Ingredients adapted to a fit for use model. APIs allowed the fit for use strategy to work. There has been a shift to designed for purpose

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2 Pharmaceutical industry borrowed ingredients from other industries Food Cosmetic Industrial Ingredients adapted to a fit for use model. APIs allowed the fit for use strategy to work that has all changed APIs pose more challenges There has been a shift to designed for purpose Ingredients designed specifically for the pharmaceutical industry to meet formulation development and manufacturing challenges. 2

3 1960s & 1970s: Co-processing initially used in food industry to improve stability, solubility, gelling Early to mid 1980s: MCC and CaCO 3 (Vitacel) Late 1980s: Lactose and cellulose powder (Cellactose 80) Lactose and MCC (MicroceLac 100) 1990s: Strong increasing number of co-processed products Pharma: Excipients (StarLac ), APIs Food applications: Fat substitutes Flavor enhancement 2000 and beyond The trend continues (RetaLac & CombiLac ) 3

4 Co-processed Excipients: Positioning Compared to Other Excipients 4

5 New chemical entity (NCE) Challenging due to regulatory approval New chemical grade of an existing excipient Co-Processed Excipients Two or more compendial /noncompendial excipients, ratios of componants may vary, physically modified properties, not achieved by physical mixing, Excipient Mixtures Acceptance Level Single Monographed Excipients 5

6 Two or more compendial or non-compendial excipients with varying composition Designed to physically modify functional properties, not achieved by physical mixing high energy input Without significant chemical change Proven by suitable techniques: SEM, FTIR, GC, NIR No limitations with regard to co-processing methods, or state New CPEs can be obtained by: New chemical excipients (NCEs) New grades of existing materials New combinations thereof 6

7 A physical combination of individual established pharmacopeial excipients Must be distinguishable (measureable) in at least one non-performance-related attribute from the corresponding physical admixture No formation of a covalently bonded entity Components must have USP NF monographs are the result of a typical manufacturing process as: Spray-drying, high-shear dispersion, granulation, melt-extrusion 7

8 Define/Identify Desired Functional Performance Selection Process Excipients Composition Choose Appropriate Manufacturing Process Assess Functional Performance Compare to Physical Mixture High Performance Co-Processed Excipient 8

9 Co-spray-drying StarLac, Avicel HFE-102, Cellactose, Ludipress, PROSOLV SMCC, MicroceLac Co-crystallization, coprecipitation Sugartab, Di-Pac Spray agglomeration RetaLac Granulation, dry (RC) Nutab Granulation, melt Calcium phosphate & glyceryl behenate Extrusion Pharmaburst Co-milling Calcium silicate, Confectioner s sugar Co-Attrition Avicel DG

10 Excipients specifically designed for pharmaceutical industry with value added performance Co-processing typically is the incorporation of one excipient into the particle level of another. Creation of an integrated, engineered particle Not separable at a particulate level ( engineered particles ) Performance cannot be achieved through simple blending of components Mostly understood: physical particle design of mono-, to oligomeric excipient systems 10

11 Thermodynamic or Physical state may change Molecular level: Crystal lattice Polymorphism & pseudo-polymorphism Amorphous state, Particle level: Morphology/shape Size Porosity Dual compaction mechanism Plastic deformation Brittle fracture Component homogeneity Bulk level: Particle size distribution Fewer fines Bulk & tapped density Hygroscopicity 11

12 Functional performance synergies Complementary Performance beyond simple mixtures of individual components Balancing Enhance desired properties Minimize/eliminate limitations Less performance variation Quality by Design (QbD) QbD drives the need for CPEs CPEs simplify QbD Convenient Reduced testing less different excipients, less paper work, less equipment needed) Easier scale-up less variability Better handling Efficient, cost effective Fewer excipients needed during development & manufacture Decreased use levels Lower cost in use Streamlined processes 12

13 100% 7% 90% 80% 16% 70% 60% 50% 40% 30% 20% 10% 0% 36% 41% Taxes R&D COGS S&GA Sales: > $ 300 billion Costs: ~ $250 billion Manufacturing Costs Personnel $22.5 Bn 24% Operations $22.5 Bn 24% Raw Materials Excipients $45 Bn 49% $1-2 Bn? ~2% Raymond H. Scherzer April

