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4th International Quality Conference

May 19th 2010


Center for Quality, Faculty of Mechanical Engineering, University of Kragujevac

Lean and Six Sigma Concepts – Application in


Katarina Pavlović 1) Pharmaceutical Industry

Vojislav Božanić1) Abstract: LEAN thinking and Six Sigma have been utilized
by manufacturing industries to decrease cost and improve
1) Faculty of Organization quality and productivity by reducing variation and
Sciences, University in production defects. Because of the dramatic successes in
Belgarde, Serbia manufacturing, there is rising interest among companies in
the pharmaceutical industry, which choose to implement
LEAN in order to accomplish such goals as decreased wait
time to release product to the market, reduce production
waste, improve communication with end users and raize
quality level both in the production and in testing
laboratories. In this article, basics of LEAN and Six Sigma
are presented and suggestion was given for application of
their concepts in pharmaceutical industry together with
harmonization with legal regulation represented by
requirements Good Manufacturing Practice (cGMP) , in
order to work “smarter”, more cost-effectively and avoid
wasting time and other resources.
Keywords: lean, six isgma, pharmaceutical industry

1. INTRODUCTION very successful in improving profits.


Six Sigma is a methodology of
Process improvement initiatives have continuous improvement aimed at
been in existence for quite some time and reducing defects by using the model
include Continuous Quality Improvement Define-Measure-Analyze-Improve-Control
(CQI)1, Process Improvement (PI)2, (DMAIC)7, which is further developed
Quality Assurance (QA)3, Quality through the Design for Six Sigma, which is
Management (QM)4 and Re-engineering5. based on creating a robust design that
In the mid-1900s, the term Six sigma was meets customer requirements and Lean Six
coined by a Motorola Engineer, Bill Smith, Sigma, which is based on the processes
to describe a new quality control process and ways to increase their efficiency.8
that merged from the Total Quality LEAN was founded by Taiichi Ohno
Management (TQM)6 strategy and was in the 1950s and arose from the Toyota
production System with key aspects
1
CQI – Continuous Quality Improvement, one of including the never-ending quest for
process improvement initiatives
2
perfection, continuous search to eliminate
PI – Process Improvement, one of process
improvement initiatives 7
3
QA – Quality assurance, one of process DMAIC – Define – Measure – Analyse –
improvement initiatives Improve - Control
8
4
QM – Quality management, one of process www.ngpharma.com ,Design for Six Sigma and
improvement initiatives Lean Six Sigma for the Pharmaceutical and Medical
5
Reengineering, one of process improvement Industries, Tania Pinilla, Six Sigma Master Black
initiatives Belt, Motorola University
6
TQM – Total Quality Management

