innovation in continuous filtration, drying and ... · innovation in continuous filtration, drying...
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International Symposium on Continuous Manufacturing of Pharmaceuticals
Salvatore Mascia
Sep 27, 2016
“On-Demand Manufacturing of Pharmaceuticals”
Technology Innovation AwardFinalist 2013
Innovation in continuous filtration, drying and formulation of drugs
• 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:
• Tablets from extruded material
• Tablets from thin-films
• Tablets from electrospun fibers
• Benefits:
– 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
Introduction
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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
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Filter Side View
Filter Top View (camera)
Throughput: 10 g/hr to > 2 kg/hrResidence time: ~ 1 minFootprint: 60 cm x 40 cm
Continuous Rotary Filter
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• Condition 3 features an optimized use and distribution of wash solvent
• Yield = 97.4%
Continuous Filtration Data
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-filmwetcake (~ 1 mm thickness)
• Scale: Throughput: 10 g/hr to > 2 kg/hr (17 ton/year continuous duty)
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Drum Dryer
Image of Drum Gap
Throughput: 10 g/hr to > 800 g/hrResidence time: ~ 1 minFootprint: 60 cm x 60 cm
Continuous Drum Dryer
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• Starting [DMSO]Slurry = 7.36 wt%
• T = 55 °C
• Residence time = 1 min
• Pressure = ~ 365 Torr
0.0%
0.2%
0.4%
0.6%
0.8%
1.0%
0 10 20 30 40 50 60
[DM
SO] p
ow
de
r(w
t%)
Operation Time (min)
Continuous Drying Data
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Spec: NMT 2.0%
• Particle size reduction capability by adjusting drum gap
Continuous Drying Data
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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)
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Agglomerates
Solvent
Powder
(API+Excipient)
Granulation TabletCompaction
Drying
Dry Blending
Extrusion Molding
Advantages:
• Solvent free
• Even API distribution
• Reduced number of unit operations
Continuous Drug Product
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Extrusion-molding set-up
Tablets with 35%-50% API
XRPD after 3 months at 40C/75RH
Courtesy of NVS-MIT Center
0
0.1
0.2
0.3
0.4
0 2 4 6 8
a) b)
1 cm
C
t / h
Mascia et al., Angew. Chem. Int. Edn http://dx.doi.org/10.1002/anie.201305429 (2013)
API
Main Impurity in DP
0
4000
8000
12000
16000
0 10 20 30 40
T = 0T= 3 months
angle
Inte
nsi
ty
Continuous Melt-Extrusion and Molding
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Amorphous
Crystalline
1 2
3
Solution with polymer and API
• Tableting methods based on co-processing of API and polymers: Fast dissolving – appropriate for low bioavailability drugs Controlled-release formulations
Courtesy of NVS-MIT Center
CastingDrying
Continuous Drug Product from Solutions
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Electrospinning Tablets
10 µm
% Drug (Acm) Res Ethanol
40_Fiber <Detection Limit
50_Fiber <DL
60_Fiber <DL
70_Fiber <DL
Drug Loading on Fibers (PVP)
Lab Set-up
Electro-spun products9/29/2016 CONFIDENTIAL 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)
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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)
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