Development of Biopharmaceuticals and Biosimilar Drug Delivery

Development of Biopharmaceuticals and Biosimilar Drug Delivery
Dr. Basavaraj K. Nanjwade M.Pharm., Ph.D KLE University’s College of Pharmacy Belgaum Cell No:

Development of NDA and BLA
24 Jan. 2010 Modern College of Pharmacy, Pune

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

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

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

Biopharmaceuticals history

Modern College of Pharmacy, Pune
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

Covalently linked Amino Acids
Polypeptides Amino Acids 24 Jan. 2010 Modern College of Pharmacy, Pune

Peptide Synthesis 24 Jan. 2010 Modern College of Pharmacy, Pune

Protein Structure Lactate Dehydrogenase: Mixed a / b
Immunoglobulin Fold: b Hemoglobin B Chain: a 24 Jan. 2010 Modern College of Pharmacy, Pune

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

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

Protein Pharmaceuticals
Insulin (diabetes) Interferon b (relapsing MS) Interferon g (granulomatous) TPA (heart attack) 24 Jan. 2010 Modern College of Pharmacy, Pune

Epogen Regranex (PDGF) Novoseven (F VIIa) Intron-A Neupogen Pulmozyme Infergen Actimmune (If g) Activase (TPA) BeneFix (F IX) Betaseron (If b) Humulin Novolin Pegademase (AD) 24 Jan. 2010 Modern College of Pharmacy, Pune

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

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

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

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

Noncovalent Processes
Denaturation Adsorption Aggregation Precipitation 24 Jan. 2010 Modern College of Pharmacy, Pune

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 RS-SR’’ + R’S- (Cys) Proteolysis - Asp-Pro, Trypsin (at Lys) or Chymotrypsin (at Phe/Tyr) 24 Jan. 2010 Modern College of Pharmacy, Pune

How to Deal with These Problems
Storage Formulation Delivery 24 Jan. 2010 Modern College of Pharmacy, Pune

Storage Refrigeration Packaging Additives Freeze-Drying 24 Jan. 2010 Modern College of Pharmacy, Pune

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

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

Protein Formulation Protein sequence modification (site directed mutagenisis) PEGylation Proteinylation Peptide Micelles Formulating with permeabilizers 24 Jan. 2010 Modern College of Pharmacy, Pune

Site Directed Mutagenesis
E343H 24 Jan. 2010 Modern College of Pharmacy, Pune

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

PEGylation + CH-CH-CH-CH-CH-CH-CH-CH-CH-CH | | | | | | | | | | OH OH OH OH OH OH OH OH OH OH 24 Jan. 2010 Modern College of Pharmacy, Pune

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

Peptide-PEG monomers Hydrophobic block Hydrophobic block Peptide Peptide 24 Jan. 2010 Modern College of Pharmacy, Pune

Protein Drug ScFv (antibody)
Proteinylation + Protein Drug ScFv (antibody) 24 Jan. 2010 Modern College of Pharmacy, Pune

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

Peptide Micelles 24 Jan. 2010 Modern College of Pharmacy, Pune

Targeted Micelles 24 Jan. 2010 Modern College of Pharmacy, Pune

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

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

Conventional ORAL Ease of administration Patient Compliance Exposure to extremely acidic pH Poor absorption of larger drugs Degradation by enzymes INTRAVENOUS Fast action No absorption issues Lesser patient compliance Fast clearance of drugs 24 Jan. 2010 Modern College of Pharmacy, Pune

Parenteral Delivery of Proteins
Intravenous Intramuscular Subcutaneous Intradermal 24 Jan. 2010 Modern College of Pharmacy, Pune

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

Drug Delivery 24 Jan. 2010 Modern College of Pharmacy, Pune

Novel Drug Delivery Useful for following types of drugs: Short half-life Insulin t1/2 < 25 min Growth hormone 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

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

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

Controlled Release of drugs 24 Jan. 2010 Modern College of Pharmacy, Pune

Polymers should be: Biodegradable Bio-compatible Non-toxic Examples: Polylactides/glycolides Polyanhydrides Polyphosphoesters 24 Jan. 2010 Modern College of Pharmacy, Pune

Diffusion of drug out of the polymer Governing equation: Fick’s laws of diffusion Drug release is concentration dependant Less applicable for large molecules 24 Jan. 2010 Modern College of Pharmacy, Pune

