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Management of COVID-19 vaccines cold chain logistics: a scoping review
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* Published: 02 March 2022

MANAGEMENT OF COVID-19 VACCINES COLD CHAIN LOGISTICS: A SCOPING REVIEW

* Mathumalar Loganathan Fahrni ORCID: orcid.org/0000-0002-9042-42901,2,
* Intan An-Nisaa’ Ismail1,
* Dalia Mohammed Refi3,
* Ahmad Almeman4,
* Norliana Che Yaakob1,5,
* Kamaliah Md Saman1,
* Nur Farhani Mansor1,
* Noorasmah Noordin6 &
* …
* Zaheer-Ud-Din Babar7

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Journal of Pharmaceutical Policy and Practice volume 15, Article number: 16
(2022) Cite this article

* 24k Accesses

* 53 Citations

* 21 Altmetric

* Metrics details

ABSTRACT

BACKGROUND

Successful mass vaccination programmes are public health achievements of the
contemporary world. While pharmaceutical companies are actively developing new
vaccines, and demonstrating results of effectiveness and safety profiles,
concerns on COVID-19 vaccine management are under-reported. We aimed to
synthesise the evidence for efficient cold chain management of COVID vaccines.

METHODS

The scoping review’s conduct and reporting were based on the PRISMA–ScR 2018
checklist. We searched from April 2020 to January 2022 for publications in
PubMed (LitCovid), Scopus and ScienceDirect. All review stages were pilot-tested
to calibrate 2 reviewers. Articles on cold chain logistics and management were
included, while publications solely describing COVID vaccines, their development
and clinical aspects of the vaccine, were excluded. To capture relevant data,
charting was conducted by one reviewer and verified by another. Results were
analysed thematically and summarised descriptively in a table and in-text.

RESULTS AND DISCUSSION

We assessed 6984 potentially relevant citations. We included 14 publications
originating from USA (n = 6), India (n = 2), Finland, Spain, Bangladesh,
Netherlands, Switzerland and Ethiopia. They were reported as reviews (4), policy
or guidance documents (3), experimental studies (2), case reports (2), expert
commentary (1), phenomenological study (1), and decision-making trial and
evaluation laboratory trial (1). The findings were presented in three themes:
(i) regulatory requirements for cold-chain logistics, (ii) packaging and
storage, and (iii) transportation and distribution. A conceptual framework
emerged linking regulatory requirements, optimal logistics operation and
formulation stability as the key to efficient cold chain management.
Recommendations were made for improving formulation stability, end-product
storage conditions, and incorporating monitoring technologies.

CONCLUSION

COVID-19 vaccines require special end-to-end supply cold chain requirements,
from manufacture, and transportation to warehouses and healthcare facilities. To
sustain production, minimise wastage, and for vaccines to reach target
populations, an efficient and resilient vaccine supply chain which is assisted
by temperature monitoring technologies is imperative.

BACKGROUND

The COVID-19 outbreak had single-handedly crippled healthcare systems, induced
political instability, and transformed cultural and social norms worldwide. At
the financial forefronts, and as part of Operation Warp Speed, the US government
had invested an initial $6.5 billion (£4.8 billion equivalent) in COVID-19
therapeutics and vaccines—an effort aimed at delivering 300 million doses of
vaccines, with first doses made available as early as January 2021 [1]. The
amount included at least $1 billion (£738 million equivalent) each to Novavax,
the University of Oxford and AstraZeneca, GlaxoSmithKline and Sanofi, and
Johnson & Johnson. Similarly, the UK government in the early stages purchased a
total of 340 million doses at fixed prices, while Australia had invested
approximately A$3.3 billion (£1.7 billion equivalent) for five different
vaccines [1].

Recently, the World Health Organisation (WHO), by observations of superspreading
events, uncovered that COVID-19 transmissions are airborne and that containing
the outbreak will, therefore, be challenging [2]. The organisation recommends
that general ventilation is supplemented with airborne infection controls, such
as local exhaust, high efficiency air filtration, and germicidal ultraviolet
lights, particularly in hospitals, schools, public buildings, workplace
environments, and aged care homes. On the parallel, maintaining hygiene and good
hand-washing techniques, practising social distancing, efficient contact tracing
and mass-testing, and droplet precautions are still advocated, at the time of
writing.

