Cold chain time- and temperature-controlled transport of vaccines（２）

Results

The mean temperature (±standard deviation, n=5) values of internal temperature of each configuration over 24 hours are shown in Fig. 1.

Among the configurations, configuration 1, using a polystyrene foam box with five coolant-packs, reached the temperature range of 2.02℃ to 7.54℃ and the temperature was maintained for 23 hours. This was the longest duration of maintenance time, in which the intended cold chain temperature range (2℃–8℃) was maintained compared to the rest of other configurations. Nonetheless, it was noted that configuration 2, using a large vaccine cold box with polyethylene interior lining, polypropylene insulation and three coolant-packs, recorded internal temperature ranges of 6.34℃ to 7.88℃ and lasted for 15 hours. The duration was 8 hours shorter compared to configuration 1. Besides, it was noted that configuration 2 required more than 30 minutes for the internal temperature to reach below 8℃. In contrast, for configuration 4, using a small vaccine cold box with polyethylene interior lining, polypropylene insulation and three coolant-packs, within 30 minutes, it reached the intended temperature, ranged 5.88℃–7.56℃ and maintained for 13.5 hours. Likewise, configuration 6, using a cooler bag, the smallest and lightest container among the type of passive containers used, with four coolant-packs recorded a temperature below 8℃ within 30 minutes after first exposure to external environment and maintained at 3.1℃–7.3℃, lasted up to 14.5 hours.

Meanwhile, both configuration 3 and 5 failed to reach below 8℃ throughout the 24 hours. Configuration 3, a polystyrene foam box with four coolant-packs, was a storage condition with only a missing a coolant-pack on top compared to configuration 1. The lowest temperature it managed to reach was 8.2℃ in first hour. Similarly, configuration 5, missing a coolant-pack on top compared to configuration 2, hit the lowest temperature only at 9.9℃ after 2 hours in the storage packing.

Table 2 shows the comparison of temperature-time profiles using pair-wise approach. Configuration 1 was used as reference profile for the comparison with the other five configurations. All had a more than 100% difference. Among the comparisons, configuration 5 had the highest differences from configuration 1, with f₁ value of 250.3 and f_1area of 2.1. In contrast, the temperature values of configuration 2, 4, and 6 compared to configuration 1 were relatively similar to each other, with 106.5, 108.4, and 115.7, respectively.

Discussion

Time- and temperature-controlled storage and transport of vaccines in compliance of manufacturer specifications is essential to ensure optimal therapeutic effect of vaccine requiring cold chain [5, 17]. Ineffective or degraded vaccines could be part of the reason of resurgence of certain vaccine-preventable diseases [18]. Degradation happens unintentionally especially for aluminum adjuvant–containing vaccines which are highly sensitive to unintentional freezing such as adjacent to frozen ice packs or refrigerator freezer coils [19].

Even though a recent review of Vaccine Adverse Event Reporting System (VAERS) by Hibbs et al. [5] indicated that the use of vaccines kept outside of recommended temperatures caused no substantial direct health risk, possible decreased protection is inevitable. Of note, with the benefit of hindsight, Shimabukuro et al. [20] reported that VAERS data are not suitable to determine the possibility of an adverse event induced by a vaccine. It is speculated that the interpretation of VAERS data alone or out of clinical context could lead to erroneous conclusions about the risk of adverse events [20].

This study was conducted to determine which packaging configuration of vaccines is the most appropriate to be used in a cold chain transport from pharmaceutical wholesalers to other healthcare clinics, hospitals and pharmacies. The findings of this study indicated that the size of storage box, packaging materials including materials used for cold box and insulator, and the number of coolant-packs, the arrangement of coolant-pack on top highly affects the cold retention, thus storage temperature and duration of intended temperature. With larger size of vaccine box, the number of coolant-packs required and the time to reach the designated storage temperature will be increased. In this study, configuration 1 was found to have the longest storage duration at desired temperature, 23 hours which are sufficient for transportation of both local and long-distance cold chain supply. The only drawback from this configuration is high possibility of freezing since the temperature went down to the lowest at 2.02℃ at first 2 hours. Additional layer of plastic wrap might be useful in order to prevent the temperature inside the vials from dropping below 2℃. Nonetheless, this measure needs to be further investigated. For transportation of small amount of vaccines at local districts, configuration 2, 4, and 6, respectively could serve as an alternative as the packaging are less bulky and lighter, thus easier for short transportation distance and time. On the other hand, the use of configuration 3 and 5 should be avoided since the internal temperature failed to fall below 8℃ at any time points.

