
(3) The toxicology and pharmaco-kinetics of an excipient used for the
first time in the pharmaceutical field shall be investigated.
(4) Where there is a possibility of significant degradation during
storage of the medicinal product, the toxicology of degradation
products must be considered.
4.2.1. Pharmacology
Pharmacology study shall follow two distinct lines of approach.
— Firstly, the actions relating to the proposed therapeutic use shall be
adequately investigated and described. Where possible, recognised
and validated assays, both in vivo and in vitro, shall be used. Novel
experimental techniques must be described in such detail as to allow
them to be reproduced. The results shall be expressed in quantitative
terms using, for example, dose-effect curves, time-effect curves, etc.
Wherever possible, comparisons shall be made with data relating to
a substance or substances with a similar therapeutic action.
— Secondly, the applicant shall investigate the potential undesirable
pharmaco-dynamic effects of the substance on physiological func-
tions. These investigations shall be performed at exposures in the2001L0083 — EN — 30.04.2004 — 003.001 — 82
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anticipated therapeutic range and above. The experimental techni-
ques, unless they are standard procedures, must be described in
such detail as to allow them to be reproduced, and the investigator
must establish their validity. Any suspected modification of
responses resulting from repeated administration of the substance
shall be investigated.
For the pharmaco-dynamic medicinal product interaction, tests on
combinations of active substances may be prompted either by pharma-
cological premises or by indications of therapeutic effect. In the first
case, the pharmaco-dynamic study shall demonstrate those interactions,
which might make the combination of value in therapeutic use. In the
second case, where scientific justification for the combination is sought
through therapeutic experimentation, the investigation shall determine
whether the effects expected from the combination can be demonstrated
in animals, and the importance of any collateral effects shall at least be
investigated.
4.2.2. Pharmaco-kinetics
Pharmaco-kinetics means the study of the fate of the active substance,
and its metabolites, within the organism, and covers the study of the
absorption, distribution, metabolism (bio-transformation) and excretion
of these substances.
The study of these different phases may be carried mainly by means of
physical, chemical or possibly by biological methods, and by observa-
tion of the actual pharmaco-dynamic activity of the substance itself.
Information on distribution and elimination shall be necessary in all
cases where such data are indispensable to determine the dosage for
humans, and in respect of chemo-therapeutic substances (antibiotics,
etc.) and substances whose use depends on their non-pharmaco-dynamic
effects (e.g. numerous diagnostic agents, etc.).
In vitro studies also can be carried out with the advantage of using
human material for comparison with animal material (i.e. protein
binding, metabolism, drug-drug interaction).
Pharmaco-kinetic investigation of all pharmacologically active
substances is necessary. In the case of new combinations of known
substances, which have been investigated in accordance with the provi-
sions of this Directive, pharmaco-kinetic studies may not be required, if
the toxicity tests and therapeutic experimentation justify their omission.
The pharmaco-kinetic program shall be design to allow comparison and
extrapolation between animal and human.
4.2.3. Toxicology
a) Single-dose toxicity
A single-dose toxicity test shall mean a qualitative and quantitative
study of the toxic reactions, which may result from a single admin-
istration of the active substance or substances contained in the
medicinal product, in the proportions and physico-chemical state in
which they are present in the actual product.
The single-dose toxicity test must be carried out in accordance with
the relevant guidelines published by the Agency.
b) Repeat-dose toxicity
Repeated dose toxicity tests are intended to reveal any physiological
and/or anatomo-pathological changes induced by repeated adminis-
tration of the active substance or combination of active substances
under examination, and to determine how these changes are related
to dosage.
Generally, it is desirable that two tests be performed: one short term,
lasting two to four weeks, the other long-term. The duration of the
latter shall depend on the conditions of clinical use. Its purpose is to
describe potential adverse effects to which attention should be paid
in clinical studies. The duration is defined in the relevant guidelines
published by the Agency.
c) Geno-toxicity
The purposes of the study of mutagenic and clastogenic potential is
to reveal the changes which a substance may cause in the genetic
material of individuals or cells. Mutagenic substances may present
a hazard to health since exposure to a mutagen carries the risk of
inducing germ-line mutation, with the possibility of inherited disor-
ders, and the risk of somatic mutations including those leading to
cancer. These studies are obligatory for any new substance.2001L0083 — EN — 30.04.2004 — 003.001 — 83
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d) Carcino-genicity
Tests to reveal carcinogenic effects shall normally be required:
1. These studies shall be performed for any medicinal product
whose expected clinical use is for a prolonged period of a
patient's life, either continuously or repeatedly in an intermittent
manner.
2. These studies are recommended for some medicinal products if
there is concern about their carcinogenic potential, e.g. from
product of the same class or similar structure, or from evidence
in repeated dose toxicity studies.
3. Studies with unequivocally geno-toxic compounds are not
needed, as they are presumed to be trans-species carcinogens,
implying a hazard to humans. If such a medicinal product is
intended to be administered chronically to humans a chronic
study may be necessary to detect early tumorigenic effects.
e) Reproductive and developmental toxicity
Investigation of possible impairment of male or female reproductive
function as well as harmful effects on progeny shall be performed
by appropriate tests.
These tests comprise studies of effect on adult male or female repro-
ductive function, studies of the toxic and teratogenic effects at all
stages of development from conception to sexual maturity as well
as latent effects, when the medicinal product under investigation
has been administered to the female during pregnancy.
Omission of these tests must be adequately justified.Depending on the indicated use of the medicinal product, additional
studies addressing development when administering the medicinal
product of the offspring may be warranted.
Embryo/foetal toxicity studies shall normally be conducted on two
mammalian species, one of which shall be other than a rodent.
Peri- and postnatal studies shall be conducted in at least one species.
If the metabolism of a medicinal product in particular species is
known to be similar to that in man, it is desirable to include this
species. It is also desirable that one of the species is the same as in
the repeated dose toxicity studies.
The state of scientific knowledge at the time when the application is
lodged shall be taken into account when determining the study
design.
f) Local tolerance
The purpose of local tolerance studies is to ascertain whether medic-
inal products (both active substances and excipients) are tolerated at
sites in the body, which may come into contact with the medicinal
product as a result of its administration in clinical use. The testing
strategy shall be such that any mechanical effects of administration
or purely physico-chemical actions of the product can be distin-
guished from toxicological or pharmaco-dynamic ones.
Local tolerance testing shall be conducted with the preparation being
developed for human use, using the vehicle and/or excipients in
treating the control group(s). Positive controls/reference substances
shall be included where necessary.
The design of local tolerance tests (choice of species, duration,
frequency and route of administration, doses) will depend upon the
problem to be investigated and the proposed conditions of adminis-
tration in clinical use. Reversibility of local lesions shall be
performed where relevant.
Studies in animals can be substituted by validated in vitro tests
provided that the test results are of comparable quality and useful-
ness for the purpose of safety evaluation.
For chemicals applied to the skin (e.g. dermal, rectal, vaginal) the
sensitising potential shall be evaluated in at least one of the test
systems currently available (the guinea pig assay or the local lymph
node assay).
5. MODULE 5: CLINICAL STUDY REPORTS
5.1. Format and Presentation
The general outline of Module 5 is as follows:
— Table of contents for clinical study reports2001L0083 — EN — 30.04.2004 — 003.001 — 84
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— Tabular listing of all clinical studies
— Clinical study reports
—Reports of Bio-pharmaceutical Studies
— Bio-availability Study Reports
— Comparative Bio-availability and Bio-equivalence Study
Reports
— In vitro — In vivo Correlation Study Report— Reports of Bio-analytical and Analytical Methods
—Reports of Studies Pertinent to Pharmaco-kinetics Using Human
Bio-materials
— Plasma Protein Binding Study Reports
— Reports of Hepatic Metabolism and Interaction Studies— Reports of Studies Using Other Human Bio-materials
—Reports of Human Pharmaco-kinetic Studies
— Healthy subjects Pharmaco-kinetics and Initial Tolerability
Study Reports
— Patient Pharmaco-kinetics and Initial Tolerability Study
Reports
— Intrinsic Factor Pharmaco-kinetics Study Reports
— Extrinsic Factor Pharmaco-kinetics Study Reports— Population Pharmaco-kinetics Study Reports
—Reports of Human Pharmaco-dynamic Studies
— Healthy Subject Pharmaco-dynamic and Pharmaco-kinetics/
Pharmaco-dynamic Study Reports
— Patient Pharmaco-dynamic and Pharmaco-kinetics/Phar-
maco-dynamic Studies Study Reports
—Reports of Efficacy and Safety Studies
— Study Reports of Controlled Clinical Studies Pertinent to the
Claimed Indication
— Study Reports of Uncontrolled Clinical Studies— Reports of Analyses of Data from More than One Study
including any formal integrated analyses, meta-analyses and
bridging analyses
— Other Study Reports
—Reports of Post-marketing Experience
— Literature references
5.2. Content: basic principles and requirements
Special attention shall be paid to the following selected elements.
a) The clinical particulars to be provided pursuant to Articles 8 (3) (i)
and 10 (1) must enable a sufficiently well-founded and scientifically
valid opinion to be formed as to whether the medicinal product
satisfies the criteria governing the granting of a marketing authorisa-
tion. Consequently, an essential requirement is that the results of all
clinical trials should be communicated, both favourable and unfa-
vourable.
b) Clinical trials must always be preceded by adequate pharmacological
and toxicological tests, carried out on animals in accordance with
the requirements of Module 4 of this Annex. The investigator must
acquaint himself with the conclusions drawn from the pharmacolo-
gical and toxicological studies and hence the applicant must
provide him at least with the investigator's brochure, consisting of
all the relevant information known prior to the onset of a clinical
trial including chemical, pharmaceutical and biological data, toxico-
logical, pharmaco-kinetic and pharmaco-dynamic data in animals
and the results of earlier clinical trials, with adequate data to justify
the nature, scale and duration of the proposed trial; the complete
pharmacological and toxicological reports shall be provided on
request. For materials of human or animal origin, all available
means shall be employed to ensure safety from transmission of
infectious agents prior to the commencement of the trial.
c) Marketing authorisation holders must arrange for essential clinical
trial documents (including case report forms) other than subject's
medical files, to be kept by the owners of the data:
— for at least 15 years after completion or discontinuation of the
trial,2001L0083 — EN — 30.04.2004 — 003.001 — 85
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— or for at least two years after the granting of the last marketing
authorisation in the European Community and when there are no
pending or contemplated marketing applications in the European
Community,
— or for at least two years after formal discontinuation of clinical
development of the investigational product.