Evidently, administering vaccines including booster shots on this scale and at
this speed has never been done. Pharmaceutical companies are focused on meeting
the demands for COVID-19 vaccine supply, and on demonstrating results of good
immune responses and reasonable safety profiles of their respective candidate
vaccines in all special interest groups. Up until May 2021, of the 170 vaccine
candidates for COVID-19 developed, researchers were testing 90 vaccines in
ongoing human clinical trials, with 27 having reached phase 3 and approved to be
used for the population in various countries and currently undergoing
post-marketing surveillance for adverse effect following immunisations [3].
While we constantly face the risks of adverse effects developing
post-immunisation, and more potent variants emerging and creating new waves of
infections, we continue to rely on the active acquired immunity offered by the
COVID-19 vaccines.

The global data for COVID-19 vaccination policy demonstrated that the delivery
and outreach of the vaccines for the different groups have been largely
universal or that at least the vulnerable groups were targeted [4]. An exception
existed for Eritrea, where none of its population was provided with the vaccine.
In Afghanistan and Liberia, the vaccines were available for either their key
workers or clinically vulnerable groups or the older-age groups. The Saudi
government recorded that by early February 2022, 59 million doses were
successfully administered, of which 1 million doses were allotted for older
adults [4]. While a few countries had failed to report their data on vaccination
provision, a majority of the countries had setup special task forces for
managing the vaccines and related data. The scenario is no different in
Southeast Asia. In Malaysia for instance, a special committee, known as the
Special Committee for Ensuring Access to COVID-19 Vaccine Supply, JKVAV, is
responsible for ensuring timely access to the COVID-19 vaccine supply. Alongside
the JKJAV, the NPRA plays a vital role in ensuring vaccines' efficacy, quality,
and safety. Six of the COVID-19 vaccines, from Pfizer-BioNTech (Cominarty),
Oxford-Astrazeneca (Vaxzevria), Sinovac (CoronaVac), COVILO (Sinopharm), Johnson
& Johnson (Janssen COVID-19 Vaccine), and CanSino (Convidecia) had received
conditional approval from the regulatory agency [5]. Following waves of rising
infections, as of 10th February 2022, 98% of the country’s adult population
eligible for vaccination had completed the required doses and were successfully
inoculated, while 53.9% had received their booster shots [6]. The plan to
vaccinate adolescents and toddlers as young as 5, and other special interest
population groups has been approved and being rolled out in phases [7].

Issues related to mass production, storage and distribution of COVID-19 vaccines
are, however, aspects which are under-researched and under-reported [8]. These
challenges, if not addressed timely, will severely impact our race to achieve
herd immunity. The "cold-chain" acts to preserve biological product quality from
the time of manufacture until the point of administration by ensuring that the
vaccines are stored and transported within the recommended temperature ranges.
Vaccines can be categorised by the method by which they were developed, i.e.,
the different approaches used, such as (1) genetic vaccines—using mRNA to cause
the body to produce viral proteins; (2) viral vector vaccines—using genetically
modified viruses such as adenovirus to carry sections of coronavirus genetic
material; (3) protein vaccines—delivering viral proteins (but not genetic
material) to induce an immune response; (4) whole vaccine—through inactivated or
attenuated coronavirus; and (5) repurposing existing vaccines, e.g., BCG [9].
The processes leading to a successful development and administration of the
delicate and fragile vaccines are to be conducted meticulously and with care, as
it involves extremes of temperature. Hence, this makes the management of its
cold chain a subject matter of high priority, and the vaccines are to be handled
with caution, failing which, the consequences can be detrimental to public
health. The aim of this scoping review is to summarise and synthesise the
evidence for efficient cold chain management of COVID-19 vaccines, and to
propose relevant practical recommendations.

METHODS

The review was both conducted and reported according to the PRISMA–ScR guidance
checklist (Additional file 1: Appendix S1). A review protocol was not registered
considering the short time frame within which the data were retrieved. All
review stages were pilot-tested to calibrate reviewers.

