Continuous Manufacturing of tablets with the help of PAT

1. .
Yash Suniel Nandwani
Production Manager,
Himalaya Meditek,
Dehradun
248001
+918411922060 | Email:yashnandwani@hotmail.com
With Application of Process Analytical Technology

2. INTRODUCTION
PROCESS METHODOLOGIES
TABLET MANUFACTURING
CONSIGMATM CONTINUOUS TABLETING
LINE
PROCESS ANALYTICAL TOOLS (PAT)
CASE STUDIES
SUMMARY
CONTINUOUS MANUFACTURING OF TABLETS
CONTENTS

3. Oral drug delivery: Most common route
of administration Ex-Tablets,
Capsules, Powders
Tablets are solid dosage forms
containing API and Excipient. Various
types are available
Unit dose, Precision drug delivery, Low
cost, Large scale manufacture and
special release profiles make it an
attractive dosage form
Of the top 20 selling prescription drugs
on a global basis in 2013,40%, were
tablets
The oral solid
dosage forms
market is
expected to
grow to about
126.8 kilo
tons in 2018.
INTRODUCTION
CONTINUOUS MANUFACTURING OF TABLETS
https://www.futuremarketinsights.com/reports/oral-soliddosagepharmaceuticalformulation market (Accessed on 15 November 2017).
1

4. Batch Manufacturing
PROCESSING METHODOLOGIES
CONTINUOUS MANUFACTURING OF TABLETS
http://www.cbinet.com/sites/default/files/files/Session%2010_Hancock_Sipe_pres.pdf (Accessed on 14 November 2017).
2
Fig. 1
Limitations
Benefits
Good for high
value products
Technology Available
Easily Regulated
Initial Cost of setup is
low

5. Continuous Manufacturing (CM)
CONTINUOUS MANUFACTURING OF TABLETS
CM
PAT
QbD
Equipment
CAGMP
CIP
SIP
Process
Intensification
Real time
Real Testing
End to End Production
Mindset of industry
Regulatory Environment
Cost Of Equipment
Integration i.e. API(1º) to Tablet(2º)
Less Information
CHALLENGES
TO CM
3
Michał Teżyk,et al. 2016. Drug Dev Ind Pharmacy, 42:8, 1195-1214

6. Flexibility
Recommended by
USFDA and ICH
Bioequivalent and
production
batches are
manufactured by
the same
production line
Decentralised
and
individualistic
More efficient
production able
to operate 24/7
No storage of
intermediates
required
Reduced floor
space and
investment
Faster response
to market
demands
Easy scale up
Less Energy,
Waste as well
as Labour
Advantages of Continuous Manufacturing
http://www.cbinet.com/sites/default/files/files/Session%2010_Hancock_Sipe_pres.pdf (Accessed on 14 November 2017).
4
CONTINUOUS MANUFACTURING OF TABLETS
Cont…

7. Dispensing/Feeding
Manual Loading of
API and Excipient.
Blending/Mixing to
ensure
homogeneity of
mixture
Coating of tablets
for protection
from environment
Granulation
which can be
dry/wet
Compression
using high speed
machinery
Sieving to obtain
correct particle size
distribution
TABLET MANUFACTURING- The conventional way
CONTINUOUS MANUFACTURING OF TABLETS
Allen L, et al. 2013. China:Lippincott William and Wilkins. p 90-257
Marshall K, et al. 1987. NewYork:Varghese Publishing House. p 293-343
5
Transfer
and
labour
delay
QC/QA
Testing
Delay
Slow
Process
QC/QA
delays
End Pt,
Off line
analysis
Cause
delay

8. Process Batch/Traditional Continuous/Mordern Modification
Granulation 1.RMG,MASS
MIXERS,Planetary,
Gral Mixer
2.Fluid Bed
Granulator
High-shear Bohle
Conti Granulator
(BCG®)
Niro and Glatt-Trough
Rounded Bed Type
Overflow system
incorporating powder
delivery by screw
conveyor and
pumping of liquid
granulating agent
along with agitation
Milling Conical screen
mills, Multi-mill
Combination milling Many mills combined,
Better PSD
Drying FBD, Tray Dryers Tunnel , Spray Drying,
Segmented Cell
Dryers
Faster movement
Blending Octagonal blender
Double Cone
MUNSON® Rotary
Continuous Mixer
No Labour required
Compression Single/Multi
station press
Fette Machine Complete Integration
Method Wet/Dry/Direct Plug and Play
Systems
Combination of all
Sieving Vibrosifters Alpine Jet Sieve Use of vacuum
Time to tablet 2-3hrs 20mins(GEA) Faster
Overview of equipment used in Batch vs. Continuous
CONTINUOUS MANUFACTURING OF TABLETS
6
Michał Teżyk,et al. 2016. Drug Dev Ind Pharm, 42:8, 1195-1214

