The document discusses various process improvement techniques and their applicability in pharmaceutical manufacturing. It describes techniques like Six Sigma, Lean Manufacturing, Lean Six Sigma, Total Quality Management, Toyota Production System/Just-in-Time, Theory of Constraints, and tools like FMEA and PDCA cycle. These techniques aim to reduce defects, waste, variation and improve efficiency in pharmaceutical operations throughout the product lifecycle from development to manufacturing to distribution. The document emphasizes applying these techniques and tools at various stages like development, manufacturing, and lifecycle management to ensure defect-free quality and efficient processes.

1. PROCESS IMPROVEMENT TECHNIQUES AND
ITS APPLICABILITY IN PHARMACEUTICAL
MANUFACTURING- AN OVERVIEW
BY:
VIKALP NAGORI
1

2. 2
“Failure of management to plan for the future and to foresee problems has brought about
waste of manpower, of materials, and of machine-time, all of which raise the manufacturer's
cost and price that the purchaser must pay.” - Deming
 As research has shown that the cost of poor quality is much higher of total budget in
manufacturing processes and observed much in pharmaceutical mfg through recalls and
regulatory inspection reports.
 Some of the concept and methodology are very much in use as recommended by many
pharmaceutical guidance and have shown tremendous impact in the form of improvement in
operation efficiencies but through specific experts only.
QBD, Risk Management and PAT tools (Process Analytical technology)
 To continue with this methodology based on observed benefits in this challenging competitive
global environment and to achieve its goal further for 0 defect and 100% efficiency utilization it is
necessary to have basic knowledge of available methodologies, tools and its applicability at
relevant stage to each professional involved in pharmaceutical operations especially in
manufacturing.
 In case of Pharmaceutical Manufacturing process where the processes are differ from each other
vastly hence difficult to adapt same Six Sigma and other tools. Because of the variability in
processes and anticipated changes throughout life cycle for pharmaceutical manufacturing,
information and knowledge of different methodologies and tools is necessary to deal with the
challenges.

3. Earlier : Quality means to segregate the good
quality product but it has lot of wastage and hence
cost to manufacturers
Now : The controls means process controls to
make 100 % good quality product where there will
not be any segregation required which will reduce
the time, resource and wastage.
Challenges for Pharmaceutical Industries
1) Ever changing regulatory requirements that too
with differences as per region or market.
2) Most complex technologies and number of
processes involved.
3) Maximum number of changes during product
lifecycle.
4) Dependency of Multiple sources for different
types of materials.
Due to above challenges the strategic emphasis
has been on developing a pipeline of new drugs
rather than on productivity improvement, supply
chain optimization, and cost reduction. Which
need to be expand for manufacturing monitoring
and continuous improvement opportunities.
FOLLOWING METHODOLOGIES HAVE BEEN
DISCUSSED IN DETAIL IN THIS PROJECT.
SIX SIGMA: A data-driven approach to reduce defects to
improve an organization's performance.
LEAN MANUFACTURING: A systematic process to minimize
waste without sacrificing productivity.
LEAN SIX SIGMA: A combination of Lean and Six Sigma
methodologies.
TOTAL QUALITY MANAGEMENT (TQM): An organization-
wide effort focused on continuous improvement to improve
customer quality.
TOYOTA SYSTEM PRODUCTION/JUST-IN-TIME:
Methodology cantered around reducing inventory costs,
manufacturing products only as they're needed.
THEORY OF CONSTRAINTS: A systematic process focused
on finding and eliminating constraints.
3
INTRODUCTION

4. SIX SIGMA
A 3s process - because 3 standard
deviations fit between target and
acceptance goalposts
3s
2s
1s
Customer
Specification
Target
Before
3s
“Defects ~ 66807 ppm”
Continuous improvement:
By reducing variability
we improve the process
Target Customer
Specification
6s
After
1s
6s
3s
“Defects ~ 3.4 ppm”
Process optimisation tools
1) The SIPOC
2) CT (critical to) tree
3) Modelling
4) Simulation
5) C and E (cause-and-effect) matrix
6) Fishbone diagram
7)FMEA (failure mode effects
analysis)
8) Capability and complexity
analysis
9) Plans
Statistical analysis tools
1) Plots and Charts
2) Time Series
3) ANOVA
4) Tolerance Analysis
5) Design of Experiments (DOE)
6) Process Capability Analysis
7) Regression
8) Multivariate Analysis
9) Measurement Systems Analysis 4

