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India can Emerge as a Key Player in the Biosimilar Segment
The biosimilars industry has been growing stupendously. In the last few years, India has seen a robust growth in its biosimilars portfolio. This article aims to identify and analyse the biosimilars market and the regulatory scenario in India.

Biosimilar, which are new versions of innovator biopharmaceutical products that are marketed after expiration of patents, have emerged as one of the fastest growing development opportunities in the biopharmaceutical sector. Regulatory agencies evaluate biosimilars based on their level of similarity to, rather than the exact replication of, the innovator drug. The need for increased analytics and the desire for compressed timelines in biosimilars development demands in particular that developers must invest early in Chemistry, Manufacturing, and Controls (CMC) type analysis to demonstrate comparability to the reference molecule at every stage, particularly during manufacturing. While conventional generics are expected to face competition and pricing pressures in most developed markets, Indian pharmaceutical companies have already started gearing up for the next big thing - biosimilars. These are generic versions of biological medicines that depend on the same mechanism of action, and are used for the same therapeutic indication, as the innovator product.
Recognising the opportunity, India has already taken its first step forward to tap the emerging opportunity in the biosimilars’ space. While almost all major Indian drug makers have outlined plans, identified products and set aside investment budgets to develop a robust product pipeline, some have even started rolling them into the market. For instance, Dr Reddy’s Laboratories has already launched a few of its significant biosimilars in emerging markets. On the other hand, companies like Cipla are making huge investments in India and outside to acquire manufacturing facilities and potential product pipelines in the biosimilar segment. The company has not only acquired facilities in India and China to develop biosimilars, more recently, it has also rejigged some of its investments in China to divert more funds towards biosimilars. Similarly, Wockhardt and Lupin have made their foray into the niche segment.

Development Challenges
Similar biologics are developed through sequential process to demonstrate the similarity by extensive characterisation studies revealing the molecular and quality attributes with regard to the reference biologic. Biosimilars must be systematically engineered to match the reference product. A comparability exercise must be followed with the innovator product at all levels of product development, including: physicochemical attributes, biological activity, preclinical in vivo comparability, Phase I PK and safety, and Phase III efficacy and safety.

This can be difficult because data for the innovator product will be lacking. The only way to get information about the components of the innovator product is from material that is already out in the marketplace. Having multiple batches of the innovator’s product, spanning a number of years, can be extremely helpful during the characterisation process. Sources of variation between manufacture of innovator biopharmaceutical and biosimilar are as given below:
• Use of different vector
• Different cell expression system
• Different cell line growth media and method of expansion
• Different operating conditions
• Different binding and elution conditions
• Different methods, reagents, reference standards

Manufacturing Process of Biopharmaceuticals
The manufacturing process for similar biologic should be highly consistent and robust. If the host cell line used for the production of reference biologic is disclosed, it is desired to use the same cell line as the reference biologic. Alternatively any cell line that is adequately characterised and appropriate for intended use can be used to develop a similar biologic, with appropriate justification in order to minimise the potential for significant changes in critical quality attributes of the product and to avoid introduction of certain types of process related impurities that could impact clinical outcomes and immunogenicity.
The data requirements for review of manufacturing process at preclinical submission stage include a complete description of the manufacturing process from development and characterisation of cell banks, stability of clone, cell culture/fermentation, harvest, excipients, formulation, purification, primary packaging interactions (if different from reference biologic), etc.

Analytical Characterisation of Biosimilars
Thorough characterisation and comparability exercise are required, and details should be provided on primary and higher-order structure, post-translational modifications, biological activity, process- and product-related impurities, the relevant immunochemical properties, and results from accelerated degradation studies and studies under various stress conditions.
In order to demonstrate that you have a similar product, you need to have your analytical assays in place during the process of development. These assays will help to best replicate what the innovator has done. Overall, the characterisation you need to do for a biosimilar will always be much higher than that for a new biological entity (NBE).
The analytical characterisation of a biosimilar should include primary, secondary, tertiary, and quaternary structural assessment, biological activity, and analysis of product and process impurities. All of these components must be understood and characterised during your comparability studies of the biosimilar to the innovator product.

