A global approach to good storage and distribution practices for the storage and distribution of pharmaceutical products.

Specialized Expertise and Technologies help ensuring Cold Chain Compliance during the Distribution of Medicinal Products to Dispensers, and up to the End-users.

Cold chain concept refers to all resources that are required to maintain temperature sensitive pharmaceutical products within temperature limits (e.g. 2-8ºC, 15-25ºC) as specified by manufacturers or producers, from production to distribution, including transportation and storage, - down to the end-user or patient.

Good Storage and Distribution Practices are natural extensions of Good Manufacturing Practices (GMPs), Good Clinical Practices (GCPs) and Good Laboratory Practices (GLPs). They now provide cold chain regulatory and compliance requirements for the storage and distribution of temperature-sensitive products, including Good Distribution Practices for Pharmaceutical Products, World Health Organization (QAS304.068), Guidelines on Good Distribution Practice of Medicinal Products for Human Use, European Medicines Agency (EMEA 94.C 63/03), Guidelines for Temperature Control of Drug Products during Storage and Transportation, IDGPSA, Health Canada (Guide-0069), Guidance for temperature-controlled medicinal products: Maintaining the quality of temperature sensitive medicinal products through the transportation process, Parenteral Drug Association (PDA, Technical report Nº39 revised 2007) and Good Storage and Shipping Practices - General Chapters, United-States Pharmacopoeia USP <1079>.

Cold chain compliance can be reached only when all the stakeholders involved in the pharmaceutical supply chain (manufacturer, wholesalers, pharmacy...) have addressed individually and as partners their quality issues in terms of handling, storage, distribution and transport of temperature-sensitive pharmaceutical products. The ideal solution consists in implementing a cold chain management plan that will cover all cold chain quality aspects.

Pharmaceutical Stakeholders to install Cold Chain Management Program
Major pharmaceutical stakeholders shall implement and maintain Cold Chain Management Program (CCMP) to upgrade and maintain cold chain compliance and to fully comply with the various guidelines and regulations for temperature control during storage and distribution of pharmaceuticals.

In the last years, Alternatives Technologie Pharma did design, implement and maintain such a CCMP in more than 40 North American pharmaceutical distribution centers. A CCMP shall address various specific key-points, including:

- Regulatory Gap Analysis
- Temperature Mapping of Warehousing and Storage areas (storage of ambient products)
- Qualification of Thermal Equipment (storage of refrigerated/frozen products)
- Qualification of temperature-controlled Transportation Systems
- Review and Writing of Quality Documents (procedures, Quality agreements)
- Regulatory Documentation Management System
- Personnel Training
- Temperature Profiles Study in Transport
- Real-time Monitoring Solutions for Warehouses and Storage areas
- Data loggers Management Systems to track Shipments and Products
- Test, Design and Qualification of Packaging Systems

Regulatory gap analysis, through a close collaboration with the logistics, quality assurance, quality control and shipping/receiving departments, is the very first step to be initiated in order to verify and establish the pertinence of the cold chain regulations to the audited facility as well as to determine cold chain compliance findings and define the CCMP extent.

Cold Chain Compliance Findings
Verifications made during audits in major North-American pharmaceutical distribution networks enabled to document the most currently observed cold chain non-compliances and non-conformities. This includes:

- Training: A lack of personnel training in regard to cold chain aspects was observed in many cases. Moreover, personnel training were not documented or training documentation was incomplete.

- Regulatory and Cold Chain Documentation: Shipping documents were incomplete in terms of required data and information. In regard to cold chain aspects, Quality agreements were totally absent or not installed with subcontractors. Out-of-range conditions for storage and distribution of pharmaceutical products were not documented correctly. In many cases, procedures did not exist or did not specifically treat about cold chain aspects and management.

- Warehousing and Storage: Many warehousing and storage areas did not have HVAC systems (only heating). Even after HVAC installation, some areas could not maintain ambient storage temperature between 15 and 25ºC or 15 to 30ºC, thus leading to close storage areas. Thermostats of warehousing and storage areas were not locked, and set points could have been modified by unauthorized staff. Racking systems close to doors were not protected from cold air during winter or warm air during summer.

- Temperature Distribution Mapping: Temperature mapping of warehousing and storage areas was not done. In other cases, if the temperature mapping was done, the warehousing and storage area configuration was changed without going through a change control procedure and without remapping.

- Thermal Equipment: Storage equipments were not properly identified with internal identification numbers and calibration of probes/controllers in storage equipment were not done properly. Refrigerators used to store sensitive products (2 to 8ºC) were crowded thus leading to a poor air circulation. In other cases, a great number of deviations were created because of wrong set points. Too many domestic refrigerators (Danby, etc.) were used for the storage of pharmaceuticals.

- Qualification: Qualification of storage equipment (IQ/OQ) had to be done or redone.

- Monitoring System: Many warehousing and storage areas had no real-time monitoring system. And if monitored, the monitoring system was not strictly related to the mapping results (hot and cold spots not monitored). Some systems used temperature probes with glycol that did not provide adequate alarms.

- Temperature Profiles in Transport: In many cases, temperature profiles were not representative of the geo-climatic realities (ISTA profiles vs Canadian profiles). Distribution centers in a same location can provide very different temperature profiles in transport. Some special locations were found with extreme temperatures (very cold profile in winter, down to

- 28ºC for 12-14 hours). Using heated transport services was highly beneficial for winter packaging systems, and can bring packaging costs down. It was also observed significant temperature differences in cargo area on airplanes.

