Arab J Sci Eng

DOI 10.1007/s13369-013-0678-y

RESEARCH ARTICLE - SYSTEMS ENGINEERING

Application of Lean Six Sigma Tools for Cycle Time Reduction

in Manufacturing: Case Study in Biopharmaceutical Industry
Abdullah Ismail · Jaharah A. Ghani · Mohd Nizam Ab Rahman ·
Baba Md Deros · Che Hassan Che Haron

Received: 23 April 2012 / Accepted: 8 July 2013

© King Fahd University of Petroleum and Minerals 2013

Abstract Recently, particularly in the highly competitive
manufacturing industry, product cost has become a main
business concern. By keeping operating expenditures to the
minimum, products can be marketed with lower prices,
thus promoting the buying power of customers. Consumers
always go for high-quality products at affordable prices.
Therefore, producers must come up with products with lower
possible cost without jeopardizing quality. Many cost-saving
measures have been introduced in the industry, and Lean
Six Sigma, which consists of many integrated tools, such as
process mapping, value stream map, cause-and-effect matrix,
and failure mode and effect analysis, is among the most pop-
ular. In this study, the Lean Six Sigma tools of DMAIC were
applied to determine wastage and to reduce the cycle time
production in a biopharmaceutical operation. The data were
analyzed using functional process mapping and value analy-
sis. Through a study in one of the selected production areas,
a significant result was obtained where approximately 54 %
of the overall production cycle is considered as waste or
non-value-adding activities that can be readily eliminated.
To obtain better result and sustain improvement, a few activ-
ities have been introduced, such as special trolley or cart
for product transportation, closing of all exposed pipings or
tubings with special head cap, installation of one unit heat
exchanger to enhance cooling capacity, and room renovation
for a wider working area and proper equipment arrangement.
In conclusion, Lean Six Sigma is a very good approach in
managing waste and variability, and it is also relevant for
application to current manufacturing management system.
By implementing Lean Six Sigma, the overall company goal
of maximizing profit can be materialized.
Keywords Lean Six Sigma · DMAIC · Functional
process mapping · Value analysis · Cycle time reduction ·
Biopharmaceutical industry

A. Ismail · J. A. Ghani (B) · M. N. Ab Rahman · B. Md Deros ·

C. H. Che Haron
Department of Mechanical and Material Engineering,
Faculty of Engineering and Built Environment,
Universiti Kebangsaan Malaysia, 43600 Bangi, Selangor, Malaysia
e-mail: jaharah@eng.ukm.my
A. Ismail
e-mail: abdullah.ismail@innobiologics.com
M. N. Ab Rahman
e-mail: mnizam@eng.ukm.my
B. Md Deros
e-mail: hjbaba@eng.ukm.my
C. H. Che Haron
e-mail: chase@eng.ukm.my

