Process Development

Introduction
 Process Development
Development of new technologies and
products is a Research and Development
(R&D) activity
Specific Goals: produce the desired product
◦ In time
◦ At planned rates
◦ At projected manufacturing cost
◦ At desired quality standards

Cost and planning are continually monitored

from lab phase(Small scale) to
production(Scale up level)
 Product type and raw materials
 Type of product determines the way Process
Development is conducted.
 Base chemicals (commodities) and
intermediates can be dictated by the type of
raw materials available.
Raw
 Base chemicals have a wide range of uses Material (10)
and a long lifetime.
Fuels(10)

Process improvement. Base Chemicals

 Benefit to lowering the cost of production. (20)

Intermediates
Product improvement. (300)
 Consumer products on the other hand,
will be quickly replaced (shorter lifetime). Consumer
products(30 K)
Base chemicals
 The technologies for the production of base chemicals and
intermediates are well established.
 Development activities usually result in minor process
improvements (example a new catalyst or a more energy
efficient equipment)
 Still can have a large impact on overall costs due to the large
volumes involved (example, saving lakhs per tonne of acetic
acid can have a large impact when you produce 500,000).
 Major new advances in processes are still worth pursuing
Consumer Products
In specialty chemicals, drive is toward modified or
new products
Motivated by market demands rather than cost
savings
Some market demands can include new products,
product quality or environmental concerns.
Some examples are environmentally friendly paints,
varied detergents, wood composites used in
building materials, new drugs, etc.
More effort is required in determining the chemical
route of manufacturing. --- a when a new drug is
approved the manufacturing route must also be
approved.
Bulk vs Specialty Chemicals
Process Development
Continuous interaction between experimentation and
economics.
Input: chemical reaction in the lab
Outcome: production plant

Development of a process to take the chemical reaction

in the lab up to a large plant scale in an economic way.

Enlargement of equipment in small steps?

Empirical method, and practical for some applications

but not generally for continuous process.
Scale Up
 Scale up in small steps is expensive especially for larger
continuous production plants.
 Large safety margins are used.
 Time scale shown is very long (8 years...need to reduce
time to process development) due to time associated
with design/construction and operation of small steps.
 Predictive models: Process steps described in a
Mathematical model with predictive value
 Predictive models are used to scale up equipment and
processes from laboratory data or pilot plant to eliminate
steps and save time.
Exploratory phase: the reaction provides
satisfactory yields.
Based on lab data and literature data, the
process concept is put together.
Individual steps are developed and tested
on a lab scale
A process flow sheet is drawn.
A small scale plant is designed (mini-
plant) to evaluate performance of the
entire process.
A pilot plant may be designed and built
for further testing.
At each stage, evaluation occurs.
Continue, stop, or go back to an earlier
stage?
Decisions are based on technical, cost and
market considerations.
Cyclic Nature of Modern Process Development
Breakdown of Steps
Exploratory Phase
◦ Discovery of a new product, a new chemical
synthesis route, or an improvement to a process
◦ Focus on chemical reaction
◦ Obtain information:
 what reactions take place
 thermodynamics and kinetics of the reaction
 selectivity and conversion rates and their dependence
on process parameters
 Catalyst and catalyst deactivation rate
 Preliminary Flowsheet
 Determine the availability and quality of raw materials (first
design step would be compare raw material costs with product
value)
 Draw up preliminary flowsheets and alternatives
 Typically underdefined, so we must make assumptions.
 What units should be used?
 How will the units be connected?
 What T, P and flowrates will be required?
 Difficult b/c there are many ways we can accomplish the goal,
problem is open ended.
Process requirements:
◦ Lowest cost
◦ Satisfies environmental constraints
◦ Easy to start up and operate
We can eliminate alternatives based on the above
considerations
Make the optimal choice based on knowledge,
experience and tools such as process simulation
 Input Information
The reactions and reaction conditions
Desired production rate
Desired product purity (vs. purity)
Raw materials ( purity info here)
Information on rate of reaction, catalyst
deactivation
Processing constraints? (ex. explosion limits,
conditions that cause polymerization, etc.)
Plant and Site data
Physical properties of all components
Information on safety, toxicity, environmental
impact of materials involved in the process.
Cost data for byproducts, equipment and utilities.
Reactor system…2. Separations
Reactor System
◦ First step
◦ Includes reactor, feed, product gas and
liquid recycle streams.
◦ Influences the yields, product distribution
and separations.
◦ example: coal gasification, the amount of H2
and CO2 formed are very different for a
moving bed, fluidized bed, and entrained
flow reactor.
◦ Determine T and P, type of catalyst, phases
of reactant and products
Reaction Information
1. Stoichiometry of reactions taking place
2. Range of T and P for the reactions
3. Phases of the reactions
4. Product distribution vs. conversion
5. Conversion vs. residence time
6. Information on the catalyst

