European Medicines Agency Activities
Related to API’s
WHO/EDQM/SFDA Conference
Quality of Pharmaceutical Ingredients
March 28, 2010
Guangxi Hotel, Beijing, China
Brendan Cuddy
Scientific Administrator
European Medicines Agency
An agency of the European Union
1.What is the European Medicines Agency?
2.API’s in the Marketing Authorisation Application
3.International Active Pharmaceutical Ingredients
(API) Inspection Pilot Programme
4.Future developments
5.Summing Up
6.Questions and Discussion
European Medicines Agency
The European Union:
493 million people – 27 countries
Member states of the European Union
Candidate countries
EMEA and the Regulatory System in the EU
 EMEA co-exists with over 40 National Competent authorities
in the EU/EEA, forming an integrated network
 A centralised procedure for Marketing Authorisation co-exists
with procedures at national level (de-centralised
procedure/mutual recognition procedure)
 EMEA co-ordinates the existing scientific resources in
Member States and provides an interface between all parties
 EMEA works towards harmonisation of regulatory and
technical requirements within the EU
 EMEA scientific guidelines apply regardless as to the
marketing authorisation procedure used
EMEA and EU System
42 National competent
4,000 European experts
EU institutions:
Commission, Parliament
and Council
Management Board
Committee for Orphan
Medicinal Products
Paediatric Committee
Industry Organisations
Committee for
Medicinal Products
Patients and consumers
Committee on
Advanced Therapies
Committee for
Medicinal Products for
Human Use
Committee ?
Committee for Herbal
Medicinal Products
API’s in the Marketing Authorisation
Key Terms
Marketing Authorisation Authorises the holder to place the
medicinal product on the market
Manufacturing site(s) for
medicinal product
Sites located in EEA including
importers must hold a
authorisation (MIA)
Manufacturing site(s) for
active substance(s)
Includes brokers who
package, label and/or
Import active substances
EU GMP Inspection System
Collective implementation of Directives into national legislation
National Manufacturing Authorisations
Concept of Supervisory Authority
Mutual recognition of inspection outcomes.
All inspections “performed on behalf of the Community”
Collective adoption of identical guidelines
Harmonised practices
Compilation of Community Procedures
Joint audit programme
Regular meetings of the GMP/GDP Inspectors Working Group
Marketing Authorisation
Applications for marketing authorisation must specify the
manufacturers of the active substance
This includes:
 all stages involved in manufacture - from the first use of the
active substance starting materials, through to the active
substance used as a starting material by the dosage form
 all companies/sites involved in manufacture of the active
substance including those (re)packaging and (re)labelling
It should be noted that importers (into EEA) of active substances
are also “Manufacturers” of the active substance.
Declarations by the Qualified Person
Each application for marketing authorisation or
relevant variation submission must be
accompanied by a declaration signed by the QP
of the manufacturing/importation authorisation
holder(s) listed as manufacturer of the dosage
 The declaration confirms that the active substance is
manufactured in accordance with GMP
 The declaration must cover all the manufacturing sites
connected with the active substance
QP Declaration: responsibilities
Batch release
site and/or
Finished product
Supervisory role of the Competent
 Inspections are carried out to verify that
Manufacturing Authorisation holders are fulfilling
their obligations
 Member States are obliged by Community
legislation to conduct inspections for this purpose
and on behalf of all Member States.
 In addition they may inspect active substance
manufacturers. These inspections are mainly
triggered by specific concerns.
 Some Member States issue manufacturing
authorisations to active substance manufacturers
Conditions For Inspection Of Active
Substance Manufacturers
No systematic routine inspection programme is
required according to Community legislation
 Where there are grounds for suspicion of noncompliance
 At request of Member State, EMEA or Commission
 To verify data submitted in application for a CEP
 At request of EDQM
 At the request of a manufacturer itself
Conditions For Inspection Of Active
Substance Manufacturers
The quality of biological medicinal products are highly dependent on the
manufacturing process and are usually characterised by it. GMP has therefore
always been applied to the biological substance.
