Some Thoughts on How to Secure Sustainable Future in Biosimilars World
Dr. Satinder Singh
Manager- R & D (IPRM)
Ipca Labs Limited, Mumbai

Sanjeev Gupta, Ph.D.,
General Manager- Advanced Biotech Lab
(Biosimilar R & D) Ipca Labs Limited, Mumbai

Dr. Ashok Kumar FRSC
President - Centre for Research &
Development Ipca Labs Limited, Mumbai

Biosimilar medicines provide a major opportunity for cost savings throughout globe. However, in order to deliver these benefi ts it is imperative that the biosimilar medicines market remains sustainable.

Biologics, the complex recombinant therapeutic proteins produced from living organisms, have created immense value to patients due to their usefulness in prevention, treatment and diagnosing a variety of diseases such as cancer, chronic kidney diseases and autoimmune disorders; otherwise nonmanageable by existing therapies. It is therefore this attribute of providing unmet medical need, which facilitated biologics to create a niche for themselves in pharma industry.

'Biosimilars', also known as 'follow-on biologics' can be vaguely considered as generic versions of the innovator products, but in reality are significantly different, than the parent molecules due to their variable composition.

Biologics versus Small Molecules

Unlike small molecules which are clearly characterizable products with well defined structures and can be produced in identical form in bulk; biologics are a mixture of related molecules with molecular weight as high as 150,000 Da, decorated by a variety of groups due to post translation modification eg .oligosaccharides, sialic acid moieties, phosphorylations etc. The post translational modifications are specific to host cell and growth conditions. It is important to note that these modifications and specific folding are very critical to the biological activity of these drugs. For example, a simple misfolding or even an aggregation can trigger immunogenicity in patients and thus can have devastating health hazards. Apart from the differences in the complex molecular structure of biologics/biosimilars versus simple small molecular drugs of molecular weight ~180 Da, the development as well as manufacturing of biologics requires highly cost intensive sophisticated infrastructure. The companies with deep pockets can well afford to have the same , but it is noteworthy that it also requires different knowledge and skill sets to handle proteins, pretty different than small molecular drugs, understanding of the living systems and the biochemistry of the host, key to sustain its life as well as expressing the desired protein.

Furthermore, compared to generic small molecules, the biological products have less shelf life and often require refrigerated conditions to maintain biological activity and prevent breakdown or aggregation. This perishable nature of biologics significantly minimizes the time frame to generate revenue out of the product, whilst inflating the shipping and storage cost .

Challenges and Remedies in Biosimilars Development

Even if the biomanufacturing process of biosimilars are followed in strict accordance with the conditions prescribed by innovator and exercising QBD, it is practically impossible to develop a replica of the parent molecule and therefore follow-on biologics are classified as 'similar' and not 'same', to the innovator product. The development and validation of multi-tier manufacturing process, therefore, requires rugged analytical and biological testing for initial and final characterization as well as efficacy and toxicity evaluation of the biosimilars.

Even a slight modification in any step during manufacturing can lead to variations in glycosylation pattern, addition of other side chains to form a secondary structure, folding to form a tertiary structure and complex interactions to form a quaternary structure and can affect safety and effectiveness of intended biosimilar. If the process is not tightly regulated during development and scale-up to commercial, significant changes in quality attributes and overall characteristics of biosimilars are inevitable. Therefore, the multisite production of a biosimilar with the established validated process may still result in variable quality attributes and different overall characteristics of finished product. Hence, a well crafted stringent control strategy at each stage of the process is must to ensure minimal batch to batch variation of a biosimilar.

Figure 1: Complete Manufacturing Process

The quality, potency, safety and efficacy of a biosimilar are of paramount importance to regulatory authorities. All the analytical methods employed to characterize the product, the functional assays carried out to assess potency and preclinica studies conducted to verify toxicity and safety should exactly resemble the one conducted by innovator to establish closest similarity to the reference product. The structural and post translational modifications should be assessed thoroughly before submitting the dossier to regulatory authorities. Even though a biosimilar is cleared by regulators, surmounting the market barrier owing to the general skepticism in patients / prescribers, considering biosimilars as substandard version of their branded product, remains a daunting task.

