# The Development of a Cold-Chain-Packaging Risk Management Model Based on Fuzzy Bayesian Network
## 5 Discussion  
Many factors can lead to product-safety-related risks for vaccines, including temperature disruptions, insufficient monitoring, fraud, poor handling, supply chain and environmental risks. For vaccines, exposure to temperatures outside the recommended temperature range can cause great damage to the vaccines. Temperature disruptions above or below the recommended range can lead to negative impacts on the safety of the vaccines. The quality of the vaccines will be harmed, which can cause adverse impacts on people's health. Also, fraud can be an issue for the safety of vaccines since fraudulent vaccines do not follow the strict guidelines during manufacturing, and insufficient refrigeration and monitoring is used in the shipping solutions. And poor handling of the shipping containers can cause damage to the vaccines as well. Exposure to heating can damage vaccines by changing the tertiary protein structure, dissociating polysaccharides from protein carriers in polysaccharide conjugate vaccines and reducing live-attenuated vaccines' infectiveness. Usually, the impact of heat damage is cumulative, and one solution is the use of Vaccine Vial Monitoring (VVM), in which a sticker or label is affixed to a vaccine vial and aims to estimate the remaining shelf life of vaccines when exposed to continuous heat [55]. The mechanism of VVM is the color change based on the Mean Kinetic Temperature (MKT), which indicates the total thermal stress a vaccine experiences in a period [56]. In addition to vial monitoring, other monitoring methods are needed in the vaccine cold chain shipping container, e.g., the use of data loggers and sensors, etc. In addition to the potential harm from heat damage, vaccines shipping containers can be subject to freezing as well. The freezing of vaccines can also affect the vaccines adversely, e.g., by causing clustering of the adjuvant particles, antigen degradation and molecular changes of vaccines, posing additional stress to the cold chain [57]. The WHO Shake Test is designed to detect whether freezing happens in a vaccine vial. During a Shake Test, first, one vial from a batch is selected as the control vial. Then, it is frozen overnight and thawed afterwards. Second, another vial is selected for testing, and then a visual comparison of the sedimentation rates of the two vials (control and testing vials) is made. When the sedimentation rate of the test vial is the same or greater than the controlled one, it is an indication that freeze/thaw occurs in this test vaccine vial. In this case, the whole batch of vaccines should be abandoned [58]. However, a shake test is usually carried out on one vial of a pack. Poor handling of the vaccine cold chain packaging can lead to product safety issues. Improper handling can lead to damage to the passive cooling systems, e.g., the leakage of PCM packs or bottles, sensors being broken, vial leakage, etc., and this can lead to hazardous consequences to vaccines and cold chain personnels. And for vaccines which require ultra-low cold chain storage and transportation, liquid nitrogen and dry ice is used sometimes, and improper handling of these substances can cause safety hazards. Also, improper handling of the vaccine packaging can harm the air circulation and compression forces, which can lead to physical damage to the packages and temperature disruption. Figure 6: Sensitivity analysis results according to manual calculations, where P(X = X1 1 W = W1) is the y axis and P(X = X1) is the x axis. Fraud and the expiration of the vaccines are other issues that can lead to vaccine safety risks. Expired vaccines have decreased potency and are more likely to cause safety issues to human bodies. Vaccines are usually monitored by government supervision departments, and random sampling tests are required to ensure vaccine safety. A lot of data will be generated along with the vaccine shipping solutions, such as batch packing records, batch production records, inspection records, inoculation records, etc. But it is still possible to tamper with the records.