The Application of Electronic
Records and Data Analysis
for Good Cold Chain
Management Practices
Summary
C
urrent global regulatory and compendial guidances indicate the need for pharmaceutical manufacturers and all of their partners such as distribu-tors, carriers, and wholesalers to monitor, document, and confirm with data that the quality and integrity of temperature-sensitive product has not been compromised in any part of the supply chain. This article will assess the regu-latory environment, monitoring devices, collection and management of data, and a proposed quality system for Good Cold Chain Management Practices (GCCMP).Introduction
The world of cold chain management has changed dramatically over the past several years. A changing pharmaceutical product portfolio, with an increased investment and focus on biologically-based products, has raised awareness of the importance of proper cold chain management [1-3]. Regulatory and standards-based organizations have repeatedly demonstrated temperature and humidity variations during shipping of drugs and vaccines. Hence, there is an increased demand for more detailed management of temper-ature-sensitive medicines including cold chain and controlled room temperature products during handling, storage, and distribution [4-20]. As a result, invest-ments in new software application development by cold chain service providers have helped organizations to better understand the environmental variations and associated risks experienced by products traveling within the complex pharma-ceutical supply chain [12,21]. These new technologies have improved cooper-ation across supply chain partners and enabled organizcooper-ations to address cold chain distribution challenges.
There are numerous opportunities to reduce costs while providing greater assurances for protecting product quality, improving supply chain efficiency, and enabling companies to adopt a risk-based approach in managing their cold
2 chain. A reliable program begins with accurate data collection of both
temperature and humidity over a specific period of time - following a pre-planned frequency of recording. Statistical analysis of the collected data will then support the quality decisions.
Monitoring Devices
Time, Temperature, and Humidity
U.S. Pharmacopeia (USP) General Chapter <1118> provides a background on the science and technology of temperature and humidity monitoring devices and their correlation to time as well as verification and validation of their performance characteristics [22]. An electronic data logger is a capable device for recording the temperature and humidity at very short time intervals. The recorded temperature history data can be downloaded into a peripheral system such as a personal computer or web-based application for further analysis. Data loggers may be permanently fixed within a storage environment or may travel with the shipment of the product. Data, compiled from loggers, can demonstrate the history of manufacturing and distribution which can be used to confirm a controlled process. Furthermore, designing properly monitored shipping stability studies will provide the necessary documentation for future distribution of the product through the various parts of the supply chain [7,23,24].
Data Collection System
Before implementing a cold chain data collection system, a user should first map all elements of their cold chain. This map of the distribu-tion network is a workflow diagram that outlines the types of products, the associated environmental restrictions for those products, and the flow of these products from raw material, manufacturing, packaging, warehous-ing, and shippwarehous-ing, through final distribution to the patient. This informa-tion can be used to establish the required elements of a cold chain data col-lection and management program. The USP presents the concept of the complex pharmaceutical supply chain, offers an assessment of its weak links, as well as its associated risks [12,21].
Depending on the role of the individual, (packaging engineer, man-ufacturer, distributor, wholesaler, or logistics service provider) the impor-tance of different types of supply chain information will vary. For exam-ple, a Packaging Engineer may want to analyze the internal or product temperatures experienced across a specific shipping lane and compare this information to the external or ambient profile for the same distribution segment. Similarly, a Logistics or Supply Chain Manager may want to analyze the performance of various carriers across a particular segment of distribution. This analysis could include evaluating variation of length of trip segment by time, temperature fluctuation, mean kinetic temperature, as well as many other variables [12]. Another primary example is the Quality Control (QC) manager, who can use a data management system to demonstrate control of the cold chain and document that the Standard Operating Procedures (SOPs) in place are delivering an outcome that is within allowable tolerances.
Examples of Cold Chain Data Management
Measurement of external/ambient and internal/product temperatures compared to the product specification of 2oC - 8oC can be used to devel-op an apprdevel-opriate shipping container. A Packaging Engineer may be inter-ested in the extremes i.e. the highest and lowest temperatures recorded. Figure 1 shows the lowest ambient and product temperature readings for multiple shipments covering four shipping lanes over a specific period of time. In this example it should be noted that in Shipping Lane “B” the product has been exposed to temperatures below the lower limit of the specification, 2o C. Another box-plot could be generated for the upper
specification, 8oC. By reviewing the ambient temperature for that same shipping lane, a Packaging Engineer can begin to evaluate the potential correlation between ambient and product temperatures for the specific sit-uation.
