Biosimilars: A biologic drug revolution
- 1. Abu Sufiyan Chhipa M. Pharm (Pharmacology) I sem.
- 2. A biopharmaceutical is as drug created by means of biotechnology, especially genetic engineering that primarily involves rDNA or monoclonal antibody techniques. These are typically derived from living organisms (animal cells, bacteria, virus and yeast). Examples include: Therapeutic proteins (cytokines, hormones, clotting factors), insulin, DNA vaccines etc.
- 3. Identify the human DNA sequence for the desired protein. Isolate the DNA sequence Selection of vector
- 4. Insert the gene into genome of host Modification of cells (rDNA technology) Separation, amplification and collection of biopharmaceutical
- 6. Biosimilars are legally approved subsequent versions of innovator biopharmaceutical products made by a different sponsor following patent and exclusivity expiry of the innovator product. Because of structural and manufacturing complexities, these biological products are considered as similar but not generic equivalents of innovator biopharmaceuticals.
- 7. WHO: A biopharmaceutical product Similar to an already licensed reference biotherapeutic product in terms of quality, safety and efficacy. They are termed as “similar biologic product (SBP).” US-FDA: A biopharmaceutical product highly similar to the reference product without clinically meaningful differences in safety, purity and potency. They are described as “Follow on Biologic (FOB)”. CANADA: Drug that enters the market subsequent to a version previously authorized in Canada with demonstrated similarity to a reference biologic drug. They are termed as “Subsequent entry biologic(SEB)”
- 8. It should be a biologic product. Reference product should be an already licensed biologic product. The biosimilar should demonstrate a high similarity of safety, quality and efficacy to that of the reference product. Similarity should be determined by comparing the biosimilar product with the reference product based on quality, non clinical and clinical studies.
- 9. Generic drugs are chemically and therapeutically equivalent to the branded, original, low molecular weight chemical drugs whose patents have expired. In other words, their pharmacological effects are exactly the same as those of their brand-name counterparts.
- 11. Unlike structurally well defined, low molecular weight chemical drugs, biopharmaceuticals are “High molecular weight compounds with complex three dimensional structure.” Example: Molecular weight of Aspirin (chemical generic) is 180Da Molecular weight of interferon (biosimilar) is 19000Da
- 12. A typical biologic drug is 100 to 1000 times larger than small molecule chemical drugs. Biologics posses a complex three dimensional structure whereas chemical generics have characterized one dimensional structure.
- 13. Due to the lack of knowledge of manufacturing process of innovator drug (proprietary knowledge) to the biosimilar manufacturers, it is impossible to accurately duplicate a protein product. As different manufacturing processes are used, it leads to heterogeneity of biopharmaceuticals. Such alterations significantly affect the pharmacokinetics ,pharmacodynamics and safety of the drug. Such unique safety issues are not observed with generics.
- 14. BIOSIMILARS Produced by living cell cultures. High molecular weight compounds. Complex dimensional structure. Unstable and sensitive to external conditions. Immunogenic GENERICS Produced by chemical synthesis. Low molecular weight compounds. Well defined structure. Stable Mostly non-immunogenic.
- 16. Issues arising from differences between the bioactivity of biosimilars and their innovator products. Example: Epoetin alpha products 11 epoetin from 4 different countries(Korea,Argentina, China, India) were analysed and significant diversions from specifications for in vivo activity were observed. Deviation varied in the range from 71 to 226%.
- 17. These are concerns regarding immunogenicity. Example : Eprex Eprex is a biosimilar of epoetin alpha produced outside the US. Change in manufacturing process by replacing human albumin stabilizer by polysorbate 80 resulted in increased immunogenicity. Resulted in increased cases of pure red cell aplasia caused by the production of neutralising antibodies against epoetin.
- 18. Prescribed chemical entity can be substituted by generic chemical. Same rule of substitution cannot be applied in case of biosimilar due to the issues related to safety and efficacy. Uncontrolled substitution of biologics can lead to severe consequences.
- 19. Developed through sequential process. Extensive comparative studies between reference drug and drug under development. Extent of testing of biosimilar is less than that of reference product. Product should meet acceptable levels of safety, efficacy and quality with the reference drug.
- 20. Should be authorized using complete dossier. Rationale for the choice of reference biologic provided by the manufacturer. The reference biologic selected should be used in all comparative studies during the development of biosimilar. Licensed in India and should be an innovator product. An existing similar biologic cannot be used as a reference biologic.
- 22. Molecular biology considerations: These include details regarding host cell cultures, vectors, gene sequences, promoters etc. They also include post translational modifications: Glycosylation, oxidation, deamidation, phosphorylation etc. Manufacturing Procedure Product characterization: Includes physicochemical properties, biological activity, purity, contamination and strength.
- 23. Conducted with the final formulation. Dosage form, strength and route of administration should be same as that of RB. Prior to conduct of studies statutory approvals from respective institutional biosafety committee (IBSC) & institutional animal ethics committee (IAEC) should be submitted.
- 24. 1. Pharmacodynamic studies In-vitro studies Done by in vitro cell based bioassay (cell proliferation assays and receptor binding assays). In vivo studies Performed for more accurate results on laboratory animals.
- 25. 2.Toxicological studies Repeat dose toxicity studies in relevant species is required to be conducted. Other toxicological studies (mutagenicity, carcinogenicity) are not generally required. 3. Immune responses in animals Test serum samples tested for reaction to host cell proteins. Immune toxicity is evaluated in target tissues by histopathology for the presence of immune complexes.