Sterile active substances
The sterilisation step in the production of a sterile active substance, where the
active substance is to be incorporated aseptically in the manufacture of the
medicinal product, is a manufacturing step of the medicinal product and has
always been subject to GMP.
Therefore subject to routine inspections
Possible Triggers
Possible Grounds for suspicion:
 Unsatisfactory evidence of audit by manufacturer of
medicinal product
 Competent authority not satisfied with measures taken
by medicinal product manufacturer
 Concerns about distribution chain
 Previous unsatisfactory inspection history
 Concerns raised through CEP scheme
 When disagreement on the conclusions of an inspection
 Non compliance with specifications
 Suspicions relating to authenticity of data
International API Inspection Pilot
Background of the project
Global supply chain for APIs / Global regulatory
environment (ICH)
Increasing demand for international collaboration
on inspection work sharing on a risk-based
Quality issues in 2008 for products with API
manufactured outside EU (e.g. heparin)
Justification of the project
Better use of International inspectional resources
allowing an increase inspectional coverage outside
participating regions
Better coordination/collaboration/information
between authorities on sites of common interest can
contribute to risk based inspection approaches and
improve inspection efficiency.
Justification of the project
Information from the retrospective data :
Out of 85 sites which were inspected by more than 2 participants
between 2005 and 2008 and for which the last inspection dates
were known :
8 sites were inspected during the same month
7 sites were inspected within 3 month
11 sites were inspected within 6 month
20 sites were inspected within 12 month
14 sites inspected within 2 years
25 sites inspected within more than 2 years
Organisation of the Pilot Program
Authorities performing significant number of inspections of APIs
outside of their territories approached by European Medicines
Agency end 2007
EU : France AFSSAPS, Germany ZLG, Ireland IMB, Italy AIFA,
United Kingdom MHRA
MRA : Australian TGA
Council of Europe : EDQM
All agreed to participate in a pilot phase to last for 18 months with
recommendation for future action.
Organisation of the Pilot Program
Always right to perform “own” inspections
Use of a common GMP standard = ICH Q7
All authorities to ensure if possible an agreed
conclusion in case of joint inspection
Each involved authority responsible for any follow-up
actions (e.g. administrative or enforcement)
Possible joint follow-up actions in case of GMP noncompliance
Tools of the Pilot Program (1)
Objectives developed into :
1.Update on a pilot project to collaborate on
international GMP inspection activities
2.Rules of engagement and procedures for
participating authorities (active pharmaceutical
ingredients/active substances)
3.Organisation of bilateral and general teleconferences
to built up the program and define a strategy for the
sites of common interest
Tools of the Pilot Program (2)
4. Confidentiality Agreements signed between the
participating authorities to allow sharing of
inspection plans
5. Template spreadsheet for exchange of inspection
planning's, retrospective and prospective, defined.
6. Creation of a master list of common sites
Sites for cooperation in 2009/2010
920 sites (entries) identified and shared
350 sites not shared
Total of : 213 common sites
sites common to 2 participants : 118 sites
sites common to 3 participants : 57 sites
sites common to 4 participants : 32 sites
sites common to 5 participants : 6
Geographic distribution of the API
China : 104 sites from which 43 are not shared
- 39 shared by 2
- 14 shared by 3
- 6 shared by 4
- 2 shared by 5
- 58 % of the sites in China are shared
Activities within the Pilot Program
Main activities to be developed within the program
based on the sharing of inspections planning:
Sharing of inspection reports of passed inspections
Sharing of inspection reports of planned inspections
with or without scope extension
Joint inspection with or without scope extension.
Scenario a: inspection report sharing
passed or future inspection
manufacturer in
third country
API 1 is used in medicinal products in EU (CAP) & US.
EU/US both interested in the inspection and agree to
delegate the inspection to one of them and to share the
inspection report.
Possible for the same scope or overall GMP compliance
Scenario b: sharing
of inspection reports of planned inspections with
extension of the scope
manufacturer in
third country
API 1 is used in medicinal products marketed in EU
(CAP) and a CEP was granted by EDQM.
