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The biopharmaceutical landscape of India is transforming in terms of regulatory policies, product development, and affordability.
The VAIshvik BHArtiya Vaigyanik (Indian diaspora scientists), VAIBHAV Summit, conceptualized as a collaborative initiative, took place in October 2020 (1). The platform offered discussion, intellectual discourse, and collaboration amongst participating academicians of Indian origin across the world, covering over 18 research areas that had been identified as verticals of national importance. “Biotherapeutics and Biosimilars” was identified as one of the horizontals under the vertical “Pharmaceutical and Biotechnology” (1). Three sessions, consisting of panel discussions, were held under the themes “Regulatory Perspectives on Biosimilars”, “Biosimilars”, and “Affordability of Biotherapeutic Products” and were hosted by the Department of Biotechnology (DBT) Center of Excellence for Biopharmaceutical Technology (CBT) at the Indian Institute of Technology (IIT) Delhi (2).
As India’s biomanufacturing is moving toward complex products and alternative routes of administration, new manufacturing and regulatory challenges lie ahead. In view of India’s global success in offering safe, efficacious, and affordable pharmaceutical products to the world, much is expected for the biotherapeutic class of products as well.
Regulators play a pivotal role in ensuring success of biosimilar manufacturing and approval, and thereby significantly impact the cost-effectiveness of these products. The conversations on the Indian regulatory landscape include the following: evolution of the regulatory framework in India and advances made toward harmonization of regulatory guidelines with other established pathways; challenges associated with interchangeability; understanding of the regulatory guidelines; and framework for collaboration/networking among regulators, academia, and industry.
The evolution of Indian regulatory guidelines has seen a steep curve since the past decade. With the country’s first guidelines for similar biologics released in 2012 and subsequent revision in 2016, India has approved more than 100 biosimilars for 35 reference products to date and efforts toward global harmonization of the guidelines continue (3,4). As a result, Indian biosimilars are gaining acceptance even in conservative international markets; for example, Biocon-Mylan’s biosimilars Ogivri (trastuzumab), Fulphila (pegfilgrastim), and Semglee (Insulin-glargine) have been approved by United States Food and Drug Administration (USFDA) and have been launched in the United States. While India is making efforts to establish “Brand India’’ as a manufacturer of economical and high-quality therapies, barriers to success, such as low public awareness, limited international visibility, and representation and lengthy approval timelines, still remain. In this regard, the DBT-supported institutes and apex national bodies such as CBT and the National Institute of Biologicals (NIB) have contributed toward this expanded awareness by publishing several quality evaluation reports on biosimilarity of marketed Indian products in the past five years (5–8). Inclusion of India as a member of the International Council for Harmonisation (ICH) is a significant move and should amplify the representation and influence of stakeholders in international forums toward policy making and development (9). Concurrently, the Indian regulatory agency, Central Drug Standard Control Organization (CDSCO), is restructuring the regulatory process by organizing pre-submission meetings between regulatory/industry from a nascent stage of biosimilar development, thereby ensuring that the agency is seen as a facilitator and not as a hurdle towards achieving affordable healthcare. CDSCO and the US FDA have signed a Memorandum of Understanding (MoU) to facilitate enhanced flow of information between the two agencies in the interest of public health and efforts by India to sign similar MoUs with other jurisdictions are underway (10,11).
With new and more complex modalities entering the market along with alternate modes of administration, Indian regulators are realizing that academic input with respect to scientific understanding of the molecule is crucial for sound policy making. Academic and regulatory collaborations are being sought to ensure subject matter expert representations in policy making. Academic institutions are also contributing through organizing training sessions for the regulators to keep them updated on global technology trends.
Over the past three decades, biosimilars have transformed the healthcare system by offering effective treatments for complex diseases with low-cost solutions. Production of biosimilars is a much more complex process as compared to generic pharmaceuticals (12). Different jurisdictions have come up with guidelines for the approval of biosimilars. The commonality shared amongst these guidelines is the presentation of evidence of similarity with the innovator based on a comprehensive analytical characterization. India is fast moving toward becoming a major biosimilar economy with proven expertise in delivering world-class efficacious biosimilars.
Major hurdles faced by biosimilar manufacturers pertaining to affordable manufacturing include challenges due to the complex nature of the bioprocesses, requirement of sophisticated infrastructure, trained expertise, and the development of manufacturing technologies to sustain product affordability. In the past six years, national funding agencies such as Biotechnology Industry Research Assistance Council (BIRAC) under DBT have made consistent efforts toward closing the above-mentioned gaps in India’s capacity and capability by supporting much required infrastructural developments across the country. Financial aid in the form of grants has been provided for high capital expenditure (CAPEX) and operational expenditure (OPEX) capacities required in establishing end-to-end biopharmaceutical research facilities. Start-ups/academia/Micro, Small and Medium Enterprises (MSMEs) have also been supported through establishment of high-end capacities (i.e., cell line repositories, process development facility, instrument intensive analytical facilities, and large-scale manufacturing plants). The National Biopharma Mission (NBM), a joint collaboration between BIRAC under DBT and World Bank, is offering sustainable funding in the form of grants to foster infrastructural development and accelerate research in biosimilar development (13).
As biosimilar development is a scientific enterprise, academia plays a major role in filling domain specific knowledge gaps. Therefore, academic research should be oriented as per the current challenges and future needs of the ecosystem. Topics to gain fundamental understanding of products include mechanistic understanding of molecular interactions through systems biology and understanding of structure to function relationships. In addition to this, choosing the right technologies to develop with respect to focus on cutting-edge research should be given importance. One of the major emerging research areas in the advancement of technology to produce biosimilars is continuous manufacturing. In the interest of affordability as well as balancing demand with supply, there is a need to move toward continuous manufacturing for products that have a high demand and consumption, globally. This needs to be complemented with advances in the field of real-time and integrated process analytics through machine learning (ML) and artificial intelligence (AI) systems. The ongoing advancements in the areas of AI/ML will further drive integration of real-time process analytics into process models to predict drug quality attributes as a function of input process parameters and material attributes.
