1. 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

2. Agenda 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

3. European Medicines Agency

4. The European Union: 493 million people – 27 countries
The European Union today is a complex political entity with 493 million citizens in 27 countries. There are 22 official languages in the EU and three official alphabets. There are more unofficial languages spoken.
In the nid-nineties it was becoming quite difficult to market innovative medicinal products, not all member states had the resources/expertise to assess the applicaitons, there was no consistency in evauaiton timetables or in indications approved / or even trade names.
A new procedure was needed to enable a consistent approach to assessment of innovative medicines to ensure access
Member states of the European Union
Candidate countries 4

5. 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

6. EMEA and EU System 6 42 National competent authorities
4,000 European experts
Management Board
Committee for
Veterinary
Medicinal Products
(CVMP)
Medicinal Products for
Human Use
(CHMP)
Committee for Orphan
(COMP)
EMEA
EU institutions: Commission, Parliament
and Council
Patients and consumers
organisations
Industry Organisations
Committee for Herbal
(HMPC)
Paediatric Committee
(PDCO)
Committee on
Advanced Therapies
(CAT)
Pharmacovigilance
Committee ? 6

7. API’s in the Marketing Authorisation

8. Marketing Authorisation Manufacturing site(s) for
Key Terms
Marketing Authorisation
Manufacturing site(s) for
medicinal product
active substance(s)
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

9. 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

10. 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.

11. 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

12. QP Declaration: responsibilities
Active substance manufacturer
AUDIT
AUDIT
Batch release site and/or importer
Finished product manufacturer

13. 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

14. 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

15. Conditions For Inspection Of Active Substance Manufacturers
Biologicals
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

16. 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

17. International API Inspection Pilot Programme

18. 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)

19. 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.

20. 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

21. 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.

22. 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

23. 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

24. 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

25. 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

26. 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

27. 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.

28. Scenario a: inspection report sharing passed or future inspection
API manufacturer in third country
API 1
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

29. API manufacturer in third country
Scenario b: sharing of inspection reports of planned inspections with extension of the scope
API manufacturer in third country
API 1
API 2
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.

30. Scenario c: joint inspection
API manufacturer in third country
API 1
API 2
API 3
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.

31. 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

32. 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

33. Next steps
Regular teleconferences and 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.

34. Future Developments Legal proposal to combat counterfeit medicines
Pedigree of API Supply Chain Security

35. EC envisages a combination of tightened requirements in the API area
Notification requirements
Tightened GMP standards
Enhanced inspections

36. Notification requirements
Mandatory notification for manufacturers/importers of APIs
Present
Proposed
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 36

37. Audit and enforceability of GMP
Enhancing audit and enforceability of GMP
Present
Proposed
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 37

38. Enhancing API GMP inspections
Present
Proposed
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 38

39. 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.

40. Overview of API’s in Marketing Authorisation
To sum up
Overview of API’s in Marketing Authorisation
Inspections of active substance manufacturers
International Pilot Programme
New initiatives e.g EC proposals
The existing approach is based on shared responsibilities and obligations – finished product manufacturers/ active substance manufacturers (including traders/brokers etc.)/competent authorities/inspectors
New climate of transparency and information sharing
Risk based approach assures best use of resources
Aim is to better assure supply chain/overall quality of medicinal products for European patients by ensuring that everyone assumes these responsibilities
Evaluation of experience to-date is ongoing

41. Questions and Discussion
European Medicines Agency
7, Westferry Circus
Canary Wharf
London E14 4HB
United Kingdom
Tel: +44 (0)
Fax: +44 (0)