9. Continuous Tableting Lines
ConsiGma™
GEA Pharma
PROMIS-line
University of
Eastern Finland
MODCOS
Fette Compaction
and Glatt
Product Company API Action
Prezista Janssen Darunavir Antiviral
Orkambi™ Vertex Lumacaftor
and ivacaftor
Cystic
Fibrosis
USFDA and EMA
Approved Products on
continuous lines
Only one continuously produced product Severin -
Nimesulide tablets by Chinion has been licensed, and is
available in the Mexican market
7
Michał Teżyk,et al. 2016. Drug Dev Ind Pharm, 42:8, 1195-1214
C-SOPS
Rutgers
University
ConsiGma™
GEA Pharma
PROMIS-line
University of
Eastern Finland
MODCOS
Fette Compaction
and Glatt

10. ConSigmaTM Continuous Tableting Line
Fonteyne M. 2014.Ghent University
CONTINUOUS MANUFACTURING OF TABLETS
8
Fig.2
Powder feeding
system
Twin screw granulator
Six-segmented fluid
bed dryer
Granule
conditioning
unit
Transfer
Line
Transfer
Line

11. »
CONTINUOUS MANUFACTURING OF TABLETS
1. Powder feeding system
Raw materials or API
are transferred through
vacuum conveyors into
LIW feeders. Mass
flow, speed and weight
are monitored
continuously.
LIW feeder
2. Twin screw granulator
Material undergoes extrusion
with the help of rotating screws
and kneading zones are
formed. Granules are
transferred to FBD
9
Fig. 3
Cont…
Fonteyne M. 2014.Ghent University

12. CONTINUOUS MANUFACTURING OF TABLETS
3.Six cell segmented fluid bed dryer 4.Granule conditioning unit
FBD
Wet granules into
cell 1
Drying time Clockwise
movement
Drying
Plate
(a) Product Control Hopper,
(b)PAT interfacing station,
(c) metering valve,
(d) Quadro comill U10, and
(e) milled product
buffer reservoir
(f) outlet valve.
10
Fig. 4
Cont…
Fonteyne M. 2014.Ghent University
Wet granule
tube rotates for
filling each cell
Outlet
Valve

13. CONTINUOUS MANUFACTURING OF TABLETS
5.Courtoy MODUL™ Rotary Tablet
Press
It works on the concept of
Exchangeable Compression Module
(ECM) which is a tightly closed
module contains all product contact
and format parts, isolating them from
the remainder of the machine. No
requirement of cleaning, therefore
changeover time is reduced
6. GEA Twin Drum
Coater
Plug flow / first-in-first-out
principle allows tracing of
product.
Short process times of a few
minutes
Homogenous Coating
Cascading movement and
enables greater fluid application
11
Fig. 5 Fig. 6
Cont…
Fonteyne M. 2014.Ghent University

14. According to FDA “PAT is a system for designing, analyzing, and controlling
manufacturing through timely measurements (i.e., during processing) of
critical quality and performance attributes of raw and in-process materials and
processes, with the goal of ensuring final product quality”.
PAT helps in achieving transition from batch to continuous manufacturing.
PAT
Multivariate
Tools
Process
Analyzers
At-Line
On-Line
In-Line
Process
Control
Knowledge
Managerment
SAMPLE
ISOLATED AND
ANALYSED
SAMPLE DIVERTED,
ANALYSED,
RETURNED TO THE
PROCESS
SAMPLE
ANALYSED IN
PROCESS
THROUGHOUT
PROCESS ANALYTICAL TECHNOLOGY (PAT)
CONTINUOUS MANUFACTURING OF TABLETS
Guidance for Industry PAT 2004. A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance.
12

