MT
Regulations, 2010
Table of Provisions (8)
Statutory Text (8 Articles)
L.N. 252 of 2010
MEDICINES ACT
(CAP. 458)
Medicines (Marketing Authorisation) (Amendment)
Regulations, 2010
IN exercise of the powers conferred by article 106 of the
Medicines Act, the Minister of Health, the Elderly and Community
Care, after consultation with the Licensing Authority, has made the
following regulations:-
(1) The title of these regulations is the Medicines
(Marketing Authorisation) (Amendment) Regulations, 2010
and they shall be read and construed as one with the Medicines
(Marketing Authorisation) Regulations, 2007, hereinafter referred
to as “the principal regulations”.
(2) These regulations lay out the requirements set
in Annex I of Directive 2001/83/EC, as amended by Directive
2003/63/EC and Directive 2009/120/EC.
In sub-regulation (1) of regulation 2 of the principal
regulations, for the definition “Annex I” there shall be substituted
the following
“ “Annex I” means Annex I of Directive 2001/83/EC as
subsequently amended and as appearing in the Schedule to
these regulations;”.
Immediately at the end of the principal regulations, there
shall be added the following Schedule
B
“SCHEDULE
ANALYTICAL, PHARMACOTOXICOLOGICAL AND CLINICAL STANDARDS AND
PROTOCOLS IN RESPECT OF THE TESTING OF MEDICINAL PRODUCTS
TABLE OF CONTENTS
Introduction and general principles
Part I: Standardised marketing authorisation dossier requirements
1. Module 1: Administrative information
1.1.
Table of contents
1.2.
Application form
1.3.
Summary of product characteristics, labelling and package leaflet
1.3.1.
Summary of product characteristics
1.3.2.
Labelling and package leaflet
1.3.3.
Mock-ups and specimens
1.3.4.
Summaries of product characteristics already approved in the Member States
1.4.
Information about the experts
1.5.
Specific requirements for different types of applications
1.6.
Environmental risk assessment
2. Module 2: Summaries
2.1.
Overall table of contents
2.2.
Introduction
2.3.
Quality overall summary
2.4.
Non-clinical overview
2.5.
Clinical overview
2.6.
Non-clinical summary
2.7.
Clinical Summary
3. Module 3: Chemical, pharmaceutical and biological information for medicinal products containing chemical and/or
biological active substances
3.1.
Format and presentation
3.2.
Content: basic principles and requirements
3.2.1. Active substance(s)
3.2.1.1. General information and information related to the starting and raw materials
3.2.1.2. Manufacturing process of the active substance(s)
3.2.1.3. Characterisation of the active substance(s)
3.2.1.4. Control of active substance(s)
3.2.1.5. Reference standards or materials
3.2.1.6. Container and closure system of the active substance
3.2.1.7. Stability of the active substance(s)
3.2.2. Finished medicinal product
3.2.2.1. Description and composition of the finished medicinal product
3.2.2.2. Pharmaceutical development
3.2.2.3. Manufacturing process of the finished medicinal product
3.2.2.4. Control of excipients
3.2.2.5. Control of the finished medicinal product
3.2.2.6. Reference standards or materials
3.2.2.7. Container and closure of the finished medicinal product
B
3.2.2.8. Stability of the finished medicinal product
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
Module 5: Clinical study reports
5.1.
Format and Presentation
5.2.
Content: basic principles and requirements
5.2.1. Reports of bio-pharmaceutics studies
5.2.2. Reports of studies pertinent to pharmaco-kinetics using human bio-materials
5.2.3. Reports of human pharmaco-kinetic studies
5.2.4. Reports of human pharmaco-dynamic studies
5.2.5. Reports of efficacy and safety studies
5.2.5.1. Study Reports of Controlled Clinical Studies Pertinent to the Claimed Indication
5.2.5.2. Study reports of uncontrolled clinical studies reports of analyses of data from more than one study and other clinical
study reports
5.2.6. Reports of post-marketing experience
5.2.7. Case reports forms and individual patient listings
Part II: Specific marketing authorisation dossiers and requirements
1. Well-established medicinal use
2. Essentially similar medicinal products
3. Additional data required in specific situations
4. Similar biological medicinal products
5. Fixed combination medicinal products
Documentation for applications in exceptional circumstances
Mixed marketing authorisation applications
Part III
Particular medicinal products
1. Biological medicinal products
1.1.
Plasma-derived medicinal product
1.2.
Vaccines
2. Radio-pharmaceuticals and precursors
2.1.
Radio-pharmaceuticals
2.2.
Radio-pharmaceutical precursors for radio-labelling purposes
3. Homeopathic medicinal products
4. Herbal medicinal products
5. Orphan Medicinal Products
Part IV: Advanced therapy medicinal products
1. Introduction
2. Definitions
2.1.
Gene therapy medicinal products
2.2.
Somatic cell therapy medicinal products
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
B
Introduction: finished product, active substance and starting materials
Specific requirements
Specific requirements for somatic cell therapy medicinal products and tissue engineered products
Introduction: finished product, active substance and starting materials
Specific requirements
Specific requirements for advanced therapy medicinal products containing devices
Advanced therapy medicinal products containing devices referred to in Article 7 of Regulation (EC) 1394/2007
Combined advanced therapy medicinal products as defined in Article 2(1)(d) of Regulation (EC) 1394/2007
4. Specific requirements regarding Module 4
Specific requirements for all advanced therapy medicinal products
Specific requirements for gene therapy medicinal products
Pharmacology
Pharmacokinetics
Toxicology
Specific requirements for somatic cell therapy medicinal products and tissue engineered products
Pharmacology
Pharmacokinetics
Toxicology
5. Specific requirements regarding Module 5
Specific requirements for all advanced therapy medicinal products
Specific requirements for gene therapy medicinal products
Human pharmacokinetic studies
Human pharmacodynamic studies
Safety studies
Specific requirements for somatic cell therapy medicinal products
Specific requirements for tissue engineered products
Pharmacokinetic studies
Pharmacodynamic studies
Safety studies
B
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 Schedule 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(1) regions (European Community, United States of America,
Japan). These five Modules shall 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 authorisation applications
irrespective of the procedure to be applied (i.e. centralised, mutual recognition or national) and of whether they are based on a
full or abridged application. It is also applicable for all types of products including new chemical entities (NCE), radio-
pharmaceuticals, plasma derivatives, vaccines, herbal medicinal products, etc.
(4)
In assembling the dossier for application for marketing authorisation, applicants shall also take into account the
scientific guidelines relating to the quality, safety and efficacy of medicinal products for human use as adopted by the
Committee for Proprietary Medicinal Products (CPMP) and published by the European Medicine Evaluation Agency (EMEA)
and the other pharmaceutical Community guidelines published by the Commission in the different volumes of The rules
governing medicinal products in the European Community.
(5)
With respect to the quality part (chemical, pharmaceutical and biological) of the dossier, all monographs including
general monographs and general chapters of the European Pharmacopoeia are applicable.
(6)
The manufacturing process shall comply with the requirements of Commission Directive 91/356/EEC laying down the
principles and guidelines of Good Manufacturing Practice (GMP) for medicinal products for human use (2) and with the
principles and guidelines on GMP, published by the Commission in The rules governing medicinal products in the European
Community, Volume 4.