14 Functional performance enhancement results Flow: Uniform dosage mass Tablets and capsules Enhance blending Blend uniformity Content uniformity Compaction Increased compactibility Improved hardness profiles Less friability Increased dilution potential Decreased lubricant sensitivity Hydration: Faster disintegration Reproducible dissolution Stability enhancement Heat & moisture exposure reduced or eliminated DC processes favored Others? Solubility/wettability? Permeability? 14

15 CPEs available > 114 Number of different components used > 72 Excipients most commonly coprocessed Unmodified cellulose (MCC & powder cellulose): 35 Lactose: 27 Mannitol: 9 CaCO 3 : 8 Frequently used manufacturing methods Co-spray dried: 28 Co-agglomerated: 7 Co-precipitated/crystalized: 7 18% 5% 77% Binary Tertiary Quartinary + 15

16 Cellactose 80 Co-spray-dried 75% α-lactose lonohydrate Ph.Eur./USP-NF/JP 25% Powdered cellulose Ph.Eur./USP-NF/JP 16

17 Relative theophyline content [%] RetaLac Uniform integrated structure Spheroidal shape Improved flow Better blending Uniformity as a Function of Blend Composition Powder Blend containing Theophylline [1%] RetaLac (co-processsed) Physical admixture PAM Discrete particles Various sizes & shapes Poor flow 17

18 Tensile strength [MPa] RetaLac Spray-agglomerated 50% α-lactose Monohydrate Ph.Eur./USP-NF/JP 50% HPMC, co-processed Ph.Eur./USP-NF/JP 2208 type K4M» ca mpa s Tensile Strength as a Function of Compression Pressure RetaLac versus an Admixture Comprising Tablettose 80 & Hypromellose K RetaLac lot L1004 A4020 RetaLac lot L1021 A4020 RetaLac lot L1033 A4020 Physical admixture 1 Physical admixture 2 Physical admixture Compression pressure [MPa] 18

19 StarLac Co-spray-dried 85% a-lactose Monohydrate Ph.Eur./USP-NF/JP 15% Corn Starch, coprocessed Ph.Eur./USP-NF/JP 19

20 Co-processed excipient versus simple mixture of individual components Simple blend combining 50% HPMC (K4M) & 50% lactose monohydrate Co-processed system integrating 50% HPMC (K4M) & 50% lactose monohydrate RetaLac Agitation in cold water PAM: No dispersion after 10 min. Co-processed: Immediate dispersion ( 20

21 CombiLac Co-spray-dried 70% α-lactose Monohydrate Ph.Eur./USP-NF/JP 20% MCC Ph.Eur./USP-NF/JP 10% Corn starch Ph.Eur./USP-NF/JP Multi-functionality Flow Compaction Hydration Disintegration 21

22 Fixed ratio of individual components Excipient manufacturer can be flexible; ratios can be altered Proprietary position/supply chain security Second production site often exists Price policy CPEs can be more expensive than traditional excipients Significant price increase upon acceptance/use FEAR Newness Regulatory uncertainties Lack of official acceptance Few CPEs are monographed» USP/NF has greatest number of CPE monographs 22

23 USP/NF has greatest number of CPE monographs Manufacturers are encouraged to develop and submit draft CPE monographs Ph.Eur. has few CPE monographs, but they do exist EDQM prefers to define individual component quality of medicinal products rather than mixtures JP treats CPEs as premixes no monographs exist Numerous CPEs listed on FDA s IID CPEs may be listed as separate components due to competition Typical for CPEs to have DMF DMF can be referenced in submission for review IPEC together with IQ consortium Novel excipients working group IQ and IPEC are currently exploring regulatory pathways for the use of novel excipients 23

24 Single, traditional excipient mixtures 1+1 = 2 n = = n i=1 24

25 Co-processed excipient n n i=1 25

26 Need for new excipients to overcome challenges presented by new APIs Excipient perception transitioning from inert and cheap to high functionality CPEs are a logical consequence of QbD They ensure product quality, reduce variability Designed performance characteristics to meet current and future challenges Novel/new excipients will play be critical role for new therapies Few NCE excipients introduced due to regulatory hurdles and costs This makes CPEs attractive to pharmaceutical industry Independent excipient assessment/approval process by regulators needed Expedite industry acceptance and use Emerging trends towards tailor made excipients Requires greater pharma-excipient trust and collaboration Communication critical for success Rules for cross-disciplinary strategies will have to be established 26

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