SEARCH STRATEGY

Two reviewers IAI and MLF independently conducted the search using the three
electronic databases: LitCovid (PubMed), Scopus, and ScienceDirect, with the aim
of retrieving publications related to cold chain management of COVID-19
vaccines. The search was performed using a combination of keywords, MeSH terms
and free texts, for example, "COVID-19 vaccine" AND “supply-chain” AND
"refrigeration OR temperature-controlled supply chain OR chiller OR cold chain”.
The retrieved citations were exported into Endnote version 20. The full PubMed
search strategy is available in Additional file 2: Appendix S2.

SELECTION PROCESS

Two reviewers (MLF and IAI) independently juxtaposed the publications retrieved
against the inclusion and exclusion criteria. The inclusion criteria were (i)
publications in English and published between April 2020 and January 2022; (ii)
publications which focused on cold chain operations throughout the vaccine
supply chain; and (iii) publications with accessible full texts. Exclusion
criteria were (i) non-English language documents, (ii) publications which
focused solely on COVID-19 vaccines and their development, and (iii)
publications discussing the clinical aspects of the COVID-19 vaccine, which were
not related to vaccine stability or did not highlight cold chain management. The
reviewers were trained and a pilot with 5 papers was performed to guarantee an
inter-reviewer agreement (until a Kappa score of > 0.75 was attained). MLF and
IAI independently performed the screening of titles and abstracts and any
discrepancies were resolved via discussion or a third reviewer consulted (KMS).

DATA COLLECTION AND ANALYSIS

Data from each study was charted individually by IAI using a standardised and
pretested Word data collection form and MLF verified the data (Additional file
3: Appendix S3).

Results were analysed thematically and summarised descriptively in a table and
in-text.

RESULTS

SEARCH RESULTS

A total of 6984 publications were retrieved from the three databases searched.
After removal of duplicates, non-English texts, and screening of titles and
abstracts, the number remaining were one hundred-forty-one (141) publications.
Full texts remaining after review was 10. Four full-text publications were
retrieved from the reference lists of relevant publications, resulting in 14
publications included this review. The flow chart for selection and elimination
of publications is shown in Fig. 1. Findings from the publications were
synthesised and presented in 3 themes: (i) requirements for cold-chain
logistics, (ii) packing and storage of COVID-19 vaccines, and finally (iii)
transportation and distribution. A conceptual framework emerged linking
regulatory requirements, optimal logistics operation and formulation stability
as the key to effective cold chain management (Table 1—Challenges, C1–12).

Fig. 1

Flow chart of the literature selection process

Full size image
Table 1 Management of COVID-19 vaccines cold chain logistics
Full size table

A descriptive summary was organised by aspects of: (i) cold chain requirements
(process flow, regulatory requirement, logistics), (ii) packing and storage
(specific for four different vaccines), and (iii) transportation and
distribution (operational and logistics).

REQUIREMENTS FOR COLD CHAIN LOGISTICS

In this section, the regulatory and operational requirements for logistics are
described.

Vaccines need to be administered by healthcare providers in clinics or
pharmacies, while many other biologics for treating chronic conditions, such as
diabetes and arthritis, were frequently delivered for self-injection at the
patient’s home. When arriving at healthcare facilities, COVID-19 vaccine
immunogenicity and effectiveness are highly dependent on the following factors:
vaccines must have been stored in the required cold chain, the cold chain must
be adequately monitored, and vaccines must be used up within critical timeframes
after being removed from the cold chain or after a puncture in the multidose
vial [9, 10]. By having appropriately trained managers on cold chain equipment
who are tasked to manage and monitor cold chain, accidental interruption of the
storage temperature conditions and hence vaccine instability can be avoided.
Consequently, fewer vaccines are rendered ineffective and wasted. [10, 11].

Cold chain can be standard (2 °C to 8 °C) or deepfreeze (as cold as −70 °C).
Cold chain requires building extensive infrastructure and is very expensive to
maintain. The complexity of the cold chain is illustrated in documents, such as
the CDC Vaccine Storage and Handling Toolkit [12]. Effective management of cold
chain logistics for vaccines will require precise coordination across processes
to ensure that the efficacy of the vaccines is preserved through
temperature-monitoring and up-to-date records for traceability [7]. Constraints
currently exist in their production, multimodal transport, storage, distribution
and equal disbursement of vaccines to those needing them. In the European
Commission (EC)-funded CHILL-ON project, most of the deviations from
high-quality standards of perishable goods (vaccines included) occurred during
the shipment and transportation process [13]. Where a deviation was detected, it
was attributed to a lack of appropriate cold chain equipment, such as cold chain
boxes, cold chain trucks and efficient refrigeration system [14]. In addition,
the role of managers who receive vaccines and maintain the relevant cold chain
equipment deserves recognition. They are also responsible for the reconstitution
syringes, safety boxes and vaccine diluents (which does not need to be
refrigerated) delivered. In addition, the manager is tasked to addressing
changing cold storage needs and making additional space should a need arise
[11].

