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Development of Biopharmaceuticals and Biosimilar Drug Delivery Dr. Basavaraj K. Nanjwade M.Pharm., Ph.D KLE University’s College of Pharmacy Belgaum-590010 E-mail: [email protected] Cell No: 00919742431000 Development of NDA and BLA 24 Jan. 2010 Modern College of Pharmacy, Pune 2 What are Biopharmaceuticals • Biopharmaceuticals are defined as pharmaceuticals manufactured by biotechnology methods, with the products having biological sources, usually involving live organisms or their active components • Biopharmaceuticals are protein or nucleic acid based pharmaceuticals (substance used for therapeutic or in vivo diagnostic purpose), which are produced by mean other than direct extraction from a native biological source. 24 Jan. 2010 Modern College of Pharmacy, Pune 3 Pharmaceutical Biotechnology • The methods and techniques that involve the use of living organisms (such as cells, bacteria, yeast and others) are tools to perform specific industrial or manufacturing process are called biotechnology • Pharmaceutical Biotechnology will continue to provide new breakthroughs in medical research in the years to come, leading to treatment in field which have previously eluded us (including AIDS, cancer asthma, Parkinson’s disease, Alzheimer disease) 24 Jan. 2010 Modern College of Pharmacy, Pune 4 Pharmaceutical Biotechnology • Biotechnology offers better product-targeting for specific diseases and patient groups, through the use of innovative technologies, in particular, genetics. Examples include, amongst others, treatment for rare diseases and cancers. • Some products are not naturally created in sufficient quantities for therapeutics purpose. • Biotechnology makes large-scale production of existing substances possible, for example, insulin in the field of diabetes treatment 24 Jan. 2010 Modern College of Pharmacy, Pune 5 Biopharmaceuticals history 24 Jan. 2010 Modern College of Pharmacy, Pune 6 Protein and peptide Proteins - Chains of amino acids, each joined together by a specific type of covalent bond Proteins formed by joining same 20 amino acids in many different combinations and sequences Protein > 50 amino acids peptide < 50 amino acids Function of a protein determined by its non-covalent 3D structure 24 Jan. 2010 Modern College of Pharmacy, Pune 7 Covalently linked Amino Acids O H H3N+ O H3N+ H R1 O H R N H R2 H N O H O H R3 N H R4 O O Polypeptides Amino Acids 24 Jan. 2010 Modern College of Pharmacy, Pune 8 Peptide Synthesis 24 Jan. 2010 Modern College of Pharmacy, Pune 9 Protein Structure Lactate Dehydrogenase: Mixed a / b 24 Jan. 2010 Immunoglobulin Fold: b Modern College of Pharmacy, Pune Hemoglobin B Chain: a 10 Classification of Proteins • According to their biological roles - Enzymes – Catalyses virtually all chemical reactions i.e. 6GDH - Transport proteins i.e. Haemoglobin of erythrocytes - Contractile or Motile proteins i.e. Actin and Myosin - Structural proteins i.e.Collagen - Defense proteins i.e. Immunoglobulins and Antibodies - Regulatory proteins i.e. insulin - Nutrient and storage proteins i.e. Ovalbumin 24 Jan. 2010 Modern College of Pharmacy, Pune 11 Protein Therapeutics • Proteins/peptides are gaining prominence • Proteins - ideal drugs as they carry out essentially all biologic processes and reactions • Recombinant DNA, hybridoma techniques, scale fermentation and purification processes brought new series of Proteins/peptides 24 Jan. 2010 Modern College of Pharmacy, Pune 12 Protein Pharmaceuticals • Insulin (diabetes) • Interferon b (relapsing MS) • Interferon g (granulomatous) • TPA (heart attack) 24 Jan. 2010 Modern College of Pharmacy, Pune 13 Protein Pharmaceuticals • Actimmune (If g) • Epogen • Activase (TPA) • Regranex (PDGF) • BeneFix (F IX) • Novoseven (F VIIa) • Betaseron (If b) • Intron-A • Humulin • Neupogen • Novolin • Pulmozyme • Pegademase (AD) • Infergen 24 Jan. 2010 Modern College of Pharmacy, Pune 14 Protein Pharmaceuticals • 77 FDA approved protein drugs • 66/77 are recombinant proteins • Protein pharmaceutical sales currently approach $25 billion/yr • By 2012 they are expected to reach $60 billion/yr 24 Jan. 2010 Modern College of Pharmacy, Pune 15 Challenges with Proteins • Very large and unstable molecules • Structure is held together by weak non-covalent forces • Easily destroyed by relatively mild storage conditions • Easily destroyed/eliminated by the body • Hard to obtain in large quantities 24 Jan. 2010 Modern College of Pharmacy, Pune 16 Problem with Proteins (in vivo – in the body) • Elimination by B and T cells • Proteolysis by endo/exo peptidases • Small proteins (< 30 kD) filtered out by the kidneys very quickly • Unwanted allergic reactions may develop (even toxicity) • Loss due to insolubility/adsorption 24 Jan. 2010 Modern College of Pharmacy, Pune 17 24 Jan. 2010 Modern College of Pharmacy, Pune 18 Problem with Proteins (in vitro – in the bottle) Noncovalent Covalent - Denaturation - Deamidation - Aggregation - Oxidation - Precipitation - Disulfide exchange - Adsorption - Proteolysis 24 Jan. 2010 Modern College of Pharmacy, Pune 19 Noncovalent Processes Denaturation 24 Jan. 2010 Adsorption Aggregation Precipitation Modern College of Pharmacy, Pune 20 Covalent processes • Deamidation - conversion of Asn-Gly sequences to a-Asp-Gly or b-Asp-Gly • Oxidation - conversion RSR’ to RSOR’, RSO2R’ or RSO3R’ (Met & Cys) • Disulfide exchange - RS- + R’S-SR’’ goes to RSSR’’ + R’S- (Cys) • Proteolysis - Asp-Pro, Trypsin (at Lys) or Chymotrypsin (at Phe/Tyr) 24 Jan. 2010 Modern College of Pharmacy, Pune 21 How to Deal with These Problems Storage Formulation Delivery 24 Jan. 2010 Modern College of Pharmacy, Pune 22 Storage • Refrigeration • Packaging • Additives • Freeze-Drying 24 Jan. 2010 Modern College of Pharmacy, Pune 23 Storage (additives) • Addition of stabilizing salts or ions (Zn+ for insulin) • Addition of polyols (glycerol and/or polyethylene glycol) to solubilize • Addition of sugars or dextran to displace water or reduce microbe growth • Use of surfactants (CHAPS) to reduce adsorption and aggregation 24 Jan. 2010 Modern College of Pharmacy, Pune 24 Storage (Freeze Drying) • Freeze liquid sample in container • Place under strong vacuum • Solvent sublimates leaving only solid or nonvolatile compounds • Reduces moisture content to <0.1% 24 Jan. 2010 Modern College of Pharmacy, Pune 25 How to Deal with These Problems Storage Formulation Delivery 24 Jan. 2010 Modern College of Pharmacy, Pune 26 Protein Formulation • Protein sequence modification (site directed mutagenisis) • PEGylation • Proteinylation • Peptide Micelles • Formulating with permeabilizers 24 Jan. 2010 Modern College of Pharmacy, Pune 27 Site Directed Mutagenesis E343H 24 Jan. 2010 Modern College of Pharmacy, Pune 28 Site Directed Mutagenesis • Allows amino acid substitutions at specific sites in a protein • i.e. substituting a Met to a Leu will reduce likelihood of oxidation • Strategic placement of cysteines to produce disulfides to increase Tm • Protein engineering (size, shape, etc.) 24 Jan. 2010 Modern College of Pharmacy, Pune 29 PEGylation 30 Modern College of Pharmacy, Pune 24 Jan. 2010 CH-CH-CH-CH-CH-CH-CH-CH-CH-CH | | | | | | | | | | OH OH OH OH OH OH OH OH OH OH + PEGylation • PEG is a non-toxic, hydrophilic, FDA approved, uncharged polymer • Increases in vivo half life (4-400X) • Decreases immunogenicity • Increases protease resistance • Increases solubility & stability • Reduces