Subject's medical files should be retained in accordance with applic-
able legislation and in accordance with the maximum period of time
permitted by the hospital, institution or private practice.
The documents can be retained for a longer period, however, if
required by the applicable regulatory requirements or by agreement
with the sponsor. It is the responsibility of the sponsor to inform the
hospital, institution or practice as to when these documents no
longer need to be retained.
The sponsor or other owner of the data shall retain all other docu-
mentation pertaining to the trial as long as the product is
authorised. This documentation shall include: the protocol including
the rationale, objectives and statistical design and methodology of
the trial, with conditions under which it is performed and managed,
and details of the investigational product, the reference medicinal
product and/or the placebo used; standard operating procedures; all
written opinions on the protocol and procedures; the investigator's
brochure; case report forms on each trial subject; final report; audit
certificate(s), if available. The final report shall be retained by the
sponsor or subsequent owner, for five years after the medicinal
product is no longer authorised.
In addition for trials conducted within the European Community, the
marketing authorisation holder shall make any additional arrange-
ments for archiving of documentation in accordance with the
provisions of Directive 2001/20/EC and implementing detailed
guidelines.
Any change of ownership of the data shall be documented.All data and documents shall be made available if requested by rele-
vant authorities.
d) The particulars of each clinical trial must contain sufficient detail to
allow an objective judgement to be made:
— the protocol, including the rationale, objectives and statistical
design and methodology of the trial, with conditions under
which it is performed and managed, and details of the investiga-
tional medicinal product used
— audit certificate(s), if available— the list of investigator(s), and each investigator shall give his
name, address, appointments, qualifications and clinical duties,
state where the trial was carried out and assemble the informa-
tion in respect of each patient individually, including case
report forms on each trial subject
— final report signed by the investigator and for multi-centre trials,
by all the investigators or the co-ordinating (principal) investi-
gator.
e) The particulars of clinical trials referred to above shall be forwarded
to the competent authorities. However, in agreement with the
competent authorities, the applicant may omit part of this informa-
tion. Complete documentation shall be provided forthwith upon
request.
The investigator shall, in his conclusions on the experimental
evidence, express an opinion on the safety of the product under
normal conditions of use, its tolerance, its efficacy and any useful
information relating to indications and contra-indications, dosage
and average duration of treatment as well as any special precautions
to be taken during treatment and the clinical symptoms of over
dosage. In reporting the results of a multi-centre study, the principal
investigator shall, in his conclusions, express an opinion on the
safety and efficacy of the investigational medicinal product on
behalf of all centres.
f) The clinical observations shall be summarised for each trial indi-
cating:
1) the number and sex of subjects treated;
2) the selection and age-distribution of the groups of patients being
investigated and the comparative tests;2001L0083 — EN — 30.04.2004 — 003.001 — 86
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3) the number of patients withdrawn prematurely from the trials and
the reasons for such withdrawal;
4) where controlled trials were carried out under the above condi-
tions, whether the control group:
— received no treatment
— received a placebo— received another medicinal product of known effect
— received treatment other than therapy using medicinal
products
5) the frequency of observed adverse reactions;
6) details concerning patients who may be at increased risk, e.g.
elderly people, children, women during pregnancy or menstrua-
tion, or whose physiological or pathological condition requires
special consideration;
7) parameters or evaluation criteria of efficacy and the results in
terms of these parameters;
8) a statistical evaluation of the results when this is called for by the
design of the trials and the variable factors involved.
g) In addition, the investigator shall always indicate his observations
on:
1) any signs of habituation, addiction or difficulty in weaning
patients from the medicinal product;
2) any interactions that have been observed with other medicinal
products administered concomitantly;
3) the criteria determining exclusion of certain patients from the
trials;
4) any deaths which occurred during the trial or within the follow-
up period.
h) Particulars concerning a new combination of medicinal substances
must be identical to those required for new medicinal products and
must substantiate the safety and efficacy of the combination.
i) Total or partial omission of data must be explained. Should unex-
pected results occur during the course of the trials, further pre
clinical toxicological and pharmacological tests must be undertaken
and reviewed.
j) If the medicinal product is intended for long-term administration,
particulars shall be given of any modification of the pharmacolo-
gical action following repeated administration, as well as the
establishment of long-term dosage.
5.2.1. Reports of bio-pharmaceutics studies
Bio-availability study reports, comparative bio-availability, bio-equiva-
lence study reports, reports on in vitro and in vivo correlation study,
and bio-analytical and analytical methods shall be provided.
In addition, an assessment of bio-availability shall be undertaken where
necessary to demonstrate bio-equivalence for the medicinal products
referred to in Article 10 (1) (a).
5.2.2. Reports of studies pertinent to pharmaco-kinetics using human bio-
materials
For the purposes of this Annex, human bio-materials shall mean any
proteins, cells, tissues and related materials derived from human sources
that are used in vitro or ex vivo to assess pharmaco-kinetics properties
of drug substances.
In this respect, reports of plasma protein binding study, hepatic metabo-
lism and active substance interaction studies and studies using other
human bio-materials shall be provided.
5.2.3. Reports of human pharmaco-kinetic studies
a) The following pharmaco-kinetic characteristics shall be described:
— absorption (rate and extent),
— distribution,
— metabolism,
— excretion.
Clinically significant features including the implication of the
kinetic data for the dosage regimen especially for patients at risk,2001L0083 — EN — 30.04.2004 — 003.001 — 87
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and differences between man and animal species used in the pre
clinical studies, shall be described.
In addition to standard multiple-sample pharmaco-kinetics studies,
population pharmaco-kinetics analyses based on sparse sampling
during clinical studies can also address questions about the contribu-
tions of intrinsic and extrinsic factors to the variability in the dose-
pharmaco-kinetics response relationship. Reports of pharmaco-
kinetic and initial tolerability studies in healthy subjects and in
patients, reports of pharmaco-kinetic studies to assess effects ofintrinsic and extrinsic factors, and reports of population pharmaco-
kinetic studies shall be provided.
b) If the medicinal product is normally to be administered concomi-
tantly with other medicinal products, particulars shall be given of
joint administration tests performed to demonstrate possible modifi-
cation of the pharmacological action.
Pharmaco-kinetic interactions between the active substance and
other medicinal products or substances shall be investigated.
5.2.4. Reports of human pharmaco-dynamic studies
a) The pharmaco-dynamic action correlated to the efficacy shall be
demonstrated including:
— the dose-response relationship and its time course,
— justification for the dosage and conditions of administration,
— the mode of action, if possible.
The pharmaco-dynamic action not related to efficacy shall be
described.
The demonstration of pharmaco-dynamic effects in human beings
shall not in itself be sufficient to justify conclusions regarding any
particular potential therapeutic effect.
b) If the medicinal product is normally to be administered concomi-
tantly with other medicinal products, particulars shall be given of
joint administration tests performed to demonstrate possible modifi-
cation of the pharmacological action.
Pharmaco-dynamic interactions between the active substance and
other medicinal products or substances shall be investigated.
5.2.5. Reports of efficacy and safety studies
5.2.5.1. S t u d y R e p o r t s o f C o n t r o l l e d C l i n i c a l S t u d i e s P e r t i n e n t t o
the Claimed Indication
In general, clinical trials shall be done as ‘controlled clinical trials’ if
possible, randomised and as appropriate versus placebo and versus an
established medicinal product of proven therapeutic value; any other
design shall be justified. The treatment of the control groups will vary
from case to case and also will depend on ethical considerations and
therapeutic area; thus it may, in some instances, be more pertinent to
compare the efficacy of a new medicinal product with that of an estab-
lished medicinal product of proven therapeutic value rather than with
the effect of a placebo.
(1) As far as possible, and particularly in trials where the effect of the
product cannot be objectively measured, steps shall be taken to
avoid bias, including methods of randomisation and blinding.
(2) The protocol of the trial must include a thorough description of the
statistical methods to be employed, the number and reasons for
inclusion of patients (including calculations of the power of the
trial), the level of significance to be used and a description of the
statistical unit. Measures taken to avoid bias, particularly methods
of randomisation, shall be documented. Inclusion of a large number
of subjects in a trial must not be regarded as an adequate substitute
for a properly controlled trial.
The safety data shall be reviewed taking into account guidelines
published by the Commission, with particular attention to events
resulting in changes of dose or need for concomitant medication,
serious adverse events, events resulting in withdrawal, and deaths. Any
patients or patient groups at increased risk shall be identified and parti-
cular attention paid to potentially vulnerable patients who may be
present in small numbers, e.g., children, pregnant women, frail elderly,
people with marked abnormalities of metabolism or excretion etc. The
implication of the safety evaluation for the possible uses of the medic-
inal product shall be described.2001L0083 — EN — 30.04.2004 — 003.001 — 88
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5.2.5.2. S t u d y r e p o r t s o f u n c o n t r o l l e d c l i n i c a l s t u d i e s r e p o r t s o f
analyses of data from more than one study and other clin-
ical study reports
These reports shall be provided.
5.2.6. Reports of post-marketing experience
If the medicinal product is already authorised in third countries, infor-
mation shall be given in respect of adverse reactions of the medicinal
product concerned and medicinal products containing the same active
substance(s), in relation to the usage rates if possible.
5.2.7. Case reports forms and individual patient listings
When submitted in accordance with the relevant Guideline published by
the Agency, case report forms and individual patient data listings shall
be provided and presented in the same order as the clinical study
reports and indexed by study.
PART II
SPECIFIC MARKETING AUTHORISATION DOSSIERS AND
REQUIREMENTS
Some medicinal products present specific features which are such that all the
requirements of the marketing authorisation application dossier as laid down in
Part I of this Annex need to be adapted. To take account of these particular
situations, an appropriate and adapted presentation of the dossier shall be
followed by applicants.
1. WELL-ESTABLISHED MEDICINAL USE
For medicinal products the active substance(s) of which has/have a
‘well-established medicinal use’ as referred to Article 10(1)(a)(ii), with
recognised efficacy and an acceptable level of safety, the following
specific rules shall apply.
