2021 IEEE 8th International Conference on Industrial Engineering and Applications
Quality Assessment Support System for Alarm Prioritization in Pharmaceutical
Plant Operations
Arjay M. Agapito Yogi Tri Prasetyo
School of Industrial Engineering and Service Engineering School of Industrial Engineering and Engineering
Management, Mapua University Management, Mapúa University
2021 IEEE 8th International Conference on Industrial Engineering and Applications (ICIEA) | 978-1-6654-2895-8/21/$31.00 ©2021 IEEE | DOI: 10.1109/ICIEA52957.2021.9436820
658 Muralla St., Intramuros, Manila 1002, Philippines 658 Muralla St., Intramuros, Manila 1002, Philippines
[Link]@[Link] e-mail: ytprasetyo@[Link]
Satria Fadil Persada A.A.N. Perwira Redi
Department of Business Management, Institut Teknologi Industrial Engineering Department, BINUS-Graduate
Sepuluh November Program – Master of Industrial Engineering, Bina
Kampus ITS Sukolilo, Surabaya 60111, Indonesia Nusantara University
e-mail: satriafp@[Link] Jakarta 11480, Indonesia
e-mail: [Link]@[Link]
Abstract—Pharmaceutical manufacturing is distinct as it has a such products, production operator & supervisor response
number of quality standards being met to make sure that the may not be quick enough to address process upsets,
products are effective and safe. Alarms help to make sure that especially if there are floods of alarms in the production floor.
critical parameters stay on a specific range and quality Due to process unfamiliarity, distinguishing alarms if it is
attributes are met. In this study, quality HAZOP is used for related to safety, quality, or just a nuisance might be difficult
alarm prioritization that helps a simulated pharmaceutical at first. Unable to respond properly to alarms that may lead
process maintain acceptable alarm rates that will allow to poor product quality may pose risks to adhering with FDA
operators respond better on process upsets. It was seen in the regulations, and at times a rework on batches/lots may be
simulation that a decrease in average alarm rates and peak needed to be considered. This activity will need additional
alarm rates upon employing this method. In this way, quality
resources, thereby adding to production cost. This also
HAZOP can also be used to train operators to respond quickly
and better, especially on novel processes being developed.
translates to delay in quality review, which quality group
may have difficulty in providing root cause analysis on some
Keywords – Quality by Design, Alarm Management, Alarm process anomalies. Kawai et al [1] proposed a quality
Rationalization, Pharmaceutical Plant Operations, HAZOP study should be done as part of implementing QbD
to coordinate recipe and equipment/operation design,
however it may still be improved. This can include other
I. INTRODUCTION
production operation such as manual operations, i.e. alarm
In pharmaceutical industry today, it is important to have operator response, alarm rationalization, and batch report
an efficient run of batch processes. Several methodologies review. These operations deal mainly in alarm and quality
are being employed by most pharmaceutical industry to management. In this study, we provide information on how
make sure that products produced are safe and within FDA to manage alarms by including quality HAZOP in QbD as
specifications. The concept of Quality-by-Design (QbD) has part of alarm management strategy, which can aid production
been adopted by most pharmaceutical companies, which operators and supervisors to respond better in process upsets.
promoted the incorporation of quality-thinking during Instead of having an extra step from the production operators
process development. As an effect, new process data are and supervisors to rationalize and respond to alarms which
generated and were integrated that helped in improving the are critical for product quality, correct alarm prioritization
production process. However, it is not only the process will be used to guide them. This may also lead to a better
design that is important, but also the people involved in the alarm rationalization, and quality group can perform quality
actual manufacturing. These can include both the production review faster and more efficient. Hence, product will be
and quality personnel. Hence, minimizing process mistakes released to the market faster.
from these group can be beneficial in releasing
pharmaceutical products faster and within required II. PHARMACEUTICAL QUALITY
specifications.