depot loss at injection sites 24 Jan. 2010 Modern College of Pharmacy, Pune 31 Peptide-PEG monomers Hydrophobic block Hydrophobic block Peptide O H H3N+ H R1 24 Jan. 2010 N H R2 H N O H Peptide O H R3 N H R4 O O H O H3N+ H R1 N H R2 H N O H Modern College of Pharmacy, Pune O H R3 N H R4 O O 32 Proteinylation + Protein Drug 24 Jan. 2010 ScFv (antibody) Modern College of Pharmacy, Pune 33 Proteinylation • Attachment of additional or secondary (nonimmunogenic) proteins for in vivo protection • Increases in vivo half life (10X) • Cross-linking with Serum Albumin • Cross-linking or connecting by protein engineering with antibody fragments 24 Jan. 2010 Modern College of Pharmacy, Pune 34 Peptide Micelles 24 Jan. 2010 Modern College of Pharmacy, Pune 35 Peptide Micelles 24 Jan. 2010 Modern College of Pharmacy, Pune 36 Targeted Micelles 24 Jan. 2010 Modern College of Pharmacy, Pune 37 Formulation with permeabilizers • Salicylates (aspirin) • Fatty acids • Metal chelators (EDTA) • Anything that is known to “punch holes” into the intestine or lumen 24 Jan. 2010 Modern College of Pharmacy, Pune 38 How to Deal with These Problems Storage Formulation Delivery 24 Jan. 2010 Modern College of Pharmacy, Pune 39 Drug Delivery • Non-conventional way of administering drugs (novel drug delivery) • Conventional way • Oral (Tablets, Capsules) • Parenteral (IV injections) 24 Jan. 2010 Modern College of Pharmacy, Pune 40 Conventional • ORAL • INTRAVENOUS – Ease of administration – Patient Compliance – Fast action – No absorption issues – Exposure to extremely acidic pH – Poor absorption of larger drugs – Degradation by enzymes – Lesser patient compliance – Fast clearance of drugs 24 Jan. 2010 Modern College of Pharmacy, Pune 41 Parenteral Delivery of Proteins • Intravenous • Intramuscular • Subcutaneous • Intradermal 24 Jan. 2010 Modern College of Pharmacy, Pune 42 Parenteral Delivery of Proteins • • • • • Route of delivery for 95% of proteins Allows rapid and complete absorption Allows smaller dose size (less waste) Avoids first pass metabolism Avoids protein “unfriendly zones” • Problems with overdosing, necrosis • Local tissue reactions/hypersensitivity • Everyone hates getting a needle 24 Jan. 2010 Modern College of Pharmacy, Pune 43 Drug Delivery DRUG DELIVERY CLASSIFICATION Drug Delivery Route of Administration Pulmonary Parenteral Transdermal Implants 24 Jan. 2010 Drug Modification Miscellaneous Ocular Oral PEGylation Pro-drug Polymer depot Nasal Modern College of Pharmacy, Pune 44 Novel Drug Delivery • Useful for following types of drugs: – Short half-life • Insulin • Growth hormone t1/2 < 25 min t1/2 < 25 min – High systemic toxicity (causing side effects) • Carmustine causes nausea, hair loss – Frequent dosing • Growth hormone Daily dosage required – Expensive drugs 24 Jan. 2010 Modern College of Pharmacy, Pune 45 Novel Drug Delivery • Adverse Drug Effects – 15 % of hospital admissions – 100,000 deaths – $136 billion in health care costs • Less patient compliance – 10 % hospital admissions • Novel Drug delivery sales – $14 billion in 1997 & $53 billion in 2002 24 Jan. 2010 Modern College of Pharmacy, Pune 46 Polymeric Drug Delivery • • • • Frequency of doses reduced Drug utilized more effectively Drug stabilized inside the polymer matrix Reduced side effects • Possibility of dose-dumping • De-activation of drug inside polymer 24 Jan. 2010 Modern College of Pharmacy, Pune 47 Polymeric Drug Delivery • Controlled Release of drugs Plasma concentration 60 50 40 Conventional 30 Controlled release MEC 20 MTC 10 0 0 1 2 3 4 5 6 7 8 Time 24 Jan. 2010 Modern College of Pharmacy, Pune 48 Polymeric Drug Delivery • Polymers should be: – Biodegradable – Bio-compatible – Non-toxic • Examples: – Polylactides/glycolides – Polyanhydrides – Polyphosphoesters 24 Jan. 2010 Modern College of Pharmacy, Pune 49 Polymeric Drug Delivery • Diffusion of drug out of the polymer • Governing equation: Fick’s laws of diffusion • Drug release is concentration dependant o o o o o o o o o o o o o o o • Less applicable for large molecules 24 Jan. 2010 Modern College of Pharmacy, Pune 50 Polymeric Drug Delivery • Drug Release by Polymer Degradation • Polymer degradation by: • Hydrolysis • Enzymatic (Phosphotases; Proteases etc.) 24 Jan. 2010 Modern College of Pharmacy, Pune 51 Microsphere Encapsulation 100 mm 24 Jan. 2010 Modern College of Pharmacy, Pune 52 Encapsulation • Process involves encapsulating protein or peptide drugs in small porous particles for protection from “insults” and for sustained release • Two types of microspheres – nonbiodegradable – biodegradable 24 Jan. 2010 Modern College of Pharmacy, Pune 53 Types of Microspheres • Nonbiodegradable – ceramic particles – polyethylene co-vinyl acetate – polymethacrylic acid/PEG • Biodegradable (preferred) – gelatin – polylactic-co-glycolic acid (PLGA) 24 Jan. 2010 Modern College of Pharmacy, Pune 54 Microsphere Release • Hydrophilic (i.e. gelatin) – best for burst release • Hydrophobic (i.e. PLGA) – good sustained release (esp. vaccines) – tends to denature proteins • Hybrid (amphipathic) – good sustained release – keeps proteins native/active 24 Jan. 2010 Modern College of Pharmacy, Pune 55 Polymer Scaffolds • Incorporate drug into polymeric matrix • Protection of drug from enzymatic degradation – particularly • Applicable to peptide and protein drugs • Release drug at known rate over prolonged duration • Drug dispersed or dissolved in suitable polymer • Release - diffusion of drug through polymer - diffusion through pores in polymer structure - therefore different release profiles result (dissolved or dispersed) 24 Jan. 2010 Modern College of Pharmacy, Pune 56 Release Mechanisms Drug Release Diffusion Polymer Degradation Combination Enzymatic degradation Hydrolysis Combination Bulk erosion 24 Jan. 2010 Surface erosion Modern College of Pharmacy, Pune 57 Magnetic Targeted Carriers (MTCs) • Microparticles, composed of elemental iron and activated carbon • Drug is adsorbed into the MTCs and transported • The drug attaches to the carbon component • The particles serve as delivery vehicles to the area of the tumor for site-specific targeting 24 Jan. 2010 Modern College of Pharmacy, Pune 58 Magnetic Targeted Carriers (MTCs) Source: http://www.magneticsmagazine.com/e-prints/FeRx.htm 24 Jan. 2010 Modern College of Pharmacy, Pune 59 Magnetic Targeted Carriers (MTCs) • FeRx Inc. is the leader in the development in this innovative technology • Founder of FeRx and pioneer of magnetic targeted drug delivery is Dr. Kenneth Widder • Began with albumin microspheres containing encapsulated drugs, and lead to present MTC technology • Present clinical trials by FeRx show that drug remains for 28-days with no redistribution from the targeted site 24 Jan. 2010 Modern College of Pharmacy, Pune 60 Liposomes Spherical vesicles with a phospholipid bilayer Hydrophilic Hydrophobic 24 Jan. 2010 Modern College of Pharmacy, Pune 61 Liposomes Drug Delivery • Potential of liposomes in drug delivery has now realized • Bloemycin encapsulated in thermosensitive liposomes enhanced antitumor activity and reduced normal tissue toxicity • S.C injection of negatively charged liposomes produced a prolonged hypoglycemic effect in diabetic dogs • Liposomes have recently been used successfully as vehicles for vaccines 24 Jan. 2010 Modern College of Pharmacy, Pune 62 Hydrogel Based Drug Delivery Hydrogels are three dimensional networks of hydrophilic polymers that are insoluble 24 Jan. 2010 Modern