INGREDIENTS USED IN THE PHARMACEUTICAL EXCIPIENTS MARKET

Transcription

1 INGREDIENTS USED IN THE PHARMACEUTICAL EXCIPIENTS Science Market Regulation UBIC C O N S U L T I N G 2015 Marketing Development Strategy Consulting Partnership searches Information systems

2 Technical & Competitive Scanning Regulations Manufacturers The purpose of this proposed study is to provide a global view of the pharmaceutical excipient sector. It describes the market trends and growth prospects, the supply and level of competition, as well as possible new entrants. On the market, excipients are currently used for tablets, pre-compression, granulation, liquids, caps, and inhalation products. STUDY Users and expectations Market size New applications Key players SUPPLY ANALYSIS Producers and range Sales and market position Strengths and weaknesses TRENDS AND PROSPECTIVE Market trends/ projections New potential entrants Barriers to entry Prospective

3 O B J E C T I V E S Users and M A R expectations K E T Market size Key players MANUFACTURERS Producers and range Sales and market position Strengths and weaknesses RESEARCH E S E A R C H New researches and new developments Emerging Role Of Excipients In The Pharmaceutical Industry Drug products contain both active pharmaceutical ingredient or API and excipients. Excipients are sub-divided into various functional classifications, depending on the role that they are intended to play in the resultant formulation: Filler & Diluent: Lactose, MCC, Calcium Carbonate Disintegrants: Sodium Starch Glycolate, crosscarmellose sodium Binders & Adhesives: PVP, HPMC Lubricants: Magnesium stearate, Stearic acid Glidants: Talc, Colloidal SiO2 Excipients play a wide variety of functional roles in pharmaceutical dosage form, including: Modulating solubility & bioavailability of APIs, Increasing the stability of active ingredients in dosage forms, Helping active ingredients maintains preferred polymorphic forms or conformations, Maintaining the ph and /or osmolarity of the liquid formulations, Acting as antioxidants, emulsifying agents, aerosol propellants. Excipients, in certain cases, interacts with the active ingredient in the final formulated dosage form or may provide a matrix that affects the critical quality attributes of the active ingredients like stability and bioavailability. Issues with excipients Solubility: almost 10% of current marketed drugs are poorly soluble and almost 40% of new chemical entities (NCE) are dropped due to solubility issues. Low solubility of drug candidates can translate into poor (and varying) bioavailability. Excipients play a significant role in bioavailability. However, excipients can have a profound effect on GI physiology. They can change the GI motility or even change the permeability of the membrane. For instance, excipients like sorbitol or manitol affect intestinal transit time. This can create some problems with low permeability drugs. Sodium pyrophosphate is a cathartic laxative, had a significant effect on ranitidine and bioavailability, reducing it by half.

4 O B J E C T I V E S Users and M A R expectations K E T Market size Key players Innovation In Pharmaceutical Excipients In general, there are three types of new excipients and the development process of these varies significantly: Modified Excipients Well known excipients with established quality standards can be modified with regard to their impurity profile or their physical properties. The development for modified excipients time is relatively short with a low R&D investment and a low associated risk. Product development of new excipients has three main goals: To demonstrate the advantage over existing materials for the target application To establish a reliable manufacturing process that leads to the desired product characteristics To demonstrate the appropriate stability of the new grade. EXCIPIENTS NEW TRENDS MANUFACTURERS Producers and range Sales and market position Strengths and weaknesses RESEARCH E S E A R C H New researches and new developments Co-Processed Excipients Two or more excipients are formulated without chemical changes in order to achieve new performance characteristics which cannot be achieved by simple physical mixing. The development of a co-processed excipient is more complex. Novel Excipients It is used for the first time in a drug product or a new route of administration. Novel excipient s development is substantially similar to the nonclinical development of a new active ingredient: A high R&D investment and a long development time. As a consequence, only very few manufacturers are willing to invest in the development of a novel excipient. Couple of new chemical materials has been introduced, less than 10 new functional excipients have been approved in the past 15 years. Only a few drug manufacturers have formulated drug products containing novel excipients in recent years. Examples: - A new class of alkylsaccharide excipients - New polymeric carriers such as hypromellose acetate succinate (HPMCAS), copolymers based on dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate, poly(vinylpyrrolidone-vinyl acetate) (PVP- VA), lauroyl macrogolglycerides (polyoxylglycerides) - Ultra-pure grades of crospovidone with the lower levels of peroxides - New grades of HPMC for direct compression

