Fine Chemicals: Development and Scale-up · • Develop a process entails the transfer of chemical...

Fine Chemicals: Development and Scale-upProf. Attilio CitterioDept. CMIC – Politecnico di Milanohttp://iscamap.chem.polimi.it/citterio/education/course-topics/

PhDIN INDUSTRIAL CHEMISTRY AND CHEMICAL ENGINEERING (CII)

http://iscamap.chem.polimi.it/citterio/education/course-topics/

1 – Introduction

overview bibliografia

PhDCHIMICA INDUSTRIALE E

INGEGNERIA CHIMICA (CII)

Attilio CitterioAttilio Citterio

Chemical/Biochemical Process Development

• Development of new (bio)chemical technologies and products is an activity difficult to define but certainly belong to Research and Development (R&D) area.

• Goal: produce a desired product In time With desired quality standards With projected manufacturing cost At planned rates Under safety and health conditions

• Cost, planning, safety and health are continually monitored• Worker training for final plant operations

8


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.

• Base chemicals have a wide range of uses and a long lifetime.

• Benefit to lowering the cost of production. Process improvement.

• Consumer products on the other hand, will be quickly replaced (shorter lifetime). Product upgrading.

• Consumer products are complex molecules and materials, collectively known as fine-chemicals and specialties.

9

Base Chemicals (~20)

Intermediates (~300)

Consumer products (~30,000)

Raw materials (~10)

Fuels (~10)


Base Chemicals (Commodities)

• The technologies for the production of base chemicals and intermediates are commonly well established.

• Development activities usually result in minor process improvements (i.e. new catalyst or more efficient energy source)

• Still can have a large impact on overall costs due to the large volumes involved (example, saving 1 euro per ton of ethanol can have a large impact when you produce 200,000 t/a).

• More general drive is sustainability and process intensification

• Major new advances in process engineering (i.e. process systems engineering) are still worth pursuing

• In specific cases radical innovation can be successful!

10


Consumer Products

• In consumer products, adaption and novelty are the driving force

• Motivated by market demands rather than cost savings

• Some market demands can include new products, product quality, environmental concerns, etc..

• More effort is required in determining the chemical route of manufacturing. For example, when a new drug is approved the manufacturing route must also be approved. If a manufacturing route is modified, approval is needed.

• Quality and reproducibility are the more important target at a reasonable cost in a robust process addressing all environmental and safety concerns.

• Examples are environmentally friendly paints, dedicated detergents, wood composites used in building materials, new drugs, new materials, new composite polymers, etc.

11


Fine Chemicals

• Fine chemicals are structurally complex, single, pure chemical substances produced in limited quantities in multipurpose plants by multistep batch (in future continuous!) chemical or biotech(nological) processes.

• Their prices are higher than 20 $/kg, based on exact specifications, and they account for 5-6% of the total $ 2.8 trillions turnover of the chemical industry. They differentiate from commodities and specialties.

12

Commodities Fine Chemicals SpecialtiesSingle pure chem.

substance ….Single pure chem.

substanceMixtures

Produced in dedicated plants

Produced in multipurpose plants

Formulated

High volume/ low price / high technol.

Low volume/ high price / low-high technol.

Undifferentiated / high Techn.

Many applications Few applications Undifferentiated

Sold on specifications Sold on specifications “what they are”

Sold on performance “what they can do”


FINE CHEMICALS

• Identified according to specifications (what they are) Advanced intermediates

Bulk drugs (80 billion $ in 2016)

Bulk insecticides

Active ingredients

Bulk vitamins

Flavor and fragrance

They are relatively pure compounds (their impurities must be known).Distinct cases: Natural specialties (mix. of natural products)

Perfume ingredients (5.3 billon $ in 2016)

13

Fine BulkRaw material consumption (kg/kg) high low

Energy consumption (kJ/kg) high low

Uses specific diverse

Value added high low

Molecular complexity high low

Characteristics of Fine versus Bulk Chemicals


SPECIALTY CHEMICALS

• Identified according to performance Adhesives Diagnostics Disinfectants Pesticides Pharmaceuticals Photographic chemicals Dystuffs Perfumes Specialty polymers

They frequently are balanced mixture of compounds.

14

The largest specialty chemical segments in 2016 were: electronic chemicals, industrial and institutional cleaners, specialty polymers, surfactants, and construction chemicals.


