3/10/2014 We are DFE Pharma Global leader in excipient solutions March 10, 2014 St John’s University 1 3/10/2014 A century long heritage With roots in dairy producing companies Our heritage 1900 – HMS (Dutch Milk Sugar Factory) founded 1926 – Six Dutch dairy producers form DMV 1946 – First lactose plant built in Kapuni NZ 1960 – DOMO starts producing pharmaceutical grade lactose 1985 – Start inhalation grade lactose by DOMO in Borculo 2003 – Superdisintegrants acquired from Avebe 2006 – DMV-Fonterra Excipients created from DMV & LNZ 2010 – DOMO-pharma integrated 2011 – Acquisition Brahmar Cellulose India 2011 – Launch new corporate brand name DFE Pharma 2013 – Global launch of MCC by DFE Pharma 3 | DFE Pharma – a joint venture between 2 leading global dairy cooperatives 50% Sales Marketing 50% HR QA R&D F&A Operations 4 | 2 3/10/2014 Our parent companies International dairy cooperative International dairy cooperative Registered head office in Auckland (New Zealand) Registered head office in Amersfoort (the Netherlands) Turnover USD 16.8 billion Turnover USD12.5 billion 17,300 employees 19,000 employees 10,600 share holder farmers 14,400 member dairy farmers | DFE Pharma Strategy Our ambition We want to grow from a lactose supplier to an excipient expert. Lactose supplier Wide range supplier Excipient expert 6 | 3 3/10/2014 Quality is guaranteed Production: cGMP production standards ICH Q7A Guidelines (API) Pharmacopoeial standards: USP/ NF ,Ph. Eur., JPE Drug Master Files ISO 9001:2008 certified production facilities, FDA inspected Shelf life guaranteed: MCC: 4 years Milled & sieved lactose: 3 years Direct compression lactose: 2-3 years (vary by grade) Starches: 2-4 years Superdisintegrants: 5 years 7 | DFE Pharma production facilities Borculo The Netherlands Nörten Hardenberg Germany Foxhol The Netherlands Veghel The Netherlands Kapuni New Zealand Cuddalore India 8 | 4 3/10/2014 Responsiveness with global presence Offices, production facilities & global distributor network 3 Production Main Office Germany Sales Office Japan The Netherlands Sales Office US Production Germany Production India Global distributors India Sales Office Sales Office Singapore Production New Zealand 9 | 5 3/10/2014 DFE Pharma excipients We supply you with one of the broadest ranges of excipients on the market Almost half the tablets manufactured each year worldwide use DFE Pharma excipients that are sourced from a variety of top quality raw materials 11 | DFE Pharma excipients We supply you with one of the broadest ranges of excipients on the market Almost half the tablets manufactured each year worldwide use DFE Pharma excipients that are sourced from a variety of top quality raw materials Filler-binder Sieved lactose • Lactochem® crystals (4 grades) • Pharmatose® 50M-125M (8 grades) Milled lactose • Lactochem® Powders (6 grades) • Pharmatose® 130M-450M (5 grades) Spray-dried lactose • Lactopress® Spray Dried (3 grades) • SuperTab® 11SD and 14SD Granulated lactose • Lactopress® Granulated • SuperTab® 30GR and 24AN Anhydrous lactose • Lactopress® Anhydrous (4 grades) • SuperTab® 21AN, 22AN and 24AN Micronised lactose • Lactochem® Microfine • Lactopress® Anhydrous Microfine Customised lactose Microcrystalline cellulose • Pharmacel® 101 • Pharmacel® 102 Diluent 51% Lactose 30% Starch Milled lactose • Lactochem® Powders (6 grades) • Pharmatose® 130M-450M (5 grades) 60% MCC Microcrystalline cellulose • Pharmacel® 101 Disintegrant 23% CCS 16% SSG Partly pregelatinised maize starch • SuperStarch® 200 Fully pregelatinised potato starch • Prejel® PA5 PH Sodium starch glycolate • Primojel® Croscarmellose sodium • Primellose® Native Potato Starch • Solani Amylum Partly pregelatinised maize starch • SuperStarch® 200 12 | % of formulations in the most prescribed drugs in the USA (OSDF type), source: RXList 2010 6 3/10/2014 Effects of Excipients on the