An assortment of endogenous chemicals, including enzymes, hormones, and antibodies, are constantly generated by the human body to ensure its own life. Drug research has, over the years, sought to address specific health issues by developing treatments that address their underlying causes. A little over twenty years ago, biological medications first appeared on store shelves. In contrast to conventional medications, which are made in laboratories via chemical synthesis, they are created from live cells utilising biotechnology procedures. Biological medications are essential in the treatment of many disorders, as stated before. Biologics, or biological therapies, have revolutionised contemporary medicine by radically improving the outlook for several uncommon and serious illnesses, including cancer, diabetes, autoimmune disorders (including rheumatoid arthritis, Morbus Crohn, MS, and severe psoriasis), and rare diseases in general. Nature or origin, manufacturing method, structural complexity and variability, sensitivity, formulation, and side effects (immunogenicity) are some of the key ways in which biologics differ from traditional pharmaceuticals. The long and dangerous development process of biologic drugs results in their high cost, which is the primary barrier to receiving these treatments. Innovative biologics are produced using biotechnology, utilising complex system cells and recombinant DNA technologies. They include active ingredients derived from live cells or creatures.

Over the last three decades, researchers have developed and commercialised biological medications for a wide range of medical conditions, including, but not limited to, cancer, hepatitis, MS, and anaemia. The use of recombinant DNA (recDNA) methods allows for the production of biotechnological pharmaceuticals in live organisms, taking advantage of the host cells' physiological capabilities. Endogenous substances found in humans, such as insulin, cytokines, growth hormones, or erythropoietin, are often mimicked. First generation biopharmaceuticals is another name for these drugs.

The pharmaceutical industry and regulatory agencies have recently substituted these biologic medications with comparable but non-innovator biologics due to the patents for these treatments having expired or are about to expire. These pharmaceuticals are part of a new class called biosimilars, and their goal is to be exactly like the reference drug in terms of safety and effectiveness. This replacement is primarily intended to shorten the approval process for entering the market and lower manufacturing costs. Biogenerics, biosimilars, comparable biological products, follow-up biologics, second entry biologics, subsequent entry biologics, multisource goods, and off-patent biotech products are some of the other names for biosimilars.

The term "generic drug" refers to a cheaper alternative to brand-name pharmaceuticals. Whenever a drug's patent expires, or if the medication has never had a patent, or if the country where the patent is not in effect allows it, the generic manufacturer may declare the branded company's patent to be invalid and unenforceable, allowing them to make the medicine at a lower cost. The inclusion of preclinical and clinical evidence to demonstrate safety and efficacy is often not required in applications for generic drugs. Producing a generic version of an innovator product just proves that the two are bioequivalent and have pharmacological equivalence.

Intended Copies, Biobetters, and Standalone Biologics

The terms biosimilar, intended copy, bio better, and standalone product are all used interchangeably yet refer to distinct ideas. Just because biosimilars are inexpensive doesn't mean doctors have to prescribe them. Scientific data and familiarity with their distinctions should underpin this choice.

Any RP that does not conform to the standards established by the EMA/FDA and the WHO is considered an intended copy. As a result, they are advertised in nations with less regulation but are unavailable in highly regulated markets such as the US, EU, and AU. Biologicals are more widely available in these nations now that they are less expensive. In India and a few South American nations, for instance, you may get rituximab substitutes such reditux and kikuzubam. The first one has shown promise in a phase III trial, but it hasn't been compared head-to-head with the original rituximab. The absence of safety and verified toxicity led to the removal of kikuzubam. There is no evidence that the reference medicine's intended duplicates are equally safe, efficacious, or of high quality.
Impurities, cluster formation, or post-translational modifications (PTMs) are just a few examples of how a molecule's pharmacological profile might change, even when its amino acid sequence remains unchanged. Clinical studies comparing the efficacy and safety of these medications, or establishing their non-inferiority or equivalentity based on a sufficient number of patients, are lacking.