Ideally, supply-chain managers will have obtained advance approvals for
acquisition of these medical countermeasures—the COVID-19 vaccines. In
preparedness for subsequent distribution, transport corridors which function as
vital routes to end-users are identified; primary and secondary transport modes
from point of entry to points of distribution are evaluated. In doing so,
assessments of the respective governments’ and non-governmental organisations’
capacity to respond to emergencies, including inspection policies, customs,
port, air, rail and road operations, storage, vaccine supply, communications,
electricity and fuel generation, supply and distribution will also be weighed in
[15]. Understanding each systemic link in the supply chain, including their
strengths and shortfalls, with potential solutions or alternatives are
essential. In addition, the functional linkages between governments, UN
agencies, NGOs, and private sector entities are all crucial aspects of
operations. It is also crucial to understand the extent of business continuity
efforts at both regional and national levels at the geographical location of
distribution [13, 16].

PACKING AND STORAGE OF COVID-19 VACCINES

Here, we present examples of four of the most common vaccines that have special
packaging requirements suitable for storage and transport throughout the cold
chain, from manufacturer to shipping to warehousing. Primary packaging materials
include glass vials and syringes, along with stoppers and seals. Packaging for
distribution, includes secondary and tertiary packaging for vaccines. Secondary
packaging assist in reducing volume, cost-saving, minimising logistical burden,
and reducing carbon footprint. Vaccine storage units at the healthcare
facilities site usually consist of purpose-built or pharmaceutical-grade (large
or compact) or household-grade refrigerator or freezer. [17].

PFIZER’S MRNA VACCINE

Pfizer’s mRNA vaccine demands the most stringent storage needs. It is required
to be stored in a − 70 °C ultra-cold freezer. Packed as a 2 mL, glass
preservative-free vial containing 5 doses, the Pfizer mRNA vaccine are packed
for delivery in trays of 195 vials each. Five trays of 4,875 doses will be
included in each shipment of dimensions 15.7″ L × 15.7″ W × 22″ H and will
require to be packed with dry ice and weigh approximately 34 kg. The vials are
subjected to quality measures so no broken vials are present. Without opening
the outer packaging (with the exception of inspecting the vial once to see if
any is broken), each shipper can be stored for up to 10 days. Dry ice are
replenished if the shipper is stored in a warmer climate and/or is opened more
frequently than once for inspection of vials. GPS-enabled temperature-monitoring
devices are placed inside to ensure end-to-end distribution occurs within the
required temperature range. Upon arrival of the shipper, the vaccine must be
transported into an ultra-cold freezer within 5 min. Simultaneously, the
GPS-enabled logger is disabled and the shipper sent back to the supplier within
10–20 days of arrival. The vaccines can be thawed in the refrigerator (2–8 °C)
for up to 5 days (120 h), after which it should be discarded. Each dose needs to
be diluted with normal saline before use and is stable for up to 6 h at room
temperature, after which time it should be discarded. Pfizer has incorporated a
QR code linked to the Emergency Use Authorisation (EUA) website, a lot number,
and an expiration date on the label for each vial for documentation purposes [9,
18]. Pfizer-BioNTech recently submitted data to the Food and Drug Administration
(FDA) to update the storage requirements to a more reasonable temperature
ranging anywhere between − 25 and − 15 °C [19].