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1 Introduction
Quality and excellence have always been the focus of the
biopharmaceutical industry. Nevertheless, comfortable prof-
its and regulatory pressures have prevented most drug makers
for decades from being part of the “quality revolution” that
swept across and transformed the automotive, electronics,
and semiconductor industries. As a result, proper manage-
ment of process waste and variability has been set aside to
meet regulatory and quality standards first. As competitive
pressures intensify, more drug makers are launching “Oper-
ational Excellence” (OE) programs through Lean Six Sigma
to maximize product quality, safety, and plant efficiency and
throughput. OE programs address overly long cycle times,
variability, waste, and “silo mentality” that prevent manufac-
turing operations in many drug companies from realizing the
“big picture.” The actual concerns have been minimization
of wasteful practices and optimization of workflow in the
facility, elimination of unnecessary equipment setups, and
implementation of changes. In some cases, changes can be
extremely simple, such as the elimination of more-frequent-
than-necessary instrument calibrations that increases labor
costs or even delay production runs but can add up to millions
of dollars in savings per year. OE also focuses on variabil-
ity, whether in raw materials, product quality, process opera-
tions, or cycle times. Currently, only after many changes have
been made and samples taken that quality problems become
apparent, which translates into many wasted processes and
even more wasted time [1]. According to Cudney et al. [2],
lean manufacturing and six sigma are powerful philosophies
backed by several tools for improving quality, productivity,
profitability and market competitiveness for any corporation,
in which lean manufacturing focuses on eliminating waste
and improving flow and six sigma is focused on reducing
process variation using problem solving and statistical tools.
Cycle time is a key measurement tool for evaluating
the performance of a number of leading-edge management
concepts, including supply-chain management, just-in-time
management, enterprise resource planning, theory of con-
straints management, and lean management. Improvement
in cycle time in any of these areas has been linked to reduced
costs, reduced inventories, and increased capacity. Reducing
cycle time translates to faster response to customer needs [3].
The resource areas measured by cycle time include measure-
ment of financial, material, and information flows. A delay or
failure in this measure for any of these cases can indicate fail-
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Arab J Sci Eng
ure in the entire business process [4]. Manufacturing cycle
time refers to manufacturing operation activities, such as the
total time required to produce a product, and it is defined
as the period required to complete one operation cycle or to
complete a function, job, or task from start to finish [5].
The life science industry today is challenged to main-
tain product quality, productivity, return-on-investment, and
compliance while producing a 10–15 % growth for their
shareholders at the same time. This objective effectively
means that biopharmaceutical companies must double the
number of new lead candidates entering the clinical trial
phases of the drug-approval process, shorten overall time to
market, and reduce R&D, clinical trial, and production costs.
The entire product life cycle, including investigational new
drug and new drug application approval, must be stream-
lined, as well as the validation of the production process [1].
A common observation in every major pharmaceutical firm is
that most key operational business processes are inefficient,
resulting in an increase in transactional costs, increased cycle
times, and, ultimately, ineffectiveness of the organization to
adequately achieve its defined goals. This situation exists
in every functional group: product development, sales and
marketing, manufacturing, compliance, and quality. Little or
no effort has been exerted on optimizing business processes
during the past few decades. These inherent inefficiencies are
rarely addressed in SWOT and/or strategy sessions. In most
cases, however, no significant repercussions are implemented
because profitability targets are continually met as high drug
prices successfully offset the internal costs associated with
inefficiencies [6].
Cycle time reduction is an underused and valuable addi-
tion to any company’s business improvement toolbox. It
offers a different perspective that can open up significant
new working capital and cost reduction opportunities in areas
of operations in a company often missed because of adop-
tion of other cost reduction approaches. More importantly,
cycle time reduction is an approach to business profitabil-
ity improvement that enhances a company’s capability to use
time as a strategic weapon to compete and win in the intensely
competitive global market [7].
Many benefits can be reaped from the reduction in mean
cycle time. In general, a shorter cycle time improves the com-
pany’s ability to respond to changing customer demands and
reduces the work-in-process inventory for any given level of
throughput. Reducing variability in cycle time is very impor-
tant as it will lead to more accurate prediction of the product
completion time, and it is critical in accurate planning and
due-date assignment, facilitating improved coordination of
up/downstream operations of products [8].
As organizations are confronted with increasing pressure
to compete in today’s fast changing business environment,
