Introduction to Pharmaceutical Freeze Drying David Debo, PE Date ASEPTIC PROCESSING & FREEZE DRYING SOLUTIONS 1 Agenda • Introduction • Stages of the process • System components ASEPTIC PROCESSING & FREEZE DRYING SOLUTIONS 2 Introduction • What is lyophilization? • What is sublimation? • Why freeze dry? • What are the major phases of freeze drying? • What components are used in freeze drying? ASEPTIC PROCESSING & FREEZE DRYING SOLUTIONS 3 Introduction • What is lyophilization? – The process of isolating a solid substance from solution by freezing the solution and vaporizing the ice away under vacuum conditions. Also called freeze-drying ASEPTIC PROCESSING & FREEZE DRYING SOLUTIONS 4 Introduction • What is sublimation? – The process of changing from a solid to a gas without passing through an intermediate liquid phase. ASEPTIC PROCESSING & FREEZE DRYING SOLUTIONS 5 Introduction • Some Commonly Freeze Dried Materials – Bacteria – Viruses – Vaccines – Plasma – Small Zoological Specimens – Fruit – Coffee ASEPTIC PROCESSING & FREEZE DRYING SOLUTIONS Introduction – What is Freeze Dried ASEPTIC PROCESSING & FREEZE DRYING SOLUTIONS 7 Introduction - History • Ancient Inca – Natural freeze drying potatoes and meat • Modern freeze drying progressed during World War II – Blood plasma ASEPTIC PROCESSING & FREEZE DRYING SOLUTIONS 8 Introduction - Advantages • The advantages of lyophilization include: – Ease of processing a liquid, which simplifies aseptic handling – Enhanced stability of a dry powder – Removal of water without excessive heating of the product – Enhanced product stability in a dry state – Rapid and easy dissolution of reconstituted product ASEPTIC PROCESSING & FREEZE DRYING SOLUTIONS Introduction - Disadvantages • Disadvantages of lyophilization include: – Increased handling and processing time – Need for sterile diluent upon reconstitution – Cost and complexity of equipment ASEPTIC PROCESSING & FREEZE DRYING SOLUTIONS Why Freeze Dry - Pharmaceuticals • Increase the shelf life of the products, such as vaccines and other injectables. • Produce tablets or wafers ASEPTIC PROCESSING & FREEZE DRYING SOLUTIONS 11 Phases of the process • Three main process phases: – Freezing – Primary drying: ‘sublimation’ – Secondary drying: removal of absorbed water ‘desorption’ ASEPTIC PROCESSING & FREEZE DRYING SOLUTIONS 12 Phase Diagram for Water 760 14.7 1000 Freezing Liquid Solid 76 1.45 100 (ice) Condensation Evaporation 7.6 0.145 10 Vapour Sublimation 0.76 0.0145 1 -40 -20 0 20 40 60 80 100 Torr PSI mBar Temperature (ºC) ASEPTIC PROCESSING & FREEZE DRYING SOLUTIONS Phase Diagram for Water Freezing 760 14.7 1000 Liquid Solid 76 1.45 100 (ice) 7.6 0.145 10 Vapour 0.76 0.0145 1 -40 -20 0 20 40 60 80 100 Torr PSI mBar Temperature (ºC) ASEPTIC PROCESSING & FREEZE DRYING SOLUTIONS Phase Diagram for Water Evacuation 760 14.7 1000 Liquid Solid 76 1.45 100 (ice) 7.6 0.145 10 Vapour 0.76 0.0145 1 -40 -20 0 20 40 60 80 100 Torr PSI mBar Temperature (ºC) ASEPTIC PROCESSING & FREEZE DRYING SOLUTIONS Phase Diagram for Water Drying 760 14.7 1000 Liquid Solid 76 1.45 100 (ice) 7.6 0.145 10 Vapour 0.76 0.0145 1 -40 -20 0 20 40 60 80 100 Torr PSI mBar Temperature (ºC) ASEPTIC