MODERNA’S MRNA VACCINE

Packed as 10 vials of 10 doses in each carton, the Moderna’s mRNA vaccine will
be shipped and delivered at a temperature of − 20 °C. One hundred doses are
loaded in a carton of dimensions 5.5″ L × 2.2″ W × 2.5″ H. One advantage these
vaccines have is that there are no special requirements for reconstitution or
preparation and the vaccines can be stored for up to 30 days in the refrigerator
at 2–8 °C until ready for use. At room temperature post-thaw, the vaccine is
stable for up to 12 h, after which it should be discarded. The vial will have a
QR code printed on the label. When the QR code is scanned with a smart device
(i.e., phone or tablet), it will link the device to the EUA-specified website.
The website will contain product information and provide access to the fact
sheets. In addition, since the expiration date will not be printed on the vial,
there will be a function to search for the date on the website by entering the
product lot number. The carton in which the vaccines were shipped will display
the same QR code as the label. In addition, the carton will have a 2D barcode
printed, which is encoded with the GTIN (product ID), lot number, and an
expiration date that is hard-coded to 12/31/2069. [9] Moderna has initiated a
trial with a vaccine that may be refrigerator-stable. [20].

JOHNSON & JOHNSON’S ADENOVIRUS-VECTORED VACCINE

Packed as 10 vials per carton and 48 cartons per shipper case of dimensions
3.66″ L × 1.5″ W × 2.13″D, the Johnson & Johnson’s adenovirus-vectored vaccine
will be delivered at a temperature of − 20 °C. Each shipper will contain 2,400
doses with five doses in each vial. The J&J vaccine require to be transported to
the refrigerator upon arrival. It can be stored for up to 3 months in the
refrigerator (2–8 °C). Stability information at room temperature is still
forthcoming. [9].

ASTRAZENECA (AZ)’S ADENOVIRUS-VECTORED VACCINE

AstraZeneca (AZ)’s adenovirus-vectored vaccine will be shipped in pallets. Each
pallet will contain 85 cases packed with 20,400 vials. 10 vials per carton will
contain 100 doses. Case dimensions are 11.6″ L × 9.3″ W × 7.4″ H. AZ’s vaccine
is required to be stored in the refrigerator at 2–8 °C upon arrival. It should
be light-protected and can be stored for up to 6 months in the refrigerator
(2–8 °C). To prevent prolonged light exposure, the vaccine must be kept in the
original packaging until use and is not to be frozen. No reconstitution or
special preparation is required. After the vial is punctured, it can be stored
in the refrigerator for up to 6 h, after which the vaccine must be discarded.
One advantage is that no reconstitution or special preparation is required for
this formulation. [9].

TRANSPORTATION AND DISTRIBUTION

In the following section, we present vaccine regulatory and logistic
requirements for transportation by air, ocean and ground networks in a
pharmaceutical-graded, temperature-controlled supply chain to healthcare
facilities and other points of administration.

First and foremost, the vaccine manufacturers will have to comply with the Food
and Drug Authority and Federal Food, Drug, and Cosmetic Act policies. As the
vaccines were authorised for use in an event of a public health emergency, the
Emergency Use Authorization (EUA) authority will then issue a letter of
authorisation that entails two fact sheets prior to the vaccine being
transported to other countries, namely:

1. (i)

Healthcare Providers Administering Vaccine (Vaccination Providers)

2. (ii)

Recipients & Caregivers [21]

There exists multiple stakeholders in the cold chain transportation processes,
namely, the sender, freight forwarder, air and road cargo transportation
companies, as well as the receiving ground handling agents [22]. They operate
optimally within a risk management taskforce which is responsible for
environmental health and safety, public and government affairs and policies,
communications, and crucially business continuity, operations and supply chain
management. Each stakeholder has a very specific role to play to complete the
entire process flow. There is a risk that the operation ceases, should any of
the processes fail to run its course, which then jeopardises the business
entity. Exposed biological products such as vaccines and equally other
biological goods to unfavourable temperatures can damage the products and
eventually render them being of no use [23].

