1.  Lee, Spray Drying Proteins, Breckenridge, July 2004 Spray Drying of Proteins Geoffrey Lee  Spray drying (SD) of protein-containing systems is not new !  Applications of SD of proteins: - inhaleable powders; - injectable powders; - stable, flowable storage-form for bulk protein.  Other considerations apply compared with freeze drying (FD) of proteins: - effects of atomization of liquid feed; - effects of thermal stress; - question of dry powder yield.

2.  Lee, Spray Drying Proteins, Breckenridge, July 2004 Feasibility of spray drying a protein 1.Product quality (peptide/protein) investigated by: - activity loss (enzymes) - change in aggregation status (HPLC, SEC) - alteration in FT-IR amide bands 2.Formulation measures: - disaccharides to improve process and/or storage stability (sorbitol versus trehalose) - residual moisture & T g measurements 3.Example I: model protein trypsinogen (Tzannis & Prestrelski, 1999 ) - ca 15 % activity loss on SD at T in /T out = 110 o C/70 o C - ca 20% loss of monomer (SEC) 4.Example II: IgG (AMG162) (Maury et al, 2004) - ca 15% increase in total aggregates on SD at 130 o C/90 o C - reduced to 1% increase with IgG/sorbitol (66:33) 5. Example III: peptide 1.7 kDa - monomer: 98.54  98.51 on SD at 130 o C/95 o C

3.  Lee, Spray Drying Proteins, Breckenridge, July 2004 Potential sources of protein damage Liquid feed Nozzle Atomizing air Drying tower 1. Adsorption 2. Shearing forces 3. Liquid/air interface expansion 4. Thermal stress Drying air

4.  Lee, Spray Drying Proteins, Breckenridge, July 2004 The 2 periods of droplet drying Constant-rate phase T = approx. T wetbulb Critical point Falling-rate phase T  T outlet Various morpholgies Spray dryer typeDroplet diameter [µm]  constant-rate [s]  falling-rate [s] Micro-Laboratory (Büchi)  10 µm 0.0010.002 Pilot maschine100 µm0.040.1 eg, T inlet /T outlet = 130 o C/90 o C Residence time: 1s – 25s

5.  Lee, Spray Drying Proteins, Breckenridge, July 2004 Assumption: Gibbs adsorption isotherm holds ! Dynamic adsorption kinetics of trypsinogen at air/water-interface After 1s  = 14 – 19 mg/m 2

6.  Lee, Spray Drying Proteins, Breckenridge, July 2004 AtomOCN BSA/Trehalose (5:95)37.6 %56.6 %5.9 % Pure Trehalose (ESCA)46.752.90 Pure BSA (ESCA)23.062.614.4 Surface composition (BSA/treh)38:6235:6541:59 Surface composition of spray dried trehalose/BSA (95:5)

7.  Lee, Spray Drying Proteins, Breckenridge, July 2004 Effects of polysorbyte 80 on surface composition of spray dried trehalose/BSA (95:5)

8.  Lee, Spray Drying Proteins, Breckenridge, July 2004 Single droplet drying levitator Acknowledgement: Niro Copenhagen !

9.  Lee, Spray Drying Proteins, Breckenridge, July 2004 Single droplet drying levitator

10.  Lee, Spray Drying Proteins, Breckenridge, July 2004 Single droplet drying levitator 1.Variable drying air temperature & humidity 2. Droplet size can be varied in ultrasonic field largest levitatable D = 2/3 ; optimal D = /3 58 kHz levitator ( amb = 5.9 mm): 2500 – 15 µm 3. Relative velocity conditions (droplet/drying air):  during SD, rel is low for most of residence time R ed (droplet/air)  1000  much higher in droplet deceleration phase R ed in levitator chamber adjustable via : D [mm]R ed (max) U air (max) 0.895849 682 0.985912 666 1.060960 651 (Source: Yarin A, et al., Phys. Fluids, 9, 3300-3314 (1997))  at very low rel, boundary layer theory applicable: Nu = Sh = 2 = questionable because of acoustic steaming !

11.  Lee, Spray Drying Proteins, Breckenridge, July 2004 Single-droplet drying kinetics of trehalose (10%)

12.  Lee, Spray Drying Proteins, Breckenridge, July 2004 Single-droplet drying kinetics of trehalose (10%) I II III IV

13.  Lee, Spray Drying Proteins, Breckenridge, July 2004 Single-droplet drying kinetics of trehalose (10%)

14.  Lee, Spray Drying Proteins, Breckenridge, July 2004 Single-droplet drying kinetics of BSA (10%)

15.  Lee, Spray Drying Proteins, Breckenridge, July 2004 Single-droplet drying kinetics of treh/BSA (9:1) (10%)

16.  Lee, Spray Drying Proteins, Breckenridge, July 2004 Constant-rate drying period: d 2 law t/r 0 2 [s/  m 2 ] r(t) 2 /r 0 2 1.0 0 = -  v [  m 2 /s]  v = Evaporation coefficient [µm 2 /s] sphere ; T constant; no convection; saturtated p v at surface; stready state vapor diffusion

17.  Lee, Spray Drying Proteins, Breckenridge, July 2004 Constant-rate drying period: evaporation coefficients & the problem of droplet surface temperature

18.  Lee, Spray Drying Proteins, Breckenridge, July 2004 Constant-rate drying period: evaporation coefficients & Sherwood number

19.  Lee, Spray Drying Proteins, Breckenridge, July 2004 SPRAY DRYING OF PROTEINS 1.Damage to proteins can occur in both phases of droplet drying: - constant rate phase: large  in ms frame; - falling-rate phase: thermal effects. 2.Single-droplet drying levitator can be used to examine particle formation in real time: - shows build-up of particle morphology; - gives continual measure of momentary drying rate before & after critical point. www.pharmtech.uni-erlangen.de