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Chapter 2
European Union & Australia

College of Pharmacy

 

The EU system for
marketing

authorization (MA)

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Introduction

• The European regulatory system aims to ensure providing
safe, efficient and good quality medicines to its citizens.
Providing patients with the necessary medicinal products
involves registering them in the different member states of
the European Union.

• The National Competent Authorities (NCAs) are dealing
with the authorisation of medicinal products through
national, decentralised and mutual recognition
procedures, with conduct of post-marketing activities,
clinical trials, providing national scientific advice and
conducting inspections for companies in their area of
responsibility.

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Introduction
• Even if the NCAs are trying to avoid duplication of assessment and

focus on sharing workload and scientific expertise, there are still
many national requirements that the applicants are to fulfil in order
to obtain the national registration of the product in all concerned
Member States. The aim of a harmonised single market, that is one
of the principles of EU foundation, is still not yet realised, due to the
additional local requirements for registering a product in the EU
Member States, different timelines for granting the approval, legal
status of medicines, other assessment disagreements.

• In case the Concerned Member States are not agreeing with the
assessment of the Reference Member States due to potential
serious risks to public health, the scientific coordination work is
done based on an Article 29(1) procedure by the coordination
group for mutual recognition and decentralised procedures, human
(CMDh) or veterinary (CMDv), respectively. As in this master thesis
only the requirements for the medicinal products for human use will
be considered, the reference will be made in the following to the
CMDh.

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Introduction
• The scope of the pharmaceutical companies is to timely

bring their medicinal products on the market, by obtaining
the marketing authorizations. Therefore, the preparation of
the dossier (clinical, non-clinical and chemical
manufacturing and control modules) for submission must
be planned well in advance. The requirements for
modules 2 to 5 are so far harmonised across EU Member
States. The differences appear usually in module 1, in the
specific Additional Data that are requested and in the
provision modality of these documents (only copies,
originally signed, notarized).

• Submission of the application is not limited to the dossier.
Samples and mock-ups of the medicinal product, payment
of fees and the different modalities of dossier submission,
electronic or paper submission, both and/or in parallel,
should be clarified and taken into consideration in order to
assure a smooth dossier submission.

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Introduction

❑ EU Pharma Legislation

Orphan
Pharmacovigilance Drugs

Notice Good
Clinical to Manufacturing
Trials Directive Applicants Regulation (EC) Practices

2001/83/EC No 726/2004
Community EMA –

Code Centralised
Herbal MRP – DCP Procedure Falsified

Generics
Medicinal Medicinal

Biosimilars
Products Products

Advanced Paediatrics
Therapies

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The EU system for Marketing
Authorization

❑ Key Milestones

1965 First EU legislation on medicinal products.
➢ To prevent a recurrence of the thalidomide disaster

➢ To safeguard public health by not allowing medicinal products
ever again to be marketed without prior authorisation

➢Authorization only granted after demonstration of the:
safety,
efficacy and quality of the product

Establishment of:
1995

➢The EU centralized authorization system for
medicinal
products

➢The European Medicines Agency (EMA)
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The EU system for Marketing Authorization

❑ Key Actors

LEGISLATION

Proposal: Adoption:

+

European European European Parliament
Commission Council

Implementing Acts: Interpretation:

+

European Committee of EU MSs European Court of
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Commission Justice

 

The EU system for Marketing
Authorization

❑ Key Actors

AUTHORIZATIONS Centralised
Procedure

Application to: Decision
:

+

European Medicines European Committee of EU
Agency Commission MSs

EMA

Appeal:

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Justice

 

The EU system for Marketing
Authorization

❑Marketing Authorizations

A medicinal product may only be placed on the market in the European
Union when a marketing authorisation has been issued:
• by the competent authority of a Member State (National authorisations)

or
• by the Commission for the whole EU (Union authorisation).

Authorisations are granted on the basis of the
criteria of QUALITY, SAFETY and
EFFICACY

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The EU system for Marketing Authorization

❑ Application requirements

▪ Authorisation of medicines in the
EU reflects the internationally

Module 1 Admin &
agreed standards

Prescribing
Information

Non-
Clinical

Clinical ▪ EU–CTD (Common Technical
Overview

Overview Document) presentation is
Module 2

applicable irrespective of the type
Quality Non-

Clinical of procedure (centralised, mutual
overall Clinical

study recognition or national).
summary Overview

▪ Companies need to submit data of
Module 3 Module 4 Module 5

tests and trials, demonstrating the
Non Clinical Clinical Study Efficacy, Safety and Quality of the

Quality
Study Reports Reports medicinal product.

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Organization and structure of EU

• European Union was founded between 1952 (the European
Coal and Steel Community) and 1956 (European Economic
Community) and includes currently 28 countries

• The European Economic Area, established 1 January 1998,
comprises besides the countries of the European Union also
Iceland, Lichtenstein and Norway. All these EEA Member States
are implementing the regulatory requirements valid in the
European Union.

• The basis for registration of the medicinal products in the
European countries was first laid down by the Directive
65/65/EEC, according to which medicinal products can be
nationally registered in one Member State. Starting with the
Regulation 75/319/EEC, the registration of medicinal products in
several EU countries is possible. The Mutual Recognition
procedure was first mentioned within the Directive 93/39/EEC

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EMA

• The European Medicines Agency (EMA) is a decentralised
agency o the European Union (EU).

• The Management Board is the European Medicines
Agency’s integral governance body.

• The Agency is responsible for the scientific evaluation,
supervision and safety monitoring of medicines developed
by pharmaceutical ompanies for use in the EU.

• EMA protects public and animal health in 28 EU Member
States, as well as the countries of the European Economic
Area, by ensuring that all medicines available on the EU
market are safe, effective and of high quality.

• EMA serves a market of over 500 million people living in
the EU.

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Mission of EMA

• The mission of the European Medicines
Agency (EMA) is to foster scientific
excellence in the evaluation and
supervision of medicines, for the benefit
of public and animal health in the
European Union (EU).

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EMA LOGO

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What EMA Regulate?

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What EMA Don’t Regulate?

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What EMA Don’t Regulate?

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How EMA Work?

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EDQM
• The EDQM (EUROPEAN DIRECTORATE FOR

QUALITY MEDICINES) is an organisation that
protects public health by enabling the development,
supporting the implementation and monitoring the
application of quality standards for medicines and
their safe use.

• The EDQM traces its origins and statutes to a
European treaty promoting the elaboration of a
common pharmacopoeia in Europe.

MISSION: to contribute to a basic human right; access
to good quality medicines and healthcare .