The International Air Transport Association (IATA) and its members are
responsible for transporting the vaccine consignments from the nation supplying
to the destination airport. Several personnel are trained on the technicalities
and assist with electricity supply to the refrigerators throughout the flight.
Once landed, a local road transportation company will provide refrigerated
trucks to transport vaccines to and from the warehouses and the airport [24].
The trucker and assistants are then responsible to maintain vaccines within
recommended temperature ranges. Local government officials provide on-field
assistance for customs clearance of vaccines at the airport, and this sometime
involves humanitarian organisations which are responsible for distribution to
those who need them [25]. At the healthcare facilities, the capacity of cold
chain equipment will also need to be upgraded; to cite an example, in Ethiopia,
only 48% health facilities had satisfactory cold chain infrastructure, while 63%
had good cold chain practices [26]. In addition, inappropriate coordination with
local organisations, lack of vaccine monitoring bodies, difficulties in
monitoring and controlling vaccine temperature, and financial support for
vaccine purchase were identified as the main challenges in the region of Asia
[27]. Another area which is also under-researched is the use of vaccines in
controlled temperature chain (CTC) or outside the cold chain (OCC) environments
[23]. One study experimented on commercially available products, such as
refrigeration container units, and retrofitted the test units to meet the
vaccine storage temperature requirement. Experimental and simulation studies
were conducted to assess the technical merits of the solution with the ability
to control temperature at − 30 °C or − 70 °C as part of the last mile supply
chain [28]. In India, an environmentally friendly, solar photovoltaic powered
thermoelectric-based micro cold storage which can function as a COVID-19 vaccine
carrier for rural areas, was designed and an experimental study conducted. From
the study, last-mile vaccine delivery was successfully done without any vaccine
degradation [29].

DISCUSSION

Notably, all the included publications in our scoping review were available in
LitCovid, an open database of COVID-19 literature, which is essentially a
curated literature hub, to track up-to-date scientific information in PubMed. We
identified 14 publications originating from USA (6), India (2), Finland, Spain,
Bangladesh, Netherlands, Switzerland and Ethiopia. They were reported as reviews
(4), policy or guidance documents (3), experimental studies (2), case reports
(2), expert commentary (1), phenomenological study (1) and decision-making trial
and evaluation laboratory trial (1).

RECOMMENDATIONS FOR BEST PRACTICE

EQUITABLE ACCESS AND PUBLIC HEALTH POLICY

There are justifiable concerns that the requirements for recipient countries to
maintain deep-freeze production, storage and transportation networks, in
particular for the Pfizer vaccines, will limit the capacity of distributors from
transporting the vaccine to low- and middle-income countries. The success in
distributing vaccines to remote areas lies in the mechanisms in place to prevent
unavoidable exposure to many stresses such as temperature, light, and agitation
that may result in loss of vaccine effectiveness. Warm climate regions and poor
intercity-connectivity pose obstacles to delivering the temperature-sensitive
biologics to the public. In Peru, for example, 30 ultracold freezers existed,
but none outside of Lima city. These specialised freezers will take 4–6 weeks to
produce and cost between $10,000 and $25,000. One of the proposed solutions is,
therefore, to top off containers with dry ice every 5 days to keep temperatures
stable although this is not a practical solution as dry ice may be scarce in
rural areas, and shipping dry ice, which sublimates and transforms into carbon
dioxide gas, is costly and dangerous [30]. Second, since the infrastructure for
2–8 °C is already in place in many communities worldwide, as opposed to
ultracold logistics, low-to-middle-income countries may opt for COVID-19 vaccine
candidates requiring the minimal cold chain requirement. Innovation was key—in
India, for example, companies that dealt with food chain and had cold storage
facilities were compelled to innovate and were subjected to a government
directive to do a minor redesign of storage spaces to accommodate such need
[31]. Third, advanced cold chain equipment such as long lasting passive cold
box, medical refrigerators, and refrigerated trucks can facilitate effective
storage and transportation system.

TECHNOLOGIES TO ASSIST COLD CHAIN LOGISTICS

Practising data logging does ease the process of monitoring temperatures.
However, for this to be done efficiently, ground handling agents will need to
open up the package or content to monitor conditions that possibly expose the
vaccines to extreme temperatures. Furthermore, this system allows inspection at
the destination, and at that stage, it may become too late for personnel to take
any corrective measure. Although financial constraints exist, fortunately in
today’s artificial intelligence era, the emergence of sophisticated
internet-of-things (IoTs), analytics, mobile and cloud technologies provide the
basis for a comprehensive cold chain feedback mechanism. It allows the reporting
of an ad-hoc and routine-base data collection, recording, checking, and analyses
of the flow of vaccines from the manufacturing to healthcare facilities. Using a
vaccine blockchain system and simulated machine learning technologies, Yong et
al. presented a method of vaccine traceability effective in preventing vaccine
record fraud and thus reducing supply risks. [32] Blockchain facilitates
transparency and effectiveness in tracking, tracing and monitoring vaccine
delivery. Using IoTs, more rigorous temperature monitoring in real time and
forecasting can be achieved, although the processing of the generated data is
questionable. Various aspects of cold chain generate experimental and numerical
data that can train deep and machine learning models to predict temperature
control, although according to Schroeder et al., a reliable method to detect a
break in the cold chain is yet to be validated [33].

