The Center for Professional Advancement Lyophilization Technology The theory and practice of freeze-drying of pharmaceuticals M. Kamat and M. Yelvigi The Center for Professional Advancement January 30-31, 2013 New Jersey, USA M. Kamat Jan, 2013

History Freeze-dried plasma/serum in WWII Even today: At-least 10 donors, 2 years RT, 200 mL water for constitution Bacteria/vaccines Food industry: coffee, fruits Military Rations/Astronaut Food/Hikers' food Museum articles Restoration of old artifacts (sunken ships, water-damaged libraries) M. Kamat Jan, 2013

M. Kamat Jan, 2013

Lyophilized Pharmaceuticals More than 140 lyophilized injectables Ampoules, syringes, vials, and large bottles > 30 biologicals, vaccines Freeze-dried skin grafts and tissues Quick-dissolve oral tablets (Claritin Reditabs) M. Kamat Jan, 2013

Definition Lyophilization is a coupled heat-mass-transfer process where the frozen solvent, usually water, is removed initially by sublimation under the conditions of reduced pressure and sub-zero temperatures, and then by desorption under the conditions of reduced pressure and above zero temperatures to yield a dry product. Whereas, freeze-drying may be defined as vacuum drying below 0 ºC (coffee, cereals, space food, animals etc.) Keywords: Required Undesirable Frozen Instability Sublimation Collapse/meltback Desorption Vial breakage Dry Product High moisture Reconstitution Problems We will use freeze drying and lyophilization as synonymous for this course M. Kamat Jan, 2013

Why Lyophilization of Pharmaceuticals Advantages: 1. Stability: Aqueous Stability To make sure that no more than 10% degradation in 2-4 years Thermal Stability : High temperature conventional drying may not be suitable 2. Improved Product Characteristics: Improved kinetic solubility (because of porosity and very large surface area) Usually freeze-dried product is amorphous Variable recon. volume to get conc. (SubC conc.?) 3. Other Advantages: Shipping advantage (low weight) Less interaction with primary package of highly alkaline solutions Less problems with glass delamination M. Kamat Jan, 2013

Why Lyophilization of Pharmaceuticals Advantages: cont. 4. Accuracy of dosage Ease of filling complex formulation as a solution Doses as low as 0.1 mL (vaccines, GF etc.) 5. Well controlled headspace Nitrogen, Argon (oxygen and some time Freon too) Vacuum Ease of Operation: Liquid filling operation: Automatic, accurate, well controlled (well established) In-line sterilization filtration in the final container M. Kamat Jan, 2013

Stability of Solution and Lyophilized Forms * From Package Insert Information M. Kamat Jan, 2013

If thermal stability is not an issue why not powder fill? API/Excipients substance need to be Sterile Handling: aseptic powder, bins, etc. Fill Accuracy <100mg powder filling (auger, piston) is difficult Particulate issues Dusting problem Environmental Factors: Humidity, Oxygen, Electrostatic Charge Powder Characteristics (difficult): Flowability and segregation Particle Size, PSD, blend uniformity, Bulk density, cohesiveness) Most of the large dose antibiotics (penicillins, cephalosporins) are powder filled in billions of quantities M. Kamat Jan, 2013

Disadvantage of lyophilization Additional unit process One more thing that can go wrong and that too irreversibly !!) Costly and complex equipment needing greater maintenance Transfer and scale-up issues compared to solution products Long cycles (up to even 7 days): Cleaning, sterilization, leak-testing may add another 24 hours M. Kamat Jan, 2013

Physical Chemistry of Lyophilization: Points to Consider : Behavior of water during freezing Heat Transfer Phenomenon Mass Transfer Phenomenon Coupling of Heat and Mass Transfer Requirements of Process M. Kamat Jan, 2013

Physical Chemistry of Lyophilization: Points to Consider Behavior of solutions during freezing Sublimation Process Heat Transfer Phenomenon Mass Transfer Phenomenon Coupling of Heat and Mass Transfer Requirements of Process M. Kamat Jan, 2013

Phase diagram of water Triple point Sublimation occurs between the solid and the vapor phase regions. Since only two phases are present (solid line), solid ice and the vapor ice are in equilibrium. The diagram also says that once Temp of ice is fixed, the vapor pressure over ice is automatically fixed, and vice-a-versa. M. Kamat Jan, 2013

Ref. point 1 mBar = 1000 µbar = 750 mTorr or 750 microns 0.33 mBar = 200 microns 1 atmosphere = 760 mm = 760,000 mTorr M. Kamat Jan, 2013

M. Kamat Jan, 2013

Energetic of Phase Change In Regular Evaporation Drying : Vaporization Liquid Water Water Vapor (Hvap) In Sublimation Drying (Lyophilization) Sublimation (no liquid) Ice Water Vapor (Hsub) M. Kamat Jan, 2013

