The purpose of Gap Analysis is to assist pharmaceutical manufacturers, distributors or 3 PLs (3rd Party Logistics Providers) to help them identify gaps in their cold chain supply chain network or systems. What you will learn: * The regulatory aspects related to the cold chain * Responsibilities in the supply chain * Requirements for the storage and handling of drug products * Packaging, transportation and distribution of drug products * Performing a gap analysis to know what needs to be done in order to fully comply with regulations and optimize your processes * Ways and means to develop an executable action plan How you will benefit: * Understand how to execute a cold chain regulatory gap analysis * Discover what should be covered when looking at cold chain compliance * Gap analysis: The first step to develop a cold chain compliance program * Uncover the requirements for the storage and distribution of drug products * Sharing the responsibilities for a good cold chain compliance

1. How to perform an efficient Cold Chain Compliance and Gap Analysis ?IQPC WorkshopPhiladelphia, PASeptember 20, 2010

2. COLD CHAINREGULATIONS & GUIDELINES Summary The pharmaceutical cold chain concept implies all necessary means to maintain therapeutic products in the specified manufacturer’s temperature limits during all the logistic and distribution process (manufacture, storage, transportation, final use). The cold chain compliance and gap analysis is the very first step to evaluate the compliance of your operations and logistics in regard to the regulatory context. The respect of the cold chain initially implies to know well constraints which surround it and traps to be avoided. How to prepare a cold chain regulatory gap analysis? What should be covered when looking at cold chain compliance? Gap analysis: a first step to develop a cold chain compliance program. What are the requirements for the storage and distribution of Drug products? How are shared the responsibilities for a good cold chain compliance?

3. Overview of Cold chainregulations & guidelines Food and Drug Administration (FDA): CFR 205: « Guidelines for State Licensing of Wholesale Prescription Drug Distributors »; CFR 211: « Current Good Manufacturing Practice for Finished Pharmaceuticals ». Food and Drug Administration (FDA): Draft Guidance for Industry, Stability Testing of Drug Substances and Drug Products” June 1998; International Conference on Harmonization (ICH), “Guidance for Industry, Q1A(R2): Stability Testing of New Drug Substances and Products,”November 2003. United States Pharmaceopaedia: Chapter 1079: « Good Storage & Shipping Practices »; Chapter 1118: « Monitoring Devices-time, temperature and humidity »; Chapter 1077: « Good packaging practices ». Parenteral Drug Association: PDA Technical Report No39, revised 27: Guidance for temperature-Controlled Medicinal Products: Maintaining the Quality of Temperature-sensitive medicinal Products through the Transportation Environment (Suppl., vol. 61, no S-2).

4. Overview of cold chainregulations & guidelines Health Distribution Management Association (HDMA): « Guidelines for Managing Cold Chain & Temperature Sensitive Products » (2009). Health Canada (HPFB Inspectorate): «Guide 069, Guidelines for temperature Control of Drug Products during Storage and Transportation »; Date Issued: October 17, 2005. International Safe Transit Association (ISTA) Test Procedure 5B : Focused simulation guide for thermal performance testing of temperature controlled transport packaging. Test procedure 7D: Thermal controlled transport packaging for parcel delivery system shipment. ISTA 7E + Standard 20. American Society for Testing and Material (ASTM) Standard Test Method D 3103-99: Thermal insulation quality of packages.

5. Overview of Cold chainregulations & guidelines International Conference on Harmonization (ICH) Note for guidance on stability testing: stability testing of drug substances and products (ICH): CPMP/ICH/2736/99 (revision of ICH/380/95). International Air Transport Association (IATA) Time and Temperature Task Force (TTTF); « The Perishable Cargo Regulations manual » Cold Chain Committee Guidelines for shippers and transport service provider’s partners involved in the distribution of pharmaceutical products registered for storage between 2°C and 8°C. Guidelines for the development of insulated shipping containers to ensure the quality of products witch have registered conditions between 2°C and 8°C.

