EN   EN 
 
 
 EUROPEAN  
COMMISSION   
Brussels, 26.4.2023  
COM(2023) 192 final  
ANNEXES 1 to 8  
 
ANNEX  
 
to the  
Proposal for a DIRECTIVE OF THE EUROPEAN PARLIAMENT AND OF THE 
COUNCIL  
on the Union code relating to medicinal products for human use, and repealing Directive 
2001/83/EC and Directive 2009/35/EC      
      
          
 
{SEC(2023)  390 final}  - {SWD(2023)  191 final}  - {SWD(2023)  192 final}  -
 {SWD(2023)  193 final}    
1 
 ANNEX I 
INFORMATION  REFERRED  TO IN THE  APPLICATION  
(1) Name or corporate name and permanent address of the applicant and, where applicable, 
of the manufacturer.  
(2) Name of the medicinal product.  
(3) Qualitative and quantitative particulars of all the constituents of the medicinal product, 
including the reference to its international non -proprietary name (INN) recommended 
by the World Health Organization, wh ere an INN for the medicinal product exists, or a 
reference to the relevant chemical name.  
(4) An environmental risk assessment (ERA) in accordance with the requirements laid 
down in Articles 22 and 23.  
(5) For medicinal product for human use containing or consisting of genetically modified 
organisms, an environmental risk assessment identifying and characterising possible 
hazards for human health, animals and the environment. The assessment shall be 
conducted in accordance with the elements described in Art icle 8 of [revised Regulation 
(EC) No 726/2004] and the requirements of Annex II to this Directive, based on the 
principles set out in Annex II to Directive 2001/18/EC of the European Parliament and 
of the Council1 taking into account the specificities of medicinal products.  
(6) Description of the manufacturing method.  
(7) Therapeutic indications, contra -indications and adverse reactions.  
(8) Posology , pharmaceutical form, method and route of administration and expected shelf 
life. 
(9) Reasons for any precautionary and saf ety measures to be taken for the storage of the 
medicinal product, its administration to patients and for the disposal of waste products, 
together with an indication of potential risks presented by the medicinal product for the 
environment.  
(10) Description of the control methods employed by the manufacturer.  
(11) A written confirmation that the manufacturer of the medicinal product has verified 
compliance of the manufacturer of the active substance with principles of good 
manufacturing practice by conducting audits,  in accordance with Article 160.  The 
written confirmation shall contain a reference to the date of the audit and a declaration 
that the outcome of the audit confirms that the manufacturing complies with the 
principles of good manufacturing practice.  
(12) Result s of: 
(a) pharmaceutical (physico -chemical, biological or micro biological) tests,  
(b) non-clinical (toxicological and pharmacological) tests,  
(c) clinical trials.  
                                                 
1 Directive 2001/18/EC of the European Parliament and of the Council of 12 March 2001 on the deliberate 
release into the environment of genetically modified organisms and repealing Council Directive 90/220/EEC - 
Commission Declaration (OJ L 106, 17.4.2001, p. 1)   
2 
 (13) Where relevant, evidence from other sources of clinical data (non -interventional clinical 
studies, regis tries).  
(14) A summary of the applicant’s pharmacovigilance system which shall include the 
following elements:  
(a) proof that the applicant has at their disposal a qualified person 
responsible for pharmacovigilance,  
(b) the Member States in which the qualified person r esides and carries out 
their tasks,  
(c) the contact details of the qualified person,  
(d) a statement signed by the applicant to the effect that the applicant has the 
necessary means to fulfil the tasks and responsibilities listed in Chapter 
VI, 
(e) a reference to the location where the pharmacovigilance system master 
file for the medicinal product is kept.  
(15) The risk management plan describing the risk management system which the applicant 
will introduce for the medicinal product concerned, together with a summary thereo f. 
(16) A statement to the effect that clinical trials carried out outside the European Union meet 
the ethical requirements of Regulation (EU) No 536/2014.  
(17) A summary of product characteristics in accordance with Article 62, a mock -up of the 
outer packaging, containing the details provided for in Annex IV, and of the immediate 
packaging of the medicinal product, containing the details provided for in Article 66, 
together with a package leaflet in accordance with Article 64.  
(18) A document showing that the manufact urer is authorised in their own country to 
produce medicinal products.  
(19) Copies of the following:  
(a) any marketing  authorisation, obtained in another Member State or in a 
third country, to place the medicinal product on the market, a summary 
of the safety data including the data contained in the periodic safety 
update reports, where available, and suspected adverse reactions reports, 
together with a list of those Member States in which an application for 
marketing  authorisation submitted in accordance with this Directive is 
under examination;  
(b) the summary of product characteristics proposed by the applicant in 
accordance with Article 62  or approved by the competent authorities of 
the Member State in accordance with Article 43 and the package leaflet 
proposed in accordance with Article 64  or approved by the competent 
authorities of the Member State in accordance with Article 76;  
(c) details of any decision to refuse marketing  authorisation, whether in the 
Union or in a th ird country, and the reasons for such a decision.  
(20) A copy of any designation of the medicinal product as an orphan medicinal product as 
defined in Article 63 of [revised Regulation (EC) No 726/2004], accompanied by a 
copy of the relevant Agency opinion.  
(21) Whe re the application concerns an antimicrobial medicinal product, the application 
shall also contain:   
3 
 a) an antimicrobial stewardship plan which shall in particular outline:  
(i) information about risk mitigation measures to limit antimicrobial 
resistance developmen t related to the use, prescription and administration 
of the medicinal product;  
(ii) how the marketing authorisation holder intends to monitor and report to 
the competent authority the resistance to the antimicrobial medicinal 
product.  
b) a description of the special information requirements outlined in Article 58  
c) details on  the pack size which  shall correspond to the usual posology and 
duration of treatment.  
(22) Where an application concerns the marketing  authorisation to market a radionuclide 
generator, in addition  to the requirements set out in Article s 6 and 9, it shall also 
contain:  
(a) a general description of the system together with a detailed description of 
the components of the system that may affect the composition or quality 
of the daughter nucleid preparation ; and  
(b) qualitative and quantitative particulars of the eluate or the sublimate.  
(23) Good manufacturing practices certificates.  
   
4 
 ANNEX II 
ANALYTICAL,  PHARMACOTOXICOLOGICAL  AND  CLININCAL  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, labell ing 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 principle s 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   
5 
 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 m aterials  
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  
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 pa tient 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 
 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 pro duct 
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.   Introduction  
2.   Definitions  
2.1.   Gene therapy medicinal product  
2.2.   Somatic cell therapy medicinal product  
3.   Specific requirements regarding Module 3  
3.1.   Specific requirements for all advanced therapy  medicinal products  
3.2.   Specific requirements for gene therapy medicinal products  
3.2.1.   Introduction: finished product, active substance and starting materials  
3.2.1.1.  Gene therapy medicinal product containing recombinant nucleic acid 
sequence(s) or  genetically modified microorganism(s) or virus(es)  
3.2.1.2.  Gene therapy medicinal product containing genetically modified cells  
3.2.2.  Specific requirements  
3.3.  Specific requirements for somatic cell therapy medicinal products and tissue 
engineered pro ducts  
3.3.1.  Introduction: finished product, active substance and starting materials  
3.3.2.  Specific requirements  
3.3.2.1.  Starting materials  
3.3.2.2.  Manufacturing process  
3.3.2.3.  Characterisation and control strategy  
3.3.2.4.  Excipients  
3.3.2.5.  Developmental studies  
3.3.2.6.  Reference materials   
7 
 3.4. Specific requirements for advanced therapy medicinal products containing 
devices  
3.4.1.  Advanced therapy medicinal product containing devices as referred to in Article 
7 of Regulation (EC) No 1394/2007  
3.4.2.  Combined advanced therapy medicinal products as defined in Article 2(1)(d) of 
Regulation (EC) No 1394/2007  
4.  Specific requirements regarding module 4  
4.1.  Specific requirements for all advanced therapy medicinal products  
4.2.  Specific requireme nts for gene therapy medicinal products  
4.2.1.  Pharmacology  
4.2.2.  Pharmacokinetics  
4.2.3.  Toxicology  
4.3.  Specific requirements for somatic cell therapy medicinal products and tissue 
engineered products  
4.3.1.  Pharmacology  
4.3.2.  Pharmacokinetics  
4.3.3.  Toxicology  
5. Specific requirements regarding module 5  
5.1.  Specific requirements for all advanced therapy medicinal products  
5.2.  Specific requirements for gene therapy medicinal products  
5.2.1.  Human pharmacokinetic studies  
5.2.2.  Human pharm acodynamic studies  
5.2.3.  Safety studies  
5.3.  Specific requirements for somatic cell therapy medicinal products  
5.3.1.  Somatic cell therapy medicinal products where the mode of action is based on 
the production of defined active biomolecule(s)  
5.3.2.  Biodistribution, persistence and long -term engraftment of the somatic cell 
therapy medicinal product components  
5.3.3.  Safety studies  
5.4. Specific requirements for tissue engineered products  
5.4.1.  Pharmacokinetic studies  
5.4.2.  Pharmacodynamic studies  
5.4.3. Safety studies  
 
 
 
 
  
8 
 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 information, Module 4 provides non -clinical 
reports and Module 5 provides clinical study reports. This presentation 
implements a common format for all ICH  (2) regions (European Community, 
United States of America, Japan). These five Modules sha ll be presented in strict 
accordance 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 authorisa tion 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 entitie s (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 biological) of the 
dossier, all monographs including general monographs and general cha pters 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 hu man use  (3) and with 
the principles and guidelines on GMP, published by the Commission in The rules 
governing medicinal products in the European Community, Volume 4.  
                                                 
2 International Conference on Harmonisation of Technical Requirement s for Registration of Pharmaceuticals for 
Human Use  
3 OJ L 193, 17.7.1991, p. 30   
9 
 (7) All information, which is relevant to the evaluation of the medicinal product 
concerned, s hall be included in the application, whether favourable 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, regulations 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  (4). 
To be taken into account duri ng 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 equivalent 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 Helsin ki. 
(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 relatin g to the application of the principles of good laboratory practice 
and the verification of their application for tests in chemical substances  (5) and 
88/320/EEC on the inspection and verification of good laboratory practice 
(GLP)  (6). 
(10) Member States shall a lso 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 provisions of the Member 
States regarding the protection of animals for exper imental 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 authorisation has been granted, any 
change to the data in the dossier shall be submitted to the competent authorities in 
accordance with the requirements of Commission Regulations (EC) No 
1084/2003  (7) and (EC) No 1085/2003  (8) 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.  
                                                 
4 OJ L 121, 1.5.2001, p. 34  
5 OJ L 15, 17.1.1987, p. 29  
6 OJ L 145, 11.6.1988, p. 35  
7 See p. 1 of this Official Journal  
8 See p. 1 of this Official Journal   
10 
 This Annex is divided in four different parts:  
— Part I describes the application format, t he summary of product characteristics, 
the labelling, the leaflet and presentation requirements for standard applications 
(Modules 1 to 5).  
— Part II provides derogation for ‘Specific applications’, i.e. well -established 
medicinal use, essentially similar products, fixed combinations, similar 
biological products, exceptional circumstances and mixed applications (part 
bibliographic and part own studies).  
—Part III deals with ‘Particular application requirements’ for biological medicinal 
products (Plasma Mast er 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 th erapy 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 packagi ng. 
 
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.  
  
11 
 The applicant shall identify the type of application and indicate what samples, 
if any, are also provided.  
 
Annexed to the administrative data shall be copies of the ma nufacturing 
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 c ountries 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 aut horisation 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 characterist ics 
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 the medicinal 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 applicable and a list of countries in 
which an application has been submitted.  
 
