The Application of Electronic Records and Data Analysis for Good Cold Chain Management Practices

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2 The Application of Electronic Records and Data Analysis for Good Cold Chain Management Practices Rafik H. Bishara, Ph.D. Summary Current global regulatory and compendial guidances indicate the need for pharmaceutical manufacturers and all of their partners such as distributors, 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 regulatory 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 temperature-sensitive medicines including cold chain and controlled room temperature products during handling, storage, and distribution [4-20]. As a result, investments 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 pharmaceutical supply chain [12,21]. These new technologies have improved cooperation across supply chain partners and enabled organizations 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 1

3 chain. A reliable program begins with accurate data collection of both temperature and humidity over a specific period of time - following a preplanned 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 webbased 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 distribution 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, warehousing, and shipping, through final distribution to the patient. This information can be used to establish the required elements of a cold chain data collection 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, manufacturer, distributor, wholesaler, or logistics service provider) the importance of different types of supply chain information will vary. For example, 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 2 o C - 8 o C can be used to develop an appropriate shipping container. A Packaging Engineer may be interested 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, 2 o C. Another box-plot could be generated for the upper specification, 8 o C. 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 situation. Figure 2 graphically depicts the performance of six carriers based on the number of alarmed states of temperature-related excursions, for a specific shipping lane over a particular time frame. When considering this one statistic, the bar-graph clearly outlines Carrier 6 as the best performing of the group. By comparison, Carrier 3 and Carrier 1 are the worst performing of the group. Using this information, a Logistics or Supply Chain Manager can begin to carefully evaluate the performance of carriers. 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 practice, multiple variables should be evaluated when making strategic decisions. 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 13 o C to -1 o C and the mean temperature inside the package experienced 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 7 o C to 5 o C and the upper and lower control limits were tightened to 9.28 o C and 0.81 o C, respectively. In this example, while the variation was reduced the results indicate that further development of the package and pack-out is required to maintain a refrigerated temperature of 2 o to 8 o 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 documents can also be made available for internal and external regulatory auditors and inspectors. The trend in today s regulatory and quality audits requires the inspector or auditor to review numerous paper copies of cold chain shipment data. While this inefficient process is common, there is the general belief that a higher quality demonstration of control is available by aggregating cold chain shipment data in a meaningful format, such as a controlchart, 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 2

4 Figure 1. Ambient and product temperature readings for four shipping lanes over a specific period of time 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 Figure 2. Performance of six carriers based on the number of alarmed states of temperaturerelated excursions 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 reinspection to ensure that problems pointed out by the agency are corrected [25]. Daniel Troy, a former FDA chief counsel, stated: ''If the re-inspection 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 reinspection specifically, the message from the FDA supports the need to increase auditing efficiency and improve overall compliance and documentation 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 followed 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 comparison 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 contracted, they are expected to assume validation of their systems. 3 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 evaluation of the disaster recovery and business continuation 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 program 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

5 Conclusion Temperature and humidity monitoring data play a vital role in identifying product quality risks in the pharmaceutical supply chain. Understanding the environmental conditions and the product s susceptibility to heat, cold, and humidity, is required to maintain product quality throughout cold chain distribution. Collection and analysis of aggregated Figure 3. Evaluation of Temperature Performance of a Cold Chain Container However, longer term opportunities also exist for implementing continuous process improvement by utilizing statistical process control. Lastly, given that regulatory agencies, and subsequently pharmaceutical manufacturers, have come to characterize temperature data loggers and the software 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. Table 1. Comparison of ISO 9000:2000 & Pharmaceutical cgmp Requirements - Part 2 Category ISO 9001:2000 Pharmaceutical GMPs Table 1. Comparison of ISO 9000:2000 & Pharmaceutical cgmp Requirements - Part 1 Category ISO 9001:2000 Pharmaceutical GMPs cold chain and supply chain data provides near-term opportunities for improvement in a risk-based approach to cold chain management. Returned & salvaged drug products References Industry Profile and Healthcare Factbook, Table 281, Estimated World Pharmaceutical Market by Market Share: 2003 Page 114, Healthcare Distribution Management Association (HDMA). 2. Biopharmaceuticals, Current Market Dynamics and Future Outlook, pp. 7, 9, 15, and 48, ASInsights Nov. 2003, 3. FDA Information Regarding Safety of Food and Biological Products, Distributed via the HAN Info Service, September Good Distribution Practices (GDP). Working Document QAS/04.68 (RESTRICTED), World Health Organization, Geneva, International Conference on Harmonization (ICH) Q1A: Stability Testing of New Drug Substances and Products, 2nd Revision, November 2003, originally published in Draft Guidance for Industry, Stability Testing of Drug Substances and Drug Products. United States Food and Drug Administration, Lucas, T. I., Bishara, R. H., and Seevers, R. H., A Stability Program for 4