5. 5
LEAN MANUFACTURING
This topic emphasise how modern manufacturing
process could be made as effective as possible
and how to address wastage primarily.
Manufacturing is defined as set of activities which convert
individual raw materials in to Finished Product and non value
added activities need to be eliminated through work study and
modifications as well through attitudinal/behavioural changes.
Inspired by Toyota Production System (TPS) by Taiichi Ohno.
This system is a socio technical system because of involvement
of people and machinery and focus on three factors
1) Cost, 2) Quality, 3) Delivery
and can be achieved by shortening the production flow by
eliminating wastage
Value Stream: identification and removal of non value added activities and wastages 7 deadly wests
1) Defects, 2) Inventory, 3) Over processing, 4) Waiting (Delay), 5) Overproduction, 6) Transport, 7) Movement
Quality: Kaizen (continuous improvement), Kanben (Sheduling cards), Poka Yoke (Mistake proofing),
5S (Seiri, Seiton, Seiso, Seiketsu, Shisuke) tools
Faster delivery to customer; The system operation should be customer pull than production push
 Lean ness is about doing more with less and entails: Highest Quality, Lowest Cost and Shortest Lead Time, Leanness keeps
the organization alert nimble for change, Leanness develops multi – skill labour and promotes employee engagement.

6. 6
All the Six Sigma tool are used mainly for Following two
framework of Lean Manufacturing
DMAIC follows these steps (For Improving Existing
Process):
1) Define the opportunity for improvement
2) Measure the performance of existing process.
3) Analyse the process to find any defects and their root causes.
4) Improve the process by addressing the root causes found.
5) Control the improved process and future process
performance to correct any deviations before they result in
defects.
DMADV follows similar steps (For Creating new process)
1) Define the process goal, keeping in line with the overall
company strategy and customer needs.
2) Measure the factors that are critical to quality (called CTQs).
3) Analyse various design and development options.
4) Design the process.
5) Verify that the design meets process goals and customer
needs.
Pilot the process and, if successful, implement the process.
LEAN SIX SIGMA
To eliminate this waste and produce the best results, an
organization must follow the below five fundamental
principles:
 Focus on the customer.
 Map out the value stream.
 Remove waste (non-value added steps)
 Communicate with your team.
 Create a culture of change and flexibility.
Based on experience of performing Six Sigma projects
recommend to designing an improvement checklist and
follow it religiously as well update it with Every new
experience to make this tools more efficient
A strategic problem solving and process improvement
strategy that combines two powerful methodologies that
focus on reducing waste and variation.
• Lean Manufacturing Principles = Waste
reduction
• Six Sigma Methodology = Variation reduction

7. 7
TOTAL QUALITY MANAGEMENT (TQM)
TQM can vary from company to company, but organizations
using TQM generally follow these principles:
 Organizations follow a strategic and systematic
approach to achieve their goals.
 Customers determine the level of quality.
 All employees work toward common goals. Effective
communication and training ensure that everyone
understands the definition of quality and strives to
achieve it.
 Organizations should define the required steps of any
process and monitor performance to detect any
deviations. They should continually look for ways to be
more effective and more competitive.
Total Quality Management predates Six Sigma and Lean
methodologies and Success results from customer
satisfaction within this system.
 Lean Manufacturing Principles = Waste reduction
 Six Sigma Methodology = Variation reduction
TQM recommend several tools to measure quality,
including
 The Ishikawa diagrams,
 Flowcharts,
 Check Sheets,
 PDCA / PDSA cycles
 FMEA