The applicant shall submit Modules 1, 2 and 3 as described in part I of
this Annex.
For Modules 4 and 5, a detailed scientific bibliography shall address
non-clinical and clinical characteristics.
The following specific rules shall apply in order to demonstrate the
well-established medicinal use:
a) Factors which have to be taken into account in order to establish a
well-established medicinal use of constituents of medicinal products
are:
— the time over which a substance has been used,
— quantitative aspects of the use of the substance,— the degree of scientific interest in the use of the substance
(reflected in the published scientific literature) and
— the coherence of scientific assessments.
Therefore different periods of time may be necessary for estab-
lishing well-established use of different substances. In any case,
however, the period of time required for establishing a well estab-
lished medicinal use of a constituent of a medicinal product must
not be less than one decade from the first systematic and docu-
mented use of that substance as a medicinal product in the
Community.
b) The documentation submitted by the applicant should cover all
aspects of the safety and/or efficacy assessment and must include
or refer to a review of the relevant literature, taking into account
pre- and post-marketing studies and published scientific literature
concerning experience in the form of epidemiological studies and
in particular of comparative epidemiological studies. All documenta-
tion, both favourable and unfavourable, must be communicated.
With respect to the provisions on ‘well-established medicinal use’
it is in particular necessary to clarify that ‘bibliographic reference’
to other sources of evidence (post marketing studies, epidemiolo-
gical studies, etc.) and not just data related to tests and trials may
serve as a valid proof of safety and efficacy of a product if an appli-
cation explains and justifies the use of these sources of information
satisfactorily.
c) Particular attention must be paid to any missing information and
justification must be given why demonstration of an acceptable level2001L0083 — EN — 30.04.2004 — 003.001 — 89
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of safety and/or efficacy can be supported although some studies are
lacking.
d) The non-clinical and/or clinical overviews must explain the rele-
vance of any data submitted which concern a product different
from the product intended for marketing. A judgement must be
made whether the product studied can be considered as similar to
the product, for which application for a marketing authorisation has
been made in spite of the existing differences.
e) Post-marketing experience with other products containing the same
constituents is of particular importance and applicants should put a
special emphasis on this issue.
2. ESSENTIALLY SIMILAR MEDICINAL PRODUCTS
a) Applications based upon Article 10(1) (a) (i) (essentially similar
products) shall contain the data described in Modules 1, 2 and 3 of
Part I of this Annex provided the applicant has been granted the
consent of the holder of the original marketing authorisation to cross
refer to the content of his Modules 4 and 5.
b) Applications based upon Article 10(1) (a) (iii) (essentially similar
products i.e. generics) shall contain the data described in Modules 1,
2 and 3 of Part I of this Annex together with data showing bio-avail-
ability and bio-equivalence with the original medicinal product
provided the latter is not a biological medicinal product (see Part II,
4 Similar biological medicinal products).
For these products the non-clinical/clinical overviews/summaries shall
particularly focus on the following elements:
— the grounds for claiming essential similarity;
— a summary of impurities present in batches of the active
substance(s) as well as those of the finished medicinal product
(and where relevant decomposition products arising during storage)
as proposed for use in the product to be marketed together with an
evaluation of these impurities;
— an evaluation of the bio-equivalence studies or a justification why
studies were not performed with respect to the guideline on ‘Inves-
tigation of Bio-availability and Bio-equivalence’;
— an update of published literature relevant to the substance and the
present application. It may be acceptable for articles in ‘peer
review’ journals to be annotated for this purpose;
— every claim in the summary of product characteristics not known
from or inferred from the properties of the medicinal product and/or its therapeutic group should be discussed in the non clinical/clin-
ical overviews/summaries and substantiated by published literature
and/or additional studies.
— if applicable, additional data in order to demonstrate evidence on
the equivalence of safety and efficacy properties of different salts,
esters or derivatives of an authorised active substance should be
provided by the applicant when he claims essential similarity.
3. ADDITIONAL DATA REQUIRED IN SPECIFIC SITUATIONS
Where the active substance of an essentially similar medicinal product
contains the same therapeutic moiety as the original authorised product
associated with a different salt/ester complex/derivative evidence that
there is no change in the pharmaco-kinetics of the moiety, pharmaco-
dynamics and/or in toxicity which could change the safety/efficacy
profile shall be demonstrated. Should this not be the case, this associa-
tion shall be considered as a new active substance.
Where a medicinal product is intended for a different therapeutic use or
presented in a different pharmaceutical form or to be administered by
different routes or in different doses or with a different posology, the
results of appropriate toxicological and pharmacological tests and/or of
clinical trials shall be provided.
4. SIMILAR BIOLOGICAL MEDICINAL PRODUCTS
The provisions of Article 10(1)(a) (iii) may not be sufficient in the case
of biological medicinal products. If the information required in the case
of essentially similar products (generics) does not permit the demonstra-
tion of the similar nature of two biological medicinal products,
additional data, in particular, the toxicological and clinical profile shall
be provided.2001L0083 — EN — 30.04.2004 — 003.001 — 90
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When a biological medicinal product as defined in Part I, paragraph 3.2
of this Annex, which refers to an original medicinal product having
been granted a marketing authorisation in the Community, is submitted
for a marketing authorisation by an independent applicant after the
expiry of data protection period, the following approach shall be
applied.
— Information to be supplied shall not be limited to Modules 1, 2 and 3
(pharmaceutical, chemical and biological data), supplemented with
bio-equivalence and bio-availability data. The type and amount of
additional data (i.e. toxicological and other non-clinical and appro-
priate clinical data) shall be determined on a case by case basis in
accordance with relevant scientific guidelines.
— Due to the diversity of biological medicinal products, the need for
identified studies foreseen in Modules 4 and 5, shall be required
by the competent authority, taking into account the specific charac-
teristic of each individual medicinal product.
The general principles to be applied are addressed in a guideline taking
into account the characteristics of the concerned biological medicinal
product published by the Agency. In case the originally authorised
medicinal product has more than one indication, the efficacy and safety
of the medicinal product claimed to be similar has to be justified or, if
necessary, demonstrated separately for each of the claimed indications.
5. FIXED COMBINATION MEDICINAL PRODUCTS
Applications based upon Article 10 (1) (b) shall relate to new medicinal
products made of at least two active substances not previously
authorised as a fixed combination medicinal product.
For those applications a full dossier (Modules 1 to 5) shall be provided
for the fixed combination medicinal product. Where applicable, infor-mation regarding the manufacturing sites and the adventitious agents,
safety evaluation shall be provided.
6. DOCUMENTATION FOR APPLICATIONS IN EXCEPTIONAL
CIRCUMSTANCES
When, as provided for in Article 22, the applicant can show that he is
unable to provide comprehensive data on the efficacy and safety under
normal conditions of use, because:
— the indications for which the product in question is intended are
encountered so rarely that the applicant cannot reasonably be
expected to provide comprehensive evidence, or
— in the present state of scientific knowledge, comprehensive informa-
tion cannot be provided, or
— it would be contrary to generally accepted principles of medical
ethics to collect such information,
marketing authorisation may be granted subject to certain specific obli-
gations.
These obligations may include the following:
— the applicant shall complete an identified programme of studies
within a time period specified by the competent authority, the
results of which shall form the basis of a reassessment of the
benefit/risk profile,
— the medicinal product in question may be supplied on medical
prescription only and may in certain cases be administered only
under strict medical supervision, possibly in a hospital and in the
case of a radio-pharmaceutical, by an authorised person,
— the package leaflet and any medical information shall draw the
attention of the medical practitioner to the fact that the particulars
available concerning the medicinal product in question are as yet
inadequate in certain specified respects.
7. MIXED MARKETING AUTHORISATION APPLICATIONS
Mixed marketing-authorisation applications shall mean marketing-
authorisation application dossiers where Module 4 and/or 5 consists of
a combination of reports of limited non-clinical and/or clinical studies
carried out by the applicant and of bibliographical references. All other
Module(s) are in accordance with the structure described in Part I of
this Annex. The competent authority shall accept the proposed format
presented by the applicant on a case by case basis.2001L0083 — EN — 30.04.2004 — 003.001 — 91
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PART III
PARTICULAR MEDICINAL PRODUCTS
This Part lays down specific requirements related to the nature of identified
medicinal products.
1. BIOLOGICAL MEDICINAL PRODUCTS
1.1. Plasma-derived medicinal product
For medicinal products derived from human blood or plasma and by
derogation from the provisions of Module 3, the dossier requirements
mentioned in ‘Information related to the starting and raw materials’,
for starting materials made of human blood/plasma may be replaced
by a Plasma Master File certified in accordance with this Part.
a) P r i n c i p l e sFor the purposes of this Annex:
— Plasma Master File shall mean a stand-alone documentation, which
is separate from the dossier for marketing authorisation which
provides all relevant detailed information on the characteristics of
the entire human plasma used as a starting material and/or a raw
material for the manufacture of sub/intermediate fractions, constitu-
ents of the excipient and active substance(s), which are part of
medicinal products or medical devices referred to in Directive
2000/70/EC of the European Parliament and of the Council of
16 November 2000 amending Council Directive 93/42/EC as
regards medical devices incorporating stable derivatives of human
blood or human plasma (
1).
— Every centre or establishment for fractionation/processing of human
plasma shall prepare and keep updated the set of detailed relevant
information referred to in the Plasma Master File.
— The Plasma Master File shall be submitted to the Agency or to the
competent authority by the applicant for a marketing authorisation
or the holder of the marketing authorisation. Where the applicant
for a marketing authorisation or the marketing authorisation holder
differs from the holder of the Plasma Master File, the Plasma
Master File shall be made available to the applicant or marketing
authorisation holder for submission to the competent authority. In
any case, the applicant or marketing authorisation holder shall take
responsibility for the medicinal product.
— The competent authority that is evaluating the marketing authorisa-
tion shall await for the Agency to issue the certificate before
deciding on the application.
— Any marketing authorisation dossier containing a human plasma-
derived constituent shall refer to the Plasma Master File corre-
sponding to the plasma used as a starting/raw material.
b ) ContentIn accordance with the provisions of Article 109, as amended by Direc-
tive 2002/98/EC, which refers to the requirements for donors and the
testing of donations, the Plasma Master File shall include information
on the plasma used as starting/raw material, in particular:
(1) Plasma origin
(i) information on centres or establishments in which blood/
plasma collection is carried out, including inspection and
approval, and epidemiological data on blood transmissible
infections.
