The Future of Co-processed Excipients

The Future of Co-processed Excipients Dave Schoneker/Brian Carlin 6 May 2010 The Future of Co-processed Excipients Overview Definition of Coprocessed Excipients Regulatory aspects of Coprocessing Technological benefits of Coprocessing Why Coprocessed Excipients are the Future 1

Types of Excipients Single entity Mixtures or blends of multiple excipients Multiple Co-processed excipients Novel Excipients New chemical entities Single (label) entity Excipients May contain other components Concomitant components Residual processing aids Additives 2

Multiple excipient mixtures or blends Simple physical mixtures or blends of two or more compendial or non-compendial excipients by means of a low- to medium-shear process where the individual excipients are mixed together without significant chemical change* For solid mixtures or blends the individual excipients remain physically separate at a particulate level ( unengineered particles ) *Excluding incidental in-situ salt formation Particle engineering Solids can be characterized at three interdependent levels:- Molecular arrangement of individual molecules in the crystal lattice and includes phenomena such as polymorphism, pseudopolymorphism and the amorphous state Particle individual particle properties such as shape, size, surface area, and porosity Bulk ensemble of particles and properties such as flowability, compressibility, and dilution potential Source: Coprocessed Excipients for Solid Dosage Forms, S.K. Nachaegari and A.K. Bansal, Pharmaceutical Technology January 2004, p.52-64 6 3

Co-processed Excipients (IPEC) Combination of two or more compendial or noncompendial excipients designed to physically modify their properties in a manner not achievable by simple physical mixing AND without significant chemical change* Co-processing methods may include: Granulation, spray drying, melt extrusion, milling, etc. Ratios of the components may vary depending on the desired performance For solid coprocessed excipients the individual excipients may not be physically separable at a particulate level ( engineered particles ) *Excluding incidental in-situ salt formation Co-processing Methods Pharma Excipient Roller Compaction Predominantly Batch, common Rare.Agglomeration only, no synergy? Wet Granulation Batch, common Less common, not continuous/large scale Extrusion Spheronisation High shear continuous mixing Spray Drying Less common,batch Dominant granulation technology, continuous, particle size control 4

Co-processing is at the higher energy end of a continuum of processing methods Multiple Component Unprocessed* Simple powder or liquid blends Low energy input Continuum Ordered mixing? Co-grinding? Multiple Component (Co)Processed *Co-processing is often the same as processes used to make single component excipients Composite particles Significant energy input* Functional synergy? New or Novel Excipients Generally, excipients not listed in the FDA Inactive Ingredient Database (IID)* are new or novel http://www.accessdata.fda.gov/scripts/cder/iig /index.cfm Chemical modifications of existing excipients New Chemical Entities *IIG listing is not an approval but excipient likely to be deemed safe for use in other products that involve use under similar circumstances, but the Agency may ask that the database be brought up to current standards in relation to even that similar use. 5

New Excipients In this guidance, the phrase new excipients means any inactive ingredients that are intentionally added to therapeutic and diagnostic products, but that: (1) we believe are not intended to exert therapeutic effects at the intended dosage, although they may act to improve product delivery (e.g., enhance absorption or control release of the drug substance); and (2) are not fully qualified by existing safety data with respect to the currently proposed level of exposure, duration of exposure, or route of administration. FDA Guidance for Industry: Nonclinical Studies for the Safety Evaluation of Pharmaceutical Excipients 2005 Novel Excipients A novel excipient is an excipient which is being used for the first time in a drug product, or by a new route of administration (ICH). It may be a new chemical entity or a well established one which has not yet been used for human administration and /or for a particular human administration pathway in the EU and/or outside the EU. EMEA GUIDELINE ON EXCIPIENTS IN THE DOSSIER FOR APPLICATION FOR MARKETING AUTHORISATION OF A MEDICINAL PRODUCT 2007 6