5 O B J E C T I V E S Users and M A R expectations K E T Market size Key players MANUFACTURERS Producers and range Sales and market position Strengths and weaknesses Market Overview Based on recent market study data, the total market for excipients was estimated at US$ xxx billion in 2014, with an average annual growth of 7% to 8% in volume and 4% to 5% in value. That is, the global excipient market is approximately % of the global pharma market, which is evaluated at US$ xxx billion. Excipient Magnesium stearate lactose MCC Stearic acid Silicon dioxide Market volume Pharmaceutical applications Usually, the market is segmented by type of process: granulation, direct compression and inhalation. It is also sub-segmented by markets: Market Share Direct Compression Vs Wet Granulation U.S. E.C. Direct Compression Wet granulation Consumption of excipient chemical compounds is often dictated by the specific delivery system into which drug actives are formulated. In terms of market value, oral products are the top dosage forms (53.1%), with topical products being about half that amount (28.3%). Injections (3.0%) and advanced delivery systems (15.6%) make up the rest of the market; however, in case of market volume, injections come out on the top (61.2%), which is followed by oral products (21.4%), topical products (12.1%) and advanced products (5.3%). RESEARCH E S E A R C H New researches and new developments Generics, which globally represent 50% of the market and ethicals Nutraceuticals and OTC. Generic products also use edible (i.e. not USP Grade) lactose for cost reasons Market Value% Market Volume% 0 Topical Oral Injections Advanced

6 O B J E C T I V E S Users and M A R expectations K E T Market size Key players MANUFACTURERS Producers and range Sales and market position Strengths and weaknesses RESEARCH E S E A R C H New researches and new developments General Consideration On The World Lactose Market The Lactose production increased since In 2012, the worldwide production was of 920,000 tons. According to producers, the market self-regulates with an average growth of 3 to 4% per year. The market for pharmaceutical (USP) lactose is believed to be between xxx and xxx tons. In its traditional applications, such as excipient, pharmaceutical lactose consumption overall is, at best, stable. More than 50% of the world s consumption of medicinal products is in the form of tablets. This provides lactose with a very stable market, in which it continues to be the leader. New applications are obtained by direct compression. This new process facilitates new galenical products and new production methods. It also is a major time saver during the production process. The market share of this product in the U.S. is already of 50%. In France, where the market for generic is a maximum of only 7%, this share is of 10/20%, although it is higher in other European countries. U.S. EU Japan Others The market for galenicals Country Market share in % The use of lactose in nutraceuticals is more developed in Europe than in the U.S, as lactose intolerance is a greater issue in the U.S. In Europe, it is the alpha monohydrate form that is the most commonly used, while in the U.S. it is rather the anhydrous form which is used. It is more a matter of habit, even if the monohydrate form is less hygroscopic than the anhydrous. However for new processes, the trend is to use DC (Direct Compression). This is particularly true for all high-tech. products, such as biomedicines where the companies do not want to lose any part of the active principal. The pharmaceutical lactose usage breakdown Country Market share in % U.S. EC Japan Others

7 O B J E C T I V E S Users and M A R expectations K E T Market size Key players MANUFACTURERS Interviews Aim of theissues interview& SOLUTIONS Interviews with producers to collect information on their pharmaceutical product range, production and capacities, sales and market trends. This will detail their opinion of the sector's evolution, and new market applications. Contributing companies are: Ashland Inc. Speciality Ingredients Croda Inc PHARMACEUTICAL COMPANIES ABBOTT LABS AKZO NOBEL ASTRA ZENECA BAYER CORP PHARMACEUTICAL DIVISION BIOGAIA AB BOEHRINGER INGELHEIM BOIRON BRISTOL MYERS SQUIBB ELI LILLY FRESENIUS KABI GLAXO SMITHKLINE GENENTECH IPSEN BIOTECH JOHNSON & JOHNSON MEDICAL Producers and range Sales and market position Strengths and weaknesses RESEARCH E S E A R C H New researches and new developments BASF Corporation EMD Millipore Shin-Estu Chemical Co., Ltd Interviews of pharmaceutical companies and contract manufacturers Interviews with users to collect information on their needs, and market trends. LABORATOIRES DOLISOS MERCK PHARMACEUTICALS NOVO NORDISK PASTEUR MERIEUX PFIZER USA SANOFI SYNTHELABO SERVIER SHERING PLOUGH SOLVAY PHARMACEUTICALS SMITHKLINE BEECHAM UCB PHARMA ZENECA PHARMACEUTICALS