(ii) information on centres or establishments in which testing of
donations and plasma pools is carried out, including inspection
and approval status.
(iii) selection/exclusion criteria for blood/plasma donors.
(iv) system in place which enables the path taken by each donation
to be traced from the blood/plasma collection establishment
through to finished products and vice versa.
(2) Plasma quality and safety
(i) compliance with European Pharmacopoeia Monographs.2001L0083 — EN — 30.04.2004 — 003.001 — 92
(1) OJ L 313, 13.12.2000, p. 22.
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(ii) testing of blood/plasma donations and pools for infectious
agents, including information on test methods and, in the case
of plasma pools, validation data on the tests used.
(iii) technical characteristics of bags for blood and plasma collec-
tion, including information on anticoagulants solutions used.
(iv) conditions of storage and transport of plasma.(v) procedures for any inventory hold and/or quarantine period.
(vi) characterisation of the plasma pool.
(3) System in place between the plasma-derived medicinal product
manufacturer and/or plasma fractionator/processor on the one
hand, and blood/plasma collection and testing centres or establish-
ments on the other hand, which defines the conditions of their
interaction and their agreed specifications.
In addition, the Plasma Master File shall provide a list of the
medicinal products for which the Plasma Master File is valid,
whether the medicinal products have been granted a marketing
authorisation or are in the process of being granted such an author-
isation, including medicinal products referred to in Article 2 of
Directive 2001/20/EC of the European Parliament and of the
Council relating to the implementation of good clinical practice in
the conduct of clinical trials on medicinal products for human use.
c ) Evaluation and Certification— For medicinal products not yet authorised, the marketing authorisa-
tion applicant shall submit a full dossier to a competent authority,
which shall be accompanied by a separate Plasma Master File
where one does not already exist.
— The Plasma Master File is subject to a scientific and technical
evaluation carried out by the Agency. A positive evaluation shall
result in a certificate of compliance with Community legislation
for the Plasma Master File, which shall be accompanied by the
evaluation report. The certificate issued shall apply throughout the
Community.
— The Plasma Master File shall be updated and re-certified on an
annual basis.
— Changes subsequently introduced to the terms of a Plasma Master
File must follow evaluation procedure laid down by Commission
Regulation (EC) No 542/95 (
1) concerning the examination of varia-
tions to the terms of a marketing authorisation falling within the
scope of Council regulation (EEC) No 2309/93 of 22 July 1993
laying down Community procedures for the authorisation and super-
vision of medicinal products for human and veterinary use and
establishing a European Agency for the Evaluation of Medicinal
Products (2). Conditions for the assessment of these changes are
laid down by Regulation (EC) No 1085/2003.
— As a second step to the provisions in the first, second, third and
fourth indents, the competent authority that will grant or has granted
the marketing authorisation shall take into account the certification,
re-certification or variation of the Plasma Master File on the
concerned medicinal product(s).
— By derogation from the provisions of the second indent of the
present point (evaluation and certification), where a Plasma Master
File corresponds only to blood/plasma-derived medicinal products
the marketing authorisation of which is restricted to a single
Member State, the scientific and technical evaluation of the said
Plasma Master File shall be carried out by the national competentauthority of that Member State.
1.2. Vaccines
For vaccines for human use and by derogation from the provisions of
Module 3 on ‘Active substance(s)’, the following requirements when
based on the use of a Vaccine Antigen Master File system shall apply.
The marketing authorisation application dossier of a vaccine other than
human influenza vaccine, shall be required to include a Vaccine
Antigen Master File for every vaccine antigen that is an active
substance of this vaccine.2001L0083 — EN — 30.04.2004 — 003.001 — 93
(1) OJ L 55, 11.3.1995, p. 15.
(2) OJ L 214, 24.8.1993, p. 1.
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a) P r i n c i p l e s
For the purposes of this Annex:
— Vaccine Antigen Master File shall mean a stand-alone part of the
marketing authorisation application dossier for a vaccine, which
contains all relevant information of biological, pharmaceutical and
chemical nature concerning each of the active substances, which
are part of this medicinal product. The stand-alone part may be
common to one or more monovalent and/or combined vaccines
presented by the same applicant or marketing authorisation holder.
— A vaccine may contain one or several distinct vaccine antigens.
There are as many active substance(s) as vaccine antigen(s) present
in a vaccine.
— A combined vaccine contains at least two distinct vaccine antigens
aimed at preventing a single or several infectious diseases.
— A monovalent vaccine is a vaccine, which contains one vaccine
antigen aimed at preventing a single infectious disease.
b ) Content
The Vaccine Antigen Master File shall contain the following informa-
tion extracted from the relevant part (Active substance) of Module 3 on
‘Quality Data’ as delineated in Part I of this Annex:
Active Substance1. General Information, including compliance with the relevant mono-
graph(s) of the European Pharmacopoeia.
2. Information on the manufacture of the active substance: this heading
must cover the manufacturing process, information on the starting
and raw materials, specific measures on TSEs and adventitious
agents safety evaluation and facilities and equipment.
3. Characterisation of the active substance4. Quality control of the active substance
5. Reference standard and materials
6. Container and closure system of the active substance7. Stability of the active substance.
c ) Evaluation and Certification
— For novel vaccines, which contain a novel vaccine antigen, the
applicant shall submit to a competent authority a full marketing-
authorisation application dossier including all the Vaccine Antigen
Master Files corresponding to each single vaccine antigen that is
part of the novel vaccine where no master file already exists for
the single vaccine antigen. A scientific and technical evaluation of
each Vaccine Antigen Master File shall be carried out by the
Agency. A positive evaluation shall result in a certificate of compli-
ance to the European legislation for each Vaccine Antigen Master
File, which shall be accompanied by the evaluation report. The
certificate shall apply throughout the Community.
— The provisions of the first indent shall also apply to every vaccine,
which consists of a novel combination of vaccine antigens, irrespec-
tive of whether or not one or more of these vaccine antigens are
part of vaccines already authorised in the Community.
— Changes to the content of a Vaccine Antigen Master File for a
vaccine authorised in the Community shall be subject to a scientific
and technical evaluation carried out by the Agency in accordance
with the procedure laid down in Commission Regulation (EC)
No 1085/2003. In the case of a positive evaluation the Agency shall
issue a certificate of compliance with Community legislation for the
Vaccine Antigen Master File. The certificate issued shall apply
throughout the Community.
— By derogation from the provisions of the first, second and third
indents of the present point (evaluation and certification), where a
Vaccine Antigen Master File corresponds only to a vaccine which
is the subject of a marketing authorisation which has not been/will
not be granted according to a Community procedure, and, provided
the authorised vaccine includes vaccine antigens which have not
been evaluated through a Community procedure, the scientific and
technical evaluation of the said Vaccine Antigen Master File and
its subsequent changes, shall be carried out by the national compe-
tent authority that has granted the marketing authorisation.
— As a second step to the provisions in the first, second, third and
fourth indents, the competent authority that will grant or has granted2001L0083 — EN — 30.04.2004 — 003.001 — 94
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the marketing authorisation shall take into account the certification,
re-certification or variation of the Vaccine Antigen Master File on
the concerned medicinal product(s).
2. RADIO-PHARMACEUTICALS AND PRECURSORS
2.1. Radio-pharmaceuticals
For the purposes of this chapter, applications based upon Articles 6 (2)
and 9 shall provide a full dossier in which the following specific details
shall be included:
Module 3
a) In the context of a radio-pharmaceutical kit, which is to be radio-
labelled after supply by the manufacturer, the active substance is
considered to be that part of the formulation which is intended to
carry or bind the radio-nuclide. The description of the manufacturing
method of radio-pharmaceutical kits shall include details of the
manufacture of the kit and details of its recommended final proces-
sing to produce the radioactive medicinal product. The necessary
specifications of the radio-nuclide shall be described in accordance,
where relevant, with the general monograph or specific monographs
of the European Pharmacopoeia . In addition, any compounds essen-
tial for the radio-labelling shall be described. The structure of the
radio-labelled compound shall also be described.
For radio-nuclides, the nuclear reactions involved shall be discussed.In a generator, both mother and daughter radio-nuclides shall be
considered as active substances.
b) Details of the nature of the radio-nuclide, the identity of the isotope,
likely impurities, the carrier, the use and the specific activity shall
be provided.
c) Starting materials include irradiation target materials.
d) Considerations on chemical/radiochemical purity and its relationship
to bio-distribution shall be provided.
e) Radio-nuclide purity, radiochemical purity and specific activity shall
be described.
f) For generators, details on the testing for mother and daughter radio-
nuclides are required. For generator-eluates, tests for mother radio-
nuclides and for other constituents of the generator system shall be
provided.
g) The requirement to express the content of active substances in terms
of the mass of active entities shall onlyapply to radio-pharmaceutical
kits. For radio-nuclides, radioactivity shall be expressed in
Becquerels at a given date and, if necessary, time with reference to
time zone. The type of radiation shall be indicated.
h) For kits, the specifications of the finished product shall include tests
on performance of products after radio-labelling. Appropriate
controls on radiochemical and radio-nuclidic purity of the radio-
labelled compound shall be included. Any material essential for
radio-labelling shall be identified and assayed.
i) Information on stability shall be given for radio-nuclide generators,
radio-nuclide kits and radio-labelled products. The stability during
use of radio-pharmaceuticals in multi-dose vials shall be docu-
mented.
Module 4
It is appreciated that toxicity may be associated with a radiation dose.
In diagnosis, this is a consequence of the use of radio-pharmaceuticals;
in therapy, it is the property desired. The evaluation of safety and effi-
cacy of radio-pharmaceuticals shall, therefore, address requirements for
medicinal products and radiation dosimetry aspects. Organ/tissue expo-
sure to radiation shall be documented. Absorbed radiation dose
estimates shall be calculated according to a specified, internationally
recognised system by a particular route of administration.
Module 5
The results of clinical trials shall be provided where applicable other-
wise justified in the clinical overviews.