1.4.    Information a bout 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,  
12 
 pharmace utical 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 anim als 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 locat ed 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 h ave suitable 
technical or professional qualifications. The professional relationship of the 
expert to the applicant 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 the environment 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 European 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  (9) shall be addressed.  
 
Information pertain ing 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;  
                                                 
9 OJ L 106, 17.4.2001, p. 1   
13 
  
 — 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 conclusion 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 Characteristics, 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 exper ience, 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, pharmaceutical 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 principl es and requirements as laid down herewith:   
14 
  
2.1.     Overall table of contents  
Module 2 shall contain a table of contents for the scientific documentation 
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 authorisation 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.  
 
Key critical parameters and issues related to quality aspects shall be 
emphasised as well as justification in cases where the relevant guidelines 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 relevant 
guidelines shall be included.  
 
Except for biological medicinal products, an assessment of the impurities and 
degradation products shall be included along with their potential 
pharmacological and toxicolo gical 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, a s demonstrated by the non -
clinical studies shall be defined and the implications of the findings for the  
15 
 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 stud ies shall be provided.  
 
A brief overview of the clinical findings, including important limitations 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 s hall 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   
16 
 A detailed, factual summary of the clinical information on the medicinal 
product included in Module 5 shall be provided. This shall include the results 
of all bio -pharmaceutics studies, of clinical pharmacology 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 Safety  
 
— 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  
G e n e r a l  I n f o r m a t i o n  
— Nomenclature  
— Structure  
— General Properties  
M a n u f a c t u r e  
— 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   
17 
 C h a r a c t e r i s a t i o n  
— Elucidation of Structure and oth er Characteristics  
— Impurities  
C o n t r o l  o f  A c t i v e  S u b s t a n c e  
— Specification  
— Analytical Procedures  
— Validation of Analytical Procedures  
— Batch Analyses  
— Justification of Specification  
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  
C o n t a i n e r  C l o s u r e  S y s t e m  
S t a b i l i t y  
— Stability Summary and Conclusions  
— Post-approval Stability Protocol and Stability Commitment  
— Stability Data  
— Finished Medicinal Product  
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  M e d i c i n a l  
P r o d u c t  
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  
— Components of the Medicinal Prod uct 
— Active Substance  
— Excipients  
— Medicinal Product  
— Formulation Development  
— Overages  
— Physicochemical and Biological Properties  
— Manufacturing Process Development  
— Container Closure System  
— Microbiological Attributes  
— Compatibility  
 M a n u f a c t u r e  
— Manufacturer(s)  
— Batch Formula  
— Description of Manufacturing Process and Process Controls  
— Controls of Critical Steps and Intermediates  
— Process Validation and/or Evaluation  
C o n t r o l  o f  E x c i p i e n t s   
18 
 — Specifications  
— Analytical Procedures  
— Validation of Analytical Procedures  
— Justification of Specifications  
— Excipients of Human or Animal Origin  
— Novel Excipients  
C o n t r o l  o f  F i n i s h e d  M e d i c i n a l  P r o d u c t  
— Specification(s)  
— Analytical Procedures  
— Validation of Analytical Procedures  
— Batch Analyses  
— Characterisation of Impurities  
— Justification of Specification(s)  
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  
C o n t a i n e r  C l o s u r e  S y s t e m  
S t a b i l i t y  
— Stability Summary and Conclusion  
— Post-approval Stability Protocol and Stability Commitment  
— Stability Dat a 
— 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  
— Medicina l 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 presentation of the finished medicinal product .  
19 
  
(2) Two main sets of information shall be provided, dealing with the active 
substance(s) and with th e finished medicinal product, respectively . 
 
(3) This Module shall in addition supply detailed information on the starting 
and raw materials used during the manufacturing operations of the active 
substance(s) and on the excipients incorporated in the formu lation 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 t ests, carried out 
at the request of the competent 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 procedures in cluded 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 applicable 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 a method liable to 
leave impurities not controlled in the pharmacopoeia monograph, these 
impurities and their maximum tolerance limits must be declared and a 
suitable test procedure must be described. In cases where a specification 
contain ed in a monograph 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 author isation holder. The 
competent authorities shall inform the authorities responsible for the 
pharmacopoeia in question. The marketing authorisation holder shall 
provide the authorities of that pharmacopoeia with the details of the 
alleged insufficiency and t he 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  
20 
 a third country pharmacopoeia can be acc epted. 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 appropriate.  
 
(7) Where the active substance and/or a raw and starting  material or 
excipient(s) are the subject of a monograph of the European 
Pharmacopoeia, 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 relevan t 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 manufacturer 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 manufacturer  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 manufa cturer of the active substance as an Active Substance Master 
File. 
 
 In this case, the manufacturer shall, however, provide the applicant 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 
particulars 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 tr ansmission 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 Transmitt ing Animal Spongiform Encephalopathy  
21 
 Agents via Medicinal Products and its updates, published by the 
Commission in the Official Journal of the European Union. Demonstration 
of compliance with the said Note for Guidance can be done by submitting 
either, pre ferably a certificate of suitability to the relevant monograph 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 adve ntitious 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 well as in relevant 
general monograph and general chapter of the E uropean 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, in accor dance with the second subparagraph  of Article  1(8) or the 
second subparagraph  of Article  1(9) of Regulation  (EU)  2017/745 of the 
European Parliament and of the Council  (10), a product is governed by this 
Directive, the marketing authorisation dossier shall include, where 
available, the results of the assessment of the conformity of the device part 
with the relevant general safety and performance requirements set out in 
Annex  I to that Regulation contained in the manufacturer's EU declaration 
of conformity or  the relevant certificate issued by a notified body allowing 
the manufacturer to affix a CE  marking to the medical device.  
 
  If the dossier does not include the results of the conformity assessment 
referred to in the first subparagraph  and where for the c onformity 
assessment of the device, if used separately, the involvement of a notified 
body is required in accordance with Regulation  (EU)  2017/745, the 
authority shall require the applicant to provide an opinion on the 
conformity of the device part with th e relevant general safety and 
performance requirements set out in Annex  I to that Regulation issued by a 
notified body designated in accordance with that Regulation for the type of 
device in question.  
 
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  a n d  r a w  m a t e r i a l s  
                                                 
10  Regulation (EU) 2017/745 of the European Parliament and of the Council of 5 April 2017 on medical 
devices, amending Directive 2001/83/EC, Regulation (EC) No 178/2002 and Regulation (EC) No 1223/2009 
and repealing Council Direc tives 90/385/EEC and 93/42/EEC (OJ L 117, 5.5.2017, p. 1)   
22 
 a)  Information on the nomenclature of the active substance shall be provided, 
including recommended Internationa l Non -proprietary Name (INN), 
European Pharmacopoeia name if relevant, chemical name(s).   
 
The structural formula, including relative and absolute stereo -chemistry, 
the molecular formula, and the relative molecular mass shall be provided. 
For biotechnologi cal 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 properties 
of the active substance, including biological activity for bi ological 
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 n ot, 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 produc ts and medicinal products 
derived from human blood and human plasma as defined, respectively in 
paragraph s (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 medici nal 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 represents 
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.   
23 
  
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 stand ards 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 product ion site or facility involved in 
manufacturing and testing shall be provided.  
 
c)  For biological medicinal products, the following additional requirements 
shall apply.  
 
The origin and history of starting materials shall be described and 
documented.  
 
Regar ding the specific measures for the prevention of the Transmission 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 Spongiform E ncephalopathy 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 production and 
beyond.  
 
Seed materials, cell banks, pools of serum or plasma and other materials 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 inevitable, 
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 base d on a seed lot system 
and on established cell banks. For bacterial and viral vaccines, the 
characteristics of the infectious agent shall be demonstrated on the seed. In  
24 
 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 colle ction, transportation and storage of 
the starting material shall be described and documented 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, information 
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 ine vitable, 
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 significa nt 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.  
  
25 
 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 specifications 
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 type  s 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 app ropriate 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  p r o d u c t  
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 function 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, 
thick eners, 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 tabl ets, films -coated tablets, etc.),  
 
— these particulars shall be supplemented by any relevant data concerning the 
type of container and, where appropriate, its manner of closure, together  
26 
 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 the other provisions in 
Article 8 (3) (c):  
 
— in respect of substances which appear in the European Pharmacopoeia or, 
failing this, in the national pharmacopoeia of one of the Member States, the 
main title at the head of the monograph in question, 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 designation shall be described by a 
statement of how and from what they were prepared, supplemented, where 
appropriate, by any other relevant details,  
 
— in respect of colouring matter, designation by the ‘E’ code assigned to them 
in Council Directive 78/2 5/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  (11) and/or European Parliament 
and Council Directive 94/36/EC of 30 June 1994 on colours for use in 
foodstuffs  (12). 
 
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 
activi ty, 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 acti ve 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, whi ch 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 
                                                 
11 OJ L 11, 14.1.1978, p. 18  
12 OJ L 237, 10.9.1994, p. 13   
27 
 products in the Member States shall have their quantitative composition stated 
in the sam e 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 biological 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 unambiguous 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, manufacturing 
process, container closure system, microbiological attribu tes 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 par ameters of the formulation 
and process attributes that can influence batch reproducibility, 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 characte ristics of the active substance that can influence 
the performance of the finished product or the compatibility of different 
active substances with each other in the case of combination products, 
shall be documented.  
 
b)  The choice of excipients, in parti cular 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 administration 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.  
  
28 
 f)  The selection and optimisation of th e manufacturing process as well as 
differences  between the manufacturing process(es) used to produce pivotal 
clinical batches and the process used for manufacturing 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 documented. A possible 
interaction between medicinal product and container may need to be 
considered.  
 
h)  The microbiological attributes of the dosage for m 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 o d u c t  
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 the nature 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 assessment can be 
made of whether the processes employed in producing the 
pharmaceutical form might have produced an adverse change in the 
constituen ts, 
 
— 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,  
  
29 
 — a detailed batch formula.  
 
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 medicinal 
product with the formula when, exceptionally, an applicant proposes an 
analytical method for testing the finished pro duct 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 c ontrol 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 ma terials 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, c olouring 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 validated.  
 
c)  Specific attention shall be paid to excipients of human or animal origin.  
 
Regarding the specific measures for the prevention of the Transmission of 
animal Spongiform Encephalopathies, the applicant must demonstrate also  
30 
 for excipients that the medicinal p roduct is manufactured 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 Spongiform Encephalopathies of 
the European Pharmacopoeia, or by the supply 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, characterisation, and 
controls, with cr oss 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 pres ented. 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. W here 
the applicant differs from the novel excipient manufacturer the said stand -
alone document shall be made available to the applicant 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 o d u c t  
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 and have undergone 
the same series of manufacturing and/or sterilisation operations or, in the case 
of a continuous produc tion process, all the units manufactured in a given 
period of time.   
31 
  
Unless there is appropriate justification, the maximum acceptable deviation 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) justification 
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 a nd 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 a nd identification. 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 s hall 
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 o d u c t  
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 appropria te; 
 
c) The post authorisation stability protocol and stability commitment shall be 
provided.  
 
4.   MODULE 4: NON -CLINICAL REPORTS  
4.1.     Format and Presentation  
The general outline of Module 4 is as follows:  
— Table of contents   
32 
 — 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 studies  
— 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   
33 
 — 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 undesirable 
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 qualitative and 
 quantitative relationship to the proposed use in human b eings. 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 evaluating the results.  
 