4th IQC May, 19 2010 259


waste and the recognition and importance methods of Lean and Six Sigma can reduce
of employee contributions.1 costs, and encourage research and
Lean and Six Sigma as methodologies development, even in this time of great
can be used independently or together. challenges.11
Today, many companies in different Pharmaceutical and medical device
industries, both large and small, adopt Six manufacturers are looking in Lean
Sigma and Lean as a regular way to manufacturing and Six sigma principles
improve the efficiency of design, the way for significant improvement of
manufacturing, business processes and operational efficiency and quality, while
intellectual property while reducing costs. facilitating compliance.
Both concepts can be successfully applied Today, manufacturers in these
in the pharmaceutical and medical device industries are focused as never before on
industry, in order to resolve the issue of reducing operational costs while ensuring
unnecessary costs that limit profitable compliance. To ensure a solid position on
innovation.11 the market and competitive advantage they
Today pharmaceutical companies are are looking to increase the efficiency of
faced with demanding tasks such as their operational and manufacturing
adjustment to the unstable and turbulent processes – optimizing resources,
market in times of economic crisis, as well improving efficiency, reducing waste and
as aiming to meet the needs of their users controlling inventory.10
in maintaining their health. This specially The good news in this situation for
comes to the fore in times of large number companies in pharmaceutical and medical
of new and untested infectious diseases device industry is that the initiatives of
such as swine flu, and its cause the virus regulatory bodies (such as the FDA11 and
H1N1. others.) support these changes with the
In order to meet all requests and risk reduction approach as the embedding
requirements and respond to the of quality in the manufacturing process
challenges these companies are struggling from the very beginning (quality by design
to find ways to reduce internal costs and - QbD)12 instead of relying on the final
cycle times by providing high quality laboratory testing (quality by testing -
services to users, through innovative QbT)13.
design and efficient response to the All previously presented elements and
unexpected increase in demand for certain current developments in the
products. However, balancing between the pharmaceutical and medical device
desire to reduce costs, on one side and industry are in favor that it is now an ideal
innovative design, on the other is often time to turn to the principles of Six Sigma
very difficult. Thus, for example, when it
comes to merging of pharmaceutical 10
www.pharmafocusasia.com, Pharmaceutical
companies, the initial intention is to Manufacturers, Embracing Lean Six Sigma, John E.
reduce costs, what in case of research and Danese, Dennis Constantinou, Life Sciences
11
development (R & D) departments means a FDA – Food and Drug Administration, USA
cut off .9 Although there is still no right regulatory agency for control of food and drugs
12
QbD – Quality by design, new FDA’s initiative
solution to these economic problems, the the focus of which is that quality should be built into
a product with a thorough understanding of the
product and process by which it is developed and
9
manufactured along with a knowledge of the risks
www.businessweek.com/technology/content/mar2009 involved in manufacturing the product and how best
, Drug Mergers: Killers for Research, When big to mitigate those risks.
13
pharmaceutical companies merge, like Merck and QbT – Quality by testing, adopted principle by
Schering-Plough or Pfizer and Wyeth, R&D always pharmaceutical industry of assuring product quality
seems to suffer, Catherine Arnst by final laboratory testing

260 K. Pavlović, V. Božanić


and Lean. transformation
In the environment which does not accept
2. UNDERSTANDING THE changes consequences have impact on
NEED FOR CHANGE quality as well. Statistics show that the
(CHANGE OF THE STATUS number of drug recalls has increased
QUO) drastically on yearly basis, three quarters
of which are attributed to manufacturing
First step towards embracing Six defects. The reject percentage in the
sigma and Lean is to understand and pharmaceutical industry ranges from 5
accept the need for change. Despite its percent to 10 percent (< 2 sigma),
focus on quality, it is the fact that compared to 0.0001 (6 sigma) in the
pharmaceutical industry has failed to keep semiconductor industry. The reject
up with other industries in terms of percentage costs the pharmaceutical
manufacturing efficiency and productivity, industry between 4.5 and 9 billion US$ per
the main reason for this being high costs year, which is quite a lot compared to 90
and burden involved in revalidating any billion spent on manufacturing.
process change, even though changes were Several important factors have led in
made in the spirit of improvement. recent years to substantial change in the
Pharmaceutical manufacturers reluctantly approach and management of
change processes which are confirmed and manufacturing operations in
validated and accepted as complainant. pharmaceutical industry. First, many
From the historical perspective, manufacturers face the fact that they can
pharmaceutical manufacturers who had not keep up with development pace and
high profit margins had not enough sustain competition from the part of
economic stimulus to introduce changes. It generic drug manufacturers.15 As such,
is obvious that this situation has changed. they see a growing need to abandon the
This already mentioned pharmaceutical status quo and to focus on improving
industry’s commitment on maintaining the productivity, efficiency and quality.
status quo has produced inefficiency and At the same time U.S. FDA and other
increament in waste. It is estimated that the regulatory bodies have come to the
world wide potential cost savings from conclusion that pharmaceutical industry
efficiency improvement in pharmaceutical has fallen behind other sectors in terms of
industry could be as high as 90 billion efficiency and quality and based on that
dollars per year. On the other hand it is a they have begun to endorse a “quality by
known fact that Reasearch and design” model instead of current “quality
Development are the major cost center in by testing”. As part of this change FDA
pharmaceutical companies, while has launched its PAT (Process Analytical
manufacturing accounts for more than Technology)16 initiative, a risk based
twice the expenses of R&D, representing
around 36% of total costs. The true costs 15
www.pharmafocusasia.com, Pharmaceutical
of manufacturing become apparent when Manufacturers, Embracing Lean Six Sigma, John E.
one considers the non value added Danese, Dennis Constantinou, Life Sciences
activities and waste which represent 80% 16
PAT – Process analytical technology, one of
and 50% respectively.14 Picture 1. show FDA’s initiatives for pharmaceutical industry in 21st
changes demanded for succesfull Lean century, which represents a system for design,
analysis and manufacturing control, by measurement
of critical quality parameters and performance
14 attributes of raw material, in process and process with
www.pharmafocusasia.com, Pharmaceutical
Manufacturers, Embracing Lean Six Sigma, John E. the goal of assuring final product quality
Danese, Dennis Constantinou, Life Sciences

