Lean perspective of Process

Intensification

SANDIP BOSE - SUN PHARMACEUTICALS INDIA LTD

INNOVATION BECOMES REALITY

Manufacturing Operations Intensification A new approach

• The pharmaceutical industry’s main goal is to extend and enhance human life while complying with various control of high cost commercial operation , Quality regulations ,pollution prevention and safety regulations

• API (Active Pharmaceutical Ingredient)

• The compound within the pill or solution that treats the disease

• Energy usage is between 50-300 MJ/kg API

• Solvent usage is around 300 kg/kg API

The Goal

Lean Manufacturing Definition

Lean has been defined in many different ways.

“A systematic approach to identifying and eliminating waste(non-value-added activities) through continuous improvement by flowing the product at the pull of the customer in pursuit of perfection.”

Muda (Waste)

Taiichi Ohno (1912-1990), the Toyota executive who was the most ferocious foe of waste human history has produced, identified the first seven types of muda in manufacturing system:

• Storage

• Transportation

• Waiting

• Motion

• Process

• Defects

• Over-production Muda is everywhere.

• Batch-based processes

• Multi-step synthesis, transformations – intermediates

• Isolations (purification)

• Extensive use of multiple organic solvents and reagents – varying degrees of toxicity

• Limited health data on intermediates

lean manufacturing is a link to green engineering

Lean &

Profit

Maximise profit by using minimum

resources

Green

Preserve & conserve natural resources

Green

Lean &

Profit

Lean & Green Solutions

Is Lean & Green results in same ?

Green Engineering Opportunities

• Investigate process early in development

• Solvent substitution – more benign solvents

• Solvent reduction

• Novel processes for material reuse/recovery

• Reduction in process steps

• “Telescoping” to eliminate intermediate identity

• Continuous flow chemistry –waste & RFT

• Challenge - maintain drug purity and yield

Green Engineering Needs (con’t)

• Metrics to measure and quantify improvements • What to measure, how to

quantify – more than just amount reduced

• Materials

• Mass intensity – amount of raw material needed to produce 1 kg of API

• Solvent intensity • Waste intensity • Water intensity

• Emissions

• Efficiency

• Energy

0

50

100

150

200

250

Lab Pilot Full

Production Scale

Mass In

ten

sit

y (

kg

/kg

AP

I)

Value Stream Mapping for ABC

VSM culminates in intensification

Pre identification - in batch • Between each step is hold time

• Same step is in cluster & cluster wastes

• Huge foot print and space barrier for plant

• High capital flow & higher maintenance

• High degree of back mixing

• Unwanted kinetic path favoured

• Low heat/mass transfer coefficient

• Process replication is empirical

• Yield , selectivity & safety compromised

Post identification – in continuous flow • No hold time on overall flow process as

reactions & unit operations can run continuously

• Each step is continuous no cluster operation , hence no waste

• Abnormally low footprint for same capacity target

• Initially high capital flow but very low maintenance

• Very high heat/mass transfer coefficients

• Process replication is real

• Yield , selectivity & safety by design

waste minimization to waste elimination

• A continuous upward Journey

• A continuous flow is an undisrupted operation

• Steady state variability close to six sigma

Non Lean Batch

process

Lean batch process with

no NVA

Lean continuus flow as Zero NVA and QBD

Lean = Green Leanest approach is the flow process intensification

Pharmaceutical Link • Process Intensification for the Chemical Industry

• What is specific to Pharma and Fine Chemistry Manufacturing?

• Manufacturing Operations Intensification

• Equipment selection to fit Manufacturing needs

• Conclusion

Process Intensification for the Chemical Industry

Switch to Continuous Process

System engineering

Typical proven technologies • Advance flow reactor – microchannel ( corning

/Chemtrix)/Vapourtec

• Coflore technlogis – AM technology ACR/ATRs

• High shear flow reactor – Kinetichem

• Spinning Disk - SPINID

Typical equipment

What is specific to Pharma and Fine Chemistry

Manufacturing

Adopt a lean culture with intensified technology solutions

Pharma & Fine Chemicals Production

• A molecule is the output of a sequence made of 10 to 15 reactive and non-reactive steps (Complexity)

•The Unit Operations are mainly discontinuous (Batch)

•Multipurpose environment (Flexibility)

•Significant use of external providers to source raw materials as well as intermediates (Planning)

Typical Pharma and Fine Chemistry Manufacturing?

• 99% operations are batch based

Batch variability is a main source of not achieving quality, production cycle & cost objectives

• Batch variability is the main barrier to deploy improvement methodologies like Lean Manufacturing and Six Sigma

Quality

Batch characteristics Organic synthesis Bio process

Each molecule or each micro-organism inside the batch vessel, is going through an history (TPC…) that can be significantly different from the others.

The repeatability of this history distribution is low from batch to batch.

Mass transfer Heat transfer Residence time distribution

Mass transfer Residence time distribution Temperature control

Develop chemistries that are less sensitive Develop equipment that are less variable

Use of solvents

Large amount of water used

Batch process variability

Impact

• Batch process variability is responsible for: • 5% batch out of specifications (from 1 to 10%) • A cost of poor quality ( COPQ) in the order of 25% due to heavy quality controls and rework operations

• The inability most of the time to deploy Lean Manufacturing and get rid of the non value added operations

• Eventually lead to a poor first pass yield and a 25-40% cost of poor execution ( COPE)

Manufacturing Operations Intensification

• Use of Advanced Manufacturing Technologies to produce manufacturing quality as

closed as possible to the final Quality delivered to the customer

- Continuous processing is part of it

• Manufacturing cost reduced by at least 25%

- Drastic increase of process capability - Elimination of the non value added rework operation

What and How for pharma/chemical space

• Process Intensification for the Chemical Industry

• What is specific to Pharma and Fine Chemistry Manufacturing? • Manufacturing Operations Intensification • Equipment selection to fit Manufacturing needs

Equipment selection: Heat Transfer

Reactor / Reaction Fit Coefficient (Laurent Falk – ENSIC Nancy –

2010)

Equipment Data Equipment Data

Equipment impact (Chemistry kept constant)

Reactor / Reaction Fit Coefficient (Laurent Falk –

ENSIC Nancy – 2010)

Pharma & Fine Chemicals Production needs

• New Markets • Manufacturing of future molecules and potential new products

• New means higher performances than existing product performances

• This search will start early on in Research

• The challenge will be: • to invent such products, • to develop processes likely requiring more heat and mass transfer • to lower the entry Capex to minimize risks

Continuous reactors with higher mass and heat transfer capability, where the chemistry will continue to deliver higher performance

Lean to Leaner by Continuous mode production

Manufacturing Operations Intensification:

• Significant increase in process capability (from 0,67 to 2)

• Avoidance of non value added rework operations for out of spec batch

• Drastic reduction of Quality control costs

Process Intensification:

• Mass and Heat transfer Optimization through characteristic dimensions reduction of the reactor (from meter to few millimeters)

• Increased product quality, yields, safety and decreased environmental impact

Production Facility Intensification

• Decrease of the footprint associated with production facility more compact, safer and cheaper

Thank you