Good Distribution Practices: What do they mean to you? Presented by: Hedley Rees, Biotech PharmaFlow, UK

Agenda Distribution in Pharmaceuticals Why has GDP become such a hot topic? What is the current global landscape? What are the issues and opportunities? Q&A session

Distribution in Pharmaceuticals

Current EU GDP Regulations EU Guidance on Wholesale Distribution Practice (94/C 63/03) Sell to retail pharmacies without alteration of product properties Quality System should ensure: Authorised Storage conditions observed (incl transport) No contamination Stock turnover Stored safe and secure Right product, right address, satisfactory time period Tracing system to allow recall

Key Elements in Regulations Responsible person (oversee Quality System) Written contract with RP Written procedures Checking Bona Fides of suppliers and customers Staff Training Records/traceability Emergency plans Counterfeit Medicines

US Guidance on Distribution Not explicitly in 21 CFR 210/211 USP <1079> often regarded as FDA benchmark Other Guidance USP <1083> The Food and Drug Administration Safety and Innovation Act (FDASIA) US Senate Health, Education, Labor & Pensions (HELP) Committee consultation of Track & Trace

Distribution in a Nutshell Storage & Transportation E2E Supply Chain

Why has GDP become such a hot topic?

The Supply Chain Fragments…. Prevailing business model vertical integration local market management presence. predominately small molecule manufactured by chemical synthesis. 1980’s Outsource non-core activities Manufacture, analytics, distribution, storage Since New business models - innovator, virtual, biotech, generic/bio-similars and speciality Pharma Biologics form important portfolio position, with temperature and time sensitivities Markets have globalised into new territories Number and location of third party contractors and service providers proliferate.

Dis-integration of the supply chain Outsourcing begins in earnest…..

Integrity issues… Economically motivated adulteration – “Heparin, supplied by Baxter, found to be adulterated, with reports of 574 adverse events and nine patient deaths estimated J&J/McNeil placed under a ‘Consent Decree’ after recalls associated with supply chain issues. Novartis shells out hundreds of millions $ in manufacturing issues Shortages in US/EU supply chains result in governments and general public questions.

Security issues….. “Abbott hit by $4m diagnostics theft in USA” (June 2011) “Eli Lilly warehouse thieves make off with $76m haul” (March 2011) Counterfeiting – “Operation Singapore, 2 million doses of counterfeit medicine enter UK supply chain in 2006/7”. “FDA is still concerned that the drug supply is increasingly vulnerable to diversion of legitimate drugs (ie stolen or sold illegally)”. Rx-360 Newsletter September 28 2011

The fall-out…. Crippling impacts in the areas of patient safety, brand image and reputation, costs of remediation, customer service and investor confidence. A UNIVERSAL CRY FOR CHANGE! From regulators, governments, other competent authorities and patient advocacy groups.

What has been the response? …EU implements Falsified Medicines Directive. …EMA consults on dramatic tightening of GDP/GMP …FDA pens “Pathway to Global Safety and Quality”. …US Congressional Committees investigate. …President Obama wades in on drug shortages. …US Pharmacopeia consults on new Chapter < 1083 >. …PEW Charitable Trust writes report “After Heparin”. …GS1 Global Traceability Standard for Healthcare (GTSH).

What is the current global landscape?

Regulators collaborating globally FDA joins Pharmaceutical Inspection Co-operation Scheme (PIC/S). FDAs “Pathway to Global Safety and Quality” for systems to collect and share data between competent authorities across the world. The Food and Drug Administration Safety and Innovation Act (FDASIA), Title VII

Directive: Falsified Medicinal Products 2011/62/EU SCOPE Extending regulation to brokers of medicines Strengthened obligations on wholesale dealers Improving controls on quality of active substances and certain excipients Regulating medicines imported for re-export – new term “introduced” and rules governing access to medicines held in free trade zones & warehouses Requiring safety features for medicines at risk of counterfeiting Addressing the internet supply of medicines Strengthening inspection and ensuring appropriate penalties for counterfeiting are in place in Member States

