1. Falsified Medicines Directive Where are we now? WQPF 7 th November 2013 This presentation is the opinion and expression of Pharmallaney Ltd and does not in any way represent that of other organisations or aim to detract from legislative requirements. Individual websites and references should be reviewed for accuracy..

2. Agenda Recent examples European transposition UK transposition/ MHRA expectations Adopted activities Pending Activities Worldwide activities Related legislation updates Copyright © Slide 2

3. Recent Examples Sept 2013 – Symbicort inhaler, UK wholesaler, legitimate B. No. – WHO notified of suspected drug intoxications involving 11 paediatric patients in Paraguay (2-9yrs) Dextromethorphan contaminated with Levomethorphan http://www.mhra.gov.uk/PrintPreview/DefaultSplashPP/CON149803?ResultCount=10&D ynamicListQuery=&DynamicListSortBy=xCreationDate&DynamicListSortOrder=Desc& DynamicListTitle=&PageNumber=1&Title=Counterfeit%20medicine%20recalls%20and %20previously%20seen%20counterfeits Copyright © Slide 3

4. European Implementation TypeActivityTarget DateStatus Delegated actGMP AS2013Closed Implementing actAS assessment criteria 2013Adopted 3 rd country listingOn-going GuidelineGDP for AS2013Consultation Feb 2013 GuidelineGMP excipients2013Consultation Feb 2013 GuidelineBrokering2013Adopted Delegated ActSafety features2014On-going Copyright © Slide 4

5. UK Transposition 20 August 2013 - The Falsified Medicines Directive is transposed through The Human Medicines (Amendment) Regulations 2013 [SI 2013/1855]. Copyright © Slide 5

6. MHRA Expectations Active substances systems in place to demonstrate – manufactured in accordance with GMP and distributed in accordance with GDP. – Evidence of audits at the sites of manufacturers, importers and/or distributors of active substances to verify compliance with GMP and GDP. http://www.rpharms.com/events-presentations-pdfs/qp-2013---mhra--- approach.pdf Copyright © Slide 6

7. MHRA Expectations Excipients – risk assessment/risk management procedure is incorporated in the Quality Management System. – There is an on-going program of work to determine the appropriate level of GMP for the excipients being used and that application of those standards can be demonstrated. Copyright © 7

8. MHRA Expectations Manufacturers, importers and distributors of active substances already operating before 2 January 2013 should have applied for registration before 2 March 2013. Copyright © Slide 8

9. Registration Existing holders of current MIA – Have to register as a manufacturer or importers of active substances. Existing holders of current WL and WDL that also import API – have to register separately as Importers and/or distributors of active substances. Copyright © Slide 9

10. Registration - API Register – API Nr – Company Name – Address – Manufacture/ import/ distribute http://www.mhra.gov.uk/home/groups/comms- ic/documents/websiteresources/con326473.pdf Copyright © Slide 10

11. Registration Brokers All activities in relation to the sale or purchase of medicinal products, except for wholesale distribution, that do not include physical handling Eight registered thus far – Registration number BRKR 11111 – Date authorised – Name – Address Copyright © Slide 11

12. Brokers (2013/C 68/01) Sept 2013 Chapter 10 QMS Personnel Documentation – Complaints/ recall – Falsified medicines notification – Recall – Checking MA status – Supply chain Copyright © Slide 12

13. Wholesaling ( 2013/C 68/01) GDP Sept 2013 Includes the requirements for – Supply chain – Identification of falsified medicines – Reporting of falsified medicines – Export to third countries Copyright © Slide 13

14. Active Substances Active substances – White list – Written confirmation – Waiver Copyright © Slide 14

15. Active Substances Assessment of manufacturing standards in the EU for active substances are those of the ‘International Conference for Harmonisation’ – ICH Q7. White list for equivalent GMP and inspection capabilities. Copyright © Slide 15

16. Active Substance White List – Switzerland 23 Nov 12 – Australia 25 Apr 13 – Japan 5 Jun 13 – USA 21 Jun 13 – Singapore – no listing – Israel- contacts on going – On-going - Brazil, New Zealand Copyright © Slide 16

17. Written Confirmation Issued by the Regulatory Authority Based on the plant each imported consignment has to be accompanied by written confirmation; a copy is permitted Copyright © Slide 17

18. Written Confirmation Independent of site inspection by an EU Member State or by the European Directorate for the Quality of Medicines (EDQM) of the Council of Europe MRA Copyright © Slide 18

19. India 15 July 2013 India’s Central Drugs Standard Control Organization (CDSCO) posted a list of granted written confirmations 57 active API manufacturing sites have been confirmed by the CDSCO based on Certificate of Pharmaceutical Product, WHO GMP guidelines, US FDA or EDQM or TGA inspection certificates. If a company does not have prior inspections or certificates, the CDSCO will conduct an inspection. http://www.cdsco.nic.in/WC%20List.%20(2)17.7.2013%20(1).xls Copyright © Slide 19

20. Others Some countries (Korea, South Africa, Ukraine) have started to issue confirmations others have confirmed that they will (Canada & Taiwan). Some countries (Mexico) have agreed to provide confirmations but will later apply for listing. Copyright © Slide 20

21. Waiver Exceptionally and where necessary to ensure the availability of medicinal products, following inspections by an EU Member State, a Member State may decide to waive the need for a written confirmation for a period not exceeding the validity of the GMP certificate. Copyright © Slide 21

