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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. Agenda. What is the European Medicines Agency?

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european medicines agency activities related to api s

European Medicines Agency Activities Related to API’s

WHO/EDQM/SFDA Conference

Quality of Pharmaceutical Ingredients

March 28, 2010

Guangxi Hotel, Beijing, China

Brendan CuddyScientific Administrator European Medicines Agency



  • What is the European Medicines Agency?
  • API’s in the Marketing Authorisation Application
  • International Active Pharmaceutical Ingredients (API) Inspection Pilot Programme
  • Future developments
  • Summing Up
  • Questions and Discussion
the european union 493 million people 27 countries
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 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
EMEA and EU System

EU institutions:Commission, Parliament

and Council

42 National competent


4,000 European experts

Committee on

Advanced Therapies


Management Board

Committee for Orphan

Medicinal Products


Committee for

Medicinal Products for

Human Use



Paediatric Committee



Committee ?

Committee for


Medicinal Products


Committee for Herbal

Medicinal Products


Industry Organisations

Patients and consumers


key terms

Marketing Authorisation

Manufacturing site(s) for

medicinal product

Manufacturing site(s) for

active substance(s)

Key Terms

Authorises the holder to place the medicinal product on the market

Sites located in EEA including importers must hold a manufacturing/importation authorisation (MIA)

Includes brokers who package, label and/or

Import active substances

eu gmp inspection system
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
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 manufacturer.
  • 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
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 form.

  • 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
QP Declaration: responsibilities

Active substance manufacturer



Batch release site and/or importer

Finished product manufacturer

supervisory role of the competent authorities
Supervisory role of the Competent Authorities
  • 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
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 non-compliance
      • 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 manufacturers15
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
background of the project
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 approach

Quality issues in 2008 for products with API manufactured outside EU (e.g. heparin)

justification of the project
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 project20
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
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
  • USA : US FDA

All agreed to participate in a pilot phase to last for 18 months with recommendation for future action.

organisation of the pilot program22
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 non- compliance

tools of the pilot program 1
Tools of the Pilot Program (1)
  • Objectives developed into :
  • Update on a pilot project to collaborate on international GMP inspection activities
  • Rules of engagement and procedures for participating authorities (active pharmaceutical ingredients/active substances)
  • 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
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
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 manufacturers
Geographic distribution of the API manufacturers
  • 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
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
Scenario a: inspection report sharingpassed or future inspection

API 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 inspection s with extension of the scope
Scenario b: sharingof inspectionreports of plannedinspections with extension of the scope

API 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
Scenario c: joint inspection

API manufacturer 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
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
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

n ext steps
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
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
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



  • API manufacture
  • & import to mandatory notification procedure
  • Information on notified parties
  • available in a Community database
  • (EudraGMP database extension)
  • legal framework for APIs only on
  • manufacture
    • activities of distributors, traders,
    • agents and brokers outside
    • scope of Community legislation
      • should be subject to the relevant GMP

Audit and enforceability of GMP

Enhancing audit and enforceability of GMP



  • Make regular audits of API suppliers on GMP compliance mandatory
    • 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
  • obligation of the MIA holder to source from GMP compliant API manufacturers
  • in practice auditing by the MIA holder (EU FP manufacturer or importer)
  • FP manufacturers test APIs supplied to them
      • other sites / other processes as declared

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):
    • GMP not equivalent to EU
    • inspection and control mechanisms insufficient
  • Need to continue cooperation with TC
    • bilateral arrangements
    • international synergies in performing inspections
  • Legal basis for any GMP API inspection
  • competent authorities (EU inspectorates) shall carry out API inspections if suspicion of non-compliance 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
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
To sum up
  • Overview of API’s in Marketing Authorisation
  • Inspections of active substance manufacturers
  • 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