In addition, the use of digital temperature sensors such as thermocouples,
resistant temperature detectors, or thermistors can provide accurate data.
Purpose-built units or pharmaceutical grade units can also be used instead of
household or dormitory-style refrigerators or freezers. The use of digital
temperature tags has proven beneficial. For example, in India, vaccine
manufacturers have begun airlifting vaccines in cold boxes with digital
temperature tags to four major depots in four major states. These were then
transported to specified facilities via airplanes or insulated vans after which
they were stored in temperature-controlled facilities at the district level.
Vaccines were held in ice-lined refrigerators in districts, then transported to
distribution centres in cold boxes, which were then transported to vaccination
sites in ice-packed vaccine carriers. Simultaneously, the COVID Vaccine
Intelligence Network, a cloud-based digitalised platform for vaccine
distribution management system, monitored the temperature of 29,000 cold-chain
points in real-time [31].

In each vaccine vial, incorporation of a vaccine-vial monitor can provide a
clear, visual guide to the vaccine's efficacy throughout the delivery or
transport to the point of administration. In addition, the monitor is capable of
warning personnel on whether or not the vaccines’ stability had been affected at
any stage of distribution before reaching the end-users. This will prevent
unnecessary wastage and facilitate vaccination outreach programmes in remote
areas, where sophisticated monitoring technology is not practical [34].

IMPROVED VACCINE FORMULATION

As mRNA vaccine is considered new technology, there was a lack of guidance on
the stability aspects of mRNA vaccines during the early phase of the vaccine
development [35]. While it is common knowledge that there are a series of
analytical methods used to determine the identity, purity, potency, safety, and
stability of mRNA bioactive and mRNA–lipid/protein complex formulations, there
is still a lack of relevant information on the monitoring of quality attributes
and on the proposed storage conditions to ensure stability for mRNA vaccines.

Improvements in the stringent cold chain storage requirements can be made by
improving vaccine formulation. One approach is to eliminate the cold chain
altogether by making vaccines that can withstand more natural temperatures.
Another method would be to stabilise vaccines through improved formulation, such
as excipient innovation, protein engineering and lyophilisation if suitable. For
instance, by making biologics such as an mRNA vaccine to withstand
lyophilisation, its cold chain requirement might be lessened from deepfreeze to
regular cold chain [12]. Few factors for consideration are selection of
excipients (for example, stabilisers and/or the inclusion of preservatives),
formulation milieu (for instance, pH and tonicifying agents), and manufacturing
processes (for example, liquid to lyophilised dosage forms or powdered form)
which can all be made without compromising vaccine potency. The improvised
formulation may not require freezing conditions for its long-term storage.
Improved understanding of the physicochemical processes underlying virus potency
loss, combined with rational approaches to minimising their occurrence, would be
highly beneficial in directing improved vaccine shelf life, which might
eventually result in the abolition of 'cold chain' requirements.

A sustained interest in making vaccines safe at room temperature has resulted in
several promising technologies—using specific polymers or sugars and optimising
the composition of vaccines, certain vaccines can be rendered insensitive to
freezing and/or stable for months at room temperatures [36]. In addition,
transforming vaccines from liquid (or frozen liquid or frozen suspension) to dry
powder for reconstitution at the point of administration can improve vaccine
stability. Powder engineering technology such as shelf freeze-drying is widely
used to transform small molecule pharmaceuticals, such as vaccines, and other
biologics into dry powders while preserving consistency and sterility, which can
then be stored for months, if not years, at room temperature [36]. This improved
formulation of virus-based COVID-19 vaccines would result in improved stability
profiles (such as shelf-life extension and conversion from freezer to
refrigerator storage). Furthermore, the number of publications addressing
mechanistic and systemic approaches to formulating and stabilising live
attenuated virus and viral vector-based vaccine products is limited, indicating
a critical area for future study. Another example is in the modification of its
packaging; for example, for the oral cholera vaccine (Euvichol®), packaging them
in plastic tubes rather than glass vials, significantly simplified the
manufacturing method, reduced the unit cost, storage, and administration and
contributed significantly to the WHO stockpile increase [37]. This had improved
logistical obstacles, improved patient access and vaccine coverage. Similar
innovations could also be emulated for COVID vaccines.