4th IQC May, 19 2010 261


guidance model which is to direct consistent and predictable quality (higher
pharmaceutical manufacturers toward sigmas).

Figure 1. Changes demanded for succesfull Lean transformation 17


The PAT approach leads to rising of rules and institutionalized tradition of drug
quality level through a deep understanding manufacturing in order to ensure the
of variability of process parameters, which safety, reliability and quality.
effect product quality from its very The current scientific risk-based
beginning.17 framework and the process analytical
In the past, pharmaceutical industry, technology (PAT) initiatives, developed by
for which the principles of Good regulatory authorities to support
Manufacturing Practice are mandatory, has innovation and efficiency in a cGMP
slowly been embracing Lean environment, suggest a new way of
manufacturing, in contrast to other sectors thinking for the 21st century.18
that adopted it relatively quickly and Since 2001, regulatory authority
successfully. Therefore, in this article policies have promoted initiatives designed
emphasis was put on the comparison of to increase the availability of new and
cGMP and Lean approach, identifying affordable medicines. This new thinking
areas of overlap, as well as the challenges should help the pharmaceutical industry
faced by pharmaceutical companies while move towards innovation in manufacturing
turning to Lean manufacturing. and alleviate the fear of lean improvement.
These fears will only be removed when
manufacturers are confident that a
3. COMPARISON OF CGMP successful lean implementation in a cGMP
AND LEAN environment can have both regulatory
approval and be technically dependable.
GMP has evolved gradually, A comparison of cGMP with lean
representing a complex system of rigorous
18
Lean Manufacturing practice in cGMP
environment, Oct 1, 2006, Anne Greene, Dermot O
17
www.pharmafocusasia.com, Pharmaceutical Rourke, Pharmaceutical Technology Europe, Vol 18,
Manufacturers, Embracing Lean Six Sigma, John E. Issue 10
Danese, Dennis Constantinou, Life Sciences

262 K. Pavlović, V. Božanić


manufacturing (Table 2) might suggest has changed very little in comparison with
that they belong to two conflicting their expectation for a personal computer
families. during the last thirty years. They still
While cGMP focuses on expect the tablet to be safe and effective,
manufacturing as a means to produce safe while they expect the computer to have
and effective products for the patient, lean improved and provide greater value in
focuses on manufacturing as a location for return for the price paid. In table 2.
improvement and value creation from a comparison of the most important
customer's perspective. For example, the attributes of Lean concept and principles
public's expectation for an aspirin tablet of cGMP were shown.
Area LEAN cGMP
Objectives Reduce waste Ensure product effectiveness
Create value Prevent harm
Focus Value stream Product development,
manufacturing and quality
assurance
Approach to manufacturing Quality balanced with Quality first
productivity

Improvement Continuous and Regulated and prudent


simultaneous

Typical goals Reduce cost Follow validated process


Improve quality Prevent deviation
Reduce cycle time
Reduce inventory
Improve delivery
Typical tools Value stream mapping Documentation
Kaizen improvement Personal qualifications and
Error proofing training
Moving to pull Cleanliness
Simple flow Validation and qualification
Training Complaint review
Quality function Audits
deployment
Table 2. Comparison of the most important attributes of Lean concept and principles of
cGMP in pharmaceutical production 21
Lean's dual objectives, to reduce or discussed.19
eliminate waste and to create value, differ Lean pharma
from cGMP's objective, which is to ensure Lean pharma can best be viewed by
that all levels of control are in place to looking across the lean landscape from a
deliver a safe and effective medicinal cGMP perspective. To do this, one has to
product. Perhaps where cGMP and lean do define in simple terms what "lean"
overlap is in a shared history in the control means.21
of the manufacturing environment. To see
the degree of overlap, a new perspective of 19
Lean Manufacturing practice in cGMP
lean, referred to as lean pharma, will be environment, Oct 1, 2006, Anne Greene, Dermot O
Rourke, Pharmaceutical Technology Europe, Vol 18,
Issue 10