Simple Physical Mixtures of Excipients Simple admixture of two or more excipients (liquids or solids) If all excipients (components) are listed in the IID, then the physical mixture is not considered new or novel Only new if mixture contains an excipient without a precedence of use Produced by short duration low-shear processing Individual components are isolated, distinct and intact Examples: color and flavor blends, immediate release film coating powder Not appropriate for monograph consideration in the United States Pharmacopia/National Formulary Co-Processed Excipients Combination ( intimate mixtures) of established excipients that possess performance advantages and improvements: increased surface area, improved flow, compaction, etc. Covalent bonds not formed May be functional synergies Produced using specialized manufacturing process: high shear dispersion, granulation, spray drying, melt extrusion Complex nature and diverse composition covering multiple functions One or more components may be formed in situ Appropriate for monograph consideration in the United States Pharmacopoeia/National Formulary Several listed in FDA Inactive Ingredient Database Defined in IPEC Composition Guide 7

Are Co-processed Excipients New or Novel? For a chemically unmodified* combination of ingredients with precedence of use:- Components Processes Component Combinations Physical Form Functionality/Utility Not novel Not novel Not novel Novel Novel *hence IPEC definition:- without significant chemical change Regulatory aspects of Co-processing Perceived regulatory barriers outweigh reality Pharmacopoeial listing eliminates barriers to adoption Few new Pharmacopoeial listings except (generic) acrylate dispersions. Avoidance inconsistent with 21 st century cgmp risk based approach Put into context:- Essentially chemically unchanged Processing of pharmaceutical products & single excipients 16 8

Monographed Co-processed Excipients (NF26) Ammonio Methacrylate Copolymer Dispersions alkalinising & antimicrobial preservative Microcrystalline Cellulose & Carboxymethylcellulose Sodium co-attrited Ethyl Acrylate & Methyl Methacrylate CoPolymer Dispersion suitable emulsifier Ethylcellulose Aqueous Dispersion Ethylcellulose, Cetanol, Sod Lauryl Sulphate Methacrylic Acid Copolymer Dispersion suitable surfactant Compressible Sugar starch, maltodextrin, or invert sugar, and suitable lubricant Confectioners Sugar? Co-ground starch sucrose (>95%) Sugar Spheres 62.5-91.5% sucrose, chiefly starch, colour permitted 17 Co-processed Excipients are the future Physical mixtures of excipients have lowest data burden but offer little added functionality. Co-processed excipients offer optimum data burden for additional functionality. Amount of Safety Data NCE Chemically Modified Excipients Non-IIG Excipients Co-processed (IIG) Excipients Mixtures of IIG Excipients IIG Excipients Degree of Newness 9

Technological Benefits of Co-processing Synergy Functionality not achievable with corresponding blend Complimentary Balancing properties eg. brittle/plastic Convenience One ingredient replaces several 19 Examples of Co-processing Co-attrition Co-crystals Granulates Modified MCCs 20 10

Co-attrition Microcrystalline Cellulose & Sodium Carboxymethylcellulose NF (Dispersible Cellulose BP) USP/NF Definition:.. a colloid-forming attrited mixture. Co-processing to form the aggregated compositions is accomplished by any of several physical processes. intensive wet co-milling or homogenization, high intensity mixing, co-extrusion, and subsequent drying in a spray dryer, bulk co-drying using a fluid bed dryer, or air drying. US 6,025,007 Name Supplier Ingredients % Manufacture Avicel RC591 FMC MCC 89 SCMC 11 Coattrited, CoSpray Dried Avicel RC581 FMC MCC 89 SCMC 11 Coattrited, Bulk Dried Avicel CL611 FMC MCC 85 SCMC 15 Coattrited, CoSpray Dried 21 Co-crystallisation Name Supplier Ingredients % Manufacture Dipac Emdex Pharmatose DCL40 Domino JRS DMV Dextrose 92 Spray Maltose 4 Crystallised Maltodextrin 4 Sucrose β Lactose 97 95 Dextrin Lactitol 3 5 SugarTab JRS Sucrose 93 Invert sugar 7 Cocrystallised Compressol S Mannitol 70-97 SPI (Pharmaburst) Sorbitol 3-30 Melt Extrusion 22 11