Additionally, it is necessary for clinicians  to be given information 
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 admin istration of the product shall be 
designed to take account of the possible induction of, and interference 
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.  
  
34 
 (3)  The toxicology and pharmaco -kinetics of an excipient used for the first 
time in the pharmaceutical field s hall 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 mus t 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 subs tance or substances 
with a similar therapeutic action.  
 
— Secondly, the applicant shall investigate the potential undesirable 
pharmaco -dynamic effects of the substance on physiological functions. 
These investigations shall be performed at exposures in the anticipated 
therapeutic range and above. The experimental techniques, 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 
pharmacological premises or by indicatio ns 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.  
  
35 
 The study of these d ifferent phases may be carried mainly by means of 
physical, chemical or possibly by biological methods, and by observation of 
the actual pharmaco -dynamic activity of the substance itself.  
 
Information on distribution and elimination shall be necessary in a ll 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 provisions of this Directive, 
pharmaco -kinetic studies may not be required, if the toxicity tests and 
therapeutic experimentation justif y 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 administration 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 tox icity 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 admin istration of the 
active substance or combination of active substances under examination, 
and to determine how these changes are related to dosage.  
  
36 
 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 disorders, and the risk of somatic mutations 
including those leading to cancer. These studies are obligatory for any new 
substance.  
 
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 necessar y 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.  
  
37 
 These tests com prise studies of effect on adult male or female reproductive 
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 ha s 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 medic inal 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 medicinal 
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 produ ct can be distinguished 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  administration in clinical use. 
Reversibility of local lesions shall be performed where relevant.  
  
38 
 Studies in animals can be substituted by validated in vitro tests provided that 
the test results are of comparable quality and usefulness 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: C LINICAL STUDY REPORTS  
5.1.     Format and Presentation  
The general outline of Module 5 is as follows:  
 
— Table of contents for clinical study reports  
— 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  
— Repor ts of Human Pharmaco -dynamic Studies  
— Healthy Subject Pharmaco -dynamic and Pharmaco -
kinetics/Pharmaco -dynamic Study Re ports 
— Patient Pharmaco -dynamic and Pharmaco -kinetics/Pharmaco -
dynamic Studies Study Reports  
— Reports of Efficacy and Safety Studies   
39 
 — 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 authorisation. Consequ ently, an 
essential requirement is that the results of all clinical trials should be 
communicated, both favourable and unfavourable.  
 
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 pharmacological and 
toxicological studies and hence the applicant must provide him at least with 
the investigator's broch ure, consisting of all the relevant information known 
prior to the onset of a clinical trial including chemical, pharmaceutical and 
biological data, toxicological, pharmaco -kinetic and pharmaco -dynamic 
data in animals and the results of earlier clinical tr ials, 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 ke pt by the owners of the data:  
 
— for at least 15 years after completion or discontinuation of the trial,  
 
— 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,   
40 
  
— 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 applicable 
legis lation 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 documentation 
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 inves tigational 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 certi ficate(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 arrangements 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 relevant 
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 investigational medicinal product used  
  
41 
 — 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 information in respect of each 
patient individually, including case report forms on each trial subject  
 
— final report signed by the inv estigator and for multi -centre trials, by all 
the investigators or the co -ordinating (principal) investigator.  
 
e) The particulars of clinical trials referred to above shall be forwarded to the 
competent authorities. However, in agreement with the competen t 
authorities, the applicant may omit part of this information. 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 symp toms 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 o bservations shall be summarised for each trial indicating:  
 
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;  
 
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 conditions, 
whether the control group:  
 
— received no treatment  
 
— received a placebo  
  
42 
 — received another medicinal product of kno wn 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 menstruation , 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 de sign 
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 unexpected  
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 modificat ion of the pharmacological action following 
repeated administration, as well as the establishment of long -term dosage.  
  
43 
 5.2.1.     Reports of bio -pharmaceutics studies  
Bio-availability study reports, comparative bio -availability, bio -equivalence 
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 fro m 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 metabolism 
and active substance interaction studies and studies using other huma n 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, and differences between man 
and animal species used in the pre clinical studies, shall be described.  
 
In addition to standard multipl e-sample pharmaco -kinetics studies, population 
pharmaco -kinetics analyses based on sparse sampling during clinical studies 
can also address questions about the contributions of intrinsic and extrinsic 
factors to the variability in the dose - pharmaco -kineti cs response relationship. 
Reports of pharmaco -kinetic and initial tolerability studies in healthy subjects 
and in patients, reports of pharmaco -kinetic studies to assess effects of intrinsic  
44 
 and extrinsic factors, and reports of population pharmaco -kinetic  studies shall 
be provided.  
 
b) If the medicinal product is normally to be administered concomitantly with 
other medicinal products, particulars shall be given of joint administration 
tests performed to demonstrate possible modification of the 
pharmacologi cal 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 concomitantly with 
other medicinal products, particulars shall be given of joint administration 
tests performed to demonstrate possible modification of the 
pharmacological action.  
 
Pharmaco -dynamic interactions between the active substance and other 
medicinal products or subs tances 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  t h e  C l a i m e d  i n d i c a t i o n  
45 
  
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 establishe d 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 
meth ods 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 substitut e 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, e vents resulting in 
withdrawal, and deaths. Any patients or patient groups at increased risk shall 
be identified and particular attention paid to potentially vulnerable patients who 
may be present in small numbers, e.g., children, pregnant women, frail elde rly, 
people with marked abnormalities of metabolism or excretion etc. The 
implication of the safety evaluation for the possible uses of the medicinal 
product shall be described.  
 
 
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  a n a l y s e s  o f  d a t a  f r o m   m o r e  t h a n  o n e             
s t u d y  a n d   o t h e r  c l i n i c a l  s t u d y  r e p o r t s  
 
These reports shall be provided.  
 
5.2.6.     Reports  of post -marketing experience  
 
If the medicinal product is already authorised in third countries, information 
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.   
46 
  
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 pro vided 
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 -ESTABL ISHED 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,  
 
— quant itative 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   
47 
  
— the coherence of scientific assessments.  
 
Therefore different periods of time may be nec essary for establishing well -
established use of different substances. In any case, however, the period of 
time required for establishing a well established medicinal use of a 
constituent of a medicinal product must not be less than one decade from the 
first systematic and documented 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 documentation, both favo urable 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, 
epidemiological 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 application 
explains and justifies the use of these sources of information satisfactorily.  
 
c)  Particular attention must be p aid to any missing information and 
justification must be given why demonstration of an acceptable level of 
safety and/or efficacy can be supported although some studies are lacking.  
 
d)  The non -clinical and/or clinical overviews must explain the relevance  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 PRO DUCTS  
 
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 marketi ng authorisation to cross refer to the content of his 
Modules 4 and 5.  
  
48 
 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 -availability 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 wi th respect to the guideline on ‘Investigation 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/clinical overviews/summaries 
and substan tiated 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 sh ould 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 association shall be considered as a new active substance.  
  
49 
 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 n ot 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 demonstration of the 
similar nature of two biological medicinal products, additional data,  in 
particular, the toxicological and clinical profile shall be provided.  
 
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 
(pharmaceut ical, 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 appropriate clinical data) 
shall be determined on a case by case basis i n 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 characteristic 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 au thorised 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 MEDI CINAL 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, information regarding  
50 
 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 a re encountered 
so rarely that the applicant cannot reasonably be expected to provide 
comprehensive evidence, or  
 
— in the present state of scientific knowledge, comprehensive information 
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 obligations.  
 
These obligations may include the following:  
 
— the applicant shall complete an identified programme of studies with in 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 ad ministered 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  
51 
 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.  
 
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 s  
For 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 startin g material and/or a raw material for the manufacture 
of sub/intermediate fractions, constituents 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 Parliamen t 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  (13). 
 
— 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 authoris ation holder for submission to the 
                                                 
13 OJ L 313, 13.12.2000, p. 22   
52 
 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 authorisation 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 corresponding to the plasma 
used as a starting/raw materi al. 
 
b)   C o n t e n t 
In accordance with the provisions of Article 109, as amended by Directive 
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 take n 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.  
 
(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.  
  
53 
 (iii)  technical characteristics of bags for blood and plasma collection, 
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 establishments on the other 
hand, which defines the conditions of their interaction and their agreed 
specifications.  
 
In addition, the Pla sma 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 authorisation, including med icinal 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)  E v a l u a t i o n  a n d  C e r t i f i c a t i o n  
 
— For medicinal products not yet authorised, the marketing authorisation 
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 m ust 
follow evaluation procedure laid down by Commission Regulation (EC) No  
54 
 542/95  (14) concerning the examination of variations 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 supervision of medicinal products for human and 
veterinary use and establishing a European Agency for the Evaluation of 
Medicinal Products  (15). 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 -certifi cation 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 
competent authority 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.  
 
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 substance s, 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.  
 
                                                 
14 OJ L 55, 11.3.1995, p. 15  
15 OJ L 214, 24.8.1993, p. 1   
55 
 — A vaccine may contain one or several distinct vaccine a ntigens. 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 vacci ne, which contains one vaccine antigen 
aimed at preventing a single infectious disease.  
 
b)   C o n t e n t 
The Vaccine Antigen Master File shall contain the following information 
extracted from the relevant part (Active substance) of Module 3 on ‘Quality 
Data’ as delineated in Part I of this Annex:  
 
Active Substance  
 
1. General Information, including compliance with the relevant monograph(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 substance  
 
4. Quality control of the active subst ance 
 
5. Reference standard and materials  
 
6. Container and closure system of the active substance  
 
7. Stability of the active substance.  
 
c)   E v a l u a t i o n  a n d  C e r t i f i c a t i o n  
— 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 fi le already exists for the single vaccine antigen. A 
scientific and technical evaluation of each Vaccine Antigen Master File  
56 
 shall be carried out by the Agency. A positive evaluation shall result in a 
certificate of compliance to the European legislation fo r 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, irrespective 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 competent authority that has granted the marketing authorisa tion. 
 
— 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 V accine 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 - 
57 
 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 processing to produce the radioactive 
medicinal p roduct. 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 essential 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/rad iochemical 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 req uired. 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 only apply  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 a nd assayed.  
  
58 
 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 documented.  
 
Module 4  
 
It is appreciated th at 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 efficacy of 
radio -pharmaceuticals shall, therefore, address r equirements for medicinal 
products and radiation dosimetry aspects. Organ/tissue exposure to radiation 
shall be documented. Absorbed radiation dose estimates shall be calculated 
according to a specified, internationally recognised system by a particular ro ute 
of administration.  
 
Module 5  
 
The results of clinical trials shall be provided where applicable otherwise 
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 present 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 environ ment.  
 
In particular, the following information where applicable shall be provided:  
 
Module 3  
 
The 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 .  
59 
  
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 relevant 
‘cold’ nuclide shall be presented.  
 
Module 5  
 
Clinical information generate d 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 ra dio-
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 3  
The 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 documents for 
authorisa tion 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 do cuments 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,  
60 
 accompanying the application shall be supplemented by additional da ta 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 components 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 th e 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 homeopathic manufacturing methods laid down in the 
relevant monogra ph of the European Pharmacopoeia or, in absence thereof, 
by an official pharmacopoeia of a Member State.  
 
c) Control tests on the finished medicinal product  
 
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 constituents shall 
be carried out. If it can be justified that an identification and/or an assay on 
all the toxicologically relevant consti tuents 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 mus t be demonstrated. 
Stability data from the homeopathic stocks are generally transferable to 
dilutions/triturations obtained thereof. If no identification or assay of the 
active substance is possible due to the degree of dilution, stability data of 
the phar maceutical form may be considered.  
 