PROCESSING & FREEZE DRYING SOLUTIONS Phase Diagram for Water 760 14.7 1000 Liquid Solid 76 1.45 100 (ice) 7.6 0.145 10 Vapour 0.76 0.0145 1 -40 -20 0 20 40 60 80 100 Torr PSI mBar Temperature (ºC) ASEPTIC PROCESSING & FREEZE DRYING SOLUTIONS Introduction – Dried Product • Sections of freeze dried material showing voids remaining after sublimation DIRECTION OF HEAT REMOVAL DURING FREEZING COMPACT SOLID RESIDUE DRY MATERIAL DRY MATERIAL CHANNELS LEFT TRANSITION IN ICE STRUCTURE BY SUBLIMED ICE DURING FREEZING ASEPTIC PROCESSING & FREEZE DRYING SOLUTIONS Freezing • Definition – Reduction of temperature to induce crystallization of the bulk of the contained water • Purpose – Prevents frothing when vacuum is applied – Prevents Shrinkage (retention of form) – Prevents concentration of solids – Minimizes temperature dependent reactions ASEPTIC PROCESSING & FREEZE DRYING SOLUTIONS 19 Freezing Solute “Freezing” 60 C Temperature of solution is lowered until the solvent freezes 0 C Note that the product is not frozen at this time Temperature of solution is lowered further until the product “freezes” -60 C ASEPTIC PROCESSING & FREEZE DRYING SOLUTIONS Freezing chamber shelves condenser product- pressure temperature temperature temperature 14.7 PSI -40.0ºC Ambient -40.0ºC duration of process step: ± 2 hr fluid frozen product product shelf at intense cooled room temperature shelf ASEPTIC PROCESSING & FREEZE DRYING SOLUTIONS Freezing – Controlled Nucleation • Controlled nucleation ensures uniformity in freezing and thus uniformity in drying ASEPTIC PROCESSING & FREEZE DRYING SOLUTIONS 22 Primary Drying • Definition: – The sublimation phase • Purpose: – Removal of Ice with minimum harm to the product – Note: Primary drying is complete when all ice has disappeared. Some moisture remains “bound” to or adsorbed by the apparently dry product. ASEPTIC PROCESSING & FREEZE DRYING SOLUTIONS Primary Drying Primary Drying 0 Bar 1 Bar 60 C The atmosphere in and around the vial is removed Heat is applied to the 0 C product Water vapor (gas phase) is evolved The product matrix is left -60 C behind ASEPTIC PROCESSING & FREEZE DRYING SOLUTIONS Primary Drying chamber shelves condenser product- pressure temperature temperature temperature Ambient 200 µ -40 →+20 ºC → → -50ºC -40 -20 ºC water vapor duration of process step: ± 10 hrs removal glass sublimation front vial moves towards vial bottom and core as dried drying proceeds product frozen conduction heat product through vial drying ‘completely dried’ product (up to 95%) powerful heated shelf ASEPTIC PROCESSING & FREEZE DRYING SOLUTIONS +50 +40 +30 +25 +25 +20 0 +10 0 -10 -20 -20 temperature (c) possibletemperature-curve in a vial -25 -25 0 0 dry dry product ASEPTIC PROCESSING & FREEZE DRYING SOLUTIONS DRYING FREEZE & PROCESSING ASEPTIC frozen product Primary Drying Primary heated heated shelf (at + 50 C) heated heated shelf (at + 50 C) glassof vial frozen interface between dry and frozen product is moving downwards Secondary Drying • Definition: – Desorption of moisture remaining after primary drying • Purpose: – To reduce the residual moisture content of primary freeze-dried material to improve stability and shelf