Logistics of Covid-19 vaccines: main challenges in theory and practice

Abstract Paper aims This paper presents the literature findings of the Covid-19 vaccines supply chain, its main challenges and best practices, which are compared and verified empirically. Originality The questionnaire developed in this study provides new empirical data about the Covid-19 vaccines supply chain, especially regarding the impacts of the Covid-19 pandemic in the chain, as these events are still recent. Research method A questionnaire was sent by e-mail to specialists working with the Covid-19 vaccine supply chain in South America. Each response was compared to the literature findings. Main findings Despite the challenges faced by vaccination programs, some countries have achieved good results due to strategies adopted at the beginning of their immunization campaigns. The empirical research confirmed that literature findings match business reality, although some empirical results vary depending on the scenario of the country regarding the impacts of the pandemic. Implications for theory and practice This paper summarizes the Covid-19 vaccine supply chain and its challenges, best practices of the most successful countries regarding the immunization process, providing a better understanding of the pandemic scenario. Some empirical data corroborate the literature, and some discrepancies allow the formulation of suppositions that may be tested in future studies.


Introduction
On March 11, 2020, the global pandemic of Covid-19 was declared by the World Health Organization (WHO) (Liu et al., 2020).Over 198 million cases and 4 million deaths were officially confirmed until August 2021, leading to a current fatality rate of 2.1% (Our World in Data, 2021a).The disease may cause fever, cough, and fatigue, similar to other severe respiratory infections (Velavan & Meyer, 2020).Most people who fall sick with Covid-19 will experience mild to moderate symptoms, recovering without special treatment.However, some will become seriously ill, requiring medical attention.The disease tends to have greater severity and mortality rate in the elderly population (Zhou et al., 2020) and immunodeficiency or chronic disease patients (Brasil, 2020).
Covid-19 characteristics make herd immunity harder to be achieved.A natural herd immunization process would require a large portion of the population to be affected, triggering millions of deaths and overloading the healthcare system.In this way, mass vaccination programs emerge as a critical element for achieving sufficient immunization coverage to end the global pandemic (Randolph & Barreiro, 2020).Global vaccine accessibility relies on the transport of doses to the last mile through distribution chains, strict quality controls, complex production processes, and raw material availability (Smith et al., 2011).Thus, its efficacy depends not only on the supply chain that distributes the final product but also on all the supply chains that support the whole manufacturer (Golan et al., 2021).
In the health context, the cold chain is a temperature-controlled supply chain with procedures and rules that ensure the proper storage and distribution of vaccines to national and local health services.The current immunization cold chain and its operations have been key elements in intensifying the provision of daily immunization services, allowing more people to be protected from vaccine-preventable diseases.Also, the importance of the cold chain is given as most of the vaccines must be at a specific temperature from its manufacture to its inoculation to maintain the expected efficacy and safety.In this sense, the cold chain needs to be flexible, as each vaccine has its temperature requirement.
Natural disasters that arise from the external environment are intrinsically challenging to manage and respond (Oliveira et al., 2019).Some of them are tough to predict, as in the case of the COVID-19 pandemic, an unprecedented event.As consequence, actions to respond to a disaster such as the COVID-19 pandemic are complex.The Covid-19 vaccine cold chain is multifaceted and highly challenging, mainly due to the global-scale demand.For months, the main challenge with the Covid-19 vaccine roll-out was that demand significantly outstripped supply.Furthermore, challenges in the production, distribution, and even the acceptance of the vaccine also emerged as barriers to the immunization process.This paper aims to present and discuss the main challenges and aspects of the Covid-19 vaccine supply chain, comparing the findings in the literature with the ones found in practice.Thus, the question posed in this study includes: Do the challenges of the Covid-19 vaccine supply chain found in the literature correspond to business practice?For this purpose, we designed two specific objectives: • Comprehend the state of the art of the Covid-19 vaccines supply chain and its main challenges and best practices; • Verify the aspects of the Covid-19 vaccine supply chain and its challenges empirically, comparing these findings with the ones found in the literature.
To verify and validate the literature findings, we conduct empirical research through a structured questionnaire with experts working in the Covid-19 vaccine supply chain in Brazil, Argentina, and Peru.Thus, this research endorses the academic discussion about the cold chain of vaccines, especially the Covid-19 vaccine supply chain, and contributes to practitioners to better comprehend the main challenges in theory validated in practice.The remainder of the paper is structured as follows.We begin by reviewing the theoretical grounds for the Covid-19 vaccine supply chain.Section 3 describes the research methodology, while Section 4 presents the main research findings and discussions.Finally, Section 5 summarizes the conclusions and limitations and raises future research on the field.