Module 4  
 
The provisions of Module 4 shall apply to the simplified registration of 
homeopathic medicinal products referred to in Article 14(1) with the following 
specifications.   
61 
  
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 3  
 
The 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)   H e r b a l  s u b s t a n c e s  a n d  h e r b a l  p r e p a r a t i o n s 
For 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 Pharmacopoeia.  
 
With respect to the nomenclature  of the herbal substance, the binomial 
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 Pharmacopo eias) 
and the laboratory code shall be provided.  
 
With respect to the nomenclature of the herbal preparation, the binomial 
scientific name of plant (genus, species, variety and author), and chemotype 
(where applicable), the parts of the plants, the definit ion 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 s tructure for herbal substance(s) and herbal 
preparation(s) where applicable, the physical form, the description of the 
constituents with known therapeutic activity or markers (molecular formula, 
relative molecular mass, structural formula, including relati ve and absolute  
62 
 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 involved in manufacturing 
and testing of the herbal preparation shall be provided, where appropriate.  
 
With respect to the descript ion of manufacturing process and process controls 
for the herbal substance, information shall be provided to adequately describe 
the plant production and plant collection, including the 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 preparation, 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 bibliographic data and the herbal 
substance(s) and herbal preparation(s), where applicable, contained as active 
substance(s) in the herbal medicinal product applied for shall be discussed, 
where appropriate.  
 
With respect to the elucidation of the structure and other ch aracteristics 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 charact eristics of the 
herbal preparation, information on the phyto - and physicochemical 
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.   
63 
  
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 validation 
information, including experimental  data for the analytical procedures used for 
testing the herbal substance(s) and herbal preparation(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 ref erence 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 f or a certificate of suitability that was 
granted by the European Directorate for the Quality of Medicines.  
 
(2)   H e r b a l  M e d i c i n a l  P r o d u c t s  
With 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 Regulation 
(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) and Part II -1 of this  
64 
 Annex (well -established medicinal use), the systematic and documented use 
of the concerned substance ca n refer — as way of derogation — to the use 
of that substance in accordance with the provisions of Article 5 of this 
Directive.  
 
PART IV  
ADVANCED THERAPY MEDICINAL PRODUCTS  
 
1.    INTRODUCTION  
Marketing authorisation applications for advanced therapy medicinal products, 
as defined in point (a) of Article 2(1) of Regulation (EC) No 1394/2007, shall 
follow the format requirements (Modules 1, 2, 3, 4 and 5) described in Part I of 
this Annex.  
 
The technical requirements for Modules 3, 4 and 5 for biologica l medicinal 
products, as described in Part I of this Annex, shall apply. The specific 
requirements for advanced therapy medicinal products described in sections 3, 
4 and 5 of this part explain how the requirements in Part I apply to advanced 
therapy medici nal products. In addition, where appropriate and taking into 
account the specificities of advanced therapy medicinal products, additional 
requirements have been set.  
 
Due to the specific nature of advanced therapy medicinal products, a risk -based 
approach may be applied to determine the extent of quality, non -clinical and 
clinical data to be included in the marketing authorisation application, in 
accordance with the scientific guidelines relating to the quality, safety and 
efficacy of medicinal products ref erred to in point 4 of the ‘Introduction and 
general principles’.  
 
The risk analysis may cover the entire development. Risk factors that may be 
considered include: the origin of the cells (autologous, allogeneic, xenogeneic), 
the ability to proliferate and /or differentiate and to initiate an immune response, 
the level of cell manipulation, the combination of cells with bioactive 
molecules or structural materials, the nature of the gene therapy medicinal 
products, the extent of replication competence of viru ses or micro -organisms 
used in vivo , the level of integration of nucleic acids sequences or genes into 
the genome, the long time functionality, the risk of oncogenicity and the mode 
of administration or use.  
 
Relevant available non -clinical and clinical da ta or experience with other, 
related advanced therapy medicinal products may also be considered in the risk 
analysis.  
 
Any deviation from the requirements of this Annex shall be scientifically 
justified in Module 2 of the application dossier. The risk analysis described  
65 
 above, when applied, shall also be included and described in Module 2. In this 
case, the methodology followed, the nature of the identified risks and the 
implications of the risk based approach for the development and evaluation 
program shall be discussed and any deviations from the requirements of this 
Annex resulting from the risk analysis shall be described.  
 
2.  DEFINITIONS  
For the purposes of this Annex, in addition to the definitions laid down in 
Regulation (EC) No 1394/2007, the de finitions set out in sections 2.1 and 2.2 
shall apply.  
 
2.1.      Gene therapy medicinal product  
 
Gene therapy medicinal product means a biological medicinal product which 
has the following characteristics:  
 
(a) it contains an active substance which  contains or consists of a recombinant 
nucleic acid used in or administered to human beings with a view to 
regulating, repairing, replacing, adding or deleting a genetic sequence;  
 
(b) its therapeutic, prophylactic or diagnostic effect relates directly to the 
recombinant nucleic acid sequence it contains, or to the product of genetic 
expression of this sequence.  
 
Gene therapy medicinal products shall not include vaccines against infectious 
diseases.  
 
2.2.  Somatic cell therapy medicinal product  
Somatic cell  therapy medicinal product means a biological medicinal product 
which has the following characteristics:  
 
(a) contains or consists of cells or tissues that have been subject to substantial 
manipulation so that biological characteristics, physiological func tions or 
structural properties relevant for the intended clinical use have been altered, 
or of cells or tissues that are not intended to be used for the same essential 
function(s) in the recipient and the donor;  
 
(b) is presented as having properties for, or is used in or administered to human 
beings with a view to treating, preventing or diagnosing a disease through 
the pharmacological, immunological or metabolic action of its cells or 
tissues.  
  
66 
 For the purposes of point (a), the manipulations listed in An nex I to Regulation 
(EC) No 1394/2007, in particular, shall not be considered as substantial 
manipulations.  
 
3.  SPECIFIC REQUIREMENTS REGARDING MODULE 3  
 
3.1.    Specific requirements for all advanced therapy medicinal products  
A description of the traceability system that the marketing authorisation holder 
intends to establish and maintain to ensure that the individual product and its 
starting and raw materials, including all substances coming into contact with 
the cells or tissues it may contain, c an be traced through the sourcing, 
manufacturing, packaging, storage, transport and delivery to the hospital, 
institution or private practice where the product is used, shall be provided.  
 
The traceability system shall be complementary to, and compatible w ith, the 
requirements established in Directive 2004/23/EC of the European Parliament 
and of the Council  (16), as regards human cells and tissues other than blood 
cells, and Directive 2002/98/EC, as regards human blood cells.  
 
3.2.      Specific requirements  for gene therapy medicinal products  
 
3.2.1.     Introduction: finished product, active substance and starting materials  
 
3.2.1.1.     Gene therapy medicinal product containing recombinant nucleic acid 
sequence(s) or genetically modified microorganism(s) or virus(es)  
 
The finished medicinal product shall consist of nucleic acid sequence(s) or 
genetically modified microorganism(s) or virus(es) formulated in their final 
immediate container for the intended medical use. The finished medicinal 
product may be comb ined with a medical device or active implantable medical 
device.  
 
The active substance shall consist of nucleic acid sequence(s) or genetically 
modified microorganism(s) or virus(es).  
 
3.2.1.2.     Gene therapy medicinal product containing genetically modif ied cells  
The finished medicinal product shall consist of genetically modified cells 
formulated in the final immediate container for the intended medical use. The 
finished medicinal product may be combined with a medical device or active 
implantable medica l device.  
                                                 
16 OJ L 102, 7.4.2004, p. 48   
67 
  
The active substance shall consist of cells genetically modified by one of the 
products described in section 3.2.1.1 above.  
 
3.2.1.3.  In the case of products consisting of viruses or viral vectors, the starting 
materials shall be the components from which the viral vector is obtained, i.e. 
the master virus vector seed or the plasmids used to transfect the packaging 
cells and the master cell bank of the packaging cell line.  
 
3.2.1.4.  In the case of products consisting of plasmids, non -viral vectors and 
genetically modified microorganism(s) other than viruses or viral vectors, the 
starting materials shall be the components used to generate the producing cell, 
i.e. the plasmid, the host bacteria and the master cell bank of recombinant 
microbial  cells.  
 
3.2.1.5.  In the case of genetically modified cells, the starting materials shall be the 
components used to obtain the genetically modified cells, i.e. the starting 
materials to produce the vector, the vector and the human or animal cells. The 
principles of good manufacturing practice shall apply from the bank system 
used to produce the vector onwards.  
 
3.2.2.     Specific requirements  
In addition to the requirements set out in sections 3.2.1 and 3.2.2 of Part I of 
this Annex, the following requireme nts shall apply:  
 
(a) information shall be provided on all the starting materials used for the 
manufacture of the active substance, including the products necessary for 
the genetic modification of human or animal cells and, as applicable, 
subsequent cultur e and preservation of the genetically modified cells, taking 
into consideration the possible absence of purification steps;  
 
(b) for products containing a microorganism or a virus, data on the genetic 
modification, sequence analysis, attenuation of virulen ce, tropism for 
specific tissues and cell types, cell cycle dependence of the microorganism 
or virus, pathogenicity and characteristics of the parental strain shall be 
provided;  
 
(c) process -related impurities and product -related impurities shall be described 
in the relevant sections of the dossier, and in particular replication 
competent virus contaminants if the vector is designed to be replication 
incompetent;  
 
(d) for plasmids, quantification of the different plasmid forms shall be 
undertaken thro ughout the shelf life of the product;   
68 
  
(e) for genetically modified cells, the characteristics of the cells before and 
after the genetic modification, as well as before and after any subsequent 
freezing/storage procedures, shall be tested.  
 
For genetically  modified cells, in addition to the specific requirements for gene  
therapy medicinal products, the quality requirements for somatic cell therapy 
medicinal products and tissue engineered products (see section 3.3) shall apply.  
 
3.3.  Specific requirements for somatic cell therapy medicinal products and 
tissue engineered products  
 
3.3.1.      Introduction: finished product, active substance and starting materials  
The finished medicinal product shall consist of the active substance formulated 
in its immediate container for the intended medical use, and in its final 
combination for combined advanced therapy medicinal products.  
 
The active substance shall be composed of the engineered cells and/or tissues.  
 
Additional substances (e.g. scaffolds, matrices, devices , biomaterials, 
biomolecules and/or other components) which are combined with manipulated 
cells of which they form an integral part shall be considered as starting 
materials, even if not of biological origin.  
 
Materials used during the manufacture of the a ctive substance (e.g. culture 
media, growth factors) and that are not intended to form part of the active 
substance shall be considered as raw materials.  
 
3.3.2.   Specific requirements  
In addition to the requirements set out in sections 3.2.1 and 3.2.2 of Part I of 
this Annex, the following requirements shall apply:  
 
3.3.2.1.    Starting materials  
(a) Summary information shall be provided on donation, procurement and 
testing of the human tissue and cells used as starting materials and made in 
accordance with  Directive 2004/23/EC. If non -healthy cells or tissues (e.g. 
cancer tissue) are used as starting materials, their use shall be justified.  
 
(b) If allogeneic cell populations are being pooled, the pooling strategies and 
measures to ensure traceability shall  be described.  
  
69 
 (c) The potential variability introduced through the human or animal tissues 
and cells shall be addressed as part of the validation of the manufacturing 
process, characterisation of the active substance and the finished product, 
development  of assays, setting of specifications and stability.  
 