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EDQM – Milestones

• A Council of Europe Directorate

• 1964: Activities based on an International

• Convention of the Council of Europe to
promote free movement of medicines in Europe
(Partial Agreement)

• Mandatory status reinforced in 1975 in the EU
pharmaceutical legislation

• 994: EU signed the EP Convention

• 1994: creation of the European Network for

• Official Medicines Control Laboratories (OMCL)

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EDQM – Milestones

• 1994: creation of the procedure of
certification of suitability to the
monographs of the European
Pharmacopoeia

• 2007: transfer of activities on blood
transfusion and organ transplantation

• 2008: transfer of activities on counterfeits,
pharmaceuticals and pharmaceutical care

• 2009: transfer of activities on cosmetics
and primary packaging for foodstuff

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EDQM Activities

1. Establishment and provision of reference
standards and materials (chemical and
biological)

2. Pharmaceutical terminology

– Standard terms for

-Dosage forms

-Routes of administration

-Containers

– ISO
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EDQM Activities

3. Certification of Suitability

• European pharmaceutical legislation requires the
applicant to demonstrate the suitability of the
pharmacopoeial monograph to control the quality of
active substances used

• EDQM’s certification scheme as the “preferred way”
for existing substances

• Recognised throughout Europe and in many other
countries (e.g. Canada)

• Includes GMP inspections for API (in line with the
EMEA “trigger document”)

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EDQM Activities

4. The OMCL Network

• General coordination of activities

– Fostering of mutual confidence & recognition

– Implementation of quality assurance system

– Audits of OMCLs by peers (EDQM and
Network members)

– Proficiency testing studies (PTS)

– Training courses (Procedures, QA and
techniques in OMCLs)

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EDQM Activities

5. Blood Transfusion

• Program based on three general
principles:

– Non-commercialisation of substances of
human origin

– Volontary and non-remunerated
donation

– Protection of health of donors and
receivers of blood transfusions

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EDQM Activities

6. Organ Transplantation

• General principles of the work program:

– To garantuee the dignity of the human
being,

– To ensure adherence to human rights and
fundamental freedom,

– To ensure the non-commercialisation of
substances of human origin

– To protect donors and receivers.
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EDQM Activities

7. Medicinal Products and Counterfeits

• Multisectoral program on the protection of public
health, risk management and risk prevention and
improvement of international cooperationbased : –

– Elaboration of model procedures for risk
management in the public and private sector,

– Establishment of an internationl network of Single
Points of Contact (SPOC)

– Training programs and conferences – Databases –
“Track-and-trace” pilot

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EDQM Activities

8. Legal Classification of Medicines

• The work program forsees harmonisation of the legal
classification of medicines with regards to their
prescription status, which has an important impact on
the safety of patients, access to medicines and the
responsible management of health expenditures.

• A specific data base for this activity, MELCLASS, is
publicly available and is linked to a network of other
international data bases on this subject.

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Marketing Authorization procedures in EU

❑ Procedures for granting a marketing Authorization

• The three described procedures are published by the
European Commission in consultation with the
competent authorities of the Member States, the
European Medicines Agency (EMEA), and interested
parties.

Mutual Decentralised Centralis
Recognition Procedure ed
Procedure (DCP) Procedur

(MRP) e (CP)

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Marketing Authorization procedures in
EU

❑ The procedural set-up

Approval in one Member State ➢ National Authorisation

➢Mutual Recognition Procedure
(MRP)

➢Decentralised Procedure (DCP)

➢Centralised Procedure (CP)

ROUTE? CHOICE?

Depends on:

• Type of product

• Authorisation history in EU

• Regulatory & marketing strategy

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Marketing Authorization procedures in
EU

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Marketing Authorization procedures in
EU

National procedures

• The majority of medicines available in the EU are
authorised at national level:

– Authorised before EMA creation

– Not in the scope of the centralize procedure

• Each EU Member State has its own national
authorization procedures

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Marketing Authorization procedures in
EU

1. The Centralised Procedure
• The Centralised Procedure (CP), having the legal basis in

the Regulation (EEC) No 2309/93 and subsequently
Regulation EC No 726/2004 is mandatory for biologicals,
orphans, medicinal products containing a new substance
not registered in the Community before 20 May 2004 and
other products as listed in the Article 3 and the Annexes
of this Regulation. The registration of a medicinal product
through the CP results in a single marketing authorization
that is valid in all EU MS.

• In the Centralized Procedure, the applicant applies to the
EMEA for marketing authorization and finally receives
one European approval, which is valid in all 28 countries
in the community, as well as Norway, Iceland and
Liechtenstein. At least seven months before submission,
the applicant should notify the EMEA of their intention to
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Marketing Authorization procedures in
EU

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Marketing Authorization procedures in
EU

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Marketing Authorization procedures in
EU

1. The Centralised Procedure

• Applicants have the opportunity to meet the EMEA in a pre-
submission meeting, to discuss any procedural or regulatory
issues. The applicant’s request for eligibility for evaluation via
the Centralized Procedure, together with a justification and other
documents is presented to all CHMP members. Following
discussion at CHMP, the EMEA informs the applicant of the
CHMP position, whether the medicinal product is eligible for
evaluation via the Centralized Procedure.

• For any scientific evaluation, a Rapporteur, and if relevant, a Co-
Rapporteur, is appointed from amongst the members of the
CHMP. The role of the Rapporteur is to perform the scientific
evaluation and to prepare an Assessment Report for the CHMP
according to the timetable approved for the evaluation
procedure. Where appropriate, the Rapporteur can be
supported by a Co-Rapporteur who prepares a separate full
Assessment Report or a critique of the Rapporteur’s report at
the discretion of the CHMP.

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Marketing Authorization procedures in
EU

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Marketing Authorization procedures in
EU

1. The Centralised Procedure Steps

• Once the application is validated as complete and the
Rapporteur and Co-Rapporteur have confirmed that they have
received the dossier, the EMEA starts the procedure at the
monthly starting date published on the EMEA website. The
Rapporteur/Co-Rapporteur’s initial Assessment Reports are
provided to the CHMP members and EMEA on Day 80.

• The CHMP members are assigned to conduct a peer review of
the Rapporteur/Co-Rapporteur’s scientific evaluation, as well as
the validity of the scientific/regulatory conclusions reached. The
adoption of the CHMP List of Questions, as well as the overall
conclusions and review of the scientific data, is sent on Day 120
to the applicant. The EMEA stops the clock in order to allow the
applicant time to prepare a response document. After receipt of
the responses from the applicant, the CHMP adopts a timetable
for the evaluation of the responses. The EMEA ensures that the
opinion of the CHMP is given in 90 additional days

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Marketing Authorization procedures in
EU

1. The Centralised Procedure Steps

• After the adoption of a CHMP positive opinion, the
applicant provides the EMEA with final translations of
the necessary documents in all EU languages
including Norwegian. Finally, within 30 days the
EMEA transmits the CHMP opinion and other
required documents to the European Commission,
and the Members of the Standing Committee, and to
Norway and Iceland. The marketing authorization is
granted by the European Commission and is valid
throughout the Community and confers the same
rights and obligations in each of the Member States
as a marketing authorization granted nationally. The
European Public Assessment Report (EPAR) will be
published on the EMEA website, once the
Commission decision has been issued.

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Marketing Authorization procedures in
EU

The
Centralised
Procedure

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Marketing Authorization procedures in
EU

❑ Centralised Procedure (CP)

Mandatory Optional

Biotech, AIDS, Diabetes, Cancer, Significant therapeutic, scientific
Orphan, Neurodegenerative or technical innovation

Application dossier sent to EMA

EMA validation (14 days) Checks application meets
criteria

CHMP starts evaluation (Day 0) Clock starts – Reviews by
rapporteur and corapporteur

List of questions sent to applicant (Day 120) Review clock stops
(up to 3 months)

Potential for
further questions Responses submitted by applicant (Day 121) Review clock restarts
and clock stops
for responses or CHMP Opinion (Day 210) Review ends
oral explanation

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Marketing Authorization procedures in
EU

❑ Centralised Procedure (CP)

CHMP Opinion (Day 210)

CompanyAppeal Within 30 days, EMA transmit:
▪Opinion

3-4 ▪ Assessment report
months ▪ Summary of Product Characteristics

▪Labelling and Package
Second Opinion to:

▪ European Commission
▪ Member States
▪ Applicant

Draft Commission Decision

Standing Committee (Member States)

Refusal Commission Decision Approval

Pubwlwicwa.tDiuolnoM inix .tchome Official Journal of the EU European Public Assessment Report (EPA4R3)

 

Marketing Authorization procedures in
EU

2. Mutual Recognition Procedure (MRP)
• The MRP has been in place in the EU since 1995.

The objective of this procedure is to obtain marketing
authorizations in one or several Member States,
when the medicinal product has already been
granted authorization by at least one country in the
European Community. In this case, the applicant
requests one or more CMS(s) to mutually recognize
the authorization granted by the RMS. If the
marketing authorization in the RMS is based on an
old dossier format, it is an obligation to reformat the
dossiers before starting the MRP.