2.2. Radio-pharmaceutical precursors for radio-labelling purposes
In the specific case of a radio-pharmaceutical precursor intended solely
for radio-labelling purposes, the primary objective shall be to present2001L0083 — EN — 30.04.2004 — 003.001 — 95
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information which would address the possible consequences of poor
radio-labeling efficiency or in vivo dissociation of the radio-labeled
conjugate, i.e. questions related to the effects produced in the patient
by free radio-nuclide. In addition, it is also necessary to present relevant
information relating to occupational hazards, i.e. radiation exposure to
hospital staff and to the environment.
In particular, the following information where applicable shall be
provided:
Module 3The provisions of Module 3 shall apply to the registration of radio-
pharmaceutical precursors as define above (indents a) to i)), where
applicable.
Module 4
Concerning single dose and repeat dose toxicity, the results of studies
carried out in conformity with the provisions related to good laboratory
practice laid down in Council Directives 87/18/EEC and 88/320/EEC
shall be provided, unless otherwise justified.
Mutagenicity studies on the radio-nuclide are not considered to be
useful in this particular case.
Information relating to the chemical toxicity and disposition of the rele-
vant ‘cold’ nuclide shall be presented.
Module 5Clinical information generated from clinical studies using on the
precursor itself is not considered to be relevant in the specific case of
a radio-pharmaceutical precursor intended solely for radio-labelling
purposes.
However, information demonstrating the clinical utility of the radio-
pharmaceutical precursor when attached to relevant carrier molecules
shall be presented.
3. HOMEOPATHIC MEDICINAL PRODUCTS
This section sets out specific provisions on the application of Modules 3
and 4 to homeopathic medicinal products as defined in Article 1(5).
Module 3The provisions of Module 3 shall apply to the documents submitted in
accordance with Article 15 in the simplified registration of homeopathic
medicinal products referred to in Article 14(1) as well as to the docu-
ments for authorisation of other homeopathic medicinal products
referred to in Article 16(1) with the following modifications.
a) Terminology
The Latin name of the homeopathic stock described in the marketing
authorisation application dossier must be in accordance with the
Latin title of the European Pharmacopoeia or, in absence thereof,
by an official pharmacopoeia of a Member State. Where relevant
the traditional name(s) used in each Member State shall be provided.
b) Control of starting materials
The particulars and documents on the starting materials, i.e. all of
the materials used including raw materials and intermediates up to
the final dilution to be incorporated into the finished medicinal
product, accompanying the application shall be supplemented by
additional data on the homeopathic stock.
The general quality requirements shall apply to all of the starting
and raw materials as well as intermediate steps of the manufacturing
process up to the final dilution to be incorporated into the finished
medicinal product. If possible, an assay is required if toxic compo-
nents are present and if the quality cannot be controlled on final
dilution to be incorporated because of the high dilution degree.
Every step of the manufacturing process from the starting materials
up to the final dilution to be incorporated into the finished medicinal
product must be fully described.
In case dilutions are involved, these dilution steps should be done in
accordance with the homeopathicmanufacturing methods laid down
in the relevant monograph of the European Pharmacopoeia or, in
absence thereof, by an official pharmacopoeia of a Member State.
c) Control tests on the finished medicinal product2001L0083 — EN — 30.04.2004 — 003.001 — 96
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The general quality requirements shall apply to the homeopathic
finished medicinal products, any exception needs to be duly justified
by the applicant.
Identification and assay of all the toxicologically relevant constitu-
ents shall be carried out. If it can be justified that an identification
and/or an assay on all the toxicologically relevant constituents is not
possible e.g. due to their dilution in the finished medicinal product
the quality shall be demonstrated by complete validation of the
manufacturing and dilution process.
d) Stability tests
The stability of the finished medicinal product must be demon-
strated. Stability data from the homeopathic stocks are generally
transferable to dilutions/triturations obtained thereof. If no identifica-
tion or assay of the active substance is possible due to the degree of
dilution, stability data of the pharmaceutical form may be consid-
ered.
Module 4The provisions of Module 4 shall apply to the simplified registration of
homeopathic medicinal products referred to in Article 14(1) with the
following specifications.
Any missing information must be justified, e.g., justification must be
given why demonstration of an acceptable level of safety can be
supported although some studies are lacking.
4. HERBAL MEDICINAL PRODUCTS
Applications for herbal medicinal products shall provide a full dossier
in which the following specific details shall be included.
Module 3The provisions of Module 3, including compliance with monograph(s)
of the European Pharmacopoeia, shall apply to the authorisation of
herbal medicinal products. The state of scientific knowledge at the
time when the application is lodged shall be taken into account.
The following aspects specific to herbal medicinal products shall be
considered:
( 1 ) Herbal substances and herbal preparationsFor the purposes of this Annex the terms ‘herbal substances and
preparations’ shall be considered equivalent to the terms ‘herbal drugs
and herbal drug preparations’, as defined in the European Pharmaco-
poeia.
With respect to the nomencRlature of the herbal substance, the bino-
mial scientific name of plant (genus, species, variety and author), and
chemotype (where applicable), the parts of the plants, the definition of
the herbal substance, the other names (synonyms mentioned in other
Pharmacopoeias) and the laboratory code shall be provided.
With respect to the nomenclature of the herbal preparation, the bino-
mial scientific name of plant (genus, species, variety and author), and
chemotype (where applicable), the parts of the plants, the definition of
the herbal preparation, the ratio of the herbal substance to the herbal
preparation, the extraction solvent(s), the other names (synonyms
mentioned in other Pharmacopoeias) and the laboratory code shall be
provided.
To document the section of the structure for herbal substance(s) and
herbal preparation(s) where applicable, the physical form, the descrip-
tion of the constituents with known therapeutic activity or markers
(molecular formula, relative molecular mass, structural formula,
including relative and absolute stereo-chemistry, the molecular formula,
and the relative molecular mass) as well as other constituent(s) shall be
provided.
To document the section on the manufacturer of the herbal substance,
the name, address, and responsibility of each supplier, including
contractors, and each proposed site or facility involved in production/
collection and testing of the herbal substance shall be provided, where
appropriate.
To document the section on the manufacturer of the herbal preparation,
the name, address, and responsibility of each manufacturer, including
contractors, and each proposed manufacturing site or facility involved2001L0083 — EN — 30.04.2004 — 003.001 — 97
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in manufacturing and testing of the herbal preparation shall be
provided, where appropriate.
With respect to the description of manufacturing process and process
controls for the herbal substance, information shall be provided to
adequately describe the plant production and plant collection, includingthe geographical source of the medicinal plant and cultivation,
harvesting, drying and storage conditions.
With respect to the description of manufacturing process and process
controls for the herbal preparation, information shall be provided to
adequately describe the manufacturing process of the herbal prepara-
tion, including description of the processing, solvents and reagents,
purification stages and standardisation.
With respect to the manufacturing process development, a brief
summary describing the development of the herbal substance(s) and
herbal preparation(s) where applicable shall be provided, taking into
consideration the proposed route of administration and usage. Results
comparing the phyto-chemical composition of the herbal substance(s)
and herbal preparation(s) where applicable used in supporting biblio-
graphic data and the herbal substance(s) and herbal preparation(s),
where applicable, contained as active substance(s) in the herbal medic-
inal product applied for shall be discussed, where appropriate.
With respect to the elucidation of the structure and other characteristics
of the herbal substance, information on the botanical, macroscopical,
microscopical, phyto-chemical characterisation, and biological activity
if necessary, shall be provided.
With respect to the elucidation of the structure and other characteristics
of the herbal preparation, information on the phyto- and physicochem-
ical characterisation, and biological activity if necessary, shall be
provided.
The specifications for the herbal substance(s) and herbal preparation(s)
where applicable shall be provided.
The analytical procedures used for testing the herbal substance(s) and
herbal preparation(s) where applicable shall be provided.
With respect to the validation of analytical procedures, analytical vali-
dation information, including experimental data for the analytical
procedures used for testing the herbal substance(s) and herbal prepara-tion(s) where applicable shall be provided.
With respect to batch analyses, description of batches and results of
batch analyses for the herbal substance(s) and herbal preparation(s)
where applicable shall be provided, including those for pharmacopoeial
substances.
Justification for the specifications of the herbal substance(s) and herbal
preparation(s) where applicable shall be provided.
Information on the reference standards or reference materials used for
testing of the herbal substance(s) and herbal preparation(s) where
applicable shall be provided.
Where the herbal substance or the herbal preparation is the subject of a
monograph, the applicant can apply for a certificate of suitability that
was granted by the European Directorate for the Quality of Medicines.
( 2 ) Herbal Medicinal ProductsWith respect to the formulation development, a brief summary
describing the development of the herbal medicinal product should be
provided, taking into consideration the proposed route of administration
and usage. Results comparing the phyto-chemical composition of the
products used in supporting bibliographic data and the herbal medicinal
product applied for shall be discussed, where appropriate.
5. ORPHAN MEDICINAL PRODUCTS
— In the case of an orphan medicinal product in the meaning of Regu-
lation (EC) No 141/2000, general provisions of Part II-6
(exceptional circumstances) can be applied. The applicant shall
then justify in the non-clinical and clinical summaries the reasons
for which it is not possible to provide the complete information
and shall provide a justification of the benefit/risk balance for the
orphan medicinal product concerned.
— When an applicant for an marketing authorisation for an orphan
medicinal product invokes the provisions of Article 10 (1)(a)(ii)2001L0083 — EN — 30.04.2004 — 003.001 — 98
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and Part II-1 of this Annex (well-established medicinal use), the
systematic and documented use of the concerned substance can refer
— as way of derogation — to the use of that substance in accor-
dance with the provisions of Article 5 of this Directive.
PART IV
ADVANCED THERAPY MEDICINAL PRODUCTS
Advanced therapy medicinal products are based on manufacturing processes
focussed on various gene transfer-produced bio-molecules, and/or biologically
advanced therapeutic modified cells as active substances or part of active
substances.
For those medicinal products the presentation of the Marketing Authorisation
application dossier shall fulfil the format requirements as described in Part I of
this Annex.
Modules 1 to 5 shall apply. For Genetically Modified Organisms deliberate
release in the environment, attention shall be paid to the persistence of the
Genetically Modified Organisms in the recipient and to the possible replication
and/or modification of the Genetically Modified Organisms when released in the
environment. The information concerning the environmental risk should appear
in the Annex to Module 1.