An imperfectly similar biologic may need to be well supported by pre -clinical toxicity, clinical efficacy and stability studies for the approval of marketing authorization from regulators, but the qualification of an improvised version of the innovator molecule justified and fortified with persuasive potency, efficacy, safety and quality data as 'biobetter' may even be more difficult and costly to sail through regulator barriers because developing a 'biobetter' warrants a new approval process. Approval of the product out of purview of biosimilars, will be considered as a new molecule and will have to go through 505(b)(1) in the USA or with the steps specified in Schedule Y, if taken up for qualification In India. It is because of these facts; obtaining "interchangeability" status for a biosimilar with an innovator's product is not easy & is currently being offered by USFDA on case by case basis. Considering the development of
Figure 2: Cell Line/Clone Development

biosimilars to be as simple as developing ANDAs and experience of generic small molecular drugs good enough to be successful in biosimilars business as well, many generic pharma companies have ridden on the biosimilar development wave to tap the global biosimilars market, which is anticipated to reach USD 25.83 billion by 2025; without thoroughly analyzing that it's a different ball game altogether, entailing huge investments, and longer timelines with no guarantee of return on investment in short to mid -term. Interestingly, allured by high sales figures, several companies across the globe whether big MNCs, midsize or small SMEs have joined the band wagon to focus and develop the same top 10-15 molecules without envisaging the Figure 2: Cell Line/Clone Development kind of market competition they may have to face by the time their molecule reach the market. It is pertinent to mention that the development of a biosimilar takes more than 7 years under evenmost favorable conditions. As evident from market information, many generic companies have either suffered heavy losses in this venture or have shut down their development program in recent past and may come true for many more players in future, if they do not learn from other's mistake.

A Model for Long Term Sustainability in Biosimilar World

A lean structure with optimum investment powered by highly qualified and skilled personnel is the key to sustainability, but to keep the company ahead of the herd by at least 7-10 years is important to avoid unwarranted competition and is not difficult to achieve if it inculcates andallows the culture of innovation to prevail.

Contrary to general belief, innovations are not the hallmark of R & D and can be implemented at any stage starting from the selection of the molecule (s) for development till strategic partnering, tactical marketing, logistics etc. based on the company's inherent strength and expertise. It is important to note that being first mover may be of some advantage to a company but does not guarantee long term sustainable growth in a generic market.

Figure 3: Use of HTP devices to achieve high titer and good quality

Based on the personal experience, authors believe that R & D should invest at least 15% of its total time in keeping abreast with the latest developments and exploring and implementing new ideas to improve or fine tune processes at every stage starting from molecular/ cell biology to upstream/downstream or formulation development before freezing the process to provide stable yet quality clones, high titers, quality and yields of the desired product giving an edge against the competitors. Development of in -house clones is most preferred to have better understanding and control of the manufacturing process.

ZSelection of apt platform for development of biosimilars shall help match critical quality attributes, such as glycoprofile pattern, aggregation, clips or truncation to that of innovator product. Single-use upstream and downstream technologies have created distinct market niches and continue to evolve. Manufacturing process should be constantly refined employing latest state of art bio-processing methods and systems to increase the efficiency, overall productivity whilst maintaining biosimilar quality, safety and potency.

In summary, the endeavour to foray into biosimilar development should be a well articulated and calculated move with long term vision, good risk appetite and sound understanding and planning. Even if company has deep pockets, collaboration with like minded MNCs to share the potential risk associated with development of biosimilars may be a wise move in long run. The same has been manifested well by Biocon-Mylan partnership in securing USFDA approval for biosimilar version of Trastuzumab. The entry of more biosimilars in the market may increase price pressure and toughen the competition further; thus compelling the manufacturers to offer greater discounts. Though EU market is most mature and has evolved a lot since 2001, when compared to relatively nascent US market with respect to scope of the guidelines, the choice of the reference product, the data required for product approval, case-by-case approach and post-marketing adverseevent vigilance system; it is relatively small in size to offer bankable returns in contrast to US because of limited adoption of biosimilars in countries like Spain, and various other factors beyond the scope of the review.