Blockchain technology in the pharmaceutical industry: a systematic review

Blockchain technology in the pharmaceutical industry

Blockchains are used in the pharmaceutical industry for different purposes. Security, which is a major challenge, is addressed through the use of cryptographic technologies that validate blocks of transactional data (Sinclair, Shahriar & Zhang, 2019). Security elements unfold in different paradigms. Falsified medications are a security threat that has been addressed through serialization (Alshahrani & Alshahrani, 2021). In this technology, the entire supply chain system is equipped with verification checks that authenticate serial numbers. Drug traceability has also been enhanced to prevent theft (Huang, Wu & Long, 2018), and quality control is achieved through the use of digital signatures; blockchain chaincodes, health information, and data miners are deployed from the manufacturer to the pharmacy to maintain consistent quality (Makarov & Pisarenko, 2019).

Counterfeit prevention

Pharmaceutical products are serialized and assigned security features that can be verified by consumers and differentiated from counterfeits. The blockchain system also enhances security through transparent and chaincode-based transactions. Trust and transparency are necessary for the pharmaceutical industry because, without trust, the counterfeiting business thrives, exposing the public to dangers arising from low-quality or substandard pharmaceuticals. When blockchains are included in quality control and the detection of counterfeit drugs, this enhances safety and saves lives (Adsul et al., 2020). Several approaches, including the Anti-Counterfeit Medicine System (ACMS), can be used to prevent counterfeiting. ACMS uses the Interplanetary File System (IPFS) networks and the Ethereum blockchain as follows:

• Establish ownership criteria for retail and non-retail medicines to prevent cloning

• Build Ethereum smart contracts for practical ACMS management, exploiting IPFS networks and Ethereum blockchain

• Implement the program for small firms

• Evaluate and analyze the proposed system (Saxena et al., 2020).

The ACMS effectively prevents fraud. Clients generate a chaincode upon initiation of a transaction. The signature is verified by endorsing peers, and the endorsements are collected and sent to the ordering services, where transaction validation is the last step (Kumar et al., 2019).

Product distribution

The presence of multiple dealers and intermediaries presents an opportunity for malpractice that undermines supply chain efficiency. Blockchain has been hailed for preventing the circulation of poor-quality pharmaceuticals (Hulea et al., 2018). Substandard pharmaceuticals are sequestered, and their entry into the pharmaceutical supply chain is investigated. Ledger systems, chaincodes, and serialization, in which serial numbers are assigned to pharmaceutical products to enable identification and differentiation, are used to facilitate pharmaceutical distribution. Blockchain information is tightly regulated to avoid unauthorized access that could jeopardize security systems (Dwivedi, Amin & Vollala, 2020). The Internet of Things (IoT) in the pharmaceutical distribution system enhances efficiency (Botcha, Chakravarthy & Anurag, 2019).

Tracking and tracing

Naturally, goods in transit should be tracked and traced from dispatch to destination. Delivery delays hamper business operations in general, but problems can lead to loss of life or exacerbation of illness in the pharmaceutical and health industries. Blockchain technology has been applied to the pharmaceutical supply chain (Schöner et al., 2020). Drug tracking and traceability are essential for business operations, patient health, and regulatory compliance. With elaborate and secure tracking and tracing technologies, goods in transit are delivered on time to the desired destinations, enabling uninterrupted pharmaceutical business and patient management. A secured international registry was created to facilitate the global distribution of drugs. Although the technology provides enormous opportunities for large pharmaceutical firms, smaller firms should also benefit (Garankina et al., 2018).

Safety and security

Since drugs are high-value commodities, security is necessary to protect them. The cryptographic features of blockchain technology are the basis of safety and security in the pharmaceutical industry (Sinclair, Shahriar & Zhang, 2019). Tracing and tracking capabilities satisfy regulatory requirements, and cryptographic technology enhances drug security (Plotnikov & Kuznetsova, 2018). Security is bolstered against theft and the introduction of counterfeit pharmaceuticals. Unauthorized drug modifications are also mitigated, blocking opportunistic pharmaceutical stakeholders who modify drugs and, in this way, undermine quality. Supply chain systems are governed based on stringent safety and security measures that raise an alarm when breached (Plotnikov & Kuznetsova, 2018).

