Life Packaging Technology

1.   Life Packaging Technology Packaging Considerations for Combination Products MDM Minneapolis 2009 Minneapolis, MN Conference Session 300 Karen K. Greene Vice President Life Packaging Technology karen@lifepacktech.com

2. MDM Minneapolis 2009 Agenda Packaging Considerations for Combination Products Regulatory Overview, Drugs, Biologics, Devices, Primary packaging and shipping systems Packaging Design Challenges Design and Testing Solutions Future Trends 2

3. MDM Minneapolis 2009 Market Size Global Market Size Navigation Consulting Inc. estimates the global market for combination products @ $9.5 billion in 2009 MedTech Executive, MX, magazine, Cannon Communications, cites that the global market for all medical devices @ $336 billion in 2008

4. MDM Minneapolis 2009 Regulatory Overview Office of Combination Products established in Dec. 2002 21(title) CFR Part 3– Definition of Primary Mode of Action of a Combination Product “A combination product is a product comprised of any combination of a drug and device; a device and a biological product; a biological product and a drug; or a drug, a device and a biological product.” A combination product contains two or more regulated components Two or more products packaged together in a single package or as a unit Separately packaged products intended for use specifically in combination with each other, in order to achieve the intended use 4 Guidance on Combination ProductsGuidance on Combination Products

5. MDM Minneapolis 2009 Regulatory Overview Office of Combination Products, continued PMOA– Depending on the primary mode of action, a division of the agency is assigned jurisdiction-- CDER—center for drug evaluation and research CBER—center for biologics evaluation and research CDRH– center for device and radiological health “FDA believes that it is important to address the scientific and technical issues raised by innovative combination products in order to develop efficient, appropriate techniques and methods to ensure the safety, effectiveness, and quality of the combination product”. 5

6. MDM Minneapolis 2009 Regulatory Overview FDA UPDATE on combination products— Proposed amendment to the post market safety reporting for combination products The proposed rule will clarify the postmarket safety reporting requirements that apply when regulated articles(drugs, devices, biologics) are combined to create a combination product. The reporter must comply with the requirements for postmarketing safety associated with the application(e.g. NDA(drugs), 510 (k)(devices)) used to approve the product as long as 5 unique specified provisions unique to each different set of regulations are complied with. Lead Center(approved the product) is responsible for the review of all post market safety reports.

7. MDM Minneapolis 2009 Regulatory Overview Drugs and Biologics— Federal Food, Drug and Cosmetic Act– mandates adequate information related to packaging materials FDA, CDER and CBER– Guidance for Industry, Container Closure Systems for Packaging Human Drugs and Biologics, Chemistry, Manufacturing and Controls, May 1999 U.S. Pharmacopeia/National Formulary—requirements for containers, defined in “General Notices and Requirements” CDER and CBER approve a container closure system used in the packaging of a drug or biologic as part of the application(NDA, ANDA, BLA) for the drug or biologic. 7

8. MDM Minneapolis 2009 Regulatory Overview Terminally Sterilized Medical Devices US FDA--- Consensus standard on CDRH website ISO 11607: 2006 Part 1 and Part 2 Developed by ISO Tech Committee 198, Sterilization of Health Care Products Part 1– Requirements for materials, sterile barrier systems and packaging systems Part 2—Validation requirements for forming, sealing and assembly processes TIR 22, Technical Information Report, Guidance for compliance to ISO 11607. EU Pathways CE Marking for compliance to relevant EU Directives Active Implants—AIMDD 90/385/EEC Med Device Directive—MDD 93/42/EEC In Vitro Diagnostics—IVDD 98/79/EC Amendments to both MDD and AIMDD came into effect in 2007 Most significant change– align requirements for active implantable med devices containing an ancillary medicinal substance with the requirements contained in the MDD. 8

9. MDM Minneapolis 2009 Regulatory Overview Shipping Regulations 9

10. MDM Minneapolis 2009 Regulatory Overview Global Shipping Regulations— World Health Organization(WHO)—International packaging and shipping of vaccines WHO—Good Distribution Practices for Pharmaceutical Products USP—General Chapter 1079, Good Storage and Shipping Practices Canada– Guide 0069--Guidelines for Temperature Control of Drug Products during Storage and Transportation EU– 94/C63/03--Guidelines on Good Distribution Practice of Medicinal Products for Human Use Irish Medicines Board’s—Guide to Control and Monitoring of Storage and Transportation Australia--- Code of Good Wholesaling Practice for Therapeutic Goods for Human Use US PDA—Technical Report No. 39, Cold Chain Guidance for Medicinal Product: Maintaining the quality of temperature sensitive medicinal products through the transportation environment. IATA—July 2009--9th Edition-The Perishable Cargo Regulations Manual—Management of time & temp sensitive goods, chapter 17. 10