6. Overview of Cold chainregulations & guidelines US FDA: Adulterated Drug Products, FD & C Act Chapter V, sec.501. Sub-chapter A, (2)(B) states: "A drug or device shall be deemed adulterated - if the methods used in, or the facilities or controls used for, its manufacture, processing, packing, or holding do not conform to or are not operated or administered in conformity with current good manufacturing practice to assure that such drug meets the requirements of this Act as to safety and has the identity and strength, and meets the quality and purity characteristics, which it purports or is represented to possess.« The use of the term holding is an interesting one. "Holding" of a drug occurs when the drug is being distributed, transported, warehoused or stored. "Storage (holding) of a drug at appropriate temperatures and under appropriate conditions is a requirement" within current Good Manufacturing Practices (cGMP). Code of Federal Regulations Title 21, Sub-chapter C, Part 205 Sec. 205.50(c)

7. Additional Regulations Additional Regulations that may impact the Storage and Distribution of Drug products include; General Security / Anti-counterfeting National Association of Boards of Pharmacy (NABP): Verified-Accredited Wholesaler Accreditation (VAWD). State Regulations (State Board of Pharmacy): Pharma Distribution, Licence, Pedigree. Transportation Security Administration (TSA): Screening of Cargos (Air, Sea, Ground); Title 49 of the Code of Federal Regulations (CFR), Chapter XII, parts 1500 - 1699. DEPARTMENT OF HOMELAND SECURITY, Transportation Security Administration, 49 CFR Parts 1520, 1540, 1542, 1544, 1546, and 1548, « Air Cargo Security Requirements ». US Department of Transportation

8. Principles The quality of drugs must be maintained throughout all distribution networks to ensure that these products will reach the hospital, and the consumer, without any deterioration of their therapeutic properties. The Quality Control service needs to ensure that conditions of storage are observed along every moment, including during transport. Standardized Operation Procedures (SOPs) should be implemented to describe all operations likely to affect the quality of Drugs or the distribution, including the reception of deliveries, storage and recording of storage conditions. Instruments and equipments used should be adequately qualified and up-to-date to ensure conservation and distribution of Drugs.

10. Documentation

11. SOPs

12. Reception area

13. Storage area

14. Monitoring of storage area

15. Transportation of Drug products

16. Monitoring of storage area

17. Transportation of Drug products

18. Monitoring of temperature in transport

19. Returned products

20. Returned of non defective products

21. Emergency plan/drug products recall

23. Analysis of Staff Members Recommendations for the training of your staff members include; Staff members should be trained to the standards of GMP/GDP relating to their specific tasks. Training should be monitored and ensured by a qualified employee Training should be in conformity with programs established by your company’s quality department and all training activities should be documented and co-signed. The effectiveness and efficiency of your company’s training processes should be evaluated on a continuous basis. Training should be offered before any application of a new or modified SOP is created. Staff working in areas where active, toxic, infectious or sensitizing products are handled, should receive a specific training for this purpose.

24. 1: not compliant 2: weaklycompliant 3: ongoing U: undetermined

25. Analysis of Documentation Processes Questions you should be asking of your company’s documentation processes include: Are your shipping documents complete? Are your storage conditions well documented? Are your documentation processes complete and include all regulatory aspects? Are you currently documenting all out-of-specs? Do you currently have Quality agreement with all your subcontractors? Recommendations for your company’s documentation processes include; Storage and shipping conditions must prevent any deterioration of the content, purity and physical characteristics of the drug. In order to show that these conditions are respected, standardized operation procedures (SOPs) and shipping / reception registers are available: Transport and storage documentation Approved shipping documentation for the products forwarding. Evidence demonstrating that shipping requirements were respected (temperature control). Drug production documentation. Documentation attesting that the drug manufacturing, packaging, labeling, storage conditions and final analysis are all in conformity with Good Manufacturing Practices requirements.

26. Analysis of Documentation Processes Documentation is performed to attest that the duration during which the drug, placed in the container in which it is sold, will remain in conformity with the specifications. Files on each Drug batch sale or manufacturing should be documented and stored. In Reception/Shipping documentation are described : Drugs description; Quantity; Name and addresses of the recipient; Name and Addresses of the shipper; Batch number; Drug scratch date; Shippingdate. All documentations should be available upon request from the quality department. All registers relating to transport, including those of monitoring, should be kept at least a year after the expiration date of the product. The statements of temperature should be available for examination. Registers containing data relating to investigations and interventions at the time of variations in the temperature compared to the fixed parameters, are kept at least a year after the expiration date of the product. When conveyors are retained, all conditions should be stipulated in a contract written between the distributor and the third party. All the subcontractors should then conform to the applicable requirements.

27. 1: not compliant 2: weaklycompliant 3: ongoing U: undetermined

28. 1: not compliant 2: weaklycompliant 3: ongoing U: undetermined

29. Analysis of Standardized operating procedures(SOP’s) Questions you should be asking of your company’s SOP processes include: Are all of your SOPs on Cold Chain well written and readily available to all employees upon request? Are your SOPs complete, covering all regulatory aspects related to cold chain compliance? Are all SOPs signed and approved? Recommendations for your company’s SOP processes include; All Cold Chain SOPs should be written and included on your QA system. It is the company’s responsibility to write SOPs, implement them, train employees, approve and secure them and document all training activities The SOPs must be available at all time and review periodically. They have to be signed and approved by the QA manager.