College of Pharmacy, Pune 63 Hydrogel Based Drug Delivery Hydrogels can swell as a result of changes in pH, Temp., ionic strength, solvent composition, pressure and the application of electric fields R O O O N N H H H2O R R NH2 O + H H R = polymer backbone Insulin has been one drug that has been incorporated in hydrogels and investigated by researchers extensively 24 Jan. 2010 Modern College of Pharmacy, Pune 64 Proteins in Pumps Infusaid Model 400 Implantable Pump 24 Jan. 2010 Modern College of Pharmacy, Pune 65 Proteins in Pumps Mechanical Insulin Pumps 24 Jan. 2010 Modern College of Pharmacy, Pune 66 Proteins in Pumps • Formulation is the beginning of successful drug delivery • Multiple potential interactions between the protein and the pump • Control of the material interface is most important • Device design and formulation need to work together and be regulated together 24 Jan. 2010 Modern College of Pharmacy, Pune 67 Oral Protein Delivery 24 Jan. 2010 Modern College of Pharmacy, Pune 68 Oral Insulin • Buccal aerosol delivery system developed by Generex • Insulin is absorbed through thin tissue layers in mouth and throat • Insulin is formulated with a variety of additives and stabilizers to prevent denaturation on aerosolization and to stabilize aerosol particles 24 Jan. 2010 Modern College of Pharmacy, Pune 69 Oral Delivery by Microsphere pH 2 24 Jan. 2010 pH 7 Modern College of Pharmacy, Pune 70 pH Sensitive Microspheres • Gel/Microsphere system with polymethacrylic acid + PEG • In stomach (pH 2) pores in the polymer shrink and prevent protein release • In neutral pH (found in small intestine) the pores swell and release protein • Process of shrinking and swelling is called complexation (smart materials) 24 Jan. 2010 Modern College of Pharmacy, Pune 71 Nasal Delivery of Proteins • Extensive microcirculation network underneath the nasal mucosa • Drug absorbed nasally can directly enter the systemic circulation before passing through the hepatic circulation • The nasal administration of peptides has attracted much interest now a days due to - Relatively rapid absorption of drug - Little metabolic degradation - Relative ease of administration - Selective to peptide structure and size 24 Jan. 2010 Modern College of Pharmacy, Pune 72 Nasal Delivery of Proteins • Enhancement of nasal absorption of insulin using polyacrylic acid as a vehicle • Enhancement in the nasal absorption of insulin entrapped in liposomes through the nasal mucosa of rabbits • Administration of insulin (1 IU/ kg) via the nasal route caused a significant decrease in the plasma glucose level • The nasal route appears to be a viable means of systemically delivering many small peptides 24 Jan. 2010 Modern College of Pharmacy, Pune 73 Pulmonary Delivery • Deep lung, an attractive site of protein delivery due to - Relatively large surface area (100m2) - Rapid absorption of drug into the blood stream through the alveoli • Dura and Inhale developed dry powder delivery systems for proteins • 40% of the insulin administered in an aerosol, to the trachea of anaesthetized rabbit was absorbed • Albumin was largely absorbed within 48 hours of instillation into the lungs of guinea pigs and dogs 24 Jan. 2010 Modern College of Pharmacy, Pune 74 Rectal Delivery • The rectal delivery offers many advantages - Avoidance of drug dilution prior to reaching the systemic circulation - Reduction in first-pass metabolism - Rapid systemic absorption - Safe and convenient especially in case of neonates and infants - Greater dose may be administered - Withdrawal of drug is possible in case of adverse effects • Administration of insulin using the rectal route shows systemic absorption 24 Jan. 2010 Modern College of Pharmacy, Pune 75 