(7)
All information, which is relevant to the evaluation of the medicinal product concerned, shall be included in the
application, whether 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 (3). To be taken into account during the assessment of an application, clinical trials,
conducted outside the European Community, which relate to medicinal products intended to be used in the European
Community, shall be designed, implemented and reported on what good clinical practice and ethical principles are concerned, on
the basis of principles, which are 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 Helsinki.
(9)
Non-clinical (pharmaco-toxicological) studies shall be carried out in conformity with the provisions related to Good
Laboratory Practice laid down in Council Directives 87/18/EEC on the harmonisation of regulations and administrative
provisions relating to the application of the principles of good laboratory practice and the verification of their application for
tests in chemical substances (1) and 88/320/EEC on the inspection and verification of good laboratory practice (GLP) (2).
(10)
Member States shall also ensure that all tests on animals are conducted in accordance with Council Directive
86/609/EEC of 24 November 1986 on the approximation of laws, regulation and administrative provisions of the Member States
regarding the protection of animals for experimental and other scientific purposes.
B
(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 (3) and (EC) No 1085/2003(4) of the Commission or, if relevant, in accordance with national
provisions, as well as the requirements in Volume 9 of Commission publication The rules governing medicinal products in the
European Community.
This Schedule is divided in four different parts
— Part I describes the application format, the 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 Master
File; Vaccine Antigen Master File), radio-pharmaceuticals, homeopathic medicinal products, herbal medicinal products
and orphan medicinal products.
— Part IV deals with ‘Advanced therapy medicinal products’ and concerns specific requirements for gene
therapy medicinal products (using human autologous or allogeneic system, or xenogeneic system) and cell therapy
medicinal products both of human or animal origin and xenogeneic transplantation medicinal products.
B
PART I
STANDARDISED MARKETING AUTHORISATION DOSSIER REQUIREMENTS
1. MODULE 1: ADMINISTRATIVE INFORMATION
Table of contents
A comprehensive table of contents of Modules 1 to 5 of the dossier submitted for marketing authorisation application
shall be presented.
Application form
The medicinal product, which is the subject of the application, shall be identified by name and name of the active
substance(s), together with the pharmaceutical form, the route of administration, the strength and the final presentation,
including packaging.
The name and address of the applicant shall be given, together with the name and address of the manufacturers and the
sites involved in the different stages of the manufacture (including the manufacturer of the finished product and the
manufacturer(s) of the active substance(s)), and where relevant the name and address of the importer.
The applicant shall identify the type of application and indicate what samples, if any, are also provided.
Annexed to the administrative data shall be copies of the manufacturing authorisation as defined in Article 40, together with a
list of countries in which authorisation has been granted, copies of all the summaries of product characteristics in accordance
with Article 11 as approved by Member States and a list of countries in which an application has been submitted.
As outlined in the application form, the applicants shall provide, inter alia, details of the medicinal product subject of
the application, the legal basis of the application, the proposed marketing authorisation holder and manufacture(s), information
on orphan medicinal product status, scientific advice and paediatric development program.
Summary of product characteristics, labelling and package leaflet
Summary of product characteristics
The applicant shall propose a summary of the product characteristics, in accordance with Article 11.
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).
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.
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.
Information about the experts
In accordance with Article 12 (2) experts must provide detailed reports of their observations on the documents and
particulars which constitute the marketing authorisation dossier and in particular on Modules 3, 4 and 5 (chemical,
B
pharmaceutical and biological documentation, non-clinical documentation and clinical documentation, respectively). The
experts are required to address the critical points related to the quality of the medicinal product and of the investigations carried
out on animals and human beings and bring out all the data relevant for evaluation.
These requirements shall be met by providing a quality overall summary, a non-clinical overview (data from studies
carried out in animals) and a clinical overview that shall be located in Module 2 of the marketing authorisation application
dossier. A declaration signed by the experts together with brief information on their educational background, training and
occupational experience shall be presented in Module 1. The experts shall have suitable technical or professional qualifications.
The professional relationship of the expert to the 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 this Schedule.
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 12March 2001 on the deliberate release into the environment of modified organisms and repealing Council
Directive 90/220/EEC (1) shall be addressed.
Information pertaining to the environmental risk shall appear as an appendix to Module 1.
The information shall be presented in accordance with the provisions of Directive 2001/18/EC, taking into account any
guidance documents published by the Commission in connection with the implementation of the said Directive.
The information shall consist of
— an introduction;
— a copy of any written consent or consents to the deliberate release into the environment of the
GMO(s) for research and development purposes according to Part B of Directive 2001/18/EC;
— the information requested in Annexes II to IV of the Directive 2001/18/EC, including detection and
identification methods as well as unique code of the GMO, plus any additional information on the GMO or the product
of relevance to evaluating the environmental risk;
— an environment risk assessment (ERA) report prepared on basis of the information specified in Annexes III
and IV of Directive 2001/18/EC and in accordance with Annex II of Directive 2001/18/EC;
— taking into account the above information and the ERA, a 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 experience, and a
statement of the author’s relationship with the applicant, shall be included.
2. MODULE 2: SUMMARIES
B
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 principles
and requirements as laid down herewith
Overall table of contents
Module 2 shall contain a table of contents for the scientific documentation submitted in Modules 2 to 5.
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.
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.
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 toxicological effects. The implications of any differences in the chirality,
chemical form, and impurity profile between the compound used in the non-clinical studies and the product to be marketed shall
be discussed.
For biological medicinal products, comparability of material used in non-clinical studies, clinical studies, and the
medicinal product for marketing shall be assessed.
Any novel excipient shall be the subject of a specific safety assessment.
The characteristics of the medicinal product, as demonstrated by the non-clinical studies shall be defined and the
implications of the findings for the safety of the medicinal product for the intended clinical use in humans shall be discussed.
Clinical overview
The clinical overview is intended to provide a critical analysis of the clinical data included in the clinical summary and
Module 5. The approach to the clinical development of the medicinal product, including critical study design, decisions related
to and performance of the studies shall be provided.
B
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 shall be presented in the following order
— Introduction
— Pharmacology Written Summary
— Pharmacology Tabulated Summary
— Pharmaco-kineticsWritten Summary
— Pharmaco-kinetics Tabulated Summary
— Toxicology Written Summary
— Toxicology Tabulated Summary.
2.7.
Clinical Summary
A detailed, factual summary of the clinical information on the 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
General Information
— Nomenclature
— Structure
— General Properties
Manufacture
— Manufacturer(s)
— Description of Manufacturing Process and Process Controls
— Control of Materials
— Controls of Critical Steps and Intermediates
— Process Validation and/or Evaluation
— Manufacturing Process Development
Characterisation
— Elucidation of Structure and other Characteristics
— Impurities
Control of Active Substance
— Specification
— Analytical Procedures
— Validation of Analytical Procedures
— Batch Analyses
— Justification of Specification
Reference Standards or Materials
Container Closure System
Stability
— Stability Summary and Conclusions
— Post-approval Stability Protocol and Stability Commitment
— Stability Data
— Finished Medicinal Product
Description and Composition of the Medicinal Product
P h a r ma c e u t i c a l D e v e l opme n t
— Components of the Medicinal Product
— Active Substance
— Excipients
— Medicinal Product
— Formulation Development
— Overages
— Physicochemical and Biological Properties
— Manufacturing Process Development
— Container Closure System
— Microbiological Attributes
— Compatibility
Manufacture
— Manufacturer(s)
— Batch Formula
— Description of Manufacturing Process and Process Controls
— Controls of Critical Steps and Intermediates
— Process Validation and/or Evaluation
B
Control of Excipients
— Specifications
— Analytical Procedures
— Validation of Analytical Procedures
— Justification of Specifications
— Excipients of Human or Animal Origin
— Novel Excipients
Control of Finished Medicinal Product
— Specification(s)
— Analytical Procedures
— Validation of Analytical procedures
— Batch Analyses
— Characterisation of Impurities
— Justification of Specification(s)
Reference Standards or Materials
Container Closure System
Stability
— Stability Summary and Conclusion
— Post-approval Stability Protocol and Stability Commitment
— Stability Data
— Appendices
— Facilities and Equipment (Biological Medicinal Products only)
— Adventitious Agents Safety Evaluation
— Excipients
— European Community Additional Information
— Process Validation Scheme for the Medicinal Product
— Medical Device
— Certificate(s) of Suitability
— Medicinal products containing or using in the manufacturing process materials of animal
and/or human origin (TSE procedure)
— Literature References
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.