6 the Distribution of Drug Products, Pharmaceutical Technology, July 2004, pp Okeke, C. C., Bailey, L. C., Medwick, T., and Grady, L. T., Temperature Fluctuations During Mail Order Shipment of Pharmaceutical Articles Using Mean Kinetic Temperature Approach, Pharmacopeial Forum, 23(3) May-June 1997, pp Okeke, C. C., Bailey, L. C., Lindauer, R. F. Medwick, T., and Grady, L. T., Evaluation of the Physical and Chemical Stability of Some Drugs when Exposed to Temperature Fluctuations During Shipment, Pharmacopeial Forum, 24(5) Sept-Oct 1998, pp Okeke, C. C., Bailey, L. C., Medwick, T., and Grady, L. T., Temperature and Humidity Conditions During Shipment in International Commerce, Pharmacopeial Forum, 25(2) Mar-April 1999, pp Okeke, C. C., Watkins, J. W. III, Williams, W., Medwick, T., Bailey, L. C., and Grady, L. T., A Study of the Temperature and Humidity Variations in the Shipping and Distribution of Anthrax Vaccines, Pharmacopeial Forum 26(3) May-June 2000, pp General Chapter <1079> Good Storage and Shipping Practices, USP 28, Suppl. 2, (August 1, 2005). 13. Guidelines for Temperature Control of Drug Products during Storage and Transportation (GUIDE-0069), Health Canada, October, Guidelines on Good Distribution Practice of Medicinal Product for Human Use, (94/C63/03), European Union, Guide to Control and Monitoring of Storage and Transportation Temperature Conditions for Medicinal Products and Active Substances, Irish Medicines Board, March Australian Code of Good Wholesaling Practice for Therapeutic Goods for Human Use. Therapeutic Goods Administration, Commonwealth Department of Health, Housing and Community Services, November, Thermal Performance of Refrigerated Transport Equipment - Specification and Testing, AS , Standards Australia. 18. Norms for the Good Distribution Practices of Medicines, Resolution by means of which the Good Distribution Practices of Medicines is Issued, Ministry of Health and Social Development, No. 253, Bolivarian Republic of Venezuela, June National Sanitary Surveillance Agency, resolution-rcd234, August 17, 2005, 3rd Article, Paragraph 5-7 and 7th Article, Paragraph 2, Brazilian Official Gazette, August 26, Good Wholesaling Practice for Wholesalers, Distributors, and Bonded Warehouses, Medicines Control Council, Department of Health, Republic of South Africa, June Bishara, R. H., and PSD Project Team, Drug Product Distribution Chain, Stimuli to the Revision Process. USP Pharmacopeial Forum, Volume 29 (3), May-June 2003, pp General Chapter <1118> Monitoring Devices Time, Temperature, and Humidity, USP Seevers, R. H., Bishara, R. H., Harber, P. J., and Lucas T. I.: Designing Stability Studies for Time-Temperature Exposure. American Pharmaceutical Outsourcing, Volume 6 (5) pp. 18, 20, 21, 23, 55 (2005). 24. Bishara, R. H., Chair, Pharmaceutical Cold Chain Discussion Group, Parenteral Drug Association: Cold Chain Guidance for Medicinal Product: Maintaining the Quality of Temperature-Sensitive Medicinal Products through the Transportation Environment. Technical Report No. 39. PDA Journal of Pharmaceutical Science and Technology, September- October 2005, Supplement Vol. 59, No. S Henderson, D., FDA Asking $22m in User Fees, Even Some Affected Firms See Promise of Faster Action, The Boston Globe, Section: Business, Technology, Biotechnology, February 20, Ames H., Sensitech, Inc. Internal Document, (Critical Component Reference). 27. Information extracted from the FDA website 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 rafikbishara2@yahoo.com This article was printed in the issue of American Pharmaceutical Outsourcing. Copyright rests with the publisher. For more information about APO and to read similar articles, visit and subscribe for free. 5