Introduction to Regulatory Affairs and Different Regulatory Bodies for Pharmaceutical Products and Impact of Digitalization on Regulatory Affairs ()
1. Introduction
The regulatory affairs (RA) field is concerned with the regulatory requirements for pharmaceutical product marketing authorization. Regulatory affairs professionals mediate the interaction between regulators (the government), the regulated [industry], and the market (consumers) to get good products to market and maintain them there while preventing poor quality and efficacy products from being sold. On the industry side, regulatory affairs professionals collaborate with research scientists, physicians, manufacturing organizations, and sales and marketing teams to ensure that the government gets the information it requires to evaluate a product. People in regulatory affairs work for the government to interpret and enforce laws passed by Congress to safeguard the public. People in regulatory affairs help keep the other two groups honest, and they provide the impetus for Congress to pass rules that control how the government and industry treat products. Basically, RA acts as an intermediary between the pharmaceutical sector and drug regulatory authorities globally. It primarily focuses on the registration of pharmaceutical goods in their various nations prior to marketing.
Recently, there has been a rise in the involvement of patients in all areas of drug development, including regulatory review, which has impacted medical product regulation [1] . Because of speedier clinical trials, drugs will be able to reach the market at an earlier stage of development, leading regulators to lay a larger emphasis on post-market oversight. To increase efficiencies at this level of development, the clinical trial business is incorporating more modeling, newer statistical methodology, and artificial intelligence [2] [3] . Furthermore, regulatory agencies are collaborating more and adopting work-sharing, dependence, and cooperative reviews to facilitate the review of these novel items entering the regulatory system [4] [5] . All these developments necessitate a workforce that is adaptable, technologically proficient, and capable of learning and adapting work practices to suit these new trends. This article will look at the many factors influencing the development of novel therapies for disease relief and how these developments affect the function of the regulatory bodies and regulatory affairs professional.
2. Key Regulatory Agencies
Some of the international regulatory agencies and organizations that play an important role in all aspects of pharmaceutical regulations include the World Health Organization (WHO), Pan American Health Organization (PAHO), World Trade Organization (WTO), International Conference on Harmonization (ICH), and World Intellectual Property Organization (WIPO).
The key problems for these regulatory authorities and organizations worldwide are to ensure the safety, quality, and efficacy of medicines and medical devices, to harmonize legislative procedures connected to drug development, and to monitor and ensure compliance with statutory requirements. They also play an important role in ensuring and increasing regulatory implementation in non-regulated areas of the world to protect the safety of those who live there.
The major challenges for these regulatory bodies are: 1) Promoting public health and protecting the public from harmful and dubious drugs; and 2) Establishing proper legalization covering all products with a medicinal claim and all relevant pharmaceutical activities, whether carried out by the public or private sector. 3) Increase global regulatory growth to ensure people’s safety. 4) Centralization of the regulatory process and control.
3. National Regulatory Bodies
The regulatory body ensures compliances in various legal and regulatory aspects of a drug. Each country has its own regulatory body which controls the registration and marketing of the medicinal products at the national level. That national level regulatory body governs the rules and regulations. Additionally, it issues the guidelines for the drug development, licensing, registration, manufacturing, marketing, and labelling of the pharmaceutical products. USFDA (USA), MHRA (UK), TGA (Australia), CDSCO (India), DRAP (Pakistan) HEALTH CANADA (CANADA), MCC (South Africa), ANVISA (Brazil), EMEA (European Union), NMPA (China), NAFDAC (Nigeria), MEDSAFE (New Zeeland), MHLW (Japan), HAS (SINGAPORE) MCAZ (Zimbabwe), SWISSMEDIC (Switzerland), and KFDA (Korea), are the few regulatory agencies and organizations established in respective countries [6] .