Performance of Bilayer Tablets Jian-Xin Li, Ph.D. Tel: 732-585-0608 jian-xin.li@dfepharma.com Market Insight: North America Pharma industry is conservative – slow evolution – Tablets remain the preferred dosage form, will not disappear in 2050 – Innovators still prefer WG, rather than DC – More IR ANDA filing than MR ANDA filing NDAs: slow growth – NCEs are poorly soluble, challenging technically – Life Cycle Management (LCM) is important due to lean NCE pipeline ANDAs: key driver for future global growth – Forced to file ANDA based on QbD starting in 2013 – Big generic players focused on MR – Active R&D and filing in US, manufacturing oversea | 7 3/10/2014 DC Excipients for Tablet Production Most important requirements for DC filler/binders Chemical compatibility High compactability Good flowability Good blending properties No (drug) segregation Physical and chemical stability 15 | Compactability What happens during compression? Compression Particle rearrangement Particle deformation Particle fragmentation De-compression Bonding Tablet relaxation 16 | 8 3/10/2014 MCC/Lactose Synergy Particle deformation and fragmentation BEFORE COMPRESSION AFTER DURING COMPRESSION COMPRESSION MCC Lactose | Why are Lactose and MCC commonly used (together) Lactose – Wide range of types for all applications – Good flow and die filling properties – Good tableting properties MCC – Plastic deformation for strong tablets – Nothing tablets better! – Tablets can be made to disintegrate quickly Together – It’s possible to balance lactose & MCC to optimise formulations easily – For ease and robustness of production – For optimal tablet properties | 9 3/10/2014 good FLOW excellent lower DENSITY / DIEFILL higher plastic COMPACTION brittle low COMPACTION FORCE medium low EJECTION FORCE medium excellent faster TABLET STRENGTH good TABLET DISINTEGRATION slower SuperTab & Lactopress Lactose Pharmacel MCC Examples | Is there an ideal DC material? 20 | 10 3/10/2014 Is there an ideal DC material? How do DC lactose and Pharmacel shape up? 21 | Particle Size & Shape Favours Spray dried and granulated lactose D10 (>30) D50 (>80) D90 (<1000) LactoPress Spray Dried 250 SuperTab 11SD EU SuperTab 11SD NZ SuperTab 21AN LactoPress Anhydrous 250 SuperTab 22AN SuperTab 24AN LactoPress Granulated SuperTab 30GR Pharmacel 101 70 48 33 10 20 63 33 56 40 156 125 119 159 136 211 123 155 144 249 233 231 335 330 373 265 291 297 19 67 135 Pharmacel 102 31 97 197 Shape 22 | 11 3/10/2014 Pharmacel® is Spray Dried MCC | Direct compression lactose Summary of production routes Crystals of pharmaceutical grade α-lactose monohydrate Spray-drying Roller drying Granulated Lactopress® Spray Dried 250 SuperTab® 11SD or 14 SD Lactopress® Anhdyrous 250 SuperTab® 22AN or 24 AN Lactopress® Granulated SuperTab® 30GR 24 | 12 3/10/2014 What lactose type should I use? Use DC-lactose (spray, anhydrous or granulated) Tablets Other solid dosage forms Lactose types Wet Granulation Dry Granulation Direct Compression Capsules Sachets Spheres Milled lactose +++ + o + o +++ Sieved lactose o o + +++ +++ o Spray-dried lactose + o +++ + ++ + Granulated lactose + o +++ +++ ++ + + +++ +++ +++ + + Anhydrous lactose +++ ++ + o Highly recommended Recommended Possible but not recommended Not advised Dry granulation in this overview includes roller compaction and slugging. Spheres in this overview are made by extrusion-spheronisation. 