(2)
Two main sets of information shall be provided, dealing with the active substance(s) and with the finished
medicinal product, respectively.
B
(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 formulation of the finished
medicinal product.
(4)
All the procedures and methods used for manufacturing and controlling the active substance and the finished
medicinal product shall be described in sufficient details to enable them to be repeated in control tests, carried out at the request
of the 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 included in the European
Pharmacopoeia, this description shall be replaced by the appropriate detailed reference to the monograph(s) and general
chapter(s).
(5)
The monographs of the European Pharmacopoeia shall be 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
contained 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 authorisation holder. The competent authorities shall inform the authorities responsible for the pharmacopoeia in
question. The marketing authorisation holder shall provide the authorities of that pharmacopoeia with the details of the alleged
insufficiency and the additional specifications applied.
In the case of analytical procedures included in the European Pharmacopoeia, this description shall be replaced in each
relevant section by the appropriate detailed reference to the monograph(s) and general chapter(s).
(6)
In case where starting and raw materials, active substance(s) or excipient(s) are described neither in the
European Pharmacopoeia nor in the pharmacopoeia of a Member State, compliance with the monograph of a third country
pharmacopoeia can be accepted. In such cases, the applicant shall submit a copy of the monograph accompanied by the
validation of the analytical procedures contained in the monograph and by a translation where 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 relevant section of this Module. Those certificates of
suitability of the monograph of the European Pharmacopoeia are deemed to replace the relevant data of the corresponding
sections described in this Module. The 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 manufacturer 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.
B
(9)
Specific measures concerning the prevention of the transmission of animal spongiform encephalopathies
(materials from ruminant origin): at each step of the manufacturing process, the applicant must demonstrate the compliance of
the materials used with the Note for Guidance on Minimising the Risk of Transmitting Animal Spongiform Encephalopathy
Agents via Medicinal Products and its updates, published by the Commission in the Official Journal of the European Union.
Demonstration of compliance with the said Note for Guidance can be done by submitting either, preferably 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 adventitious agents, information assessing the risk with respect to potential contamination with
adventitious agents, whether they are non-viral or viral, as laid down in relevant guidelines as well as in relevant general
monograph and general chapter of the European Pharmacopoeia, shall be provided.
(11)
Any special apparatus and equipment, which may be used at any stage of the manufacturing process and
control operations of the medicinal product, shall be described in adequate details.
(12)
Where applicable and if needed, a CE marking which is required by Community legislation on
medical devices shall be provided. Special attention shall be paid to the following selected elements.
Active substance(s)
3.2.1.1. General information and information related to the starting and raw materials
a)
Information on the nomenclature of the active substance shall be provided, including recommended
International Non-proprietary Name (INN), European Pharmacopoeia name if relevant, chemical name(s).
The structural formula, including relative and absolute stereo-chemistry, the molecular formula, and the
relative molecular mass shall be provided. For biotechnological medicinal products if appropriate, the schematic amino
acid sequence and relative molecular mass shall be provided.
A list shall be provided of physicochemical and other relevant properties of the active substance, including
biological activity for biological medicinal products.
b)
For the purposes of this Schedule, starting materials shall mean all the materials from which the
active substance is manufactured or extracted.
For biological medicinal products, starting materials shall mean any substance of biological origin such as
micro-organisms, organs and tissues of either plant or animal origin, cells or fluids (including blood or plasma) of
human or animal origin, and biotechnological cell constructs (cell substrates, whether they are recombinant or not,
including primary cells).
A biological medicinal product is a product, the active substance of which is a biological substance.
A biological substance is a substance that is produced by or extracted from a biological source and that needs
for its characterisation and the determination of its quality a combination of physicochemical-biological testing,
together with the production process and its control. The following shall be considered as biological medicinal
products: immunological medicinal products and medicinal products derived from human blood and human plasma as
defined, respectively in paragraphs (4) and (10) of Article 1; medicinal products falling within the scope of Part A of
the Annex to Regulation (EEC) No 2309/93; advanced therapy medicinal products as defined in Part IV of this
Schedule.
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.
B
3.2.1.2. Manufacturing process of the active substance(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.
b)
All materials needed in order to manufacture the active substance(s) shall be listed, identifying where each
material is used in the process. Information on the quality and control of these materials shall be provided. Information
demonstrating that materials meet standards appropriate for their intended use shall be provided.
Raw materials shall be listed and their quality and controls shall also be documented.
The name, address, and responsibility of each manufacturer, including contractors, and each proposed production site
or facility involved in manufacturing and testing shall be provided.
c)
For biological medicinal products, the following additional requirements shall apply. The origin and history of
starting materials shall be described and documented. Regarding 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 Encephalopathy Agents via Medicinal Products and its
updates, published by the Commission in the Official Journal of the European Union.
When cell banks are used, the cell characteristics shall be shown to have remained unchanged at the passage level used
for the 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 based 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 addition, for live vaccines, the
stability of the attenuation characteristics shall be demonstrated on the seed; if this proof is not sufficient, the attenuation
characteristics shall also be demonstrated at the production stage.
For medicinal products derived from human blood or plasma, the origin and the criteria and procedures for collection,
transportation and storage of the starting material shall be described and documented in accordance with provisions laid down in
Part III of this Schedule.
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 inevitable, the correspondent material shall be
used only when further processing ensures their elimination and/or inactivation and this shall be validated in the section dealing
with viral safety evaluation.
f)
A description and discussion of the significant changes made to the manufacturing process during
development and/or manufacturing site of the active substance shall be provided.
3.2.1.3.1.
Characterisation of the active substance(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 immunochemical and/or
biological methods, as well as information on impurities shall be provided.
B
3.2.1.3.2.
Control of active substance(s)
Detailed information on the specifications used for routine control of active substance(s), justification for the choice of
these specifications, methods of analysis and their validation shall be provided. The results of control carried out on individual
batches manufactured during development shall be presented.
3.2.1.3.3.
Reference standards or materials
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. Container and closure system of the active substance
A description of the container and the closure system(s) and their specifications shall be provided.