API 2 is used in a product in Australia
EDQM/European Medicines Agency/TGA are interested
in the inspection and agree to delegate the inspection to
one of them, extending the scope of the inspection to
cover API 1/2 and to share the inspection report.
Scenario c: joint inspection
in third country
API 1 and API 2 are used in medicinal products marketed
in EU (CAP) , in US and in Australia.
API 2 and API 3 were granted a CEP by EDQM.
EDQM/European Medicines Agency/FDA/TGA are
interested in the inspection and agree to organise a joint
inspection done by two of them, covering API 1/2/3 and
share the inspection report with all.
Joint inspections
Feb. 2010
EDQM , 5 joint inspections :
3 TGA - 1 MHRA - 1 European Medicines Agency
European Medicines Agency, 2 joint inspections
1 FDA - 1 EDQM
FDA, 2 joint inspections
1 European Medicines Agency – 1 TGA
TGA, 5 joint inspections
3 EDQM - 1 FDA - 1 MHRA
Key Performance Indicators
Increased transparency and visibility of participants
inspections planning
Decrease in “duplicate inspections” i.e inspections of
the same product or sites carried out by more than
one authority within a similar time period
Increase in number of inspections of value to more
than one authority performed
Positive assessment of the deliverables
Next steps
Regular teleconferences and e-mail exchanges for the
development of the program.
Improving the knowledge of each other’s organisation
and constraints
Improve the exchange of information by gathering
and sharing more data on site inspections planning
(all sites, APIs inspections schedules and reporting
tools (e.g. feedback forms)
Reliance on each other’s inspections will increase
resource available to cover more sites.
Future Developments
Legal proposal to combat counterfeit medicines
Pedigree of API Supply Chain Security
EC envisages a combination of tightened requirements
in the API area
Notification requirements
Tightened GMP standards
Enhanced inspections
Notification requirements
Mandatory notification for manufacturers/importers of APIs
legal framework for APIs only on
activities of distributors, traders,
agents and brokers outside
scope of Community legislation
should be subject to the
relevant GMP
API manufacture
& import to mandatory notification
Information on notified parties
available in a Community database
(EudraGMP database extension)
Audit and enforceability of GMP
Enhancing audit and enforceability of GMP
obligation of the MIA holder to
source from GMP compliant API
in practice auditing by the MIA
holder (EU FP manufacturer or
FP manufacturers test APIs
supplied to them
other sites / other
processes as declared
Make regular audits of API
suppliers on GMP compliance
auditors sufficiently qualified
third-party audits by
accredited companies
Control of APIs via discriminating
analytical techniques
Principles of GMP for APIs into a
legal act of Community law
API GMP inspections
Enhancing API GMP inspections
inspections by competent
authorities restricted to
suspected non-compliance
with GMP
Particular concerns for
manufacturing in third
countries (TC):
1. GMP not equivalent to
2. inspection and control
mechanisms insufficient
Need to continue cooperation
with TC
bilateral arrangements
international synergies in
performing inspections
Legal basis for any GMP API
competent authorities (EU
inspectorates) shall carry out API
inspections if suspicion of noncompliance with GMP
The competent authority shall
carry out repeated inspections in
the exporting country (TC) if
GMP in TC not at least
equivalent to EU
mechanisms for supervision
and inspections not at least
equivalent to EC
Pedigree of API Supply Chain
Proposal for amendment of GMP Guide to introduce a
pedigree concept for API’s.
Proposal still very much in draft form
Work anticipated to continue on the proposal
throughout 2010.
To sum up
Overview of API’s in Marketing
Inspections of active substance
International Pilot Programme
New initiatives e.g EC proposals
Questions and Discussion
European Medicines Agency
7, Westferry Circus
Canary Wharf
London E14 4HB
United Kingdom
Tel: +44 (0) 20 7418 8400
Fax: +44 (0) 20 7418 8416

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