11. MDM Minneapolis 2009 Packaging Design Challenges Packaging Design Challenges 11

12. MDM Minneapolis 2009 Packaging Design Challenges Combo Product Package Design Requirements: Containing a terminally sterilized medical device The goal of a terminally sterilized medical device package system is multi-purposed: Allow sterilization Provide physical protection Maintain sterility to point of use Facilitate/allow aseptic presentation to the sterile field Drugs and biologics must cope with terminal sterilization methods Product stability is no longer just a physical trait for devices—drug stability Bioburden—keep it low to facilitate the effectiveness of terminal sterilization and the final product safety and efficacy Drugs must be tested after terminal sterilization to ensure that the drugs have not been altered in any unacceptable aspect. 12

13. MDM Minneapolis 2009 Packaging Design Challenges Combo Product Package Design Requirements: Oxygen barrier—products that are sensitive to oxygen. Moisture barrier—products sensitive to moisture or loss of moisture. Consider that terminal sterilization via EO gas may be required for drug and device efficacy—package design must be porous for gas sterilization process but NON-porous for shelf life UV barrier– ultraviolet light impacts product efficacy. 13

14. MDM Minneapolis 2009 Packaging Design Challenges Combo Product Package Design Requirements: Kitted Drug/Device Package Design Thermoformed tray design to accommodate separately packaged drug Addition of separately packaged drug to occur in a secondary packaging operation which then requires subsequent terminal sterilization Increases package design complexity and validation requirements 14

15. MDM Minneapolis 2009 Packaging Design Challenges Combo Product Package Design Requirements: Temperature Controlled Packaging 15

16. MDM Minneapolis 2009 Packaging Design Challenges Combination Products—Bioengineered Drugs Bioengineered drugs are large molecule drugs, more susceptible to temperature and humidity variations— Daphne Allen, PMP News, Feb 2008 Pharma-Bio Transport---”Biotech enabled drugs and medical devices are not just changing healthcare. They are changing the supply chain, transforming a good portion of it into a cold chain. New packaging and monitoring technology will be key.” 16

17. MDM Minneapolis 2009 Packaging Design Challenges 17

18. MDM Minneapolis 2009 Packaging Design Challenges Package Design Challenges Summary: Combo products with terminally sterilized medical device Terminal sterilization process must not compromise drugs and biologics Moisture and oxygen barrier requirements and requirement for gas sterilization, EO—requires porous substrate Hybrid pouch design– porous header strip, sealed and removed post sterilization Kitted combo products require multiple packaging operations and sterilization processes Temperature control requirements, especially with long devices and unique temperature protection requirements 18

19. 19 MDM Minneapolis 2009 Testing Solutions

20. MDM Minneapolis 2009 Testing Solutions Medical Device Testing—Device and Package Shelf life studies ASTM F 1980---Accelerated aging, thermodynamic model Transportation/Distribution Simulation ASTM D 4169-05, -08 all distribution channels ASTM D7386-08, single parcel delivery ISTA Simulation Performance Test Procedures Package Integrity Testing ASTM F 2096 Gross Leaks by Bubble Leak testing ASTM D 3078-02(2008) bubble emission, packages with headspace ASTM F 1929 Dye Penetration for Seal Integrity ASTM D 4991 Leakage Testing of empty rigid containers by vacuum testing ASTM F1886-98 Visual inspection for seal integrity PDA Technical Report #27– Pharmaceutical Package Integrity Package Strength Testing ASTM F 88 Seal Strength of Flexible Barrier Materials Thermal Performance Testing Custom temperature profiles with instrumented packages ISTA 7D Thermal Controlled Transport Packaging for Parcel Delivery System Shipment PDA Technical Report #39—Temperature Sensitive Products Through Transportation 20