25 | Starting Formulation Component Example API Start at <1% to 20% Fillerbinder Pharmacel PH 102 SuperTab 11SD SuperTab 21AN SuperTab 30GR QS to 100% Superdisintegrant Primojel (SSG) Primellose (CCS) 3% Lubricant Magnesium stearate 0.5% | 13 3/10/2014 DC Formulation Strategies High Dose API’s (greater than 50mg) | Tablet Formulation Optimization Algorithm Add 0.1% 0.3% glidant / Coarser API N Starting formulation & process N Flow OK Y Poor intrinsic dissolution: mill API finer / add a wetting agent) End Y Uniformity OK Y N Improve mixing plan | Poor disintegration: Use Primellose / Increase disintegrant/ replace mg stearate Use SuperTab AN or 14SD / reduce mag stearate / add 20% Pharmacel Hardness OK N Ejection OK Y Granulation may be necessary if flow and compaction cannot be achieved N Sticking: Increase lubricant / polish punches Y Capping: Decrease pressure / increase SuperTab / add Pharmacel N Dissolution OK N Y Friability OK Y N Increase compaction / add 20% Pharmacel 14 3/10/2014 Bilayer or Multi-layer FDC Tablets Business/market driver: life cycle management – Improve patient compliance – Improve therapeutic outcomes – Decrease adverse reactions – Motivation by regulatory agencies Need for bilayer or multi-layers of tablets – Chemical incompatibility of APIs – Different release profiles – Core for osmotic pump 29 | Adapted from Koo, 2013 AAPS Arden Conference Manufacture of single and bilayer tablets utilizing uniaxial compaction. A - Die filling, B - Compression, C - Decompression, D - lower punch removal and reapplication of load to the upper punch, E - Tablet fully ejected. 1 refers to the final compaction conditions. 30 | S.J. Inman , et. al. Powder Technology, Volume 188, Issue 3 , 2009 283 - 294 15 3/10/2014 Different stages occurring during bilayer tablet uniaxial compaction A) Initial layer die filling and compaction. B) Initial layer compaction showing the predominant stress transmission profile. C) Density profile of initial layer before die filling of the final layer. D) Final layer die filling and compaction. E) Final layer compaction showing the predominant stress transmission profile. F) Density profile of bilayer tablet before ejection. G) Ejection of a bilayer tablet, dashed arrows show the postulated radial expansion due to energy dissipation. 31 | S.J. Inman , et. al. Powder Technology, Volume 188, Issue 3 , 2009 283 - 294 Delamination of bilayer tablets X-ray micro-computed tomography cross-section images obtained after 2D reconstruction of the defective MCC–starch bilayer tablet compacted 32 | Akseli , et al, Powder Technology 236 (2013) 30–36 16 3/10/2014 Temperature distribution throughout tablet at end of compaction (a) internal view 33 | (b) external view Klinzing et al. Computers and Chemical Engineering 34 (2010) 1082–1091 Diametrical strain differential upon equilibration to different levels of relative humidity 34 | Klinzing et al. Pharm Res, 2013 DOI 10.1007/s11095-012-0969-0 17 3/10/2014 Formulation challenges for bilayer tablets Insufficient hardness Inaccurate individual layer mass control Cross contamination between the layers due to punch sticking Elastic mismatch between adjacent layers Delamination after compaction, during coating or storage Damage during accelerated stability test | Adapted from Koo, 2013 AAPS Arden Conference Factors for bilayer tablet formulation/ process design Materials: brittle and plastically deforming materials First-Layer Force: interfacial strength Second-Layer Force: main compression force Compaction Speed: dwell time Layer Weight Ratio Lubricant Level 36 | Adapted from Koo, 2013 AAPS Arden Conference 18 3/10/2014 Delamination occurs at a higher maximum compression force 18 KN 9 KN 3 KN Fracture patterns for crushed bilayer tablets 20%MCC+80%lactose (MCC 1st) 37 | C.-Y. Wu, J.P.K. Seville / Powder Technology 189 (2009) 285–294 Delamination occurs at a higher maximum compression force 18 KN 9 KN 3 KN Fracture patterns for crushed bilayer tablets 20%MCC+80%lactose (lactose 1st) 38 | C.