Introduction to Pharmaceutical Freeze Drying

Transcription

1 Introduction to Pharmaceutical Freeze Drying David Debo, PE Date 1

2 Agenda Introduction Stages of the process System components 2

3 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? 3

4 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 4

5 Introduction What is sublimation? The process of changing from a solid to a gas without passing through an intermediate liquid phase. 5

6 Introduction Some Commonly Freeze Dried Materials Bacteria Viruses Vaccines Plasma Small Zoological Specimens Fruit Coffee

7 Introduction What is Freeze Dried 7

8 Introduction - History Ancient Inca Natural freeze drying potatoes and meat Modern freeze drying progressed during World War II Blood plasma 8

9 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

10 Introduction - Disadvantages Disadvantages of lyophilization include: Increased handling and processing time Need for sterile diluent upon reconstitution Cost and complexity of equipment

11 Why Freeze Dry - Pharmaceuticals Increase the shelf life of the products, such as vaccines and other injectables. Produce tablets or wafers 11

12 Phases of the process Three main process phases: Freezing Primary drying: sublimation Secondary drying: removal of absorbed water desorption 12

13 Phase Diagram for Water Freezing Liquid Solid (ice) Condensation Evaporation Vapour Sublimation 0.76 Torr PSI 1 mbar Temperature (ºC)

14 Phase Diagram for Water Freezing Solid (ice) Liquid Vapour 0.76 Torr PSI 1 mbar Temperature (ºC)

15 Phase Diagram for Water Evacuation Solid (ice) Liquid Vapour 0.76 Torr PSI 1 mbar Temperature (ºC)

16 Phase Diagram for Water Drying Solid (ice) Liquid Vapour 0.76 Torr PSI 1 mbar Temperature (ºC)

17 Phase Diagram for Water Solid (ice) Liquid Vapour 0.76 Torr PSI 1 mbar Temperature (ºC)

18 Introduction Dried Product Sections of freeze dried material showing voids remaining after sublimation COMPACT SOLID RESIDUE DRY MATERIAL DIRECTION OF HEAT REMOVAL DURING FREEZING DRY MATERIAL CHANNELS LEFT BY SUBLIMED ICE TRANSITION IN ICE STRUCTURE DURING FREEZING

19 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 19

20 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

21 Freezing chamber pressure 14.7 PSI shelves temperature -40.0ºC condenser temperature Ambient producttemperature -40.0ºC duration of process step: ± 2 hr fluid product shelf at room temperature frozen product intense cooled shelf

22 Controlled nucleation ensures uniformity in freezing and thus uniformity in drying Freezing Controlled Nucleation 22

23 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.

24 Primary Drying Primary Drying 0 Bar 1 Bar 60 C The atmosphere in and around the vial is removed 0 C Heat is applied to the product Water vapor (gas phase) is evolved -60 C The product matrix is left behind

25 Primary Drying chamber pressure 200 µ shelves temperature ºC condenser temperature Ambient -50ºC producttemperature ºC water vapor removal duration of process step: ± 10 hrs glass vial dried product frozen product sublimation front moves towards vial bottom and core as drying proceeds conduction heat through vial drying completely dried product (up to 95%) powerful heated shelf

26 Primary Drying 0 heated shelf (at + 50 C) glass of vial possible temperature-curve in a vial frozen interface between dry and frozen product is moving downwards dry product frozen product heated shelf (at + 50 C) 0 temperature (c)

27 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.

28 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

29 Secondary Drying chamber pressure shelves temperature condenser temperature producttemperature 25 µ ºC ºC ºC glass vial dried product water vapor removal adsorbed moisture conduction heat through vial duration of process step: ± hrs adsorbed moisture drying heated shelf completely dried product (up to 98%) increased heated shelf

30 Venting Purpose: To raise the pressure in the product chamber for stoppering and unloading.

31 Stoppering Purpose: To force the stoppers into the vial prior to unloading.

32 Stoppering Stoppering Ram Bellows Compressed Chamber Bellows Extended Stoppering Bellows Operation

33 Stoppering chamber pressure 12.0 PSI shelves temperature +18 ºC off condenser producttemperature temperature +25 ºC duration of process step: ± 3 mins stopper on vial with vent open stopper is fully closing the vial shelf at room temperature

34 Basic Freeze Dryer Components Product Chamber Ice Condenser Vacuum System Refrigeration System

35 Simple Freeze Drying Apparatus

36 Freeze Dryer Basic Elements Product Chamber Ice Condenser Refrigeration System Vacuum System

37 Laboratory Scale Freeze Drying

38 Pilot and Production Equipment

39 Techniques used Refrigeration Heating Vacuum Control Time Temperature Pressure

40 Refrigeration - Compressor Reciprocating Compressor Screw Compressor

41 Refrigeration Liquid Nitrogen 3.4 Kg/sec Liquid Nitrogen Absorbed Heat 2.4 Kg/sec LN 2 Inlet 1.1 MPa N 2 Gas Exhaust 0.7 MPa

42 Freeze Drying Technology Shelf Heating and Cooling Silicone Oil Heat Exchangers Silicone Oil Heater

43 Freeze Dryer Shelves

44 Freeze Dryer Shelf Construction

45 Freeze Dryer Shelf Construction Fusion Welded

46 Sub Systems - Heating (Shelves) heating system productshelf distributor (part of) cooling system to ice condenser piping filled with silicone oil piping filled with refrigerant circulation pump electrical heater heat exchanger compressor

47 Freeze Dryer Chambe r Condenser Vapor Heat Exchanger Heater Compresso r #2 Vacuum Pump Compressor #1 Condenser Sublimation Freezing Cooling Evacuation Desorption

48 Vacuum Pumps

49 Vacuum Control Two Methods of Control Calibrated Leak Preferred method! Uses an MKS electronically controlled needle valve to bleed inert gas into chamber Vacuum Valve Control Not common in Europe or America, Mostly in Japan. Allows for vacuum sweep control. Modulating valve used in calibrated leak

50 Vacuum control Initial part of drying Higher concentration of water vapor Less calibrated leak 50

51 Vacuum control End of drying Less water vapor More calibrated leak 51

52 Typical process schedule 1 CIP 2 Sterilize 3 Leak test system and bellows 4 Load 5 Freeze 6 Primary Dry 7 Secondary Dry 8 Pre-aerate 9 Stopper 10 Aerate 11 Unload 12 Defrost

53 Typical Freeze Dryer Features 316 SS Product Chamber Fluid Circulated Product Shelves Hydraulic Stoppering Mechanism Refrigeration System Vacuum Pumping System Isolation Valve Between Chamber and Condenser Clean in Place and Steam Clean Option

54 SCADA User Interface

55 Evaluation Questions 60

56 Questions & Thank you David Debo, PE Engineering Manager IMA LIFE 2175 Military Rd. Tonawanda, NY Office: , ext Cell: