Projects per year
Abstract
Introduction of the Process Analytical Technolo
gy (PAT) Initiative, the
Quality by Design (QbD)
approach and the Continuous Improvement (CI)
methodology/philosophy is considered as a huge
milestone in the modern pharmaceutical indust
ry. The above concepts, when applied to a
pharmaceutical production process, should enable
better designs of products and processes.
Furthermore, easier process monitoring, control and au
tomation are just some of the advantages that
can be achieved as a consequence.
Traditional production methods of Active Pharmaceuti
cal Ingredients (APIs) are based on batch and
semi-batch processes which include plenty of
supportive actions defined as non-value added
activities (NVAs) or simply waste.
It is therefore desirable to im
plement a switch from batch based
production to continuous manufacturi
ng modes in order to minimize NVAs, as well as to enable
easier satisfaction of the demands defined by the PA
T Initiative. This approach could be considered
as establishing a Lean Production System (LPS) whic
h is usually supported
with tools associated
with Process Intensifaction (PI) a
nd Process Optimization (PO).
Development of continuous processes is often c
onnected with many obstacles due to the very long
reaction sequences, inhomogenous reaction mixtures,
the presence of slurries.... It is therefore
important to adapt the reaction
conditions as much as possible
to the desired production in
continuous mode. Small-scale manufacturing could be
supported with modern
PI tools, such as
microwave assisted organic synthesis (MAOS),
ultrasounds, meso-scale flow chemistry and
microprocess technology. Furthermore, developmen
t of chemical catalysts and enzymes enabled
further acceleration of some chemical reactions that
were known as very slow or impossible to be
performed.
The main goal of this work is to develop a PI
strategy that would include
different chemical and
physical approaches with the main
purpose to accelerate slow chemi
cal reactions and adapt them to
continuous manufacturing modes.
Detailed insight into the PAT,
QbD, CI and Lean Production
System (LPS) is additionally provided in the in
troduction. The practical implementation of the PI
strategy is covered with three different examples.
The first example process
is the dehydration of 9
‐
Allyl
‐
2
‐
Chlorothioxanthen
‐
9
‐
Ol (“N714-
Allylcarbinol”) to the mi
xture of cis and trans 9H
‐
thioxanthene,2
‐
chloro
‐
9
‐
(2
‐
propenylidene)
‐
(9CI)
(“N746-Butadienes”). Both components are in
termediate products in the synthesis of
Zuclopenthixol – a product of H. Lundbeck A/S. Su
ccessful transfer from
batch towards meso-flow
chemistry is performed together w
ith demonstration of th
e potential for in-/at
- and off-line process
monitoring.
The second example proce
ss is the anti-Markovnikov hydroa
mination between the “N746-
Butadienes” and 1-(2-hydroxyethyl)piperazine (H
EP) resulting into a mixture of cis/trans
4
‐
[3
‐
(2
‐
Chlorothioxanthen
‐
9
‐
ylidene)propyl]
‐
1
‐
piperazineethanol (Clopenthixol). This chemical
reaction is well-known as very slow
and difficult to be accelerated
by applying chemical catalysts.
vi
Some authors claim that hydroamination of unsatur
ated hydrocarbons is known as one of the “ten
challenges for homogeneous catalysis”. Neverthele
ss, implementation of th
e PI strategy by using
microwave irradiation resulted in
significant improvements.
The third example process includes the small-s
cale production of (2-Bromophenyl)(phenyl)sulfane.
This important API intermediate is receiving si
gnificant attention in the pharmaceutical industry
due to the fact that there are pl
enty of APIs which in
cludes C-S bonds in thei
r chemical structure.
The production of such compounds is based on Car
bon-Sulfur cross coupling reactions, involving
expensive chemical catalysts, chemical ligands,
bases and unfriendly solvents. Implementation of
the PI strategy with a significantly modified chemi
cal pathway resulted in several benefits from an
economic, environmental and manufacturing point of view.
Considering the results achieved in the case
studies, it can be concluded that successful
implementation of the PI strategy has been ac
hieved while satisfying the PAT demands and
implementing Lean Production System. Significant
accelerations of often considered difficult
chemical reactions have been achieved, and therefor
e it can be concluded that
a successful transfer
from batch towards continuous manufacturing has been achieved.
Original language | English |
---|
Publisher | Technical University of Denmark, Department of Chemical and Biochemical Engineering |
---|---|
Number of pages | 281 |
Publication status | Published - 2014 |
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Dive into the research topics of 'Operational Aspects of Continuous Pharmaceutical Production'. Together they form a unique fingerprint.Projects
- 1 Finished
-
Operational aspects of continuous pharmaceuical production
Mitic, A. (PhD Student), Gernaey, K. V. (Main Supervisor), Dam-Johansen, K. (Supervisor), Skovby, T. (Supervisor), Jensen, A. D. (Examiner), Aelterman, W. (Examiner) & Hessel, V. (Examiner)
15/11/2010 → 02/07/2014
Project: PhD