• RMS= Reference Member State
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Marketing Authorization procedures in
EU

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Marketing Authorization procedures in
EU

❑Mutual Recognition Procedure

➢ Starts from an already existing national
marketing authorisation granted by one
Member State – the Reference Member State
(RMS)

➢One or more Member States – the Concerned
Member States (CMS) – are asked to
recognize the authorization granted by the

CMS
Reference Member State.

RMS
➢ In case of disagreement the matter is referred

CMS
to:

CMS
➢ – the CMDh (60 days), and, if needed, to
➢ – the CMPH (60 days).

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Marketing Authorization procedures in
EU

2. Mutual Recognition Procedure (MRP)

• An application for this procedure can be sent to
one or more Member States. The applications
sent should be similar and all Member States
must be informed of them. When a Member
State decides to assess the application (at this
point it becomes the “Reference Member State”
RMS), it announces the decision to other
Member States (which then become the
“Concerned Member States” CMS), to whom
applications have also been submitted by the
applicant. At this juncture the CMS will suspend
their evaluations on the particular application and
waits for the RMS’s decision on the application.

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Marketing Authorization procedures in
EU

❑Mutual Recognition Procedure (MRP)

Authorisation in one Member State, the Reference
Member State (RMS) (210 days)

Submission to chosen Concerned Member States
(CMS) for recognition of Authorisation

(90 days)

In case of disagreement
Authorisation in CMS

referral to CMD(h)/CHMP
(within 30 days)

(60 + 60 days)

CMD(h) : Coordination Group for Mutual Recognition
and Decentralised Procedures – Human ! Referral to

Serious risk to public
CMD(h)

health
CHMP : Commwitwtwe.eD uflooMr Mix.ceodmicinal Products for 48

Human Use (EMA)

 

Marketing Authorization procedures in
EU

CHART FOR THE
MUTUAL
RECOGNITION
PROCEDURE

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Marketing Authorization procedures in
EU

2. DECENTRALISED PROCEDURE:

• The new Decentralised procedure came into effect in the
European Union in 2005 and is regulated by Directive
2004/27/EC. The main purpose of this procedure is to acquire
marketing authorizations in several Member States, even
though there are no marketing authorization has been granted
in the European area.

• The objective of this procedure is to obtain marketing
authorizations in several Member States, when no marketing
authorization has been granted in the European Community.

• The applicant should send an application to the competent
authorities of each of the Member States, where there is intent
to obtain a marketing authorization. The applicant may
designate a country to act as the Reference Member State
(RMS). Selection of the RMS depends on many
considerations including workload, previous experience,

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interests, and acceptance of the dossier by the RMS.

 

Marketing Authorization procedures in
EU

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Marketing Authorization procedures in
EU

❑ Decentralised Procedure

➢No pre-existing marketing authorisation
granted by one Member State.

CMS

➢ Simultaneous application to a RMS and
several CMS.

RMS
CMS ➢ Assessment by RMS and reactions by the

CMS.

➢ In case of disagreement the matter is referred
to:

CMS
➢ – the CMDh (60 days), and, if needed, to
➢ – the CMPH (60 days).

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Marketing Authorization procedures in
EU

Steps involved in Decentralized procedure (DCP):

The applicant has to send an application to the respective
authorities of each and every member States, where there is plan
to attain a marketing authorization. Unlike MRP, here the applicant
may assign a country to act as the Reference Member State. This
selection can be based on many criteria like workload, previous
experience, interests of the applicant and acceptance of the
applied dossier by the RMS.

The RMS will commence the assessment after the application is
decided to be complete by both the RMS and all the CMS(s). The
RMS then forwards a preliminary Assessment Report on the
submitted dossier to the CMS(s) and the applicant in a period of 70
days. The CMS(s) is requested to give comments on the proposed
national prescription status and to inform the RMS.

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Marketing Authorization procedures in
EU

Steps involved in Decentralized procedure (DCP):

On day 105, the RMS will forward all observation and remarks
from the CMS(s) to the applicant and stops the clock if necessary,
until the applicant prepares a response document for the
comments sent. The RMS prepares a Draft Assessment Report on
day 120 and may close the procedure if a consensus has been
reached between the CMS(s) and the RMS. Otherwise the CMS(s)
has 90 more days to approve the Draft Assessment Report, and
other documents.

Authorities of the RMS and the CMS(s) agree to a decision within
30 days after acknowledgement of their agreement to the
Assessment Report and other documents. Upon the positive
agreement, a national marketing authorization will be issued in the
RMS and each of the CMS(s).

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Marketing Authorization procedures in
EU

❑ Decentralised Procedure (DCP)

• No MA existing in EEA
• Application to RMS & CMS
• Initial assessment by RMS and comments

by CMS (120 days)

Second phase of assessment and
position by Member States (90 days)

Authorisation in CMS In case of disagreement referral
(within 30 days) to CMD(h)/CHMP (60+ 60 days)

CMD(h) : Coordination Group for Mutual
Recognition and Decentralised

Serious risk to
Procedures – Human ! Referral

to
CHMP Committee for Medicinal public

CMD(h)
: Products for Human Use (EMA) health

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Marketing Authorization procedures in
EU

CHART FOR THE
Decentralized
procedure

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Active Substance Master Files
(ASMF) system in EU

1. Introduction (background)

The main objective of the Active Substance Master File
(ASMF) procedure, formerly known as the European
Drug Master File (EDMF) procedure, is to allow
valuable confidential intellectual property or ‘know-
how’ of the manufacturer of the active substance
(ASM) to be protected, while at the same time
allowing the Applicant or Marketing Authorisation (MA)
holder to take full responsibility for the medicinal
product and the quality and quality control of the
active substance. National Competent Authorities/EMA
thus have access to the complete information that is
necessary for an evaluation of the suitability of the use
of the active substance in the medicinal product.

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Active Substance Master Files
(ASMF) system in EU

2. Scope

• This Guideline is intended to assist Applicants/MA
holders in the compilation of the active substance
section of their dossiers for a Marketing Authorisation
Application (MAA) or a Marketing Authorisation Variation
(MAV) of a medicinal product. It is also intended to help
ASMF holders in the compilation of their ASMFs.

• 3. Legal basis

Annex I to Directive 2001/83/EC as amended Part I, 3.2
Basic principles and requirements, (8) Active Substance
Master File (for Human medicinal products) and Annex I
to Directive 2001/82/EC as amended, Part 2.C.1
General Requirements, 1.1. Active Substances (for
Veterinary medicinal products).