they often search for an issue that can provide them with com-
petitive advantage, often seeking methods to reduce cycle
Arab J Sci Eng
time so that production cost is reduced and/or customer ser-
vice is improved [9].
In successful implementations so far, majority of Six
Sigma projects have been selected for measurable bottom-
line or customer impacts that are completed within 2–
6 months. The projects are implemented through the appli-
cation of a well-defined set of statistical tools and process
improvement techniques by well-trained people in an organi-
zation who understand that Six Sigma is a career accelerator
[10].
In practice, companies view Six Sigma in two aspects: a set
of powerful tools for improving processes and products and
an approach for improving both process- and people-related
aspects of business performance. Six Sigma is used as a
hands-on approach in developing leadership and in changing
management skills [11]. Companies that achieved the great-
est benefits from Six Sigma leverage the linkages between
people, processes, customer, and culture [12].
Lean and Six Sigma each have their own strengths in dif-
ferent applications and the two methodologies can be com-
bined or applied in different situations to achieve the best
results [13]. LSS also was applied in an airline company [14],
and the findings suggest that the factors that influence the
implementation of LSS are leadership and strategic orienta-
tion, quality-driven organizational culture, continuous train-
ing, teamwork, customer satisfaction, and technical system.
Results on Six Sigma survey to identify the best practices in
the use of the Six Sigma methodology in Brazil were pre-
sented by Miguel and Andrietta [15]. They found that some
practices which stand out are the adoption and training of the
professionals involved with the program (blackbelts, green
Fig. 1 Main process area
belts, etc.). Furthermore, organizational costs can be grouped
as process cost, cost of quality, and cost of poor quality, there-
fore managers should be trained in the theory and application
of Lean-Six Sigma, including the seven categories of waste
and how to remove them [16]. In healthcare, financial exec-
utives should work with managers in eliminating waste to
improve service and reduce costs [16].
In the current study, the Lean Six Sigma tools of DMAIC
were applied in biopharmaceutical manufacturing to reduce
the cycle time in one of the selected production areas. The
data were analyzed using functional process mapping (FPM)
and value analysis.
2 Case Study and DMAIC Methodology
This study was conducted in one biopharmaceutical com-
pany in Malaysia, namely, Inno Biologics. Figure 1 shows
the three main process areas in Inno Biologics business oper-
ation: (1) protein expression; (2) process development; and
(3) manufacturing. The area involved in this study was man-
ufacturing or biomanufacturing, where all scale-up activities
from laboratory to manufacturing fall within this operation.
Basically, Six Sigma has two branches, depending on
the focus of improvement efforts. For existing products
and processes, the DMAIC methodology is applied. For
new products and processes, the DMADV methodology is
adopted. The first three phases for each case are similar:
define, measure, and analyze. For DMAIC, the last two
phases focus on improving and controlling existing prod-
uct or process inputs. For DMADV, the final phase focuses
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on designing and verification of future product or process
inputs. In this study, the DMAIC methodology is applied as
roadmap in the project implementation.
The DMAIC methodology for existing products and
processes consists of the following phases:
Define identification of project goals and objectives; cre-
ation of a team charter that lists the roles and responsibilities
of team members, including, of course, the customers; and
defining the boundaries of the project, including the products
and processes to be examined.
Measure establishment of the capability of current prod-
ucts or processes to be measured (i.e., the outputs); defin-
ing the performance standards for these outputs; creating a
data-collection plan for gathering data on the outputs; and
performing a measurement system analysis to determine the
capability of all measuring devices to accurately measure the
output (Y s).
Analyze establishment of the capability of the current prod-
ucts or processes in statistical terms (i.e., identifying the cur-
rent sigma quality level); identifying a transfer function that
relates the inputs to the outputs; and identifying sources of
both random cause variation and special cause variation in
the inputs (X s).
Improve using design-of-experiment techniques to determine
which inputs should be the focus of improvement efforts;
determining the effects of improved inputs by performing
a sensitivity analysis; and establishing acceptable operating
tolerances for the inputs.
Control performance of a measurement system analysis
to determine the capability of all measuring devices to
accurately measure the inputs and implementing statistical
process control measures on the inputs to ensure that they
remain within acceptable operating tolerances.
2.1 Definition of Project Details
These questions are addressed in this phase. (1) Who is the
(internal or external) customer? (2) Who are in the project
team? (3) What are the process boundaries? The results of
the define phase are as follows:
• Customer: next process (finished-product storage and sales
department)
• Team: bioprocess engineer, facility engineer, quality-
control and assurance executive
• Process boundaries: upstream process steps in biomanu-
facturing.
The process consisted of seven main steps. A trolley or