Development and Regulatory Approval of Biosimilars

Biosimilars have a development timeframe of seven to eight years, which is much longer than the two to four years usually needed for generic pharmaceuticals, and prices that are about 100 times more than generic drugs. Thus, a thorough structural and functional characterisation and comparison with the reference drug form the cornerstone of biosimilar medicine development. Determining the characteristics and fingerprint of the reference drug is the first step in developing a biosimilar medicine. This sets the limits of the biosimilar's possible variability. A new method has to be developed to guarantee fingerprint matching because the reference molecule's production procedure is secret. As the process progresses, it is necessary to experiment with different cell lines and make constant adjustments to the cell culture and purification settings in order to get the maximum degree of resemblance. Complete molecular characterisation, well defined protocols, and confirmed molecular similarity are the lynchpins of the putative biosimilar's path to clinical trials.

Biosimilar development is a lengthy and intricate process that begins with cell line selection and continues through culture, manufacturing, isolation, purification, and finally formulation, filling, and finishing. Building a cell line is a crucial step in developing a biosimilar since it determines the biosimilar's final profile and, by extension, the glycosylation patterns, which are necessary for the expression of the target protein. In the next step, a complementary DNA vector—which may originate from human or microbial cell lines—is cloned into the appropriate gene. Because of their uniform folding, high yield, stability against variations in pH and oxygen levels, and capacity to grow in suspension, Chinese hamster ovary cells are often used by the industry for expression cells. Clone selection follows, with the goal of finding clones that are genetically identical to the target product fingerprint. Because each biologic is made from a different producer's cell line, it's important to remember that no two biologics are the same.

Developing an appropriate molecule is the first step in the lengthy and arduous process of gaining clearance for novel biological therapies, which usually takes about twelve years. The chemical is then evaluated extensively throughout the preclinical stage, an important part of developing drugs. I, II, III, and IV are the conventional steps in the process of bringing a medicine to market. Phase IV occurs after a medicine has been commercialised. The procedure is less involved with generic medications as the drug molecule is already known and understood. The only remaining steps are manufacturing the final product and conducting bioequivalence testing. Due to the fact that biosimilars are basically carbon copies of already-existing molecules with known product attributes, the discovery or effectiveness phase (phase II) is unnecessary, cutting research expenses by 10–20% and lowering the development time to eight years or less.

Post-Translational Modifications (PTMs)

A number of variables may influence how similar the proposed biosimilar is to the RP, and PTMs pose a significant problem for the pharmaceutical sector. The manufacture, purification, and storage procedures of mAbs expose them to a wide range of changes, leading to a variety of forms. The order of amino acids in a protein is dictated by its genetic sequence, but its stability, function, and structure are decided by its PTMs. A protein may go through a proteolytic methylation, a proteolytic cleavage, or a proteolytic destruction event. Proteolytic methylation, oxidation, mismatched S-S bridges, truncation, glycosylation, glycation, phosphorylation, sulfation, alkylation, N-and C-terminal alterations, and deamination are common post-translational changes (PTMs) that recombinant monoclonal antibodies undergo. Glycosylation is the one that affects biological function the most.

During polypeptide synthesis or in the cellular endoplasmic reticulum and Golgi apparatus, proteins are glycosylated, which involves the addition of carbohydrate portions. Glycosylation may be either O-linked or N-linked, and both are common in proteins. Glycans are attached to amino acid residues of serine or threonine via an oxygen atom in a process known as O-linked glycosylation. Alternatively, N-linked glycosylation starts when a high-mannose-based structure is attached to an asparagine amino acid residue in an Asn-X-Ser/Thr consensus sequence while translation is underway. X may stand for any amino acid other than proline (Pro), and the alteration takes place in the Golgi apparatus and endoplasmic reticulum downstream.

