International Trade in

Medicinal and
Pharmaceutical Products

By
Dr. Ahmed Diab
Bogotá, August 2019
Crear un documento

Outline

• API regulation in EU

• Supplier qualification

• Trade in pharmaceutical products

• Marketing authorization regulation and requirements

• Upcoming EU regulations
API Regulation in EU

• What is API?
Any substance or mixture of substances intended to be used in the manufacture of a medicinal
product and that, when used in its production, becomes an active ingredient of that product
intended to exert a pharmacological, immunological or metabolic action with a view to restoring,
correcting or modifying physiological functions or to make a medical diagnosis.
• List or guidelines

✓ - good manufacturing practice guide for active pharmaceutical ingredients (ICH Q7)

✓ Part II - Basic Requirements for Active Substances used as Starting Materials

✓ Principles of Good Distribution Practice of active substances for medicinal products for human use (19 March 2015 )
API Manufacturing
API Import into EU (Human use)

Can imported only if:

✓ Written confirmation on GMP for API

✓ USA, Switzerland, Australia, Japan, Brazil, Israel, south Korea under assessment:,
New Zealand, Canada

✓ Exceptionally EU GMP certificate

Written confirmation

• Who issues the written confirmation?

✓ Issued by the regulatory authority of the country where the manufacturing site is located

• Is written confirmation also required where there is a ‘mutual recognition agreement’ between
any listed country and the EU?

✓ Yes. The process of written confirmation is independent of the existence of ‘mutual

recognition agreements’
Material classification

the materials classified into the

four categories based on quality
criticality to the API
manufacturing process and on
risk related to potential for
harm to the patients
Supplier qualification
Supplier Qualification
Process steps to adequately manage suppliers through the complete life cycle of the product:

1) Supplier Selection Process:

✓ - based on user requirements with as minimum a specification

2) Due Diligence Process:

✓ necessity based on risk assessment for critical raw materials and API starting materials

✓ not applicable to non-critical raw materials

3) Quality Assessment of all suppliers

4) Change Control and production assessment (as necessary)

5) Supply Chain security

6) Ongoing monitoring and Evaluation

1- Supplier Selection
Pre-requisite following information:
✓ Specifications
✓ Manufacturing/Packaging/Labeling details
✓ Materials safety data sheets
✓ Logistic information
✓ Certificates regarding Quality Systems
✓ BSE/TSE evaluation
✓ Analytical test methods
1- Supplier Selection

• For Critical raw materials (including API SM) intermediates and API’s more
comprehensive selection criteria need to be verified.
✓ Assurance of Supply
✓ Quality & Regulatory Compliance
✓ Cost/Procurement aspects
✓ Communication capabilities & responsiveness

• Potential need to evaluate a material sample to support Go/No Go decision

2- Due Diligence
Purpose
Assemble documented evidence to support the Go/No Go decision
✓ Evaluate the possibility to establish a long term business relationship
✓ Asses and challenge implemented systems and facility to evaluate the capability of
the supplier to comply with the customer’s requirements
✓ Assess assurance of continuous supply based on capability of:
»Process Equipment
»Facility Containment
»Quality of utilities
»Analytical equipment availability including stability chambers
»Potential for process and analytical development and validation
»Ability or demonstrated performance of preparing regulatory submission
2- Due Diligence
Areas to be challenged:
»General Product information
»Quality System
»Plant tour and organization
»Documentation and organization
»Process (synthesis and manufacturing process)
»Physical material properties
»Analytics and Stability
»Regulatory
»Intellectual property
»Safety, Environment & Health
3- Quality Assessment
3- Quality Assessment
4- Change control and Production assessment

The change control and production assessment process follows

Five main steps:

✓ -Initiation of the change,
✓ -Execution of the change,
✓ -Evaluation of the change,
✓ -Closure of the temporary change control package,
✓ -Preparation for ongoing monitoring.
5- Supply Chain Security

In General:

✓ The entire supply chain from the manufacturer of an API, registered intermediates or
critical raw material to the customer should be assessed and qualified from a quality
perspective by applying mainly related quality system, transportation, storage and
related conditions as well of traceability of the material.