(d) For xenogeneic cell -based products, information on the source of animals 
(such as geographical origin, animal husbandry, age), specific acceptance 
criteria, measures to prevent and monitor infection s in the source/donor 
animals, testing of the animals for infectious agents, including vertically 
transmitted micro -organisms and viruses, and evidence of the suitability of 
the animal facilities shall be provided.  
 
(e) For cell -based products derived from  genetically modified animals, the 
specific characteristics of the cells related to the genetic modification shall 
be described. A detailed description of the method of creation and the 
characterisation of the transgenic animal shall be provided.  
 
(f) For the genetic modification of the cells, the technical requirements 
specified in section 3.2 shall apply.  
 
(g)  The testing regimen of any additional substance (scaffolds, matrices, 
devices, biomaterials, biomolecules or other components), which are 
combined  with engineered cells of which they form an integral part, shall be 
described and justified.  
 
(h) For scaffolds, matrices and devices that fall under the definition of a  
medical device or active implantable medical device, the information 
required under section 3.4 for the evaluation of the combined advanced 
therapy medicinal product shall be provided.  
 
3.3.2.2 . Manufacturing process  
(a) The manufacturing process shall be validated to ensure batch and process 
consistency, functional integrity of the cells  throughout manufacturing and 
transport up to the moment of application or administration, and proper 
differentiation state.  
 
(b) If cells are grown directly inside or on a matrix, scaffold or device, 
information shall be provided on the validation of the cell culture process 
with respect to cell -growth, function and integrity of the combination.  
 
3.3.2.3.  Characterisation and control strategy  
(a) Relevant information shall be provided on the characterisation of the cell 
population or cell mixture in terms of identity, purity (e.g. adventitious 
microbial agents and cellular contaminants), viability, potency, karyology,  
70 
 tumourigenicity and suitability for the intended medicinal use. The genetic 
stability of the cells shall be demonstrated.  
 
(b) Qualitative an d, where possible, quantitative information on product - and 
process -related impurities, as well as on any material capable of introducing 
degradation products during production, shall be provided. The extent of the 
determination of impurities shall be just ified.  
 
(c) If certain release tests cannot be performed on the active substance or 
finished product, but only on key intermediates and/or as in -process testing, 
this shall be justified.  
 
(d) Where biologically active molecules (such as growth factors, cyt okines) are 
present as components of the cell -based product, their impact and 
interaction with other components of the active substance shall be 
characterised.  
 
(e) Where a three -dimensional structure is part of the intended function, the 
differentiation s tate, structural and functional organisation of the cells and, 
where applicable, the extracellular matrix generated shall be part of the 
characterisation for these cell -based products. Where needed, non -clinical 
investigations shall complement the physicoc hemical characterisation.  
 
3.3.2.4.    Excipients  
For excipient(s) used in cell or tissue -based medicinal products (e.g. the 
components of the transport medium), the requirements for novel excipients, as 
laid down in Part I of this Annex, shall apply, unles s data exists on the 
interactions between the cells or tissues and the excipients.  
 
3.3.2.5.  Developmental studies  
The description of the development program shall address the choice of 
materials and processes. In particular, the integrity of the cell population as in 
the final formulation shall be discussed.  
 
3.3.2.6.  Reference materials  
A reference standard, relevant and specific for the active substance and/or the 
finished product, shall be documented and characterised.  
 
3.4.    Specific requirements  for advanced therapy medicinal products 
containing devices  
 
3.4.1.      Advanced therapy medicinal product containing devices as referred to in 
Article 7 of Regulation (EC) No 1394/2007   
71 
 A description of the physical characteristics and performance of the p roduct 
and a description of the product design methods shall be provided.  
 
The interaction and compatibility between genes, cells and/or tissues and the 
structural components shall be described.  
 
3.4.2.  Combined advanced therapy medicinal products as defined in Article 2(1)(d) 
of Regulation (EC) No 1394/2007  
 
For the cellular or tissue part of the combined advanced therapy medicinal 
product, the specific requirements for somatic cell therapy medicinal products 
and tissue engineered products set out in section 3.3 shall apply and, in the 
case of genetically modified cells, the specific requirements for gene therapy 
medicinal products set out in section 3.2 shall apply.  
 
The medical device or the active implantable medical device may be an 
integral part o f the active substance. Where the medical device or active 
implantable medical device is combined with the cells at the time of the 
manufacture or application or administration of the finished products, they 
shall be considered as an integral part of the f inished product.  
 
Information related to the medical device or the active implantable medical 
device (which is an integral part of the active substance or of the finished 
product) which is relevant for the evaluation of the combined advanced therapy 
medici nal product shall be provided. This information shall include:  
 
(a) information on the choice and intended function of the medical device or 
implantable medical device and demonstration of compatibility of the 
device with other components of the product;  
 
(b) evidence of conformity of the medical device part with the essential 
requirements laid down in Annex I to Council Directive 93/42/EEC  (17), or 
of conformity of the active implantable device part with the essential 
requirements laid down in Annex 1 to Co uncil Directive 90/385/EEC  (18); 
 
(c) where applicable, evidence of compliance of the medical device or 
implantable medical device with the BSE/TSE requirements laid down in 
Commission Directive 2003/32/EC  (19); 
 
                                                 
17 OJ L 169, 12.7.1993, p. 1  
18 OJ L 189, 20.7.1990, p. 17  
19 OJ L 105, 26.4.2003, p. 18   
72 
 (d) where available, the results of any assessment of the medical device part or 
the active implantable medical device part by a notified body in accordance 
with Directive 93/42/EEC or Directive 90/385/EEC.  
 
The notified body which has carried out the assessment referred to in point (d) 
of this section shall make available on request of the competent authority 
assessing the application, any information related to the results of the 
assessment in accordance with Directive 93/42/EEC or Directive 90/385/EEC. 
This may include information and document s contained in the conformity 
assessment application concerned, where necessary for the evaluation of the 
combined advanced therapy medicinal product as a whole.  
 
4.  SPECIFIC REQUIREMENTS REGARDING MODULE 4  
4.1.      Specific requirements for all advanced  therapy medicinal products  
The requirements of Part I, Module 4 of this Annex on the pharmacological 
and toxicological testing of medicinal products may not always be appropriate 
due to unique and diverse structural and biological properties of advanced 
therapy medicinal products. The technical requirements in sections 4.1, 4.2 and 
4.3 below explain how the requirements in Part I of this Annex apply to 
advanced therapy medicinal products. Where appropriate and taking into 
account the specificities of advan ced therapy medicinal products, additional 
requirements have been set.  
 
The rationale for the non -clinical development and the criteria used to choose 
the relevant species and models ( in vitro  and in vivo ) shall be discussed and 
justified in the non-clinical overview. The chosen animal model(s) may 
include immuno -compromised, knockout, humanised or transgenic animals. 
The use of homologous models (e.g. mouse cells analysed in mice) or disease 
mimicking models shall be considered, especially for im munogenicity and 
immunotoxicity studies.  
 
In addition to the requirements of Part I, the safety, suitability and 
biocompatibility of all structural components (such as matrices, scaffolds and 
devices) and any additional substances (such as cellular product s, 
biomolecules, biomaterials, and chemical substances), which are present in the 
finished product, shall be provided. Their physical, mechanical, chemical and 
biological properties shall be taken into account.  
 
4.2.  Specific requirements for gene therapy  medicinal products  
In order to determine the extent and type of non -clinical studies necessary to 
determine the appropriate level of non -clinical safety data, the design and type 
of the gene therapy medicinal product shall be taken into account.  
 
4.2.1.   Pharmacology   
73 
 (a) In vitro  and in vivo  studies of actions relating to the proposed therapeutic 
use (i.e. pharmacodynamic ‘proof of concept’ studies) shall be provided 
using models and relevant animal species designed to show that the nucleic 
acid sequence r eaches its intended target (target organ or cells) and provides 
its intended function (level of expression and functional activity). The 
duration of the nucleic acid sequence function and the proposed dosing 
regimen in the clinical studies shall be provide d. 
 
(b) Target selectivity: When the gene therapy medicinal product is intended to 
have a selective or target -restricted functionality, studies to confirm the 
specificity and duration of functionality and activity in target cells and 
tissues shall be provi ded. 
 
4.2.2.   Pharmacokinetics  
(a) Biodistribution studies shall include investigations on persistence, clearance 
and mobilisation. Biodistribution studies shall additionally address the risk 
of germline transmission.  
 
(b) Investigations of shedding and risk of transmission to third parties shall be 
provided with the environmental risk assessment, unless otherwise duly 
justified in the application on the basis of the type of product concerned.  
 
4.2.3.   Toxicology  
(a) Toxicity of the finished gene therapy medicinal product shall be assessed. 
In addition, depending on the type of product, individual testing of active 
substance and excipients shall be taken into consideration, the  in vivo  effect 
of expressed nucleic acid sequence -related products which are no t intended 
for the physiological function shall be evaluated.  
 
(b) Single -dose toxicity studies may be combined with safety pharmacology 
and pharmacokinetic studies, e.g. to investigate persistence.  
 
(c) Repeated dose toxicity studies shall be provided whe n multiple dosing of 
human subjects is intended. The mode and scheme of administration shall 
closely reflect the planned clinical dosing. For those cases where single 
dosing may result in prolonged functionality of the nucleic acid sequence in 
humans, repe ated toxicity studies shall be considered. The duration of the 
studies may be longer than in standard toxicity studies depending on the 
persistence of the gene therapy medicinal product and the anticipated 
potential risks. A justification for the duration shall be provided.  
 
(d) Genotoxicity shall be studied. However, standard genotoxicity studies shall 
only be conducted when they are necessary for testing a specific impurity or 
a component of the delivery system.   
74 
  
(e) Carcinogenicity shall be studied. Standard lifetime rodent carcinogenicity 
studies shall not be required. However, depending on the type of product, 
the tumourigenic potential shall be evaluated in relevant  in vivo/in 
vitro  models.  
 
(f) Reproductive and developmental toxicity: Studies on t he effects on fertility 
and general reproductive function shall be provided. Embryo -foetal and 
perinatal toxicity studies and germline transmission studies shall be 
provided, unless otherwise duly justified in the application on the basis of 
the type of pr oduct concerned.  
 
(g) Additional toxicity studies  
 
— Integration studies: integration studies shall be provided for any gene 
therapy medicinal product, unless the lack of these studies is 
scientifically justified, e.g. because nucleic acid sequences will n ot enter 
into the cell nucleus. For gene therapy medicinal products not expected 
to be capable of integration, integration studies shall be performed, if 
biodistribution data indicate a risk for germline transmission.  
 
— Immunogenicity and immunotoxicity: potential immunogenic and 
immunotoxic effects shall be studied.  
 
4.3. Specific requirements for somatic cell therapy medicinal products and 
tissue engineered products  
 
4.3.1.   Pharmacology  
(a) The primary pharmacological studies shall be adequate to demonstrate the 
proof of concept. The interaction of the cell -based products with the 
surrounding tissue shall be studied.  
 
(b) The amount of product needed to achieve the desired effect/the effective 
dose, and, depending on the type of product, the freque ncy of dosing shall 
be determined.  
 
(c)  Secondary pharmacological studies shall be taken into account to evaluate 
potential physiological effects that are not related to the desired therapeutic 
effect of the somatic cell therapy medicinal product, of the tissue engineered 
product or of additional substances, as biologically active molecules besides 
the protein(s) of interest might be secreted or the protein(s) of interest could 
have unwanted target sites.  
 