4th IQC May, 19 2010 263


Lean landscape as standard operating procedures (SOPs)21,
In 1999, Spear and Bowen identified testing methods, environmental controls
four rules that describe the make-up of the and training programmes. This
lean manufacturing system.20 documentation can be divided into
• Standard work — all work must technical standards and operational
be specified as to content, procedures.
sequence, timing and outcomes. Technical standards, such as product
• Clear relationships and specifications, validated settings and
communications — every internal production conditions, can only change
customer-supplier connection following a change control exercise.
must be direct with unambiguous Operational procedures, such as the way
ways to send requests and receive people interact with equipment and the
responses. way that product flows, are based on
• Simple flow — the pathway for custom and experience, and will change
every product and service must be regularly in response to deviation or safety
simple, direct and followed. concerns.
• Scientific method — The essence of lean pharma is
improvement should be made determining how current operational
using scientific methodology, procedures can be modified to support
under the guidance of a teacher short-term improvement, while
and at the lowest possible level in maintaining the technical standards — thus
the organization. ensuring no risk to the product. An attempt
They identified the lean is made to do this, from a cGMP
manufacturing paradox; the existence of perspective, for each of the four rules
rigidly documented processes that operate defined here.21
in a flexible and adaptable environment. It
is the combination of being able to Rule 1: Standard work
perform the simple things right, while also Standard work in lean manufacturing
having the ability to change and adapt to is an agreed set of work procedures that
customers' demands, which makes lean establish the best and most reliable
such a successful improvement methods and sequences for each process
methodology and business survival tool. and employee.4 It is a detailed instruction
For the purpose of this article, it will be on how a task can best be performed
assumed that these four rules must be today, with the understanding that it can be
followed for a traditional manufacturing improved tomorrow.
culture to reach the tipping point to Standard work procedures are
transform into a lean manufacturing communicated simply and easily; more
culture. chart and display than paragraphs and
pages. The employees who work with the
process write the standard work
4. GMP PERSPEPCTIVE procedures and their descriptions reflect
what actually happens in the work place
rather than what might happen. It is written
One of the characteristics of a cGMP
after the manufacturing step has been
manufacturing environment is the
optimized to ensure product quality is
abundance of documented processes such
reproducible and product flow is
continuous.
20
S. Spear and H. K. Bowen, Decoding the DNA
of the Toyota Production System (Harvard Business
21
Review, Boston, MA, USA, 1999) SOP – Standard Operating Procedure

264 K. Pavlović, V. Božanić


Standard work is desired because if take-off plate".
you can standardize a process then you can In a lean pharma plant, SOPs and other
control it; and if you control it, then you manufacturing instructions would be
can improve it. This is the essence of this viewed as a means to expose problems and
rule. encourage improvement. Technical
In lean manufacturing, every step in standards will be identified and fixed in
every operation is performed in a line with regulatory requirements; all other
predictable manner. The time, sequence, operational procedures would be reviewed
outcomes and inventory levels for each on a systematic basis and standardized
step are specified. The work time to with respect to time, sequence, content and
perform a task is independent of the outcome. For example, the batch
operator, so if it changes (increases or manufacturing instruction could still
decreases) a problem has occurred. This contain the term "charge the blender", but
immediately alerts the team leader to a the work standard for the blender would be
problem as it happens, thus ensuring real– written by the people who perform the
time control.22 action and would appear in a separate
Looking at the pharmaceutical form, possibly as a chart or on-line
industry, it may appear that standard work display.21
is already in situ, with SOPs,
manufacturing instructions, testing Key points:
methods and validation protocols. 1. cGMP and Lean overlap with a
However, these documents are often shared history in the control of
written by team leaders or scientists the manufacturing environment
following validation and are only updated 2. In a lean pharma manufacturing
in response to a deviation, safety or quality environment cGMP and Lean
issue. must be equal partners
In the cGMP environment, critical 3. FDA’s PAT initiative is well
specifications and technical standards are aligned with Lean manufacturing
very well defined, deviations from which The challenge for the pharmaceutical
are obvious and thus action can be taken. industry in turning to lean is the design of
Operational procedures, however, are often new operational procedures that are
light on detail and as a result, variations in consistent with all external regulatory
these may not be detected. For example, requirements, but also support continuous
the way an operator sets up a workstation improvement.
may vary with respect to time and
outcomes. A check sheet may ensure that Rule 2: Clear relationships
critical steps have been completed, but the In the lean manufacturing
manner in which the end-result was environment, every customer-supplier
achieved is not obvious. It is then possible connection is direct with unambiguous
for work variation to enter if people use ways to communicate. There is a clear and
slightly different methods to achieve the agreed way to send requests and receive
same result. Typical finished dose responses. Product and information flows
manufacturing working instructions may from one department to another and the
include "charge the blender...", "set up barriers between departments are reduced.
The overall goal is to keep product
22
Real time – term which defines reaction in a flowing. Consistent cycle time is an
specific moment when something occurs, implying indicator of good internal supplier-
interactive releationship with a phenomenon, process customer relationships.
and participants in order to be able to control and
manage. In the cGMP environment, product