Research question

We used a previously published methodology to define our research question (Liberati et al., 2009). In this section, we elaborate on our selection of the research questions listed in the introduction.

RQ1 aims to review previous studies of blockchain technology in the pharmaceutical industry. We focused on studies that have developed proof-of-concept blockchain frameworks in the pharmaceutical industry. Many white papers and vision papers have been published on the use of blockchain technology in the pharmaceutical industry, but our primary goal was to present insights on real-world applications.

RQ2 defined four primary areas in which blockchain technology has been applied in the pharmaceutical industry: counterfeit prevention, product distribution, tracking and tracing, and safety and security. In addition, RQ3 aims to identify the limitations associated with pharmaceutical industry-based blockchain research. Finally, RQ4 explores future research directions proposed in the literature.

Study protocol and workflow

The proposed review is based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement (Liberati et al., 2009). The process is shown in Fig. 4.

Inclusion and exclusion criteria

To be eligible for inclusion in this SLR, articles needed to meet the seven criteria shown in Table 1.

Information sources and search process

Seven databases were searched to identify relevant articles: namely, SpringerLink, Web of Science, ScienceDirect, Scopus, Google Scholar, IEEE Xplore Digital Library, and ACM Digital Library. In addition, the search keywords were:

• Blockchain

• Smart Contract

• Smart Contracts

• Distributed Ledger Technology (DLT)

• Pharma

• Drug

• Medicine

• Prescription

The final search term used for all seven databases was (Blockchain OR DLT OR “Smart Contract” OR “Smart Contracts” OR “Distributed Ledger Technology”) AND (Pharma* OR Drug* OR Medicine* OR Prescription*).

Study selection and data collection

Seven researchers performed the data collection process, and the rest of the team provided guidance, support, and process verification. After extracting studies from the databases, the researchers independently screened each study’s title and abstract for eligibility. Eligibility disputes were settled by discussion until consensus was reached. The complete texts of the identified potentially eligible studies were retrieved and independently assessed for suitability.

First, we searched for relevant studies addressing blockchain technology in the pharmaceutical industry by entering the search term (see ‘Tracking and Tracing’) into each database’s search engine. In turn, the results were exported to a reference management system (in this case, Mendeley: (https://www.mendeley.com/) to eliminate duplicate entries. The papers were exported from Mendeley into Rayyan (Ouzzani et al., 2016), a tool that facilitates collaboration on screening and selecting research papers by multiple users. It is a free web and mobile app that uses semi-automated methods to expedite the initial screening of abstracts and titles (Ouzzani et al., 2016). Seven researchers independently screened the papers in Rayyan and scored them as “Include,” “Exclude,” or “Maybe.” The team met to discuss and reach a consensus on the 27 papers marked as “Maybe,” identifying 10 papers for inclusion and excluding the remaining 17. The final count at the end of this step was 82 papers marked for inclusion and 2,128 excluded.

Quality assessment was applied to the remaining 82 papers by using a modified method described elsewhere (Table 2) (Liao et al., 2020). The quality assessment yielded 28 papers for inclusion in the final analysis. A ranking system was applied (Erokhin, Koshechkin & Ryabkov, 2020) in which six questions were asked for each paper, where questions were scored as 1 for “yes,” 0.5 for “partially true,” and 0 for “no.” Papers with scores of 3 or more were retained.

After identifying the high-quality papers, we applied forward and backward snowballing (Jalali & Wohlin, 2012). This involved the following:

• Searching journal articles and conference papers to obtain a starting collection of papers

• Apply backward snowballing by checking the reference lists in step 1 and step 2 for related studies (iterate until no new papers are identified)

• Apply forward snowballing by finding papers that reference the studies

The articles retrieved from forward and backward snowballing (n = 10) were also tested against the quality assessment questions. This yielded a final count of 38 relevant articles for the SLR.