4.3.2.   Pharmacokinetics   
75 
 (a) Conventional pharmacokinetic studies to investigate absorption, 
distribution, metabolism and excretion shall not be required. However, 
parameters such as viability, longevity, distribution, growth, differentiation 
and migration shall be investigated, unless otherwise d uly justified in the 
application on the basis of the type of product concerned.  
 
(b) For somatic cell therapy medicinal products and tissue engineered products, 
producing systemically active biomolecules, the distribution, duration and 
amount of expression  of these molecules shall be studied.  
 
4.3.3.   Toxicology  
(a) The toxicity of the finished product shall be assessed. Individual testing of 
active substance(s), excipients, additional substances and any process -
related impurities shall be taken into consid eration.  
 
(b) The duration of observations may be longer than in standard toxicity studies 
and the anticipated lifespan of the medicinal product, together with its 
pharmacodynamic and pharmacokinetic profile, shall be taken into 
consideration. A justificat ion of the duration shall be provided.  
 
(c) Conventional carcinogenicity and genotoxicity studies shall not be required, 
except with regard to the tumourigenic potential of the product.  
 
(d) Potential immunogenic and immunotoxic effects shall be studied.  
 
(e) In the case of cell -based products containing animal cells, the associated 
specific safety concerns such as transmission to humans of xenogeneic 
pathogens shall be addressed.  
 
5.  SPECIFIC REQUIREMENTS REGARDING MODULE 5  
5.1.      Specific requirements  for all advanced therapy medicinal products  
5.1.1.  The specific requirements in this section of Part IV are additional requirements 
to those set in Module 5 in Part I of this Annex.  
 
5.1.2.   Where the clinical application of advanced therapy medicinal products requires 
specific concomitant therapy and involve surgical procedures, the therapeutic 
procedure as a whole shall be investigated and described. Information on the 
standardisation and optimisation of those procedures during clinical 
development sh all be provided.  
 
Where medical devices used during the surgical procedures for application, 
implantation or administration of the advanced therapy medicinal product may  
76 
 have an impact on the efficacy or safety of the advanced therapy product, 
information on these devices shall be provided.  
 
Specific expertise required to carry out the application, implantation, 
administration or follow -up activities shall be defined. Where necessary, the 
training plan of health care professionals on the use, application, i mplantation 
or administration procedures of these products shall be provided.  
 
5.1.3.  Given that, due to the nature of advanced therapy medicinal products, their 
manufacturing process may change during clinical development, additional 
studies to demonstrat e comparability may be required . 
 
5.1.4.  During clinical development, risks arising from potential infectious agents or 
the use of material derived from animal sources and measures taken to reduce 
such risk shall be addressed.  
 
5.1.5.  Dose selection and sc hedule of use shall be defined by dose -finding studies.  
 
5.1.6.   The efficacy of the proposed indications shall be supported by relevant results 
from clinical studies using clinically meaningful endpoints for the intended 
use. In certain clinical condition s, evidence of long -term efficacy may be 
required. The strategy to evaluate long -term efficacy shall be provided.  
 
5.1.7.  A strategy for the long -term follow -up of safety and efficacy shall be included 
in the risk management plan.  
 
5.1.8.   For combined advanced therapy medicinal products, the safety and efficacy 
studies shall be designed for and performed on the combined product as a 
whole.  
5.2.  Specific requirements for gene therapy medicinal products  
 
5.2.1.   Human pharmacokinetic studies  
Human pharmacokinetic studies shall include the following aspects:  
 
(a) shedding studies to address the excretion of the gene therapy medicinal 
products;  
 
(b) biodistribution studies;  
 
(c) pharmacokinetic studies of the medicinal product and the gene expression 
moieties (e.g. expressed proteins or genomic signatures).   
77 
  
5.2.2.   Human pharmacodynamic studies  
 
Human pharmacodynamic studies shall address the expression and function of 
the nucleic acid sequence following administration of the gene therapy 
medicinal product.  
 
5.2.3.   Safety studies  
Safety studies shall address the following aspects:  
 
(a) emergence of replication competent vector;  
 
(b) emergence of new strains;  
 
(c) reassortment of existing genomic sequences;  
 
(d) neoplastic proliferation due to insertional mutagenicity.  
 
5.3.  Specific requirements for somatic cell therapy medicinal products  
 
5.3.1.      Somatic cell therapy medicinal products where the mode of action is based on 
the production of defined active biomolecule(s)  
For somatic cell therapy medicinal products where the mode of action is based 
on the production of defined active biomolecule(s), the pharmacokinetic 
profile (in particular distribution, duration and amount of expression) of those 
molecules shall be addressed, if feasible.  
 
5.3.2.      Biodistribution, persistence and long -term engraftment of the somatic cell 
therapy medicinal product components  
The biodistribution, persistence and long -term engraftment of the somatic cell 
therapy medicinal product components shall be addres sed during the clinical 
development.  
 
5.3.3.      Safety studies  
Safety studies shall address the following aspects:  
(a) distribution and engrafting following administration;  
(b) ectopic engraftment;  
(c) oncogenic transformation and cell/tissue lineage fidelity.  
  
78 
 5.4.      Specific requirements for tissue engineered products  
 
5.4.1.      Pharmacokinetic studies  
Where conventional pharmacokinetic studies are not relevant for tissue 
engineered products, the biodistribution, persistence and degradation of the 
tissue engineered product components shall be addressed during the clinical 
development.  
 
5.4.2 .     Pharmacodynamic studies  
Pharmacodynamic studies shall be designed and tailored to the specificities of 
tissue engineered products. The evidence for the  ‘proof of concept’ and the 
kinetics of the product to obtain the intended regeneration, repairing or 
replacement shall be provided. Suitable pharmacodynamic markers, related to 
the intended function(s) and structure shall be taken into account.  
 
5.4.3.      Safety studies  
 
Section 5.3.3 shall apply.  
   
79 
 ANNEX III 
CONDITIONS  FOR  QUALIFICATION  OF A QUALIFIED  PERSON  
1. The qualified person shall hold a university degree in one or more of the following 
scientific disciplines: pharmacy, medicine, veterinary medicine,  chemistry, 
pharmaceutical chemistry and technology, biology.  
2. The qualified person shall have acquired practical full -time experience over at least two 
years, in one or more undertakings that are authorised manufacturers, obtaining 
sufficient knowledge of manufacture, testing, supply chains, good manufacturing 
practice and pharmaceutical quality systems as well as regulatory processes a nd dossier 
content for ensuring the quality of medicinal products.  
3. A qualified person shall be in possession of a diploma, certificate or other evidence of 
formal qualifications awarded on completion of a university course of study, or a course 
recognised as equivalent by the Member State concerned, extending over a period of at 
least four years of theoretical and practical st udy in one of the following scientific 
disciplines: pharmacy, medicine, veterinary medicine, chemistry, pharmaceutical 
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 theoretical and practical training of a 
minimum duration of one year and including a training period of at least six months in a 
pharmacy open to the public, corroborated by an examination at university level.  
Where two universit y courses or two courses recognised 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 qua lifications awarded on completion of a university course or its recognised 
equivalent shall be considered to fulfil the condition of duration referred to in the 
second subparagraph in so far as the diplomas, certificates or other evidence of formal 
qualifi cations awarded on completion of both courses are recognised as equivalent by 
the Member State in question.  
The course shall include theoretical and practical study bearing upon at least the 
following basic subjects:  
(a) Experimental physics  
(b) General and inorga nic chemistry  
(c) Organic chemistry  
(d) Analytical chemistry  
(e) Pharmaceutical chemistry, including analysis of medicinal products  
(f) General and applied biochemistry (medical)  
(g) Physiology  
(h) Micro biology  
(i) Pharmacology  
(j) Pharmaceutical technology  
(k) Toxicology  
(l) Pharmacognosy (study of the composition and effects of the natural 
active substances of plant and animal origin).   
80 
 Studies in these subjects should be so balanced as to enable the person concerned to 
fulfil the obligations specified in Article 153 . 
In so far as certain d iplomas, 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 evidenc e of adequate knowledge of the subjects involved.  
4. The qualified person shall have acquired practical experience over at least two years, in 
one or more undertakings or not -for-profit entities that are authorised to manufacture 
medicinal products, in the activities of qualitative analysis of medicinal products, of 
quantitative analysis of active substances and of the testing and checking necessary to 
ensure the quality of medicinal products.  
5. A person engaging in the activities of the person referred to in Article 152  from the time 
of the application of Second Council Directive 75/319/EEC20, in a Member State 
without complying with the provisions of this Annex shall be eligible to continue to 
engage in those activities within the Union.  
6. The holder of a diplom a, certificate or other evidence of formal qualifications awarded 
on completion of a university course — or a course recognised  as equivalent by the 
Member State concerned — in a scientific discipline allowing them to engage in the 
activities of the person  referred to in Article 48 in accordance with the laws of that 
Member State may — if they began their course prior to 21 May 1975 — be considered 
as qualified to carry out in that Member State the duties of the person referred to in 
Article 152  provided th at they have previously engaged in the following activities for at 
least two years before 21 May 1985 following notification of this directive in one or 
more undertakings or not -for-profit entities authorised  to manufacture: production 
supervision or quali tative and quantitative analysis of active substances, and the 
necessary testing and checking under the direct authority of the person referred to in 
Article 152  to ensure the quality of the medicinal products.  
  
                                                 
20 Second Council Directive 75/319/EEC of 20 May 1975 on the approximation of provisions laid down 
by Law, Regulation or Administrative Action relating to proprietary medicinal products (OJ L 147, 
9.6.1975, p. 13).  Directive is not in force anymore.   
81 
  
ANNEX IV 
LABELLING  PARTICULARS  
The following particulars shall appear on the outer packaging of medicinal products or, 
where there is no outer packaging, on the immediate packaging:  
(a) the name of the medicinal product , including in Braille,  followed by its 
strength and pharmaceutical form, an d, if appropriate, whether it is 
intended for babies, children or adults; where the medicinal  product 
contains up to three active substances, the international non -proprietary 
name (INN) shall be included, or, if one does not exist, the common 
name;  
(b) a stat ement of the active substances expressed qualitatively and 
quantitatively per dosage unit or according to the form of administration 
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 medicinal  product;  
(d) a list of those excipients known to have a recognised action or effect and 
included in the detailed guidance published pursuant to Article 68;  
(e) the method of administration and, if necessary, the route of 
administration. 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 a ppropriate, 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 the holder to 
represent them;  
(l) the number of the marketing  authorisation 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;  
(o) for medicinal products other than radiopharmaceuticals referred to in 
Article 67(1), safety features enabling wholesale distributors and persons 
authorised or entitled to supply medicinal products to the public to:  
(i)  verify the authenticity of the medicinal product, and  
(ii) identify individual packs,   
82 
  as well as a device allowing verific ation of whether the outer packaging 
has been tampered with.    
83 
 ANNEX V 
CONTENTS  OF SUMMMARY  PRODUCT  CHARACTERISTICS  
The summary of 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 of the 
excipient, knowledge of which is essential for proper administration of the medicinal 
product. The usual common name  or chemical description shall be used.  
(3) pharmaceutical form.  
(4) clinical particulars:  
(a) therapeutic indications,  
(b) posology and method of administration for adults and, where necessary 
for children,  
(c) contra -indications,  
(d) special warnings and precautions for use and , in the case of 
immunological medicinal products, any special precautions to be taken 
by persons handling such medicinal  products and administering them to 
patients, together with any precautions to be taken by the patient,  
(e) interaction with other medicina l products and other forms of interactions,  
(f) use during pregnancy and lactation,  
(g) effects on ability to drive and to use machines,  
(h) undesirable effects,  
(i) overdose (symptoms, emergency procedures, antidotes).  
(5) pharmacological properties:  
(a) pharmacodynamic properti es, 
(b) pharmacokinetic properties,  
(c) non-clinical safety data.  
(6) pharmaceutical particulars:  
(a) list of excipients,  
(b) major incompatibilities,  
(c) shelf life, when necessary after reconstitution of the medicinal product or 
when the immediate packaging is opened for the fi rst time,  
(d) special precautions for storage,  
(e) nature and contents of container,  
(f) special precautions for disposal of a used medicinal product or waste 
materials derived from such medicinal product, if appropriate. In case of 
antimicrobial medicinal products in  addition to the precautions a warning 
that inappropriate disposal of the medicinal product contributes to 
antimicrobial resistance.   
84 
 (7) marketing authorisation holder.  
(8) marketing authorisation numbers.  
(9) date of the first marketing  authorisation or renewal of th e marketing  authorisation.  
(10) date of revision of the text.  
(11) for radiopharmaceuticals, full details of internal radiation dosimetry.  
(12) for radiopharmaceuticals, additional detailed instructions for extemporaneous 
preparation and quality control of such preparati on and, where appropriate, maximum 
storage time during which any intermediate preparation such as an eluate or the ready -
to-use pharmaceutical will conform with its specifications.  
For marketing  authorisations under Articles 9 to 12 and subsequent variatio ns, those parts of 
the summary of product characteristics of the reference medicinal product referring to 
indications or dosage forms that are still covered by patent law at the time when a generic or 
biosimilar medicinal product is placed on the market ne ed not be included.  
   