In production of new pharmaceutical products such as A. Quality by Design
vaccines and medicines developed to address pandemic such Quality by Design (QbD) is a concept first defined by Dr.
as the Corona Virus Disease 2019 (COVID-19), processes Joseph M. Juran. This is driven by needs of high-quality
should be fast and efficient. Hence, this includes operations products, especially in pharmaceutical space. In this concept,
from production and quality personnel. Due to the novelty of Dr. Juran believed that quality should be designed into a
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product, and most of quality issues arises to the way a visualization of alarm is suggested by Hu et al [3]. As seen in
product was designed in the first place. It was then US Food Fig 1., it was proposed that alarm system can be measured in
and Drug Administration (US FDA) encouraged adoption of five ways with respect to performance: (1) predictive, (2)
QbD principles in drug development, manufacturing, and robust, (3) stable, (4) reactive, and (5) overloaded. They
regulation. QbD has the following elements: (1) quality proposed that this plot is capable of comparing metrics with
target product profile (QTPP) to target the critical quality industrial benchmarks, allowing easier comparison of
attributes (CQAs); (2) product design and understanding performance. The goal of improving the alarm management
including identification critical material attributes (CMAs); is to go from overloaded to predictive. In this way, operators
are able to respond properly on the process upsets, thereby
(3) process design and understanding including
ensuring smoother operations and acceptable product quality.
identification of critical process parameters (CPPs), linking
CMAs and CPPs to CQAs; (4) a control strategy that
includes specifications for the drug substance(s),
excipient(s), and drug product as well as controls for each
step of the manufacturing process; and (5) process
capability and continual improvement.
B. Quality Hazard and Operability (HAZOP) Study
To provide a quality HAZOP study, it is important to
define two items as proposed by Kawai et al [1]. These are
(1) quality/process deviation list and (2) hazard propagation
list. Quality/process deviation list is defined as critical
parameters which are outside the in-process control (IPC)
range. These critical parameters are considered as
acceptance criteria for CQAs, therefore the goal is to keep
them within a certain normal operation range (NOR).
Hazard propagation list shows the NOR and IPC
deviations attributed from any failure in the process or
equipment. A product or process deviation list provides the
NOR and IPC relationships until CQA deviation is triggered.
Deviations of the rejection limits of IPC and CQAs are Figure 1. Alarm system overall performance evaluation proposed by Hu
et al [3].
defined as process hazards. The two lists are easily
incorporated as Quality HAZOP by bridging the same
deviation items of the NOR and IPC. Hence, these instances B. Learning Knowledge from Alarm Data
from manufacturing failure to process hazard is termed as Wang et al [4] proposed that alarm system may be
Quality HAZOP Kawai et al [1]. studied through a Bayesian network. Bayesian network is
defined as probabilistic graphical model with conditional
III. ALARM MANAGEMENT dependencies operating at directed acyclic graph (DAG).
The methodology is summarized at Fig. 1 and consists of
A. Industrial Alarm Overview three significant steps: (1) learning the Bayesian network
Alarm system is defined as integration of hardware and structure from Distributed Control System (DCS) alarm data;
software that serves as a core asset in complex industrial (2) learning the parameters of the Bayesian network from the
facilities to notify operators of abnormal conditions or structure and the dataset; and (3) calculating the link
equipment malfunctions. When an alarm occurs, it is strengths between related variables. Using this approach, the
presented to the operators in an audible and visual form and performance of alarm management may be improved
is displayed in screen in textual format [2]. Operator then gradually through time, reducing nuisance alarms and
responds to this alarm by acknowledging and addressing it so minimizing alarm flooding. However, on a context of a new
that process will return to normal state. process to be used in production of novel pharmaceutical
Alarm flooding is one of the biggest problems in alarm drugs, the number of alarms may not be available to improve
systems and industrial processes. Alarm flooding is defined its management. correct alarms based on its prioritization
as the number of alarms being generated is greater than that especially during alarm flooding. The integrity of this model
an operator can effectively manage, e.g. more than 10 alarms is only as good as the number of history of data logged on
per 10 min. In a pharmaceutical process, a specific alarm can the system.
yield to a product quality constraint therefore it should be
addressed right away by operations before it can cause
further product degradation. Several studies have been made
to address alarm management. One study proposed in
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leading them to decide poorly in addressing This approach is
Chemical process
often times used to train
IV. METHODOLOGY
The method of developing quality HAZOP for creating
deviation list is proposed to be integrated with alarm
Collect alarm data management and prioritization as described in Fig. 2. This
makes the process more robust and product deviations
minimized.
