Supercritical Fluid (SCF) Drying of Pharmaceuticals Peter York Chief Scientist, CrystecPharma

Transcription

1 Supercritical Fluid (SCF) Drying of Pharmaceuticals Peter York Chief Scientist, CrystecPharma APS Focus Group Meeting, Loughborough 28 th January 2015

2 Presentation overview Introduction to SCF technologies Background to SCF particle formation Progress and current status of SCF for particle design for drug delivery systems Applications of SCF drying for biopharmaceuticals and water soluble drugs Summary

3 What is a supercritical fluid? p supercritical region solid liquid critical point Critical Point for CO 2 P= 73.8 bar T= 31.1 C gas T

4 Supercritical fluids Defined as a fluid at or above its critical pressure and critical temperature Unique set of properties High diffusivity, low viscosity and low surface tension (compared with liquids) Highly compressible (compared with ideal gas): thus large change in fluid density with small change in pressure gives highly controllable solvation power Many supercritical fluids are gases at ambient conditions, and create non-oxidising and/or nondegrading atmospheres (e.g. CO 2 )

5 Why supercritical carbon dioxide? Widely used in SCF manufacturing and processing (e.g. decaffeination of coffee) Critical point of 31.4 C and 73.8 bar Non-toxic, non-flammable Provides non-oxidising reaction atmosphere Highly selective Cheap Provides needed cleanliness for food and drug industries Opportunity for sterile processing

6 Particle formation options using SCF for particle design for drug delivery systems SCF AS SOLVENT - DRUG SOLUBLE IN SCF/INSOLUBLE IN WATER DRUG REDUCE TEMP SCF DRUG DISSOLVES AND PRESSURE, IN SCF DRUG PRECIPITATES SCF AS ANTISOLVENT - DRUG INSOLUBLE IN SCF AND WATER SCF SCF + ORGANIC SOLVENT DRUG IN ORGANIC SOLVENT SOLUTION DRUG PRECIPITATES

7 The SCF antisolvent (SAS) process Particle formation vessel at supercritical condition Drug solution in organic solvent contacts flow of SC-CO 2 Solvent rapidly extracted into SC-CO 2 Rapid precipitation of drug and particle formation (milliseconds) SC-CO 2 /solvent exits particle formation vessel Drug particles retained in vessel High yields (>90%) SCF process is inherently sterile Facile inclusion of functional excipients to feed lines Single step process from drug solution to dry drug/composite particles

8 Standard and SCF Processed Powders Standard Crystallization Powder SCF Processed Powders Crystalline powders (nano- to micron size)

9 Particle formation by SCF antisolvent processing Components Phase Behaviour SCF (typically CO2) Solvent(s) Solute (drug substance) (Additive(s)) COMPLEX!

10 Mass transfer limitations Changes in product morphology and residual solvent content with alternative processing pathways A A B B L V+L V residual solvent 133 ppm x(co 2 ) residual solvent 5885 ppm

11 Particle size control and uniformity for BCS Class II cardio-vascular drug

12 Bioavailability of BCS Class II NCE compound effect of surface area Micronised Starting material SCF material Surface area, m 2 /g SCF processed particles Size between 2-5 μm (VMD) Particle aspect ratio 2-3 Particle thickness < 1 μm Surface area can be altered by choice of solvent(s) and process conditions

13 Batch reproducibility particle size distributions Seven batches x50 1.9µm ± 0.1µm, VMD 2.2µm ± 0.1µm Excellent inter-batch reproducibility of particle size distributions

14 SCF particle formation rigs Crystec lab scale kit Small sample sizes at lab scale Scale up and tech transfer GMP plant/fda approved process and plant Pilot scale plant

15 SCF produced API for Semprana PK profiles of DHE in plasma following IV and inhaled administration 1 mg IV 0.88 mg dose 0.44 mg dose Repurposed drug - dihydroergotamine mesylate MDI product for rapid treatment of migraine via lung drug delivery Expected launch 2015 (Allergan/Actavis) Simplified MDI formulation with demanding particle size, solid state specifications

16 SCF as alternative drying technology for parenterals Single step SCF process is inherently sterile Facile inclusion of micro-filtration systems to feed lines Batch sizes from milligrams to kilograms Ultra-fine particles size/high surface area facilitates rapid dissolution on reconstitution Uniform inter-particle composition for multicomponent formulations Impressive batch-batch reproducibility SCF antisolvent process proven at scale and GMP

17 SCF drying of biopharmaceuticals and aqueous soluble drugs and additives Drug (and additives) requiring drying from aqueous solution(s) for parenterals Limited solubility of water in SC-CO 2 Complex multiphase phase behaviour Recovery of native state of macromolecules on reconstitution of dried powders in aqueous media Antisolvent principle is the preferred SCF option Considerable evidence of success, with reconstituted products exhibiting room temperature stability and full potency