Figure 2 graphically depicts the performance of six carriers based on the number of alarmed states of temperature-related excursions, for a spe-cific shipping lane over a particular time frame. When considering this one statistic, the bar-graph clearly outlines Carrier 6 as the best perform-ing of the group. By comparison, Carrier 3 and Carrier 1 are the worst per-forming of the group. Using this information, a Logistics or Supply
Chain Manager can begin to carefully evaluate the performance of
carri-ers. Information and best practices gathered from the top performers can be shared with the laggards to improve their performance, modify Standard Operating Procedures, or ultimately support decisions for changes in service providers. While information contained in the graph is meaningful and actionable, it is representative of one example. In prac-tice, multiple variables should be evaluated when making strategic deci-sions.
Figure 3 shows a Control Chart which is at the heart of statistical process control. The upper and lower control limits (UCL) (LCL) are at plus and minus three standard deviations and roughly 99.73% of random variation falls within these limits. The control limits are a function of the way the process performs over time.
The image graphically depicts the internal or product temperature performance of a specific cold chain container. The example shows that from September 24 through October 12 the (UCL) and the (LCL) ranged from 13oC to -1oC and the mean temperature inside the package experi-enced large variation. Beginning October 12, a new package design was tested with a modified pack-out. The results show that the new packaging and pack-out had dramatically improved thermal characteristics. The mean temperature was brought down from 7oC to 5oC and the upper and lower control limits were tightened to 9.28oC and 0.81oC, respectively. In this example, while the variation was reduced the results indicate that fur-ther development of the package and pack-out is required to maintain a refrigerated temperature of 2o to 8o C during the shipping process. A
Packaging Engineer could use this type of information to thoroughly
evaluate the performance of thermal containers used in specific shipping lanes and during specific times of year. Similarly, a QC Manager or a
Regulatory Auditor could use this information to determine if the system
is operating within allowable tolerance levels and whether or not the process is in control.
A Collaborative Approach to Managing
Cold Chain Data
While cold chain documentation can help to prove that a system is operating in a controlled manner it can also provide evidence to show how a suspect shipment was evaluated and what final decisions were made regarding disposition or further distribution. Therefore, it is critical that a cold chain management application provide the capability to create and share reports both internally and with supply chain partners. These docu-ments can also be made available for internal and external regulatory audi-tors and inspecaudi-tors.
The trend in today’s regulatory and quality audits requires the inspector or auditor to review numerous paper copies of cold chain ship-ment data. While this inefficient process is common, there is the general belief that a higher quality demonstration of control is available by aggre-gating cold chain shipment data in a meaningful format, such as a control-chart, with accompanying statistical analysis. A cold chain management program will deliver proper analysis of cold chain data, further supporting the inspector’s or auditor’s desire to increase the efficiency of the audit
process. As an example, the FDA recently asked Congress to approve $22 million in new user fees to be paid by companies whose plants require re-inspection to ensure that problems pointed out by the agency are corrected [25]. Daniel Troy, a former FDA chief counsel, stated: ''If the
re-inspec-tion involves FDA being in the plant for a fair amount of time . . . then the cost could be relatively substantial," While this quote is referring to a re-inspection specifically, the message from the FDA supports the need to increase auditing efficiency and improve overall compliance and docu-mentation of control. A properly implemented cold chain management program accomplishes this task.
Critical Components of Cold Chain
Management
Based on audits from the regulatory agencies, pharmaceutical and biologic manufacturers consider temperature data loggers and the systems used to manage the information they collect as “critical components” of overall cold chain management [26]. Therefore, the quality systems fol-lowed by cold chain management service providers should be evaluated thoroughly.
