1. Regulation of vaccines CEMDC-PharmaTrain Module 7.
Zsuzsanna TÓTH
11 February, 2017

2. Sanofi Pasteur Heritage - Four Paths, One Destiny
One goal – protecting people from infectious diseases
Institute Pasteur, France => Pasteur Serums & Vaccines .
Institute Mérieux, France
Connaught Laboratories, Toronto, Canada
Pocono Biological Laboratories, Swiftwater, Pennsylvania
Today
Part of Sanofi
Headquarters in Lyon with 15 production and R&D sites
More than 1 billion doses of vaccines produced yearly to immunize more than 500 million people in the world
Largest product range available, against 20 infectious diseases
More than €1.5 billion euros invested in the last 5 years.
Our credo: we believe in a world in which no one suffers or dies from a vaccine-preventable disease.
Regulation of vaccines

3. Legal framework governing medicinal products for human use in the EU
EUROPEAN COMMISSION/COUNCIL/
PARLIAMENT
Regulations, directives, resolutions
MEMBER STATES
National law
THE EUROPEAN PHARMACOPOEIA COMMISSION
monographs, general chapters and other texts of European Pharmacopoeia
Court of Justice of European Union
decisions
EU COMMISSION,
EUROPEAN MEDICINES AGENCY,
INTERNATIONAL COUNCIL FOR HARMONIZATION (ICH)
Scientific guidelines
European Centre for Disease Prevention and Control

4. European medicines regulatory network
European Medicines Agency
BENEFITS?
Scientific Committees
EMA Secreteriat
Working Parties
CHMP
National Competent Authorities
Hungary
National Institute of Pharmacy and Nutrition
National Centre of Epidemiology

5. Lifecycle of a vaccine (post-approval)
Variations
Registration
Cessation/
Withdrawal
Renewal
Regulation of vaccines

6. Registration
Regulation of vaccines

7. Marketing authorization of medicinal products Registration
A medicinal product may only be placed on the market in the European Economic Area when
a marketing authorisation has been issued by the competent authority of a Member State for its own territory (national authorization) or
when an authorisation has been granted in accordance with Regulation (EC) No 726/2004 for the entire Union (an Union authorization).
Authorities/Agencies evaluates if the tests and studies performed with the candidate medicinal product is in compliance with official and scientific regulations in terms of:
Quality
Safety
Risk/benefit ratio
Effectiveness
Efficacy
Regulation of vaccines

8. Types of applications (legal basis)
Depends on the particulars and documents which must be accompanied of the application for marketing authorisation (how efficacy and safety proven)
full application - Article 8(3) of Directive 2001/83/EC
pharmaceutical (physico-chemical, biological or microbiological) tests,
preclinical (toxicological and pharmacological) tests,
clinical trials
relevant published literature
generic, hybrid or similar biological applications - Article 10
reference can be made to the dossier of a reference medicinal product for which a marketing authorisation has been granted in the Union
well-established use application - Article 10a
supported by bibliographic literature
fixed combination application - Article 10b
informed consent application- Article 10c
Regulation of vaccines

9. EU Authorization/registration procedures
Centralized Procedure (CP)
application is assesses by European Medicines Agency, the authorization is issued by the European Commission
valid for the entire EU market
Products of major publich health interest (therapeutic innovations), biosimilars,
National procedure
strictly limited to medicinal products which are not to be authorized in more than one Member State
Mutual Recognition procedure (MRP)
the new product has been authorized at least in one European country in the time of submission of the application
Decentralized procedure (DCP)
 the new product has not been authorized in any European coutries in the time of the submission of the application
Cyprus close (Article 126a of Directive 2001/83/EC)
justified public health reason
- in the absence of a marketing authorisation or of a pending application for authorisation for a medicinal product, which has already been authorised in another Member State, a Member State may for justified public health reasons authorise the placing on the market of that medicinal product
Regulation of vaccines

10. Comparison of procedures
Concerned member states
ALL
SELECTED
ONE
Type of procedure
Centralized Procedure
National Procedure
MRP
DCP
Timelines
210 days + clock stop
National phase: 210 d
AR: 90 d MRP: 90 d
1st evaluation phase: 120 d Clock stop 90 d 2nd evaluation phase: 90 days
210 days
Type of Marketing Authorization
Centralized MA
National MA
Regulation of vaccines