wheeled cart was used in the movements between each oper-
ation, as shown in Fig. 2. In addition, each operation can
be performed in multiple locations and in multiple areas,
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which increased motion or movement time. All works were
inspected before moving to the next operation to eliminate
additional rework steps. Minor set up was required at each
step in the process.
The process steps are listed as follows:
1. Preparation of cold WFI
2. Weighing of chemicals
3. Pre-dissolving of chemicals into concentrated solution
4. Transferring of chemicals into a larger tank—RTU con-
centration
5. pH measurement and adjustment
6. Filtering and distribution
7. Sampling and storage.
2.2 Measuring the Current Condition (Benchmarking)
In this phase, the product or process to be measured is
selected, performance standards for outputs are defined, and
“CTQ Flowdown” (critical to quality) is performed to deter-
mine the relationship between inputs and outputs. An exam-
ple of CTQ Flowdown is shown in Fig. 3.
• Primary CTQ: cycle time; from receipt of instruction order
for delivery to the next process (downstream)
• Performance target: zero-day delay from master schedule
plan.
The diagram above shows that the primary CTQ manu-
facturing cycle is a function of parameters that are under our
control, such as buffer preparation times, changeover times,
downtimes, and utilization of movable cart. Such other fac-
tors as product variation and holiday schedules must also be
taken into account.
2.3 Improvement Plan (Elimination of Root Causes)
The goal of the “Improve” phase is to identify a solution to
the identified problem. Many tools, such as the Poka Yoke,
future step value stream mapping (VSM), standard work
and standard operating procedures, visual management, 5S
method, Kaizen event, and total productive maintenance, can
be applied during this phase. In this study, we will focus
more on future state process mapping, which involves brain-
storming of potential solutions, subjecting the solutions to
a test, and evaluating the results of the implemented solu-
tions. The solution selection matrix is an effective method to
choose for the correct improvement activity before starting
with improvement implementation. The solution selection
matrix shown in Fig. 4 contains the following:
(a) The problems that are to be solved
(b) The root causes attached to the problem in sideway-
branching tree diagram
Arab J Sci Eng
Fig. 2 Buffer preparation
process steps
Fig. 3 CTQ flow down [17]
(c) The practical solutions attached to each root cause—a
root cause can have several practical solutions.
This exercise needs to be done as a team activity involving
the right process owner and decision makers to be effective.
This exercise has the potential to create strong supporters or
strong resistors; all decisions can only be finalized from a
cumulative data score.
Poka Yoke, a technique for avoiding simple human error
in the workplace, is one of the improvement techniques
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Fig. 4 Solution selection matrix [18]
employed in this study. It is also known as mistake-proofing,
goof-proofing, or fail-safe work method. Poka Yoke is sim-
ply a system designed to prevent inadvertent errors made by
workers in performing a process. Poka Yoke can be as simple
as an incorrectly placed steel pin on a fixture that prevents
parts from fitting properly, or it can be as complex as a fuzzy
logic neural network used to automatically detect tool break-
age and immediately stop a machine. Surprisingly, simple
low-cost devices tend to be the majority cases. For instance,
airplane lavatory lights turn on only when the door lock is
engaged. This technology keeps users from failing to lock
the door.
To obtain the baseline data for this study, a proper
approach that illustrates the process flow should be put in
place. From the macro level, the process is broken down
further to smaller units, called micro view. At this level, all
value-added and non-value-added (NVA) components can be
determined.
Fig. 5 SIPOC diagram [19]
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A supplier, input, process, output, and customer (SIPOC)
diagram is a method used in identifying process flow in the
macro view or perspective [19]. In this diagram, operation
steps from the supplier to the customer are listed in one direc-
tion, flowing down from top to bottom. SIPOC also requires
determination of the input of the current problem and the
output from the current processes. The process steps from
supplier to customer using the SIPOC diagram are shown in
Fig. 5.
This diagram is also called the “bird’s view” of the oper-
ation, and from these processes, the input and the output are
stated for purposes of general information and understanding.
2.4 Measuring the Baseline in Preparation for In-Process
Solution
Three types of solution preparation processes exist in the
biomanufacturing operation. Every batch or one completed
process of a product needs to prepare all these solutions in
their operation as stated below:
1. Preparation of in-process solution in mobius tank
2. Preparation of in-process solution in buffer preparation
tank (150 L)
3. Preparation of in-process solution in carboy/bottle.
In this study, historical data were collected from January
2010 to July 2010. The data were also used as reference for
the current status (sometimes called benchmark data) and are
tabulated in Table 1.
The average process time for all three processes was
1,310 min (D) and shown in Fig. 6.
Every month, the company finishes approximately 20 run-
ning cycles to meet production demand. The running cycle
Arab J Sci Eng