✓ The shorter the supply chain the more secure it will be

5- Supply Chain Security
Specific:
✓ Set up a Supply Chain Quality system
✓ Evaluate against pre-defined KPI’s
✓ Build up a secure customer/supplier relationship
✓ Assure end to end traceability
✓ Use of tamper-resistant packaging closure
✓ Label evaluation
✓ Data loggers for temperature and/or humidity sensitive products
6- Ongoing monitoring and Evaluation
The Quality Unit is responsible for the ongoing evaluation and the re-approval of the
supplier.
• Elements of monitoring and rating:
o Ongoing monitoring: on each supplied batch, examples are:
✓ Compliance to specifications, sealing, packaging, labeling, quantities…
✓ Deviations should be monitored and managed according to the company complaint SOP
Periodic evaluation / supplier’s performance: typically annual, examples are:
✓ Periodic full testing
✓ Quality eg No. of not first-time deliveries
✓ Reaction on audit remediation
✓ Response times for complaints and questions
o Summary report as basis for rating and review (Rating the supplier)
Trade in Pharmaceutical Products
Export and Imports of pharmaceutical product

EU-28 export, imports and trade balance in medicinal and pharmaceutical products, 2002-2018 (EUR billion)
180

160

140

120

100

80

60

40

20

0
2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018

Source: Eurostat (online data code: DS-018995) Balance Export Import

Export and Imports of pharmaceutical product

Main extra EU-28 partners for exports and imports of medicinal and pharmaceutical
products, 2018 (%) Imports
Exports

Other
12 %
South Korea
3%
Israel
Other United States 4% United States
35 % 34 % Singapore 37 %
4%

China
5%

Canada
3 % Russia Switzerland
4 % Japan China 12 %
5% 6% Switzerland
35 %

Source: Eurostat (online data code: DS-018995)

Export and Imports of pharmaceutical product
EU-28 trade with the United States in medicinal and pharmaceutical products, 2002-
2018 (EUR billion)
50

40

30

20

10

0
2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018

Balance Export Import

Source: Eurostat (online data code: DS-018995)
Export and Imports of pharmaceutical product
EU-28 trade with Switzerland in medicinal and pharmaceutical products, 2002-2018
(EUR billion)
30

20

10

-10

-20
2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018

Balance Export Import

Source: Eurostat (online data code: DS-018995)
 Export and Imports of pharmaceutical product
Top 3 partners for extra EU-28 exports of medicinal and pharmaceutical products by
Member State, 2018 (%)
100
AO Angloa
BA Bosnia and Herzegovina
BY Belarus
JP CA Canada
80
KZ CH Switzerland
CH BA UA
CN China
UZ
CN HK Hong Kong
60 UA
UA HK RU IN India
CN RU CH US US CA
JP UA BY NO IQ Iraq
XS JP
UA CH UA CN JP Japan
CN US IN
RU CH SG KR South Korea
US UA AO
40 CA XS JP CN CH CN US
US CN RU US KZ Kazakhstan
CH CH CA CH
CN IQ UA NO Norway
RU RU Russia
US RU US
20 IQ CH VN
US RU RU RU
US
US US
TR CH RU US RU SG Singapore
KR US US US TR Turkey
US RU CH RU CN
CN UA United Arab Emirates
CN
0
US United States
Spain

Portugal

Sweden
Belgium

Czechia

Germany
Estonia

Netherlands

Slovakia
Lithuania

Poland

Finland
Bulgaria

Greece

Italy

Latvia

Romania
Austria
Denmark

France
Croatia

Cyprus

Luxembourg

Malta
Hungary

Slovenia
Ireland

United Kingdom
UZ Uzbekistan
VN Vietnam
XS Serbia

Source: Eurostat (online data code: DS-018995) First partner Second partner Third partner Other
 Export and Imports of pharmaceutical product
Top 3 partners for extra EU-28 imports of medicinal and pharmaceutical products by
Member State, 2018 (%)
100
BR Brazil
CN
CN CH CA Canada
CN BR NO
SG TR CH Switzerland
IN TR US
80 CN
SG US CN SG US US CN China
SG IN MX CH IN
IL US IN
US CN
CN US CH IL Israel
SG
IN IL CH CA IN India
CN CH CN
US CH CH SG CN IN
CH CN CN CN KR South Korea
60 US
US US MX Mexico
NO NO Norway
VN CH SG Singapore
40 CH CH TR Turkey
US CH
CH US CH US United States
CH IN US
CH
KR CH CH CH CH VN Vietnam
US CH CH KR
US US
US CH
20 CH
CH CH US
NO

