Continuous Manufacturing &
Process Analytical Chemistry Environmental Contributions
Rodolfo J. Romañach, Ph.D.
Department of Chemistry
Recinto Universitario de Mayagüez
rromanac@yahoo.com
rodolfoj.romanach@upr.edu
Inter-American
University, San Germán
October 22, 2012
ENGINEERING RESEARCH CENTER FOR
STRUCTURED ORGANIC PARTICULATE SYSTEMS
RUTGERS UNIVERSITY
PURDUE UNIVERSITY
NEW JERSEY INSTITUTE OF TECHNOLOGY
UNIVERSITY OF PUERTO RICO AT MAYAGÜEZ
10/11/2005
1
“Drug Substances in their purified state usually
exist as crystalline or amorphous powders or as
viscous liquids. The majority of drug substances
exist as white or light-colored crystalline powders.
Although drugs were dispensed as such in powder
papers as recently as several decades ago, this
practice is virtually unknown in pharmacy practice
today. With the possible exception of the
anesthetic gases, all drugs in legitimate
commerce are now presented to the patient as
drug products.”
Modern Pharmaceutics, Third Edition, Volume 72 Drugs and the Pharmaceutical Industry, Ed. G.S.
Banker and C.T. Rhodes, Marcel Dekker, 1995, page 14.
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Formulation Examples
• A CT Halcion tablet has about 0.125 mg of
drug substance (API), but weighs about
100 mg.
• An CT Ibuprofen tablet will have over 70%
(w/w) drug substance content.
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Development of a New Drug Product
Pharmaceutical scientists contribute to the evaluation of the
safety and medical utility of drug candidates, and the
industrialization (manufacturing) of approved drugs.
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A Drug Delivery System
Modern Pharmaceutics, Third Edition, Volume 72 Drugs and the
Pharmaceutical Industry, Ed. G.S. Banker and C.T. Rhodes, Marcel Dekker,
1995, page 15.
5
Common Unit Operations in Pharmaceutical
Manufacturing (Preparation of Drug Products)
•
•
•
•
•
•
Milling
Blending (Mixing)
Granulation
Lyophilization
Tablet compression
Sterilization
These occur during box (lots are manufactured) in next
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diagram.
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30 cubic feet V-blender Courtesy of Mova Pharmaceuticals.
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R.J. Romañach, “Pharmaceutical Analytical Chemistry: Bringing the Pharmaceutical
Industry to the Classroom”, Journal of Process Analytical Technology, 2004, 1(2), 19 –
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Batch Manufacturing Process Flow
Intragranular materials
dispensing and screening at
Pharmacy area
API addition
to the IBC with
intragranulars
Initial blend &
lubrication
Roller compaction
Extragranular
addition,
blending and
lubrication
Final blend
Compression
Tablet bins
Coating
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Environmental & Economic Consequences of
Batch Manufacturing
Environmental
• Need large manufacturing
areas, different rooms for
the equipment used.
• May need areas for
different sizes of the same
equipment or need a
storage area.
• The equipment are shared
between different
processes – requiring
cleaning.
• May produce more product
than needed.
Economic
• Energy costs.
• Cleaning costs.
• Cost of maintaining a sate
in-doors environment.
• Efforts to maintain
pressure differences
between areas.
• Cost of storage of
equipment.
• Cost of products stored.
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Continuous Manufacturing
You will have orange juice as long as
you continuously feed oranges.
You decide how much orange juice
you need.
Photo used for educational
purposes
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Batch Manufacturing
•Always work with 100,000
oranges.
•The juice is accumulated
at evaporator, which is
large and does not work
well with less than 100,000
oranges.
• Blender , freezers, and all
other parts also require a
minimum of 100,000
oranges.
•Total amount of juice
passed from one part to
the other.
http://foodmapper.wordpress.com/2008/04/16/when-local-doesnt-work-orange-juice
Used for educational purposes
/
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Continuous Mixing Process
Continuous – there is no
accumulation of mass within
system. The material is mixed and
volume in the mixer is maintained by
equal amounts of materials that are
introduced by feeders.
P.M. Portillo , M. Ierapetritou, F.J. Muzzio,
Powder Technology 182 (2008) 368–378.
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Definition of lot
• Lot specific quantity produced expected to have uniform
properties. cGMPs 210.3 definition #10.
• (10)Lot means a batch, or a specific identified portion of 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.
• (11)Lot number, control number, or batch number means
any distinctive combination of letters, numbers, or symbols,
or any combination of them, from which the complete
history of the manufacture, processing, packing, holding,
and distribution of a batch or lot of drug product or other
material can be determined.
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15
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Beginning of blending process, blades can
be seen (not at steady state).
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Monitoring of Continuous Mfg. Process
APAP %
(w/w)
Mean
(%)
Standard
Deviation
2
1.42
0.15
3
3.00
0.20
6
6.85
0.64
8
8.36
0.50
10
10.11
0.29
Each NIR scan interacting with about 260 mg sample.
RMSEP ≈ 0.34 % (w/w).
Each measurement every 0.5 secs.
Chemical Engineering Science, 2010, 65(21), 5728 – 5733.
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Design, Analysis & Control of Mfg
with measurements obtained during
processing for critical quality and
In-line
performance attributes
of raw and in process
On-line materials to ensure final
product quality
Off-line
At-line
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Analytical Methods
 Majority will be in-line or on-line methods,
that do not require sample preparation.
 In-line methods monitor the process as it is
occurring, and the sample is not removed
from the process stream.
 On-line methods – a sample is diverted from
the manufacturing process but may returned.
 Near line – sample is taken to an analytical
instrument located near process line.
 Off-line – remote lab, current system.
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Process Analytical Chemistry (PAC)
PAC is a branch of Analytical Chemistry dedicated to
obtaining real time quantitative and qualitative information
about a chemical process.
to monitor and control a process
efficient use of energy, time and raw material
Callis, Illman, Kowalsky. Process Analytical Chemistry. Analytical Chemistry. Vol 59(9). 1987
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PAT & QbD in the Manufacturing Process
Raw
Material
Range
Process
Monitoring
& Control
Final Product
Variation in Raw Materials is expected and understood.
Process Provides a Design Space or Boundaries for Raw
Materials.
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Roller Compaction
• Force fine powders
into two counter
rotating rolls. As the
volume decreases
through the region of
maximum pressure,
the material is
formed into a solid
compact or sheet.
To visualize see:
http://www.fitzmill.pharmaceutical/dry_granulation/dry_granulation_pharma.html
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Roller Compaction
Material for Milling
Adapted from Alexanderwerk Roller Compaction Presentation,
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Advantages of Roller Compaction
• Powder densification without need for drying vs. wet
granulation.
• Eliminates aqueous degradation (some compounds
not stable in water).
• Facilitates powder flow
• Facilitates a continuous powder manufacturing
process.
Based on presentation by Garnet Peck, Near Infrared Monitoring of
Roller Compaction, Garnet Peck Symposium, Purdue University, 2006.
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Densification in Roller Compaction
The volume of material in Vα must be reduced to Vθ, requiring
that the bulk densities (γα and γθ) and volumes be related.
R.W. Miller and P.J. Sheskey, Roller Compaction Technology for the
Pharmaceutical Industry, Handbook of Pharmaceutical Technology.
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D. Acevedo, A. Muliadi, A. Giridhar, J.D. Litster, R. J. Romañach,
AAPSPharmscitech, DOI: 10.1208/s12249-012-9825-0.
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NSF Engineering Research Center for
Structured Organic Particulate System
(http://ercforsops.rutgers.edu/)
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Engineering of Pharmaceutical Materials
& Processes
Given active organic substances & administration/delivery
requirements, have integrated framework with predictive models to
systematically design:
Particles (Material)
Composite
Product
(Manufacturing
Science)
With a minimum number of supportive experiments !!
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UPRM-Resources for Pharmaceutical
Industry