Table 1 Total process time

(in minutes) Type of process Individual process time (min)

Jan Feb Mar Apr May Jun Jul Average

In MOBIUS tank (A) 473 465 475 474 464 473 466 470
In buffer preparation tank (B) 475 479 469 472 479 474 477 475
In carboy/bottle (C) 369 368 362 363 366 365 362 365
Total process time 1,317 1,312 1,306 1,309 1,309 1,312 1,305 1,310
D = (A + B + C)

Fig. 6 Total process time Total Process Time (Minute)

(minute) 1318 1317
1316
1314
1312 1312
1312
1310
1310 1309 1309
1308
1306
1306 1305
1304
1302
1300
1298
Jan-10 Feb-10 Mar-10 Apr-10 May-10 Jun-10 Jul-10 Average

Table 2 Total process cycle

time Type of process Individual process time (min)

Jan Feb Mar Apr May Jun Jul Average

Total process time 1,317 1,312 1,306 1,309 1,309 1,312 1,305 1,310
D = (A + B + C)
Running cycle/month (F) 21 22 21 18 19 20 19 20
Total process cycle time 27,657 28,864 27,426 23,562 24,871 26,240 24,795 26,200
G = (D × F)

time per month from January 2010 through July 2010 is tab-
ulated in Table 2.
The total process time (D) was multiplied by the running
cycle per month (F) to determine the total process cycle time.
For instance, in January 2010, the total process time (D) of
1,317 min is multiplied by 21 running cycles per month (F),
yielding a total process cycle time of 27,657 min.
out the deficiency in the current process before improvement
plans are implemented. Maps and flowcharts make the system
visible, therefore improves communication and understand-
ing [20]. Furthermore, analyzing the process using maps will
help to identify the action required to reduce process cycle
time, decrease defects, reduce costs, reduce NVA-steps, and
increase productivity.

3 Data Analysis Using Lean Six Sigma 3.1 FPM and Value Analysis

Lean Six Sigma consists of many tools applicable in man-
ufacturing operation, and the right tools must be chosen to
ensure intangible and positive results. Failure in identifying
the right tools can lead to wrong improvement implementa-
tion, where, in some cases, the process can be worse than
the previous operation. In this study, FPM was used to find
FPM was used instead of VSM, which has a similar con-
cept of drawing individual process step or process flow in
the buffer solution preparation. FPM displays the activities
depicted in a process in sequential order and illustrates where
each activity is performed. It has three categories of standard
value-added components:

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Fig. 7 Preparation of in-process solution in MOBIUS tank (current state)
• Customer value add (CVA): what the customer pays or
willing to pay for
• Operational value add (OVA): work elements that actually
transform raw materials into product
• NVA: component that generates a zero or negative return
on investment of resources and can usually be eliminated
without impairing a process.
All process steps were classified into three categories
based on color coding: green is for CVA, light blue is for
OVA, and yellow is for NVA, which can be removed or elim-
inated from the process.
The value analysis format was used to determine the time
spent along the process. Basically, the format of the value-
adding analysis was divided into three categories: CVA,
OVA, and NVA, and the time consumed for every step in
the process was measured.
3.1.1 Analysis on the Preparation of In-Process Buffer
Solution in the Mobius Tank
The FPM diagram analysis started with the preparation of
in-process solution in the mobius tank, called current-state
analysis. Every single step involved in this process was
mapped to provide visual data in the diagram. Through this
mapping diagram, understanding the process flow and waste
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Arab J Sci Eng
identification became more effective. The FPM for the prepa-
ration of in-process buffer solution in the mobius tank is
shown in a simplified form in Fig. 7.
The preparation of in-process solution in the mobius tank
involved 24 steps. After the process flow mapping, the data
were transformed from the FPM diagram into value analy-
sis format, which was used to determine the time con-
sumed throughout the process. Segregation between the
value-adding (customer and operation) and NVA activities
was done during this process. The data from this study pro-
vided information to the production staff on time wastage in
their respective process. The value analysis for the prepara-
tion of in-process solution in the mobius tank is summarized
in Table 3.
Based on the value analysis in Table 3, the total process
time was 470 min. For the value-added activities (CVA and
OVA), the process time was 220 min (47 %), and for the
NVA activities, the process time was 250 min (53 %), slightly
higher than the value-added activities.
From Table 3, the future state of the preparation of in-
process solution in the mobius tank can be predicted. In this
future state, the FPM of all NVA activities are removed from
the process flow, and the total process steps are reduced
from 24 to 13 steps. Figure 8 illustrates how the future
state of preparation of in-process solution in MOBIUS
tank.
Arab J Sci Eng