85 
 ANNEX VI 
CONTENTS  OF PACKAGE  LEAFLET  
The package leaflet shall contain, in the order indicated below, the following information:  
(1) for the identification of the medicinal product:  
(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. The common name shall be 
included where the medicinal  product contains only one active 
substance an d if its name is an invented name;  
(b) the pharmaco -therapeutic group or type of activity in terms easily 
comprehensible for the patient;  
(2) the therapeutic indications;  
(3) a list of information that is necessary before the medicinal product is 
taken:  
(a) contra -indicat ions;  
(b)  appropriate precautions for use;  
(c) forms of interaction with other medicinal products and other 
forms of interaction (e.g. alcohol, tobacco, food) that may affect 
the action of the medicinal product;  
(d)  special warnings;  
(4) the necessary and usual instruct ions for proper use, and in particular:  
(a) the dosage,  
(b) the method and, if necessary, route of administration;  
(c) the frequency of administration, specifying if necessary the 
appropriate time at which the medicinal product may or must be 
administered;  
 and, as app ropriate, depending on the nature of the medicinal  
product:  
(d) the duration of treatment, where it should be limited;  
(e) the action to be taken in case of an overdose (such as symptoms, 
emergency procedures);  
(f) what to do when one or more doses have not been taken ; 
(g) indication, if necessary, of the risk of withdrawal effects;  
(h) a specific recommendation to consult the doctor or the 
pharmacist, as appropriate, for any clarification on the use of the 
medicinal  product;  
(5) a description of the adverse reactions that may occ ur under normal use of 
the medicinal product and, if necessary, the action to be taken in such a 
case;  
(6) reference s to the following:   
86 
 (a) the expiry date indicated on the label, with  a warning against 
using the medicinal  product after that date;  
(b) where appropria te, special storage precautions;  
(c) if necessary, a warning concerning certain visible signs of 
deterioration;  
(d) the full qualitative composition (in active substances and 
excipients) and the quantitative composition in active substances, 
using common names, for each presentation of the medicinal 
product;  
(e) for each presentation of the medicinal  product, the pharmaceutical 
form and content in weight, volume or units of dosage;  
(f) information on where the leaflet is available in formats accessible 
for persons with d isabilities;  
(g)  the name and address of the marketing authorisation holder and, 
where applicable, the name of their appointed representatives in 
the Member States;  
(h) the name and address of the manufacturer . 
(7) the date on which the package leaflet was last revis ed; 
(8) for antimicrobials, a warning that improper use and disposal of the 
medicinal product contributes to antimicrobial resistance.  
The list set out in point (3) shall:  
(a) take into account the particular condition of certain categories of users 
(children,  pregnant or breastfeeding women, older adults, persons with specific 
pathological conditions  and persons with disabilities ); 
(b) mention, if appropriate, possible effects on the ability to drive vehicles or to 
operate machinery;  
(c) list those excipients the knowledge of which is important for the safe and 
effective use of the medicinal product and that are included in the detailed 
guidance referred  to in Article 77.  
   
87 
 ANNEX VII 
AREAS  FOR  ADAPTED  FRAMEWORKS  REFERRED  TO IN ARTICLE  28 
Phage -containing  medicinal products, in cases where the medicinal product has a variable 
composition depending on the specific clinical context.  
   
88 
  
ANNEX VIII  
CORRELATION  TABLE  
 
Directive 2001/83 (EC)  Regulation (EC) No 1901/2006  This Directive  
Art. 2(1)   Art. 1(1) and (2)  
Art. 2(2)   Art. 1(4)  
Art. 2(3)   Art. 1(3) and 142(1), second 
sentence  
Art. 3 (1), (2) and (3)   Art. 1(5), point (a), (b) and (c)  
Art. 3 (7)   Art. 2 (1) and (2)  
Art 4(4)   Art. 1(10), point (a)  
Art. 110   Art. 1(7)  
Art. 4(3)   Art. 1(9) 
Art. 4(5)   Art.1(8)  
Art. 5(1)   Art. 3(1)  
Art. 5(2)   Art. 3(2)  
Art. 5(3)   Art. 3(3)  
Art. 5(4)   Art. 3(4)  
Art. 6(1)   Art. 5  
Art. 6(2)   Art. 16(1)  
Art. 7   Art. 16(2)  
Art. 6(1)   Art. 5(1)  
Art. 8(3)   Art. 6(2) and Annex I  
Art. 8(3), 2nd and 3rd 
subparagraphs   Art. 6(3) and (4)  
 Art. 7 and Art. 8  Art. 6(5)   
89 
  Art. 9  Art. 6 (6)  
Art. 12   Art. 7  
Art. 10(1), 1st subparagraph   Art. 9(1)  
Art. 10(2), point (b), 3th sentence   Art. 9(3), second subparagraph  
Art. 10(1), 3rd subparagraph   Art. 9(3)  
Art. 10(2), point (b), 2nd sentence   Art. 9(4)  
Art. 10(3)   Art. 10  
Art. 10(4)   Art. 11  
Art. 10a   Art. 13  
Art. 10c   Art. 14  
Art. 17(1), 1st subparagraph   Art. 30  
Art. 17(1), 2nd subparagraph   Art. 33(1) and (2), Art. 35  
Art. 17(2)   Art. 33(3)  
Art. 18   Art. 33(4)  
Art. 19(1)   Art. 29(1), points (a), (b) and 
(c) 
 Art. 23(1)  Art. 48(1) and (2)  
 Art. 23(2), 1st subparagraph, 
introductory sentence and 
points (a) and (b)  Art. 48(3)  
 Art. 23(2), 2nd subparagraph  Art.48(4)  
 Art. 23(3), 2nd subparagraph  Art. 48(5)  
 Art. 24  Art. 48(6)  
 Art. 28(1), 2nd subparagraph  Art. 49(1)  
 Art. 28(2)  Art. 49(2)  
 Art. 28(3), 1st sentence  Art. 49(3)   
90 
  Art. 29, 3rd subparagraph  Art. 49(4)  
Art. 20, 1st subparagraph   Art. 8  
Art. 21   Art. 43  
Art. 21a, 1st subparagraph   Art. 44(1), points (a) to (f)  
Art. 21a, 2nd subparagraph   Art. 44(2)  
Art. 22   Art. 45(1) and (2)  
Art. 26(1)   Art. 47(1), points (a), (b) and 
(c) 
Art. 26(2) and (3)   Art. 47(2) and (3)  
Art. 6(1a)   Art. 56(1)  
Art. 23a, 1st subparagraph   Art. 56(2)  
Art. 8(2)   Art. 56(6)  
Art. 23a, 3rd subparagraph   Art. 56(9)  
Art. 25   Art. 61  
Art. 70   Art. 50  
Art. 71(1)   Art. 51(1), points (a) to (d)  
Art. 71(2)   Art. 51(3)  
Art. 71(3)   Art. 51(4)  
Art. 71(4) and (5)   Art. 51(5) and (6)  
Art. 72   Art. 52  
Art. 73   Art. 53  
Art. 74   Art. 54  
Art. 74a   Art. 55  
Art. 11, 1st subparagraph, 
introductory sentence  
 
  
 
 
 