Immunogenicity

When it comes to immunogenicity, proteins might trigger an unwanted immune response just by being proteins. Extremely uncommon cases of this response resulting in diminished effectiveness or other serious side effects do occur. The drug's properties, treatment-related external circumstances, and patient-or disease-specific factors are some of the variables that affect immunogenicity. Because of their effects on the drug's characteristics and impurity profile, quality concerns including changes to manufacturing procedures, formulations, or packaging might influence immunogenicity. Be very careful that the medicine's effectiveness and safety are not jeopardised in any way by making these alterations. Comparability experiments have shown that there is no substantial increase in aggregates or contaminants despite these adjustments, hence it is very unlikely that an unfavourable immunological response would develop. Comparability studies between batches, physicochemical and structural assessments, functional in vitro experiments, and regulatory authorities' active monitoring of biosimilar medications' immunogenicity are among methods used.

The European Medicines Agency (EMA) has stressed the importance of collecting immunogenicity data before approving a biological medicinal product. This data should include things like the frequency, intensity, and duration of antibodies against the product, as well as results from neutralisation tests, an evaluation of the product's clinical effects, and procedures to control the product's immunogenic potential. Nevertheless, these numbers are very context dependent, depending on factors such as the specific biological drug in question, its intended use, and product attributes.

Extrapolation

As a tried-and-true scientific principle, extrapolation seeks to determine how closely a biosimilar matches a reference medicinal product in terms of safety and effectiveness within a certain therapeutic indication. These results may be extrapolated to other reference product authorised indications because of how comparable they are. This extrapolation is consistently backed by scientific data from comparison studies, which has practical implications in that it may sometimes imply fewer clinical trials with biosimilars are needed. Common extrapolation criteria include action mechanism, intended research population, clinical context, safety profile, and immunogenicity information. Additional study may be required to prove commonality in behaviour; however, the active substance's mechanism of action should include the same receptor. Data from one indication may not simply translate to another, leading to changes in dose, pharmacokinetics, or mechanism of action depending on the clinical setting. Therefore, further studies may be required. Before extrapolating safety data, it is necessary to establish a similar safety profile for a given indication. Due to the special nature of immunogenicity data, they need extensive justification and further complicate the process.

Biosimilar in India

In India, a biosimilar is a biological product or drug made using genetic engineering that is said to be "similar" to an innovator's product in terms of quality, safety, and effectiveness. It has to have a full dossier and a history of safe use in India to be approved for marketing in India.

Here are few factors that facilitate the development and uptake of Biosimilar in India.

·        Domestic biologic firms and private sector collaborations may take advantage of loopholes in patent enforcement rules to advance biosimilar research.

·   Indian indigenous biologics are priced much cheaper than their originators due to lenient regulatory criteria and minimal research and development expenditures.

·     Because of limited health insurance coverage, people still have trouble getting their hands on biologic medications, even if biosimilars are cheaper than the original brands.

·    Patients and doctors are nonetheless worried about problems with patient education and the safety and quality of some biosimilars made in the United States.

Biosimilar manufacturing in India: rules and restrictions The New India Guidelines, "Draft Guidelines on Similar Biologics: Regulatory Requirements for Marketing Authorisation in India," were issued in June 2012 by the Department of Biotechnology (DBT). The regulatory procedure for a comparable biologic to declare itself similar to an existing reference biologic is mentioned in these recommendations.

For comparable biologics, the standards address production method, safety, efficacy, and quality. In addition to outlining the post-market regulatory requirements for Similar Biologics, the recommendations include the pre-market regulatory requirements, quality comparability exercises, preclinical and clinical investigations, and the like.

1.     To study on Development and Regulatory Approval of Biosimilars

2.     To study on Role of Biosimilar Medicines and Risk  Management

Search Strategy

Although "state of the art" approach was also used, the primary framework for this study was the criteria for systematic reviews. We searched the following database for studies that could be of interest: from 2018 to 2020 in PubMed, the Cochrane Library, and Science Direct. Use these keywords: "biosimilar," "biologics," "biosimilars," "follow on biologics," "biologics, subsequent entry," "subsequent entry biologics," "knowledge," "practice," "perception," "awareness," questionnaire, and survey" to help you find what you're looking for while researching biosimilars in clinical practice. For each database program, we customised the search model by combining keywords with Boolean connections. Our second objective was to make use of trustworthy regulatory data obtained from the EMA. For each database program, we customised the search model by combining keywords with Boolean connections. Our second objective was to employ trustworthy regulatory data obtained from the FDA and the European Medicines Agency (EMA).