Classification of papers

Product distribution

In supply chain management, products are transferred between multiple parties, none of whom are aware of any other exchange that occurred within the chain. Significantly, the drug supply chain lacks the infrastructure to ensure comprehensive manufacturer-to-end-user tracking (Sahoo et al., 2019).

The manufacturer first distributes drugs to wholesalers, who then distribute the drugs to hospitals or pharmacies. Every transaction in this process should be tracked. Blockchain is a suitable technology to solve distribution process problems such as the circulation of counterfeit or illegal drugs (Fernando et al., 2020). Serialization may be used to allow reconstruction of the packaging hierarchy and product history (Dwivedi, Amin & Vollala, 2020).

One prototype identified four nodes: the manufacturer, the wholesaler, the retailer, and the Food and Drug Administration (FDA) (Sylim et al., 0000). The FDA is responsible for authorizing manufacturers and storing the authorization as a smart contract on a blockchain network. The system’s back-end is a distributed file system that supports a private blockchain network. On the front-end, it is stored in each node, and the interfaces reflect only the part of the supply chain in which a given user account is involved. There is a section for displaying performed transactions and the distribution chains, as well as a dashboard for anomaly detection. Each participant will create drug manufacture pedigrees, shipping pedigrees, and receipt pedigrees, sign them, and append them to the pedigree that is visible along the supply chain.

Other supply chain applications have focused on logistics to ensure quality, which is the practical management of products from the central unit to delivery. The proposed modum.io monitors transport data by using IoT sensors with blockchain technology (Bocek et al., 2017). A smartphone or tablet is preferred because it is the most convenient way to capture and scan barcodes. Another application is on pharmaceutical cold chain management, where a framework was proposed in Hulea et al. (2018) to track products during the distribution process, along with the supply chain, to ensure the delivery of information to all stakeholders. The Sawtooth Distributed Ledger is a permissioned blockchain where only approved participants can validate transactions or any change in network state.

Tracking and tracing

The distribution of substandard and counterfeit drugs has led to deaths, prompting government agencies worldwide to implement trace and track systems to oversee pharmacy supply chains (Sylim et al., 0000). Blockchain provides new opportunities to ensure the traceability of medications (Raj, Rai & Agarwal, 2019). Blockchain also enables quality assurance and tracking through all drug production phases from manufacturer to consumer (Jangir et al., 2019; Ahmadi et al., 2020; Sahoo et al., 2019; Surjandy et al., 2019; Sahoo, Singhar & Sahoo, 2020).

Different approaches have been proposed to solve drug counterfeiting and improve pharmaceutical traceability (Raj, Rai & Agarwal, 2019), including the use of the Ethereum blockchain and distributed ledger technologies to manage the supply chain (Pham, Tran & Nakashima, 2019). This framework helps track drugs, user privacy, quality management, non-repudiation, transparency of the supplied drug, and demand-supply management with enhanced trust between users (Jangir et al., 2019). Drugledger, a scenario-oriented blockchain system for drug regulation and traceability, uses a peer-to-peer architecture (Huang, Wu & Long, 2018). System management for the drug supply chain is deployed using Hyperledger Fabric to continuously track drug delivery in the pharmaceutical industry (Abbas et al., 2020). A quantitative analysis was used in India to characterize key blockchain characteristics such as accountability, authenticity, and the ability to track drug information (Kumar et al., 2019). IoT devices have also been used to ensure data source authenticity and assess the current status of pharmaceutical products at any time and any place. Blockchain helps to mediate data storage and sharing, thereby guaranteeing that data are transparent and traceable (Shi, Yi & Kuang, 2019). Notably, the Italian pharmaceutical industry adopted a serialization regulation and blockchain-based technological solution (Dwivedi, Amin & Vollala, 2020).

