Global Good Distribution Practice Update

1. Global Good Distribution Practice Update Karl Kussow Manager, Quality: FedEx Custom Critical

2. GDP Highlights • “Cold Chain” to “Temperature-Control Chain” • Monitoring • Security / Serialization • Quality Agreements • Complexity due to many countries and organizations, despite their common objective Disclaimer: This presentation is not legal advice. Please seek appropriate legal counsel for answers to your regulatory compliance questions.

3. Elements of Good Distribution Practice (GDP) • Security • Pedigree • Environmental monitoring • Temperature control • Auditable data record • Data access (QA/QP release, International Customs) • Quality systems • Procedures and Training for sustainability and continuous improvement • Flexibility for individual products

4. Regulatory and Standards-Based Guidance Driving GDP… European Directive for GDP transport and storage -- dir_2003_94_en CFR-21 Regulatory Guidance WHO GDP guide is often used by default when country or regional guidance is not published MHRA Romania Singapore Saudi Arabia S. Africa S. Korea Venezuela WHO Argentina Australia Austria Brazil Canada China Czech Rep. Egypt EU FDA ICH India Ireland Israel Italy Mexico Guide 0069 Best Practices PDA TR No. 39, 46, 52,53 Standards USP <1079> IATA PCR,ISTA, AFF et SFSTP * * Guide Pratique: Chaine du froid du medicament Reference: Rafik H. Bishara, “The Impact of USP <1079> on Cold Chain Management”, March 7, 2006 (Sensitech Sponsored Webinar), Revised March 21, 2010

5. Security: A Growing Concern • Cargo Screening (TSA and Local Countries) • 100% screening • Access controls • Chain of custody • Customs Trade Partnership Against Terrorism (C-TPAT) • Supply Chain Security Guidelines • Anti Counterfeiting / Diversion (HHS/FDA, CBP) • Standardized Numerical Identification / Serialization • E-Pedigree • PREDICT, Good Importer Practices

6. Security and Temperature: VISIBILITY + CONTROL • Controls have similar characteristics • Chain of Custody • Monitoring systems: real time for situational awareness • Track and Trace • Alert mechanisms: overlapping tiers • Clear instructions with training • Procedural controls • Ability to react to protect cargo while enroute

7. Traceability Know where the products are and verify they are the same as shipped • Some requirements found in 21 CFR 211.80, 150; 820.65, 86 • Containers indentified with a distinctive code and current status • Defined distribution system • Identify units in order to facilitate corrective action • Verify status at every step from mfg to end user • Only continue to distribute accepted units • Anti-Counterfeiting and Diversion prevention a priority of FDA • April 28, 2010, Letter: FDA Urges Industry to Prevent Cargo Theft • March 2010, FDA Guidance: Standardized Numerical Identification for Prescription Drug Packages • September 27, 2007, FD&C Act amended: FDA required to develop standards …for the purpose of securing the drug supply chain against counterfeit, diverted, subpotent, substandard, adulterated, misbranded, or expired drugs

8. Cold Chain Protection • Key Topics: • 21CFR 211.142 • Store in appropriate conditions • WHO QAS/04.068 • GDP applicable to all pharmaceutical products • Temperature mapping of vehicles • Health Canada Guide 0069 • Supply-chain rules • Temperature monitoring of distribution chain • Brazil • For import release, all incoming biological products must have temperature-monitoring records showing proper storage temperatures. • EU • Ensure storage conditions at all times • Controlled temperature products (15-25 °C) should be transported by appropriate means • Temperature review is part of QP release • Integrated Approach to temperature protection • Stabilize the ambient temperature profile through procedure • Contingency Response through near-real-time monitoring • In-transit infrastructure / procedure • Temperature records • Easily available upon arrival at port of entry for customs/regulatory release • Balance Product stability, Process Control, and Package

9. Country Regulations and Guidance: Continued Development • Ireland • Medicinal products should be stored and transported under conditions which ensure that their quality is maintained • EU (GDP guide) • Ensure storage conditions at all times. Controlled temperature products (15-25 °C) should be transported by appropriate means • Saudi Arabia and Brazil very similar • Electronic datalogger in every shipment • For import release, all incoming biological products must have temperature monitoring records showing proper storage temperatures • India • Constant temperature monitoring • Refrigerated vans should be qualified. Qualification should be done by keeping sufficient temperature monitors to cover all parts of the van • Product Serialization • United States, Europe, Turkey, Brazil and India

10. GDP Quality Systems – Recent Updates Canada, Guide 0069, Updated January 2011 • Label claim and Transport environmental requirements supported by stability and technical justification. [1.0, 2.0] • ANY environmental category • Qualified equipment / environmental controls [3.1, 3.2**, 3.3*] • Calibration, Monitor locations, alarms, recorded [3.1, 3.2, 3.3] • Properly loaded [3.1] • Protect from weather during transfer (load/unload) [3.2, 3.4] • Written agreements / procedures [2.0, 3.1, 3.2, 3.5] • Training [3.1] • Transportation Records including monitoring records [3.5] • Audits [3.2]

11. Supply Chain GDP Guidance Implement effective cold-chain management to ensure a product’s safety, efficacy, and pedigree are not affected by the distribution process. PDA TR-52 Topics addressed by the guidance 3.0 Requirements 3.1 Stability 3.1.1 Storage Temperatures 3.1.2 Shipping Temperatures 3.1.3 Stability Testing to Support Distribution 3.2 Distribution Control Management 3.3 Performance Management 3.4 Supply Chain Partner Management Table: Seven Pillars of Good Distribution Practices Source: PDA Technical Report No. 52 , Guidance for Good Distribution Practices (GDPs) For the Pharmaceutical Supply Chain Purchase online from the PDA at www.pda.org

12. IATA Perishable Cargo Regulations Chapter 17 Safeguarding the temperature-control chain • Service Level Agreement • Common Quality Systems expectations • Label provides consistent identification of temperature-sensitive pharma cargo with the correct handling instructions to care for them Shipment-specific temperature instruction noted here.

13. Quality Agreements – tool for communication and compliance • Common to regulation, standard, and best practice guidance • Integrate competing viewpoints: Product vs. Service Level • Quality Agreement specific to transport • Service Guide as resource

14. Temperature-Control Transportation Best Practice • Quality Management System • Communication • Real time • Transparent access • Manual and automated alarms • Qualified equipment • Mapped vehicles • Properly located temperature monitors • Calibrated monitors • Properly trained personnel • Balanced Process: Risk, Product / Compliance, System / Equipment Capability • Compliant audit record

15. Challenges for HPCL industry • Temperature Control = not just “Cold” Chain • Quality System activities: • Pre-shipment (SOP/Agreement and Qualification) • Enroute (Exception Detection, Intervention) • Post shipment (Investigation and CAPA) • Integrated Approach • Service level integrated with product requirements • Options to achieve the right balance • Value: quality, risk, protection, controls, flexibility, sustainability, scalability, cost • Temperature Controls: Packaging/Container • Temperature Controls: Transport Service Level • Controls • Transit time • Temperature profile • Contingency response options

16. Opportunities for Transportation • Temperature-control infrastructure • Enhanced controls during transport • Improved contingency response • Combine data streams into one interface for monitoring and reporting • Temperature (and other environmental factors as needed) • Location • Status (who has custody right now) • Door-open (and/or light) • Identity confirmation (enabling authentication at delivery)