1. GENE THERAPY MEDICINAL PRODUCTS (HUMAN AND XENO-
GENEIC)
For the purposes of this Annex, gene therapy medicinal product shall
mean a product obtained through a set of manufacturing processes
aimed at the transfer, to be performed either in vivo or ex vivo, of a
prophylactic, diagnostic or therapeutic gene (i.e. a piece of nucleic
acid), to human/animal cells and its subsequent expression in vivo.
The gene transfer involves an expression system contained in a delivery
system known as a vector, which can be of viral, as well as non-viral
origin. The vector can also be included in a human or animal cell.
1.1. Diversity of gene therapy medicinal products
a) Gene therapy medicinal products based on allogeneic or xenogeneic
cells
The vector is ready-prepared and stored before its transfer into the
host cells.
The cells have been obtained previously and may be processed as a
cell bank (bank collection or bank established from procurement of
primary cells) with a limited viability.
The cells genetically modified by the vector represent an active
substance.
Additional steps may be carried out in order to obtain the finished
product. By essence, such a medicinal product is intended to be
administered to a certain number of patients.
b) Gene therapy medicinal products using autologous human cells
The active substance is a batch of ready-prepared vector stored
before its transfer into the autologous cells.
Additional steps may be carried out in order to obtain the finished
medicinal product.
Those products are prepared from cells obtained from an individual
patient. The cells are then genetically modified using a ready-
prepared vector containing the appropriate gene that has been
prepared in advance and that constitutes the active substance. The
preparation is re-injected into the patient and is by definition
intended to a single patient. The whole manufacturing process from
the collection of the cells from the patient up to the re-injection to
the patient shall be considered as one intervention.
c) Administration of ready-prepared vectors with inserted (prophy-
lactic, diagnostic or therapeutic) genetic material
The active substance is a batch of ready-prepared vector.
Additional steps may be carried out in order to obtain the finished
medicinal product. This type of medicinal product is intended to be
administered to several patients.2001L0083 — EN — 30.04.2004 — 003.001 — 99
▼M2
Transfer of genetic material may be carried out by direct injection of
the ready-prepared vector to the recipients.
1.2. Specific requirements regarding Module 3
Gene therapy medicinal products include:
— naked nucleic acid
— complex nucleic acid or non viral vectors
— viral vectors
— genetically modified cells
As for other medicinal products, one can identify the three main
elements of the manufacturing process, i.e.:
— starting materials: materials from which the active substance is
manufactured such as, gene of interest, expression plasmids, cell
banks and virus stocks or non viral vector;
— active substance: recombinant vector, virus, naked or complex plas-
mids, virus producing cells, in vitro genetically modified cells;
— finished medicinal product: active substance formulated in its final
immediate container for the intended medical use. Depending on the
type of gene therapy medicinal product, the route of administration
and conditions of use may necessitate an ex vivo treatment of the
cells of the patient (see 1.1.b).
A special attention shall be paid to the following items:
a) Information shall be provided on the relevant characteristics of the
gene therapy medicinal product including its expression in the target
cell population. Information concerning the source, construction,
characterisation and verification of the encoding gene sequence
including its integrity and stability shall be provided. Apart from
therapeutic gene, the complete sequence of other genes, regulatory
elements and the vector backbone shall be provided.
b) Information concerning the characterisation of the vector used to
transfer and deliver the gene shall be provided. This must include
its physico-chemical characterisation and/or biological/immunolo-
gical characterisation.
For medicinal products that utilise a micro-organism such as bacteria
or viruses to facilitate gene transfer (biological gene transfer), data
on the pathogenesis of the parental strain and on its tropism for
specific tissues and cell types as well as the cell cycle-dependence
of the interaction shall be provided.
For medicinal products that utilise non-biological means to facilitate
gene transfer, the physico-chemical properties of the constituents
individually and in combination shall be provided.
c) The principles for cell banking or seed lot establishment and charac-
terisation shall apply to gene transfer medicinal products as
appropriate.
d) The source of the cells hosting the recombinant vector shall be
provided.
The characteristics of the human source such as age, sex, results of
microbiological and viral testing, exclusion criteria and country of
origin shall be documented.
For cells of animal origin, detailed information related to the
following items shall be provided:
— Sourcing of the animals
— Animal husbandry and care
— Transgenic animals (methods of creation, characterisation of
transgenic cells, nature of the inserted gene)
— Measures to prevent and monitor infections in the source/donor
animals
— Testing for infectious agents
— Facilities
— Control of starting and raw materials.
Description of cell collection methodology including location, type
of tissue, operating process, transportation, storage and traceability
as well as controls carried out during the collection process shall
be documented.
e) The evaluation of the viral safety as well as the traceability of the
products from the donor to the finished medicinal product, are an
essential part of the documentation to be supplied. E.g., the presence2001L0083 — EN — 30.04.2004 — 003.001 — 100
▼M2
of replication competent virus in stocks of non-replication competent
viral vectors must be excluded.
2. SOMATIC CELL THERAPY MEDICINAL PRODUCTS (HUMAN
AND XENOGENEIC)
For the purposes of this Annex, somatic cell therapy medicinal products
shall mean the use in humans of autologous (emanating from the patient
himself), allogeneic (coming from another human being) or xenogeneic
(coming from animals) somatic living cells, the biological characteris-
tics of which have been substantially altered as a result of their
manipulation to obtain a therapeutic, diagnostic or preventive effect
through metabolic, pharmacological and immunological means. This
manipulation includes the expansion or activation of autologous cell
populations ex vivo (e.g., adoptive immuno-therapy), the use of allo-
geneic and xenogeneic cells associated with medical devices used ex
vivo or in vivo (e.g., micro-capsules, intrinsic matrix scaffolds, bio-
degradable or not).
Specific requirements for cell therapy medicinal products regarding
Module 3
Somatic cell therapy medicinal products include:
— Cells manipulated to modify their immunological, metabolic or
other functional properties in qualitative or quantitative aspects;
— Cells sorted, selected and manipulated and subsequently undergoing
a manufacturing process in order to obtain the finished medicinal
product;
— Cells manipulated and combined with non-cellular components (e.g.
biological or inert matrixes or medical devices) and exerting the
principle intended action in the finished product;
— Autologous cell derivatives expressed in vitro under specific culture
conditions;
— Cells genetically modified or otherwise manipulated to express
previously unexpressed homologous or non-homologous functional
properties.
The whole manufacturing process from the collection of the cells from
the patient (autologous situation) up to the re-injection to the patient
shall be considered as one single intervention.
As for other medicinal products, the three elements of the manufac-
turing process are identified:
— starting materials: materials from which the active substance is
manufactured, i.e., organs, tissues, body fluids or cells;
— active substance: manipulated cells, cell lysates, proliferating cells
and cells used in conjunction with inert matrixes and medical
devices;
— finished medicinal products: active substance formulated in its final
immediate container for the intended medical use.
a) General information on active substance(s)
The active substances of cell therapy medicinal products consist of
cells which as a consequence of in vitro processing display prophy-
lactic, diagnostic or therapeutic properties different from the original
physiological and biological one.
This section shall describe the type of cells and culture concerned.
Tissues, organs or biological fluids from which cells are derived as
well as the autologous, allogeneic, or xenogeneic nature of the dona-
tion and its geographical origin shall be documented. Collection of
the cells, sampling and storage prior further processing shall be
detailed. For allogeneic cells, special attention shall be paid to the
very first step of the process, which covers selection of donors. The
type of manipulation carried out and the physiological function of
the cells that are used as active substance shall be provided.
b) Information related to the starting materials of active substance(s)
1 . Human somatic cells
Human somatic cell therapy medicinal products are made of a
defined number (pool) of viable cells, which are derived from a
manufacturing process starting either at the level of organs or tissues
retrieved from a human being, or, at the level of a well defined cell
bank system where the pool of cells relies on continuous cell lines.
For the purposes of this chapter, active substance shall mean the
seed pool of human cells and finished medicinal product shall2001L0083 — EN — 30.04.2004 — 003.001 — 101
▼M2
mean seed pool of human cells formulated for the intended medical
use.
Starting materials and each step of the manufacturing process shall
be fully documented including viral safety aspects.
(1) Organs, tissues, body fluids and cells of human origin
The characteristics of the human source such as age, sex, microbio-
logical status, exclusion criteria and country of origin shall be
documented.
Description of sampling including site, type, operating process,
pooling, transportation, storage and traceability as well as controls
carried out on sampling shall be documented.
(2) Cell banking systems
Relevant requirements depicted in part I shall apply for the prepara-
tion and quality control of cell banking systems. This may
essentially be the case for allogeneic or xenogeneic cells.
(3) Ancillary materials or ancillary medical devices
Information shall be provided on the use of any raw materials (e.g.,
cytokines, growth factors, culture media) or of possible ancillary
products and medical devices e.g., cell sorting devices, biocompa-
tible polymers, matrix, fibres, beads in terms of bio-compatibility,
functionality as well as the risk of infectious agents.
2 . Animal somatic cells (xenogeneic)
Detailed information related to the following items shall be
provided:
— Sourcing of the animals
— Animal husbandry and care— Genetically modified animals (methods of creation, characterisa-
tion of transgenic cells, nature of the inserted or excised (knock
out) gene)
— Measures to prevent and monitor infections in the source/donor
animals
— Testing for infectious agents including vertically transmitted
micro-organisms (also endogenous retro viruses)
— Facilities— Cell banking systems— Control of starting and raw materials.
a) Information on the manufacturing process of the active
substance(s) and the finished product
The different steps of the manufacturing process such as organ/tissue
dissociation, selection of the cell population of interest, in vitro cell
culture, cell transformation either by physico-chemical agents or
gene transfer shall be documented.
b) Characterisation of active substance(s)
All of the relevant information on the characterisation of the cell
population of interest in terms of identity (species of origin, banding
cytogenetics, morphological analysis), purity (adventitious microbial
agents and cellular contaminants), potency (defined biological
activity), and suitability (karyology and tumorigenicity tests) for the
intended medicinal use shall be provided.
c) Pharmaceutical development of finished medicinal product
Apart from the specific method of administration used (intravenous
infusion, site-injection, transplantation surgery), information shall
also be provided on the use of possible ancillary medical devices
(bio-compatible polymers, matrix, fibres, beads) in terms of bio-
compatibility and durability.
d) Traceability
A detailed flow chart shall be provided insuring the traceability of
the products from the donor to the finished medicinal product.2001L0083 — EN — 30.04.2004 — 003.001 — 102
▼M2
3. SPECIFIC REQUIREMENTS FOR GENE THERAPY AND
SOMATIC CELL THERAPY (HUMAN AND XENOGENEIC)
MEDICINAL PRODUCTS REGARDING MODULES 4 AND 5
3.1. Module 4
For gene and somatic cell therapy medicinal products, it is recognised
that conventional requirements as laid down in Module 4 for non-clin-
ical testing of medicinal products may not always be appropriate due to
unique and diverse structural and biological properties of the products
in question, including high degree of species specificity, subject speci-
ficity, immunological barriers and differences in pleiotropic responses.
