Manufacturing of Materials That Are Useful (Fortunately) As Pharmaceutical Excipients Tim Cabelka – Senior Product Research Chemist, Dow Chemical (Retired) 1

Three Key Aspects What is/are the intended primary markets for the material? What is the scale of manufacturing, and what are the implications? What type of processes are used, and what does that mean for overall process control and product variability? 2

Materials Used As Excipients Are Usually Quite Versatile Many materials used by the pharmaceutical industry as excipients have large applications in other industries – Three Examples: Hypromellose: construction, production of catalytic converters and diesel particulate filters, food, home and personal care products PEGs: paint, ink, wood treating, agricultural applications, ceramic binder, mold release agent Propylene Glycol: composite materials, construction, coatings, deicing and heat transfer fluids, home and personal care products, cosmetics In terms of production volume, use as an excipient may be a relatively small fraction – However, this is a fortunate situation for the pharmaceutical industry—ensures that there is on-going production, broad availability and reasonable costs for excipients 3

Scale of Manufacturing To take advantage of “economy of scale,” the production capacity of manufacturing plants tends to be determined by global demand for the material across all applications – There are, of course, some limitations (local and regional supply and demand, shipping, continuity of supply, etc.) Combination of large scale facility + specific application needs can require that a plant be operated on a “campaign” basis – Multiple specifications and periodic changes in production target greatly complicates the calculation of a classical “process capability” 4

Manufacturing Processes The manufacturing process is highly dependent on scale, synthesis complexity, properties of raw materials, purification (removal of by-products), properties of final product, packaging – The resulting overall process drives production flexibility, degree of process control, overall process capability and lot size – Many large scale excipient plants have sophisticated process controls in place that far exceeds some of the controls present in typical pharmaceutical processes Since excipient users usually do not know the manufacturing process and raw material variation for any given excipient, the extent of product variability cannot be known or even estimated by users – This is why producer-user interaction is critical 5

Types of Manufacturing Processes Type #1 : A single product, very simple synthetic route, consistent raw materials – Examples: propylene glycol, synthetic glycerin – Continuous process – Very high degree process control, very low variability Type #2 : A family of closely related products, relatively simply synthetic route, consistent raw materials – Example: PEG (only varies in MW) – Production campaigns – Batch size: > 90 MT – Continuous (MW 1000) – High degree process control, low variability 6

Type #3 : A family of related products, more complex synthetic route, raw material variability – Examples: methylcellulose/hypromellose (HPMC); ethylcellulose (all three vary in both MW and chemical composition) – Variability in cellulose raw material – Production campaigns – MC/HPMC batch size: ca. 7.2 MT – EC batch size: ca. 7.7 MT – Batch/continuous/batch – Higher overall product variability More detail on this type of manufacturing process follows Types of Manufacturing Processes 7

Conversion of cellulose into cellulose ethers Methylcellulose cellulose Hydroxypropyl Methylcellulose NaOH + CH 3 Cl (1) NaOH + CH 3 Cl (2) CH 2 CHCH 3 \ / O Methylcellulose is produced by heating cellulose with sodium hydroxide and methyl chloride. The three hydroxyl groups (-OH) on C2, 3 and 6 are partial substituted by methyl groups (-CH 3 ) Hypromellose (Hydroxypropyl Methylcellulose, HPMC) is derived from cellulose treated with sodium hydroxide, methyl chloride and propylene oxide resulting in partial substitution of the hydroxyl groups Heterogenous Reaction 8

METHOCEL* Cellulose Ethers Process Flow Diagram Sample Points: Viscosity, MEO / HP, Moisture, Chloride Sample Points: Particle Size, Viscosity Sample Points: Viscosity, Moisture Pulp Pulp Storage Grinder Reactor Slurry Tank Filter / Wash Dryer Storage Silo Size Reduction Storage Silo LV Reactor Homogenizing Unit Packaging Finished Product NaOH PO MeCl Water To Waste Treatment HCl Neutralization (Sodium Bicarbonate) Sample Points: Viscosity, Chloride, Moisture, Iron, Particle Size, pH Sample Points: Complete Finished Product Testing per Spec Removal of Oversize and Metal Particles * Trademark of The Dow Chemical Company 9

ETHOCEL* Ethylcellulose Process Flow Diagram * Trademark of The Dow Chemical Company 10

Thank you! 11