4th IQC May, 19 2010 265


cycle time is quality driven; it may take resolved across the plant.
longer to release a batch than it does to
produce it. Different departments usually Rule 3: Simple flow
have clear individual responsibilities and In lean manufacturing, the pathway
objectives. Departments often have for every product and service must be
separate responsibilities and objectives, simple and direct. Simple in that there is
resulting in teams working in isolation or only one way to move forward and direct
in conflict with one another. Individual in that there are no loops, forks or fast
departments are often unaware of the paths.
impact that their delays or problems have In the cGMP environment, the product
on overall product flow. path tends to be direct but far from simple
In the lean pharma environment, cycle because of batch manufacturing. This
time and quality would be of equal batch production method is inherent in
importance. This overlaps with FDA's cGMP to prevent cross-contamination.
PAT framework of reducing production Each process step usually has a holding
cycle time. When a deviation in cycle time for work in process, thus encouraging
occurs, it may indicate potential quality intermittent flow. Typically, a
issues. For example, if it typically takes an pharmaceutical facility operates with
operator 40 minutes to set up a tablet press surplus capacity to keep the product
but a batch takes longer, this indicates a moving, rather than flowing; however, this
problem with that batch. In lean pharma, a operational mode obstructs simple flow.
request for help would be made by the For example, when a batch of tablets is
operator at 41 minutes, thus commencing scheduled to run on a blister pack line and
an investigation. three lines are available, surplus capacity
The need to ask for help when product at packaging exists. This will hide the
flow is interrupted may lead to the reasons for any excessive downtime and
identification of quality issues that slow changeover on the lines.
otherwise might have been hidden from Having available surplus capacity
view or only detected during final release. does not encourage continuous
For example, when an operator in a improvement or problem identification.
traditional pharma plant is required to From the customer's perspective, the fact
produce a tablet to a specified that a pharmaceutical plant is running with
disintegration time, the time it takes to set surplus capacity should have little
up the tablet press to produce tablets consequences in the short-term. The
meeting the required technical standard is product will still be delivered on time, at
not controlled. In a lean pharma plant, the the right quality and in accordance with
operator would have a work time standard. cGMP, but the plant with surplus capacity
If it is not possible to produce the tablet to available has higher operating costs.
the required disintegration specification In the lean pharma plant, product or
within this time, a call for help would be services would not flow to the next
made. This may expose a problem in the available person or tool, but to a specified
upstream process, in this case granulation, person or item of equipment. This rule
which would otherwise be masked. enforces the economies of repetition — the
The challenge for pharma in moving more times you take a certain path the
towards lean is to reduce the grey zones of more familiar you are with that path. Each
responsibility, slow response and late calls time the product takes the same path, an
for help when problems occur, and move experiment will occur to uncover variation
towards an environment where problems and expose problems. This encourages
are immediately identified, shared and continuous learning over the life cycle of a

