LYOPHILIZATION. First of Four Lectures. Introduction to Freeze-Drying. Introduction to Freeze-Drying. J. Jeff Schwegman, Ph.D. AB BioTechnologies

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1 LYOPHILIZATION Introduction to Freeze-Drying First of Four Lectures Introduction to Freeze-Drying J. Jeff Schwegman, Ph.D. AB BioTechnologies P.O. Box 1430 Bloomington, Indiana,

2 Lyophilization What is Lyophilization? Lyophilization is the process we use to remove water from a formulation at low temperatures (prevents thermal degradation) through a process of sublimation. 2

3 Basic System Components Typical Lyophilizer Components Vacuum Pump Temperature Controlled Shelves Condenser (External or Internal) *Compressible Shelves Temperature Monitoring Devices Vacuum Monitoring Devices Bleed Valve Data Recording Device 3

4 Basic System Components 4

5 Tray System Components Chamber Sample Thief Vacuum Pump For Thief Vacuum Pump Condenser 5

6 Manifold System Components Shelves with Manual stoppering Valves Manifold Condenser is in Cabinetry Vacuum Pump 6

7 Tray Drying 7

8 Lyophilization Water Without water, living processes cease to function or go dormant Water can however induce damage Hydrolysis Spoilage and growth promotion of organisms 8

9 Lyophilization The Effects of Water can be: Immobilized by Freezing Eliminated by Drying The Effects of Water can be Slowed Down by: High Salt Content High Sugar Content 9

10 Lyophilization History Eskimos and Vikings preserved fish by setting them outside. The low temperatures and low relative humidity freeze-dried the fish albeit at a very slow rate 10

11 Lyophilization History 1935 Mudd and Flosdorf developed a freeze-dryer and a process to aseptically freeze-dry blood plasma for the WWII battlefields Freeze-Drying became an art 11

12 Lyophilization Why do we Lyophilize (Freeze-Dry)? Products are not stable (< 10% degradation) in the solution state at controlled room temperature for at least 2 years* 12

13 Why Freeze-Dry? Compatible with aseptic operations Drying takes place at low temperatures compared to conventional drying: Minimizes chemical decomposition Filling vials as liquid allows more precise fill weight control and avoids crosscontamination/containment problems Reduced weight 13

14 Limitations of Freeze-Drying Drug may not be stable as a freeze-dried solid example: many cephalosporins Many biological molecules are damaged by the stresses associated with freezing, freezedrying, or both Not all materials can be freeze-dried to form a pharmaceutically acceptable cake Cost? 14

15 What can be Freeze-Dried? Non Biologicals ~ Reactive Chemicals (Small Molecules) Non Living Bio Products Such as: Vacinnes Enzymes Hormones Vitamins Blood Products Antibodies Tissues for Surgery Foods Living Organisms ~ Seed Cultures Miscellaneous ~ Museum Specimens/Taxidermy 15

16 What Can t be Freeze-Dried? Oil Rich Products Sugar Rich Materials Products that Form an Impervious Skin High Salt Containing Products (Tg suppressing substances 16

17 What is Freeze-Drying? Liquid Pressure (atm) 1 Solid Vapor Triple point (0 o C, 4.5 mm Hg) Temperature, C 17

18 Why Lyophilization Works Sublimation: 1: (chemistry) a change directly from the solid to the gaseous state without becoming liquid * Ice sublimes in an attempt to achieve vapor equilibrium. When chamber pressure = ice vapor pressure, sublimation stops 18

19 Steps of Lyophilization 1. Product Freezing (I & II) 2. Thermal Treatment (Annealing) 3. System Evacuation (Vacuum) 4. Primary Drying (Removal of Ice) 5. Secondary Drying (Removal of Unfrozen Water) 6. Backfill with Inert Gas 19

20 Stages of Freeze-Drying Freezing Secondary Drying Primary Drying 20

21 Pharmaceutically Elegant Product 21

22 Lyophilization Sublimation occurs from the top of the frozen plug to the bottom. The interface between the frozen layer and the dried layer where sublimation is actively occurring is termed the Sublimation Front. Sublimation should proceed horizontally through the plug (not reality) and water vapor travels through the dried layer (capillaries) out of the top of the vial down to the condenser 22

23 Lyophilization Theoretical Actual Dried Layer Sublimation Front Frozen Layer 23

24 Lyophilization The difference in vapor pressure between the sample at the sublimation front and at the condenser is the driving force of lyophilization and Not Temperature. Neither a large vacuum pump nor an extremely cold condenser increase the rate of sublimation 24

25 Alternative Solvents Additional solvents can be used in freezedrying: Methanol, IPA, EtOH, Dimethyl Sulfoxide and t-butyl Alcohol* to enhance solubility and or decrease hydrolysis. These should be used with caution due to lowered freezing point, non-condensability, flammability, and residual solvent in the product. 25

26 Accurately and precisely measuring temperature and vacuum within a freezedryer is critical because these determine the relative rates of heat and mass transfer to and from the product which in turn determines the critical quality attributes and the efficiency of the process. 26

27 Temperature Sensors: Resistance Temperature Detectors (RTD s) Thermocouples Thermistors 27

28 Vacuum Sensors: Mercury Manometer Thermal Conductivity Gauge Mechanical Manometer Capacitance Monometer Pirani Gauge 28

29 Temperature Sensor Performance Characteristics Need to Consider Range Repeatability Accuracy Stability Linearity Interchangeability Response Time Ruggedness Economy 29

30 Resistance Temperature Detectors Temperature determined based on resistance changes in metals. Sensing element is a coil of wire (platinum, copper, or nickel) wrapped around a ceramic coated platinum tube. The entire unit is then covered with glass or ceramic. 30

31 The sensor is placed in a Wheatstone bridge circuit which compares the voltage drop across the measuring element with the drop across a standard resistor carrying the same current. The system has a fairly linear response over a wide temperature range (-200 to 600 C) 31

32 Advantages: RTD s Accurate Repeatable and Stable (NIST -260 to 630 C) High Output (High voltage drop vs. Temperature) Economical Many configurations (tape sensors for surfaces) 32

33 Disadvantages: RTD s Self heating Resistance decreases with temperature (decreased sensitivity at low temperatures can be overcome by using a 3-wire system) Result is an average over entire probe 33

34 Thermocouples Two wires of different metals joined at the ends form a circuit. The junction is exposed to different temperatures and an electrical potential (emf) develops which is directly related to the temperature difference and a current flow. Most widely used for industrial applications 34

35 Temperature/Vacuum Sensors 35

36 36

37 Thermocouples Type S R J T K E Materials Platinum-Platinum 10% Rhodium Platinum-Platinum 10% Rhodium Iron-Constantan Copper-Constantan (most widely used) Chromel-Alumel Chromel-Constantan (acceptable) 37

38 Thermocouples Advantages (compared to RTD s): Fast Response (thin wires = 2-3 msec) Rugged (mechanical shock) Wide Temperature Range Point Sensing Cost (cheap) Representative of Batch (no self-heating) Versatile (surface probes available) 38

39 Thermocouples Disadvantages (compared to RTD s): Less repeatable and less stable Non linear response (very sensitive to calibration) Accuracy (wider error limits) Only thermocouple wire may be used (expensive for remote locations) 39

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42 Thermocouple Placement Correct thermocouple placement is critical to for lyophilization cycle development and for systems using thermocouple driven primary drying endpoint detection Thermocouples should be just touching the bottom, center of vials. Tray drying should have probes distributed throughout the tray 42

43 Good Placement: Touching Bottom/Center of Vial Off Center Perfect Too High 43

44 Pressure/Vacuum Measurement As with temperature, accurate and precise pressure measurement is critical to freezedrying as both heat and mass transfer are affected by pressure. Beware that not all probes are created equal, and don t give the same information in the presence of water vapor (good and bad) 44

45 Mercury Manometer The mercury manometer is the most basic type of pressure measuring device providing a direct measurement of system pressure. This device is considered a primary standard; however, it is not used in modern commercial systems. 45

46 The McLeod gauge 46

47 Thermal Conductivity Gauge The conductivity gauge works based on the principal that energy is dissipated from a heated surface in a gas at low pressure by radiation and conduction. If constant energy is supplied to a filament placed in a low pressure gas, the change in surface temperature of the filament in response to pressure change can be measured with a thermocouple 47

48 Thermal Conductivity Gauge Energy loss due to conduction α = accommodation coefficient Λ M = Free molecular heat conductivity Pµ = Vapor pressure 48

49 Thermal Conductivity Gauge Energy loss due to radiation ε 0 /ε 1 = Emissivity heated surface/cold surface T 0 /T 1 = Temperature (Kelvin) heated surface/cold surface 49

50 Points to note: Energy loss by conduction increases linearly with pressure Energy loss from the filament due to radiation is infinitesimal compared to loss from conduction Free molecular flow: lower pressures ( μm) 50

51 Points to note: Requires a constant gas composition Platinum probes typical due to low ε Contamination/oxidation can increase ε Don t do well under CIP/SIP conditions* 51

52 Thermal Conductivity Gauge Sensitivity vs. Pressure Sensitivity Useful Region Log P (µm Hg) 52

53 Thermal Conductivity Gauge Is known as a Pirani Gauge when the change in resistance is monitored as a function of pressure, using a Wheatstone Bridge circuit and when the current is held constant 53

54 Capacitance Manometer With capacitors, the capacitance is directly proportional to the dielectric constant of the medium to that of air, and to a geometry factor. With a change in chamber pressure, a change in the geometry of the capacitance monometer occurs. If the dielectric constant is unchanged, vacuum levels can be calculated. 54

55 Capacitance Manometer A flexible metal diaphragm is placed between two fixed electrodes. The reference side is sealed under a fixed vacuum while the sample side is open to the sample chamber. As chamber pressure changes, the diaphragm deflects which changes the capacitance, which in turn changes the output voltage which is used to calculate pressure. 55

56 Capacitance Manometer 56

57 Capacitance Monometer Advantages: Independent of gas composition Good sensitivity over 0.1 to 1000 μm Hg Accurate to 0.05% to 3% of reading CIP and SIP acceptable models 57

58 Capacitance Monometer Disadvantages: Error from temperature effects Error from over-pressurization 58

59 Thank you. The next lecture in this series is April 11 th at 6:30 am & 10:00 am (NY time) Experts in Formulation, Lyophilization Cycle Design/Optimization, Thermal Characterization, and Education and Training in the Development of Injectable Drug Products and Diagnostics J. Jeff Schwegman, Ph.D. For more information about AB Biotechnologies and their services, go to 59

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