4. Key Trends and Global Problems
Getting the better understanding of the sole global trends can positively help the regulatory affairs professionals to predict the future impact on their role and their responsibilities. The increased push by countries to manufacture vital pharmaceutical items locally, in response to the COVID-19 pandemic, reflects geopolitical instability [7] . The COVID-19 pandemic has emphasized the dangers of infectious diseases, which are expected to worsen because of climate change. Antimicrobial resistance, an ageing population’s growing chronic health burden, increased pressures on mental health, and budget limits on healthcare spending will all have an impact on the pharmaceutical industry. More optimistically, the prospect of precision medicine, more digital connectivity across the healthcare system, a shift towards a learning healthcare system, and an emphasis on wellbeing and preventative medicine will lead to future healthcare advancements as well as possibilities for industry [8] [9] [10] . The evolution of harmonization, convergence, and reliance has led to the establishment of a work-sharing arrangement known as the ACCESS Consortium. The original “ACSS” collaboration, created in 2007, included the national regulatory authorities of Australia, Canada, Singapore, and Switzerland. The MHRA joined in October 2020, and the group’s name was changed to “Access”. The MHRA will begin accepting work-sharing applications from Access partners on January 1, 2021. This arrangement involves comparable, mid-sized national regulatory authorities from Australia, Canada, Singapore, Switzerland, and the United Kingdom. Additionally, these countries are active partners in Project ORBIS, which was initiated by FDA Oncology Center of Excellence (OCE) in May 2019 for providing a framework for submission and review of oncology products between international partners. The trend of work sharing has evolved over time through the establishment of robust information sharing mechanisms and the cultivation of trust among participating regulatory bodies. This has led to a system where these regulatory authorities divide the review of Modules, while adhering to confidentiality agreements and memoranda of understanding that have been mutually agreed upon. Each participant maintains their individual autonomy in decision-making; however, the process alleviates the burden on regulators and facilitates the exchange of expertise across various geographical regions.
5. Digital Disruption
The overview of digital disruption in regulatory affairs highlights the advancements in technology that have revolutionized how regulatory affairs professionals carry out their work. The impact of technology on regulatory processes includes automation, data analytics, and artificial intelligence, which have led to increased efficiency and accuracy in regulatory activities. Examples of digital disruption in regulatory affairs include the use of regulatory information management systems, electronic submissions, and real-time monitoring of compliance. While digital disruption presents challenges for regulatory affairs professionals, such as the need for new skills and adapting to changing regulations, it also offers opportunities for innovation and efficiency in regulatory practices. Strategies for adapting to digital disruption involve leveraging technology, embracing a digital mindset, and collaborating with stakeholders to ensure effective and compliant regulatory processes in the digital era.
The drug development process is increasingly being affected by digital disruption, which encompasses several stages such as early-stage discovery and validation of target molecules, optimization of candidate drug structure, manufacturing processes, and regulatory clearances by national regulatory bodies. One of the primary difficulties encountered in the initial phases of drug development is the determination of the structure of target proteins, followed by the identification and optimization of suitable drug candidates capable of interacting with these proteins to impede or modify their functionality. Artificial intelligence (AI) and machine learning (ML) are becoming a progressively significant role in the field of drug discovery [11] . The implementation of their application is expected to decrease the incidence of failure in the initial stages of drug research and development, while also expediting this phase in the overall process [12] [13] [14] . Additionally, it is expected to mitigate the potential hazards and financial burdens associated with the process of pharmaceutical development.
Digital disruption has significantly impacted the field of regulatory affairs, transformed traditional processes and introducing new challenges and opportunities [15] [16] [17] . One example of digital disruption in regulatory affairs is the use of artificial intelligence (AI) and machine learning algorithms to automate and streamline regulatory processes. These technologies can analyze large amounts of data, identify patterns, and make predictions, reducing the time and resources required for regulatory compliance. Another example is the emergence of blockchain technology, which provides a secure and transparent platform for sharing and storing regulatory information. This allows for improved data integrity and traceability, enhancing regulatory oversight and compliance [18] [19] [20] . Additionally, digital disruption has led to the development of regulatory technology (RegTech) solutions, such as software applications and platforms, that enable regulatory professionals to manage and streamline regulatory processes more efficiently [21] [22] [23] . These innovations have the potential to drive innovation and efficiency in regulatory affairs, but also present challenges such as data privacy and security concerns. As the regulatory landscape continues to evolve in the digital era, regulatory affairs professionals must adapt their strategies and embrace these digital disruptions to effectively navigate the changing regulatory environment. To enhance trust in the use of AI/ML, it is imperative to build robust governance structures and ethical frameworks Also, the organizations that heavily rely on these systems must have well-defined quality assurance and auditing methods. Regulatory professionals must possess a high level of confidence in effectively communicating the intricacies of these technologies, guaranteeing their adherence to governmental regulations, and collaborating with regulatory authorities during the registration process of medicinal goods based on artificial intelligence and machine learning. Organizations must possess the capability to incorporate these systems into their established benefit-risk decision-making procedures and effectively convey this integration both internally and externally to relevant stakeholders.