Granulated Excipients (1) Name Supplier Ingredients % Manufacture TimerX PenWest Xanthan Locust Bean Gum Calcium Sulphate Filler Granulate Ludipress Starlac 100 Xylitab 100 Xylitab 200 StarCap 1500 Advantose FS BASF Meggle Danisco Danisco Colorcon SPI Lactose α Lactose monohydrate Xylitol Xylitol Corn Starch Fructose 96.5 85 96.5 98 85-95 95 PVP Maize Starch Polydextrose SCMC Pregelatinised Starch Starch 3.5 15 3.5 2 5-15 5 Spray dried compound Granulate Granulate Co-spray dried Codried 23 Granulated Excipients (2) Name Supplier Ingredients % Manufacture Mannitol 90 Ludiflash BASF PVA latex solids 5 Granulated Crospovidone 5 MCC PanExcea MHC Covidien HPMC Crospovidone Granulated Cellactose 80 Meggle α Lactose monohydrate 75 Cellulose 25 Spray dried compound Formaxx EMD Calcium Carbonate 70 Coprocessed (unique Sorbitol 30 process) Microcelac 100 Meggle α Lactose monohydrate 75 MCC 25 Spraydried mixture Starlac 100 Meggle α Lactose monohydrate 85 Maize Starch 15 Spray dried compound 24 12

Modified Microcrystalline Cellulose Name Supplier Ingredients % Manufacture Avicel HFE ProSolv Avicel CE15 Avicel DG FMC JRS FMC FMC MCC 90 CoSpray Dried Mannitol 10 MCC 98 CoSpray Dried Colloidal Silicon Dioxide 2 MCC 85 CoSpray Dried Guar 15 MCC 75 CoSpray Dried DiCalcium Phosphate 25 25 Risk Assessment of Co-processed Excipients Bridge to previously studied individual components with regard to physical state, pharmacokinetics, toxicological data, level of unreacted monomers, impurities Use of abbreviated safety studies, if necessary Use weight of evidence evaluation Submit data to FDA in Drug Master File 13

Co-Processed Excipients Detailed analytical studies needed to confirm absence of chemical reactions or degradation during the co-processing. The types of studies required will depend on the chemistry of each excipient and potential for reaction under co-processing conditions. Co-Processed Excipients The better the chemical evidence for no reaction or degradation the less risk that abbreviated safety studies will be required Safety assessment (including toxicology expert opinion) must still be made even if relying on chemistry argument of no reaction/degradation to bridge to existing data on the individual excipients. 14

Existing Situation No process exists for excipient safety to be independently reviewed outside of the FDA drug approval process (NDA) Confusion exists about the level of newness. Would extensive safety data be required by regulators for co-processed excipients Pharmaceutical users are cautious to use coprocessed excipients due to perceived risks of delays This results in difficulties for excipient suppliers trying to introduce co-processed excipients into the marketplace Independent Evaluation: the IPEC New Excipient Evaluation Procedure Excipient manufacturers submit dossiers in DMF format to independent committee who evaluate:- Newness Bridging arguments Safety data FDA/global health authority would consider results during drug registration Retain authority to approve final drug product Positive appraisal from committee limits risk of rejection based on excipient Could encourage innovation 15

Excipient Expert Committee Objectives Evaluation limited to safety for specific intended uses and exposure levels Use FDA criteria (US) and ICH Safety Evaluation Criteria (ex-us) as basis for review Level of Newness is determined to evaluate the level of data needed Include composition profile in evaluation CMC safety issues other than composition should be evaluated separately (e.g. IPEC/GMP audit) New IPEC Concepts Initial discussions have taken place with USP concerning the use of the pending standards approach for new monographs for excipients (including co-processed excipients) which have gone through the IPEC NEEP IPEC Safety Committee will be submitting a proposal to USP to consider this approach during mid-2010. Could encourage innovation and reduce fear to use these materials the first time in a drug 16

Conclusion Very few new chemical entities will be introduced as new excipients Co-processed excipients are the trend to introduce new functionalities with minimum data burden Risk assessment should be on a case by case basis IPEC New Excipient Evaluation Procedure should be used for co-processed excipients to reduce regulatory uncertainties 17