3.2.1.7. Stability of the active substance(s)
a)
The types of studies conducted, protocols used, and the results of the studies shall be summarized
b)
Detailed results of the stability studies, including information on the analytical procedures used to generate the
data and validation of these procedures shall be presented in an appropriate format
c)
The post authorisation stability protocol and stability commitment shall be provided
3.2.2. Finished medicinal product
3.2.2.1. Descriotion and composition of the finished medicinal product
A description of the finished medicinal product and its composition shall be provided. The information shall include the
description of the pharmaceutical form and composition with all the constituents of the finished medicinal product, their amount
on a per-unit basis, the 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, thickeners, emulsifiers, flavouring and aromatic substances, etc.,
— the constituents, intended to be ingested or otherwise administered to the patient, of the outer covering of
the medicinal products (hard capsules, soft capsules, rectal capsules, coated tablets, films-coated tablets, etc.),
— these particulars shall be supplemented by any relevant data concerning the type of container and, where
appropriate, its manner of closure, together with details of devices with which the medicinal product will be used or
administered and which will be delivered with the medicinal product.
The ‘usual terminology’, to be used in describing the constituents of medicinal products, shall mean, notwithstanding
the application of 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
78/25/EEC of 12 December 1977 on the approximation of the rules of the Member States concerning the colouring
matters authorised for use in medicinal products (1) and/or European Parliament and Council Directive 94/36/EC of 30
June 1994 on colours for use in foodstuffs (2).
B
In order to give the ‘quantitative composition’ of the active substance(s) of the finished medicinal products, it is
necessary, depending on the pharmaceutical form concerned, to specify the mass, or the number of units of biological activity,
either per dosage-unit or per unit of mass or volume, of each active substance.
Active substances present in the form of compounds or derivatives shall be designated quantitatively by their total
mass, and if necessary or relevant, by the mass of active entity or entities of the molecule.
For medicinal products containing an active substance, which is the subject of an application for marketing
authorisation in any Member State for the first time, the quantitative statement of an active substance, which is a salt or hydrate
shall be systematically expressed in terms of the mass of the active entity or entities in the molecule. All subsequently authorised
medicinal products in the Member States shall have their quantitative composition stated in the same way for the same active
substance.
Units of biological activity shall be used for substances, which cannot be defined molecularly. Where an International
Unit of 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. Pharmaceutical development
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 attributes and usage instructions are
appropriate for the intended use specified in the marketing authorisation application dossier.
The studies described in this chapter are distinct from routine control tests conducted according to specifications.
Critical parameters of the formulation and process attributes that can influence batch 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 characteristics 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 particular relative to their respective functions and concentration shall be
documented.
c)
A description of the development of the finished product shall be provided, taking into consideration the
proposed route of 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.
f)
The selection and optimisation of the manufacturing process as well as differences between the manufacturing
process(es) used to produce pivotal clinical batches and the process used for 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 form in relation with non-sterile and sterile products shall be in
accordance with and documented as prescribed in the European Pharmacopoeia.
B
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. Manufacturing process of the finished medicinal product
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 constituents,
— in the case of continuous manufacture, full details concerning precautions taken to ensure the homogeneity
of the finished product,
— experimental studies validating the manufacturing process, where a non-standard method of manufacture is
used or where it is critical for the product,
— for sterile medicinal products, details of the sterilisation processes and/or aseptic procedures used,
— a detailed batch formula.
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 product which does not include the assay of all the active
substances (or of all the excipient constituents subject to the same requirements as the active substances).
The same applies where the quality control of the finished product depends on in-process control tests, particularly if
the medicinal product is essentially defined by its method of preparation.
c)
Description, documentation, and results of the validation studies for critical steps or critical assays used in the
manufacturing process shall be provided.
3.2.2.4. Control of excipients
a)
All the materials needed in order to manufacture the excipient(s) shall be listed identifying where each
material is used in the process. Information on the quality and control of these materials shall be provided. Information
demonstrating that materials meet standards appropriate for their intended use shall be provided.
Colouring matter shall, in all cases, satisfy the requirements of Directives 78/25/EEC and/or 94/36/EC. In addition,
colouring matter shall meet purity criteria as laid down in Directive 95/45/EC, as amended.
b)
For each excipient, the specifications and their justifications shall be detailed. The analytical procedures shall
be described and duly validated.
B
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 for excipients
that the medicinal product 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 cross references to supporting safety data, both non-clinical and clinical, shall
be provided according to the active substance format previously described.
A document containing the detailed chemical, pharmaceutical and biological information shall be presented. This
information shall be formatted in the same order as the chapter devoted to Active Substance(s) of Module 3.
Information on novel excipient(s) may be presented as a stand-alone document following the format described in the
former paragraphs. Where the applicant differs from the novel excipient manufacturer the said stand-alone document shall be
made available to the 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. Control of the finished medicinal product
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 production process, all the units manufactured in a
given period of time.
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. Reference standards or materials
Reference preparations and standards used for testing of the finished medicinal product shall be identified and
described in detail, if not previously provided in the section related to the active substance.
3.2.2.7. Container and closure or the finished medicinal product
A description of the container and the closure system(s) including the identity of each immediate packaging material
and their specifications shall be provided. The specifications shall include description and 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 shall be provided.
3.2.2.8. Stability of the finished medicinal product
a)
The types of studies conducted, protocols used, and the results of the studies shall be summarized;
B
b)
Detailed results of the stability studies, including information on the analytical procedures used to generate the
data and validation of these procedures shall be presented in an appropriate format; in case of vaccines, information on
cumulative stability shall be provided where appropriate;
c)
The post authorisation stability protocol and stability commitment shall be provided.
4. MODULE 4: NON-CLINICAL REPORTS
4.1.
Format and Presentation
The general outline of Module 4 is as follows
— Table of contents
— Study reports
— Pharmacology
— Primary Pharmaco-dynamics
— Secondary Pharmaco-dynamics
— Safety Pharmacology
— Pharmaco-dynamic Interactions
— Pharmaco-kinetics
— Analytical Methods and Validation Reports
— Absorption
— Distribution
— Metabolism
— Excretion
— Pharmaco-kinetic Interactions (non-clinical)
— Other Pharmaco-kinetic Studies
— Toxicology
— Single-Dose Toxicity
— Repeat-Dose Toxicity
— Genotoxicity
— In vitro
— In vivo (including supportive toxico-kinetics evaluations)
— Carcinogenicity
— Long-term studies
— Short- or medium-term studies
— Other 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
evaluation
— Local Tolerance
B
— Other Toxicity Studies
— Antigenicity
— Immuno-toxicity
— Mechanistic studies
— Dependence
— Metabolites
— Impurities
— Other
— Literature references
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 beings. All results must be reliable and of general applicability.
Whenever appropriate, mathematical and statistical procedures shall be used in designing the experimental methods and
in 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 administration 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.
(3)
The toxicology and pharmaco-kinetics of an excipient used for the first time in the pharmaceutical field shall
be investigated.
(4)
Where there is a possibility of significant degradation during storage of the medicinal product, the toxicology
of degradation products must be considered.
Pharmacology
Pharmacology study shall follow two distinct lines of approach.
— Firstly, the actions relating to the proposed therapeutic use shall be adequately investigated and described. Where
possible, recognised and validated assays, both in vivo and in vitro, shall be used.
Novel experimental techniques must be described in such detail as to allow them to be reproduced.
B
The results shall be expressed in quantitative terms using, for example, dose-effect curves, timeeffect curves, etc.
Wherever possible, comparisons shall be made with data relating to a substance or substances with a similar therapeutic action.
— Secondly, the applicant shall investigate the potential undesirable pharmaco-dynamic effects of the substance on
physiological 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 indications of therapeutic effect. In the first case, the pharmaco-dynamic study shall
demonstrate those interactions, which might make the combination of value in therapeutic use. In the second case, where
scientific justification for the combination is sought through therapeutic experimentation, the investigation shall determine
whether the effects expected from the combination can be demonstrated in animals, and the importance of any collateral effects
shall at least be investigated.