LIMITATION OF REVIEW

The lack of primary data on vaccine wastage or impact of a breach in the cold
chain, for instance, has presented limitations in the reporting of the review.
Waste handling post-vaccination is another major challenge which has not been
addressed in this review. Disposal of primary packaging (vials and syringes),
secondary packaging (cartons), and tertiary packaging (corrugating boards and
cushioning materials) are valid concerns. Indeed, matters pertaining to the
disposal of vaccine packaging material, and the disposal of personal protective
equipment kits are of prime concern. A comprehensive set of guidelines for waste
disposal has not been established, as yet.

CONCLUSION

Vaccines are to be administered to all population in a timely manner.
Establishing a secure cold chain management of global vaccine chain supply is
critical. As a result, innovative technologies and techniques are needed to
simplify vaccine distribution, by minimising the need for a cold chain, reducing
packaging footprint, streamlining administration, and reducing waste. Potential
practices include using renewable energy during production, storage,
transportation, and waste treatment processes. In addition, equitable vaccine
access can be promoted by using better packaging designs, utilising the Internet
of Things and big data analytics for monitoring of logistics, as well as,
managing real-time databases and coordination platforms to track vaccine
deliveries and outreach to the relevant public vaccination programmes. Finally,
COVID-19 vaccine storage, dosing, and scheduling could potentially vary over
time, and there is, therefore, a need to continually educate and update
healthcare providers, especially those who are involved in the vaccination
programmes.

DATA AVAILABILITY

All relevant data are within the manuscript.

ABBREVIATIONS

PRISMA–ScR:

Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for
Scoping Reviews

COVID-19:

Coronavirus disease

SARS-CoV-2:

Severe Acute Respiratory Syndrome Coronavirus 2

WHO:

World Health Organisation

JKJAV:

Special Committee for Ensuring Access to COVID-19 Vaccine Supply

NPRA:

National Pharmaceutical Regulatory Agency

DEMATEL:

Decision-making-trial-and-evaluation-laboratory

USA:

United States of America

BCG:

Bacillus Calmette–Guérin

MeSH:

Medical Subject Headings

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FUNDING

Universiti Teknologi MARA (UiTM), Malaysia and Qassim University, Saudi Arabia.

AUTHOR INFORMATION

AUTHORS AND AFFILIATIONS

1. Faculty of Pharmacy, Universiti Teknologi MARA, Selangor Branch Puncak Alam
Campus, 42300, Bandar Puncak Alam, Malaysia

Mathumalar Loganathan Fahrni, Intan An-Nisaa’ Ismail, Norliana Che
Yaakob, Kamaliah Md Saman & Nur Farhani Mansor

2. Collaborative Drug Discovery Research (CDDR) Group, Communities of Research
(Pharmaceutical and Life Sciences), Universiti Teknologi MARA (UiTM),
Selangor Darul Ehsan, Malaysia

Mathumalar Loganathan Fahrni

3. Pharmacy Department, Prince Sultan Armed Forces Hospital, Al-Madinah
Al-Munawarah, Saudi Arabia

Dalia Mohammed Refi

4. College of Medicine, Pharmacology Department, Qassim University, Buraydah,
Saudi Arabia

Ahmad Almeman

5. Faculty of Pharmacy, Universiti Sultan Zainal Abidin (UniSZA) Kampus Besut,
22200, Besut Terengganu, Malaysia

Norliana Che Yaakob

6. Rhazes Consultancy Services Sdn Bhd, Seksyen U19, 40160, Shah Alam,
Selangor, Malaysia

Noorasmah Noordin

7. University of Huddersfield, Huddersfield, HD1 3DH, West Yorkshire, UK

Zaheer-Ud-Din Babar

Authors
1. Mathumalar Loganathan Fahrni
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