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

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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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Thank you!

www.continuuspharma.cominfo@continuuspharma.com

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