4.2.2.
Pharmaco-kinetics
Pharmaco-kinetics means the study of the fate of the active substance, and its metabolites, within the organism, and
covers the study of the absorption, distribution, metabolism (bio-transformation) and excretion of these substances.
The study of these different phases may be carried mainly by means of physical, chemical or possibly by biological
methods, and by observation of the actual pharmaco-dynamic activity of the substance itself. Information on distribution and
elimination shall be necessary in all cases where such data are indispensable to determine the dosage for humans, and in respect
of chemo-therapeutic substances (antibiotics, etc.) and substances whose use depends on their non-pharmaco-dynamic effects
(e.g. numerous diagnostic agents, etc.).
In vitro studies also can be carried out with the advantage of using human material for comparison with animal material
(i.e. protein binding, metabolism, drug-drug interaction).
Pharmaco-kinetic investigation of all pharmacologically active substances is necessary. In the case of new
combinations of known substances, which have been investigated in accordance with the provisions of this Directive, pharmaco-
kinetic studies may not be required, if the toxicity tests and therapeutic experimentation justify their omission.
The pharmaco-kinetic program shall be design to allow comparison and extrapolation between animal and human.
4.2.3.
Toxicology
a)
Single-dose toxicity
A single-dose toxicity test shall mean a qualitative and quantitative study of the toxic reactions, which may result from
a single 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 toxicity test must be carried out in accordance with the relevant guidelines published by the Agency.
b)
Repeat-dose toxicity
Repeated dose toxicity tests are intended to reveal any physiological and/or anatomo-pathological changes induced by
repeated administration of the active substance or combination of active substances under examination, and to determine how
these changes are related to dosage.
Generally, it is desirable that two tests be performed: one short term, lasting two to four weeks, the other long-term.
The duration of the latter shall depend on the conditions of clinical use. Its purpose is to describe potential adverse effects to
which attention should be paid in clinical studies. The duration is defined in the relevant guidelines published by the Agency.
c)
Geno-toxicity
B
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 necessary to detect early tumorigenic effects.
e)
Reproductive and developmental toxicity
Investigation of possible impairment of male or female reproductive function as well as harmful effects on progeny
shall be performed by appropriate tests.
These tests comprise studies of effect on adult male or female 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 has been administered to the female during pregnancy.
Omission of these tests must be adequately justified.
Depending on the indicated use of the medicinal product, additional studies addressing development when
administering the medicinal product of the offspring may be warranted. Embryo/foetal toxicity studies shall normally be
conducted on two mammalian species, one of which shall be other than a rodent. Peri- and postnatal studies shall be conducted
in at least one species. If the metabolism of a medicinal product in particular species is known to be similar to that in man, it is
desirable to include this species. It is also desirable that one of the species is the same as in the repeated dose toxicity studies.
The state of scientific knowledge at the time when the application is lodged shall be taken into account when
determining the study design.
f)
Local tolerance
The purpose of local tolerance studies is to ascertain whether 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 product 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. 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).
B
5. MODULE 5: CLINICAL STUDY REPORTS
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
— Reports of Human Pharmaco-dynamic Studies
— Healthy Subject Pharmaco-dynamic and Pharmaco-kinetics/Pharmaco-dynamic Study
Reports
— Patient Pharmaco-dynamic and Pharmaco-kinetics/Pharmaco-dynamic Studies Study
Reports
— Reports of Efficacy and Safety Studies
— Study Reports of Controlled Clinical Studies Pertinent to the Claimed Indication
— Study Reports of Uncontrolled Clinical Studies
— Reports of Analyses of Data from More than One Study including any formal integrated
analyses, meta-analyses and bridging analyses
— Other Study Reports
— Reports of Post-marketing Experience
— Literature references
Content: basic principles and requirements
Special attention shall be paid to the following selected elements.
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. Consequently, 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 Schedule. 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 brochure, 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 trials, with adequate data to justify the nature, scale and duration of the proposed trial; the complete
pharmacological and toxicological reports shall be provided on request. For materials of human or animal origin, all available
means shall be employed to ensure safety from transmission of infectious agents prior to the commencement of the trial.
Marketing authorisation holders must arrange for essential clinical trial documents (including case report
forms) other than subject’s medical files, to be kept by the owners of the data
— for at least 15 years after completion or discontinuation of the trial,
— or for at least two years after the granting of the last marketing authorisation in the European Community
and when there are no pending or contemplated marketing applications in the European Community,
— or for at least two years after formal discontinuation of clinical development of the investigational product.
Subject’s medical files should be retained in accordance with applicable legislation and in accordance with the
maximum period of time permitted by the hospital, institution or private practice.
The documents can be retained for a longer period, however, if required by the applicable regulatory
requirements or by agreement with the sponsor. It is the responsibility of the sponsor to inform the hospital, institution
or practice as to when these documents no longer need to be retained.
The sponsor or other owner of the data shall retain all other 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
investigational product, the reference medicinal product and/or the placebo used; standard operating procedures; all
written opinions on the protocol and procedures; the investigator’s brochure; case report forms on each trial subject;
final report; audit certificate(s), if available. The final report shall be retained by the sponsor or subsequent owner, for
five years after the medicinal product is no longer authorised.
In addition for trials conducted within the European Community, the marketing authorisation holder shall
make any additional 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.
The particulars of each clinical trial must contain sufficient detail to allow an objective judgment 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
— 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
B
— final report signed by the investigator and for multi-centre trials, by all the investigators or the co-
ordinating (principal) investigator.
The particulars of clinical trials referred to above shall be forwarded to the competent authorities. However, in
agreement with the competent authorities, the applicant may omit part of this 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 symptoms of over dosage. In reporting the results of a multi-centre study, the principal
investigator shall, in his conclusions, express an opinion on the safety and efficacy of the investigational medicinal
product on behalf of all centres.
The clinical observations 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
—
received another medicinal product of known effect
—
received treatment other than therapy using medicinal products;
5) the frequency of observed adverse reactions;
6) details concerning patients who may be at increased risk, e.g. elderly people, children, women
during pregnancy or 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 design of the trials and the variable
factors involved.
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.
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.
B
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
modification of the pharmacological action following repeated administration, as well as the establishment of long-term dosage.
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 bioequivalence for
the medicinal products referred to in Article 10 (1) (a).
Reports of studies pertinent to pharmaco-kinetics using human bio-materials
For the purposes of this Schedule, human bio-materials shall mean any proteins, cells, tissues and related materials
derived from human sources that are used in vitro or ex vivo to assess pharmaco-kinetics properties of drug substances.
In this respect, reports of plasma protein binding study, hepatic metabolism and active substance interaction studies and
studies using other human bio-materials shall be provided.
5.2.3. Reports of human pharmaco-kinetic studies
a)
The following pharmaco-kinetic characteristics shall be described
— absorption (rate and extent),
— distribution,
— metabolism,
— excretion.
Clinically significant features including the implication of the kinetic data for the dosage regimen especially
for patients at risk, and differences between man and animal species used in the pre clinical studies, shall be described.
In addition to standard multiple-sample pharmaco-kinetics studies, population pharmaco-kinetics analyses
based on sparse sampling during clinical studies can also address questions about the contributions of intrinsic and
extrinsic factors to the variability in the dose- pharmaco-kinetics response relationship. Reports of pharmaco-kinetic
and initial tolerability studies in healthy subjects and in patients, reports of pharmaco-kinetic studies to assess effects of
intrinsic 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 pharmacological
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,
B
— 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 substances shall
be investigated.