Quality HAZOP
Preprocess alarm
data
Quality HAZOP in Effect on Operator
Alarm Prioritization Response
Alarm Management &
Prioritization
Learn correlations
between monitored
variables Figure 3. Methodology
A simulated reactor and cooler process is considered in
Y this study. It is assumed that the output of the reactor will be
directly charged to the cooler. A simple temperature effect
on the product quality will be considered. This is described
Learn parameters in the Fig 3. Hazard propagation list is also included in this
between related
variables figure to give emphasis on alarms as either a parameter being
out of NOR or it will be leading towards CQA deviation.
Out of CPP out of CQA
NOR NOR affected
Calculate link
strength between
related variables REACTOR
Out of CPP out of CQA
NOR NOR affected
Update alarm
data
COOLER
N Figure 4. Reactor – cooler process considering different alarms being
generated from out of range parameters.
Stop In this figure, it is assumed that all parameters that goes
out of range in the process will generate an alarm. Hence, it
is undistinguishable if these are Out of NOR, CPP out of
Figure 2. Methodology of learning knowledge from alarm data as NOR, or CQA affected alarms. Also, it will be assumed to
described by Wang et al [2]. have multiple combination of parameters per reactor and
cooler that exhibits this alarm properties. Two sets of process
In addition, production operators and supervisors may simulations are conducted, and the simulated alarm instances
take time to fully be familiar on the new process; thereby, are then produced. The first run of the batch process will
have alarm assignments categorized (out of NOR, CPP of
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NOR, CQA affected), while the second run of the batch B. Effect on Operator Response
process will have alarms assignments uncategorized. From Since this is only a simulation, the operator response may
these data, average and peak alarm rates will be determined only be deduced from the number of alarms they can respond
and will be used to determine overall performance of alarm with at a given time. Having Figure 5 as the basis of this
systems suggested by Hu et al [3]. These comparison of approach, we are seeing that alarm
alarm data will be the basis for gauging operator response, Moreover, learning to respond properly to a process upset
whether they can respond better or not based on the alarm will be faster and training for the operator will be minimally
number generation. required. This enables new operators to respond faster to the
process effectively and effciently.
V. DISCUSSIONS
VI. CONCLUSION
A. Quality HAZOP in Alarm Prioritization
In this study, a simulation of the process provides a
Quality HAZOP can be integrated with the learning picture in helping operators respond better to a process by
knowledge from alarm data proposed by several studies [2, minimizing alarms they process per unit time. Correct
5,6]. A different console can be considered for alarms that prioritization of alarms definitely helps their response time
may lead to quality anomaly. This can be done by providing and this also helps newer operators to be more familiar with
correct prioritization of alarms. From a process model if all process parameters that can affect the product quality.
alarms are considered to be equal, it may cause alarm Moreover, this approach allows quality review to be faster as
flooding for the operator. Hence, it may be a good approach the quality anomalies can be quickly be investigated since
to separate a alarms that may generally effect the product the alarms are properly attributed. It may be useful to explore
integrity using its quality HAZOP. Fig 5 below shows the this study on an actual process, especially on novel processes
effect of this as described in decline of alarms on the console. such as vaccine and medication development for COVID-19.
ACKNOWLEDGMENT
The authors would like to thank Mapua University
Directed Research for Innovation and Value Enhancement
(DRIVE) for supporting this study.
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