Dr. Carlos Velazquez (Chemical Engineering)
carlos.velazquez9@upr.edu – heat transfer, mass transfer,
control strategies, pharmaceutical blending, control of wet
granulation.

Dr. Rafael Mendez (Chemical Engineering) – powder
technology.

Dr. Aldo Acevedo (Chemical Engineering) - Electrorheological
fluids; complex fluids; rheology.

Dr. Madeline Torres (Chemical Engineering) - Biomedical
Engineering, Materials, and Polymers. Teaching Interests:
Polymers, Thermodynamics.
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Test Bed 2: Manufacture
of Strip Film Unit dosage
Goal: Develop the scalable methods, experimental setups and material
knowledge base for forming films loaded with engineered particles of
sub-micron and low micron size to achieve desired delivery
properties
Benefits/Impact
•
•
•
•
•
Processing of sub-micron and micron particles within suspensions
avoids contamination/safety and handling issues of dry powder
processing – the output can be a final dosage or an intermediate one
Engineered particle dispersion into gel/polymer matrix allows
consistent loading of low dosage and/or low solubility actives
Manufacturing is inherently continuous
Full (100%) automated inspection possible
Drug dissolution may be controlled by particle size & coating
Leader: Raj Dave, NJIT
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Thin Films
ZUPLENZ (ondasentron) first quick-dissolving film prescription
product that is approved. Approved for nausea and vomitting.
http://www.zuplenz.com/
Benzocaine films by Zengen.
Triaminic and Theraflu by Novartis.
J. I. Jérez Rozo, A. Zarow , B. Zhou, R. Pinal, Z. Iqbal, R.J. Romañach, “Complementary Near-Infrared
and Raman Chemical Imaging of Pharmaceutical Gel Strip Films”, Published online in Wiley Online
Library (wileyonlinelibrary.com). DOI 10.1002/jps.22653
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L.Sievens-Figueroa, A. Bhakay; J.I Jerez-Rozo; N. Pandya; R. Romañach; B. MichniakKohn ; Z. Iqbal; E. Bilgili; R.N Dave, Int J Pharmaceutics (2012), 423, 496 – 508.
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Test Bed 3: Multi-layered Architectures
Using Drop-on-Demand Technology
Goal: Integrated application of dropon-demand technology for
predictable & controllable deposition
of active substances on edible
substrate to form3-D dosage
structures with engineered release
profile
Impact
•
•
•
•
•
Compact small scale manufacture for
clinical trial quantities, hospital
dispensaries
Linearly scalable
High precision dose control
Customized, patient specific dosage
formulations
Delivery of multiple active components
Ink-jet printing
Micro-arraying
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Scientific Challenges:
• Understand & predict formation of drops of uniform size
from complex fluids
• Understand impact & spread of drops of complex fluids on
solid substrates
• Understand and predict active-carrier interactions
• Understand and predict drop-substrate interactions
• Understand and control morphology of drug during
solidification
Mike Harris, Osman Basaran (ChE)
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