30. 1: not compliant 2: weaklycompliant 3: ongoing U: undetermined

31. 1: not compliant 2: weaklycompliant 3: ongoing U: undetermined

32. Topics to be included in SOPs

33. Analysis of Reception / Storage Area Questions you should be asking of your company’s reception/storage processes include; Do you have systems to control the temperature and humidity in your storage area (HVAC system)? Are thermostats secure as to not allow access to change set-points by unauthorized employees? Is your tracking far enough away from doors to ensure the protection of your products from out-of-specs? Do you regularly perform mapping of all your storage area during both the winter and summer season? Recommendations for your reception/storage processes include; The receiving area should protect deliveries from bad weather, during the unloading of Drugs. The entrance to the receiving zone should be separated from the storage area. The shipping/receiving area should not allow a direct access to the production area. Precautions should be taken to prevent unauthorized people from entering the storage area

34. Analysis of Reception / Storage Area The storage area should be frequently cleaned and the frequencies of cleaning schedules should be well documented. Areas where drugs and returned products are placed in quarantine should be clearly identified and access should only be granted to the appropriate staff. Storage areas should be well lit to facilitate all operations for successful storage. The temperature and moisture levels (when necessary) should be controlled, so that, raw materials, finished products, samples and standards of reference are not faded. Special conditions (of temperature, moisture, light, etc) that are necessary for the storage of products in transit should be established. Check-outs should be carried out and documentation should be readily available.

35. Analysis of Storage Equipment Questions you should be asking about the storage of your equipment include: Are all of your sensors and probes calibrated at least once every year? Is all your equipment accurately identified? Have all employees been thoroughly trained on storage related SOPs? Are all equipment files (SOPs) readily available for employees. Are all critical components of our equipment clearly identified? Is the temperature distribution inside the equipment within the specified range? Recommendations for the storage of your equipment include; Instruments and devices used to monitor and regulate the temperature need to be calibrated at least once a year. Analysis of the temperature distribution in warehousing areas dedicated to temperature sensitive products are effectively performed. The uniformity of the temperature distribution is demonstrated (Equipment Qualification). All storage equipment should be identified as well as Critical components of storage equipment . Each equipment should have an up-to-date file that is readily available. An effective maintenance program should be in place for all storage equipment. The storage process for equipment should be covered by a specific SOP.

36. Receiving Area 1: not compliant 2: weaklycompliant 3: ongoing U: undetermined

37. 1: not compliant 2: weaklycompliant 3: ongoing U: undetermined

38. Analysis of the Monitoring of Storage Areas Questions you should be asking about the monitoring of your storage areas include: Do you have an HVAC system that controls the temperature and humidity throughout the storage area? Did you perform mapping of all storage areas during the winter and summer seasons? Do you have a validated, real-time monitoring system? Do your sensors monitor hot & cold spots throughout your storage area? Are all probes and sensors calibrated at least once every year? Recommendations for the monitoring of your storage areas include; Temperature distribution studies should be carried out on all cooled storage areas; the uniformity of the temperature distribution must be demonstrated. The temperature in refrigerators and cold rooms should be measured on a continuous basis. The data of the temperature recordings should be available and documented regularly. Alarms used to monitor the temperatures of storage enclosures should be examined regularly. Instruments used to supervise and control the temperature of products in stock should be calibrated at least once a year.

39. Monitoring of warehousing area 1: not compliant 2: weakly compliant 3: ongoing U: undetermined

40. Continuous monitoring Temperature Monitoring System for Storage and Transportation

42. xTag Sensors act as relays.

43. xTag Sensors can work as Data Loggers.

45. Global Monitoring Applications Example of an international supply chain with the ATP-Mirador™ global monitoring solution (combined real-time and continuous modes)

47. Map Storage areas

48. Perform Qualification of Storage equipment

49. Perform Profile Analysis in Transport

50. Monitor Warehousing / Storage areas

52. Temperature/R.H.

53. Reusable / Single-use

54. Pigtail

55. Thermoocouples

57. Analysis of DrugTransportationProcesses During the transport of drugs in cold chain process, insulating containers should be used, in an effort to avoid direct contact with the drug and its conditioner, thus preventing the drugs from the possibility of freezing. The means of transport for drugs requiring a specific storage temperature should be provided with recorders and temperature sensors that are capable of taking acquisitions of temperature ranges throughout the duration of the transportation. Temperature data that is recorded through the transportation process should be analyzed for every delivery. There must be a procedure to apply corrective actions in case of unfavourable events during transportation. Temperature data that is should be readily available for any additional analysis. Instruments used for the monitoring of temperatures during transportation should be checked out regularly and calibrated at least once every year.