Often available from the literature

Identify any side reactions that may take place
Decision 1: Batch vs. Continuous?
 Production rates
◦ Capacity ≥ 10x106 lb/year, usually continuous
◦ Capacity≤ 1 x 106 lb/year usually batch.
◦ Multiple products in same equipment?
 Market Forces
◦ Seasonal products (fertilizer)
◦ Products with a short lifetime
 Operational Problems
◦ Reaction is very slow
◦ Slurry pumping, materials handling considerations.
◦ Rapidly fouling materials
Conceptual Design
Continuous Process:
◦ Select the units needed
◦ Choose the interconnections between these
units.
◦ Identify process alternatives that should be
considered.
◦ List the dominant design variables.
◦ Estimate optimum processing conditions.
◦ Determine the best processing option
Conceptual Design
Batch process (in addition to previous
decisions)
◦ Which units in the flowsheet should be batch
and which should be continuous?
◦ Which steps can be carried out in a single
vessel vs. using a special separate vessel for
each step?
◦ Is it advantageous to use parallel batch units?
Think about scheduling.
◦ Intermediate storage requirements?
Decision 2: inputs and outputs
Should you purify the feed streams before
they enter the process?
Should you remove or recycle a by
product?
Should you use a gas recycle or purge
stream?
Should you recycle unreacted reactants?
How many product streams will there
be?
Decision 3: Separations
◦ Reaction product contains multiple
components, you must decide how they will
be separated and at what conditions.
◦ Look at the components and how they differ
(ie boiling point, solubility)
◦ Identify possible unit operations (ie.
Distillation, absorption, adsorption, solvent
extraction, etc.)
◦ If reactor effluent is a liquid, use liquid
separation system
 distillation
 liquid extraction, etc.
 Avoid gas absorbers, gas adsorbers.
If reactor effluent is a 2 phase mixture, send liquid to a liquid

system, cool the vapour and send to vapour recovery

 Condenser

 Absorption

 Adsorption

 membrane separations).

◦If either stream has reactants, recycle these.

◦Reactor effluent all vapour – cool to attempt to condense liquid.

◦Follow up by sending vapour to vapour recovery, liquid to liquid

recovery.
Heuristic rules for distillation
sequence
 Remove corrosive or hazardous components as soon as
possible
 Remove reactive components or monomers as soon as
possible
 Remove products as distillates
 Remove recycles as distillates, particularly if they are
recycled to a fixed bed reactor
 Remove most plentiful first
 Remove Lightest first
 High recovery separation last
 Difficult separation last
Example: Production of
cyclohexanone
Product mixture:
◦ cyclohexane 94%
◦ Light products 0.5% Boiling point
◦ Cyclohexanone 3.0%
◦ Cyclohexanol 1.5%
◦ Heavy products 1.0%