Portugal
Estonia

Spain

Slovakia

Sweden
Belgium

Czechia

Germany

Netherlands
Latvia

Finland
Lithuania
Bulgaria

Greece

France

Austria
Poland
Italy
Cyprus

Malta

Romania
Luxembourg
Hungary
Denmark

Ireland

Croatia

Slovenia

United Kingdom
Source: Eurostat (online data code: DS-018995) First partner Second partner Third partner Other
Export and Imports of pharmaceutical product
Extra EU trade (EUR million) Share in total extra-EU trade (%)
Export Import Balance Export Import
EU-28 169'270 78'016 91'254 8.7 ||||||||||||||||| 3.9 |||||||
Belgium 19'859 14'319 5'540 18.5 ||||||||||||||||||||||||||||||||||||| 10.6 |||||||||||||||||||||
Bulgaria 323 180 143 3.7 ||||||| 1.5 |||

Extra EU trade in Czechia

Denmark
323
8'848
401
983
-78
7'864
1.2 ||
24.6 |||||||||||||||||||||||||||||||||||||||||||||||||
1.1 ||
3.8 |||||||

medicinal and Germany

Estonia
39'745
14
13'379
23
26'367
-9
7.3 ||||||||||||||
0.3
3.7 |||||||
0.6 |

pharmaceutical Ireland 24'917 3'774 21'143 35.9 ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| 11.9 |||||||||||||||||||||||

products by Member Greece

Spain
242
5'603
398
3'721
-156
1'882
1.5 |||
5.7 |||||||||||
1.5 ||
2.7 |||||

State, 2018 (EUR France

Croatia
15'071
304
4'561
273
10'510
30
7.5 ||||||||||||||
6.4 ||||||||||||
2.6 |||||
5.1 ||||||||||

million and %) Italy

Cyprus
10'887
158
7'422
62
3'465
96
5.4 ||||||||||
5.3 ||||||||||
4.3 ||||||||
1.6 |||
Latvia 231 73 158 5.2 |||||||||| 1.8 |||
Lithuania 245 47 198 2.1 |||| 0.5
Luxembourg 1 31 -31 0.0 1.3 ||
Hungary 1'484 1'042 443 7.7 ||||||||||||||| 4.0 ||||||||
Malta 43 165 -122 4.0 ||||||| 11.1 ||||||||||||||||||||||
Netherlands 14'157 13'572 585 9.0 |||||||||||||||||| 4.6 |||||||||
Austria 4'368 4'010 358 9.8 ||||||||||||||||||| 10.9 |||||||||||||||||||||
Poland 767 804 -37 1.8 ||| 1.2 ||
Portugal 351 256 95 2.5 ||||| 1.4 ||
Romania 218 281 -63 1.4 || 1.3 ||
Slovenia 1'424 724 700 16.0 |||||||||||||||||||||||||||||||| 6.2 ||||||||||||
Slovakia 40 155 -115 0.3 1.0 |
Finland 402 207 195 1.5 ||| 1.0 ||
Sweden 4'915 710 4'204 8.6 ||||||||||||||||| 1.6 |||
United Kingdom 14'330 6'442 7'887 6.6 ||||||||||||| 2.4 ||||

Source: Eurostat (online data code: DS-018995)

Export and Imports of pharmaceutical product

Main countries in worldwide trade in medicinal and pharmaceutical products, 2017

Marketing Authorization Regulation and Requirements
European Medicines Agency (EMA)
✓ 28 EU member states + 3 EEA members states

✓ ~50 National Regulatory Authorities, 4500 Experts ~500 million citizens

• Decentralized agency of the EU

• founded in 1995

• responsible for coordinating the evaluation, supervision and pharmacovigilance of medicinal products:

• Facilitate development and access to medicines

• Evaluate applications for marketing authorisation (over 1000 medicines recommended for authorisation)