 
 Art. 62(1)  
Art. 11, 2nd subparagraph   Art. 62(2)   
91 
 Art. 11, 4th subparagraph   Art. 62(3)  
Art. 58   Art. 63(1)  
Art. 63(2), 1st subparagraph, 1st 
sentence   Art. 63(2)  
Art. 58   Art. 63(4)  
Art. 59(1), 1st subparagraph, 
introductory sentence   Art. 64 (1) 
Art. 59(1), 3rd subparagraph   Art. 64 (2) 
Art. 59(3)   Art. 64 (3) 
Art. 54, introductory sentence   Art. 65 (1) 
Art. 54a   Art. 67  
Art. 66   Art. 68(1), (2) and (3)  
Art. 67   Art. 68(4)  
Art. 56   Art. 70  
Art. 56a   Art. 71  
Art. 57   Art. 72  
Art. 62   Art. 73  
Art. 63(1), 1st and 2nd 
subparagraphs   Art. 74(1) and (2)  
Art. 63(2), 1st subparagraph, 2nd 
sentence   Art. 74(3)  
Art. 63(3), 2nd sentence   Art. 74(4)  
Art. 63(3), 1st sentence   Art. 75, introductory sentence 
and points (a) and (b)  
Art. 61   Art. 76  
Art. 60   Art. 78  
Art. 64   Art. 79  
Art. 65   Art. 77   
92 
 Art. 10(5)   Art. 81(2), point (d)  
Art. 10(6)   Art. 85  
Art. 27   Art. 37  
Art. 28(1)   Art. 34(1) and (2), Art. 36(1) 
and (2)  
Art. 28(2)   Art. 36(5) and (6)  
Art. 28(3)   Art. 34(5)  
Art 28(4) and (5)   Art. 34(6) and (7), Art. 36(6) 
and (8)  
Art. 29(1), (2) and (3)   Art. 38(1), (2) and (3)  
Art. 29(4), 1st sentence   Art. 38(4)  
Art. 29(6)   Art. 38(5)  
Art. 30(1)   Art. 39  
Art. 30(2)   Art. 40  
Art. 32(1), (2) and (3)    Art. 41(1), (2) and (3)  
Art. 32(4), 1st subparagraph, 
introductory sentence and points 
(a) to (d)   Art. 41(4), 1st subparagraph, 
introductory sentence and 
points (a) to (d)  
Art. 32(4), 2nd and 3rd 
subparagraph   Art. 41(4), 2nd and 3rd 
subparagraph  
Art. 32(5)   Art. 41(5)  
Art. 33   Art. 42  
Art. 81, 3rd subparagraph   Art. 56(3), 2nd subparagraph  
 Art 33  Art.59  
 Art. 35  Art. 60  
Art. 34   Art. 42  
 Art. 36(1)  Art. 86(1)  
 Art. 36(2)  Art. 86(2)   
93 
  Art. 36(3)  Art. 86(3)  
 Art. 36(5)  Art. 86(4)  
Art. 22a, 1st subparagraph, 
introductory sentence and points 
(a) and (b)   Art. 87(1), 1st subparagraph, 
introductory sentence and 
points (a) and (b)  
Art. 22a, 2nd subparagraph   Art. 87(1), 2nd subparagraph  
Art. 22a(2) and (3)   Art. 87(2) and (3)  
Art. 22b   Art. 88  
Art. 22c   Art. 89  
Art. 23(1), (2) and (3)   Art. 90(1), (2) and (3)  
Art. 23(4), 1st subparagraph   Art. 90(4), 1st sentence  
Art. 23(4), 2nd subparagraph   Art. 90(5)  
Art. 23b(1)   Art. 92(2)  
Art. 23b(2)   Art. 92(3), 1st and 2nd sentence  
Art. 23b(2a)   Art. 92(4), introductory 
sentence and points (a) and (b)  
Art. 35   Art. 93  
 Art. 45(1)  Art. 94(1)  
 Art. 46(3)  Art. 94(3)  
 Art. 46(4)  Art. 94(4)  
 Art. 46(5)  Art. 94(5)  
Art. 31(1), 1st subparagraph   Art. 95(1), 1st subparagraph, 1st 
sentence  
  Art. 95(1), 1st subparagraph, 
2nd sentence  
Art. 31(1), 2nd to 5th 
subparagraph   Art. 95(1), 2nd to 5th 
subparagraph  
Art. 31(2), (3) and (4)   Art. 95(2), (3) and (4)   
94 
 Art. 101   Art. 96  
Art. 102, 1st subparagraph, points 
(a) to (e)   Art. 97(1)  
Art. 102, 2nd subparagraph   Art. 97(2)  
Art. 103   Art. 98  
Art. 104(1) and (2)   Art. 99(1), (2) and (3)  
Art. 104(3), 1st subparagraph   Art. 99(4)  
Art. 104(3), 2nd subparagraph   Art. 99(5)  
Art. 104(4)   Art. 99(6)  
Art. 104a   Art. 100  
Art. 105   Art. 101  
Art. 106   Art. 102(1) , introductory 
sentence and points (a) to (c), 
(e) 
Art. 107l   Art. 103  
Art. 106a   Art. 104  
Art. 107   Art. 105(1) to (5)  
Art. 107a(1), 1st subparagraph, 
1st sentence   Article 106 (1), 1st 
subparagraph, 1st sentence  
Art. 107a(1), 1st subparagraph, 
2nd sentence   Article 106 (1), 1st 
subparagraph, 3rd sentence  
Art. 107a(1), 2nd subparagraph   Art. 106(1), 2nd subparagraph  
Art. 107a(2) to (6)   Article 106 (2) to (6) 
Art. 107b(1), 1st subparagraph   Art. 107(1), 1st subparagraph  
Art. 107b(1), 2nd and 3rd 
subparagraph   Art. 107(2)  
Art. 107b(2) and (3)   Art. 107(3) and (4)  
Art. 107c   Art. 108  
Art. 107d   Art. 109   
95 
 Art. 107e   Art. 110  
Art. 107f   Art. 111  
Art. 107g   Art. 112  
Art. 107h   Art. 113  
Art. 107i   Art. 114  
Art. 107j   Art. 115  
Art. 107k   Art. 116  
Art. 107m   Art. 117  
Art. 107n   Art. 118  
Art. 107o   Art. 119  
Art. 107p   Art. 120  
Art. 107q   Art. 121  
Art. 108   Art. 122  
Art. 108a   Art. 123  
Art. 108b   Art. 124  
Art. 13   Art. 125  
Art. 14   Art. 126  
Art. 15   Art. 127  
Art. 39   Art. 128  
Art. 68   Art. 129  
Art. 69   Art. 130  
Art. 100   Art. 131  
Art. 124   Art. 132  
Art. 16(1) and (2)   Art. 133  
Art. 16(3), 53, 85, 119   Art. 133(3)   
96 
 Art. 16a   Art. 134  
Art. 16b   Art. 135  
Art. 16c   Art. 136  
Art. 16d   Art. 137  
Art. 16e   Art. 138  
Art. 16f   Art. 139  
Art. 16g   Art. 140  
Art. 16h(1)   Art. 141(1)  
Art. 16h(2)   Art. 141(2), 1st and 2nd 
subparagraph  
Art. 16h(2), 5th subparagraph   Art. 141(2), 3rd subparagraph  
Art. 16h(3) and (4)   Art. 141(3) and (4)  
Art. 40(1)   Art. 142(1)  
Art. 40(2), 1st subparagraph   Art. 142(2)  
Art. 40(2), 2nd subparagraph   Art. 142(3), introductory 
sentence and point (a)  
Art. 40(3)   Art. 142(4)  
Art. 40(4)   Art. 142(5)  
Art. 41, 1st subparagraph   Art. 143(1), introductory 
sentence and points (a), (b) and 
(c) 
Art. 41, 2nd subparagraph   Art. 143(2)  
Art. 42   Art. 144(1), 1st subparagraph, 
144(2) and (3)  
Art. 43   Art 144(1), 2nd subparagraph  
Art. 44   Art. 145  
Art. 45   Art. 146  
Art. 46   Art. 147(1) and (2)   
97 
 Art. 47a   Art. 149  
Art. 52b(1)   Art. 150(1)  
Art. 118b   Art. 150(2)  
Art. 52b(2)   Art. 150(3)  
Art. 48(1) and (2)   Art. 151(1) and (2)  
Art. 49(1)   Art. 152(1)  
Art. 51   Art. 153(1), (2) and (3)  
Art. 52   Art. 154  
Art. 52a   Art. 157  
Art. 47, 1 to 4th subparagraph   Art. 160  
Art. 47, 5th subparagraph   Art. 161  
Art. 127   Art. 155  
Art. 46a   Art. 156  
Art. 52a   Art. 157  
Art. 46b(1), (2) and (3)   Art. 158(1), (2) and (3)  
Art. 46b(4)   Art. 158(4)  
Art. 111b   Art. 159  
Art. 76   Art. 162  
Art. 77   Art. 163  
Art. 78   Art. 165(1), 2nd sentence  
Art. 79   Art. 164  
Art. 80    Art. 166(1) to (4)  
Art. 81   Art. 167  
Art. 82   Art. 168  
Art. 83   Art. 169   
98 
 Art. 85a   Art. 170  
Art. 85b(1)   Art. 171(1)  
Art. 85b(2), 1st and 3rd 
subparagraph   Art. 171(2)  
Art. 85b(3) and(4)   Art. 171(3) and (4)  
Art. 85c(1) and (2)   Art. 172(1) and (2)  
Art. 85c(6)   Art. 172(3)  
Art. 85c(3)   Art. 173(1) and (2)  
Art. 85c(4)   Art. 174(1)  
Art. 85c(5)   Art. 174(2)  
Art. 85d   Art. 174(3)  
Art. 86   Art. 175  
Art. 87   Art. 176(1), (2) and (3)  
Art. 88   Art. 177  
Art. 89   Art. 178  
Art. 90   Art. 179  
Art. 91   Art. 180  
Art. 92   Art. 181  
Art. 93   Art. 182  
Art. 94   Art. 183  
Art. 95   Art. 184  
Art. 96(1)   Art. 185(1)  
Art. 96(2)   Art. 185(3)  
Art. 97   Art. 186  
Art. 98   Art. 187  
Art. 111(1)   Art. 188(1), (2) and (6)   
99 
 Art. 111(1a)   Art. 188(3), point (a)  
Art. 111(1b), 1st subparagraph   Art. 188(3), point (b)  
Art. 111(1b), 2nd subparagraphs, 
points (a) and (b)   Art. 188(5), points (b), (d) and 
(f) 
Art. 111(1c)   Art. 188(6)  
Art. 111(1d)   Art. 188(5), point (g)  
Art. 111(1g)   Art. 188(7)  
Art. 111(1h)   Art. 188(8)  
Art. 111(3), first subparagraph   Art. 188(9)  
Art. 111(3), 2nd subparagraph   Art. 188(10)  
Art. 111(3), 3rd subparagraph   Art. 188(11)  
Art. 111(4)   Art. 188(12)  
Art. 111(5), 1st subparagraph   Art. 188(13)  
Art. 111(6)   Art. 188(15)  
Art. 111(7)   Art. 188(16)  
Art. 111(8)   Art. 188(17)  
Art. 111a, 1st subparagraph   Art. 190(1)  
Art. 111a, 2nd subparagraph   Art. 190(2)  
Art. 112   Art. 191  
Art. 113   Art. 192  
Art. 114   Art. 193  
Art. 115   Art. 194  
Art. 116, 1st subparagraph   Art. 195(1)  
Art. 116, 2nd and 3rd 
subparagraph   Art. 195(3) and (4)  
Art. 118(1)   Art. 195(5)   
100 
 Art. 117(1)   Art. 196(1), introductory 
sentence and points (a) to (e)  
Art. 117(2) and (3)   Art. 196(2) and (3)  
Art. 117a(1) to (3)   Art. 197  
Art. 118(2)   Art. 198  
Art. 126   Art. 199  
Art. 118a   Art. 206  
Art. 118(c)   Art. 201(2)  
Art. 122   Art. 202  
Art. 123   Art. 203  
Art. 125   Art. 204  
Art. 126a(1) to (4)   Art. 205  
Art. 126b   Art. 208  
Art. 127b   Art. 207  
Art. 5a   Art. 209(1)  
Art. 8(2a), (2b), 1st subparagraph   Art. 209(2), 1st subparagraph  
Art. 8(2b), 2nd subparagraph   Art. 209(2), 2nd subparagraph  
Art. 18a(1) and (2)   Art. 209(3) and (4)  
Art. 20, 2nd subparagraph   Art. 209(5)  
Art. 40(1a), 1st subparagraph   Art. 209(6)  
Art. 40(3a)   Art. 209(7)  
Art. 48(3)   Art. 209(8)  
Art. 104(3), 3rd subparagraph   Art. 209(9)  
Art. 127d(1)   Art. 209(10)  
Art. 111c   Art. 210  
Art. 8(2b)   Art. 211(1)   
101 
 Art. 20, 2nd subparagraph   Art. 211(2)  
Art. 40(1a)   Art. 211(3)  
Art. 40(3a)   Art. 211(4)  
Art. 126c   211(5)  
Art. 127d   Art. 211(9)  
Art. 127c   Art. 212  
Art. 120   Art. 213  
Art. 121(1)   Art. 214(1)  
Art. 121(2), 1st subparagraph   Art. 214(2)  
Art. 121(3), 1st subparagraph   Art. 214(3)  
Art. 121(4)   Art. 214(4)  
Art. 121a   Art. 215  
Art. 8(3), points (a) to (c)   Annex I, points (1), (2) and (3)  
Art. 8(3), points (d) to (i)   Annex I, points (6) to (12)  
Art. 8(3), points (ia) to (m)   Annex I, points (14) to (20)  
Art. 9   Annex I, point (22)  
Annex I   Annex II  
Art. 49(2)  
  Annex IV, point (1)  
Art. 49(2)   Annex IV, point (4)  
Art, 49(3), 1st subparagraph   Annex IV, point (5)  
Art. 50(1)   Annex IV, point (6)  
Art. 50(2), 1st subparagraph   Annex IV, point (7)  
Art. 54   Art. 65; Annex V  
Art. 11   Annex VI  
Art. 59   Annex VII, points (1) to (7)   
102