Energetic of Phase Change Sublimation Drying (Lyophilization) Sublimation (no liquid) Ice Vapor state (Hsub) Sublimation involves solid, liquid, and gas transitions and need energy H2Oice (-40 C) H2Ovapor (25 C), Hsub 1. H2Oice (-40 C) H2Oice (0 C), H1 2. H2Oice (0 C) H2Oliq (0 C), H2 3. H2Oliq (0 C) H2Oliq (25 C), H3 4. H2Oliq (25 C) H2Ovapor (25 C), H4 Adding all these reactions, Hsub = H1 + H2 + H3 + H4 M. Kamat Jan, 2013

Heat Energy Must Be Provided for Sublimation to Continue: How much heat to be supplied ? 676 calories/gm of ice to be sublimed at ºC Latent heat of fusion (78 Calories) + Latent heat of vaporization (598 Calories) If excess heat (more than required for phase change) is supplied, the heat will be used to raise the temperature of the product (not just for phase change) and .....Eventually melt the ice. M. Kamat Jan, 2013

Probe in pot-full of water Boiling Water in Kettle Temp=100 C Temp= ~600 C Boiling Water (Phase Change) Temp= ~600 C Probe in pot-full of water on hot plate Probe in emptied pot on hot plate M. Kamat Jan, 2013

Heat Energy Must Be Provided for Sublimation to Continue: What is the heat source - From the heated shelves in the lyophilizer Chamber (some cases: ambient heat, IR, MW etc.) How to increase the rate of sublimation - Increase the driving force Increase the heat supply (shelf temperature) Increase the product temperature Limit: (maximum allowable temperature) For every 10 ºC rise in product temp, the rate of drying doubles M. Kamat Jan, 2013

Important The low pressure above the ice keeps the product frozen The heat is transferred into the Vial (Heat-Transfer) The water vapor is transferred out of vial (Mass-Transfer) The two transfer processes must be equal to keep the product frozen and sublimation process to continue M. Kamat Jan, 2013

The Water Vapor Is Transferred Out of Vial The vapor then flows out of chamber into the condenser section and gets deposited as ice on cold surfaces of condenser plates. In old times : chemical traps (P2O5, silica desiccants) (and in food industry) directly to the pump/ballast (and then oil change) The coldness of condenser does not affect the drying rate as long as it is colder than the product temperature Above certain temperature, though, the ice condensation power may decrease Very low condenser temperatures are not needed for sublimation to happen: Just collect the sublimate M. Kamat Jan, 2013

Heat Transfer Phenomena Flow of Heat : Heating Medium Shelf Interior Shelf Surface (thru the trays) Under the Vial Bottom Surface of Vial Bottom of Ice Through the Ice Sublimation Front Rate of heat input = Where,  is the thermal conductivity of the container, d is the thickness of the base of the container Ts = Shelf temperature Tc,i = Temperature at the ice interface M. Kamat Jan, 2013

Mass Transfer Phenomenon Vent We will discuss This later M. Kamat Jan, 2013

M. Kamat Jan, 2013

Heat and Mass transfer processes Energy (in) = Energy (out) (heat) (sublimation) Heat transfer rate = Hs X mass transfer rate Rate of heat input = Heat of sublimation X Rate of mass transfer M. Kamat Jan, 2013

Effect of Resistance to Mass Transfer M. Kamat Jan, 2013

Key Process Parameters Tp (product temperature): Keep the product below Tcritical Pc (chamber pressure): Keep sublimation process on Ts (shelf surface temp): Provide energy for sublimation M. Kamat Jan, 2013

Factors Which May Affect the Cycle Action Effect on Cycle Increase Product temperature Short Decrease dried product resistance Short (Freezing modifications) Use of Trays Long Better Contact of Glass Short Increase Chamber Pressure Short (Up to certain limits) M. Kamat Jan, 2013

Process Parameters Independent Parameters (all programmable variables) Not affected by the characteristics and the load of the product Shelf Temperature (fluid) Time Duration (soaks) Ramping Dependent Parameters (non-programmable variables) Affected by the characteristics and the load of the product Condenser Temperature Chamber Pressure Product Temperature Product drying Time M. Kamat Jan, 2013

Stages of Lyophilization Fill the solution in the vials. Place stoppers Freezing the product on FD Shelves Start Cooling the condenser Produce Vacuum in the dryer Open the isolation Valve Check Pressure and Heat the product Start Primary drying Continue with Secondary Drying End-of-Drying Stopper and Remove the Product QC Testing M. Kamat Jan, 2013

Schematics of a Lyophilizer From: Sundaram et al; BioPharm International, Volume 23, Issue 9, Sep 2010 M. Kamat Jan, 2013

Lyophilizer Chamber M. Kamat Jan, 2013

Lyophilizer Units Condenser Chamber Vacuum Pumps M. Kamat Jan, 2013

M. Kamat Jan, 2013

FREEZE DRYING OF COFFEE INVOLVES FOUR STEPS: Pre-freezing coffee concentrate (40-45%) up to -5/-10 °C followed by foaming. Freezing of the pre-frozen coffee liquor at -50 °C in a blast freezer. Sizing of the fr0zen coffee particles to a granular size of 3X3mm. Sublimation of the ice in a vacuum freeze dryer (VFD) under vacuum (0.5 torr) and controlled temperature. M. Kamat Jan, 2013