• Monitor the safety of medicines across their life cycle

• Provide information on human and veterinary medicines to healthcare professionals and patients
Mutual Recognition Agreements
➢ In 1998, the EU and the US signed a broad MRA, which included a Pharmaceutical Annex
providing for anticipated and limited reliance on each other’s GMP inspections. However,
this Agreement was never fully implemented
➢ mutual recognition of inspections took effect on 1 November 2017.
➢ Austria, Croatia, France, Italy, Malta, Spain, Sweden and United Kingdom. Czech
Republic, Greece, Hungary, Romania, Ireland ,Lithuania, Portugal, Belgium, Denmark,
Finland , Latvia, Estonia, Poland , Slovenia, Bulgaria , Cyprus, Luxembourg ,the
Netherlands, Germany, Slovakia.
➢ legal framework to allow authorities to accept conclusions of GMP inspections performed
by other party
➢ share information on inspections and quality defects;
➢ agreements recognise the equivalence of systems regarding oversight wrt GMP
➢ waive batch testing of products on import into their territories
Mutual Recognition Agreements

➢ Product excluded

✓ Veterinary products are not immediately included in the operational scope of the agreement (end 2019)

✓ Human vaccines and plasma-derived products are not immediately included within the operational scope
(july 2022)

✓ Human blood, plasma, tissues and organs as well as veterinary immunologicals are excluded from the scope.
Authorization of new Medicines 2018
Authorization of new Medicines 2018
Authorization of new Medicines 2018

https://www.ema.europa.eu/en/documents/annual-report/2018-annual-report-european-medicines-
agency_en.pdf
Medicinal Products from Outside the EU (EEA)
➢ EU law requires all medicinal products to obtain a Marketing Authorisation (MA) before they can be placed
on the market
➢ If the manufacturing site of the finished product is located outside the EU (EEA) these medicinal products
are considered imported medicinal products. The competent authorities of the EU (EEA) must ensure that
the import of medicinal products into their territory is subject to an authorisation in accordance with Article
40(3) of Directive 2001/82/EC. The authorisation is granted when a number of conditions, as defined in
Articles 41 and 42 of Directive 2001/83/EC, are fulfilled (e.g. availability of a qualified person within the
EU (EEA), GMP inspection).
➢ The marketing authorisation holder will therefore need to specify an authorised importer established in
the EU (EEA).
➢ In addition, in accordance with Article 51(b) of Directive 2001/83/EC the marketing authorisation holder
will need to specify a site of batch control in the EU/EEA where each production batch can undergo
upon importation a full qualitative analysis, a quantitative analysis of at least all the active substances
and all the other tests or checks necessary to ensure the quality of medicinal products in accordance with the
requirements of the marketing authorisation.
Medicinal Products from Outside the EU (EEA)
Legal basis
Directive 2001/83/EC Of The European Parliament And Of The Council Of 6 November 2001 On The
Community Code Relating To Medicinal Products For Human Use

Regulation (EC) No 726/2004 Of The European Parliament And Of The Council Of 31 March 2004 Laying
Down Community Procedures For The Authorisation And Supervision Of Medicinal Products For Human And
Veterinary Use And Establishing A European Medicines Agency
Market authorization

Who grants MA in EU?

Market authorization
National Procedure

Most of medicines available in the EU are authorized at national level:

✓ Authorised before EMA creation

✓ Not in the scope of the centralized procedure

✓ One Mamber state is Involved

Mutual recognition procedures (MRP)

✓ The Principle of recognition of an already existing national MA by one or more EU

Member States

✓ The concerned Member State refers to the reference Member State that issued
National Marketing authorization
Decentralized procedure (DCP)

✓ For MP not filling with the mandatory scope of the Centralized procedure

✓ No existing MA in the EU

✓ The applicant may request one or more concerned member state and chose one
reference state and all other rely on their decision.
Centralized Procedure (CP)

✓ One single MA application to EMA

✓ One assessment procedure (scientific committee’s opinion) based on individual

assessments by Member States

✓ Common decision making process (one European Commission decision)

✓ One MA valid in all EU member states and EEA

Centralized Procedure (CP)

Which products must be centrally authorised?