11. Fees in HU Centralized Procedure National Procedure MRP/DCP (RMS)
MRP/DCP (CMS)
MA application
From €278800
€4500
€10100
€7200
Renewal
€2,100
€5100
€3600
Annual Fee
€100000
€870
Type II variation
€83700
€1100
€1500
Regulation of vaccines

12. Common Technical Documentation
Beadvány
Regulation of vaccines

13. Plasma Master File (PMF) Vaccine Antigen Master File (VAMF) certification system
Optional certification procedure
Centralised assessment of the PMF/VAMF application dossier submitted by the applicant or marketing authorisation holder => certificate of compliance to Union legislation, issued by the EMA, valid in European Union.
The VAMF is a stand-alone part of the marketing authorisation application dossier for a vaccine. One given VAMF contains all relevant information of biological, pharmaceutical and chemical nature for one given vaccine antigen, which is common to several vaccines from the same applicant or marketing authorisation holder.
The PMF is a stand-alone documentation, which is separate from the dossier for marketing authorisation. It 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 incorporating stable derivatives of human blood or human plasma.
Regulation of vaccines

14. 1. Module 1: ADMINISTRATIVE INFORMATION
1.1 Table of contents.
1.2. Application form.
1.3. Summary of product characteristics, labelling and instructions for medical use:
Summary of product characteristics.
Labelling. – Braille excemption
Instructions for medical use.
Mock-ups and specimens.
Summary of product characteristics already approved in the manufacturer/applicant- country.
1.4. Information about the independent experts:
1.5 Specific requirements for different types of applications.
1.8 Information relating to Pharmacovigilance – Risk Management Plan
1.10 Information relating to Paediatrics
Annex to Module 1. Environmental risk assessment
Module 1 should contain region‑specific administrative and product information.
Regulation of vaccines

15. Validity of MA Certificate
Marketing authorisation (MA) is valid for five years from the date of notification
Once renewed, the MA will be valid for an unlimited period
Conditional MAs granted under Article 14(7) of Regulation (EC) No 726/2004
the benefit-risk balance of the product is positive;
the benefit of immediate availability outweighs the risk of less comprehensive data than normally required
it is likely that the applicant will be able to provide comprehensive data;
unmet medical needs will be fulfilled;
For example
Avian influenza vaccine, March 2006 (prevention of an infectious disease)
Ebola vaccine (rare disease, not enough patient – probability of favourable risk/benefit ration is high – data will be/was provided later)
Valid for 1 year, can be extended for 1 more year
Regulation of vaccines

16. Content of Marketing Authorization certificate
Decision
Name, registration number (OGYI-T-XXXXX/YY),
pack sizes, MAH, batch release site,
Confidential part
Composition, shelf-life, information on storage, packaging,
manufacturing sites (DP, DS),
Summary of product charteristics
Patient information leaflet
Labelling
Drug database
available online:
Regulation of vaccines

17. Specific release procedures for vaccine batches
Vaccine batch manufactured
Batch release by manufacturer
Batch release by independent national laboratory (OCABR)
Issue European Batch Release Certificate
Delivery the vaccine batch to Hungary
Local release by National Institute of Pharmacy and Nutrition
Local release by National Centre for Epidemiology
Release by distributor
Market
Regulation of vaccines

18. VARIAtion
Regulation of vaccines

19. Variation
A variation is a change to the terms of a marketing authorisation.
Legal basis: COMMISSION REGULATION (EC) No 1234/2008 of 24 November concerning the examination of variations to the terms of marketing authorisations for medicinal products
 Type IA variations – minor variation
Where no immediate notification is needed;
where immediate notification is needed;
Type II variations
major variation that may have a significant impact on the quality, safety or efficacy of a medicinal product
Extension – certain changes that fundamentally alter the terms of MA
certain changes to the active substance; pl. different salts
changes to the strength, pharmaceutical form and route of administration; Adacel vial – prefilled syringe
Type IB variations;
Murphy's law - Anything that can go wrong, will go wrong.
Regulation of vaccines