-Y. Wu, J.P.K. Seville / Powder Technology 189 (2009) 285–294 19 3/10/2014 Interfacial strength test for bilayer tablets 39 | Kottala et al., AAPS PharmSciTech, Vol. 13, No. 4, December 2012 DOI: 10.1208/s12249-012-9845-9 Bilayer tablet tensile tester | Akseli , et al, Powder Technology 236 (2013) 30–36 20 3/10/2014 Force–displacement curve during the fracture of an examined MCC-MCC bilayer tablet (MCC (compressed to 8 kN)–MCC (compressed to 6 kN) bilayer tablet | Akseli , et al, Powder Technology 236 (2013) 30–36 Effect of materials on the strength of bilayer tablets Lactose-Lactose MCC-Lactose Lactose-MCC MCC-MCC MCC =MCC (Ex1=material in layer 1; Ex2=material in layer 2) Total tablet weight 500 mg with each individual layer being 250 mg. | Kottala et al., AAPS PharmSciTech, Vol. 13, No. 4, December 2012 DOI: 10.1208/s12249-012-9845-9 21 3/10/2014 Effect of storage condition and storage time on the strength of MCC-Lactose bilayer tablets Total tablet weight 500 mg with each individual layer being 250 mg. 43 | Kottala et al., AAPS PharmSciTech, Vol. 13, No. 4, December 2012 DOI: 10.1208/s12249-012-9846-8 Effect of storage condition and storage time on the strength of Lactose –MCC bilayer tablets Total tablet weight 500 mg with each individual layer being 250 mg. 44 | Kottala et al., AAPS PharmSciTech, Vol. 13, No. 4, December 2012 DOI: 10.1208/s12249-012-9846-8 22 3/10/2014 Lactose is good for bilayer tablets Bilayer tablets made with brittle materials (lactose) in both layers are strongest. For lactose–lactose tablets, an increase in adhesion between layers was observed, due to the formation of solid bridges upon storage. More significant fracture is induced when MCC is the bottom layer (MCC 1st) than when it is compressed as the top layer (lactose 1st). Interface was weakest for the compacts made with plastic materials (MCC) in both layers. Spray dried lactose monohydrate was used in the study. 45 | Kottala et al., AAPS PharmSciTech, Vol. 13, No. 4, December 2012 Anhydrous lactose Excellent recompactability for roller compaction Hard tablets are formed irrespective of the first compaction implying robust formulations are achievable. 300 SuperTab 21AN powder Densified granules 250 Tablet crushing strength (N) Anhydrous lactose granules have essentially the same compaction profile as the original powder. 200 150 100 50 0 0 100 200 Tableting pressure (MPa) 300 46 | 23 3/10/2014 Anhydrous lactose Low lubricant sensitivity 250 SuperTab 21AN unlubricated Compaction speed 300 mm/s Lubrication with 0.5 % magnesium stearate SuperTab 21AN lubricated Tablet hardness (N) 200 SuperTab 22AN unlubricated SuperTab 22AN lubricated 150 SuperTab 21AN and 22AN also have a low sensitivity to speed of compaction : < 20 % reduction in tablet hardness from 3 mm/s to 300 mm/s (not shown here) 100 50 0 0 5 10 15 20 25 30 35 Compaction force (kN) 47 | SuperTab® 24AN Product Properties - visualization Light Microscope SEM 48 | 24 3/10/2014 SuperTab® 24AN Description Combines the key properties of granulated and anhydrous lactose – High powder flowability (granulation) – Quick disintegration time (granulation) – Excellent mixing properties (granulation) – High compactability (granulation of anhydrous material) – Low moisture content below 1.0 % H2O (anhydrous material) Product is an anhydrous lactose according to Pharmacopeia | SuperTab® 24AN and 30GR Comparative Compaction 250 200 Tablet Hardness (N) 150 100 SuperTab 24AN 50 SuperTab 30GR SuperTab 21AN 0 9 10 11 12 13 14 15 16 Compaction Force (kN) 250mg tablets 9mm flat bevel edged tooling RoTab rotary tablet machine | 25 3/10/2014 SuperTab® 24AN Product properties - flow P owder F low (DC-Grade E xcipients ) 30 F lodex (flow through orifice) 27 24 21 18 15 12 9 6 3 0 Regular Anhydrous Lactos e P -P GS MCC 102 S uperTab® 24AN Granulated Lactos eMonohydrate S pray Dried Lactos eMonohydrate Excellent flow: comparable to granulated/spray-dried lactose 51 | SuperTab® 24AN Product properties – low moisture uptake < 0.7% of water uptake up to 90% RH when measured by Dynamic Vapour Sorption (DVS) 52 | 26 3/10/2014 Principles and considerations guiding first layer selection and tableting Free flowing, more re-compactable powder mixture selected