All products are similar in terms of corrosiveness,

hazard and reactivity.
1) Remove cyclohexane first (most plentiful and lightest)
2) Separating cyclohexanone and cyclohexanol is the
most difficult, so do this last.
3) Remove heavy or light components next? Heavy since
they are more plentiful.
4) Remove light products
Draw the flowsheet of selected operations
Sizing of unit operations is done based on
available information at that time (this is
preliminary as not all data is available yet,
an iterative process).
Develop and test the individual steps.
Laboratory tests conducted on mixtures
prepared from pure materials, typically
short duration, may not show some
problems.
Pilot plants are the next step
Pilot Plants
 An experimental system that represents the part it
corresponds to in an industrial unit.
 Can range in size from lab scale (mini plant) to
commercial unit (demonstration plant).
 Used to :
◦ generate more product to develop a market
◦ confirm feasibility of the process
◦ check design calculations
◦ solve scaleup problems on novel processes
◦ gain operational know-how
◦ Determine long term effects of operation
 Typically run to 10% of the commercial plant cost.
Mini-plant
 To demonstrate process feasibility or generate design
data for a process, then a mini plant may be more
appropriate than a pilot plant.
 Includes all recycle streams and can be extrapolated
reliably
 Uses same components as the lab testing (ie pumps,
etc.), which is often standardized and can be used in
many other mini plants
 Operated continuously for weeks or months so some
automation is required.
 Is used in combination with process modeling and
simulation of the industrial scale process.
 Typically produces 0.1-1 kg product per hour.
 Relationships of scale

Production rate Scale Up Factor

(kg/h)
Industrial 1000-10,000 -
Plant
Pilot Plant 10-100 10-1000
Miniplant 0.1-1 1000-100,000
Miniplants
Can help to speed up process
development and at a lower cost.
Useful to test catalyst stability under
practical conditions.
Incorporate recycle streams to detect
buildup and effect of impurities.
Some unit operations not easily scaled
from miniplant data (extraction,
crystallization, fluidized beds) due to flow
characteristics.
See fig 5for some scaleup values
Figure 5 Maximum scale up values for process steps
Requirement for Pilot Plant Testing
Reactor Scale Up
 Homogeneous Reactors (single fluid phase)
 Easier to scale up than heterogeneous
 Batch or semi-batch reactor
◦ Main issue is heat removal in highly exothermic reactions
 Continuous tubular reactor
◦ Main issue is heat transfer and T profile in the reactor, kinetic
modeling of reactions is used to relate the reaction to
temperature
 Continuous stirred tank reactor
◦ Scale up from batch reactor kinetic data
Heterogeneous Reactors
Examples include steam reforming,
ammonia synthesis, hydrotreating.
Main issues are T control, P drop and
Catalyst deactivation
Temperature control
◦ In endothermic reactions the T drop may be
severe resulting in an excessively long reactor
◦ Reaction mixture must be heated rapidly to
keep the reaction rate at a high enough level
◦ One way of doing this is to conduct reaction in
tubes in a furnace (steam reforming)
Temperature control
◦ Exothermic reactions need to be cooled
◦ This can be done by external heat exchangers,
injection of cold feed gas.
Pressure Drop
◦ Pressure drop across a catalyst bed must be
limited
◦ Reduce the bed height, use larger particles, apply
axial flow or structure the reactor.
Catalyst deactivation
◦ Design strategies depend on the mechanism of
catalyst deactivation
Catalyst deactivation
◦ For example, if the catalyst is deactivated by coke
deposits, regeneration occurs by burning off coke.
This can be done in a fluid bed reactor.
◦ Impurities may build up in the system that are
undetected at lab scale (low concentration), that
may affect the catalyst if they are recycled.
◦ Larger scale reactions are needed to detect these
so processes can be established to deal with them.
◦ Install pretreatment units, purge some of the
recycle stream.
Hyrodynamics

◦ Fluid distribution in a heterogeneous reactor

may change as you make a reactor larger.
◦ Gas-liquid, solid-liquid contacting
◦ Parameters include diameter and height,
residence time, catalyst particle size
Safety and Loss Prevention
 Chemical plants involve process, storage and transport
of hazardous materials.
 Increasing plant size increases risks
 Plants are often located close to dense populations.
 Loss prevention: identify the hazards of a chemical
process plant and eliminate them.
 Major hazards:
◦ Explosion
◦ Fire
◦ Release of toxic substance
Causes of Chemical Plant Accidents as based on survey
 Flammability
Fires and explosions
Fuel, oxidizer and ignition source
Toxicity and Flammability characteristics of liquids & gases
 Toxicity
“The dose makes the poison”
 Hazard depends on the inherent toxicity
 Frequency and duration of exposure
 Acute vs. chronic effects
 LD50: lethal dose that kills 50% of test animals
 TLV: threshold limit value, conc of exposure for 8 hours
a day, 5 days a week, without harm.
 Strategies: substitution, containment, ventilation,
disposal provisions, Good manufacturing practices
(GMP)
Reactivity Hazards
Exothermic runaway reactions
Reactions can occur anywhere
Unused Catalysts may mediate undesired
reactions
Have good knowledge of reaction
chemistry and reaction enthalpies
Use of nitrogen blanket to keep systems
inert
Process Evaluation
Evaluate at each stage of development
Is the process technically feasible?
◦ This is determined at the laboratory, flowsheet
design, and pilot plant level
Is it economically attractive?
How big is the risk
(economically, technically)?
Process chemistry
Important part of pharmaceutical chemistry concerned with the
development and optimization of a synthetic scheme and pilot plant
procedure to manufacture compounds for the drug development phase.

Process chemistry/medicinal chemistry- it is arm of pharmaceutical

chemistry tasked with designing and synthesizing molecules on small
scale in the early drug discovery phase.

Medicinal chemistry is involved in synthesizing a large number of

compounds as quickly as possible from easily tunable chemical building
blocks (usually for SAR studies).

In general, the repertoire of reactions utilized in discovery chemistry is

somewhat narrow (for example, the Buchwald-Hartwig amination, Suzuki
coupling and reductive amination, Negishi* Reaction. Heck* Reaction. Stille
Reaction. ,Suzuki* Reaction. Sonogashira Reaction are commonest
reactions).

Identifying a chemical process that is safe, cost and labor efficient,

“green,” and reproducible, among other considerations.

Oftentimes, in searching for the shortest, most efficient synthetic route,

GOALS OF PILOT PLANT OPERATION

Before proceeding with planning, building, and running a pilot plant, the
goals of the pilot plant need to be delineated.

Specific goals of a pilot plant operation can include:

• Demonstrating the process on a continuous basis, including yields and
product purity.
• Providing design data for scaling the commercial-scale plant.
• Determining the reagent consumptions expected in the commercial plant.
• Providing data for evaluating process economics, including capital and
operating costs.
• Obtaining environmental data for permitting.
• Testing materials of construction.
• Determining the potential for scale buildup in processing equipment and
methods to minimize scaling.
• Providing product for customer evaluation representative of what will be
made in the commercial plant.
PILOT PLANT PLANNING
Once the goals of the pilot plant program have been
established, detailed plans for the design and operation can be
made,

The data that must be collected to design the commercial

plant with a particular attention.

It is highly recommend that the engineering firm that will be

responsible for building the commercial plant be included in the
pilot planning to ensure all of the data needed for the
commercial design and operation are gathered during the pilot
plant program.

 It should be kept in mind that a pilot plant should be a scaled-

down version of the commercial operation, not a scaled-up
version of the laboratory apparatus
 There is no rule-of-thumb about the appropriate size of a pilot
plant.

 There is always a trade-off between keeping the pilot plant

small (smaller plants are less expensive to operate, require
less feed material, and generate less wastes)

 and having a large pilot plant that reduces the scaleup factor
between the pilot plant and the commercial plant.

 As per Lowenstein (1985), the most important factor is to make

certain that the equipment used in the pilot plant is scalable to
commercial size.

 The design engineers and outside financing entities may

dictate a certain size to increase their comfort level with scaling
to commercial size
 Material handling issues can also dictate the minimum pilot size,
especially when handling solids.

 The feed particle size to the process may be fairly large, and the size
of the feeding equipment necessary to transport these solids may set
the pilot plant size.

 Small diameter tubing and piping are much more prone to plugging,
so a larger-sized plant with larger-diameter transport lines may be
necessary to minimize plugging.