The implementation of virtual or in silico clinical trials will have a significant impact on regulatory professionals, as ensuring the integrity of the data will become of utmost importance. The process of digitizing regulatory operations will be facilitated by various initiatives, including the adoption of the International Organization for Standardization’s (ISO) Identification of Medicinal Products (IDMP) standards. These standards necessitate the management of substance, product, organization, and referential [SPOR] data [24] .
The statement is based on the growing inclination towards structured data formats. This inclination facilitates the instantaneous transfer of data to national regulatory agencies through cloud-based systems like Accumulus Synergy. In the forthcoming years, there will be a growing reliance on data flows rather than document flows within the regulatory field. Consequently, regulatory professionals will need to enhance their digital literacy skills to effectively participate to these evolving data processes [25] .
6. Global Regulatory Harmonization and Centralization of the Regulatory Bodies
Considering the progress made in the field of complex pharmaceuticals, regulatory bodies are displaying a growing inclination to collaborate through a range of techniques, including harmonization, convergence, dependence, collaborative review, and work-sharing. The global COVID-19 pandemic has further expedited this trend [26] [27] [28] . Harmonization refers to the procedure of incorporating both national and worldwide standards to enhance the effectiveness and streamline the global development and regulation of pharmaceuticals [29] . One notable illustration involves the incorporation of the International Council for Harmonization [ICH] standards by regulatory bodies at the national level [30] .
7. Digitalization of Regulatory Affairs
The different regulatory bodies are switching from paper based to eCTD submission. Various authorities have stopped accepting CTD (paper based) submissions. This step has been taken to centralize the process and also to speed up the process of submissions. The roadmap of the change in global regulatory Affairs to adopt digital adoption is mentioned in Figure 1. The transition from paper-based to electronic Common Technical Document (eCTD) submission has had a significant impact on regulatory processes globally. The acceptance of eCTD format submissions has led to optimization of resources, increased efficiency, and improved tracking of applications during review [31] . This transition has also ensured that the content of submissions is consistent with global standards [31] [32] . Practical examples of how eCTD submission is being implemented globally can be seen in various countries. In the United States, the Food and Drug Administration (FDA) has implemented eCTD submission requirements for various types of applications, including new drug applications, biologics license applications, and abbreviated new drug applications [33] . The implementation of eCTD submission has had a positive impact on regulatory processes. Studies have shown that individuals with eCTD experience have been able to shorten their total time to approval and demonstrate cost savings compared to paper submissions [34] . This has been observed across different types of companies, regardless of their size or number of submissions [34] . To enable dynamic, timely updating of regulatory data, a fundamental digital revolution in the regulatory submission and evaluation process is essential, and the use of eCTD has facilitated this process [35] . The organized collection and storage of manufacturing information, including in-process release testing, specification testing, and batch release data, in a structured format within data lakes would enhance the ability to gather and share data to meet regulatory compliance needs [36] . The automation of eCTD compilation facilitates the more effective transfer of data into the current eCTD format for regulatory filings. At present, the process of eCTD creation necessitates human supervision and understanding of the information included within the papers. These documents are often in a portable
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Figure 1. Global digital adoption in regulatory affairs.
document format (pdf), which lacks the capability to facilitate automated traceability to the original data sources or enable data mining for enhanced insights [37] . The utilization of structured content and data management systems holds the potential to enhance the efficiency of data management processes, as well as facilitate the creation and dissemination of regulatory documents.
Until now, several organizations have been creating customized internal structured content management systems, specifically for clinical data. However, it is necessary for enterprises and regulatory bodies to adopt shared approaches to facilitate the efficient interchange of data and documents [36] [37] [38] . Local and international regulatory authorities frequently solicit feedback on the draft regulations they want to enact in the future. There is a significant requirement for collaboration among enterprises, industries, and authorities to establish connectivity and exchange information to initiate system harmonization. This process has become significantly easier due to digital advancements and approaches. The widespread adoption of the ICH Q12 guideline is also playing a role in promoting the use of more structured formats for both clinical and CMC data packages [36] [37] . Simultaneously, the implementation of more systematic benefit-risk assessments by National Regulatory Authorities (NRAs) has the potential to enhance worldwide harmonization of benefit-risk assessment and establish a framework that can be integrated into health authorities’ benefit-risk algorithms [38] .
In conclusion, the transition from paper-based to eCTD submission has brought about significant improvements in regulatory processes globally. The acceptance of eCTD format submissions has optimized resources, increased efficiency, and facilitated tracking of applications during review. Practical examples of eCTD implementation can be seen in countries like Japan and the United States. The impact of eCTD submission has been demonstrated through shorter approval times and cost savings. Overall, the adoption of eCTD has led to harmonized electronic submission and review initiatives, enhancing regulatory processes in the pharmaceutical industry.