as first layer – Better control of fill and weight for each layer – First layer undergoes 2 compressions Optimization of individual layer composition for improved inter-layer adhesion – Lactose is good for bilayer tablets – Layers with similar compaction/relaxation properties – Layers with similar expansion (thermal or moisture driven) Optimization of compaction pressure and tableting speed – Strength of the tablet and interfacial adhesion between layers 53 | Adapted from Otilia Koo, 2013 AAPS Arden Conference Impact Factors of Interfacial Bonding Strength of Bilayer Tablets S-Y. Chang1, J. Li2, and C.C. Sun1 27 3/10/2014 Methodologies 1. Shearing test 2. Pulling test Force Force 0.5 mm Holder Blade Tablet Holder 1 mm Tablet 55 1. Bilayer tablet thickness: 5.8~6.0 mm 2. Weight: 210 mg for MCC layer; 200 mg for Lactose layer 3. Glue: Ethyl Cyanoacrylate, Hydroquinone 4. For shearing test, blade is padded with tape Diametrical Tabletability (single layer) MCC Pharmacel with 0.5% MgSt Lactose SuperTab 24 AN with 0.5% MgSt Lactose SuperTab 11SD with 0.5% MgSt Lactose SuperTab 30GR with 0.5% MgSt 11 Tensile strength (MPa) 10 9 8 7 6 5 4 3 2 1 0 0 50 100 150 200 250 300 350 400 Compaction pressure (MPa) Tabletability: MCC >> 24AN >11SD>30GR 56 28 3/10/2014 Pulling test vs Shearing test Shearing Test at First layer(20MPa)/Second layer (200MPa) Pulling Test at First layer(20MPa)/Second layer(200MPa) Shear/Tensile strength (MPa) 3 2 1 0 Second First MCC 11SD 24AN 30GR MCC 24AN 11SD MCC 11SD 24AN 30GR MCC 24AN 30GR MCC MCC MCC MCC 11SD 11SD 11SD 24AN 24AN 24AN 24AN 30GR 30GR 30GR Layer combination 57 Pulling test vs Shearing test First layer inside 2.5 Shearing test at 20MPa/200MPa Second layer inside 2.0 1.5 1.0 0.5 0.0 0.0 0.5 1.0 1.5 2.0 Pulling test at 20MPa/200MPa 58 29 3/10/2014 Effect of Ejection direction Top Ejection direction (pushed out from) is indicated. Die 1.2 Bottom 1 0.8 Top Bottom 0.6 Top 0.4 Top 0.2 Punch 0 First/Second Bottom Ejection direction affects breaking strength 1.4 2nd 1st Bottom 1.6 Shear strength (MPa) Punch 1.8 30GR/30GR 24AN/24AN 11SD/11SD Layer combination 031-Chang-29 First (20MPa)/Second (200MPa) (n=3) Breakage mode First/Second 11SD/11SD 24AN/24AN 30GR/30GR Pushed from First Top 1 2 Bottom 1 2 Interface Second Top 3 Bottom Ejection direction affects breakage mode 3 Top 3 Bottom 3 59 Axial T.S. of bilayer tablets of mixtures 2.5 First (20MPa)/Second (200MPa) Tensile strength (MPa) 2.0 diamonds: repeated data squares: initial data 1.5 1.0 0.5 0.0 24AN 20% MCC 80% 24AN 40% MCC 60% 24AN 60% MCC 40% 24AN 80% MCC 20% 24AN MCC Layer combination Complex but reproducible trend! 60 30 3/10/2014 Confirmation of the trend with 3 additional mixtures % of 24AN in the mixture 100% First (20MPa)/Second (200MPa) Tensile strength (MPa) 2 Breakage mode (n=3 -5) First Interface Second 3/3 90% 3/3 80% 5/5 70% 3/3 60% 5/5 40% 5/5 20% 5/5 10% 3/3 0% 5/5 1 0 24AN 10% MCC 20% MCC 30% MCC 40% MCC 90% 24AN 80% 24AN 70% 24AN 60% 24AN 60% MCC 40% 24AN 80% MCC 90% MCC 20% 24AN 10% 24AN MCC Layer combination Conclusions 1. There is a satisfactory correlation between data from shearing and pulling tests. Tablet strength by shearing test is higher than that by pulling test. 2. Interfacial bonding strength is sensitive to 1st layer pressure, materials, and ejection direction 3. With 1st MCC layer compressed at 20 MPa, axial tensile strength following the order of 24AN >> 30GR >≈ 11SD when they are used as the 2nd layer materials (failures are always in lactose layer). 4. When 1st MCC layer is compressed at 100 MPa, no strong interfacial bonding forms irrespective of the 2nd layer material. 5. First layer formulation rich in 24AN, less sensitive to 1st pressure, therefore, more robust formulation for manufacturing. 6. 24AN is better than other grades of lactose (including Fast Flo) for bilayer tablets 62 31 3/10/2014 63 32