The rationale underpinning the non-clinical development and the
criteria used to choose relevant species and models shall be properly
captioned in Module 2.
It may be necessary to identify or develop new animal models in order
to assist in the extrapolation of specific findings on functional endpoints
and toxicity to in vivo activity of the products in human beings. The
scientific justification for the use of these animal models of disease to
support safety and proof of concept for efficacy shall be provided.
3.2. Module 5
The efficacy of advanced therapy medicinal products must be demon-
strated as described in Module 5. For some products and for some
therapeutic indications, however, it may not be possible to perform
conventional clinical trials. Any deviation from the existing guidelines
shall be justified in Module 2.
The clinical development of advanced therapy medicinal products will
have some special features owing to the complex and labile nature of
the active substances. It requires additional considerations because of
issues related to viability, proliferation, migration and differentiation
of cells (somatic cell therapy), because of the special clinical circum-
stances where the products are used or because of the special mode of
action through gene expression (somatic gene therapy).
Special risks associated with such products arising from potential
contamination with infectious agents must be addressed in the applica-
tion for marketing authorisation for advanced therapy medicinal
products. Special emphasis should be put on both the early stages of
development in one hand, including the choice of donors in the case
of cell therapy medicinal products, and on the therapeutic intervention
as a whole, including the proper handling and administration of the
product on the other hand.
Furthermore, Module 5 of the application should contain, as relevant,
data on the measures to surveying and control of the functions and
development of living cells in the recipient, to prevent transmission of
infectious agents to the recipient and to minimise any potential risks to
public health.
3.2.1. Human pharmacology and efficacy studies
Human pharmacology studies should provide information on the
expected mode of action, expected efficacy based on justified end-
points, bio-distribution, adequate dose, schedule, and methods of
administration or modality of use desirable for efficacy studies.
Conventional pharmaco-kinetic studies may not be relevant for some
advanced therapy products. Sometimes studies in healthy volunteers
are not feasible and the establishment of dose and kinetics will be diffi-
cult to determine in clinical trials. It is necessary, however, to study the
distribution and in vivo behaviour of the product including cell prolif-
eration and long-term function as well as the extent, distribution of the
gene product and duration of the desired gene expression. Appropriate
tests shall be used and, if necessary, developed for the tracing of the
cell product or cell expressing the desired gene in the human body and
for the monitoring of the function of the cells that were administered or
transfected.
The assessment of the efficacy and safety of an advanced therapy
medicinal product must include the careful description and evaluationof the therapeutic procedure as a whole, including special ways of
administration, (such as transfection of cells ex vivo, in vitro manipula-
tion, or use of interventional techniques), and testing of the possible
associated regimens (including immuno-suppressive, antiviral, cytotoxic
treatment).2001L0083 — EN — 30.04.2004 — 003.001 — 103
▼M2
The whole procedure must be tested in clinical trials and described in
the product information.
3.2.2. Safety
Safety issues arising from immune response to the medicinal products
or to the expressed proteins, immune rejection, immuno-suppression,and breakdown of immuno-isolation devices shall be considered.
Certain advanced gene therapy and somatic cell therapy medicinal
products (e.g. xenogeneic cell therapy and certain gene transfer
products) may contain replication-competent particles and/or infectious
agents. The patient may have to be monitored for the development of
possible infections and/or their pathological sequelae during pre- and/
or post-authorisation phases; this surveillance may have to be extended
to close contacts of the patient including health-care workers.
The risk of contamination with potentially transmissible agents cannot
be totally eliminated in the use of certain somatic cell therapy medic-
inal products and certain gene transfer medicinal products. The risk
can be minimised, however, by appropriate measures as described in
Module 3.
The measures included in the production process must be comple-
mented with accompanied testing methods, quality control processes
and by appropriate surveillance methods that must be described in
Module 5.
The use of certain advanced somatic cell therapy medicinal products
may have to be limited, temporarily or permanently, to establishments
that have documented expertise and facilities for assuring a specific
follow up of the safety of the patients. A similar approach may be rele-
vant for certain gene therapy medicinal products that are associated
with a potential risk of replication-competent infectious agents.
The long term monitoring aspects for the development of late complica-
tions shall also be considered and addressed in the submission, where
relevant.
Where appropriate, the applicant has to submit a detailed risk manage-
ment plan covering clinical and laboratory data of the patient, emerging
epidemiological data, and, if relevant, data from archives of tissue
samples from the donor and the recipient. Such a system is needed to
ensure the traceability of the medicinal product and the rapid response
to suspicious patterns of adverse events.
4. SPECIFIC STATEMENT ON XENO-TRANSPLANTATION MEDIC-
INAL PRODUCTS
For the purposes of this Annex, xeno-transplantation shall mean any
procedure that involves the transplantation, implantation, or infusion
into a human recipient of either live tissues or organs retrieved fromanimals, or, human body fluids, cells, tissues or organs that have under-
gone ex vivo contact with live non-human animal cells, tissues or
organs.
Specific emphasis shall be paid to the starting materials.
In this respect, detailed information related to the following items shall
be provided according to specific guidelines:
— Sourcing of the animals
— Animal husbandry and care
— Genetically modified animals (methods of creation, characterisation
of transgenic cells, nature of the inserted or excised (knock out)
gene)
— Measures to prevent and monitor infections in the source/donor
animals
— Testing for infectious agents— Facilities— Control of starting and raw materials
— Traceability.2001L0083 — EN — 30.04.2004 — 003.001 — 104
▼B
ANNEX II
PART A
Repealed Directives, with their successive amendments (referred to by
Article 128)
Council Directive 65/65/EEC (OJ 22, 9. 2. 1965, p. 369/65)
Council Directive 66/454/EEC (OJ 144, 5. 8. 1966, p. 2658/66)
Council Directive 75/319/EEC (OJ L 147, 9. 6. 1975, p. 13)
Council Directive 83/570/EEC (OJ L 332, 28. 11. 1983, p. 1)
Council Directive 87/21/EEC (OJ L 15, 17. 1. 1987, p. 36)Council Directive 89/341/EEC (OJ L 142, 25. 5. 1989, p. 11)
Council Directive 92/27/EEC (OJ L 113, 30. 4. 1992, p. 8)
Council Directive 93/39/EEC (OJ L 214, 24. 8. 1993, p. 22)
Council Directive 75/318/EEC (OJ L 147, 9. 6. 1975, p. 1)
Council Directive 83/570/EEC
Council Directive 87/19/EEC (OJ L 15, 17. 1. 1987, p. 31)
Council Directive 89/341/EEC
Commission Directive 91/507/EEC (OJ L 270, 26. 9. 1991, p. 32)Council Directive 93/39/EECCommission Directive 1999/82/EC (OJ L 243, 15. 9. 1999, p. 7)
Commission Directive 1999/83/EC (OJ L 243, 15. 9. 1999, p. 9)
Council Directive 75/319/EEC
Council Directive 78/420/EEC (OJ L 123, 11. 5. 1978, p. 26)
Council Directive 83/570/EECCouncil Directive 89/341/EEC
Council Directive 92/27/EEC
Council Directive 93/39/EECCommission Directive 2000/38/EC (OJ L 139, 10. 6. 2000, p. 28)
Council Directive 89/342/EEC (OJ L 142, 25. 5. 1989, p. 14)
Council Directive 89/343/EEC (OJ L 142, 25. 5. 1989, p. 16)Council Directive 89/381/EEC (OJ L 181, 28. 6. 1989, p. 44)
Council Directive 92/25/EEC (OJ L 113, 30. 4. 1992, p. 1)
Council Directive 92/26/EEC (OJ L 113, 30. 4. 1992, p. 5)
Council Directive 92/27/EEC
Council Directive 92/28/EEC (OJ L 113, 30. 4. 1992, p. 13)
Council Directive 92/73/EEC (OJ L 297, 13. 10. 1992, p. 8)2001L0083 — EN — 30.04.2004 — 003.001 — 105
▼B
PART B
Time-limits for transposition into national law (referred to by Article 128)
Directive Deadline for transposition
Directive 65/65/EEC 31 December 1966
Directive 66/454/EEC —
Directive 75/318/EEC 21 November 1976
Directive 75/319/EEC 21 November 1976
Directive 78/420/EEC —Directive 83/570/EEC 31 October 1985
Directive 87/19/EEC 1 July 1987
Directive 87/21/EEC 1 July 1987
1 January 1992 (
1)
Directive 89/341/EEC 1 January 1992
Directive 89/342/EEC 1 January 1992
Directive 89/343/EEC 1 January 1992
Directive 89/381/EEC 1 January 1992
Directive 91/507/EEC 1 January 1992 (2)
1 January 1995 (3)
Directive 92/25/EEC 1 January 1993
Directive 92/26/EEC 1 January 1993
Directive 92/27/EEC 1 January 1993
Directive 92/28/EEC 1 January 1993
Directive 92/73/EEC 31 December 1993
Directive 93/39/EEC 1 January 1995 (4)
1 January 1998 (5)
Directive 1999/82/EC 1 January 2000
Directive 1999/83/EC 1 March 2000
Directive 2000/38/EC 5 December 2001
(1) Deadline for transposition applicable to Greece, Spain and Portugal.
(2) Except Section A, point 3.3 in Part II of the Annex.
(3) Deadline for transposition applicable to Section A, point 3.3 in Part II of the Annex.
(4) Except with regard to Article 1(6).