Occular Delivery • Gelfoam eye device enhances the absorption of sodium insulin with an absorption enhancer • Many proteins and peptides that have been investigated for ocular delivery - Enkephalins - Thyrotropin releasing hormones, - Leutanizing hormone-releasing hormone, - Glucagon and Insulin • All these peptides were absorbed into the blood stream to some extent 24 Jan. 2010 Modern College of Pharmacy, Pune 76 Patch Delivery 24 Jan. 2010 Modern College of Pharmacy, Pune 77 Mucoadhesive Patch • Adheres to specific region of GI tract • Ethylcellulose film protects drugs from proteolytic degradation • Composed of 4 layers – – – – Ethylcellulose backing Drug container (cellulose, citric acid) Mucoadhesive glue (polyacrylic acid/PEG) pH Surface layer (HP-55/Eudragit) 24 Jan. 2010 Modern College of Pharmacy, Pune 78 Patch Delivery 24 Jan. 2010 Modern College of Pharmacy, Pune 79 Transdermal Patches Micro fabricated needles to facilitates permeation of peptide drugs 24 Jan. 2010 Modern College of Pharmacy, Pune 80 Transdermal Patches • Proteins imbedded in a simple matrix with appropriate additives • Patch is coated with small needles that penetrate the dermal layer • Proteins diffuse directly into the blood stream via capillaries • Less painful form of parenteral drug delivery 24 Jan. 2010 Modern College of Pharmacy, Pune 81 Role of a Pharmaceutical Engineer • Modeling of drug delivery systems • Prediction of kinetics/thermodynamics • Novel polymer research • Temperature sensitive polymers; pH sensitive polymers • Development of new drug delivery techniques • Novel techniques for new therapies • Development of purification processes • Solvent Removal; Removal of impurities etc. • Process development • Design & Development of robust processes; GMP Validation • Scale-up of processes 24 Jan. 2010 Modern College of Pharmacy, Pune 82 Protein X • Natural protein • Specific enzymatic activity • Negligible side effects • Frequent injections (up to twice a day) • Expensive 24 Jan. 2010 Modern College of Pharmacy, Pune 83 Protein X delivery • Applicable alternative techniques • Pulmonary delivery • Non-invasive; Good patient compliance • Poor efficiency; Requires patient training • PEGylation • Improved stability; reduced frequency of injections • Protein X activity? • Polymeric delivery • Long-term delivery;improved patient compliance • May improve protein X utilization • Stability of protein X in polymer? 24 Jan. 2010 Modern College of Pharmacy, Pune 84 Protein X delivery • Improved protein utilization – Less protein gets wasted – Drives down product cost Plasma concentration • Economical advantages 60 50 40 Conventional 30 Controlled release 20 MEC 10 0 0 1 2 3 4 5 6 7 8 Time (days) • Improved patient compliance 60 Plasma concentration – Reduced frequency of dosing – Improved patient compliance – Less medical expenditure from events due to missed doses 50 40 30 20 10 0 0 1 2 3 4 5 6 7 8 Time (days) 24 Jan. 2010 Modern College of Pharmacy, Pune 85 BIOSIMILARS 24 Jan. 2010 Modern College of Pharmacy, Pune 86 What is a biosimilar medicine • A biosimilar medicine is a medicine which is similar to a biological medicine that has already been authorized (the ‘biological reference medicine’) • The active substance of a biosimilar medicine is similar to the one of the biological reference medicine 24 Jan. 2010 Modern College of Pharmacy, Pune 87 What is a biosimilar medicine • Biosimilar and biological reference medicines are used in general at the same dose to treat the same disease • Since biosimilar and biological reference medicine are similar but not identical • The name, appearance and packaging of a biosimilar medicine differ to those of the biological reference medicine 24 Jan. 2010 Modern