8 TABLE OF CONTENTS 1.OBJECTIVES OF THE RESEARCH 8 2.EXCUTIVE SUMMARY 11 GENERAL OVERVIEW 12 Definition 12 Functional Role 12 Main issues with excipients 12 Innovation in Pharmaceutical Excipients 13 New trends in excipients world 13 BIOAVAILABILITY 14 Solid Excipients affecting Bioavailibility 15 INTRODUCTION TO THE PHARMACEUTICAL EXCIPIENT 16 Market Overview EXCIPIENT SCIENTIFIC BACKGROUND 19 MAIN ISSUES WITH EXCIPIENTS 20 Interaction of drug with excipient residues/ impurities 23 Incompatibilities of pharmaceutical excipients with active pharmaceutical ingredients 23 Examples of excipients and their incompatibilities with API s 25 INNOVATION IN PHARMACEUTICAL EXCIPIENTS 27 Types of new excipients 28 Novel excipients 31 New excipient cost of Goods 33 New excipients 37 Other new excipients 42 DEVELOPMENTS OF NEW EXCIPIENTS 44 Emerging Excipients in Parenteral Medications 49 EXCIPIENT MANUFACTURING 51 EXCIPIENT SOURCES 54 BIOAVAILABILITY 59 Self Emulsifying Drug Delivery Systems (SEDDS) 60 Nanocrystals formulations 61 Solid dispersions via Hot Melt Extrusion (HME) 61 Solid dispersions via spray drying 62 Solid Excipients affecting Bioavailibility 63 Novelty in Excipients Market 63 Interview 65 THE ROLE OF EXCIPIENTS IN BIOTHERAPEUTICS 72 Considerations In The Formulation Of Biotherapeutics 72 HSA and Gelatin: Use As Excipients 73 Recombinant Protein Excipients 73 Benefits Of Recombinant Protein Excipients 74 GENERAL CONSIDERATION ON THE WORLD LACTOSE 75 The world pharmaceutical lactose market 75 Pharmaceutical lactose market applications 77 Technical properties and functionality researched and provided by pharmaceutical lactose Positive and inhibiting factors in the use of lactose (e.g. product composition, declaration in pharmaceutical formula) 78 Conclusion regarding the future of lactose 79 LACTOSE VS OTHER EXCIPIENTS 81 Microcrystalline cellulose 81 Polyols SEGMENTATION STRUCTURE OUTLOOK 84 SUPPLIERS REGULATORY OVERVIEW 90 USA 91 EU 91 JAPAN 91 CHINA COMPANY PROFILES 92 LACTOSE MANUFACTURERS 93 BIOLAC Gmbh (G) 94 DFE PHARMA (G) 96 FOREMOST (USA) 105 MEGGLE GROUP WASSERBURG (G) 108 SHEFFIELD PRODUCTS (KERRY) (USA) 113 Lactose Monohydrate N.F. 113 Anhydrous Lactose N.F. 115 POLYOLS STARCH MANUFACTURERS 117

9 TABLE OF CONTENTS ROQUETTE (F) 118 CYDEX PHARMACEUTICALS Inc. (Ligand Pharmaceutical) (USA) 120 CARGILL (USA) 122 OTHER EXCIPIENTS MANUFACTURERS 124 AVANTOR PERFORMANCE MATERIALS (USA) 126 BASF Pharma Ingredients (G) 129 Novozymes Biopharma US Inc 133 Colorcon, Inc. (USA) 135 EMD MILLIPORE Corporation 138 FMC Health and Nutrition (USA) 140 GATTEFOSSÉ (F) 144 ASHLAND (USA) 148 JRS PHARMA (G) 151 JLS FOODS INTERNATIONAL (USA) 157 LIPOID GmbH (De) 158 SPI PHARMA, Inc (USA) 160 UNDESA (SP) 162 CRODA (UK) 163 TEMBEC (CDN) 163 DISTRIBUTORS 165 AZELIS ( F) 166 UNIPEX (F) 167 IMCD FRANCE (F) 171 PHARMACEUTICAL CONTRACT MANUFACTURERS 173 AENOVA GROUP (G-CH) 174 VITAMINS FOR LIFE (USA) 177 GEPHAR FOOD SRL (I) 178 CARDINAL HEALTH (G) 179 GEFA LABORATOIRES (F) 181 BMP PRODUCTION GMBH (G) 182 PHARMACEUTICAL COMPANIES 183 ABBOTT LABS (USA) 185 ASTRA ZENECA (SW) 186 SANOFI (F) 190 BASF (G) 194 BAXTER (USA) 197 BOIRON (F) 200 BOEHRINGER INGELHEIM (G) 201 DEBIOPHARM (CH) 202 ELI LILLY (USA) 205 GLAXO SMITHKLINE (F) 207 IPSEN (F) 208 MERCK Kga (G) 210 MERCKLE Gmbh (G) 213 MSD (Merck Sharp & Dohme - NL/USA) 214 NOVARTIS PHARMA (CH) 219 CAPSUGEL (USA) 221 SCHERING- PLOUGH (F) 222 SERVIER (F) 224 PFIZER WYETH (F) 226 ROCHE PHARMA (CH) 228 IND SWIFT LABORATORIES Ltd (India) ANNEX 233 ORGANIZATIONS 236 Cefic 236 IPEC federation 237 IPEC Americas 237 IPEC Europe 239 IPEC India 241 IPEC Japan 241 IPEC China 241 EFPIA (European Federation of Pharmaceutical Industries and Associations) 242