Covid-19 vaccines supply chain
The Covid-19 pandemic gathered the attention of a large audience, especially researchers worldwide, who have been targeting efforts toward the development and distribution of a safe and effective vaccine.Usually, vaccine development occurs linearly in eight distinct phases (World Health Organization, 2020), as shown in Figure 1.This type of development reduces the stakeholders' risk and the installed infrastructure once the effectiveness, the feasibility of production, and clinical studies must be validated before proceeding with each phase (Golan et al., 2021).
The development of the Covid-19 vaccine, in turn, had to follow an accelerated schedule due to the pandemic severity.The phases needed to overlap to accomplish the accelerated development schedule (World Health Organization, 2020) (Figure 2).With the global demand for vaccines, this acceleration overloaded the supply chain (Golan et al., 2021), inherently complex.To understand the entire vaccine supply chain, from manufacturing to the last mile, it is essential to model the whole network and consider its interactions (Golan et al., 2021).The US Centers for Disease Control and Prevention (2021a) segregates the vaccine cold chain into 5 stages, named: vaccine manufacturing, distribution, vaccine arrival at the provider facility, vaccine storage and handling at the provider facility, and vaccine administration (see Figure 3).Vaccine manufacturing is a complex and multistep process.These steps involve the virus culture, purification and inactivation, vaccine formulation, packaging, and shipment.This entire process usually takes from 6 to 36 months, being 70% of this time dedicated to quality tests done by different authorities worldwide (Sanofi, 2019).Regulatory licenses are not limited to biological entities, but also the entire production and testing process.Therefore, significant changes to the manufacture, such as raw material or equipment changes, will demand new regulatory requirements to ensure that the vaccine is still effective and comparable to its prior version.The regulatory licenses configure an obstacle to optimizing and improving the production process, with the manufacturers having to choose between reaching the market earlier or having a manufacturing optimization process.The former has been advantageous to the short term and the latter to the long term (Plotkin et al., 2017).
Covid-19 vaccine manufacturing proved to be very challenging, as it needed to be rapid and on a large scale.For mRNA vaccines, challenges were more remarkable.These vaccines use novel technologies, and no preexisting manufacturing infrastructure that could be utilized was ready (Amanat & Krammer, 2020) as this was the first time mRNA technology has been authorized outside of clinical trials (Smith et al., 2011).At this stage of the supply chain, main challenges include (i) a long and complex multistep manufacturing process (Sanofi, 2019); (ii) strict regulatory licenses (Plotkin et al., 2017); (iii) global demand for Covid-19 vaccines production (Amanat & Krammer, 2020).
The covid-19 vaccine distribution process involves existing networks, processes, and partnerships to make vaccines available worldwide, maintaining product integrity.The proper storage and distribution of vaccines to health services are ensured by the cold chain, a temperature-controlled supply chain.Vaccines are sensitive biological substances that can lose effectiveness and potency if exposed to temperatures (heat and/or cold) outside of the required temperature range for the specific product or when exposed to light (Canadian, 2021).The cold chain aims to maintain vaccines in proper conditions during transport, storage, and distribution until the moment of dose administration (Brasil, 2014).This chain is essential for maintaining the initial characteristics of the product, avoiding changes in the potency, components, and efficacy of the immunobiological.Gunn (2020) reiterates that the main challenges of the cold chain are related to maintaining the vaccines within a constant temperature range, not necessarily low.Too much cold can compromise the integrity of the product.
The most significant risk of losses in the cold chain is related to the freezing of the vaccine and not to the heat (Hubbard, 2020).Failure to adhere to vaccine handling and cold chain requirements can reduce vaccine potency and increase local reactions at the vaccine administration site.The loss of vaccine effectiveness due to cold chain exposures to adverse conditions is permanent, cumulative, and irreversible (Amanat & Krammer, 2020).Thus, at this stage of the supply chain, the main challenges are related to maintaining vaccines at appropriate temperatures and not modifying their characteristics.