5.2.5.
Reports of efficacy and safety studies
5.2.5.1. Study Reports of Controlled Clinical Studies Pertinent to the Claimed
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 established
medicinal product of proven therapeutic value rather than with the effect of a placebo.
(1)
As far as possible, and particularly in trials where the effect of the product cannot be objectively measured,
steps shall be taken to avoid bias, including methods of randomisation and blinding.
(2)
The protocol of the trial must include a thorough description of the statistical methods to be employed, the
number and reasons for inclusion of patients (including calculations of the power of the trial), the level of significance to be used
and a description of the statistical unit. Measures taken to avoid bias, particularly methods of randomisation, shall be
documented. Inclusion of a large number of subjects in a trial must not be regarded as an adequate substitute for a properly
controlled trial.
The safety data shall be reviewed taking into account guidelines published by the Commission, with particular attention
to events resulting in changes of dose or need for concomitant medication, serious adverse events, events resulting in
withdrawal, and deaths. Any patients or patient groups at increased risk shall be identified and particular attention paid to
potentially vulnerable patients who may be present in small numbers, e.g., children, pregnant women, frail elderly, people with
marked abnormalities of metabolism or excretion etc. The implication of the safety evaluation for the possible uses of the
medicinal product shall be described.
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
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.
5.2.7. Case reports forms and individual patient listings
B
When submitted in accordance with the relevant Guideline published by the Agency, case report forms and individual
patient data listings shall be provided and presented in the same order as the clinical study reports and indexed by study.
B
PART II
SPECIFIC MARKETING AUTHORISATION DOSSIERS ANDREQUIREMENTS
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 Schedule need to be adapted. To take account of these particular situations, an
appropriate and adapted presentation of the dossier shall be followed by applicants.
1. WELL-ESTABLISHED MEDICINAL USE
For medicinal products the active substance(s) of which has/have a ‘well-established medicinal use’ as referred to
Article 10(1)(a)(ii), with recognised efficacy and an acceptable level of safety, the following specific rules shall apply.
The applicant shall submit Modules 1, 2 and 3 as described in part I of this Schedule.
For Modules 4 and 5, a detailed scientific bibliography shall address non-clinical and clinical characteristics.
The following specific rules shall apply in order to demonstrate the well-established medicinal use
a)
Factors which have to be taken into account in order to establish a well-established medicinal use
of constituents of medicinal products are
— the time over which a substance has been used,
— quantitative aspects of the use of the substance,
— the degree of scientific interest in the use of the substance (reflected in the published scientific
literature) and
— the coherence of scientific assessments.
Therefore different periods of time may be necessary for 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 favourable and unfavourable, must be communicated. With respect to the
provisions on ‘well established medicinal use’ it is in particular necessary to clarify that ‘bibliographic reference’ to other
sources of evidence (post marketing studies, 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 paid 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 judgment must be made whether the product studied can be
considered as similar to the product, for which application for a marketing authorisation has been made in spite of the existing
differences.
e)
Post-marketing experience with other products containing the same constituents is of particular importance
and applicants should put a special emphasis on this issue.
2. ESSENTIALLY SIMILAR MEDICINAL PRODUCTS
B
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 Schedule provided the applicant has been granted the consent of the holder of the original
marketing authorisation to cross refer to the content of his Modules 4 and 5.
b)
Applications based upon Article 10(1) (a) (iii) (essentially similar products i.e. generics) shall contain the data
described in Modules 1, 2 and 3 of Part I of this Schedule together with data showing bioavailability and bio-equivalence with
the original medicinal product provided the latter is not a biological medicinal product (see Part II, 4 Similar biological
medicinal products).
For these products the non-clinical/clinical overviews/summaries shall particularly focus on the following elements
— the grounds for claiming essential similarity;
— a summary of impurities present in batches of the active substance(s) as well as those of the finished
medicinal product (and where relevant decomposition products arising during storage) as proposed for use in the
product to be marketed together with an evaluation of these impurities;
— an evaluation of the bio-equivalence studies or a justification why studies were not performed with respect
to the guideline on ‘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 substantiated by published literature and/or additional studies.
— if applicable, additional data in order to demonstrate evidence on the equivalence of safety and efficacy
properties of different salts, esters or derivatives of an authorised active substance should be provided by the applicant
when he claims essential similarity.
3. ADDITIONAL DATA REQUIRED IN SPECIFIC SITUATIONS
Where the active substance of an essentially similar medicinal product contains the same therapeutic moiety as the
original authorised product associated with a different salt/ester complex/derivative evidence that there is no change in the
pharmaco-kinetics of the moiety, pharmaco-dynamics and/or in toxicity which could change the safety/efficacy profile shall be
demonstrated. Should this not be the case, this association shall be considered as a new active substance.
Where a medicinal product is intended for a different therapeutic use or presented in a different pharmaceutical form or
to be administered by different routes or in different doses or with a different posology, the results of appropriate toxicological
and pharmacological tests and/or of clinical trials shall be provided.
4. SIMILAR BIOLOGICAL MEDICINAL PRODUCTS
The provisions of Article 10(1)(a) (iii) may not be sufficient in the case of biological medicinal products.
If the information required in the case of essentially similar products (generics) does not permit the 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 Schedule, which refers to an original
medicinal product having been granted a marketing authorisation in the Community, is submitted for a marketing authorisation
by an independent applicant after the expiry of data protection period, the following approach shall be applied.
— Information to be supplied shall not be limited to Modules 1, 2 and 3 (pharmaceutical, chemical and
biological data), supplemented with bio-equivalence and bio-availability data. The type and amount of additional data
(i.e. toxicological and other non-clinical and appropriate clinical data) shall be determined on a case by case basis in
accordance with relevant scientific guidelines.
B
— 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 authorised medicinal product has more than one
indication, the efficacy and safety of the medicinal product claimed to be similar has to be justified or, if necessary,
demonstrated separately for each of the claimed indications.
5. FIXED COMBINATION MEDICINAL PRODUCTS
Applications based upon Article 10 (1) (b) shall relate to new medicinal products made of at least two active substances
not previously authorised as a fixed combination medicinal product.
For those applications a full dossier (Modules 1 to 5) shall be provided for the fixed combination medicinal product.
Where applicable, information regarding the manufacturing sites and the adventitious agents, safety evaluation shall be
provided.
5. DOCUMENTATION FOR APPLICATIONS IN EXCEPTIONAL CIRCUMSTANCES
When, as provided for in Article 22, the applicant can show that he is unable to provide comprehensive data on the
efficacy and safety under normal conditions of use, because
— the indications for which the product in question is intended are encountered so rarely that the applicant
cannot reasonably be expected to provide comprehensive evidence, or
— in the present state of scientific knowledge, comprehensive 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 within a time period specified by the
competent authority, the results of which shall form the basis of a reassessment of the benefit/
risk profile,
— the medicinal product in question may be supplied on medical prescription only and may in certain cases be
administered only under strict medical supervision, possibly in a hospital and in the case of a radio-pharmaceutical, by
an authorised person,
— the package leaflet and any medical information shall draw the attention of the medical practitioner to the
fact that the particulars available concerning the medicinal product in question are as yet inadequate in certain specified
respects.