8. 8
TOYOTA PRODUCTION SYSTEM/JUST-IN-TIME
Purpose of these approaches is to eliminate waste, reduce
variability and improve throughput
Waste considered here is any activity that does not add
value to the customer
Seven Categories of
Waste:
1. Overproduction
2. Queues
3. Transportation
4. Inventory
5. Motion
6. Over processing
7. Defects
Five Ss to get rid of these
wastes:
a) Seicri / Sorting,
b) Sciston /setting order,
c) Seiso / cleanliness,
d) Seiketsu / standardizing,
e) Shituske / Self decipline.
Challenge
Form a long term vision, meeting challenges with courage and creativity.
Kaizen
Improve our business operations continuously, always driving for
innovation and evolution.
Genchi Genbutsu
Go and see for yourself!......go to the source to find the facts to make
correct decisions, build consensus and achieve goals at our best speed.
Continuous
Improvement
Respect for
People
Respect
Respect others, respect yourself, and make every effort to understand
each other, take responsibility and do our best to build mutual trust.
Teamwork
Stimulate personal and professional growth, share the opportunities of
development and maximize individual and team performance.

9. 9
Customer First
The House of TPS
TOYOTA PRODUCTION SYSTEM/JUST-IN-TIME

10. 10
THEORY OF CONSTRAINT
The Theory of Constraints is a methodology for identifying
the most important limiting factor (i.e. constraint) comes in
the way of achieving a goal and then systematically
improving that constraint until it is no longer the limiting
factor. In manufacturing, the constraint is often referred to
as a bottleneck.
The Theory of Constraints takes a scientific approach to
improvement. It hypothesizes that every complex system,
including manufacturing processes, consists of multiple
linked activities, one of which acts as a constraint upon the
entire system (i.e. the constraint activity is the “weakest
link in the chain”), means system is like a chain or network
of chains and a system is only as strong as its weakest
link.
According to TOC, organizations will always face at least
one constraint, meaning that there will always be
something to be improved.
Mean Improvement by TOC are reported by following well
known parameters
a) Lead Times: Mean Reduction
b) Cycle Times: Mean Reduction
c) Due Date-Performance: Mean Improvement
d) Inventory Levels: Mean Reduction
e) Revenue: Mean Increase
f) Throughput: Mean Increase
g) Profitability: Mean Increase
Drum-Buffer-Rope (DBR) is a method of synchronizing
production to the constraint while minimizing inventory and work-
in-process.
The “Drum” is the constraint.
The “Buffer” is the level of inventory needed to maintain
consistent production.
The “Rope” is a signal generated by the constraint indicating that
some amount of inventory has been consumed.

11. 11
Theory of Constraint
The Theory of Constraints provides a powerful set of following three tools for helping to achieve that goal, including:
1. Five focusing steps:
I. Identify the constraint.
II. Decide how to exploit the constraint.
III. Subordinate and synchronize to the constraint.
IV. Alleviate the constraint.
V. Repeat the process as needed.
2. The Thinking Processes
The Thinking Processes are used to answer the following three questions, which are essential to TOC:
I. What needs to be changed?
II. What should it be changed to?
III. What actions will cause the change?
3. Throughput Accounting
I. Throughput - The rate at which system generate money through sales.
II. Investment - Money that is tied up in physical things: product inventory, machinery and equipment, real estate,
etc.
III. Operating Expense - All the money the system spends in turning inventory in to throughput, other than truly
variable costs (e.g. payroll, utilities, taxes, etc.). The cost of maintaining a given level of capacity.

12.  IDEA GENERATION: During Idea
Generation One Must consider the
DROP ERRORS (Like Xerox by
Walmart) and GO ERRORS (Like K
Mart and Amul Pizzas)
 IDEA SCREENING: Generated Ideas
should be screened based on Strategic
risk (like genuine need) , Market Risk,
Internal Risk
 PROJECT PLANNING: Initially By
Analysing rough form and estimated
cost, Establishing the Budget after
review with the management
 PRODUCT DEVELOPMENT: Evaluated
from portfolio, Engineering,
Manufacturing followed by R&D
Prototype Development and
Development report preparation
 TEST MARKETING: Through
Marketing Mix like Interaction with
Buyers
 COMMERCIALISATION: Introducing
the product into the market place.
Eliminate bugs in design of
Production  Costing Quality
ControlMarketing
 LIFECYCLE MANAGMENT: Continuous
monitoring  Change Management 
Continuous Improvement
 **Highlighted In Red Font are the
stages where the all methodologies and
tools will be utilized to ensure Defect
free Quality of product along with
efficient process through out life cycle.
12
PRODUCT LIFE CYCLE STAGES