Due to the need to keep the product at controlled temperatures, the cold chain presents high operating costs (Costa et al., 2017).The operational cost can be greater depending on the specificities of each vaccine and each country.In Brazil, for example, Covid-19 vaccine distribution is made through land transportation, with a fleet of 100 refrigerated delivery vehicles (Brasil, 2014).Maintaining the vaccines at proper temperatures during land transport frequently leads to a higher freight cost.According to the National Land Transportation Agency (Portuguese acronym: ANTT) (Brasil, 2021), the cost for land transportation of refrigerated cargo is higher than general cargo.The mileage cost of refrigerated cargo is, on average, 19% higher than a general cargo and the cost of loading and unloading is 21% higher.
Challenges in vaccine storage are also common due to the limited storage capacity of providers and the lack of predictability of supply and demand.Customs and regulatory procedures, which vary according to the country, and the import regulations which are frequently changed are also highlighted as challenges.In addition, there is an impasse that suppliers have with obtaining certification and qualifications (DHL Research and Innovation GmbH, 2020).
Regarding the last mile stage -vaccine administration, Gevaers et al. (2011) define it as the final stage of the delivery process, often being the most expensive and least efficient supply chain segment.The last mile is especially important for the vaccine supply chain, as it involves delivering the product to the end user in a medically compliant manner (Golan et al., 2021).For economic reasons, vaccines are usually delivered through multi-dose vials (Schiffling & Breen, 2021).However, it increases the open vial wastage, as there will be more unused spoiled doses in the opened vials.Leftovers are the primary source of vaccine wastage, reaching up to 50% for vials with 20 or more doses (Schiffling & Breen, 2021).Mass vaccination centers allow better supply and demand matching, using open vials more efficiently, as there will be batches of vaccinated people, dwindling this kind of wastage (World Health Organization, 2019).
To overcome the several challenges of the Covid-19 vaccine supply chain, reduce vaccine losses, and make the immunization process more efficient, strategies and best practices had to be developed.The first dose of a fully tested Covid-19 vaccine was administered in December 2020 in the United Kingdom.Thenceforth, several countries have joined the race toward immunization.At earlier vaccination stages, Israel and the United Arab Emirates (UAE) stood out due to their efficiency in conducting the Covid-19 vaccination campaigns, reducing vaccine losses, and developing best practices to overcome the challenges.These countries still lead the current Covid-19 vaccine doses administered per 100 people (Our World in Data, 2021b).
Countries such as Israel, Chile, and the United States of America (USA) used a decentralized strategy, in which several organizations were responsible for each priority group (McKee & Rajan, 2021; TRT World, 2021; U.S. Department of Health and Human Services 2021).In Israel, for example, health workers were vaccinated by their own companies, while people over 60 years old or with pre-existing medical conditions were covered by non-profit health plans (McKee & Rajan, 2021).Israel and the UAE already counted with a robust online registration system for vaccination, which was rapidly adapted to the Covid-19 vaccination campaign, providing real-time data on the vaccine effectiveness, and allowing the follow up of adverse events after the inoculation (McKee & Rajan, 2021; Emirates News Agency, 2020).These countries also developed communication strategies in multiple channels, such as social media, corporate websites, and mass media (Choi et al., 2021;Khaleej Times, 2020), to encourage the population to get the vaccine, which generated excellent adherence.The UAE, USA, and Israel used multiple vaccination sites, which allowed the rapid implementation of the Covid-19 vaccination program by increasing its reach and access (Choi et al., 2021;Syal, 2021;Centers for Disease Control and Prevention, 2021b).
Israel also modified the initial manufacturer's requirements for the transportation, storage, and distribution of Covid-19 vaccines (Choi et al., 2021).The manufacturer's technical specifications pose a significant challenge for vaccinating individuals on a smaller scale, particularly in rural areas.To solve this problem and optimize the supply chain, Israel was authorized by the supplier to repackage the large ultra-frozen pallets into smaller insulated boxes, enabling the vaccine to be distributed in smaller quantities (Choi et al., 2021).
