Spray-drying Biotherapeutics

Transcription

1 Spray-drying Biotherapeutics Richard Kaye Investigator Product Development GSK R&D APS Freeze Drying and Alternative Drying Technologies for Parenterals Burleigh Court, Loughborough 28th January 2015

2 Contents 1. What is the spray-drying process? 2. Scalability of the spray-drying process 3. Why consider spray-drying for biopharmaceuticals? 4. Importance of process parameters 5. Formulation considerations 6. Issues to contemplate Presentation title 2

3 What is spray-drying? Schematic of a Buchi Spray Dryer Compressed gas Heating element Nozzle Product Drying chamber Filter Cyclone Aspirator Drip collector Collecting vessel

4 Contents 1. What is the spray-drying process? 2. Scalability of the spray-drying process 3. Why consider spray-drying for biopharmaceuticals? 4. Importance of process parameters 5. Formulation considerations 6. Issues to contemplate Presentation title 4

5 Scalability of the spray-drying process Lab scale Buchi spray-dryer

6 Scalability of spray-dryers Pilot scale GEA Niro SD Micro (e.g. PhI clinical manufacture) 6

7 Scalability PSD-1 Presentation title 7

8 Spray-dryer scale PSD-3 larger pharmaceutical applications Presentation title 8

9 Spray-dryer scalability Coffee production Presentation title 9

10 Spray-dryer scalability Mineral ore 10

11 Contents 1. What is the spray-drying process? 2. Scalability of the spray-drying process 3. Why consider spray-drying for biopharmaceuticals? 4. Importance of process parameters 5. Formulation considerations 6. Issues to contemplate Presentation title 11

12 Why consider spray-drying (Vs freeze-drying)? (This is a freeze-drying seminar) Similar ability to formulate for solid state stability Without need to consider frozen state properties Potentially more cost-effective (3-8x) Reduced plant foot print and cycle time hours Vs days Bulk production process Biopharmaceutical industry spent roughly $7.7 billion in 2011 on cold chain logistics* Particle engineering Powder production for filling, inhalation, encapsulation Small particle size/high surface area rapid dissolution Micro particulate formulations Less solution concentration critical Filtration process saving *Pharmaceutical Commerce s Biopharma Cold Chain Sorucebook, 4 th ed., is Published, Pharmaceutical Commerce April 17,

13 Contents 1. What is the spray-drying process? 2. Scalability of the spray-drying process 3. Why consider spray-drying for biopharmaceuticals? 4. Importance of process parameters 5. Formulation considerations Presentation title 13

14 Importance of process parameters Schematic of a Buchi Spray Dryer Compressed air Heating element Nozzle T in Product Parameters Inlet temperature (T in ) Aspiration/Chamber Gas Flow Atomisation Gas Flow Liquid Pump Drying chamber Filter T out Cyclone Aspirator Drip collector Collecting vessel

15 Temperature experienced by the product Inlet gas is applied to the product product does not initially experience a temperature increase due to the latent heat of evaporation As the particles dry, the temperature will increase, usually approximately to that of the outlet gas (may be higher for rapidly drying droplets Outlet temperature is governed by inlet temperature, gas flow/aspirator rate and liquid flow rate Important for thermally labile compounds... Also important not to exceed the Tg (sticky point) (see Ozmen & Langrish, 2002, 20:1177)

16 Spray-drying outlet temperature impact on a protein UV-detected protein content following dissolution of a spray dried formulation Vs spray-drying outlet temperature (~63% theoretical content) CLEAR CLOUDY 60 Assay Result from Filtered Solution (% of formulation) y = x x Spray Dry Temperature

17 Droplet size (atomisation gas/dispersion energy) Impact on particle size distribution Respirable or not Powder flow properties Surface area Surface area of drying droplet Niven et al., 1996, Int J Pharm 127:191

18 Drying behaviour of biopharmaceutical solutions Vehring et al (2007) applied the Peclet number to describe drying behaviour Pe (dimensionless Peclet number) K evaporation rate D diffusion coefficient There is reduced mobility (diffusion) with increasing molecular weight This results in biopharmaceutical proteins having a peclet number >1 Diffusion of solute is slower than shrinkage of the drying droplet leading to formation of shell crust Can be further exaggerated by surface activity Hollow particles Smooth/collapsed spheres But can be manipulated by drying rate

19 Effect of drying rate on particle morphology Rapid drying Slower drying

20 Contents 1. What is the spray-drying process? 2. Scalability of the spray-drying process 3. Why consider spray-drying for biopharmaceuticals? 4. Importance of process parameters 5. Formulation considerations 6. Issues to contemplate Presentation title 20

21 Spray-dried Formulation considerations Dehydrating proteins alone likely to cause denaturation/aggregation Sugar/Polyol excipient required as a water replacer form H-bonds with protein, holding it in stable conformation. For sugars with a high glass transition temperature (Tg) stabilisation by glassy immobilisation also possible Also recommended for success in the spray-drying process sticky point Choice of sugar: Lactose Sucrose Mannitol Trehalose Advantages Inhaled history, good aerosolisation, high Tg Non-reducing, suitable stabiliser in FD Good aerosolisation properties, non-reducing Very high Tg, non-reducing Disadvantages Reducing sugar Particularly Hygroscopic Lower Tg Low Tg, crystallises Not the best aerosolisation properties, Expensive

22 Formulation: how much excipient? Trehalose required to stabilise IgG (Andya et al. (1999) Pharm Res, 16:350): No more than 200:1 (trehalose:protein) for good aerolisation 100:1 sufficient to prevent aggregation 200:1 ~ 33:66 mass ratio

23 Formulation: how much excipient? Maury et al. (2005) Eur J Pharm Biopharm 59:251

24 Other excipients for consideration Surfactants likely to lead to particle agglomeration/poor powder properties (Adler & Lee, 1999, J Pharm Sci 88:199) Hydrophobic amino acids reduce hygroscopicity and improve aerosolisation properties (Seville et al., 2007, Powder Tech, 178:40) Salts increase density (Pulmatrix ) Polymers/lipids solvent solutions/emulsion/dispersion systems Modified release, drug delivery etc

25 Contents 1. What is the spray-drying process? 2. Scalability of the spray-drying process 3. Why consider spray-drying for biopharmaceuticals? 4. Importance of process parameters 5. Formulation considerations 6. Issues to contemplate Presentation title 25

26 Issues to contemplate (when considering spray-drying as an alternative to freeze-drying) Yield 70-80% at best Scale up by size or by replication? Downstream powder handling required Safety containment Hygroscopicity (humidity control?) Residual solvent (moisture) content Effect on Tg Temperature limitation may mean a compromise Static Aseptic processing Possible, but requires consideration Dissolution time?