Revised Guidelines on GDP - Consultation Quality Management (Ch 1) Senior management commitment Management of outsourced activities Risk management Personnel (Ch 2) Responsible Person Organisation chart Training in GDP Operations (Ch 5) Marketing Authorisation Holder (MAH) informed Qualification of suppliers and customers

Revised Guidelines on GDP (cont’d) Suspected falsified medicines (Ch 6) Distributors must inform competent authority and MAH immediately – procedure defined. Contract Operations (Ch 7) Written agreement allocating responsibilities Transportation (Ch 9) Delivery drivers trained in GDP Maximum limit of 24 hours for transport hubs Wholesalers distribution authorisation Specific provisions for Brokers (Ch 10) Register and have quality management system

GMP/GDP Regulations tightening Traceability to be reflected in Chapter 5 of GMP Guidelines, which will require “A record of where each active substance (including its critical starting materials) is manufactured, propagated, processed and handled prior to its use in the manufacture of a medicinal product. Tightening of requirements to check ‘Bona Fides’ of supply sources and other trading partners. Safety features required for products at risk of counterfeiting (eg. serialisation/authentication).

Regulations tightening (continued) Quality/Technical Agreements required between all actors in the supply chain with the Marketing Authorisation Holder (MAH) shouldering more responsibility. More stringent control in storage whereby some actor/logistics providers, holding product for greater that 24 hours, may require a Wholesale Dealer Licence (WL). A New guidance from EMA on GDP for active substances.

Barriers to traceability Links between MAHs and Distributors Brokers/Agents/Intermediaries Documentation eg C of A Commercial secrecy Drug Master Files (DMFs) Scope of Technical Agreements/Contracts Complex and expensive technology options Ownership of the process of change

Improvement Opportunities Quality/Technical Agreements defining mutual engagement processes, not tick boxes. Well defined processes for product and material procurement . Properly negotiated supply agreements that include risk sharing and performance criteria. Ownership amongst CMOs and Distributors Direction from sponsor companies (esp virtual) Proper briefing and requirements specs for 3PLs. Application of risk-based approaches to target resources at critical areas.

What is the long-term solution? Integrate strategically upstream and downstream Build shared processes and practices with business partners Aim to look at principles behind the regulations and manage risk Keep an end-to-end perspective on the supply chain at all times

Useful links EU GDP Consultation: http://ec.europa.eu/health/files/eudralex/vol-4/2011-07_gdpguidline_publicconsultation.pdf Responses to EU GDP Consultation: http://ec.europa.eu/health/human-use/good_distribution_practice/developments/2011_pc_gdp_en.htm EU Good Manufacturing Practice Directive (2003/94/EC): http://ec.europa.eu/health/files/eudralex/vol-1/dir_2003_94/dir_2003_94_en.pdf EU Good Distribution Practice Directive (94/C 63/03): http://ec.europa.eu/health/files/eudralex/vol-4/gdpguidelines1.pdf EU GMP/GDP: http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/document_listing/document_listing_000154.jsp&mid=WC0b01ac0580027088&jsenabled=true DIRECTIVE 2001/83/EC OF THE EUROPEAN PARLIAMENT http://www.emea.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2009/10/WC500004481.pdf Supply Chain Management in the Drug Industry: Delivering Patient Value for Pharmaceuticals and Biologics, J Wiley & Sons, NJ, February 2011. http://www.amazon.com/Supply-Chain-Management-Drug-Industry/dp/0470555173/ref=pd_rhf_gw_p_t_1

Questions? If there are any further questions, you can get to me in a number of ways: T: +44(0)1656 667710 M: +44(0)7718 884816 E: h.rees@pharmaflowltd.co.uk W: http://www.pharmaflowltd.co.uk LinkedIn: http://www.linkedin.com/profile/view?id=2432076&trk=tab_pro