It goes without saying that the current global pandemic has highlighted the need for the development of indigenous technologies. This is important, as the present-day manufacturing technologies to a large extent depend on consumables and equipment that are mostly imported. Therefore, academic research in strengthening in-house capabilities is essential to break the current dependency on technologies exported, such as bioreactors, biosimilar clones, and culture media (to name a few).
The intensive development, manufacturing, storage, and regulatory processes requires huge investment, and hence, these products end up being highly expensive as compared to generics, making affordability a major issue. While India is moving fast toward adulthood in biosimilar manufacturing, the status of affordability of biotherapeutics in India (in comparison to other markets) along with challenges unique to India in achieving sustainable affordability are some of the key deliberation points (14,15). In addition, the role of academic research in understanding factors influencing pricing and in developing pricing models that balance these factors while prioritizing affordability needs to be integral to the pricing policy.
Apart from some of the small protein therapeutics such as insulin and other products such as vaccines, biotherapeutics in general are highly costly. However, the insurance policies in developed countries such as the US make these products affordable to those who are insured. But in developing countries such as India, the economic status of the population is quite diverse, and the affordability of these products is a major challenge (15,16). For many of the countries, accessibility to basic health care services is a major bottleneck, and due to inadequate health care systems and policies, the reach of the general public to biopharmaceutical products remains poor. Additional factors that affect affordability are hospital and treatment related expenses, lack of in-house capabilities for development and manufacturing along with associated start-ups, isolated collaborations, lack of investment for the development of novel molecules, and lack of synergistic work cultures (17). Some other challenges include lack of applied research, data analysis, and poor implementation of simulation and artificial intelligence. Affordability is also associated with regulatory challenges, existing policies, and intent of policy makers. There is a need, therefore, for a sustainable system for reducing the cost and enhancing the affordability. It can be summarized that the issue of affordability of biopharmaceutical proteins is a global challenge.
Developing countries such as India contribute significantly to the number and share of therapeutic proteins sold to consumers in developed countries such as the US, and the products are considered as safe and efficacious. This shows the potential of the manufacturing capability of a developing nation, and the suitable redesigning of policies, collaborative framework, and innovations can further reduce the cost and make the product more affordable. However, the cost of production is high, which is a concern for small- and medium-scale manufacturers. Collaboration between industry and health systems can be helpful in innovation, investment, and sustainable availability of biopharmaceutical products and essential medicines, which in turn can help in designing suitable strategies to manage resources that can regulate the cost. Academia can contribute by developing innovative technologies for manufacturing that can result in reduced cost. Collaborations between industry and government for process and product development partnerships, innovative financing mechanisms, licensing, and non-asset declarations across the biopharmaceutical sector can be helpful in finding new ways to manage the cost (18).
Establishing infrastructure for developing new technologies and analytical platforms for processes and consumables that are imported can help in smoother and affordable operation of small- and medium-scale industries. Provision of suitable training on existing and new technologies is of utmost importance. Structured
collaborations between academia and industry with suitable assistance of government, where the innovation originated in academia can be matured into affordable commercial processes, is required. Provisions for the use of locally available resources into effective and efficient use of research is required. Further, effective use of mathematical models that can include a variety of factors is required as a cost analyzing and designing strategy. The model should consider a variety of factors concerning private players, policies, and regulatory guidelines. The government bodies should further provide suitable funding schemes that can lead to innovative technologies, and open venture centers across multiple places that can assist players operating from smaller towns away from big cities. Suitable modes for obtaining information for mathematical modeling should be obtained, with structured involvement of government, academia, and industries.
As an outcome of the deliberations amongst the panel members, the following recommendations were made:
Fostering a healthier, mutually beneficial collaborative environment amongst the three main arms of the biopharmaceutical ecosystem example: sponsored research (industry-academia); collaboration towards interpretation of regulations (industry-regulatory); and increased academic representation in regulatory agencies and creating provisions for scientifically sound policy making (academia-regulatory) and building mission mode consortium of academic and industry partner
Increased regulatory convergence via mutual recognition agreements with the World Health Organization and ICH and a simplified regulatory process.
Focus on evaluation of regulatory preparedness for complex biosimilars and addressing complex issues such as interchangeability
Focus on changing global opinion on quality of Indian biosimilars by means of increasing visibility of stakeholders on international forums
Deeper inclusion of subject matter experts in decision making with regards to regulatory policy renovations, long-term technology investments, and models for affordable pricing.
Encouragement in building tech prospects and dedicated institutes where the mandate should be development of biopharmaceutical products.
This work was funded by the Centre of Excellence for Biopharmaceutical Technology grant under the Department of Biotechnology, Government of India (BT/COE/34/SP15097/2015).
Dr. Srishti Joshi and Dr. Rozaleen Dash are postdoctoral fellows at Centre of Excellence, Biopharmaceutical Technology, Indian Institute of Technology New Delhi. Neh Nupur and Shravan Sreenivasan are research scholars at the Department of Chemical Engineering, Indian Institute of Technology New Delhi. Dr. Anurag S. Rathore*, firstname.lastname@example.org, is a professor in the Department of Chemical Engineering, Indian Institute of Technology New Delhi and a member of BioPharm International’s Editorial Advisory Board.
*To whom all correspondence should be addressed.
Volume 34, Number 11
When referring to this article, please cite it as A. Rathore et al., " Emergence of India as a Global Manufacturing Hub for Biosimilars," BioPharm International 34 (11) 2021.