Safety and security

The design features of traditional drug supply chain management cannot transmit necessary information safely and reliably. In many cases, data can be deleted, modified, and tampered with easily. Many researchers have recently turned to blockchain technology as a way to transmit data through drug supply chains. The blockchain architecture consists of a set of immutable data blocks that are arranged in sequence and timestamped. Each block has a hash function, which is a digital fingerprint of data. Since all blockchain transactions are timestamped and immutable, blockchain technology can help preserve the integrity and reliability of drug data. In this section, we summarize how researchers have discussed various proposed blockchain-based solutions to keep drug data safe and reliable throughout the network.

Bera et al. (2020) examined how blockchain can be applied to meet the pharmaceutical supply chain’s security compliance requirements. They developed a prototype using blockchain to support the Drug Supply Chain Security Act requirements. The prototype was implemented using the Hyperledger Composer tool, modeling the various supply chain entities and access control rules. The result was faster development of blockchain applications and faster integration with supply chain businesses. Sahooet et al. (Xie et al., 2019) also discussed blockchain technology’s potential to prevent problems when managing the pharmaceutical supply chain transparently and securely; these authors extensively used the Elliptic Curve Digital Signature Algorithm (ECDSA). In their proposal, the drug supply chain relies on a trusted blockchain and IoT-guided network, where controlled details such as temperature and location can be recorded using wireless sensors and GPS devices attached to the packages. Pharmaceutical bottles are marked with serial numbers and the unique fingerprints of their manufacturers. Therefore, when a consumer finally purchases a drug, they can scan the label with a smartphone and learn everything about it.

Ying et al. (Bocek et al., 2017) proposed a system for supplying prescription drugs using blockchain technology. This architecture can protect patient privacy because a dynamic identity is provided, and an effective authentication protocol is designed between the participating parties. Furthermore, the architecture can meet the security requirements and computational requirements of healthcare systems, including authentication, secure data sharing, visibility, user privacy, and efficiency. Makarov and Pisarenko (Fernando, 2019) were also interested in data integrity; they proposed a blockchain model for drug production and supply. It traces the origin of raw materials and medicinal products to ensure the quality of any drugs entering the pharmacy warehouse. Under this system, the product manufacturer, pharmacy warehouse, and pharmacy have access to complete, reliable, and secure information about the origin and quality of the drugs registered on the blockchain. Jamil et al. (Huang, Wu & Long, 2018) contributed to preserving drug data by proposing a novel blockchain-based system for drug supply chain management. In their system, Hyperledger Fabric was used in a smart hospital to facilitate the secure handling of drug supply chain records.

Electronic prescriptions and patient information are efficiently stored and shared in a secure authorized network chain across various hospital departments. Smart contracts have been used to ensure the consistency of drug data and other health-related information, in addition to granting time-limited access to electronic drug records and electronic patient health records. An access control policy is also defined to authorize the request for transactions in the proposed system. The authors proposed a novel method for integrating and deploying a CouchDB for each node to avoid data duplication across the blockchain file system. Kim et al. (Hulea et al., 2018) used IPFS to store data to develop a patient-centered drug history recording system that could help collect drug history more conveniently and reliably using the blockchain, and also prevent tampering with drug data. The patients’ encrypted prescription data are stored in QR codes. The data hash value is stored in the blockchain to prevent data tampering and fraud. Dwivedi, Amin & Vollala (2020) proposed the blockchain-based PSCM to securely share information in a pharmaceutical supply chain system with smart contracts and consensus mechanisms. The proposed system also provides a mechanism to securely distribute the required cryptographic keys to all participants using smart contract technology. Every new transaction made in the network is stored in an immutable block and timestamped to trace the specific product in the chain end-to-end, thereby ensuring that the block details are not modified. Gürsoy et al. (Archa, Alangot & Achuthan, 2018) designed a proprietary smart contract to efficiently store and query pharmacogenomics data using the Ethereum blockchain with a multi-map, index-based approach. The nodes store each genomic note (a trio of genetic drugs with results) in a searchable mapping by a unique identifier, allowing for efficient storage and query time and space.