It is important to have well-defined strategies to better respond to the disaster.Lamenza et al., (2019) highlight specific methodologies on purchasing strategies for relief items in humanitarian operations.Countries such as the UAE, Chile, the USA, and Israel developed efficient procurement strategies that contributed to the Production, 33, e20220036, 2023 | DOI: 10.1590/0103-6513.202200365/10 good performance of the vaccination campaign in these countries (Syal, 2021;Abramovich, 2021;National Institutes of Health, 2020).The strategy of supplier diversification acquired by UAE, Chile and USA was important since the vaccines available in the market were not proven to be effective yet (Abramovich, 2021).Regarding the early acquisition of the vaccines, Israel was one of the Covid-19 vaccine early buyers, which contributed to accelerating its vaccination process (Abramovich, 2021).Besides, just as necessary as the early acquisition of the immunizer is its use approval.The UAE, Chile, and the USA have fast-tracked the authorization process for the Covid-19 vaccine (Syal, 2021;Abramovich, 2021;National Institutes of Health, 2020).In September 2020, in the UAE, for example, emergency approvals were already issued for the administration of Covid-19 vaccines to frontline healthcare workers (Syal, 2021).Host trials were also performed in the UAE, Chile, USA (Syal, 2021); Abramovich, 2021;National Institutes of Health, 2020).The host of clinical trials facilitates the negotiations, such as acquisition priority, allowing the vaccination program to start earlier than other countries.Finally, the acceleration of Covid-19 vaccine authorization processes proved to be effective in Chile (Financial Times, 2021) and United Arab Emirates (Syal, 2021).Table 1 summarizes the good practices found in the literature.(Syal, 2021;Financial Times, 2021) Source: The authors.

Research methodology
For results interpretation and discussions in practice, we developed a structured questionnaire based on the results obtained from the theoretical foundation.The questionnaire aimed to bring the empirical foundation of the subject addressed in this research.It was prepared in Survey Monkey Platform and sent to the respondents through e-mail, successfully reaching 3 of the 4 intended respondents.Our sample of respondents included specialists working with the Covid-19 vaccine supply chain in Peru, Argentina, and Brazil.The respondents were identified as A, B, and C, with the following profiles: • Respondent A: works in the Disaster Risk Management Affairs sector in Peru, handling the Sinopharm vaccine.
• Respondent B: works as a logistic operator in Argentina, with the Sputnik V, Oxford/AstraZeneca, and Sinopharm vaccines, handling approximately 4 million doses monthly.Its operations are mainly through the land (95%) and the air (5%).
• Respondent C: works as logistics planner with Sinovac, BioNTech/Fosun Pharma/Pfizer, and Oxford/AstraZeneca vaccines in Brazil.Its operations are mainly through the air.
The questionnaire was available in Portuguese and English, taking approximately 11 minutes to be fully answered.It was composed of closed and opened questions, divided into 3 sections: (i) General information; (ii) Storage, transportation, and distribution; (iii) Logistics challenges.The first section focused on obtaining information about Respondents A and B reported a significant influence of temperature on vaccine losses during storage and transportation, classified as medium and high influence for the respondents, respectively.These results are consistent with the literature since vaccines are highly sensitive to temperature, which must be controlled and monitored all along the supply chain.
The main reason for vaccine wastage informed by respondent A is theft.It is worth noting that robberies may be associated with poor socio-economic conditions of the region, requesting, therefore, investments in security.Consequently, this may lead to increases in freight costs.Indeed, respondents A and C pointed out the freight cost as high in their operations.Particularly, respondent A pointed out security as having a high influence on freight costs of its operations.The complexity of the Covid-19 vaccine supply chain impacts the cost of distribution.Refrigerated cargo transportation requires extra resources, such as refrigeration equipment, resulting in additional costs to the companies.In Brazil, for example, the travel cost of land refrigerated transportation is approximately 19% higher than general cargo (Brasil, 2021).However, despite the higher cost of refrigerated cargo, respondents A and C pointed out other items as more significant for the cost of freight, such as urgent delivery, travel time, and mode of transport.This can be explained by the particularities of Covid-19 vaccines compared to other vaccines and refrigerated products.Also, because of the severity and consequences of the Covid-19 pandemic, there is an urgent need for vaccine distribution, impacting the freight cost and possibly diluting the impact of the higher freight cost of refrigerated cargo.All respondents stated that shelf life (when the product can be stored without impairing its integrity) has little influence on Covid-19 vaccine losses.This is consistent with the current reality of supply and demand.
The last part of the questionnaire aimed to measure the impact of the challenges in the Covid-19 vaccine supply chain, qualitatively.All three respondents stated 'demand planning and inventory control' as very challenging, as the lack of predictability of supply and demand is enormous (DHL Research and Innovation GmbH, 2020).A good practice used by Israel (Choi et al., 2021) and the United Arab Emirates (Emirates News Agency, 2020) to better manage supply and demand is developing a well-structured information system, which allows better tracking of the administered doses, enabling a better demand forecasting.