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Active Substance Master Files
(ASMF) system in EU

• 4. Content of the Active Substance Master File

• The overall content of the ASMF should contain detailed
scientific information as indicated under the various
headings of the relevant Notice to Applicants for
Marketing Authorisations for Medicinal Products in the
Member States of the European Union (NtA).

• ASMFs linked to human medicinal products should be
presented in the format of the Common Technical
Document (CTD.

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Active Substance Master Files
(ASMF) system in EU

• 4. Content of the Active Substance Master File

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Active Substance Master Files
(ASMF) system in EU

• 5. Use of the Active Substance Master File
Procedure

• An ASMF can only be submitted in support of an MAA or
MAV. The relationship between the quality of the active
substance and its use in the medicinal product needs to
be justified in this MAA.

• Although the ASMF procedure is developed to keep
intellectual property of the ASM confidential, it is also
permissible to use the procedure when there is no
confidentiality issue between the Applicant/MA holder
and the ASM (e.g. when the Applicant/MA holder
synthesises the active substance himself). It is expected
that the ASM is also the holder of the ASMF.

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Active Substance Master Files
(ASMF) system in EU

• 5. Use of the Active Substance Master File
Procedure

• The ASMF procedure can be used for the following
active substances, including herbal active
substances/preparations. i.e.:

• A. New active substances;

• B. Existing active substances not included in the
European Pharmacopoeia (Ph. Eur.) or the
pharmacopoeia of an EU Member State;

• C. Pharmacopeial active substances included in the Ph.
Eur. or in the pharmacopoeia of an EU Member State.

• The ASMF procedure cannot be used for biological active
substance.

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Active Substance Master Files
(ASMF) system in EU

• 5. Use of the Active Substance Master File
Procedure

• The ASMF holder may have an ASMF as well as a
Certificate of Suitability (CEP) issued by EDQM for a
single active substance. Generally, it is however not
acceptable that the Applicant/MA holder refers to an
ASMF as well as to a CEP for a single active substance
of a particular MAA/MAV. In cases where the CEP
contains too little information (e.g. stability) the
National Competent Authorities/EMA may decide that
additional information should be provided in the dossier.
In such case it may be acceptable to refer both to an
ASMF and a CEP.

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Active Substance Master Files
(ASMF) system in EU

6. Changes and updates to the Active Substance
Master File

• As for medicinal products, ASMF holders should keep
the content of their ASMFs updated with respect to the
actual synthesis/manufacturing process. The quality
control methods should be kept in line with the current
regulatory and scientific requirements.

• ASMF holders shall not modify the contents of their
ASMF (e.g. manufacturing process or specifications)
without informing each Applicant/MA holder and each
National Competent Authority/EMA. This obligation
remains valid until the Letter of Access has been
withdrawn by the ASMF holder.

• ASMF holders should provide the updated ASMF to all
interested parties with reference to the revised version
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Content and approval process of IMPD

What is IMPD?

• The Investigational Medicinal Product Dossier (IMPD) is
one of several pieces of Investigational Medicinal
Product (IMP) related data required whenever the
performance of a clinical trial is intended in one or more
European Union Member States. The IMPD includes
summaries of information related to the quality,
manufacture and control of any IMP, and data from non-
clinical and clinical studies.

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Content and approval process of IMPD

Guidance and Legal Basis

• Guidance concerning IMP Dossiers can be found in the
communication from the European Commission titled.

• The guidance is based on Regulation (EU) No 536/2014
on Clinical Trials on Medicinal Products for Human Use
(Repealing Directive 2001/20/EC) on the approximation
of 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.

• The Regulation comes into force in 2016, harmonising
the laws, regulations and administrative provisions of
the Member States relating to the implementation of
Good Clinical Practice (GCP) in the conduct of clinical
trials on medicinal products for human use

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Content and approval process of IMPD

Full and Simplified IMPDs

• When applying for a clinical trial authorisation, a full
IMPD is required when little or no information about an
IMP has been previously submitted to competent
authorities, when it is not possible to cross-refer to data
submitted by another sponsor and/or when there is no
MA in the Community.

• A simplified IMPD may be submitted if information has
been assessed previously as part of a Marketing
Authorisation in any MS or a clinical trial to that
competent authority.

• There are also situations where the Summary of product
characteristics (SmPC) of a Marketed Product will
suffice as the IMPD. A SmPC may be submitted if the
IMP has a Marketing Authorisation in any EU Member
State and is being used in the same form, for the same
indicwwaw.tDiuoloMnix.comand with a dosing regimen covered by t6h7 e
SmPC.

 

Content of IMPD

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Content of IMPD

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Content of IMPD

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Content of IMPD

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Content of IMPD

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Regulatory considerations for
manufacturing, packaging and
labeling of pharmaceuticals in

EU

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Regulatory considerations for manufacturing: EU

• All medicinal products for human use manufactured or imported into
the EU, including medicinal products intended for export, are to be
manufactured in accordance with the principles and guidelines of
Good Manufacturing Practice (GMP).

• GMP is that part of quality assurance which ensures that medicinal
products are consistently produced and controlled to the quality
standards appropriate to their intended use and as required by the
marketing authorisation (MA). GMP is concerned with both
production and quality control.

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Regulatory considerations for manufacturing:
EU

• Good Manufacturing Practice Inspections

• GMP inspections are conducted to assess compliance
with EU GMP Guidelines as specified in the provisions of
the Medicines Act, 2003 and relevant EU Directives.
These inspections also ensure that the conditions of the
manufacturing licence are being met. By ensuring that
EU GMP standards are met during the production of
medicinal products one is ensuring that medicines that
reach the patient are safe, of good quality and
efficacious. The inspection process is a vital safeguard
to public health.

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Regulatory considerations for manufacturing:
EU

There are various types of GMP inspections:

• New applications – These types of inspections are conducted
following an application for a manufacturing licence. A
manufacturing license can be recommended or rejected depending
on the outcome of the inspection.

• Renewals of manufacturing licenses – Manufacturing license sites are
periodically inspected to assess compliance with GMP.

• Follow up inspections – These inspections are conducted to follow up
a previous inspection.

• For cause inspections – These types of inspections may be warranted
in specific circumstances or following a complaint.

• Variation inspections – Variation inspections are conducted when an
application to vary the manufacturing license is received from the
license holder.

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Regulatory considerations for manufacturing:
EU

• Good Manufacturing Practice Guidelines

• EudraLex – Volume 4 Good manufacturing practice
(GMP) Guidelines

• S.L. 458.42 – Good Manufacturing Practice in Respect
of Medicinal and Investigational Medicinal Products for
Human Use Regulations.

• S.L. 458.36 – Manufacture and Importation of
Medicinal Products for Human Use (Amendment)
Regulations.

• S.L. 458.47 – Good Clinical Practice and Requirements
for Manufacturing or Import Authorisation of
Investigational Medicinal Products (Human Use)
Regulations.

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Regulatory considerations for Packaging: EU

• The Packaging (Essential Requirements)
Regulations 2015 (SI 2015/1640) (“the
Regulations”) consolidates and revokes all earlier
Regulations. 2. The Regulations implement those
provisions of the European Parliament and Council
Directive on Packaging and Packaging Waste
(94/62/EC) (“the Directive”) that relate to the
essential requirements for packaging.