21. MDM Minneapolis 2009 Future Trends Future Trends Temperature Controlled Packaging Medical Device Packaging 21

22. MDM Minneapolis 2009 Future Trends The Last Mile Temperature Protection and Control- Increasing regulatory focus on the control and qualification of packaging systems designed to deliver the temperature controlled drug/device/biologic to the ultimate end user and final use venue USP 1079 Good Storage and Shipping Practices—General Chapters 22

23. MDM Minneapolis 2009 Future Trends USP 1079 Good Storage and Shipping Practices—General Chapters Guidance on Shipment from pharmacy to patient or customer Labeling Documentation Patient Communication Packaging Storage Monitoring 23

24. MDM Minneapolis 2009 Future Trends 24

25. MDM Minneapolis 2009 Future Trends The Last Mile-- Cryopak Case Studies—Alternatives Technologie Pharma– Canada—ATP Mirador Express Software and Database(vendor hosted) Real time, remote cold chain monitoring Vendor hosted, internet access 21 CFR part 11 compliant(electronic signatures/records) Adaptable RF sensors network Proxim Pharmacy and Shoppers Drug Mart chain in Canada Controlled by cold chain compliance specialists Qualifications– IQ/OQ by ATP. 25

26. MDM Minneapolis 2009 Future Trends 26

27. MDM Minneapolis 2009 Future Trends 27

28. MDM Minneapolis 2009 Future Trends Sustainability and Medical Devices Medical Device Developments “Initiatives and Incentives”, 3/31/09 edition-- U.S. purchasing groups and large hospital conglomerates moving in the direction of more sustainable medical device supply—patients, doctors, staff Green suppliers network The Green Suppliers Network is a collaborative venture --U.S. EPA-Environmental Protection Agency, and the U.S. Department of Commerce's National Institute of Standards and Technology's Manufacturing Extension Partnership (NIST MEP), Green Suppliers Network works with large manufacturers to engage their small and medium-sized suppliers in low-cost technical reviews that focus on process improvement and waste minimization. EPA provides program support and funding. Environmental Benefits Calculator– for industry use 28

29. MDM Minneapolis 2009 Conclusion Conclusion Effective Package Design and Validation = Your Combination Product’s Ultimate Integrity Assurance Expert knowledge of applicable regulations Effective drug stability studies design and execution, if applicable Thorough understanding of terminal sterilization methods such as EO, gamma and e-beam radiation and their effects on drugs and biologics The importance of packaging design to ensure drug and biologic efficacy and allow for effective terminal sterilization Temperature control expertise, if applicable Novel package design solutions, experience! Package testing resources and execution expertise 29

30. MDM Minneapolis 2009 References Individuals: William Hingle, Operations Director, TCP Reliable, Edison, NJ Anthony Alleva, Technical Services Manager, TCP Reliable, Edison, NJ Jan Gates, President, Southern CA Chapter, IoPP Hal Miller, Pace Solutions Yong Cho, LightSciences Oncology Daphne Allen, Pharmaceutical and Medical Packaging News 30

31. MDM Minneapolis 2009 Works Cited Allen, Daphne, ed. "Keys to the Cold Chain." Pharma-Bio Transport Supply Chain Ideas for HealthCare Feb. 2008: 4-4. Bishara, Rafik, and Kevin O'Donnell. "Developing Temperature Profiles for Medicinal Products in Distribution." Pharmaceutical and Medical Packaging News Sept. 2007: 36-47. Butschli, Jim, ed. "Testing, standards drive medical device packaging session." Healthcare Packaging Apr. 2009: 18-20. "Combination Products." U S Food and Drug Administration Home Page. 07 June 2009 <http://www.fda.gov/CombinationProducts/default.htm>. "Drugs." U S Food and Drug Administration Home Page. 07 June 2009 <http://www.fda.gov/Drugs/default.htm>. ISO 11607, Packaging for Terminally Sterilized Medical Devices,Parts 1 and 2. 2006th ed. AAMI, 2006. <http://www.epa.gov/greensuppliers/>. Medical Device Developments 31 Mar. 2009. 7 June 2009 <www.medicaldevice-network.com>. "Medical Devices." U S Food and Drug Administration Home Page. 07 June 2009 <http://www.fda.gov/MedicalDevices/default.htm>. "U.S. Pharmacopeia General Chapters 1079." 31

32. MDM Minneapolis 2009 Karen K. Greene, Life Packaging Technology LLC Thank You! Questions? 32 www.lifepackagingtechnology.com