Study Selection

After retrieving the studies from the databases, the first step was to assess and analyse the ones that satisfied the qualifying requirements. These criteria were used to choose 5 studies out of 50 for the analysis. Poor quality did not justify the exclusion of any research. Despite our focus on research performed between 2018 and 2020, two systematic reviews spanning 2014 to 2020 were considered for inclusion.

Medical experts in fields where biologics play a larger role, including cancer, rheumatology, endocrinology, gastroenterology, dermatology, nephrology, haematology, and general practitioners, chemists, nurses, consultants, and care managers were the intended recipients. Four studies from different nations were considered. We identified three main areas of clinical and regulatory concerns surrounding biosimilars based on healthcare professionals' existing knowledge, attitudes, and perceptions: interchangeability, extrapolation, and pharmacovigilance reporting. The fact that there are still knowledge gaps among research regarding the basic principles of biologics and biosimilars provides justification for the expressed concerns. It is clear that healthcare providers still have a long way to go before they fully understand biosimilars, including their creation, regulatory clearance, extrapolation, interchangeability, and post-marketing monitoring.

Table 1. Overview of studies included in the review.

Role of Biosimilar Medicines

In the current socioeconomic climate, biosimilars in medicines have the potential to solve various treatment techniques. Biosimilars meet the urgent requirements of the community by lowering the prices of reference biological medications. They are appropriate for satisfying healthcare needs in the short and medium term, according to research that demonstrate their effectiveness. When it comes to therapies that are often reserved for later phases of therapy, individuals with more advanced illness, or those with more critical conditions, it may be said that biosimilars would allow more people to receive these drugs faster. Biosimilars might help bring down costs, but then that extra money could go into novel and/or underserved cures, which would add to already high costs or make the budget inadequate. Biosimilar medications are now available. They stand for a world that is both complicated and inventive, but one that has enormous potential to become a major player in society. The desired and required harmonisation of recommendations should not remain a theoretical but a practical reality, and it is anticipated that investments would be made to strengthen biosimilar laws. Biosimilar drugs have shown themselves to be valuable and effective in the fight against illnesses, particularly for the benefit of persons who have contracted a disease for different causes.

Risk Management

The first step in managing the risks associated with biosimilar drug products is to systematically identify all known and potential dangers. This is done by drawing on the existing body of information on the reference product, which is accessible in published forms. The likelihood and predictability of the prospective biosimilar product's expected outcomes are based on a systematic and educated decision-making process that provides more insight into patient safety hazards, promotes quality by design, and is constantly improved upon. This encompasses not only the features of the biosimilar medicine product's analytical performance but also any potential side effects linked to its intended usage. In addition, such risks include any inadequacies in meeting expressed and inferred promises. Intentional patients would be most at risk from potentially harmful diagnoses or treatment. Potentially detrimental treatment delays are another risk. Prior to entering the market, the following aspects of the prospective biosimilar's life-cycle risk management strategy must be considered:

Hazard Identification

·        Risk analysis

·        Risk evaluation

·        Quality Control

·        Production and post-production data monitoring

At the heart of any reliable biosimilar quality system architecture is quality risk management (QRM). The patient's risk of adverse effects from improper therapy may be better assessed and mitigated with its use in establishing criteria and process parameters for the production of biosimilar drugs. It is feasible to identify probable injury situations when a list of potential dangers has been developed. To determine the likelihood that each danger may materialise in a real-world setting, a standard risk analysis examines each hazard individually. Early risk identification via a preliminary hazard analysis allows for their systematic elimination or at least acceptable reduction during biosimilar product design or manufacturing process controls. The likelihood of damage to the target user is the basis for risk management choices.