18 Phase behaviour Isobaric isothermal phase tetrahedron Homogenous phases in white LV-equilibrium in blue SL- and SV-equilibria in pink SLV-equilibrium in orange Critical point, UCEP and LVtielines in red Process triangle with saturated solution as feed in grey Process line in purple

19 Modified SCF processing rig for processing biopharmaceuticals Organic solvent (e.g. EtOH) CO 2 Aqueous solution of biopharmaceutical (and adjuvant(s)) Particle Formation Vessel (at supercritical temperature and pressure) Product CO 2 + Solvent + [water] From knowledge of phase behaviour, can titrate levels of water remaining in powder particles

20 Additional features of SCF processing Benign, oxygen and light free process Minimal exposure of biopharmaceutical to organic solvent and rapid particle precipitation No air/liquid interfaces minimal material aggregation From milligram to kilo batch size Inherently sterile process, with additional options of sterile filtration of all feed lines SCF regarded as a green technology Rapid process with low energy costs

21 SCF drying of solutions of water soluble parenteral excipients Trehalose - changing SCF processing conditions to obtain different particle size of product

22 SCF processing of insulin Does the SCF process provide a free flowing powder with good solution reconstitution characteristics? Can macromolecular structure and potency be maintained? Study a range of different antisolvents Determine the effects of processing temperature and pressure on product quality

23 Insulin molecular structure Computer-generated image of six insulin molecules assembled in a hexamer, highlighting the threefold symetry, the zinc ions holding it together, and the histidine residues involved in zinc binding. Human insulin is a peptide hormone composed of 51 amino acids and has a molecular weight of 5808 Da.

24 Insulin SCF processing conditions Feed solution - 40mg/ml insulin in 20Mm HCl Optimal processing temperature and pressure 35 C; 100 bar Range of co-solvents studied EtOH, MeOH, Me 2 CO, IPA, DCM:EtOH mixtures Modified nozzle configuration co-solvent fed from additional feed line and / or pre-introduced into SCF carbon dioxide

25 SCF processed insulin Non agglomerated, free flowing 1 5 micron sized particles were obtained Particle size and morphology were affected by process conditions (temperature, pressure, antisolvent and insulin solution / anti-solvent flow rates) SCF processed insulin particles rapidly formed solution on reconstitution

26 Insulin - particle size data d (10%) d (50%) d(90%) Unprocessed SCF processed

27 SCF processed insulin potency and other chemical data Potency (U/mg) HMWP (%) A21 (%) Moisture (%) Zinc (%) Unprocessed SCF processed Target 27.5 <0.5 <1.0 <10.0 as unprocessed sample Peak assignment Unprocessed SCF Processed Total beta sheet character 16% 15% Total alpha helix character 61% 65% Total unassigned character 23% 20%

28 SCF processed human insulin summary Successful dry particle formation single step process from aqueous solution Free flowing 1 5 micron sized particles showed rapid solution formation on reconstitution Potency, structure and chemical integrity maintained at selected processing conditions Low temperature stability data match those of starting material

29 Plasmid DNA macromolecular structure Closed circle supercoiled Open circular Linear

30 SCF processing of plasmid DNA - influence of ph control supercoiled open circular linear % content unprocessed processed unbuffered ph control

31 Biotechnology-derived macromolecules successfully processed using SCF Albumin Antibody Fab fragments b-lactamase Catalase Deslorelin Insulin Leuprolide Lipase HGH Myoglobin Plasmid DNA Peptides (various) Antibiotics (various) Ribonuclease mab

32 Plasma-time profiles iv and MDI SCF processed co-formulated peptide particles Serum Leuprolide / ng ml IV bolus Inhalation IV bolus SCF drug formulation c max /ng ml ±1.2 T max /h ±0.4 AUC(0- )/ng h/ml 91±24 16±6 T 1/2 /h 3.5± ± Time / h Bioavailability of SCF processed drug in MDI: 17±3 %

33 Biopharmaceuticals - SCF processing opportunities SCF is a viable process alternative to existing process technologies for drying of aqueous solutions of biopharmaceuticals Provide dry free flowing particles with high yield Ability to tune particle size with narrow size distribution, and tune residual water content in powder product Ability to provide pure or composite forms (e.g. addition of stabilisers and / or coating material) SCF provides an environment where there is no surface tension SCF processed biomaterials exhibit low aggregation At optimal process conditions biomacromolecular integrity retained Potency, structure and chemical integrity Contact with organic co-solvent kept to a minimum Can introduce the bio-macromolecule in an aqueous feed SCF is a very good scavenger for the organic solvent-water mixture SCF offers a sterile, oxygen and light free processing opportunity

34 Summary SCF antisolvent based drug particle formation operating at scale GMP, and FDA approved process Viable alternative to current drying operations with distinct advantages Highly reproducible, high yield process Milligram to kilogram batches, nanometer to micron sized particles Proven success at particle design for preparing drug substances alone and co-formulated particles Suitable for small organic molecules and drying aqueous solutions of water soluble macromolecules

35 Thanks for your attention any questions?