10 LIST OF TABLES Table 1 List of Consulted Interviews 10 Table 2 Market share of excipients by delivery systems 18 Table 3. MAIN ISSUES WITH EXCIPIENTS 22 Table 4: Impurities found in common excipients 23 Table 5: Types of Incompatibility 24 Table 6: Analytical techniques used to detect Drug-Excipient Compatibility 24 Table 7: List of common solid-state incompatibilities 24 Table 8 Examples of Marketed Coprocessed Excipients 29 Table 9 Overview of new excipients 31 Table 10 Excipient synergies and multifunctionality 34 Table 11 Some examples of brand drugs containing novel excipients 37 Table 12 A Selection of Marketed Pharmaceuticals with β-cyclodextrin SulfoButyl Ether Sodium as excipient 38 Table 13 Advances in formulations and drug delivery systems and examples of new excipients 43 Table 14Preclinical Studies for Recent Excipients under Development or Used in Marketed Drug Products 46 Table 15: Summary of Emerging Excipients 49 Table 16. Market share Direct Compression vs Wet granulation 52 Table 17. Breakdown of Sales by Product Category 52 Table 18. Comparison of major steps involved in the granulation methods 53 Table 19. The main excipients used 54 Table 20. Excipients used in different drug delivery forms 54 Table 21. Example of tablets formulation 55 Table 22. Various methods used to prepare directly compressible excipients with their limitations 56 Table 23. Advantages / disadvantages of excipients 57 Table 24 : Commonly used excipients in biotherapeutic formulations 72 Table 25 : Selection of Therpeutic Products Containing HSA as an Excipient 73 Table 26. World Lactose Production 75 Table 27. The market for galenicals, 76 Table 28. The pharmaceutical lactose usage breakdown 76 Table 29. Lactose prices 76 Table 30. US - Lactose Price (edible), , in US$/lbs 76 Table 31. ADVANTAGES / DISADVANTAGES OF LACTOSE 78 Table 32. Factors for a new player 80 Table 33. Comparative prices of excipients 81 Table 34. Market share Direct Compression vs Wet granulation 83 Table 35. Break-down of sales by product category 83 Table 36. Main Pharmaceutical Lactose producers and market share 85 Table Top Excipients Manufacturers 87 Table 38 Top 25Pharmaceutical Companies 184 Table 39 Some of the most common excipients and their suggested use levels 233 Table 40. Dry powder Inhalers available on the Dutch Market 235 LIST OF FIGURES Figure 1 Fate of water soluble drugs during passage of the GI tract 14 Figure 2 Fate of water insoluble drugs during passage of the GI tract 14 Figure 3 Marketed vs. pipeline drugd: trend toward low solubility 20 Figure 4 Development of the three types of new excipients 32 Figure 5: Anticipated pricing history for totally new excipient. 33 Figure 6: The stabilization effect of ProTek excipients 40 Figure 7. Comparative developmental time lines for a drug product and a new chemical excipient. 44 Figure 8: Fate of water soluble drugs during passage of the GI tract 59 Figure 9: Fate of water insoluble drugs during passage of the GI tract 59 Figure 10 : Technologies to disrupt the crystal lattice of drug substances leading to various drug product intermediates 60 Figure 11: Structure of Soluplus 62 Figure 12 : Soluplus principle of action 62

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