Current Knowledge and Attitudes of Healthcare Professionals toward Biosimilar Prescription

Research shows that doctors and nurses are well-versed on biosimilars and understand the fundamentals. On the other hand, healthcare providers lacked adequate understanding of pharmacovigilance, extrapolation, and interchangeability. However, there is a significant gap in healthcare providers' understanding and expertise across nations, research, and patient populations. Consultants, nurses, and chemists in the research by Aladul et al. were enthusiastic about using biosimilars in first-line therapy because of their high level of biosimilar expertise. Although 79.2% of cancer prescribers assess their biosimilar expertise as average to high, only 36.3% of them got the questions on interchangeability right, according to Giuliani et al. Leonard et al. discovered a general lack of biosimilar awareness and poor prescribing comfort by methodically examining 17 European and 3 American trials. According to the Latin American research, rheumatologists aren't well-informed on biosimilars, automatic replacement, or even the proper terminology for these drugs. Only 20% of Russian physicians in the research thought biosimilars aren't the same as generics. In contrast, 88% of dermatologists, rheumatologists, and gastroenterologists were familiar with the term "biosimilars," according to Teeple et al. According to the Spanish research, only 27% of primary care doctors are familiar with the term "biosimilar," and an even more alarming 84% have no idea what biosimilar clinical development entails. Biosimilars were unfamiliar to 6% of healthcare workers (mostly nurses) in a 2019 study by Aladul et al.

According to research by Cook et al., academic cancer doctors had mixed views on biosimilars and generics, with 74% unsure of what they were and 40.3% thinking the two terms meant the same thing. Among Asian gastroenterologists surveyed by Park et al., 66.2% were familiar with biosimilars and their principles, but only 6% were comfortable using biosimilar monoclonal antibodies in patient care. More than 90% of the healthcare professionals surveyed by Ismailov and Khasanova—including oncology/hematology nurses, nurse practitioners, medical assistants, and patient navigators—got the definition, regulation, interchangeability, and safety of biosimilars right after receiving printed educational materials. Biosimilars were known to 49%-76% of healthcare professionals, according to Sarnola et al., whereas 2%-25% were unaware of their existence.

Table 2. Major clinical and regulatory concerns of healthcare professionals related to biosimilars.

Challenges Faced by the Biosimilars

Production procedure The term "biologics" is often used to describe pharmaceuticals that have their origins in organic compounds or that have been extracted from live organisms like fungi, bacteria, or animal cell lines. Following a series of stages that often include choosing the right genetic sequence, vector, cell expression system, quality control, and purification methods, the end-product is typically produced using specialised genetically modified vectors. Each of these elements has the potential to significantly affect the final biological product's structure. In addition, the end-product's structure may be affected by even the most fundamental factors, such as pH, temperature, or the storage and packing equipment utilised. As an example, various expression systems may result in distinct glycosylation patterns for granulocyte colony stimulating factor (G-CSF) and interferon- γ. Here we have EPO (erythropoietin), a molecule that has caused immunogenicity difficulties in some circumstances, even though this safety issue is related to the original manufacturer. This is because of small alterations made during production. Therefore, even little adjustments to the production method may alter the product's properties, which in turn can have a significant influence on the clinical result.

In most cases, it is best to leave the production process of biosimilars unchanged from the original. Even when the patent expires, the innovator manufacturer retains ownership of the reference product's production data, so biosimilar producers cannot access it. Consequently, alterations are inevitable.

Extrapolation of different indications

By considering the drug's efficacy and safety in the context of the overall information gathered from the comparability exercise, the idea of extrapolation across indications suggests that clinical data generated for one therapeutical indication of a biological drug can be extended to other indications. Extrapolation from one indication to another may be considered in the context of biosimilars if the biosimilarity to the reference product has a comprehensive comparability, including safety, efficacy, and immunogenicity, which is suitable to detect clinically relevant differences. This is especially true if the active substance's mechanism of action and the target receptor(s) are the same. Biosimilars of EPO, filgrastim, and infliximab have been effectively used in Europe to execute this approach.