8. Challenges Due to Artificial Intelligence (AI) and Machine Learning (ML)
Artificial intelligence (AI) and machine learning (ML) are becoming increasingly prevalent, which is causing regulatory affairs to face new questions and issues. Artificial intelligence is being used in governance in ways that go beyond regulation and influence the state’s ability to impose coercion and redistribution [38] . In drone and unmanned traffic control, AI may enable safe operations and interoperability with manned aircraft. Big data, artificial intelligence, and machine learning by fintech lenders in the financial services industry presents opportunities for financial inclusion but also raises concerns about fair lending and regulatory safeguards. Ethics in AI, ML, and data science require practical answers and responsible innovation [39] . Artificial intelligence has shown promise in healthcare, but it raises questions about algorithm trustworthiness, patient data protection, and transparency [40] . These concerns highlight the need for regulatory frameworks that balance innovation, ethics, and law in artificial intelligence and machine learning. Several difficulties related to each trend must be addressed since they affect drug development, medical practice, and regulatory officials. Governance and ethics are the biggest challenges to AI and ML. Ethics include protecting autonomy, well-being, and privacy. Deep learning models used in AI and ML must be transparent and explainable. Additionally, proper technology use is essential. Promoting inclusion and equity to reduce bias and responsive and sustainable AI are also crucial [41] . Governance problems in managing data for training artificial intelligence and machine learning systems encompass various aspects. The European Union has presented a draft regulation on the Data Governance Act, which is the first step in implementing governance tools for data management [42] . AI governance aims to leverage AI through effective data use and minimize associated costs and risks. However, there is limited work on AI governance targeted towards companies and corporations [43] . Big Data Algorithmic Systems (BDAS) based on AI and machine learning face challenges in managing varied, dynamic, and real-time data. To overcome these challenges, organizations are developing advanced data governance capabilities [44] . Information data plays a strategic role in corporate governance systems, serving as an identifier of potential opportunities and support for strategic initiatives [45] . Data management problems can be addressed using machine learning techniques to identify and manage relevant data in information systems [46] .
The phenomenon of digital disruption presents significant challenges for enterprises in terms of enhancing the skills and knowledge of their workforce as there are skill and knowledge gaps which need [47] . Overcoming cultural barriers is key to implementing digital change management in enterprises. These include creating a culture of continuous learning, encouraging agility, and including all employees in digital transformation.
Organizations must assess their leadership styles, staff skills needed for a successful transition, and incentives for continued professional development. To support personnel during this transformation, deeply rooted attitudes and systems must be examined and changed. The rapid increase in change velocity causes staff fatigue and a feeling of inability to adjust. Create a robust and supportive work environment to reduce the risk of highly skilled personnel departing due to job responsibilities. To establish a stable workforce that can perform well in both remote and in-person environments, strong organizational change management strategies are needed. These strategies help create an organizational culture that encourages employees to adapt and develop to meet company needs and work-based learning [48] . One potential solution to address these challenges is the implementation of a mentorship program, wherein proficient staff members provide guidance and assistance to their less confident counterparts during their transition period.
9. Skills Needed for the Future Regulatory Affairs
In the fast-changing regulatory environment, skilled people who can navigate complicated regulations are essential. Compliance with laws, rules, and standards in healthcare, pharmaceuticals, food and beverage, cosmetics, and medical devices is the responsibility of regulatory affairs experts. As regulations and standards change, regulatory affairs professionals' jobs get more complicated. Thus, these professionals must have skills to adapt and succeed in the ever-changing regulatory framework. We shall examine the essential abilities for future regulatory affairs professionals in this paper.
1) Adaptability and agility: A future regulatory affairs professional must have the ability to adapt quickly to changes in regulations and guidelines. They should be well-versed in understanding new regulations, assessing their impact on company operations, and implementing necessary changes to ensure compliance. This requires being agile and flexible in their approach, as regulations can change rapidly and vary among different regions and industries [49] . Data analytics, continuous pollution monitoring, and computerised reporting can make regulatory implementation flexible. Regulatory administrators need clear criteria, public engagement, enforcement, and results measurement to succeed [50] . Innovation regulation requires managing stakeholder expectations and maintaining a good reputation [51] . Regulation requires skill, adaptability, and excellent management to navigate shifting laws and norms [52] .