Regulatory Issues of Concern for the Use of Biosimilars
In order to make foray in to the global regulated markets, Indian manufactures will have to resolve the following issues on the priority basis due to different sources of variations between manufacture of innovator biopharmaceutical and manufacture of biosimilars:
1. Quality Issues
2. Efficacy Issues
3. Safety Issues
4. Pharmacovigilance
5. Substitution
6. Naming and Labeling
7. Regulatory Approval

Regulatory Landscape in India
Due to the complexity of biologics, a product can only be made that is similar to the innovator drug, not identical.
Basically, it’s impossible for two different manufacturers to produce two identical products even identical host expression systems, processes, and equivalent technologies are used. Therefore, we have to rely on analytics to compare the biosimilar to the innovator product on the market.
Advances in current state-of-theart analytical methods enhance the likelihood that a product will be highly similar to another product through better targeting of the original product’s physicochemical and functional properties. Sponsors with compelling comparability data observe a reduced regulatory burden.
The Department of Biotechnology, along with the drug regulator (CDSCO), has also got into action and has floated guidelines in 2012" Guideline on similar biologics: Regulatory Requirements Marketing Authorisation in India "for biosimilar drugs. The proposed norms outline specific requirements for pre-marketing and post-marketing data, apart from guidelines for pre-clinical and clinical trials for biosimilars.
The move is aimed at upgrading and maintaining the quality of biosimilar products that are manufactured in India. In the development of these guidelines, the department of biotechnology and the drug regulator (CDSCO) have given references of ICH guidelines so that products developed and imported in India will be per the global regulatory standards so that the Indian manufactures can leverage the technological advantage to manufacturing quality, safe and effective products.
Regulatory applications and approvals issued at different stages of biosimilars product development in India are shown in Figure 2.

The applicant should comply with the established pharmacopoeia requirements while testing the excipients and as well as biological product for which monograph is available in Indian Pharmacopoeia.

Challenge of Manufacturing Biosimilars:
For a generic drug manufacturer to win approval of a generic version of a traditional prescription drug, the product must have the same active ingredient, strength, dosage form and route of administration as the original drug. This means that generic drugs are the exact same chemically as their brand name counterparts and they act the same way in the body.
Such a process is not possible with biologics. Biologics manufacturers must ensure that the manufacturing process remains the same over time by tightly controlling the source and nature of starting materials and consistently employing hundreds of process controls that guarantee predictable results. When a biosimilar is created, it requires a new manufacturing process with new starting materials. As a result, it will produce a product that is different from and not therapeutically equivalent with that of the brand name biologic.
For new entrants, biosimilars pose very different challenges to those presented by small molecule generics, with more demanding requirements in terms of :
• Sophisticated technologies
• Clinical development, clinical trial expertise and proving bioequivalence
• Market access
• Manufacturing in dedicated manufacturing facility
• Sales and marketing capabilities

Because of the complex process of manufacturing biologics, the only way to establish whether there are differences that affect the safety and effectiveness of the biosimilars is to conduct clinical trials on each new product. The human body is more sensitive than any laboratory test and that’s why these tests are necessary to determine if biosimilars have any adverse impact in humans.

Advantage to Manufacturing Biosimilars
The "Guideline on similar biologics: Regulatory Requirements Marketing Authorisation in India" have been developed by taking the international regulatory standards in to consideration so that Indian manufactures can manufacture the biosimilars as per global GMP regulations and can make foray in to the world markets like US, Europe, Japan etc with more confidence beating all pursuing challenges.
The Indian government has also taken several initiatives towards streamlining the way biosimilars/SBP will be regulated in our country thereby showcasing India as a key player in the biosimilar segment.
Some of these include dissemination of applicable guidance documents; creating additional levels of checks (prescreening checklist for filing, NDAC referral), drafting of the Biotechnology Regulatory Authority of India bill, creating public awareness through several meetings with stakeholders and hosting clarifications on CDSCO site. These steps would ensure more affordable biosimilar drugs being manufactured and made available to patients both in domestic and export markets.
It's an exciting time for biosimilars. The need of the hour is to conduct "SWOT" analysis and strengthen our competence and confidence by understanding the regulatory guidelines and implementing them as per current requirements. As such the regulatory guidelines will continue to evolve as we get more experienced and biosimilars continue hitting the market. We will also see demand for biosimilar CMC development continue to grow as it plays a critical role in demonstrating comparability to the reference product. As we are dealing with an inherently variable system, we need to look at biosimilars development from an integrated standpoint. Biotechnological medicines shall become an important part of future healthcare landscape. With patent expiration of innovator products, the biosimilars will increasingly become available. Awareness of the deviations between biosimilars and innovator products in terms of efficacy, safety and immunogenicity is essential for proper prescription and safety of the patients.