life. ASEPTIC PROCESSING & FREEZE DRYING SOLUTIONS Secondary Drying Secondary Drying 0 Bar 1 Bar 60 C Additional Heat is applied to the product “Bound” water is removed 0 C A dry product matrix is left behind -60 C ASEPTIC PROCESSING & FREEZE DRYING SOLUTIONS Secondary Drying chamber shelves condenser product- pressure temperature temperature temperature 25 µ +20 →+35 ºC -50 → -70 ºC -20 → +30 ºC duration of process step: ±±± 3...12 hrs water vapor removal glass adsorbed vial moisture adsorbed moisture dried product conduction heat through vial drying completely dried product (up to 98%) heated shelf increased heated shelf ASEPTIC PROCESSING & FREEZE DRYING SOLUTIONS Venting • Purpose: – To raise the pressure in the product chamber for stoppering and unloading. ASEPTIC PROCESSING & FREEZE DRYING SOLUTIONS Stoppering • Purpose: – To force the stoppers into the vial prior to unloading. ASEPTIC PROCESSING & FREEZE DRYING SOLUTIONS Stoppering Stoppering Ram Bellows Compressed Chamber Bellows Extended Stoppering Bellows Operation ASEPTIC PROCESSING & FREEZE DRYING SOLUTIONS Stoppering chamber shelves condenser product- pressure temperature temperature temperature 12.0 PSI +18 ºC off +25 ºC duration of process step: ± 3 mins stopper on vial stopper is fully with vent open closing the vial shelf at room temperature ASEPTIC PROCESSING & FREEZE DRYING SOLUTIONS Basic Freeze Dryer Components • Product Chamber • Ice Condenser • Vacuum System • Refrigeration System ASEPTIC PROCESSING & FREEZE DRYING SOLUTIONS Simple Freeze Drying Apparatus ASEPTIC PROCESSING & FREEZE DRYING SOLUTIONS Freeze Dryer Basic Elements Product Chamber Ice Condenser Refrigeration System Vacuum System ASEPTIC PROCESSING & FREEZE DRYING SOLUTIONS Laboratory Scale Freeze Drying ASEPTIC PROCESSING & FREEZE DRYING SOLUTIONS Pilot and Production Equipment ASEPTIC PROCESSING & FREEZE DRYING SOLUTIONS Techniques used • Refrigeration • Heating • Vacuum • Control – Time – Temperature – Pressure ASEPTIC PROCESSING & FREEZE DRYING SOLUTIONS Refrigeration - Compressor • Reciprocating Compressor • Screw Compressor ASEPTIC PROCESSING & FREEZE DRYING SOLUTIONS Refrigeration – Liquid Nitrogen Liquid Nitrogen 3.4 Kg/sec LN 2 Inlet 1.1 MPa Absorbed 2.4 Kg/sec Heat N2 Gas Exhaust 0.7 MPa ASEPTIC PROCESSING & FREEZE DRYING SOLUTIONS Freeze Drying Technology Shelf Heating and Cooling Silicone Oil Heat Exchangers Silicone Oil Heater ASEPTIC PROCESSING & FREEZE DRYING SOLUTIONS Freeze Dryer Shelves ASEPTIC PROCESSING & FREEZE DRYING SOLUTIONS Freeze Dryer Shelf Construction ASEPTIC PROCESSING & FREEZE DRYING SOLUTIONS Freeze Dryer Shelf Construction Fusion Welded ASEPTIC PROCESSING & FREEZE DRYING SOLUTIONS Sub Systems - Heating (Shelves) heating system product- distributor shelf (part of) cooling system to ice condenser piping filled with silicone oil piping filled with refrigerant circulation electrical heat compressor pump heater exchanger ASEPTIC PROCESSING & FREEZE DRYING SOLUTIONS Freeze Dryer Chambe r Condenser Vapor Heat Exchanger Vacuum Heater Pump Compresso r #2 Condenser Cooling SublimationDesorptionFreezing Compressor Evacuation #1 ASEPTIC PROCESSING & FREEZE DRYING SOLUTIONS Vacuum Pumps ASEPTIC