 Needle valves, tube fittings, and flowmeters tend to easily plug or

become fouled at the small scale, so larger sizes and/or alternatives
should be considered.

 sometimes, one unit operation require much larger equipment for

proper scaleup than the remaining steps.

 A careful examination of the overall process is necessary to

determine if this will provide data that are representative of the
commercial operation. If the feed or products from the step are prone
to alteration from aging, the entire pilot plant may need to be scaled
up to match this single step. Also, if recycle streams used in the
process affect this step, a larger pilot plant will be necessary.
what portions of a process should be piloted?

No hard-and-fast rule; each process needs to be evaluated to determine if

all steps should be piloted or if some can be excluded from the pilot plant
operation.

For instance, off the-shelf technology, such as distillation of an ethanol–

water solution, probably does not need to be piloted.

However, if the ethanol or water stream will be recycled back to the process,
distillation should be included in the pilot plant operation, so that any
adverse effects of impurities in the recycled streams on process
performance can be ascertained.

Countercurrent decantation (CCD) circuits are used in many commercial

operations to settle and wash solids. However, they are extremely difficult to
operate at pilot scale.

Generally separation and wash solids on filters, using wash ratios that
simulate CCD operation is done

To provide the design criteria for the commercial plant, fresh slurry is
collected from the pilot operation and bench-scale tests are conducted to
provide the required design parameters
A pilot plant is a pre-commercial production system that employs new
production technology and/or produces small volumes of new technology-
based products, mainly for the purpose of learning about the new technology.

The knowledge obtained is then used for design of full-scale production

systems and commercial products, as well as for identification of further
research objectives and support of investment decisions.

Other (non-technical) purposes include gaining public support for new

technologies and questioning government regulations.

 Pilot plant are typically smaller than full-scale production plants, but are built
in a range of sizes.

pilot plants are intended for learning, they typically are more flexible, possibly
at the expense of economy.

Some pilot plants are built in laboratories using stock lab equipment, while
others require substantial engineering efforts, cost millions of dollars, and are
custom-assembled and fabricated from process equipment, instrumentation
and piping.

They can also be used to train personnel for a full-scale plant. Pilot plants
tend to be smaller compared to demonstration plants.
RISK MANAGEMENT

Pilot plants are used to reduce the risk associated with construction of large
process plants.

They do so in several ways:

Computer simulations and semi-empirical methods are used to determine the
limitations of the pilot scale system. These mathematical models are then
tested in a physical pilot-scale plant.

Various modeling methods are used for scale-up.

These methods include:

 Chemical similitude studies
 Mathematical modeling
 Aspen Plus/Aspen HYSYS modeling
 Finite Elemental Analysis (FEA)
 Computational Fluid Dynamics (CFD)
These theoretical modeling methods return the following:
 Finalized mass and energy balances
 Optimized system design and capacity
 Equipment requirements
 System limitations
 The basis for determining the cost to build the pilot module
They are substantially less expensive to build than full-scale plants.

The business does not put as much capital at risk on a project that may be

inefficient or unfeasible.

Further, design changes can be made more cheaply at the pilot scale and
kinks in the process can be worked out before the large plant is constructed.

They provide valuable data for design of the full-scale plant.

Scientific data about reactions, material properties, corrosiveness, for

instance, may be available, but it is difficult to predict the behavior of a
process of any complexity.

Engineering data from other process may be available, but this data can not
always be clearly applied to the process of interest.

Designers use data from the pilot plant to refine their design of the
production scale facility.

If a system is well defined and the engineering parameters are known, pilot

plants are not used.
For instance, a business that wants to expand production capacity by
building a new plant that does the same thing as an existing plant may
choose to not use a pilot plant.

Additionally, advances in process simulation on computers have increased

the confidence of process designers and reduced the need for pilot plants.

However, they are still used as even state-of-the-art simulation cannot

accurately predict the behavior of complex systems.

Scale dependence of plant properties

As a system increases in size, system properties that depend on quantity of
matter (with extensive properties) may change.