7. MIXED MARKETING AUTHORISATION APPLICATIONS
Mixed marketing-authorisation applications shall mean marketing-authorisation application dossiers where Module 4
and/or 5 consists of a combination of reports of limited non-clinical and/or clinical studies carried out by the applicant and of
bibliographical references. All other Module(s) are in accordance with the structure described in Part I of this Schedule. The
competent authority shall accept the proposed format presented by the applicant on a case by case basis.
B
PART III
PARTICULAR MEDICINAL PRODUCTS
This Part lays down specific requirements related to the nature of identified medicinal products.
1. BIOLOGICAL MEDICINAL PRODUCTS
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)
Principles
For the purposes of this Schedule
— Plasma Master File shall mean a stand-alone documentation, which is separate from the dossier for
marketing authorisation which provides all relevant detailed information on the characteristics of the entire human
plasma used as a starting material and/or a raw material for the manufacture of sub/intermediate fractions, 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 Parliament and of the Council of 16 November 2000 amending Council
Directive 93/42/EC as regards medical devices incorporating stable derivatives of human blood or human plasma (1).
— Every centre or establishment for fractionation/processing of human plasma shall prepare and keep updated
the set of detailed relevant information referred to in the Plasma Master File.
— The Plasma Master File shall be submitted to the Agency or to the competent authority by the applicant for
a marketing authorisation or the holder of the marketing authorisation. Where the applicant for a marketing
authorisation or the marketing authorisation holder differs from the holder of the Plasma Master File, the Plasma
Master File shall be made available to the applicant or marketing authorisation holder for submission to the competent
authority. In any case, the applicant or marketing authorisation holder shall take responsibility for the medicinal
product.
— The competent authority that is evaluating the marketing 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 material.
b)
Content
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 taken by each donation to be traced from the blood/ plasma
collection establishment through to finished products and vice versa.
B
(2)
Plasma quality and safety
(i) compliance with European PharmacopoeiaMonographs.
(ii) testing of blood/plasma donations and pools for infectious agents, including information on test methods
and, in the case of plasma pools, validation data on the tests used.
(iii) technical characteristics of bags for blood and plasma 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 Plasma Master File shall provide a list of the medicinal products for which the Plasma Master File is
valid, whether the medicinal products have been granted a marketing authorisation or are in the process of being granted such an
authorisation, including medicinal products referred to in Article 2 of Directive 2001/20/EC of the European Parliament and of
the Council relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for
human use.
c)
Evaluation and Certification
— For medicinal products not yet authorised, the marketing 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 must follow evaluation procedure
laid down by Commission Regulation (EC) No 542/95 (1) 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 (2). Conditions for the assessment of these
changes are laid down by Regulation (EC) No 1085/2003.
— As a second step to the provisions in the first, second, third and fourth indents, the competent authority that
will grant or has granted the marketing authorisation shall take into account the certification, re-certification or
variation of the Plasma Master File on the concerned medicinal product(s).
— By derogation from the provisions of the second indent of the present point (evaluation and certification),
where a Plasma Master File corresponds only to blood/plasma-derived medicinal products the marketing authorisation
of which is restricted to a single Member State, the scientific and technical evaluation of the said Plasma Master File
shall be carried out by the national 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)
Principles
B
For the purposes of this Schedule
— Vaccine Antigen Master File shall mean a stand-alone part of the marketing authorisation application
dossier for a vaccine, which contains all relevant information of biological, pharmaceutical and chemical nature
concerning each of the active substances, which are part of this medicinal product. The stand-alone part may be
common to one or more monovalent and/or combined vaccines presented by the same applicant or marketing
authorisation holder.
— A vaccine may contain one or several distinct vaccine antigens. There are as many active substance(s) as
vaccine antigen(s) present in a vaccine.
— A combined vaccine contains at least two distinct vaccine antigens aimed at preventing a single or several
infectious diseases.
— A monovalent vaccine is a vaccine, which contains one vaccine antigen aimed at preventing a single
infectious disease.
b)
Content
The Vaccine Antigen Master File shall contain the following information extracted from the relevant part (Active
substance) of Module 3 on ‘Quality Data’ as delineated in Part I of this Schedule
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 substance
5. Reference standard and materials
6. Container and closure system of the active substance
7. Stability of the active substance.
c)
Evaluation and Certification
— For novel vaccines, which contain a novel vaccine antigen, the applicant shall submit to a competent
authority a full marketing-authorisation application dossier including all the Vaccine Antigen Master Files
corresponding to each single vaccine antigen that is part of the novel vaccine where no master file already exists for the
single vaccine antigen.A scientific and technical evaluation of each Vaccine Antigen Master File shall be carried out by
the Agency. A positive evaluation shall result in a certificate of compliance to the European legislation for each
Vaccine Antigen Master File, which shall be accompanied by the evaluation report. The certificate shall apply
throughout the Community.
— The provisions of the first indent shall also apply to every vaccine, which consists of a novel combination
of vaccine antigens, irrespective of whether or not one or more of these vaccine antigens are part of vaccines already
authorised in the Community.
B
— 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 authorisation.
— 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 Vaccine Antigen Master File on the concerned medicinal product(s).
2. RADIO-PHARMACEUTICALS AND PRECURSORS
Radio-pharmaceuticals
For the purposes of this chapter, applications based upon Articles 6 (2) and 9 shall provide a full dossier in which the
following specific details shall be included
Module 3
a)
In the context of a radio-pharmaceutical kit, which is to be radio-labelled after supply by the manufacturer, the
active substance is considered to be that part of the formulation which is intended to carry or bind the radio-nuclide. The
description of the manufacturing method of radiopharmaceutical kits shall include details of the manufacture of the kit and
details of its recommended final processing to produce the radioactive medicinal product. The necessary specifications of the
radio-nuclide shall be described in accordance, where relevant, with the general monograph or specific monographs of the
European Pharmacopoeia . In addition, any compounds 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/radiochemical purity and its relationship to bio-distribution shall be provided.
e)
Radio-nuclide purity, radiochemical purity and specific activity shall be described.
f)
For generators, details on the testing for mother and daughter radio-nuclides are required. For generator-
eluates, tests for mother radio-nuclides and for other constituents of the generator system shall be provided.
g)
The requirement to express the content of active substances in terms of the mass of active entities shall
onlyapply to radio-pharmaceutical kits. For radio-nuclides, radioactivity shall be expressed in Becquerels at a given date and, if
necessary, time with reference to time zone. The type of radiation shall be indicated.
B
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 radiolabelled compound shall be included. Any
material essential for radio-labelling shall be identified and assayed.
i)
Information on stability shall be given for radio-nuclide generators, radio-nuclide kits and radiolabelled
products. The stability during use of radio-pharmaceuticals in multi-dose vials shall be documented.
Module 4
It is appreciated that toxicity may be associated with a radiation dose. In diagnosis, this is a consequence of the use of
radio-pharmaceuticals; in therapy, it is the property desired. The evaluation of safety and efficacy of radio-pharmaceuticals
shall, therefore, address requirements 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 route 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 environment.
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 defined above (indents
a) to i)), where applicable.
Module 4
Concerning single dose and repeat dose toxicity, the results of studies carried out in conformity with the provisions
related to good laboratory practice laid down in Council Directives 87/18/EEC and 88/320/EEC shall be provided, unless
otherwise justified.
Mutagenicity studies on the radio-nuclide are not considered to be useful in this particular case.
Information relating to the chemical toxicity and disposition of the relevant ‘cold’ nuclide shall be presented.