58. Drug transportation According to the nature of Drug to transport, adequate precautions should be taken (ex: control of temperature...). Drugs should be transported so that: Their identification is clear and available; They do not contaminate, and are not contaminated by other products; Precautions are taken to avoid any damage and breaking; They will not be exposed to conditions likely to deteriorate their therapeutic quality (heat, cold, light, moisture...). During the preparation of a delivery, following information should be taken into account: Destination; Transportation duration; Seasons; Nature of Drugs.

59. Drug products transportation 1: not compliant 2: weaklycompliant 3: ongoing U: undetermined

60. Drug Product Transportation 1: not compliant 2: weakly compliant 3: ongoing U: undetermined

61. Drug Product Transportation 1: not compliant 2: weakly compliant 3: ongoing U: undetermined

62. Drug Product Transportation 1: not compliant 2: weakly compliant 3: ongoing U: undetermined

63. Drug Products During Transportation Security (Air Transportation) Background Provide screening of all property, cargo, carry-on and checked baggage, along with other articles, that will be carried aboard a passenger aircraft operated by either a domestic or foreign air carrier. Establish a system to screen, inspect, or otherwise ensure the security of freight that is to be transported in all-cargo aircraft as soon as practicable. Screening Air Cargo Certified Cargo Screening Program (CCSP) : A key component of TSA’s response to the 9/11 Act mandate is the Certified Cargo Screening Program (CCSP). Under CCSP TSA will certify cargo screening facilities located throughout the United States that screen cargo prior to providing it to airlines for shipment on passenger flights. Participation in the program is voluntary and designed to enable vetted, validated and certified supply chain facilities to meet the 100 percent screening requirement. Today, there is a multi-layered approach to air cargo security: allowing only known and established shippers to offer cargo to passenger airlines for shipment, randomly screening a significant percentage of all cargo, deploying explosive detection canine teams at high volume cargo airports and conducting covert tests and no-notice inspections of cargo operations by hundreds of inspectors.

64. Drug Product Transportation (Air) Certified Cargo Screening Program (CCSP) Screening 100 percent (100%) of cargo on passenger aircraft is designed to ensure the safety of the traveling public. TSA designed CCSP to provide businesses with the option to screen cargo in a cost effective manner and at various points of the supply chain. CCSP allows businesses to: Screen cargo where it is packaged Maintain in-house packaging integrity Avoid screening log jams at the airport Build bulk configurations to minimize cost CCSP: Is supported by the air freight and air carrier industries Leverages best practices from global supply chain programs Allows businesses to choose the best and most effective model for their needs

65. Drug Product Transportation (Air) Certified Cargo Screening Program (CCSP) Who can be involved ? Any facility that tenders cargo directly to an air carrier or indirect air carrier (IAC) may apply for the Certified Cargo Screening Program. Includes: Manufacturers, Warehouses, Distribution Centers, Third Party Logistics Providers, Indirect Air Carriers, Airport Cargo Handlers, Independent Cargo Screening Facilities. CCSP Requirements: Certified Cargo Screening Facilities must meet the rigorous security requirements for their physical location, personnel, and screening. Security: CCSP participants must have processes in place to screen prospective employees and contractors to TSA standards. Routine reviews of employees with access to cargo after screening must be conducted. Security threat assessments must be conducted on all employees as described in CCSP regulatory documents. Specialized training is also required for all person who will conduct screening, handle cargo, or have access to designated screening areas. Screening: CCSP participants must have procedures in place to prevent unauthorized access to cargo facilities where cargo is screened, prepared, or stored. Physical barriers must be in place at cargo handling and storage facilities as well as designated screening areas.

66. Drug Product Transportation (Air) Certified Cargo Screening Program (CCSP) Chain of Custody: Supply chain participants are required to maintain chain of custody standards for screened cargo. The standards must include all of the following: Documentation: Information must be documented and included with the shipment Methods- must be employed to ensure the cargo is secure and maintained throughout the shipping process Authentication- documentation and methods must be authenticated upon receipt by each party and at each point in the supply chain. Key Considerations: Each business should carefully examine the options and determine which method of screening program is right for their entity. Some factors to consider: Are your shipments carried on passenger aircraft? Will your shipments be comprised if opened for screening? What will screening cost? Are you products sensitive to shipping delays? Are you participating in other supply chain programs? (C-TPAT, cGMP, TAPA or other) Does the amount of shipping justify in-house screening?