22. Pending Activities GMP for excipients GDP for AS Sales at a distance Safety features Copyright © Slide 22

23. Excipients Draft guidance issued in Feb 2013 – Embraces ICHQ9 Type of excipient – quality/ safety/ function Identity of appropriate GMP – QMS focus Confirmation – supplier review EXiPACT – has anyone used this route? NSF-IPEC 363- American std for those not wanting ISO standard. Under consultation http://ec.europa.eu/health/files/gmp/2013-02_guidelines_excipients_cons.pdf Copyright © Slide 23

24. GDP Active Substances Under consultation Typical requirements of GDP Records - Identity and address of original manufacturer, batch number Purchase orders Bills of lading, transportation and distribution records Receipt documents Name or designation of active substance Authentic Certificates of Analysis, including those of the original manufacturer Copyright © Slide 24

25. Sales at a distance to the public Sales of certain medicines are permitted in the UK but the supplier to be a person authorised or entitled to supply medicines to the public. The General Pharmaceutical Council holds a register of pharmacies, including those that supply of medicines via the internet a voluntary logo scheme provides some assurance to the public that the service provided is authentic Copyright © Slide 25

26. Sales at a Distance The person selling medicinal products at a distance must – provide the contact details of the body with which the service is registered – Every page of a person’s website displays a common EU logo – a hyperlink to the national website of the Member State in which that person and their business is established. Each national website must – provide information on the national legislation relevant to the sale of medicines at a distance, – the purpose of the national logo, – a list of suppliers of medicines at a distance in that country, – information on the risks of purchasing medicines illegally from the internet – a link to the website to be established by the European Medicines Agency. Copyright © Slide 26

27. Copyright © Slide 27

28. Safety Features The delegated act expected by 2014. Member States will have three years after adoption of the act to put the requirements in place Concept paper Nov 2011 pending further information. Copyright © Slide 28

29. Safety Features Consultation Paper – All prescription products must contain safety features – to identify an individual pack of medicinal products ('unique identifier') – verify whether the outer packaging has been tampered with (tamper evidence) Copyright © Slide 29

30. Safety Features Consultation paper Non-prescription products do not require safety features unless: – They are at risk of being falsified – The risk arising may be a potential hazard Copyright © Slide 30

31. Safety Features Assessment of non-prescription – Price of the product – Sales volume – Previous incidents of falsification – Characteristic of the product – Seriousness of the condition being treated Copyright © Slide 31

32. Worldwide Activities

33. FDA 20 th August 2013 FDA Launches Secure Supply Chain Pilot Program (SSCPP) – to assist FDA in preventing the importation of adulterated, misbranded, or unapproved drugs Applicants must – NDA/ANDA sponsor, or the foreign manufacturer, of the imported finished drug product or API. – Foreign drug manufacturers and U.S. establishments receiving drugs comply with GMP – have a validated secure supply chain protocol per the U.S. Customs and Border Protection’s C-TPAT program as either C-TPAT Tier II or Tier III. http://www.fda.gov/Drugs/DrugSafety/DrugIntegrityandSupplyChainSecurity/ucm365626.htm Copyright © Slide 33

34. China China will issue written confirmation for APIs from manufacturing sites that are under the supervision of its own FDA. Serialisation mandatory for some therapeutic areas Falsification introduced into (2010) 237. Copyright © Slide 34

35. Brazil April 2013 The National System of Drug Control by ANVISA provides for serialized drug identity and supply chain-wide drug traceability Serialized identification on secondary packaging (and hospital packs), using a 2D DataMatrix, which includes ANVISA drug registration number, unique randomized serial number, lot number, expiration date. These combine to form the ANVISA Unique Identifier of Medicines (IUM). ANVISA 11.903 2009 Copyright © Slide 35

36. Argentina National Food, Drug and Technology Administration ANMAT National Medicines Traceability System Regulation 3683/ 2011, Resolution 435/2011 The traceability system shall consist of the individually and uniquely identifying each unit Format not specified Copyright © Slide 36

37. Comparators Marketed medicinal products covered by FMD but not clinical trials. MHRA discussion PQG March 2012 – Value obtaining direct from originators Does anyone have something they can share with regards FMD and comparators? Copyright © Slide 37

38. FMD and GMP updates Eudralex Vol. 4 Chapter 1 …use of the correct starting and packaging materials, the selection and monitoring of suppliers and for verifying that each delivery is from the approved supply chain PQR - …. review of supply chain traceability of active substances. Copyright © Slide 38

39. FMD and GMP updates Eudralex Vol 4 Chapter 7 The Contract should describe clearly who undertakes each step of the outsourced activity, … supply chain, Any records ……complaints or a suspected defect or to investigating in the case of a suspected falsified product must be accessible and specified in the relevant procedures of the Contract Giver. Copyright © Slide 39

40. FMD and GMP updates Chapter 5 – proposed Supplier selection… ‘supervision should be proportionate to the risks posed by the individual materials, …. source, manufacturing process, supply chain complexity and.. final.. in the medicinal product. approval and maintenance of suppliers of active substances and excipients……… Copyright © Slide 40

41. FMD and GMP updates Chapter 8 – Proposed All concerned competent authorities should be informed in case of a quality defect (….., detection of falsification..) Special attention should be given to establishing whether a quality defect relates to falsification Copyright © Slide 41

42. FMD and GMP updates Annex 16 –Draft The entire supply chain of the medicinal product ….. is documented and available for the QP. The active substances …..have been manufactured in accordance with GMP ….and distributed to GDP Copyright © Slide 42

43. FMD and GMP updates Annex 16 –Draft The excipients ….have been manufactured … in accordance with the ascertained manufacturing practice Copyright © Slide 43

44. Thank you!!