Table 3 Value analysis for Detail process step Customer value Operational value Non-value
preparation of in-process (preparation of in-process added (CVA) added (OVA) added (NVA)
solution in MOBIUS tank solution in MOBIUS tank)

Receive chemicals from QA store room 10

Prepare apparatus, equipment 10
Fill WFI into buffer prep tank (1st cycle) 10
Cooling WFI to 30 ◦ C 10
Transfer cold WFI to MOBIUS and carboy 10
Fill WFI into buffer prep tank (2nd cycle) 10
Cooling WFI to 30 ◦ C 10
Transfer chemicals from MAL to bench 10
Locate MOBIUS onto floor scale 5
pH/conductivity calibration 15
Weigh chemicals 30
Pre-dissolve chemicals into concentrated solution 60
Transfer concentrated solution near to MOBIUS 5
Pump concentrated solution into MOBIUS 10
Mixing 30
pH, conductivity measurement and adjustment 30
Top-up WFI from buffer prep tank 15
Connect storage bag to MOBIUS 10
Filter and transfer to storage container 90
Remove tank linear and dispose waste 15
Sampling 15
Send to QC lab 20
Storage of buffer 10
Total (min) 10 210 250

Fig. 8 Preparation of
in-process solution in MOBIUS
tank (future state)

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Fig. 9 Preparation of in-process solution in buffer preparation (150 L) tank (current state)
By implementing waste elimination using FPM for the
preparation of in-process solution in the mobius tank (future
state), the manufacturing process was able to reduce the
process time by 53 % (250 min).
3.1.2 Analysis on the Preparation of In-Process Solution
in the Buffer Preparation (150 L) Tank
The same method was applied to the next process, the prepa-
ration of in-process solution in the buffer preparation (150 L)
tank. All three standard formats were replicated in the new
process flow as follows:
1. FPM in the current state
2. Value analysis
3. FPM in future state.
The FPM in the current state for the preparation of in-process
solution in the buffer preparation (150 L) tank is shown in
Fig. 9, similar to the previous FDPM where all process steps
were classified into three categories based on color coding:
green is for CVA, light blue is for OVA, and yellow is for
NVA, which can be removed or eliminated from the process.
The preparation of the in-process solution in the buffer
preparation tank involved 23 steps, which contained value-
adding and NVA activities. All these steps were transformed
into value analysis format to measure the time spent in this
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process. The value analysis for the preparation of the in-
process solution in the buffer preparation tank (150 L) is
summarized in Table 4.
Based on the value analysis in Table 4, the total cycle time
was 475 min. The time spent for the value-added activities
(CVA and OVA) was 215 min (45 %), and that for the NVA
activities was 260 min (55 %), higher than the value-added
activities.
The next step involved FPM in future state for the prepa-
ration of in-process buffer solution in the buffer preparation
tank (150 L), as shown in Fig. 10.
All NVA activities were removed from the process flow,
and the total process steps were reduced from 23 steps to 12
steps. Consequent to this waste elimination, the manufactur-
ing process time was reduced from 475 to 215 min.
3.1.3 Analysis on the Preparation of In-Process Solution
in Carboy
The same method was also employed in the preparation of
in-process solution in carboy. All three standard formats were
replicated in the new process flow as follows:
1. FPM in the current state
2. Value analysis
3. FPM in future state.
Arab J Sci Eng