Other

Other uses of blockchain in the pharmaceutical industry are described in this section.

a) Data Governance

Blockchain and IoT technology have been used to improve data governance and supply chains (Jalali & Wohlin, 2012). IoT has also been used to ensure medical product regulatory compliance (Ahmadi et al., 2020). The Drugledger system tracks traceability and regulations and has been used in vaccine production to ensure organizational and regulatory compliance (Sinclair, Shahriar & Zhang, 2019). In the future, the technology will also include vaccine circulation (Surjandy et al., 2019).

b) Data Quality

IoT technology has been used to ensure quality throughout the transport of medical products (such as temperature control) and to satisfy GDP regulations, where sensor devices control each parcel’s temperature during shipping (Ahmadi et al., 2020). Likewise, IoT can be applied to track the temperature of medical products during distribution, which informs all stakeholders to take action if needed (Tseng et al., 2018). Moreover, another IoT technology tracks drug authenticity (Sylim et al., 0000). Some studies have used it to detect low-quality drugs due to its power in data management (transparency and immutability) (Badhotiya et al., 2021). Another system encourages different stakeholders to engage in transparent management throughout the recall process (Sahoo, Singhar & Sahoo, 2020). Recall management can improve efficiency and accountability, and it can also safeguard the credibility of product recall data. Most of the market does not have open management or tamper resistance, but stochastic simulations have been used to protect drug products from theft and temperature deviations (Liberati et al., 2009).

c) Pharmaceutical Turnover

Blockchain technology (in this case, Hyperledger Fabric) has been used to control pharmaceutical turnover, but its future utility in this function is so new as to be uncertain (Shi, Yi & Kuang, 2019).

d) Prescription Drug Monitoring

The RxCoin smart contract was adopted to combat the opioid crisis, which is based on a form of digital currency used to describe drugs electronically with Ethereum blockchain technology (Ying et al., 2019). RxCoin demonstrated the potential for prescribing drugs via the blockchain, and as a result, a database of prescription data was created. RxCoin’s components include data and function calls that provide the smart contract with the prescription function and mint. The main advantage of the RxCoin smart contract is how it handles authorized refills. RxCoin contracts do not show how the blockchain can be used to provide the functionality of a Prescription Drug Monitoring System (PDMP), nor do they consider HIPAA privacy requirements for personal health information stored on the blockchain. User interfaces for RxCoin are under development. In addition to using digital signatures as identities for members of the system, researchers are working diligently to harden RxCoin contracts to fill existing gaps.

Blockchain security

Some of the features that blockchain technology offers, primarily due to decentralization, are information security and privacy. However, this requires extra computational power. Around half of the power is spent in deceiving attacks by malicious users; otherwise, users can suffer losses from theft and the loss of goods due to a lack of robust tracking and tracing (Plotnikov & Kuznetsova, 2018). When blockchains are distributed, this creates a more complex environment that makes it difficult to overcome through fraudulent block transactions. Also, permissionless blockchains –in which any user can join –can also be secured using Hyperledger. Specifically, Hyperledger makes permissionless blockchains more secure and only allows the users who are involved in the transaction to join.

Standardization

Blockchains can facilitate secure banking transactions globally, but a significant challenge relates to interoperability issues. To standardize blockchain operations, distributed ledger technology (DLT) can be utilized. The International Telecommunication Union (ITU) works to identify and standardize DLT applications and their services, but further research is needed to identify the best practices for implementation.

Complexity of big data

Due to the use of cloud computing, edge computing, and smart IoT applications, the availability of data has grown substantially. Due to this enormous growth, there are many challenges associated with blockchain implementation, including data management, accessibility issues, data redundancy, and data privacy. They also suffer from malpractice and poorly functioning supply chains, and have sought to employ blockchains to harness operations and streamline tracing and tracking, medical transactions, and patient safety (Sinclair, Shahriar & Zhang, 2019). Therefore, the complexity of data must be handled in a blockchain by leveraging big data handling algorithms and other state-of-the-art techniques (Kim et al., 2019; Gürsoy, Brannon & Gerstein, 2020; Hu et al., 2019). Figure 7 shows the distribution of papers by the year of publication.