Immunogenicity

One major worry with biosimilars is that they might trigger an immunological response, particularly when given in large quantities over an extended period of time. The immunogenicity of EPO and other biotechnological medications is a well-known example. Rarely seen in patients treated with EPO for chronic renal disease anaemia, this instance included the patient's immune system producing antibodies that neutralise EPO. This condition is called Ab-mediated pure red cell aplasia (PRCA). Neutralising antibodies were produced against both endogenous and recombinant EPO in the PRCA patients, which occurred when immunological tolerance to rhEPO therapy broke down, especially with subcutaneous delivery. However, it should be emphasised that, in addition to the biotechnological product in question, other variables that may induce immune responses should be taken into account. These include variations in glycosylation patterns, denaturation or aggregation, impurities in the solution, dosage, administration route, treatment duration, genetic traits of patients, and so on. Therefore, it is crucial to thoroughly study the immunogenicity of biosimilars at all times.

Table 3:  Challenges faced by the biosimilars.

Post-marketing surveillance (Pharmacovigilance)

Adverse effects that were not apparent during development may be revealed by long-term consumption data in a large population, new findings, and pharmaceutical progress, even though drugs are only marketed after satisfying the Regulatory Authority's requests for their quality, efficacy, and safety. While this is generally true, it is especially crucial for biosimilars that producers arrange for long-term post-market monitoring in order to catch the immunogenic phenomena and determine the effectiveness in various illnesses. In order for a biosimilar to be registered, the pharmacovigilance strategy must be included, according to the biosimilar criteria.

Interchangeability issues

The full acceptability of biosimilars depends on establishing interchangeability. Products with the same indication approval may be used interchangeably for that indication. Using one product in place of another for the same therapeutic purpose is what the word "substitutable" means; this is not the same thing. The general consensus is that generic versions of a medicine are just as effective as the original. Substitution is allowed in certain instances. Two biologic pharmaceuticals probably wouldn't work precisely the same, and it's clear that biotechnological medications are different from chemical ones. Without consulting the prescribing physician, switching biotechnology medications might pose distinct hazards, according to a large agreement among scientific, regulatory, and business groups. Therefore, you shouldn't replace them without a doctor's prescription. Consequently, the Regulatory Authorities may be hesitant to recognise biosimilars as equivalent because to concerns about immunogenicity, effectiveness, safety, and clearance.

When it comes to increasing people's access to treatments and medications, biosimilars are powerful weapons that have already gained widespread recognition and established themselves in clinical settings. Using these medications ensures that providing health systems can remain financially stable, since they are far less expensive than the reference biologics. They will enable more patients to benefit from innovative medicines since they are more cost-effective without sacrificing safety, quality, or effectiveness. Biosimilars, on the other hand, provide unique difficulties for the pharmaceutical industry in comparison to generics. Because producing a biosimilar requires substantial capital and technical expertise, the high expense of clinical development could be a negative. The fact that biosimilar regulations are still in their infancy in most places makes it difficult to compare and contrast their approval processes with those of generic drugs. Furthermore, it is critical to alleviate safety worries and win over health experts and consumers; nevertheless, this requires substantial investment in marketing teams. Constant scientific and regulatory updates are necessary for the expansion of these products' markets, which forces corporations to innovate. All parties concerned must perform their duties as efficiently as feasible if the profits from biosimilars are to be maximised. In order for doctors to feel more comfortable prescribing biosimilars, they need learn more about them. Nocebo effects may restrict treatment adherence and induce unfavourable expectations, therefore it's important for doctors and patients to be aware of this and work together to overcome it. In order to maintain PV systems, guarantee product quality, and adapt rapidly to market changes, manufacturers must be able to provide competitive pricing. So, to achieve biosimilar development, it is essential for all parties concerned to work together effectively. Ensuring patients get the beneficial effects of biological therapy while simultaneously bolstering the sustainability of the healthcare system is the main objective. As a result, pharmaceutical companies are pouring resources into research and development of novel medicines, such as mAbs fragments, which have the same therapeutic targets as full-length mAbs but have a reduced molecular weight.