While providers of software applications for managing cold chain data are not held to the standards of cGMP and therefore not audited by regulatory agencies, they may follow other standards such as ISO. There is a lot of overlap between ISO and Current Good Manufacturing Practices (cGMP); however, there are elements of (cGMP) that simply do not apply to a manufacturer of cold chain hardware and software applications. As a result, leading application service providers do work to fill the gap between ISO-based Quality standards and cGMP. Table 1 shows a com-parison between ISO and cGMP [27].
cGMP Customer Expectations from a
Leading Provider of Cold Chain
Management Solutions
Pharmaceutical companies are committed to Quality and seek to do business with other companies that share the same philosophy. In this regard, the pharmaceutical industry is required to meet the Current Good Manufacturing Practices (cGMP) such as 21 CFR Part 11, 210, 211, and standards set forth by global regulatory agencies. Where a cold chain provider of hardware and software products and services is con-tracted, they are expected to assume validation of their systems.
Examples of areas to be examined include but are not limited to the following:
• Documented system requirements specifications
• Documented process and results of structural and challenge testing of the software
• Documented process for the control and administration of electronic access privileges to the data center, system hardware, and network
• Documented process for the control and administration of electronic access privileges to the system software source code
• Documented process and results of formal testing of software under expected load conditions
• Documented process and results of formal periodic testing and evalu-ation of the disaster recovery and business continuevalu-ation planning for the software application
• Documented system development and validation
Quality System
It is pragmatic for the client and service provider to agree on establishing a Quality Assurance Program. An example of such a pro-gram would include but is not limited to the following items: A. General Organizational Information
B. Quality Systems a. General b. Document Control c. Management Review d. Internal Audits e. Training f. Record Retention C. Software Quality Assurance
a. General Questions b. Quality Planning Phase c. Requirements Phase d. Design Phase
e. Construction and Coding Phase f. Testing Phase
g. Operation and Maintenance Phase h. Decommissioning Phase
i. Defect Tracking and Corrective Action D. Security/Disaster Recovery
E. Customer Support
Figure 2. Performance of six carriers based on
the number of alarmed states of
temperature-related excursions
Figure 1. Ambient and product temperature
readings for four shipping lanes over a specific
period of time
Conclusion
Temperature and humidity monitoring data play a vital role in iden-tifying product quality risks in the pharmaceutical supply chain. Understanding the environmental conditions and the product’s susceptibil-ity to heat, cold, and humidsusceptibil-ity, is required to maintain product qualsusceptibil-ity throughout cold chain distribution. Collection and analysis of aggregated
cold chain and supply chain data provides near-term opportunities for improvement in a risk-based approach to cold chain management.
However, longer term opportunities also exist for implementing continu-ous process improvement by utilizing statistical process control. Lastly, given that regulatory agencies, and subsequently pharmaceutical manufac-turers, have come to characterize temperature data loggers and the soft-ware systems that manage cold chain data as “Critical Components” of a pharmaceutical manufacturer’s supply chain, it is important to carefully evaluate the quality systems used by a supplier of cold chain solutions.
References
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4
Figure 3. Evaluation of Temperature Performance
of a Cold Chain Container
Returned & salvaged drug products
Table 1. Comparison of ISO 9000:2000 &
Pharmaceutical cGMP Requirements - Part 1
ISO 9001:2000 Pharmaceutical GMPs
C a t e g o r y
Table 1. Comparison of ISO 9000:2000 &
Pharmaceutical cGMP Requirements - Part 2
ISO 9001:2000 Pharmaceutical GMPs
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Rafik H. Bishara, Ph.D., is the current Chair of the Pharmaceutical Cold Chain Discussion Group (PCCDG), Parenteral Drug Association (PDA). Dr. Bishara retired from his position as Director, Quality Knowledge Management and Technical Support, Eli Lilly and Company after a 35-year career. During his tenure at Eli Lilly and Company, Dr. Bishara was responsible for the Quality Knowledge Management, Global Compendial Affairs, Stability and Distribution Excellence, Global Product Protection, Special Security Substances and Controlled Substances Administration. Dr. Bishara frequently presents at industry leading conferences, has authored numerous articles, and technically advised several organizations on Good Cold Chain Management Practices. Dr. Bishara received his Ph.D. from Purdue University, Indiana, USA.
To correspond with the author, please e-mail: [email protected]