• The Regulations also implement relevant
provisions of EU instruments amending the
Directive: Directives 2004/12/EC, 2013/2/EU and
(EU) 2015/720 and Commission Decisions
1999/177/EC, 2001/171/EC, 2006/340/EC and
2009/292/EC.

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Regulatory considerations for labeling : EU

• Display of information about a product on its
container , packaging, or the product itself.

• In Europe , Labeling of drug for human controlled
by CHMP under EMA.

• All the requirements and items are listed in Title V
of Directive 2001/83/EC.

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Regulatory considerations for labeling : EU

• RECOMMENDATIONS FOR THE LABELLING

• Labelling covers both outer packaging and inner packaging.

• Labelling ensures that the critical information is legible, easily

• accessible.

• The recommendations given in the package leaflet (section A) may
be applicable

• to labelling .

• The particulars appearing on the label of all medicinal products
should be

• printed in characters of at least 7 points, leaving a space between
lines of at least 3 mm.

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Regulatory considerations for labeling : EU
• Legal Framework

• According to Article 54, Article 55 and Article 59 of Directive 2001/83/EC of
the European Parliament, medicinal products for human use medicinal
products must be accompanied by outer and/or immediate packaging
information (labeling) and a package leaflet.

• Article 58 of Directive 2001/83/EC allows for the omission of a package
leaflet where all the required information can be directly conveyed on the
packaging.

• Article 56 of Directive 2001/83/EC requires that the particulars to be
included in the labeling shall be easily legible, clearly comprehensible and
indelible.

• According to Article 57 of Directive 2001/83/EC, additional labelling
requirements may apply in particular Member States in respect of price, legal
status for supply and identification and authenticity.

• Labelling must contain all elements required by Article 54 of Directive
2001/83/EC or a lesser set of elements where the provisions of Article 55 of
the same Directive apply.

• Neverwthwwe.lDeulsoMs,ix .ocofm the information items listed in Article 54 of Directive 81

2001/83/EC, certain items are deemed critical for the safe use of the medicine.

 

Regulatory considerations for labeling : EU

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Regulatory considerations for labeling : EU

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Regulatory considerations for labeling : EU

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Regulatory considerations for labeling : EU

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Regulatory considerations for labeling : EU

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Regulatory considerations for labeling : EU

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Regulatory considerations for labeling : EU

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Regulatory considerations for labeling : EU

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Regulatory considerations for labeling : EU

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Regulatory considerations for labeling : EU

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Regulatory considerations for labeling : EU

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Regulatory considerations for labeling : EU

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Regulatory considerations for labeling : EU

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Regulatory considerations for labeling : EU

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Regulatory considerations for labeling : EU

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Regulatory considerations for labeling : EU

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Regulatory considerations for labeling : EU

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Regulatory considerations for labeling : EU

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Regulatory considerations for labeling : EU

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Regulatory considerations for labeling : EU

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EudraLex
(The Rules Governing Medicinal Products in

the European Union)

• EudraLex is the collection of rules and regulations
governing medicinal products in the European Union.

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EudraLex
• EudraLex consists of 10 volumes:
Concerning Medicinal Products for Human use:

• Volume 1 – Pharmaceutical Legislation

• .Volume 2 – Notice to Applicants.

– Volume 2A deals with procedures for marketing authorisation.

-Volume 2B deals with the presentation and content of the application dossier.

-Volume 2C deals with Guidelines.

• Volume 3 –Guidelines

Concerning Medicinal Products for human use in clinical trials (investigational medicinal products)

• Volume 10 – Clinical trials.

Concerning Veterinary Medicinal Products:

• Volume 5 – Pharmaceutical Legislation.

• Volume 6 – Notice to Applicants.

• Volume 7 – Guidelines.

• Volume 8 – Maximum residue limits.

• Concerning Medicinal Products for Human and Veterinary use:

• Volume 4 – Good Manufacturing Practices.

• Volume 9 – Pharmacovigilance.

• Miscellaneous: Guidelines on Good Distribution Practice of Medicinal Products for Human Use (94/C 63/03)

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Eudralex (directives for human medicines)

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EudraLex

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Eudralex (directives for human medicines)

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EudraLex

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Eudralex (directives for human medicines)

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EudraLex

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Eudralex (directives for human medicines)

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Variations & extensions EU

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Variation

• What is a Variation….?

A variation to the terms of a marketing authorization is an amendment
to the contents of the documents of the approved dossier

• Variations in European Union (EU) are regulated by following
regulations and Guidelines:

• Commission Regulation (EC) No. 712/2012 of 3 August 2012
amending Regulation (EC) No. 1234/ 2008 concerning examination of
variations to the terms of marketing authorisations

• for medicinal products for human use and veterinary medicinal
products.

• Annex I – Extensions of marketing authorisations.

• Annex II –Classification of variations.

• Annex III – Cases for grouping variations.

• Annex IV – Elements to be submitted.

• Annex V –Variations concerning a change to or addition of therapeutic indication,
addition of

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non-food producing target species, replacement or addition of a stereotype, strain,
antigen etc.

 

Variation

• Guidelines of 16.05.2013 on the details of the various
categories of variations, on the operation of the
procedures laid down in Chapters II, IIa, III and IV of
Commission Regulation (EC) No 1234/2008 of 24
November 2008 concerning the examination of
variations to the terms of marketing authorisations for
medicinal products for human use and veterinary
medicinal products and on the documentation to be
submitted pursuant to those procedures.

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Variation

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Variation

• In general changes are categorized into three types:

Administrative
changes

CMC (Quality
changes)

Safety, PV,
Efficacy etc..

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TYPES OF VARIATIONS

• Variations are classified into following types –

Type IB
(Minor

Variation)

Type IA Type II
(Minor Variations (Major

Variation) Variation)

Extension
(new

application)

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Type IA variations

➢ Type lA variations: Type lA variations are the minor variations which
have only a minimal impact or no impact at all, on the quality, safety
or efficacy of the medicinal product, and do not require prior approval
before implementation (“Do and Tell” procedure).

Such a minor variations are “classified” two subcategories, which impact
on their submission:

• Type lA variations requiring immediate notification (‘IA IN‘)

• Type lA variations NOT requiring immediate notification (‘lA’)
(Variations which do not require immediate notification may be
submitted by the marketing authorisation holder (MAH) within 12
months after implementation).

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Type IA variations

➢ Why certain minor variations of Type IA require immediate
notification ?

Certain minor variations of Type IA require immediate notification after

implementation, in order to ensure the continuous supervision of

the medicinal product.

➢ When should I submit my Type IAINvariation?
This should be submitted immediately and generally within 2 weeks of
implementation of the change.

➢ What is meant by ‘implementation’ for Type IA variations?
For quality changes, implementation is when the company makes
the change in its own quality system.

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EXAMPLES OF TYPE IAVARIATIONS

Type IA Changes – Only a minimal impact or no impact at all, on
the quality, safety or efficacy of the medicinal product (“Do and
Tell” procedure ):

➢ Examples of Type IAIN variation:

▪ Change in the name and/or address of the marketing authorisation holder

▪ Change in the name and/or address of a manufacturer/importer of
the finished product (including batch release or quality control
testing sites)

▪ Changes in imprints, bossing or other markings

▪ Change in the shape or dimensions of the pharmaceutical form
perticularly Immediate release tablets,
capsules, suppositories and pessaries.

➢ Examples of Type IA variation:

▪ Addition of physico-chemical test in specification.