20. Evaluation Type Duration of the validation period
Duration of the procedure (assessment)
Date of implementation IA –
30 days
date stated by the applicant
IA IN -
date of submission IB
7 days
31. day of the procedure II
14 days
60 days
90 days
with the date of issuing the decision
Regulation of vaccines

21. Grouping of variations
Group several Type IA and IAIN variations under a single notification to the same relevant authority
Several IA or -IAIN affecting one medicinal product
One IA or IAIN affecting several medicinal products from the same MAH
Several IA or IAIN affecting several medicinal products from the same MAH, provided that these variations are the same for all medicinal products and are submitted to the same relevant authority
Regulation of vaccines

22. Worksharing of variations
Aim: to avoid duplication of work in the evaluation of variations
Submit:
the same Type IB or Type II variation, or
the same group of variations affecting more than one marketing authorisation from the same MAH in one application.
possible to include a group of type IA and IAIN variations 
One authority is chosen amongst the competent authorities of the Member States and the Agency, will examine the variation on behalf of the other concerned authorities.
Product
Dultavax
Tetraxim
Pentaxim
Hexacima
Valences
DT-IPV
DTaP-IPV-HIB
HepB
Registr.
National
MRP CP
Submit the same Type IB or Type II variation, or the same group of variations affecting more than one marketing authorisation from the same MAH in one application.
it is possible to include a group of type-IA and -IAIN variations with a type-IB or a type-II variation, which is submitted for a worksharing procedure
Changes to multiple generic marketing authorisations (MAs) containing the same active substance.
Changes to the active-substance master file.
Update of the Certificate of European Pharmacopeia.
Revision of test method for the active substance.
Regulation of vaccines

23. National scope variations
Transfer of the marketing authorisation to a new holder („MAH transfer”)
Change in the legal status of the product
Combination of the registration numbers
Include/exclude pack sizes in the Hungarian Marketing Authorisation within the values approved in MRP/DCP
Evaluation: 21 days
Implementation: with the date of issuing the decision
Directive 2001/83 61(3) Notification
a change to an aspect of the Labelling and/or Package Leaflet (PIL) text not connected with the Summary of Product Characteristics (SmPC). E.g. local representative, abbreviation of batch number, combined packaging
Evaluation 90 days
Implementation: 91. day of the procedure
Regulation of vaccines

24. Annual update for human influenza vaccine strain(s)
As the influenza virus is constantly changing, WHO reviews the recommendation twice a year and recommends vaccine composition since
mid-February: for the following winter in the Northern hemisphere (November to April).
September: for the following winter in the Southern hemisphere (May to October)
Hány törzs van az influenza vakcinában?
Mennyit ajánl a WHO/EMA
How many stains are in the vaccine?
How many strains does the WHO/EMA recommend?
Summary of annual process of development, manufacturing and distribution of influenza vaccines in the northern hemisphere. 1
1.Hannoun C. Expert Rev Vaccines 2013; 12(9): 2.
Regulation of vaccines

25. Annual update of human influenza vaccine strain(s)
EU annual strain(s) and reassortant recommendations on the EMA website
Type II#B.I.a.5 variation in ‘two step’ approach
First step– Submission of the application
Administrative information (SmPC)
Chemical-pharmaceutical and biological information for chemical active substances and biological products
no need to provide non- clinical/clinical data
Second step– Submission of additional data (if requested)
Regulation of vaccines

26. END OF LIFECYCLE
Regulation of vaccines

27. Product is not available – potential reasons
Cessation of marketing or placing on the market
product, a pharmaceutical form or strength of a medicinal product in at least one Member State
Withdrawal - initiated by MA holder
Low sales
Production problems
Discovery of serious side effects
Apprearance of modern vaccines
Withdrawal initiated by HA – Sunset Close
If an authorised product is not placed on the national market within three years of its granting OR not marketed for three consecurive year, the Medical Products Agency will decide that the authorisation shall cease to be valid. 
Regulation of vaccines

28. Thank you for your attention
Regulation of vaccines