On-Demand Manufacturing of Pharmaceuticals

Transcription

1 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

2 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

3 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

4 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

5 Continuous Filtration Data Condition 3 features an optimized use and distribution of wash solvent Yield = 97.4% 9/29/2016 CONFIDENTIAL 5

6 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

7 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

8 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% Operation Time (min) 9/29/2016 CONFIDENTIAL 8

9 Continuous Drying Data Particle size reduction capability by adjusting drum gap 9/29/2016 CONFIDENTIAL 9

10 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 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

11 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

12 Intensity Continuous Melt-Extrusion and Molding XRPD after 3 months at 40C/75RH T = 0 T= 3 months b) angle API Extrusion-molding set-up C 0.2 Main Impurity in DP cm Tablets with 35%-50% API /29/2016 CONFIDENTIAL 12 Courtesy of NVS-MIT Center Mascia et al., Angew. Chem. Int. Edn (2013) t / h

13 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 Amorphous Solution with polymer and API Crystalline 9/29/2016 CONFIDENTIAL 13

14 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

15 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

16 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

17 Thank you! 9/29/2016 CONFIDENTIAL 17