On-Demand Manufacturing of Pharmaceuticals Innovation in continuous filtration, drying and formulation of drugs International Symposium on Continuous Manufacturing of Pharmaceuticals Salvatore Mascia Sep 27, 2016 Finalist 2013 Technology Innovation Award
Introduction There are examples of successful continuous manufacturing implementations Challenges for end-to-end integration (API+DP) still remain Novel solutions for continuous solid-handling steps, i.e. filtration and drying post API crystallization Opportunities to rethink about OSD forms using polymer: Benefits: Tablets from extruded material Tablets from thin-films Tablets from electrospun fibers Enabling Integration Reduce number of unit operations by eliminating corrective steps Effectively remove impurities and solvents, without API degradation Avoid particle agglomeration, eliminate solid-handling steps and improve mixing 9/29/2016 CONFIDENTIAL 2
Conventional Filtration/Drying Approaches Regular Nutsche filter units, Nutsche filter/dryer, agitated oven dryer, fluidized bed dryer Large units Thick wet cake Operate in batch/continuous Long residence time (potential for product agglomeration and degradation) Nutsche filter Fluidized Bed Dryer 9/29/2016 CONFIDENTIAL 3
Continuous Rotary Filter Filter Side View Throughput: 10 g/hr to > 2 kg/hr Residence time: ~ 1 min Footprint: 60 cm x 40 cm Filter Top View (camera) 9/29/2016 CONFIDENTIAL 4
Continuous Filtration Data Condition 3 features an optimized use and distribution of wash solvent Yield = 97.4% 9/29/2016 CONFIDENTIAL 5
Continuous Rotary Filter Highlights Solution: It addresses challenges in continuous solid-liquid filtration post-crystallization; it helps purge difficult to remove impurities Uniqueness: It features a unique design that generates a thin-film wetcake, very short residence time (~ 1 min) Limitations: Filters clog; CIP with solvents to avoid clogging. Manufacture of the filter disks is limited in size Market Differentiation: Truly continuous and portable filtration system requiring no scale-up from R&D to Manufacturing Driving Force: Vacuum driven filtration of an evenly distributed thin-film wetcake (~ 1 mm thickness) Scale: Throughput: 10 g/hr to > 2 kg/hr (17 ton/year continuous duty) 9/29/2016 CONFIDENTIAL 6
Continuous Drum Dryer Drum Dryer Throughput: 10 g/hr to > 800 g/hr Residence time: ~ 1 min Footprint: 60 cm x 60 cm Image of Drum Gap 9/29/2016 CONFIDENTIAL 7
Continuous Drying Data Starting [DMSO] Slurry = 7.36 wt% T = 55 C Residence time = 1 min Pressure = ~ 365 Torr 1.0% Spec: NMT 2.0% [DMSO] powder (wt%) 0.8% 0.6% 0.4% 0.2% 0.0% 0 10 20 30 40 50 60 Operation Time (min) 9/29/2016 CONFIDENTIAL 8
Continuous Drying Data Particle size reduction capability by adjusting drum gap 9/29/2016 CONFIDENTIAL 9
Continuous Drum Dryer Highlights Solution: It addresses challenges in continuous drying post-filtration; it helps with hard to remove solvents while operating at low T Uniqueness: : It features a unique design that generates a thin-film for fast drying. It combines drying and particle size reduction (if needed) Limitations: Slurry can drip between the rollers (careful start-up) Market differentiation: Truly continuous and portable drying system requiring no scale-up from R&D to Manufacturing; It dries pharmaceuticals within specifications in ~ 1 min, not hours Driving Force: Thin-film evaporation under application of vacuum and T. Thickness of 25-500 µm allows for effective evaporation of solvent Scale: Throughput: 10 g/hr to > 800 g/hr (~ 7 ton/year continuous duty) 9/29/2016 CONFIDENTIAL 10
Continuous Drug Product Solvent Drying Dry Blending Powder Granulation Agglomerates Compaction Tablet (API+Excipient) Advantages: Extrusion Solvent free Even API distribution Reduced number of unit operations Molding 9/29/2016 CONFIDENTIAL 11
Intensity Continuous Melt-Extrusion and Molding 16000 12000 XRPD after 3 months at 40C/75RH T = 0 T= 3 months 8000 4000 b) 0.4 0.3 0 0 10 20 30 40 angle API Extrusion-molding set-up C 0.2 Main Impurity in DP 0.1 1 cm Tablets with 35%-50% API 0 0 2 4 6 8 9/29/2016 CONFIDENTIAL 12 Courtesy of NVS-MIT Center Mascia et al., Angew. Chem. Int. Edn http://dx.doi.org/10.1002/anie.201305429 (2013) t / h
Continuous Drug Product from Solutions Tableting methods based on co-processing of API and polymers: Fast dissolving appropriate for low bioavailability drugs Controlled-release formulations Casting Drying Courtesy of NVS-MIT Center 1 2 3 Amorphous Solution with polymer and API Crystalline 9/29/2016 CONFIDENTIAL 13
Electrospinning Tablets Lab Set-up 10 µm Drug Loading on Fibers (PVP) % Drug (Acm) Res Ethanol 40_Fiber 50_Fiber 60_Fiber 70_Fiber <Detection Limit <DL <DL <DL 9/29/2016 CONFIDENTIAL Electro-spun products 14
Continuous Electrospinning Highlights Solution: it streamlines continuous manufacturing of OSD Uniqueness: Provides powder-free solid dosage forms with enhanced dissolution Limitations: maintain structural integrity of fibers during post processing; fibers formation depends on solution properties Market differentiation: powder-free continuous process for OSD with very uniform mixing and effective removal of residual solvent Driving Force: fiber production method which uses electric force to draw charged threads of polymers from solutions Scale: a single collecting electrode of 30 cm can produce 500 g/h or 12 kg/day (higher potential, increase width of collecting electrode, multiple units) 9/29/2016 CONFIDENTIAL 15
How should Companies Evaluate It? 1. Companies can not buy all interesting technologies 2. Identify targeted problems with current batch technology, e.g: Difficult to remove impurities or solvents Problem with continuous handling of post-crystallization material Unmet content uniformity and dissolution requirement Need for different characteristic of dosage forms 3. Run a laboratory evaluation 1. CONTINUUS has the technology and can run an evaluation for interested companies (no need to purchase the technology upfront) 9/29/2016 CONFIDENTIAL 16
Thank you! www.continuuspharma.com info@continuuspharma.com 9/29/2016 CONFIDENTIAL 17