13. (Plan, Do, Check, Act) :
Businesses use it for continual process
improvement, listing out the proposed plan,
testing the plan, and checking the plan's
success.
Further improvements were made and the
newest version was developed as Plan-Do-
Study-Act or PDSA cycle.
The main purpose of this philosophic
approach is to develop, test and implement
changes which would lead to the
improvement by initiating immediate actions
based on careful study.
13
PDCA CYCLE

14. FAILURE MODE & EFFECTS ANALYSIS (FMEA)
Failure Mode & Effects Analysis is one of the Problem Solving technique
With foresight-problems could have been avoided if only someone had asked
“What could go Wrong?” or anticipating the things that could possibly go wrong at
design stage can cheaply solve problems.
 FMEA provides a useful approach for reviewing existing processes or systems,
so that problems with these can be identified and eliminated.
 It builds on tools like Risk Analysis and Cause and Effect Analysis- try to predict
failure before they happen.
Thus FMEA is a systematic method of identifying and preventing – System, product
and process problems before they occur
Developed by the Aerospace industry and spread to the Automotive industry and
now used extensively in pharmaceutical industry as Design stage, Product Stage
and Process Stage.
14

15. Stages
 Start by looking in detail at proposed solution
 Identify systematically all the points where it could fail
 Upon identification rate the potential consequences of each according to following three
factors
1) Severity
2) Occurrence
3) Detection
 Ranking based on most serious threats
 Alter the design to minimize or eliminate the likelihood of failure
 Its worth repeating the FMEA in case of redesigned the solution
FMEA Provides a systematic process to:
 Identify and Evaluate Potential failure modes and potential causes of the failure
 Identify and quantify the impact of potential failures
 Identify and prioritize actions
 Implement action plan based on assigned responsibilities with completion time line 15
(FMEA)

16. Guide to do Process FMEA
Step 1 Scope of Project
Step 2 Brainstorm all potential failure modes
Step 3 Identifying potential effects of failures
Step 4  Determine severity Ranking
Step 5  Identify causes of failure
Step 6  Determination Occurrences Ranking
Step 7  Define current control methods
Step 8  Determine Detection ranking
Step 9  Calculate Risk Priority Numbers
(RPN=Severity x Occurrence X Detection Ranking)
Step 10  Prioritise corrective actions
Benefits
FMEA is focused on preventing problems and increasing customer satisfaction
Has potential to be used in project management
Proactively prevent & Solve problems
Reduce costs by identifying system, product and process improvements early in the development
cycle
Create more robust processes and build quality into the product & process
Recommended to use at all the stages of product lifecycle by revisiting the initial and
updating along with change management
16
(FMEA)

17. 17
The discussion under this project provides principles & examples of tools that can be applied to different
aspects of pharmaceutical operations throughout the lifecycle of drug substances, drug (medicinal) products.
Emphasis given here to specific area of Manufacturing stage during Product Development, Product
Manufacturing and Product Life Cycle.
Based on published recommendations under regulatory guidance the purpose of the discussed
tools and techniques is to provide a general overview of and references for some of the primary
tools that might be used in quality risk management and efficient manufacturing process design by
pharmaceutical industry. It is important to note that no one tool or set of tools is applicable to every
situation in which a quality risk management procedure is used.
Following are the basic tools with which all pharmaceutical manufacturing professionals should be aware of;
1 Basic risk management facilitation methods
 Flowcharts;  Check Sheets;  Process Mapping;  Cause and Effect Diagrams (also called an Ishikawa
diagram or fish bone diagram).
2 Failure Mode Effects Analysis (FMEA)
3 Fault Tree Analysis (FTA)
4 Risk ranking and filtering
5 Supporting statistical tools
CONCLUSION

18. LEARNING
continued…..