67. Drug Products During Transportation& Effective Packaging Packaging for Drug products Must fulfill the users’ specifications requirements Must be designed thermally Must be related to Temperature Profile(s)/Logistic history Must be qualified thermally Must be verified Must be maintained (periodic control) Standards/guidelines: ISTA (5B, 7D, 7E, Standard 20) PDA Technical Report No39, revised 27

68. Drug Products During Transportation& Effective Packaging ISTA 7E & Standard 20: New ISTA 7E Profile: Based on 83 routes, on 12 months From Louisville, KY, star pattern distribution scheme, destinations close to known pharmaceutical distribution hubs were chosen. The profile is not intended to be geographically-specific, these profiles have global applicability. The ISTA 7E profiles have been developed by mapping the temperatures experienced in the 'shipping lanes' and not the temperature a particular geography was experiencing during those months. Experts in thermal shipping have agreed that these profiles encompass perhaps well over 90% of the shipping thermal challenge encountered in all seasons.

69. Drug Products During Transportation& Effective Packaging ISTA 7E & Standard 20: Standard 20 Standard 20 is a design and qualification process for insulated shipping containers. It is a comprehensive set of requirements to achieve a certified package according to ISTA 7E. ISTA Standard 20 Certification: for Labs Audited by certified ISTA auditor Provides Certified Thermal Professional ISTA 7E Certification Mark for Package A certified package signified that the shipper has been qualified to all the requirements of ISTA 7E. The documentation is complete for any purpose since the testing is comprehensive. Users with internal SOP's calling for further testing can follow those, but no further testing is required to comply with Standard 20. Users with known exceptions can perform field testing to determine which Certified shippers are appropriate in those instances.

70. Drug Product Transportation Packaging ISTA 7E & Standard 20: ISTA Standard 20 Process Step 1. ISTA Standard 20 ispurchasedfrom ISTA. Step 2. Standard 20 Laboratory Certification application issubmitted to ISTA. Step 3. 1-2 keylaboratory personnel becomecertified thermal professionalslevel I and II. Step 4. Laboratoryisaudited and approved by ISTA CertifiedAuditors. Step 5. ISC istested in accordance to ISTA Standard 20. Step 6. ISC testingresults and documentation submitted to ISTA. Step 7. ISTA reviewresults and issue Standard 20 certification mark for ISC.

71. Follow-up Following the Regulatory Gap Analysis, a Cold Chain Compliance program can be established: Staff members Documentation SOPs Reception area Storage area Monitoring of storage area Transportation of drug products Monitoring of temperature in transport Returned products Returned of non defective products Emergency plan/drug products recall Quality agreements

72. Recommendations With Regards to the existing processes and regulatory requirements, it is usually recommended to implement the following steps: Training: Training sessions should be scheduled for management, employees and all staff who handles sensitive products. Documentation: The company must have documents that demonstrate that drug (refrigerated and ambient) warehousing conditions comply with regulatory requirements in terms of external conditions like temperature, but also handling and transportation. SOPs: The company shall revise, complete and publish its SOPs, notably for its narcotics, and its thermal equipments. Mapping & Qualification: The company must complete the mapping and qualification of its warehouses, vaults, fridges, freezers, walk-in, to determine temperature distributions and to efficiently store its products in a manner that doesn’t affect its characteristics

73. Recommendations Monitoring: Temperature and humidity have to be controlled, and data must be available every time via a real time monitoring system. This system should be fully compliant, with alarms management, audit trail and reports management for authorized employees only. All data have to be filed in a secure system and be easily available for legal requests. Temperature Profile: The company should determine the temperature distribution profiles that apply to its sensitive products along the entire distribution and transportation process during warm and cold weather conditions. Qualified Packaging Methods: The company should design and use insulated containers, conditioning materials or other methods for shipments and storage, that are proven to maintain an the internal temperature determined to be compliant with the products labelling, during the entire transportation and storage processes (including receiving) until the product is packed-out and stored in the desired temperature range. Such packaging and shipping methods shall be consistent with the distribution conditions it was qualified for. Quality agreement: Agreements have to be signed with all subcontractors.

75. Train your staff and personnel about Cold Chain aspects and SOPs; Documentation and SOPs on Cold Chain processes

76. Mapping and Qualification: Comply with USP Chapter <1079>

77. On all Storage areas.

78. Changes in Storage Conditions: Comply with CFR 211

79. In Warehouses and Equipments (Change Control)

80. Monitoring: Comply withUSP Chapter <1079>, <1118>

82. To be installed and periodically controlled and updated (Cold Chain Maintenance).

83. New Regulations:

84. Be aware about new regulations and constraints during Transports (Air, Ground, Sea): TSA

85. Quality Agreements: Comply with USP Chapter <1079>