✓ All human medicines derived from biotechnology and other high-tech processes
✓ all advanced therapy medicines and medicinal products containing new active
substances intended for the treatment of
• HIV/AIDS
• Cancer
• Diabetes
• Neurodegenerative diseases
• Auto-immune and other immune dysfunctions
• Viral diseases
• all designated orphan medicines intended for the treatment of rare diseases
Types of marketing authorisations
✓ Normal or Full MA..... all saftey and cliniacl trial are complete (5 years)

✓ Conditional MA
• this medicine addresses an unmet medical need the conditional authorisation allows
for early approval on the basis of less complete clinical data than normally
required. This authorisation is subject to specific postauthorisation obligations to
generate complete data on the medicine

✓ Exceptional circumstances MA
• comprehensive data cannot be obtained, either because there are only very few
patients with the disease, or the collection of complete information on the efficacy
and safety of the medicine would be unethical, or there are gaps in the scientific
knowledge.
Steps involved in obtaining an EU marketing authorisation
• Submission of eligibility request
− between 18 to 7 months before submission
• Notification of intention to submit an application
− 7 months before submission
• Appointment of Rapporteurs
− 7 months before submission
• Pre-submission Meeting
− 7 months before submission
• Submission of Application
• Scientific evaluation
− 210 days of assessment
• CHMP scientific opinion
• European Commission decision
Requirements for the content of the European application

Common Technical Document e-CTD format.

Article 8 (3)
the application shall be accompanied by all particulars and documents, submitted in
accordance with Annex I” P.120

Directive 2001/83/ec
Diagrammatic Representation of the Organization of the CTD
Application types and requirements

➢ Article 8(3) Full Application

✓ Full dossier; quality, nonclinical and clinical data

➢ Article 10 (1) „Generic“

✓ Reference product on the market no less than 8 years
✓ Same qualitative, quantitative compositions
✓ Same pharmaceutical form
✓ Bioequivalence
Application types and requirements

➢ Article 10 (3) Hybrid (mixed) Application

• Additional non-clinical/clinical data in case:
✓ Product does not meet definition of generic
✓ No bioequivalence
✓ in case of changes in the active substance(s)
✓ Change to active substance, therapeutic indications, strength, pharmaceutical form or
route of administration
Application types and requirements

➢ Article 10 (4) Biosimilars

• Additional non-clinical/clinical data required in case of:
✓ product does not meet definition of generic,
▪ esp. differences relating to raw materials or
▪ Differences in manufacturing processes of biological product and reference biological
product
Application types and requirements

➢ Article 10(a) Well established use

✓ Well-established medicinal use of active substance for at least 10 years
✓ Non-clinical and clinical trial results replaced by appropriate scientific literature

➢ Article 10(b) Fixed combination products

✓ Active substances used in composition of authorised medicinal products but not in
combination
✓ New non-clinical and clinical data relating to the combination are required
Application types and requirements

➢ Article 10 (c) Informed consent / Duplicate

✓ MAH allows reference to data on file to support assessment of other medicinal
products with same qualitative and quantitative composition of active substance and
same pharmaceutical form
Upcoming regulation

Regulation (EU) 2019/6

QUESTIONS?
Article 43
The Member States shall take all appropriate measures to ensure that the time taken for the procedure for
granting the manufacturing authorization does not exceed 90 days from the day on which the competent
authority receives the application.
Article 51 (b)

in the case of medicinal products coming from third countries, irrespective of whether the product has been
manufactured in the Community, that each production batch has undergone in a Member State a full
qualitative analysis, a quantitative analysis of at least all the active substances and all the other tests or checks
necessary to ensure the quality of medicinal products in accordance with the requirements of the marketing
authorisation
Article 40 (3)

Authorization referred to in paragraph 1 shall also be required for imports coming from third countries into a
Member State; this Title and Article 118 shall have corresponding application to such imports as they have to
manufacture.
Evaluation process
Timelines DCP
Timelines MRP

210 Days - National Registration

90 Days – preparation AR
Day 0 – Start procedure
Day 50 - CMS Comments
Day 60 - Applicants’s Response
Day 75 - CMS Comments
Day 85 - Final CMSs position
Day 90 - Consensus/close of procedure
Timelines Centrale Procedure

Day 1 – Start Procedure

Day 80 – Preliminary Assessment Report
Day 120 – List of questions
Clockstop
Day 121 - Submission responses
Day 157 – Joint Assessment Report
Day 180 – CHMP discussion
Day 181 – Restart of the clock and oral explanation
Day 181 – 210 - Preparation final product information
Day 210 – CHMP opinion
Applications for which a full dossier needs to be submitted in CP

Council Regulation (EC) No 297/95 of 10 February 1995 on fees

payable to the European Agency for the Evaluation of Medicinal Products