The surface area to liquid ratio in a chemical plant is a good example of

such a property.
On a small chemical scale, in a flask, say, there is a relatively large surface
area to liquid ratio.
However, if the reaction in question is scaled up to fit in a 500-gallon tank,
the surface area to liquid ratio becomes much smaller.

As a result of this difference in surface area to liquid ratio, the exact nature
of the thermodynamics and the reaction kinetics of the process change in a
non-linear fashion.
This is why a reaction in a beaker can behave vastly differently from the
same reaction in a large-scale production process.

Other factors
Other factors that may change during the transformation to a production
scale include:
•Reaction kinetics
•Chemical equilibrium
•Material properties
•Fluid dynamics
•Thermodynamics
•Equipment selection
•Agitation
•Uniformity / homogeneity
After data has been collected from operation of a pilot plant, a larger
production-scale facility may be built.

Alternatively, a demonstration plant, which is typically bigger than a pilot

plant, but smaller than a full-scale production plant, may be built to
demonstrate the commercial feasibility of the process.

Businesses sometimes continue to operate the pilot plant in order to test

ideas for new products, new feedstocks, or different operating conditions.

Or as production facilities, augmenting production from the main plant.

Recent trends try to keep the size of the plant a small as possible to save
costs.

This approach is called miniplant technology.

The flow chemistry takes up this trend and uses flow miniplant technology

for small-scale manufacturing.
Bench scale vs pilot vs demonstration

The differences between bench scale, pilot scale and demonstration scale are
strongly influenced by industry and application.

Some industries use pilot plant and demonstration plant interchangeably.

Some pilot plants are built as portable modules that can be easily transported
as a contained unit.

For batch processes, in the pharmaceutical industry

Eg - bench scale is typically conducted on samples 1–20 kg or less, whereas

pilot scale testing is performed with samples of 20–100 kg.

Demonstration scale is essentially operating the equipment at full commercial

feed rates over extended time periods to prove operational stability.

For continuous processes, in the petroleum industry for example, bench scale
systems are typically microreactor or CSTR systems with less than 1000 mL of
catalyst, studying reactions and/or separations on a once-through basis.
Pilot plants will typically have reactors with catalyst volume between 1 and
100 litres, and will often incorporate product separation and gas/liquid
recycle with the goal of closing the mass balance.

Demonstration plants, also referred to as semi-works plants, will study the

viability of the process on a pre-commercial scale, with typical catalyst
volumes in the 100 - 1000 litre range.

The design of a demonstration scale plant for a continuous process will

closely resemble that of the anticipated future commercial plant, with a goal
to study catalyst performance and operating lifetime over an extended
period, while generating significant quantities of product for market testing.
In the development of new processes, the design and operation of the pilot
and demonstration plant will often run in parallel with the design of the
future commercial plant, and the results from pilot testing programs are key
Steps to creating a custom pilot plant
oCustom pilot plants are commonly designed either for research or
commercial purposes.

oThey can range in size from a small system with no automation and low
flow, to a highly automated system producing relatively large amounts of
products in a day.

The steps to designing and fabricating a working pilot plant are :

oPre-engineering - completing a process flow diagram (PFD),
obasic piping and instrumentation diagrams (P&ID's) and initial equipment
layouts.
oEngineering modeling and optimization - 2D and 3D models created by
simulation software to model the process parameters and scale the
chemical processes( help determine system limitations, non-linear
chemical and physical changes, and potential equipment sizing)
oMass and energy balances, finalized P&ID's and general arrangement
drawings are produced.
o Automation strategies for the system are developed (if needed). Controls
system programming begins and will continue through fabrication and
assembly
o Fabrication and assembly - after an optimized design has been
determined, the custom pilot is fabricated and assembled. Pilot plants can
either be assembled on-site or off-site as modular skids that will be
constructed and tested in a controlled environment.
o Testing - testing of completed systems, including system controls, is
conducted to ensure proper system function.
o Installation and startup - if constructed offsite, pilot skids are installed
onsite. After all equipment is in place, full system startup is completed by
integrating the system with existing plant utilities and controls. Full
operation is tested and affirmed.
o Training - operator training is complete and full system documentation is
handed over.