▪ Deletion of non-significant test (ex: Identification test in Stability study).

▪ Tightening of specification limits (ex: Tightening of test limit for water
content, Residual solvents and Related
substances..etc.

▪ CEP updates/renewal.

▪ API and FP Batch size increase/decrease within 10 fold.
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Type IB variations

• Commission Regulation (EC) No 1234/2008 (‘the Variations

Regulation’) defines a minor variation orType 1B as a variation which

is neither a Type lA variation nor Type II variation nor an Extension.

• Such minor variations must be notified to the National Competent

Authority/European MedicinesAgency by the Marketing

Authorisation Holder (MAH) before implementation.

• However, the MAH must wait a period of 30 days to ensure that the

notification is acceptable by the Agency before implementing the

changwwew .(DTuloeMlilx,.c oWm ait and Do procedure).
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EXAMPLES OF TYPE IB VARIATIONS

Type IB Changes – Min to moderate impact on
product quality (Tell, Wait and Do procedure):

➢Major change the approved Analytical method

➢ FP Mfg. site changes

➢Shelf-life extension

➢Change in storage condition

➢Minor changes to approved manufacturing process

➢Change in batch size beyond 10 fold category

➢SmPC /PIL changes in-line with innovator product

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Type II variations

• Commission Regulation (EC) No 1234/2008 (‘the Variations Regulation’)
defines a major variation of Type II as a variation which is not an
extension and which may have a significant impact on the Quality, Safety
or Efficacy of a medicinal product.

EXAMPLES OF TYPE II VARIATIONS
Type II Changes (Significant impact on product quality,
safety & efficacy):

➢ Addition of alternate/new API DMF supplier

➢ Relaxation of approved specification

➢ Major change in approved manufacturing process

➢ Major change in approved composition

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Extension Applications

• Definition for Extension of marketing authorisation:

Changes to a marketing authorisation listed in Annex I of Commission Regulation (EC)
No1234/2008 are regarded as “extensions” of the marketing authorisation.

Examples of extension changes:
1. Changes to the active substance(s)

– replacement of a chemical active substance by a different salt/ester

complex/derivative. with the same therapeutic moiety, where the efficacy/safety

characteristics are not significantly different;

2. Change to strength, pharmaceutical form, route of administration

• Change of bioavailability;

• Change of pharmacokinetics e.g. change in rate of release;

• Change or addition of a new strength/potency;

• Change or addition of a new pharmaceutical form;

• Change or addition of a new route of administration.

• Such applications will be evaluated in accordance with the same procedure as for the
granting of the initial

marketing authorisation to which
it relates.

• The extension can either be granted as a new marketing authorisation or will be
includwewdw i.nDu tlohMeixi.ncoitmial marketing authorisation to which it relates.

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CHANGE/VARIATION IMPLEMNTATION CRITERIA

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Grouping of variations

• It is possible to group variations of different categories the same
marketing authorisation (MA) and submit them in one
submission, under a single application form, to the same relevant
authority. This is permissible where variations are covered under
the cases listed in Annex Ill to the variations regulation.

• Examples are any group of lA changes, a group comprising a Type
IB or Type II change plus one or more of the same or lower
category which are consequential to the first, and a group of
administrative changes to labelling.

• If a projected group is not listed in Annex Ill, the regulation and
supporting guidances permit the MAH to request agreement of the
relevant authority(ies) to grouping of related changes where a
single data package and evaluation are meaningful.

• 14 cases of Groupings listed in Annex Ill

• CMDh Guidance for Examples for Acceptable and Not-
Acceptable Groupings for MRP/DCP Products
-Doc. Ref: CMDh/173/2010/Rev.10 July 2013

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Documentation required for variation filling

➢ The following documents should be submitted for filing of Variations
applications:

• Cover letter.

• The completed EU variation application form

• Reference of variation guidelines, indicating that all conditions and
documentation requirements are met.

• Relevant documentation in support of the proposed variation including
any documentation specified in the Annex to these guidelines.

• In case that the variations affect the summary of product
characteristics, labelling or package leaflet:
the revised product information presented in the appropriate format.

• Update or Addendum to the detailed critical summaries (quality, safety,
efficacy as appropriate)

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VARIATION APPROVAL TIMELINE

➢ How shall my Type IA/ IAin notification be processed (timetable)
by Health Authority?

A ‘notification of receipt’ letter would be issued by the Agency within five days of receipt of a
Type IA
application.

Within 30 days of receipt, the notification would be reviewed. The Health authority will check the
correctness of the application form, ensure the required documentation is present and compliance
with the required conditions.

The outcome of the process, an approval and/or refusal, would be communicated to the MAH via the
post or the portal.

There will be no interaction with the marketing authorisation holder (MAH) during the
procedure, and no
request to provide missing information

Type IA notification is a ‘Do and tell’ procedure, therefore changes must be implemented prior to
submission of notification.

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VARIATION APPROVAL TIMELINE

How shall my Type IB notification be processed (timetable) by
Health Authority?

For Type IB notifications, the target pre-assessment processing time is 14
days.

Substantive assessment is done within 30 days, and leads either to
approval or a request for further information (RFI) letter within that 30
days.

The company’s response to the RFI letter needs to be received within 30
days.

Assessment of that response is within a further 30 days.

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VARIATION APPROVAL TIMELINE

➢ How shall my Type II notification be processed (timetable) by
Health Authority?

Type II variations follow a 30-day, 60-day or 90-day procedure (Depending upon complexity of the
variation
application)

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Compliance of European
Pharmacopoeia (CEP)/

Certificate of Suitability (CoS)

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European Directorate for the Quality of Medicines
& HealthCare (EDQM)

A Council of Europe Directorate, based on the Convention on the
Elaboration of a European Pharmacopoeia (PA, 1964)

Mission: to contribute to a basic human right: access to good quality
medicines and healthcare

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European Pharmacopoeia (Ph. Eur.)

• Protecting public health – one common compulsory standard.

•The Ph. Eur. is the official pharmacopoeia in Europe –
complemented by national pharmacopoeias for texts of
interest to only one Member State.

•Mandatory at the same date in 37 Member States (CoE) and
the EU.

•Legally binding quality standards for ALL medicinal products
in its member states, i.e. raw material, preparations, dosage
forms, containers must comply with the Ph. Eur. requirements
when they exist.

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European Pharmacopoeia Monographs Today

• Active substances (organic, inorganic)

• Excipients

• Substances of biological origin and biotechnology (insulin,
somatropin…)

• Herbal drugs, essential oils and fats, preparations

• Radiopharmaceuticals

• Vaccines, sera (human, veterinary), blood derivatives

• Homeopathic preparations

• General monographs on dosage forms

• General texts on quality issues and standard analytical methods

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General Notices

Put at the very beginning of the Ph. Eur., they address
general issues and are aimed at providing basic information
to the user.

► Apply to all texts

► Rules to understand texts, conventional expressions

Essential reading before starting to use Monographs

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Flexibility in the Ph.Eur. -Alternative
methods

• Ph. Eur. tests are reference methods, essential in cases of
dispute.

• Compliance is required, but alternative methods may be
used as long as they lead to the same pass/fail result. It is
the responsibility of the user to demonstrate their
suitability. Approval of the competent authority is
necessary in many cases.