15. In Blending
In Granulation
In Milling
In Compaction
In Drying
In Coating
In Packaging
Laser Light Diffraction
High Speed Imaging Camera
VisioNIR AS System
Dynamic Imaging Analysis
Spatial Filtering Velocimetry, Photostereo
Imaging and FTNIR
Light Induced Fluorecence
CONTINUOUS MANUFACTURING OF TABLETS
Process Analytical Technology Tools (PAT Tools)
Accoustic Emission in Chilsonator
13

16. Principle
Photon absorption by a molecule leads to
the promotion of an electron to an excited
state. Radiative relaxation is analyzed by
the detector.
Wired/Wireless signal
acquisition is triggered
by blender rotation and
blend uniformity is
assessed using tiered
criteria proposed by
USFDA
Measurement
50-60% small
molecule API exhibit
fluorescence
CONTINUOUS MANUFACTURING OF TABLETS
Light Induced Fluorescence
Shah IG, Stagner WC .2016. AAPS PharmSciTech 17(4):951-957
IN BLENDING
Fig. 7
14

17. 1. Spatial Filtering Velocimetry (Parsum™ Probe)
CONTINUOUS MANUFACTURING OF TABLETS
Burggraeve A et al. 2010. Eur. J. Pharm. Biopharm.76(1):138-146.
IN GRANULATION
Measurement: Parsum
probe is placed between
the sidewall of granulator
and outer part of spray.
An air connection is
used for sending
particles via aperture.
Principle: Patented
optic counting
principle which
projects laser beam
onto particles and
casts shadows onto
a array of optics.
Burst
signal
Second
Signal
Chord Length
Real Time Analysis
Fig. 8
15

18. 2. Photometric Stereo Imaging
(FlashSizerTM 3D)
Two Light
Souces
placed at
180º
Samples imaged
through a window and
images are captured
Resulting gradient
fields give info
about the surface
CONTINUOUS MANUFACTURING OF TABLETS
Soppela I et al.2011. Aaps Pharmscitech 12(2):476-484.
Cont…
Fig. 9
Fig. 10
16

19. CONTINUOUS MANUFACTURING OF TABLETS
Kumar V, et al.2013. AAPS PharmSciTech. 14(2):523-530.
17
Cont…
Principle
Chord length
determined by laser
beam which is reflected
back on contact with
particles until it reaches
opposite edge of
particle
Particle size determined using
distance between the two
edges and thousands of chord
lengths are acquired per
second.Probe is placed below
the mill and log channels are
used for a range 1-1000 µm
Measurement
Fig. 11

20. Principle
• NIR REGION:780nm-2526nm
• Different Modes are transmittance
and reflectance
• Water bands appear at 1940nm
• Fourier Transform: Fellgett and
Jaquinot advantages
• Probe placed at interfaces in the
FBG and InGaAS detector acquires
data which is interpreted
CONTINUOUS MANUFACTURING OF TABLETS
Gerald Rajan M et al.2010. American Pharmaceutical Review 13(6):128.
18
Cont…
Fig. 12
Fig. 13

21. Dynamic Imaging Analysis
(XPT and QICPIC SENSOR)
Principle:
Milled particles play an
important role in hardness,
content, uniformity, flow
and drug release. DIA
provides images of fast
moving particles and
sensitive to size and shape
characters. Projected area
and perimeter are
calculated.
• QICPIC- Particles flow
through image plane
and get separated due
to dispersion and
overlapping is avoided.
• XPT-Xenon Light
illuminates particles and
CCD acquires image in
sync.
CONTINUOUS MANUFACTURING OF TABLETS
Nalluri VR et al.2010. . Int. J. Pharm 391(1):107-114
19
IN MILLING
Fig. 14

22. Schematic representation of experimental device
(1) Piezoelectric sensor
(2) Preamplifier.
(3) Amplifier. (4) Events counter. (5) Oscilloscope control.
(6) Data acquisition
Acoustic Emission(AE) in Roller Compaction
AE is the phenomenon of
radiation of elastic waves in
solid when a material
undergoes irreversible
changes in internal structure
Souces are non stationary
dislocation and annihilation
process related to Frank-Read
source during plastic
deformation of crystals.
Represented by bursts on the
oscilloscope which counts
events occurring as a function
of time.
CONTINUOUS MANUFACTURING OF TABLETS
Hakanen A, Laine E. 1993.DRUG DEV IND PHAR 19(19):2539-2560
20
IN COMPACTION STUDIES
Fig.15