2) Regulatory intelligence: Regulatory affairs professionals must know their industry's rules, regulations, and norms. They must stay abreast of changes and communicate them to internal stakeholders. This requires watching regulatory organizations, attending conferences and workshops, and networking with other experts to obtain regulatory intelligence [53] .
3) Attention to detail: In the regulatory landscape, even the smallest error or oversight can have significant consequences. Therefore, it is essential for a regulatory affair professional to have a keen eye for detail and a meticulous approach to their work. They must be thorough in their review of documents, labeling, and submissions to ensure compliance with regulations [54] .
4) Analytical and problem-solving skills: The ability to analyze complex information and identify potential issues or gaps is crucial for a regulatory affair professional. They must possess strong critical thinking and problem-solving skills to come up with effective solutions to compliance challenges [55] . This requires having the ability to assess risks and find innovative ways to overcome them while staying within the regulatory framework.
5) Interpersonal skills: Regulatory affairs specialists interact with internal teams, regulators, and external partners. This work requires social and communication skills. They must engage with other departments and external partners, clarify technical and challenging regulatory content for internal teams, and interact well with regulators [56] .
6) Project management skills: Managing regulatory projects requires knowledge and skills in project management. A future regulatory affairs professional must have the ability to plan, organize, and coordinate tasks and resources to meet regulatory deadlines. This involves setting priorities, managing timelines, and effectively communicating with cross-functional teams to achieve compliance goals [57] .
7) Global regulatory knowledge: With globalization, regulatory affairs professionals are increasingly required to have international experience and knowledge. This includes understanding and keeping track of global regulations, as well as understanding cultural and business practices in different regions. With many companies expanding their operations globally, having a global perspective and knowledge of international regulations is an asset for a regulatory affair professional [58] .
8) Technological proficiency: As the regulatory landscape continues to evolve, technology is playing an increasingly significant role. A future regulatory affairs professional must be proficient in using various regulatory software and tools to compile, track, and report regulatory information. Regulatory Technology (RegTech) and Supervisory Technology (SupTech) should be used to enhance regulatory effectiveness [59] [60] . They must also be able to adapt to new technologies and use them to streamline processes and improve efficiency.
9) Business acumen: In addition to being knowledgeable in regulations, a regulatory affairs professional must also have a strong understanding of their industry’s business operations. This includes a clear understanding of the company’s products and services, market trends, and financial considerations. Having business acumen allows them to make informed decisions that not only ensure compliance but also support business growth and success.
10) Continuous learning and development: The regulatory landscape is constantly evolving and adapting to changes in technologies, market dynamics, and consumer demands. Therefore, a future regulatory affairs professional must have a growth mindset and a commitment to continuous learning and development [53] . This involves seeking out new opportunities for professional growth, staying updated on industry developments, and continuously developing new skills to stay relevant in the field.
11) Teamwork: Regulatory affairs specialists often work closely with cross-functional teams, so the ability to collaborate and work well with others is essential. This includes being able to build relationships and resolve conflicts in a professional manner.
12) Ethical Standards: As regulatory affairs specialists are responsible for ensuring compliance with laws and regulations, they must have a strong sense of ethical standards and integrity. This includes being able to make decisions that prioritize compliance and ethical practices over business interests.
Future regulatory affairs professionals must be versatile to manage the ever-changing regulatory world. Adaptability, regulatory intelligence, attention to detail, analytical and problem-solving skills, effective communication, project management, global regulatory knowledge, technical competence, business acumen, and a dedication to continuous learning and improvement. Enhancing these skills will ensure compliance and help the company prosper in a changing regulatory environment.
10. Conclusions
Globally, regulatory bodies and organisations must ensure the safety, quality, and efficacy of medicines and medical devices and harmonise drug development, monitoring, and compliance procedure legislation. Various factors, including digital disruption, will shape the regulatory affairs profession’s exciting future.
The ubiquitous problem of digital disruption affects many fields of labour. The COVID-19 pandemic and rapid advances in machine learning and artificial intelligence algorithms have exacerbated this influence. The rapid advance in scientific understanding of diseases has led to the development of new therapeutic ways for treating and possibly curing some diseases, which will shape this profession.
Recent global regulatory changes have raised the significance of strategic partnerships, alignment, and integration among national regulatory agencies. This tendency should continue. It will be interesting to see how these factors affect regulatory professionals, medicine development, and medical practice in the future. These changes need regulatory affairs professionals to improve their skills and adopt a growth attitude. This new paradigm encourages individuals to actively manage their professional development, be adaptable, and value ongoing learning. By doing so, these experts can influence product creation and better their society.