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Flexibility in the Ph.Eur. –General Notices

“An article is not of Pharmacopoeia quality unless it
complies with all the requirements stated in the
monograph. This does not imply that performance of all
the tests in a monograph is necessarily a prerequisite for
a manufacturer in assessing compliance with the
Pharmacopoeia before release of a product…..
An enhanced approach to quality control could utilise
process analytical technology (PAT) and/or real-time
release testing (including parametric release) strategies
as alternatives to end-product testing alone.”

(Suppl. 8.2.)

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What does compliance mean?

• Compliance with a monograph

• All mandatory parts of a monograph.

• Compliance until time of use for raw materials, ingredients.

• Compliance throughout period of validity for preparations.

• In-use compliance decided by licensing authority for each
preparation.

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What must comply?

• Mandatory for all substances for pharmaceutical
use

• Ingredients (incl. excipients) of final formulation
• Components of solvents, buffers etc. in or used

to make up final formulation

• Reagents? Not usually needed for upstream use

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Validation of Pharmacopoeial
methods

The test methods …. have been validated ….. Unless otherwise
stated in the monograph or general chapter, validation of the test
methods by the analyst is not required.”

“When implementing a pharmacopoeial method, the user must
assess if and to what extent the suitability of the method under
the actual conditions of use needs to be demonstrated «

8th edition

139

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Why general chapters?

Analytical methods:

• Editorial convenience: avoid repeating standard methods in
each monograph

• Provide standard methods that can be used where there is
no monograph

• Give general requirements for equipment, equipment
verification

• Not mandatory “per se” but when referred to in a
monograph, they become part of the standard Also other
types of general chapters…

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Examples
• Chapter 5.10 Control of impurities in substances for

pharmaceutical use ➔ cross referenced in General
monograph 2034 Substances for pharmaceutical use ➔

chapter 5.10 is to be applied to all API (whether or not
an individual monograph exists in the Ph. Eur.)

• Chapter 5.2.8 Minimising the risk of transmitting animal
spongiform encephalopathy agents via human and
veterinary medicinal products ➔ creation of General
monograph 1483Products with risk of transmitting
agents of animal spongiform encephalopathies which
cross-references the chapter 5.2.8 ➔ chapter 5.2.8 is
legally binding

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Why general monographs?

Two types:

• General monographs on classes of substances

• General monographs on dosage forms

• Apply to all products (“General monographs apply to
all substances and preparations within the scope of
the Definition section of the general monograph,
except where a preamble limits the application, for
example to substances and preparations that are the
subject of a monograph of the pharmacopoeia.”
General notices)

• No cross-reference in individual monographs

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General monographs (cont.)

• “Classes” defined by different criteria: production method,
origin, risk factors

• Aspects that cannot be treated in each individual monograph

➢ Residual solvents
➢ TSE/BSE
➢ Pesticides in herbals
➢ etc. …

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Which has priority, a general monograph or an
individual monograph?

• Basic principle is that general and individual
monographs are complementary and one does not
overrule the other.

• Exceptions are clearly indicated either in the
general monograph or in the individual one.

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Substances for pharmaceutical use
(2034)

• Requirements laid down in this general monograph
apply to all substances for pharmaceutical use whether
or not the substance is covered by an invidual
monograph.

• “Where a substance for pharmaceutical use not described
in an individual monograph of the Pharmacopoeia is used
in a medicinal product prepared for the special needs of
individual patients, the need for compliance with the
present general monograph is decided in the light of a
risk assessment that takes account of the available
quality of the substance and its intended use”.

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Pharmaceutical Preparations (2619)

• reference source of standards in the European
Pharmacopoeia on active substances, excipients and
dosage forms, which are to be applied in the
manufacture/preparation of pharmaceuticals, but not a
guide on how to manufacture as there is specific guidance
available covering methods of manufacture and associated
controls.

• does not cover investigational medicinal products, but
competent authorities may refer to pharmacopoeial
standards when authorising clinical trials using
investigational medicinal products.

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General monographs on dosage forms

• Contain requirements common to all dosage
forms of the type defined (tablets, capsules,
parenteral preparations, etc.)

• Classified by pharmaceutical form/route of
administration

• Applied during licensing
• Framework specification: acceptance criteria

and extra tests are proposed by manufacturer
and approved by competent authority

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The Certification Procedure

• To demonstrate that the quality of a substance is
controlled by the Ph. Eur. monograph and additional
tests if needed (“Chemical CEP” or “Herbal CEP”)

• To guarantee compliance with the Products with TSE
risk (“TSE CEP”)

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The Certification Procedure (cont.)

•CEPs are accepted in 37 Member States + EU,
and beyond (e.g. Canada, Australia, Singapore,
South Africa, etc.)

•Directive 2003/63/EC: Where the active
substance and/or raw and starting material or
excipient(s) are the subject of a monograph of
the EP, the applicant can apply for a certificate of
suitability that, where granted by the EDQM, shall
be presented in the relevant section of the
Module. Those certificates of suitability …are
deemed to replace the relevant data of the
corresponding sections described in the Module…

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The CEP procedure (cont.)

Provides:

• Centralised assessment – saves time and resources

• Information on the need to update Ph. Eur. monographs

• Facilitates management of MAAs and variations

• Application submitted directly to EDQM by the manufacturer
of the pharmaceutical substance

• Confidentiality of data

•Governing document for the Certification procedure :

•Resolution AP-CSP (07) 1

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Scope of the CEP Procedure

• Substances described in monographs in the
Ph. Eur. (Active substances, excipients,
herbal drugs / herbal preparations)
•→ “Chemical” or “Herbal” CEP

• Products with risk of TSE (SM, intermediates,
reagents,..)
•→ “TSE” CEP

• Open to any manufacturer regardless of
geographical origin

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Out of Scope of the CEP Procedure

• Substances not included in Ph. Eur.

• Biologicals (PA/PH/CEP (09) 152 rev 01)

• Human tissues derivatives, blood derivatives,
vaccines

• Mixtures of API with excipients (unless
justified)

• Substances which do not comply with the
Definition section of the monograph

• Finished products

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How to apply for a CEP

• Application form (for new application) available on the
website. It contains tables to be filled in, statements and
declarations to be signed

• Quality Overall Summary (see template on the
EDQM website)

• Fees:

• Electronic submissions encouraged (eCTD, NeeS, pdf)

• Dossier in English (preferably) or French (see documents
on the EDQM website)

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How it works

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What does it mean?

• A chemical CEP certifies that the quality of the substance

is suitably controlled by the Ph. Eur. monograph with

addition of tests if necessary (mentioned on the CEP)

• A TSE CEP certifies that the substance complies with the

EMA NfG on minimising the TSE risk. It DOES NOT

certify that the quality of the substance is suitably

controlled by a specific Ph. Eur. monograph

• It DOES NOT replace a certificate of analysis

• It IS NOT a GMP certificate

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Certification – Inspection

• Integral part of the Certification Procedure

• Article 111 of Directive 2001/83/EC and Article 80
of Directive 2001/82/EC, Compilation of
Community Procedures)

• Performed before or after the CEP is granted

• Aim: to verify the compliance with

✓ Submitted dossier

✓ EU GMP Part II

✓ EU GMP Annexes (e.g. Annex 1 / sterile substances)

Actions are taken immediately after the inspection in
case of major or critical deficiencies (public health
issue)

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Marketing Authorization (MA)
transfers

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Marketing Authorization (MA) transfers

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Marketing Authorization (MA) transfers

Article 1
This Regulation lays down the procedure for the examination
of applications for the transfer of a marketing authorization
granted in accordance with Council Regulation (EC) No
2309/93, except for the situations covered by point 3 of
Annex I to Commission Regulation (EC) No 542/95.

