9th ANNUAL PHARMACEUTICAL

TECHNOLOGY SEMINAR 2017

NOVEL SYSTEMS FOR

CONTINUOUS GRANULATION
AND
ON-TABLET IMPRINTING
Jamie Frizzell
Technical Sales Manager
jamie.frizzell@freund-vector.com
 Continuous Manufacturing
• Engineering / Equipment Definition:
– Batch Manufacturing – All materials are charged
before the start of processing and discharged at the
end of processing.
 Continuous Manufacturing
• Batch manufacturing examples:
– Bin Blending

– Tablet Coating
 Continuous Manufacturing
• Batch manufacturing examples:
– Fluid Bed Drying
or Granulation

– High Shear
Granulation
 Continuous Manufacturing
• Engineering / Equipment Definition:
– Continuous Manufacturing – Material is
simultaneously charged and discharged from the
process.
 Continuous Manufacturing
• Continuous manufacturing examples:
– Continuous
Blending

– Continuous Direct Compression

• Continuous feeding / blending combined with
a tablet compression machine.
 Continuous Manufacturing
• Continuous manufacturing examples:
– Roll Compaction
(Dry Granulation)
 Continuous Manufacturing
• Regulatory Definitions:
– Batch – 21 CFR 210.3 – A specific quantity of a drug
or other material that is intended to have a uniform
character and quality, within specific limits, and is
produced according to a single manufacturing order
during the same cycle of manufacture.
– Batch refers to the quantity of material and does not
specify the mode of manufacture.
 Continuous Manufacturing
• Regulatory Definitions:
– Lot – 21 CFR 210.3 – A batch, or specific identified
portion or a batch, having uniform character and
quality within specified limits; or, in the case of a
drug product produced by continuous process, it is a
specific identified amount produced in a unit of time
or quantity in a manner that assures its having
uniform character and quality within specified limits.
– Definition of both “batch” and “lot” are applicable
to continuous processes.
 Continuous Manufacturing
• Why are these definitions important under cGMP?
– Laboratory determination of final specification for release
• 21 CFR 211.165(a) – For each batch of drug product, there shall be appropriate
laboratory determination of satisfactory conformance to final specifications for the
drug product. Prior to release.
– Documentation of Manufacturing
• 21 CFR 211.188 – Batch product and control records shall be prepared for each batch of
drug product produced and shall include complete information relating to the
production and control of each batch.
– Extended investigations of unexplained discrepancies
• 21 CFR 211.192 – The investigation shall extend to other batches…that may have been
associated with the specific failure or discrepancy.
– Recall situation
• 21 CFR 211.150(b) – Distribution procedures shall include…a system by which the
distribution of each lot of drug product can be readily determined to facilitate its
recall if necessary.
 Continuous Manufacturing
• Controlling product quality in CM
– Production time period (shift / day / week)
– Production variation (different lots of API /
excipients)
– Dependent on equipment cycling capability
• i.e. how long can equipment be operated continuously
before shutdown required
– Other definition?
 Examples of CM Products
• ORKAMBI® - Vertex Pharmaceuticals
– Cystic Fibrosis
• PREZISTA® - Janssen Pharmaceuticals
– HIV-1
• SEVERIN® N.F. – Chinoin Pharmaceutical
– NSAID
 Continuous Manufacturing
• Controlling product quality in CM
– By nature of the integrated process with fewer
steps, risk are reduced
– Quality by Design (QbD)
• Design based on thorough formulation and process
understanding
• Process understanding links manufacturing controls to
critical quality attributes (CQAs).
– Process Analytical Technology (PAT)
• a mechanism to design, analyze, and
controlpharmaceutical manufacturing processes through
the measurement of CriticalProcess Parameters (CPP)
which affect Critical Quality Attributes (CQA).
 Continuous Manufacturing
• Controlling product quality in CM
– Process Analytical Technology (PAT)
• A mechanism to design, analyze, and control
pharmaceutical manufacturing processes through the
measurement of Critical Process Parameters (CPP) which
affect Critical Quality Attributes (CQA)
• Traditional batch processes utilize analytical instruments
for controlling temperature, flow, pressure, etc.
• Continuous processes require more advanced tools to
provide continual feedback for analytical and control
purposes
 Continuous Manufacturing
• Process Analytical Technology (PAT)
– NIR (Near-infrared Reflectance)
– Moisture Measurement
• Based on the way in which water in the process interacts
with infrared light
• Measuring moisture content of granule in a wet
granulation process
• Measuring moisture content of granule in a drying process
 Continuous Manufacturing
• Process Analytical Technology (PAT)
– NIR Spectroscopy
• Absorbance / reflection of infrared light
– Absorbance spectra are used for the qualitative and quantitative
determination of product composition
• Measuring incoming material attributes
• Measuring incoming material blend uniformity
• Measuring granule content uniformity
 Continuous Manufacturing
• Process Analytical Technology (PAT)
– Raman Spectroscopy
• Relies on inelastic scattering (Raman scattering) of
monochromatic light, typically from a laser, in the visible,
near infrared or near ultraviolet range.
• Measuring film coating thickness
 Continuous Manufacturing
• Process Analytical Technology (PAT)
– Laser Diffraction Particle Size Measurement
• Measures the angular variation in intensity of light
scattered as a laser beam passes through a dispersed
particulate sample. Large particles scatter light at small
angles relative to the laser beam and small particles
scatter light at large angles
• Provides particle size distribution data in real-time.
 Continuous Manufacturing
• Process Analytical Technology (PAT)
– Examples of PAT Instruments
• NIR Moisture Measurement
 Continuous Manufacturing
• Process Analytical Technology (PAT)
– Examples of PAT Instruments
• Laser Diffraction Particle Size Measurement
 Continuous Manufacturing
• Freund-Vector Granuformer®
– Continuous Granulation System
 Continuous Manufacturing
• Freund-Vector Granuformer®
– Consists of:
• Powder Feeder/Blending System
• Twin-Screw Extruder with Liquid Introduction System
• Vertical Wet Mill
• Spiral Dryer
• Product Collection System (Cyclone)
• Onboard PAT
– NIR – Product Moisture
– Laser Diffraction – Particle Size Distribution
 Continuous Manufacturing
• Freund-Vector Granuformer®
 Continuous Manufacturing
• Freund-Vector Granuformer®
 Continuous Manufacturing
• Freund-Vector Granuformer®
 Continuous Manufacturing
• Freund-Vector Granuformer®
 Continuous Manufacturing
• Freund-Vector Granuformer®
– Onboard PAT