(5) Deadline for transposition applicable to Article 1(7).2001L0083 — EN — 30.04.2004 — 003.001 — 106
ANNEX III
CORRELATION TABLE
This Dir. 65/65/EEC 75/318/EEC 75/319/EEC 89/342/EEC 89/343/EEC 89/381/EEC 92/25/EEC 92/26/EEC 92/27/EEC 92/28/EEC 92/73/EEC
Art. 1(1) to (3) Art. 1(1) to
(3)
Art. 1(4) Annex Art. 1(1) and
(2)
Art. 1(5) Art. 1
Art. 1(6) to (9) Art. 1(2)Art. 1(10) Art. 1(1)
Art. 1(11) to
(16)Art. 29b, 1st
paragraph
Art. 1(17) and
(18)Art. 1(2)
Art. 1(19) Art. 1(2), 2nd
sentence
Art. 1(20) to
(26)Art. 1(2)
Art. 1(27) Art. 8(1)
Art. 1(28) Art. 10(1)Art. 2 Art. 2(1)Art. 3(1) and
(2)Art. 1(4) and
(5)
Art 2(3), 1st
indent▼B2001L0083 — EN — 30.04.2004 — 003.001 — 107
This Dir. 65/65/EEC 75/318/EEC 75/319/EEC 89/342/EEC 89/343/EEC 89/381/EEC 92/25/EEC 92/26/EEC 92/27/EEC 92/28/EEC 92/73/EEC
Art. 3(3) and
(4)Art.2(3), 2nd
and 3rd
indents
Art. 3(5) Art. 1(1)Art. 3(6) Art. 1(2)
Art. 4(1) Art. 1(3)
Art. 4(2) Art. 1(3)
Art. 4(3) Art. 3, 2nd
subparagraph
Art. 4(4) Art. 6Art. 5 Art. 2(4)Art. 6(1) Art. 3(1)
Art. 6(2) Art. 2, 1st
sentence
Art. 7 Art. 2, 2nd
sentence
Art. 8(1) and
(2)Art. 4(1) and
(2)
Art. 8(3)(a) to
(e)Art. 4, 3rd
para., points 1
to 5Art. 1, 1st
paragraph
Art. 8(3)(f) to
(i)Art. 4, 3rd
para., points 6
to 8.1
Art. 8(3)(j) to
(l)Art. 4, 3rd
para., points 9
to 11▼B2001L0083 — EN — 30.04.2004 — 003.001 — 108
This Dir. 65/65/EEC 75/318/EEC 75/319/EEC 89/342/EEC 89/343/EEC 89/381/EEC 92/25/EEC 92/26/EEC 92/27/EEC 92/28/EEC 92/73/EEC
Art. 9 Art. 3
Art. 10(1) Art. 4, 3rd
paragraph,
point 8.2
Art. 10(2) Art. 1, 2nd
paragraph
Art. 11, points
1 to 5.3Art. 4a, points
1 to 5.3
Art. 11, point
5.4Art. 4a, point
5.4Art. 3
Art. 11, points
5.5 to 6.4Art. 4a, points
5.5 to 6.4
Art. 11, point
6.5Art. 4a, point
6.6
Art. 11, point 7 Art. 4a, point
6.5
Art. 11, points
8t o9Art. 4
Art. 12(1) Art. 1
Art. 12(2) and
(3)Art. 2
Art. 13 Art. 6(1) and
(2)
Art. 14(1) and
(2)Art. 7(1) and
(4)
Art. 14(3) Art. 4, 2nd
paragraph▼B2001L0083 — EN — 30.04.2004 — 003.001 — 109
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Art. 15 Art. 8
Art. 16 Art. 9
Art. 17 Art. 7
Art. 18 Art. 7a
Art. 19 Art. 4Art. 20 Art. 5Art. 21 Art. 4b
Art. 22 Art. 10(2)
Art. 23 Art. 9aArt. 24 Art. 10(1)Art. 25 Art. 9
Art. 26 Art. 5
Art. 27 Art. 8Art. 28(1) Art. 9(3)Art. 28(2) Art. 9(1)Art. 28(3) Art. 9(2)
Art. 28(4) Art. 9(4)
Art. 29 Art. 10Art. 30 Art. 11Art. 31 Art. 12▼B2001L0083 — EN — 30.04.2004 — 003.001 — 110
This Dir. 65/65/EEC 75/318/EEC 75/319/EEC 89/342/EEC 89/343/EEC 89/381/EEC 92/25/EEC 92/26/EEC 92/27/EEC 92/28/EEC 92/73/EEC
Art. 32 Art. 13
Art. 33 Art. 14(1)
Art. 34 Art. 14(2) to
(4)
Art. 35 Art. 15
Art. 36 Art. 15a
Art. 37 Art. 15b
Art. 38 Art. 15c
Art. 39 Art. 14(5)
Art. 40 Art. 16
Art. 41 Art. 17
Art. 42 Art. 18
Art. 43 Art. 20(1)
Art. 44 Art. 20(2)
Art. 45 Art. 20(3)
Art. 46 Art. 19
Art. 47 Art. 19a
Art. 48 Art. 21
Art. 49 Art. 23
Art. 50 Art. 24▼B2001L0083 — EN — 30.04.2004 — 003.001 — 111
This Dir. 65/65/EEC 75/318/EEC 75/319/EEC 89/342/EEC 89/343/EEC 89/381/EEC 92/25/EEC 92/26/EEC 92/27/EEC 92/28/EEC 92/73/EEC
Art. 51(1) and
(2)Art. 22(1)
Art. 51(3) Art. 22(2)
Art. 52 Art. 25
Art. 53 Art. 3
Art. 54 Art. 2(1)
Art. 55 Art. 3
Art. 56 Art. 4(1)
Art. 57 Art. 5(2)
Art. 58 Art. 6
Art. 59 Art. 7(1) and
(2)
Art. 60 Art. 5(1) and
Art. 9
Art. 61 Art. 10(1) to
(4)
Art. 62 Art. 2(2) and
Art. 7(3)
Art. 63(1) Art. 4(2)
Art. 63(2) Art. 8
Art. 63(3) Art. 10(5)
Art. 64 Art. 11(1)▼B2001L0083 — EN — 30.04.2004 — 003.001 — 112
This Dir. 65/65/EEC 75/318/EEC 75/319/EEC 89/342/EEC 89/343/EEC 89/381/EEC 92/25/EEC 92/26/EEC 92/27/EEC 92/28/EEC 92/73/EEC
Art. 65 Art. 12
Art. 66 Art. 5
Art. 67 Art. 6(1)
Art. 68 Art. 2(2)
Art. 69 Art. 7(2) and
(3)
Art. 70 Art. 2
Art. 71 Art. 3
Art. 72 Art. 4
Art. 73 Art. 5(1)
Art. 74 Art. 5(2)
Art. 75 Art. 6(2)
Art. 76 Art. 2
Art. 77 Art. 3
Art. 78 Art. 4(1)
Art. 79 Art. 5
Art. 80 Art. 6
Art. 81 Art. 7
Art. 82 Art. 8
Art. 83 Art. 9▼B2001L0083 — EN — 30.04.2004 — 003.001 — 113
This Dir. 65/65/EEC 75/318/EEC 75/319/EEC 89/342/EEC 89/343/EEC 89/381/EEC 92/25/EEC 92/26/EEC 92/27/EEC 92/28/EEC 92/73/EEC
Art. 84 Art. 10
Art. 85 Art. 9
Art. 86 Art. 1(3) and
(4)
Art. 87 Art. 2
Art. 88 Art. 3(1) to
(6)
Art. 89 Art. 4
Art. 90 Art. 5
Art. 91 Art. 6
Art. 92 Art. 7
Art. 93 Art. 8
Art. 94 Art. 9
Art. 95 Art. 10
Art. 96 Art. 11
Art. 97(1) to
(4)Art. 12(1) and
(2)
Art. 97(5) Art. 12(4)
Art. 98 Art. 13
Art. 99 Art. 14
Art. 100 Art. 6(3)▼B2001L0083 — EN — 30.04.2004 — 003.001 — 114
This Dir. 65/65/EEC 75/318/EEC 75/319/EEC 89/342/EEC 89/343/EEC 89/381/EEC 92/25/EEC 92/26/EEC 92/27/EEC 92/28/EEC 92/73/EEC
Art. 101 Art. 29e
Art. 102 Art. 29aArt. 103 Art. 29c
Art. 104 Art. 29d
Art. 105 Art. 29fArt. 106(1) Art. 29gArt. 106(2) Art. 29b, 2nd
paragraph
Art. 107 Art. 29hArt. 108 Art. 29i
Art. 109 Art. 3(1) to
(3)
Art. 110 Art. 3(4)
Art. 111(1) Art. 26, 1st
and 2nd para-
graph
Art. 111(2) Art. 4(1)Art. 111(3) Art. 26, 3rd
paragraph
Art. 112 Art. 8 Art. 27Art. 113 Art. 4(2) Art. 4(2)Art. 114(1) Art. 4(3)Art. 114(2) Art. 4(3)▼B2001L0083 — EN — 30.04.2004 — 003.001 — 115
This Dir. 65/65/EEC 75/318/EEC 75/319/EEC 89/342/EEC 89/343/EEC 89/381/EEC 92/25/EEC 92/26/EEC 92/27/EEC 92/28/EEC 92/73/EEC
Art. 115 Art. 4(1)
Art. 116 Art. 11
Art. 117 Art. 28Art. 118 Art. 29
Art. 119 Art. 4(1)
Art. 120 Art. 2a, 1st
paragraph
Art. 121 Art. 2b Art. 37a
Art. 122 Art. 30Art. 123 Art. 33Art. 124 Art. 5
Art. 125 Art. 12 Art. 31 Art. 4(2) Art. 11(2) Art. 12(3)
Art. 126, 1st
paragraphArt. 21
Art. 126, 2nd
paragraphArt. 32
Art. 127 Art. 28a
Art. 128 — — —————————
Art. 129 — — —————————
Art. 130 — — —————————
Annex I Annex▼B2001L0083 — EN — 30.04.2004 — 003.001 — 116
This Dir. 65/65/EEC 75/318/EEC 75/319/EEC 89/342/EEC 89/343/EEC 89/381/EEC 92/25/EEC 92/26/EEC 92/27/EEC 92/28/EEC 92/73/EEC
Annex II — — —————————
Annex III — — —————————▼B2001L0083 — EN — 30.04.2004 — 003.001 — 117