266 K. Pavlović, V. Božanić


product. which is to produce product in a controlled
A batch moving from manufacturing and consistent manner.
to finished goods would only slow down Traditional improvements in the cGMP
for a value adding step. There would be a environment come out of reaction to
continuous programme to reduce batch deviation rather than from the need for
queues and a move towards small-scale variation reduction. The fear of change and
equipment to improve efficiency and the current systems to control it, together
manage variability. In lean pharma, the make continuous improvement very
focus would be to reduce your batch size, difficult. However, some pharmaceutical
move towards single unit flow, and thus
plants already operate with well-controlled
improve responsiveness to changes in
and optimum processes. For these plants
customers demand.
the move towards lean should not be such
The challenge for pharma in moving
towards lean is to introduce simple flow a challenge.
for products and services and expose areas The challenge for the pharmaceutical
where improvement in flow will reduce industry in moving towards lean is to
cycle time and cost. To move forward implement FDA's risk-based approach,
from batch manufacturing towards single which is firmly based on science and
unit flow. engineering principles.24

Rule 4: Scientific improvement


The first three rules are project rules, 5. CONCLUSION
which show how to set up operations as
experiments, with an expectation to control In a lean pharma manufacturing
the process and to ensure it is reproducible. environment, cGMP and lean must be
The fourth is the rule on improvement. equal partners. The cGMP standards
together with lean principles must be
Once you can do the job consistently every
embedded into the culture of an
time, then you can improve. Attempting to
organization and the business strategy
improve a process that has too much
must reflect this. This challenge is less
variation often makes the process slower problematic because of recent changes in
or reduce the effect of any improvements. regulatory thinking. The principles of
In lean manufacturing, the scientific FDA's PAT initiative appear to be
methodology is the driving force to total extremely well aligned with lean
quality. Without this, the manufacturing manufacturing thinking, suggesting a
process is too variable and unstable to positive outlook for lean pharma, which
enable the introduction of a lean has successfully been implemented in
manufacturing philosophy.23 companies such as Astra Zeneca, Johnson
The cGMP environment is already rich in & Johnson, Pfizer and others.
science. Science is used to develop the
batch manufacturing process, support
laboratory testing and evaluate product
release to market. The employees who
"handle" the product have a defined role,

23
H. Thomas, Transforming the Pharma Industry:
24
Lean Thinking Applied to the Pharmaceutical US Food and Drug Administration (5600
Manufacturing, Section 2, World Congress of Fishers Lane, Rockville, MD 20857–0001, USA),
Chemical Engineering (WCCE7), Glasgow, UK, Jul Pharmaceutical cGMPs for the 21st Century — A
2005 Risk-Based Approach, September 2004.

4th IQC May, 19 2010 267


REFERENCES:

[1] An Introduction to Lean, Deborah Blecker-Shelly and Joel E. Mortensen, Continuing


Education Topics & Issues, August 2008
[2] www.ngpharma.com ,Design for Six Sigma and Lean Six Sigma for the Pharmaceutical
and Medical Industries, Tania Pinilla, Six Sigma Master Black Belt, Motorola University
[3] www.businessweek.com/technology/content/mar2009, Drug Mergers: Killers for
Research, When big pharmaceutical companies merge, like Merck and Schering-Plough or
Pfizer and Wyeth, R&D always seems to suffer, Catherine Arnst
[4] www.pharmafocusasia.com, Pharmaceutical Manufacturers, Embracing Lean Six Sigma,
John E. Danese, Dennis Constantinou, Life Sciences
[5] Lean Manufacturing practice in cGMP environment, Oct 1, 2006, Anne Greene, Dermot O
Rourke, Pharmaceutical Technology Europe, Vol 18, Issue 10
[6] S. Spear and H. K. Bowen, Decoding the DNA of the Toyota Production System (Harvard
Business Review, Boston, MA, USA, 1999)
[7] H. Thomas, Transforming the Pharma Industry: Lean Thinking Applied to the
Pharmaceutical Manufacturing, Section 2, World Congress of Chemical Engineering
(WCCE7), Glasgow, UK, July 2005
[8] US Food and Drug Administration (5600 Fishers Lane, Rockville, MD 20857–0001,
USA), Pharmaceutical cGMPs for the 21st Century — A Risk-Based Approach,
September 2004.

268 K. Pavlović, V. Božanić