As recent systematic review has indicated that 29 vaccine freezing cases reported in 45 included studies [21]. The review suggested that a temperature fall below 2℃ is more common compared to the temperature rises above 8℃ during cold chain transportation. Several studies on effectiveness of cold chain supply of vaccines have been carried out globally [21]. All of these studies concluded that the cold chain transport systems were not up to standard to ensure the quality and stability of the vaccine during transportation. Yauba et al. [22] at Cameroon examined the vaccine exposure to temperatures outside the recommended range during storage and transport. Using experimental study design, 48 shipment boxes containing 10 vials of Diphtheria-Tetanus and Pertussis containing vaccines and a data logger were prepared and dispatched to various target health facilities throughout Cameroon [22]. Of note, 83% of shipments were exposed to freezing (−0.5℃ to −23.8℃) at least once during their study. Meanwhile, a study conducted at regional and district vaccine stores and rural health facilities of India showed the temperatures in the boxes exceeded 8℃ ranged from 8.3% to 14.7% of their combined storage times and fell below 0℃ from 0.2% to 10.5% of these times. Up to 18% and 7% of the carrier boxes exposed to combined times in transit at <0 and >8℃, respectively [17].

Meanwhile, in capital city of Kenya, Nairobi, a study on the influence of cold chain supply logistic on the safety of vaccines [23]. The four influences being studied were the storage condition, packaging, transport system, and technical capacity. In the study on transport system, the research confirmed that the quality and conditions of transportation vans and carrier boxes were poor, along with the issue of improper documentation of actual temperature and timing of cold chain medicines throughout the transport process [23].

Challenges in managing the cold chain in storage and during transportation could be overcome with a robust experimental study. Firstly, enhancement of good distribution practice requirements especially on management of cold chain products up to end users (clinics and private sector) is the necessary step to maintain quality, safety, and efficacy of products. The training also could increase awareness of new requirement and knowledge. Furthermore, vaccine lot release should also be implemented with proper documentation and review of lot summary protocol (LSP), along with cold chain inspection (CCI) comprising of physical checking and temperature monitoring. With satisfactory evaluation of LSP and CCI, then only vaccine lot release certificate will be issued by the drug regulatory agency.

The store personnel needs to be trained on Good Storage Practice especially the cold chain capacity requirements of a vaccine supply chain. Guidance on the number of vials, vaccine volumes and how to calculate cold chain storage needs for coolant-packs, the use of vaccine cold boxes, and the dry-storage capacity needed for immunization-related commodities should also be given [2]. If the efficiency of the existing method is found to be low, attempt should be made to develop an effective supply chain method for the pharmaceutical wholesalers to deliver the vaccines to its customers without jeopardizing the cold chain. Overall, three core components of comprehensive vaccine cold chain management, as demonstrated in previous studies, are regular equipment maintenance, staff refresher course, and proper alert system connected to an auxiliary power [24, 25, 26, 27].

In conclusion, this study generated much needed evidence on duration and temperature maintenance of cold chain for the supply of quality vaccines and other biological products by pharmaceutical wholesalers. Polystyrene foam box could be effectively used if sealed with minimum five ice packs whereas large vaccine cold box with polyethylene interior lining and polypropylene insulation could be effectively used if sealed with minimum three ice pack. The configuration of packaging with coolant-pack, the size and material of the storage containers have a direct impact on the maintenance of cold chain temperature to ensure proper transportation of vaccines.

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