Respondents A and C consider the impact of 'customs and regulatory procedures' as high.It can be induced that customs and regulatory procedures are challenging due to their complexity and lack of agility.However, such impacts can be mitigated by accelerating Covid-19 vaccine authorization processes, proven effective in Chile (Financial Times, 2021) and United Arab Emirates (Syal, 2021).
The respondents had different perceptions regarding the items 'cold chain' and the 'risk of wastage due to product fragility, temperature, and shelf life' in their operations.Nevertheless, these obstacles are existent in all operations, and their intensity may change according to the mode of transport, area of operation, and equipment used.It is noted that respondent B is the only one who confirmed the use of refrigerated boxes in transport operations and pointed the 'cold chain' as being very challenging, which is related to the cargo packaging mode used by company B operations.
The perceptions of A and C were opposite regarding the item 'dose administration (last mile)' .Respondent A ranked it as high and can be explained by the higher incidence of vaccine losses during the last mile, reported in Table 1, which does not occur for respondent C. Making modifications in vaccine packages with the manufacturer's authorization, as done by Israel (Choi et al., 2021), may lead to an optimized supply chain and a potential reduction of vaccine losses in the last mile stage.
The last two items are related to preventive measures, such as the 'use of personal protective equipment/ social distancing' and 'labor shortages and absenteeism' due to suspected or confirmed Covid-19 cases.These challenges are perceived differently in respondents' opinions.This difference may be related to the size, area, number of employees of the respondent's operations, and the pandemic scenario in each country.The questionnaire provided qualitative insights regarding the challenges and logistical aspects of Covid-19 vaccines addressed in the literature review.
It is important to highlight that the small sample does not allow us to draw general conclusions about the subject, but rather discuss different companies' perceptions of the logistics of Covid-19 vaccines.In this way, the results found empirically look for elucidating empirical responses and compare them with the literature findings, allowing researchers to start taking steps toward developing the Covid-19 vaccine logistics.

Conclusion
The Covid-19 vaccine supply chain has been complex and highly challenging.Besides the challenges presented in the conventional vaccine supply chain, such as the regulatory procedures involved in developing immunizers and temperature maintenance during the entire cold chain, the Covid-19 vaccine supply chain had to deal with the urgency of a highly contagious disease.The speed with which the disease spread through the world, overloading health care systems, required the development of an urgent vaccine.Despite the challenges faced by vaccination programs globally, some countries such as Israel, the UAE, Chile, and the USA have achieved goods results due to strategies adopted at the beginning of the immunization schedule, such as decentralizing responsibility for the vaccination program and the purchase of vaccines from diversified suppliers.Also, it is important to highlight that a robust structured healthcare system also contributed to the good performance of the Covid-19 vaccination campaign in Israel, UAE, and Chile, reinforcing the importance of investments and policies in public health.
The objectives proposed in this paper were achieved.Our theoretical foundation summarizes the Covid-19 vaccine supply chain literature, its challenges, and best practices.Then, we compare the literature findings with empirical research.For this purpose, we develop a structured questionnaire and apply it to specialists from Peru, Argentina, and Brazil.Thereby, this work contributes to endorsing discussions about the Covid-19 vaccine supply chain both in theory and in practice.Regarding the empirical results obtained through the questionnaire, we identify discrepancies in the answers, especially regarding classifying the intensity of some items, such as 'cold chain' and 'administration of doses (last mile)', which can be explained due to different perceptions of the respondents and their different areas of operation.
This study also presents some limitations.The small sample of respondents precludes us from raising more robust and confirmatory conclusions about the subject.Also, this sample only encompasses South American countries, which further restricts the insights.The questionnaire is essentially composed of qualitative questions, which are highly based on respondents' perceptions.It is worth mentioning that some partially answered responses and the reduced sample made it challenging to propose more assertive conclusions.Thereby, future complementary works are suggested to explore a larger and global sample, delimiting a quantitative research bias and making it possible to quantify the impact of the challenges.Furthermore, researches are suggested to quantify the good practices found in countries that positively impacted vaccination campaigns, such as Israel, United Arab Emirates, and Chile.