College of Pharmacy, Pune 88 What is a biosimilar medicine • As biosimilars are not generics, the generic substitution rules should not apply to biosimilars 24 Jan. 2010 Modern College of Pharmacy, Pune 89 Characteristics of therapeutic proteins • Size - 100 – 500 times larger than classic drugs - Can not be completely characterized by physicochemical methods • Immunogenicity • Structural heterogeneity • Relatively high biological activity • Relatively unstable 24 Jan. 2010 Modern College of Pharmacy, Pune 90 Factors influencing activity of therapeutic proteins • • • • • • • Gene and promotor Host cell Culture conditions Purification Formulation Storage and handling Unknown factors 24 Jan. 2010 Modern College of Pharmacy, Pune 91 What is in a name • • • • • • • • Biogenerics Second entry biologicals Subsequent entry biologicals Off-patent biotech products Multisource products Follow-up biologics Biosimilars Similar biological medicinal products 24 Jan. 2010 Modern College of Pharmacy, Pune 92 Pioneer Company Genentech Abbott Products Indication(s) US Patent/ Market Exclusivity Expires EU Patent/ Market Exclusivity Expires NutropinTM (somatropin) AbbokinaseTM (eudurase urokinase) HumulinTM (recombinant insulin) Ceredase TM (algucerase): Cerezyme TM (imiglucerase) Streptase TM (streptokinase) Intron ATM (IFN-alfa-2b) Serotim TM (somatropin) Humatrope TM (somatropin) Growth disorders Ischemic events Expired Expired Expired Expired Diabetes Gaucher disease Expired Expired Expired Expired Ischemic events Hepatitis B and C AIDSwasting Growth disorders Expired Expired NA NA Anemia Roche Genetech InterMune EpogenTM, Procrit TM, EpresTM (erythropoietin) NeoRecormonTM (erythropoietin) TNKaseTM (tenecteplase TNK-tPA) ActimmuneTM (IFN-gamma-Ib) Expired Expired Expired Expired ODE 2013 Genentech Activase TM, Alteplase TM (tPA) Anemia Acute myocardial infarction Chronic granulomatous Disease (CGD), malignant obsteopetrosis Acute myocardial infaretion Chiron ProleukinTM (IL-2) HIV Eli Lilly Genzyme AstraZeneca Biogen/Roche Serono Eli Lilly Amgen Amgen NeupogenTM (filgrastim G-CSF) Anemia, leukemia, neutropenia 24 Jan. 2010 Modern College of Pharmacy, Pune Expired NA Expired Expired Expired Expired Expired Expired Expired 2012 Expired Expired 2010 Expired, Expired 2012 Expired, Expired 2012, 2015 93 Main elements CHMP guidelines concerning biosimilars • The concept of similar biological products is applicable to any biological medicinal product. But it is more likely applied to highly purified products, which can be thoroughly characterized • In order to support pharmacovigilance monitoring, the specific product given to the patient should be clearly identified 24 Jan. 2010 Modern College of Pharmacy, Pune 94 Main elements CHMP guidelines concerning biosimilars • The active substance of the biosimilar product must be similar in molecular and biological terms to the active substance of the reference medicinal product e. IFN alpha 2a is not similar to IFN alpha 2b • The same reference product throughout the comparability program • The pharmaceutical form, dose and route of administration of the biosimilar and the reference product should be the same 24 Jan. 2010 Modern College of Pharmacy, Pune 95 Main elements CHMP guidelines concerning biosimilars • If the reference product has more than one indication, the safety and eficacy for all indications have to be justified or demonstrated for each indication separately • The clinical safety must be monitored on an ungoing basis after marketing approval • The issue of immunogenicity should always be addressed, and its long-term monitoring is necessary 24 Jan. 2010 Modern College of Pharmacy, Pune 96 Thank You 24 Jan. 2010 Modern College of Pharmacy, Pune 97