Table 4 Value analysis of

Detail process step Customer value Operational value Non-value
preparation of in-process
[preparation of in-process solution added (CVA) added (OVA) added (NVA)
solution in buffer preparation
in buffer preparation (150 L) tank]
tank (150 L)
Receive chemicals from QA store room 10
Prepare apparatus, equipment 10
pH/conductivity calibration 15
Install pH/conductivity probe to tank 15
Fill WFI into buffer prep tank 10
Cooling WFI to 30 ◦ C 10
Transfer cold WFI to carboy 30
Transfer chemicals from MAL to bench 10
Weigh chemicals 30
Pre-dissolve chemicals into concentrated solution 60
Weigh chemicals 30
Pre-dissolve chemicals into concentrated solution 60
Transfer concentrated solution near buffer prep tank 5
Pump concentrated solution into buffer prep tank 10
Mixing 30
pH, conductivity measurement and adjustment 30
Top-up WFI 15
Connect disposable bag with filter (in LAF) 10
Connect storage bag to buffer prep tank 10
Filter and transfer to storage container 90
Clean/flush buffer prep tank 15
Uninstall pH/conductivity probe from tank 15
Sampling 15
Send to QC lab 20
Storage of buffer 10
Total (min) 10 205 260

Fig. 10 Preparation of
in-process solution in buffer
prep tank—150 L (future state)

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Fig. 11 Preparation of in-process solution in carboy (current state)
The FPM in the current state for the preparation of in-process
solution in carboy is shown in Fig. 11.
The process involved 19 steps. After process flow map-
ping, the data were transformed into value analysis format
for segregation between value adding and NVA, as shown in
Table 5.
From the value analysis of the preparation of in-process
solution in carboy, NVA activities were removed, and only
12 process steps remained in the future FPM, as shown in
Fig. 10.
The next step involved the preparation of FPM in future
state for in-process buffer solution in carboy, as shown in
Fig. 12.
4 Result and Discussion
The processing times of the in-process solution preparation in
the mobius tank, buffer preparation tank (150 L), and carboy
are summarized in the value analysis in Table 6. A difference
between value adding (CVA and OVA) and NVA is clear. The
NVA time is 700 min (54 %), whereas the value-adding (CVA
and OVA) time is 610 min (46 %). If the average running cycle
of 20 cycles/month is considered, i.e., the data collected are
multiplied by 20 cycles, a large amount of NVA waste is
found.
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Arab J Sci Eng
For example, when the NVA time of 700 min/cycle is
multiplied by 20 cycles, the wastage is 14,000 min/month
or 233 h. Surprisingly, many NVA activities occur in the
manufacturing process, all making contributions to financial
waste. Elimination of all NVA activities led to shorter manu-
facturing cycle time. Figure 13 shows the process cycle times
before and after NVA elimination through FPM implemen-
tation. Table 7 shows the savings per year of MYR 141,480
than can be obtained by the company by implementing the
lean sigma concept with the current scenario.
The finding of the present study agreed with The Wall
Street Journal report that the top 16 drug companies spent
over USD 90 billion in manufacturing drugs in 2001.
Roughly half that amount was wasted [21]. From the FPM
and value analysis results in Table 6, 54 % of the process
cycle time was identified as NVA, which can be eliminated.
This result also supported the statement of Deming [22],
“initially, cycle time focuses on process problems and not
people because 85 % of the problems are process problems,
and only15 % are people problems.” Improving quality by
reducing process cycle time, eliminating NVA process activi-
ties, and maximizing throughput while minimizing resources
will greatly improve performance and increase profitability
[7].
In the cycle time study by Lander [1] using evidence gath-
ered from 15 companies through MIT’s “Program on the
Arab J Sci Eng

Table 5 Value analysis for Detail process step Customer value Operational value Non-value
preparation of in-process (preparation of in-process added (CVA) added (OVA) added (NVA)
solution in carboy solution in carboy/bottle)

Receive chemicals from QA Store room 10

Prepare apparatus, equipment 10
pH/conductivity calibration 15
Fill WFI into buffer prep tank 10
Cooling WFI to 30 ◦ C 10
Transfer cold WFI to carboy 30
Transfer chemicals from MAL to bench 10
Weigh chemicals 30
Dissolve chemicals into ready-to-use solution 60
pH, conductivity measurement and adjustment 30
Top-up WFI from buffer prep tank 15
Connect disposable bag with filter (in LAF) 10
Connect storage bag to carboy/bottle 10
Filter and transfer to storage container 60
Transfer to storage container 10
Sampling 15
Send to QC lab 20
Storage of buffer 10
Total (min) 10 225 130