23. CONTINUOUS MANUFACTURING OF TABLETS
21
.
IN DRYING
Laser Light Diffraction
Principle
It utilizes
diffraction
patterns of laser
beam through any
object to measure
size of particles.
Theories of
laser
diffraction
Fraunhofer
Theory
𝑰𝒏𝒕𝒆𝒏𝒔𝒊𝒕𝒚 𝒐𝒇 𝒍𝒊𝒈𝒉𝒕
∝ 𝑷𝒂𝒓𝒕𝒊𝒄𝒍𝒆 𝒔𝒊𝒛𝒆
And
𝑨𝒏𝒈𝒍𝒆 𝒐𝒇 𝒃𝒆𝒂𝒎
∝
𝟏
𝒑𝒂𝒓𝒕𝒊𝒄𝒍𝒆 𝒔𝒊𝒛𝒆
Mie’s Theory
Light
intensity
distribution
can be used
to calculate
particle
sizes.
Applicable
to < 𝟓𝟎µ
Installed in exit line
to measure entire
flow in its “in
process state with
no sample
preparation.

24. High Speed Imaging Camera (Eyecon™)
Naidu VR, Deshpande et al.2017. Pharmaceutical development and technology:1-6.
• Wurster Process is a common method
for coating.
• EyeconTM is a imaging system that
generates real time on screen images in
the range of 50-300µ
• Use of LED’s from different angles
which aids in development of a 3D
orientation after which surface height
maps are developed.
• Aspect ratio and Sphericity is
determined using Dmax and Dmin
• Values calculated every 30mins to
calculate the radial coating thickness of
particles.
CONTINUOUS MANUFACTURING OF TABLETS
22
Fig.17
IN COATING

25. .http://www.gea.com/en/binaries/Successful%20Tableting%20Supplement_tcm11-31710.pdf Accesed on:15/11/2017
Tablet
colour,
position ,
geometry
on
packaging
lines are
important
in
detecting
defects
Each
tablet is
targeted
with a
spot light
Reflected
Radiation
is sent to
the diode
array
detector
Spectral
chart is
prepared.
100%
inspection
is possible.
Product
compositi-
on is also
determined
CONTINUOUS MANUFACTURING OF TABLETS
23
Fig.18
IN PACKAGING
VisioNIR™ AS System- Combination of
High Resolution Imaging + NIR

26. » NIR transmittance and reflectance spectroscopy is used in content
uniformity testing.
» Transmission spectra of tablets with different amounts of drug are
calculated. The various peaks determined the amounts of API present.
Moes JJ et al.2010. Int. J. Pharm 357(1):108-118.
CONTINUOUS MANUFACTURING OF TABLETS
24
Fig.19
CASE STUDIES

27. Compaction pressure affects the hardness, dissolution and disintegration of
tablets. It also affects the API release rate. As the compaction pressure
increases from 74Mpa, 111Mpa, 148Mpa, 222Mpa up to 370Mpa, it causes a
shift in NIR bands
Moes JJ et al.2010. Int. J. Pharm 357(1):108-118.
CONTINUOUS MANUFACTURING OF TABLETS
25
Cont…
Fig. 20

28. Particle size distribution can also be studied using NIR spectra.
The absorbance of NIR can be correlated to the particle size which
varies in a proportional manner
Blanco M et al.2010. Journal of pharmaceutical and biomedical analysis 51(4):797-804.
CONTINUOUS MANUFACTURING OF TABLETS
26
Cont…
Fig.21

29. CONTINUOUS MANUFACTURING OF TABLETS
27
• PAT can be considered as the heart of continuous
manufacturing in today’s scenario with increasing sales of
medicines and the consequent high demand
• Along with Qbd , DOE, CMC and RTRT, PAT can play a link to
integrate the complex functioned processes in a tableting line
• A few challenges such as fouling of probes while handling
powders is quite common. Solutions to it are the FBRM probe
with scraper as well as Parsum with an air purge
• Continuous Manufacturing of tablets is certainly possible and it
is high time that we do away with the traditional methods with
the basic goal of achieving quality in product by combining hi-
tec equipment and technology
SUMMARY