NIR Laser Diffraction

Moisture Particle Size
 Continuous Manufacturing
• Freund-Vector Granuformer®
 Continuous Manufacturing
• Freund-Vector Granuformer®
– Continuously Feeding Tablet Press
 On-Tablet Imprinting
• On-tablet imprinting – definition
– Printing a logo, drug name, dosage or image directly
onto the surface of a tablet
 On-Tablet Imprinting
• Tablet Imprinting Technologies
– Laser Etching
• Uses a UV laser in combination with UV-sensitive
pigments such as titanium dioxide
• Results in a single color (gray) printing / image
• Requires film coating solutions specially formulated for
printing
 On-Tablet Imprinting
• Tablet Imprinting Technologies
– Pad Printing / “Tampo”
• Ink is transferred to an etched printing plate which is then
“stamped” onto the tablets to imprint the image
• Typically limited to a single color ink
• Difficult to imprint uncoated tablets due to dust
 On-Tablet Imprinting
• Tablet Imprinting Technologies
– Gravure
• Ink is transferred to rotating cylinders or rolls instead of
linear, up/down pads
• Typically limited to a single color ink
• Difficult to imprint uncoated tablets due to dust
 On-Tablet Imprinting
• Tablet Imprinting Technologies
– Inkjet
• Ink is printed directly on the tablet with no direct contact
with tablet surface
• Multiple colors can be printed at the same time
• Uncoated tablets can be imprinted
 On-Tablet Imprinting
• Possible applications for tablet imprinting
– Tablet identification
• Company name / company logo
• Product name / dosage
• Unique identification for each strength
– Anti-counterfeiting measures
– Reduction of dispensing errors at hospitals /
pharmacies
On-Tablet Imprinting
 On-Tablet Imprinting
• Freund Tabrex Rev®
– Uses Inkjet Printing Technology
– Capacity 100,000 tablets per hour
– Capable of Imprinting Both Sides of Tablet
– Capable of Printing Multiple Colors
– Capable of Printing Bar Codes / QR Codes
– Capable of Printing on Tablet Edge
– Capable of Printing w/UV “Invisible” Inks
– Incorporates Complete Tablet Inspection System
 On-Tablet Imprinting
• Freund Tabrex Rev®
– Tablet Identification
• Reduces tooling cost – product name / dose can be
imprinted rather than embossed with tooling
• Simplify coating operations – rather than coating each
strength in a different color – strength can be imprinted
• Imprinting allows more complex designs compared with
traditional tooling
 On-Tablet Imprinting
• Freund Tabrex Rev®
– Tablet Identification
 On-Tablet Imprinting
• Freund Tabrex Rev®
– Anti-Counterfeiting Measures
• Imprinting technology difficult to reproduce
• UV “invisible” inks can be used so detail is only shown
under UV light
 On-Tablet Imprinting
• Freund Tabrex Rev®
– Reduction of Dispensing Errors
• Improved identification leads to reduction in errors
• Bar code / QR code can allow for identification by
scanning to ensure proper medication is being dispensed
 On-Tablet Imprinting
• Freund Tabrex Rev®
– Onboard Inspection System
• Improves product quality by rejecting tablets with either
compression or coating defects
• Ensures proper tablet imprinting by rejecting tablets with
printing defects
 On-Tablet Imprinting
• Freund Tabrex Rev®
– Serialization?
• Current serialization regulations require unique
identification at the packaging level
• Could the future require serialization at the dosage level?
• Continuous manufacturing could lead to this requirement
9th ANNUAL PHARMACEUTICAL
TECHNOLOGY SEMINAR 2017

QUESTIONS?

Jamie Frizzell
Technical Sales Manager
jamie.frizzell@freund-vector.com