Module 5
Clinical information generated from clinical studies using on the precursor itself is not considered to be relevant in the
specific case of a radio-pharmaceutical precursor intended solely for radio-labelling purposes.
However, information demonstrating the clinical utility of the radio-pharmaceutical precursor when attached to relevant
carrier molecules shall be presented.
3. HOMEOPATHIC MEDICINAL PRODUCTS
B
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 authorisation of other
homeopathic medicinal products referred to in Article 16(1) with the following modifications.
a)
Terminology
The Latin name of the homeopathic stock described in the marketing authorisation application dossier must be in
accordance with the Latin title of the European Pharmacopoeia or, in absence thereof, by an official pharmacopoeia of a
Member State. Where relevant the traditional name(s) used in each Member State shall be provided.
b)
Control of starting materials
The particulars and documents on the starting materials, i.e. all of the materials used including raw materials and
intermediates up to the final dilution to be incorporated into the finished medicinal product, accompanying the application shall
be supplemented by additional data on the homeopathic stock.
The general quality requirements shall apply to all of the starting and raw materials as well as intermediate
steps of the manufacturing process up to the final dilution to be incorporated into the finished medicinal product. If
possible, an assay is required if toxic 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 the final dilution to be incorporated into the finished medicinal product must be fully described.
In case dilutions are involved, these dilution steps should be done in accordance with the Homeopathic
manufacturing methods laid down in the relevant monograph of the European Pharmacopoeia or, in absence thereof, by
an official pharmacopoeia of a Member State.
c)
Control tests on the finished medicinal 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 constituents is not possible e.g. due to their
dilution in the finished medicinal product the quality shall be demonstrated by complete validation of the
manufacturing and dilution process.
Stability tests
The stability of the finished medicinal product must 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 pharmaceutical 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.
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
B
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)
Herbal substances and herbal preparations
For the purposes of this Schedule 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 nomencRlature 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 Pharmacopoeias) 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 definition of the herbal preparation, the ratio
of the herbal substance to the herbal preparation, the extraction solvent(s), the other names (synonyms mentioned in other
Pharmacopoeias) and the laboratory code shall be provided.
To document the section of the structure for herbal substance(s) and herbal preparation(s) where applicable, the
physical form, the description of the constituents with known therapeutic activity or markers (molecular formula, relative
molecular mass, structural formula, including relative and absolute stereo-chemistry, the molecular formula, and the relative
molecular mass) as well as other constituent(s) shall be provided.
To document the section on the manufacturer of the herbal substance, the name, address, and responsibility of each
supplier, including contractors, and each proposed site or facility involved in production/collection and testing of the herbal
substance shall be provided, where appropriate.
To document the section on the manufacturer of the herbal preparation, the name, address, and responsibility of each
manufacturer, including contractors, and each proposed manufacturing site or facility involved in manufacturing and testing of
the herbal preparation shall be provided, where appropriate.
With respect to the description of manufacturing process and process controls for the herbal substance, information
shall be provided to adequately describe the plant production and plant collection, 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 characteristics of the herbal substance, information on the
botanical, macroscopical, microscopical, phyto-chemical characterisation, and biological activity if necessary, shall be provided.
With respect to the elucidation of the structure and other characteristics of the herbal preparation, information on the
phyto- and 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.
B
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 reference standards or reference materials used for testing of the herbal substance(s) and herbal
preparation(s) where applicable shall be provided.
Where the herbal substance or the herbal preparation is the subject of a monograph, the applicant can apply for a
certificate of suitability that was granted by the European Directorate for the Quality of Medicines.
(2)
Herbal Medicinal Products
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 Schedule (well-established medicinal use), the systematic and documented use of the concerned
substance can refer —as way of derogation —to the use of that substance in accordance with the provisions of Article 5 of this
Directive.
B
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 Schedule.
The technical requirements for Modules 3, 4 and 5 for biological medicinal products, as described in Part I of this
Schedule, 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 medicinal 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 referred 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 viruses 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 data or experience with other, related advanced therapy medicinal products
may also be considered in the risk analysis.
Any deviation from the requirements of this Schedule shall be scientifically justified in Module 2 of the application
dossier. The risk analysis described 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 Schedule
resulting from the risk analysis shall be described.
2. DEFINITIONS
For the purposes of this Schedule, in addition to the definitions laid down in Regulation (EC) No 1394/2007, the
definitions set out in sections 2.1 and 2.2 shall apply.
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.
Somatic cell therapy medicinal product
B
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 functions 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.
For the purposes of point (a), the manipulations listed in Annex 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, can 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 with, the requirements established in
Directive 2004/23/EC of the European Parliament and of the Council, 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
combined 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 modified 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
medical device.
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.
B
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.
Specific requirements
In addition to the requirements set out in sections 3.2.1 and 3.2.2 of Part I of this Schedule, the following requirements
(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 culture 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 virulence, 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 throughout the shelf life of
the product;
(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.
Specific requirements for somatic cell therapy medicinal products and tissue engineered products
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 active 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.
Specific requirements
In addition to the requirements set out in sections 3.2.1 and 3.2.2 of Part I of this Schedule, the following requirements
3.3.2.1. Starting materials
B
(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.
(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 infections in the
source/donor animals, testing of the animals for infectious agents, including vertically transmitted
microorganisms 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, tumourigenicity and suitability for the intended medicinal use. The genetic stability of the cells
shall be demonstrated.
(b) Qualitative and, 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 justified.
(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.
B
(d) Where biologically active molecules (such as growth factors, cytokines) 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 state, 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 physicochemical 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 Schedule, shall apply, unless 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.
Specific requirements for advanced therapy medicinal products containing devices
Advanced therapy medicinal product containing devices as referred to in Article 7 of Regulation (EC) No 1394/2007
A description of the physical characteristics and performance of the product 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.
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 of 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 finished
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 medicinal
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, or of conformity of the active implantable device part with the essential
requirements laid down in Annex 1 to Council Directive 90/385/EEC;
B
(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;
(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 documents
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
Specific requirements for all advanced therapy medicinal products
The requirements of Part I, Module 4 of this Schedule 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
Schedule apply to advanced therapy medicinal products. Where appropriate and taking into account the specificities of advanced
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 immunogenicity 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 products, 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.
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.
Pharmacology
(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 reaches 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 provided.
(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 provided.
Pharmacokinetics
(a) Biodistribution studies shall include investigations on persistence, clearance and mobilisation.
Biodistribution studies shall additionally address the risk of germline transmission.
B
(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.
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 not 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 when 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, repeated 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.
(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 the 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 product
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 not
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.
Specific requirements for somatic cell therapy medicinal products and tissue engineered products
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 frequency 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
B
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.
Pharmacokinetics
(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 duly 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 consideration.
(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 justification 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
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
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 shall be provided.
Where medical devices used during the surgical procedures for application, implantation or administration of the
advanced therapy medicinal product may 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, implantation or administration
procedures of these products shall be provided.
Given that, due to the nature of advanced therapy medicinal products, their manufacturing process may change during
clinical development, additional studies to demonstrate 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.
B
Dose selection and schedule 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 conditions, evidence of long-term efficacy may be required. The
strategy to evaluate long-term efficacy shall be provided.
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.
Specific requirements for gene therapy medicinal products
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).
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.
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.
Specific requirements for somatic cell therapy medicinal products
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.
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 addressed during the clinical development.
B
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.
Specific requirements for tissue engineered products
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.
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.
Safety studies
Section 5.3.3 shall apply.”.
B
€5.31