0.0 0.1 0.2 0.3 10 12 14 16 18 20 22 C"PEAK /pF Time /h Primary drying 0.244 pF ≡2 g water Drying rate (dm/dt) ~ 0.3 g/h DRIED PRODUCT RESISTANCE (RP) DETERMINATION o C"PEAK from TVIS is proportional to the amount of ice; therefore it is estimated for drying rate (dm/dt) o Partial pressure of ice (PICE) and condenser (PCONDENSER) calculated from temperature of ice (TICE) and condenser (TCONDENSER) by using Clausius- Clapeyron derived equation -70 -60 -50 -40 -30 10 12 14 16 18 20 Temperature/oC Time / h Temperature of ice (TICE) Temperature of condenser (TCONDENSER) Shelf temperature (TSHELF) The Application of Through Vial Impedance Spectroscopy (TVIS) for Optimization Freeze-Drying Process Yowwares Jeeraruangrattana and Bhaskar Pandya Leicester School of Pharmacy, Faculty of Health and Life Sciences, De Montfort University Supervisors: Professor Geoff Smith and Dr Irina Ermolina TVIS TECHNOLOGY In-line monitoring system for the freeze drying process consisting of: oFreeze-drying vial with external electrodes oPass through for cabling oExternal Impedance spectrometer. TVIS TECHNOLOGY PRINCIPLE Process analytical technology based on impedance spectroscopy o Electrical impedance determines the ability of materials to conduct electricity under an applied voltage . o Impedance is a function of dielectric and conductive properties and therefore the physical state of vial and its contents. o Principal parameter effecting measured impedance is resistance/conductivity of sample within the vial. o Changes in electrical parameters mirror the condition of the sample throughout the lyophilisation process. o The capacitance spectrum is related to the resistance/ conductivity and capacitance of the vial contents. o Data viewing software (LyoView ™) identifies the peak frequency (FPEAK) and the peak amplitude (CʺPEAK) in the imaginary part of the capacitance spectrum o FPEAK can be used to monitor phase behaviour (ice formation, glass transitions) and product temperature o CʺPEAK can be used to monitor the amount of ice remaining during primary drying, from which the drying rate and the end point may be determined. TVIS ADVANTAGE 1.Non-invasive, real time full cycle lyophilisation monitoring including : o Cooling rate, Freezing and Annealing o Primary and Secondary Drying end point 2. Optimization of the primary drying process by: o Heat Transfer Coefficient (KV) Determination o Dried Product Resistance (RP) Determination 3. Can be applied in standard freeze dryers 4. Integrated, bench top, single vial, TVIS enabled analytical freeze dryer “Non-invasive, real time lyophilisation process monitoring would increase process understanding and accelerate development of stabilized biopharmaceutical formulations at room temperature.” 101 102 103 104 105 106 -0.5 -0.4 -0.3 -0.2 -0.1 0 Frequency (Hz) C'' / pF Freezing 24.1 oC 12 oC -5.7 oC -24.3 oC 101 102 103 104 105 106 -0.3 -0.2 -0.1 0 0.1 Frequency (Hz) C'' / pF 11 h 12 h 13 h 15 h 14 h 17 h 16 h 18 h 19 h Primary Drying TVIS APPLICATIONS HEAT TRANSFER COEFFICIENT (KV) DETERMINATION o The product temperature (TPRODUCT) derived by TVIS is one of the parameters needed for KV determination o Sublimation rate or drying rate (dm/dt) is estimated by TVIS 𝐾𝐾𝑉𝑉= 𝑑𝑑𝑚𝑚 𝑑𝑑𝑑𝑑× 2844 𝐽𝐽ȉ 𝑔𝑔−1 0.00045𝑚𝑚2 𝑇𝑇𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆−𝑇𝑇𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃 TPRODUCT and dm/dt from TVIS KV determination 0.00 0.02 0.04 0.06 0.08 0.10 10 12 14 16 18 20 Drying rate (g/h) Time /h RP determination 𝑅𝑅𝑝𝑝= 𝑃𝑃𝐼𝐼𝐼𝐼𝐼𝐼−𝑃𝑃𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶 𝑑𝑑𝑚𝑚 𝑑𝑑𝑑𝑑 ȉ 3.8 𝑐𝑐𝑐𝑐2 0 10 20 30 40 50 60 70 0 10 20 30 40 50 60 70 80 0 30 60 90 Heat radiation (% of total heat transfer) Over all heat transfer Coefficient (O.H.T.C) (w/m-2k-1) Pressure (Pa) O.H.T.C (water exp.) O.H.T.C (ice exp.) Heat radiation (water exp.) Heat radiation (ice exp.) Kv from TVIS dm/dt from TVIS Figure 2. KV values for 10 mL tubing vials (Brülls et al. 2002) Kv from TVIS = 37 Figure 3. The ratio of Rp and dry thickness as the function of dry thickness References 1. BRÜLLS, M. and RASMUSON, A.