- Packaging: Qualification of cold chain packaging systems was not supported by any temperature profile study in transport. The use of two seasons (winter/summer) can be hazardous and costly. When you qualify packaging systems against extremes temperature, packaging materials can be very expensive. Furthermore, the rationale for selecting a summer packaging system or a winter packaging system was not clearly defined.

In many cases, packaging methods used to distribute pharmaceuticals were not qualified. Performance qualification and field testing on packaging methods are not done. Packaging systems were still observed with frozen gels close to pharmaceutical products. Gels and conditioning materials for packaging systems are not conditioned efficiently.

Such non-compliance findings in regard to the storage and distribution of pharmaceuticals show how it is important to install and maintain a well-sound and optimal CCMP.

Cold chain regulatory and compliance expertise is undoubtedly linked to a number of new technologies that greatly helps controlling and managing the pharmaceutical cold and temperature chains. Such technological tools should be carefully chosen and applied as a part of your compliance program.

New Technologies will support Cold Chain Control and Compliance
New technologies are today available to monitor temperatures during storage, warehousing and distribution. Available technologies provide advantageous integrated and automated monitoring systems which enables to provide low-risk storage environments for sensitive materials.

Implementing such technologies enables to develop tools that ensure to meet quality and safety standards. They should be part of your strategy to improve the storage and distribution of pharmaceuticals. For temperature, humidity, or other parameters, selecting the right monitoring hardware and software systems for your environment and needs is crucial.

Selected cold chain monitoring systems should provide security, reliability, flexibility, and easiness to use:

- Data have to be recorded accurately and in real-time, and should be provided in custom reports, charts, and graphs. Reporting of out-of-range and alarms should be done through automatic, electronic recordkeeping. Web-based systems enable to have online database and to provide secure access to authorized users.

- Monitoring systems should be developed in compliance with various standards and regulations (21CFR, GAMP), should come with procedures and should be qualified (Installation/Operational Qualification).

- Automated data monitoring provides priceless reliability advantages as compared to human-based manual measurements. Alarm limits should be set by authorized users to automatically alert responsible staff via personnel alarms in case of out-of-range or incidents. Sensors should buffer and collect continuously data even during network outages, the buffered data being sent to host server when the connection is re-established.

- While performing complex operations, such systems should be user-friendly systems, thus allowing users to get maximal performances. Web-based system emphasizes the easiness of use, with dashboards enabling to trace operations and activities, to see and follow-up all alarms, and to compile data into preformatted reports.

- Adaptability to specific environments or requirements is a key advantage: multiple remote sites can be centrally monitored; monitoring systems can be tailored for small-scale or large-scale facilities, systems can be vendor-hosted or installed onsite, easy future expansions and upgradeability.

- All parameters related to sensors and alarms should be configured and customized by users. Alarms including audible, visual and messaging alarms should allow authorized users to be alerted via e-mail, phone or text messaging.

- Wireless systems, being supported on a local area network, are easier to install and be daily used, and cuts down on cost/time for installation and maintenance. Systems with combined wireless and wired components can be run as needed by the facility, and enable more complex monitoring operations. Moreover, such systems should ideally support various sensor/logger models and technologies, existing or to come, such as RFID sensing technologies.

While a CCMP can be complex in terms of compliance expertise and monitoring technologies to be applied through entire storage, transport and distribution networks, partnering with a specialized cold chain compliance solutions provider should be seriously considered by pharmaceutical stakeholders to benefit from the most recent cold chain compliance background and technological insights.

Outsourcing Cold Chain Compliance Services
From a general perspective, cold chain management is as complex as the pharmaceutical supply chain can be and involves many stakeholders, starting with the drug product label owners and going up to the drug product end-users.

The implementation of a CCMP in more than 40 North American pharmaceutical distribution centers has led Alternatives Technologie Pharma to work on several cold chain aspects:

- Engineering and technical services, regulatory services and monitoring and packaging solutions were required to correct or prevent cold chain non-compliances and non-conformities.

- Complex warehousing and storage areas had to be (re-)mapped according to winter and summer conditions.

- All storage equipment such as refrigerators, walk-in and pick coolers, and freezers had to be re-setted, pre-qualified and qualified (IQ/OQ).

- Winter, summer and spring/autumn temperature profiles were determined for same-day, 24-hr, 48-hr and other shipping lanes.

- New packaging methods, such as single-use insulated shippers and reusable distribution containers, had to be (re-)designed, tested, qualified and supplied for each distribution network.

- Personnel and staff training specific to cold chain compliance and monitoring systems had to be provided and cold chain regulatory and quality documentation had to be reviewed and reworked when necessary.

- All warehousing sites were prepared and equipped with a central monitoring system that was tailored to meet the specific requirements of each site and each distribution network (temperature, relative humidity, wired/wireless, alarm types setting etc). Such a monitoring system was qualified onsite, and came with customized support/service plan and annual calibration program.

- Also all sites were supplied with data loggers and data loggers management system which enables to ensure cold chain control and maintenance. The monitoring solution was qualified onsite, and had to be provided with customized support/service plan and annual calibration program.

Today's specialized cold chain expertise and technologies are available and can be advantageously outsourced to help pharmaceutical stakeholders such as wholesalers and distribution networks in being a lot more safe and compliant for pharmaceutical products and for patients. By partnering with a cold chain compliance services partner, pharmaceutical stakeholders can have access to a progressive, continuous and effective transfer of knowledge and expertise in terms of cold chain control and management as well as cold chain monitoring technology.

Outsourcing a specialized servicing company in order to implement and maintain a cold chain management program is certainly an efficient approach to implant a global approach to Good Storage and Distribution Practices for the handling, storage, distribution and transport of pharmaceutical products.