Fig. 12 Preparation of
in-process solution in carboy
(future state)

Pharmaceutical Industry” project to benchmark best prac-
tices in pharmaceutical manufacturing, a team looked at
existing and potential opportunities for cost savings. The
key results from that study included preliminary evidence
that indicates that more than 95 % of cycle time is spent on
activities that added no value, and cycle time reduction in
manufacturing presents a very large opportunity for overall
cost savings.
The achievement of the current study in cycle time reduc-
tion was also supported by Rath and Strong [23] in their
earlier study where they claimed that reducing cycle time
by 75 % in a manufacturing area or product line is phys-
ically possible in as short as three months, and that it can
routinely be done in six months. This statement was based
on empirical evidence gathered from companies in the US
and Canada, which showed that companies that reduce total

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Table 6 Value analysis for all

processes type No. Process type Customer value Operational value Non-value
(buffer preparation) added (CVA) added (OVA) added (NVA)

1 Preparation of in-process solution 10 210 250

in MOBIUS tank
2 Preparation of in-process solution 10 205 260
in buffer preparation (150 L)
3 Preparation of in-process solution 10 165 190
in carboy/bottle
Total 30 580 700
Value add/non-value-add 610 700
% VA vs NVA 46 54

To ensure that the improvement is sustained, encourage-

ment must be given to all staff to express ideas that should
be put in place. In addition, rewards and recognition to any-
one who produce a tangible project result should be given
because incentives can promote a positive working environ-
ment. Besides, training of the professionals involved with the
program is very important as found from survey conducted
by Miguel and Adrietta [15].

Fig. 13 Process cycle time before–after FPM implementation 5 Conclusion

Lean Six Sigma is a business operation approach, which con-

Table 7 Monetary saving sists of a wide range of tools. In this study, only a few related
Saving description Saving calculation tools have been used to study the causes of long cycle time in a
biomanufacturing process. Reducing process cycle time was
Saving per month (min) 14,148 a key contribution in the overall production lead time, which
Saving per year (min) 169,776 resulted in manufacturing cost reduction. It also maximized
Saving per year (h) 2,829.6 the number of production cycles in a month and increased
5 workers per process 5 × MYR 10/h = MYR 50/h productivity and flexibility. A famous lean manufacturing
Total saving per year (MYR) 2,829.6 h× MYR 50 = MYR 141,480 method, called seven waste identifications, was used to iden-
tify the wastage in this process by categorizing the waste into
three groups: CVA, OVA, and NVA. Surprisingly, 54 % of
the process cycle time involved NVA activities and can be
manufacturing cycle time by 75 % will double their produc- removed from the process. FPM has also been proven as an
tivity, reduce break-even point by 20 %, grow at three times effective tool in identifying NVA activities in the process. The
the industry average, and have double the industry average lesson from this study is that the company should establish
margin. a dedicated team to focus on industrial engineering espe-
After the implementation of the Lean Six Sigma approach cially in waste elimination and reduce the variation through
and tools, the long cycle time was determined to be caused the process such as in-house training on lean manufacturing.
by inefficient WFI supply, water contamination, difficulty in The limitations of this study are as follows: focusing only on
movement of the buffer solution from one point to another, the upstream processes which occupy only 50 % of the whole
and limited working space and equipment. Subsequently, manufacturing operation due to the time constraints and dif-
improvement ideas were solicited from team members, and ficulty in managing the operation team for data collection;
all three major contributors to longer cycle time improved. in brainstorming session, longer time was taken in drafting
The new average process cycle time improved from 1,310 to and decision making since all the participants were not expe-
592.5 min after completion of the project. rienced in doing this exercise. In future, this method can be

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replicated for other processes which use the same equipment
and process flow. Therefore, the company is able to reduce
study and analysis time to realize another time saving.
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