Definition
Article 2

For the purposes of this Regulation, “transfer of a marketing
authorization” means the procedure of changing the
addressee (hereinafter referred to as “the holder”) of the
marketing authorization decision adopted pursuant to Article
10 (1) and (2) or Article 32 (1) and (2) of Council Regulation
(EEC) No 2309/93, the new holder not being the previous
holder.

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Marketing Authorization (MA) transfers
Administrative Procedure
Article 3
1. To obtain a transfer of a marketing authorization, the

holder of this authorization shall submit an application to
the European Agency for the Evaluation of Medicinal
Products (hereinafter referred to as “the Agency”),
accompanied by the documents mentioned in the Annex
to this Regulation.

2. Such an application shall only concern the transfer of one
marketing authorization and shall be accompanied by the
relevant fee provided for by Council Regulation (EC) No
297/95 on fees payable to the European Agency for the
Evaluation of Medicinal Products (1).

Article 4
1. The Agency shall submit, within 30 days following receipt

of an application within the meaning of Article 3 (2), an
opinion concerning this application to the holder of the
marketing authorization, to the person to whom the

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transfer shall be granted and to the Commission.

 

Marketing Authorization (MA) transfers
Administrative Procedure
Article 5
1. The Agency’s opinion referred to in Article 4 can only be

unfavourable if the documents submitted in support of
the application are incomplete or if it appears that the
person to whom the transfer shall be granted is not
established within the Community.

Article 6
1. In the case of a favourable opinion and without prejudice

to the application of other provisions of Community law,
the Commission shall immediately amend the decision
taken in accordance with Articles 10 or 32 of Council
Regulation (EEC) No 2309/93.

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Marketing Authorization (MA) transfers
Administrative Procedure
Article 7
1. The transfer of the marketing authorization shall be

authorized from the date of notification of the amendment of
the Commission decision referred to in Article 6 (2).

2. The date on which the transfer actually takes place shall be
set by the Agency by mutual agreement with the holder of
the marketing authorization and the person to whom the
transfer is to be granted. The Agency shall immediately
inform the Commission of this date.

3. The transfer of a marketing authorization shall not affect any
of the time limits provided for in Articles 13 and 35 of
Council Regulation (EC) No 2309/93.

Article 8
1. This Regulation shall enter into force on the third day

following its publication in the Official Journal of the
European Communities.

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Marketing Authorization (MA) transfers

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Qualified Person (QP) in EU

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Certification by a Qualified Person and Batch Release

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Certification by a Qualified Person and Batch Release

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Certification by a Qualified Person and Batch Release

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Certification by a Qualified Person and Batch Release

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Certification by a Qualified Person and Batch Release

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Certification by a Qualified Person and Batch Release

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Certification by a Qualified Person and Batch Release

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Certification by a Qualified Person and Batch Release

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Certification by a Qualified Person and Batch Release

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Certification by a Qualified Person and Batch Release

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Certification by a Qualified Person and Batch Release

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Certification by a Qualified Person and Batch Release

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Certification by a Qualified Person and Batch Release

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Certification by a Qualified Person and Batch Release

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Legislation and regulations for
import,

manufacture, distribution and
sale of cosmetics in European

Union & Australia

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Europe Cosmetic Requirements

National authorities in each EU country are in charge of
reviewing the safety assessments and checking
products already on the market. Cosmetics Legislation
requires that every cosmetic product placed on the
market in Europe is safe to use. The EU Cosmetic
Regulation 1223/2009 came into force in 2013 and
concerns 31 European countries (28 countries of the EU
+ Norway + Iceland + Lichtenstein).

The regulation is based on three principles:
• Safety of Raw Materials and Ingredients
• Good manufacturing practices
• Invigilating of cosmetic market

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Europe Cosmetic Requirements

These principles translate into requirements for the
cosmetic brand (non-exhaustive list):
• Designate a Responsible Person (RP)
• Prepare a Product Information file (PIF) including a
Safety Assessment
• Respect the Good manufacturing practices (GMP) for
cosmetics
• Comply with Labeling and Packaging requirements
• Ensure notification via the Cosmetic Products
Notification Portal (CPNP)

With this regulation, the European Union sets a higher
level of transparency for finished cosmetic products,
prevents the placing on the market of hazardous
substances, and strengthens safety for consumers

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Europe Cosmetic Requirements

The Product Information File: PIF is the mandatory
compilation of technical documentation required for each
cosmetic product to be placed on the EU market. According
to the EU Cosmetics Regulation 1223/2009/EC, the elements
of the PIF include but are not limited to:

• Product Description
• Safety Report:
• Part A: Cosmetic Product Safety Information
• Part B: Cosmetic Product Safety Assessment
Report
• Method of Manufacturing, Evidence of compliance
with Good Manufacturing Practices (GMP), Proof of the
effect claimed (where justified), Data on Animal
Testing, Labeling (taking into account the container and
outer packaging), Data on Serious Undesirable Effects

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Europe Cosmetic Requirements

I. Labelling: In EU regulations they have as well
systematic mandatory information that must be printed
in “indelible, easily legible and visible lettering”:

•Name and address of the Responsible Person: If
applicant is outside the EU, it is mandatory to designate
Responsible Person (RP), in order to market the product. If
cosmetic brand based in the EU, applicant will be acting as
the RP by default.
List of ingredients: In decreasing order of weight, except
for ingredients below 1%.

Country of origin: Add the mention: “Made in country”
unless the product is made in Europe in which case such
mention is not mandatory. Note: the “Made in” expression
does not need any translation.

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Europe Cosmetic Requirements

Nominal content: The nominal content must appear in
grams (g) or milliliter (ml) and in first position.

Date of minimum durability (DOMD) & Period after
opening (PAO): If the durability is inferior or equal to 30 months,
manufacturer need to indicate the “hour glass” symbol and print date (MMYY
/ DDMMYY). If the durability is superior to 30 months then you must
indicate the PAO. Manufacturer will need to print the “open jar” symbol with
the number of months (M) or year (Y) inside or next to the open jar.
Particular precautions of use and warnings: Depending on the type of
cosmetic product, some particular precautions of use and warnings might be
useful to consumers or even mandatory in certain cases.

Batch number: is mandatory, although no particular format is required.
Product function: The function of the product must be clearly indicated, e.g.:
hand moisturizer as to prevent any misuse.

Product claims: In the labelling, making available on the market and
advertising of cosmetic products, text, names, trademarks, pictures and
figurative or other signs shall not be used to imply that these products have
characteristics or functions which they do not have

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Europe Cosmetic Requirements

II. Observation of EU cosmetic regulations:

Cosmetics in EU to avoid the complex have clarified by
establishing the “Illustrative list by category of Cosmetic
Products”. EU has stringent laws where companies are
required to submit the proof of the claims made by the
product as borderline cosmetic products are already
classified. EU cosmetic regulations expressly prohibit the use
of any substances determined to be carcinogenic,
mutagenic, or toxic to reproductive systems. The EU’s
Cosmetic Regulation also specifies those colorants,
preservatives and UV-filters that are approved for use in
cosmetic products. Toward this end, manufacturers are
responsible for identifying a “responsible person” who can
address issues of non-compliance identified by authorities.

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