Drug Release by Polymer Degradation Polymer degradation by: Hydrolysis Enzymatic (Phosphotases; Proteases etc.) 24 Jan. 2010 Modern College of Pharmacy, Pune

Microsphere Encapsulation
100 mm 24 Jan. 2010 Modern College of Pharmacy, Pune

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

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

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

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

Release Mechanisms 24 Jan. 2010 Modern College of Pharmacy, Pune

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

Source: 24 Jan. 2010 Modern College of Pharmacy, Pune

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

Liposomes Spherical vesicles with a phospholipid bilayer Hydrophilic
Hydrophobic 24 Jan. 2010 Modern College of Pharmacy, Pune

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

Hydrogel Based Drug Delivery
Hydrogels are three dimensional networks of hydrophilic polymers that are insoluble 24 Jan. 2010 Modern College of Pharmacy, Pune

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 Insulin has been one drug that has been incorporated in hydrogels and investigated by researchers extensively 24 Jan. 2010 Modern College of Pharmacy, Pune

Proteins in Pumps Infusaid Model 400 Implantable Pump 24 Jan. 2010
Modern College of Pharmacy, Pune

Proteins in Pumps Mechanical Insulin Pumps 24 Jan. 2010 Modern College of Pharmacy, Pune

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

Oral Protein Delivery 24 Jan. 2010 Modern College of Pharmacy, Pune

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

Oral Delivery by Microsphere
pH pH 7 24 Jan. 2010 Modern College of Pharmacy, Pune

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

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

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

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

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

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

Patch Delivery 24 Jan. 2010 Modern College of Pharmacy, Pune

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

Patch Delivery 24 Jan. 2010 Modern College of Pharmacy, Pune

Transdermal Patches Micro fabricated needles to facilitates permeation of peptide drugs 24 Jan. 2010 Modern College of Pharmacy, Pune

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

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

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

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

Protein X delivery Economical advantages Improved protein utilization Less protein gets wasted Drives down product cost Improved patient compliance Reduced frequency of dosing Less medical expenditure from events due to missed doses 24 Jan. 2010 Modern College of Pharmacy, Pune

BIOSIMILARS 24 Jan. 2010 Modern College of Pharmacy, Pune

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

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

As biosimilars are not generics, the generic substitution rules should not apply to biosimilars 24 Jan. 2010 Modern College of Pharmacy, Pune

Characteristics of therapeutic proteins
Size - 100 – 500 times larger than classic drugs - Can not be completely characterized by physico- chemical methods Immunogenicity Structural heterogeneity Relatively high biological activity Relatively unstable 24 Jan. 2010 Modern College of Pharmacy, Pune

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

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

Pioneer Company Products Indication(s) US Patent/ Market Exclusivity Expires EU Patent/ Genentech NutropinTM (somatropin) Growth disorders Expired Abbott AbbokinaseTM (eudurase urokinase) Ischemic events Eli Lilly HumulinTM (recombinant insulin) Diabetes Genzyme Ceredase TM (algucerase): Cerezyme TM (imiglucerase) Gaucher disease AstraZeneca Streptase TM (streptokinase) Biogen/Roche Intron ATM (IFN-alfa-2b) Hepatitis B and C Serono Serotim TM (somatropin) AIDSwasting NA Humatrope TM (somatropin) ODE Amgen EpogenTM, Procrit TM, EpresTM (erythropoietin) Anemia 2013 Roche NeoRecormonTM (erythropoietin) Genetech TNKaseTM (tenecteplase TNK-tPA) Acute myocardial infarction InterMune ActimmuneTM (IFN-gamma-Ib) Chronic granulomatous Disease (CGD), malignant obsteopetrosis 2012 Activase TM, Alteplase TM (tPA) Acute myocardial infaretion 2010 Chiron ProleukinTM (IL-2) HIV Expired, 2012 NeupogenTM (filgrastim G-CSF) Anemia, leukemia, neutropenia Expired, 2012, 2015 24 Jan. 2010 Modern College of Pharmacy, Pune

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 CHMP- Committee for medicinal products for human use 24 Jan. 2010 Modern College of Pharmacy, Pune

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

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

Thank You 24 Jan. 2010 Modern College of Pharmacy, Pune

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