Fine Chemicals: Market Size

Useful fine chemicals include… Food additives, fertilisers, dyestuffs, paints, pigments and pharmaceuticals;

US: € 17.18 billion in 2005

€ 23.10 billion in 2011€ 28.50 billion in 2017

Europe: € 8.43 billion in 2005 €14.66 billion in 2017

India: > € 1 billion in 2005

15


EU Chemicals

• In 2004, 29% of EU chemicals exported compared to: 19% for the USA and 19% for Japan

• Only 18% of the EU chemicals demand was imported from the non-EU regions*

• Profitability eroding: Intense Asian competition New chemical entity (NCE) approvals rate

reduced

*In 2003, India-China imports were 8%, they were increased to 40% in 2015-16

16


Unit Labor Costs¹17

010203040506070

Swiss. Italy Poland India ChinaCoastal

ChinaInner

K Euro/ p/y

¹Includes fringe/other benefits*Source: A.D. Little (2014)


Transformation Costs*18

02468

101214161820

Swiss Italy Poland India ChinaCoastal

ChinaInner

Euro/Kg

*Source: A.D. Little (2014)


Understand Chemical Processes

• Chemical processes are used to produce chemicals and are by definition processes which include chemical transformation(s).

• Specific products produced by the pharmaceutical and chemical industry include: aspirin, ibuprofen, L-methionine, etc.

• These compounds (e.g. active pharmaceutical ingredients (APIs)) are produced by chemical reactions involving organic chemicals, via (bio)organic complex routes.

To understand a chemical process is necessary to know:• Route (materials, steps, operations etc.)• ‘Recipe’ (materials, quantities, steps, analyses)• Plant equipment (operations)• Process operating conditions

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Chemical Processes

• Specific processes have been developed to produce specific chemicals. Particularly well established processes are given names. For example the process used to manufacture sulphuric acid is called the ‘Contact’ process.

• In several cases a chemical may be produced by more than one process.

• Classification of Chemical Product:• Bulk chemicals, e.g. sulphuric acid• Fine chemicals, e.g. ‘ibuprofen’• Speciality chemicals, e.g. adhesives• Inorganic/organic• Natural products• Bio products

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Bulk chemicals are characterised by a combination of two parameters – large volume production, which is supported by market demand, and lower unit costs, where the principle of economy of scale is important. Fine chemicals are produced on a relatively smaller scale in more versatile (less dedicated generally) production units using batch operations. Product specifications may be more exacting and unit cost is relatively higher. Fine chemicals may be used as ingredients in formulations or as intermediates in the production of more complex chemicals. For example bulk pharmaceuticals.


Product and Process Lifecycle21

Product design /Conceptual

Process Design

Process Devpt / Process

Engineering

Detailed Engineering

Construction/ Start-up

Operations/ Maintenance/

Asset Mgt

Finance/ Planning/

R&D

Commodities

Product and process lifecycle• Innovation has different emphasis depending on industry drivers• Commodities: focus mainly on process improvement• Specialities/Fine chemicals: focus on product performance and market dissemination

Pilot / Scale-up / Process

Engineering

Detailed Engineering

Construction/ Start-up

Operations/ Maintenance/

Asset Mgt

Finance/ Planning/

R&D

Discovery /Conceptual

Process Design

Specialties / Fine Chemicals


Process Development Sections22

Process Development

Center

MANUFACTURINGANALYTICAL RESEARCH &

SERVICES

ENGINEERING

PROCESSENGINEERING

CHEMICALRESEARCH

APPLICATION TESTING


General Factors (Issues) to be Considered

• Yield, conversion, selectivity/mass balances• Energy usage/energy balances• Kinetics/rates and productivity (kg/hr)• Number of synthetic reaction steps/reaction chemistry• Scale of operation• Manufacturing costs• Separations required• Operating conditions• Environmental factors – waste, environmental impact, emissions, effluent,

solid waste, hazardous waste • Health and safety factors – process safety/operating conditions, hazard• Material availability• Quality issues• By products and co products• etc.

23


Documentation:Batch Records and Review

Frequently large documentation must be provided to ensure appropriate customer support and CHEMICAL HAZARD/RISK ASSESSMENT and REGULATION for regional/national/international authorities.

• REACH (2006-2018)• IPPC (Directive 2008/1/EC)• BAT (Best Available Techiques)• VOC-SE (Directive 199/13/EC)• Safety regulation (dir. 96/82/EC)• RoHS (restriction of Hazardous

Substances)

• ISO 9000; ISO 9001-2015(Sistema di gestione per la Qualità)

• ISO 14001 (standard di gestione ambientale (SGA)

24


Analytical Capabilities25

Core analytical equipments: NMR, FTIR, UV/VIS ICP-AES and GF-AA for low-level

metal detection XRF, XRD SEM, optical microscopy GC, HPLC, GPC Mass spectrometry, (GC/LC,

quadruple/high resolution) Physical property measurements Classical chemical analysis Thermal analysis

FullCapability


Not only Chemistry! Example of Problem: Shortage of Affordable Aroma Chemicals

26

Example: Nootkatone(grapefruit flavor)

Extracted from a natural source

Shortage of raw material

Low volume / high cost

$ 4,000 – 10,000 per kg

O

http://upload.wikimedia.org/wikipedia/commons/b/b5/Citrus_paradisi_(Grapefruit,_pink).jpg


A Possible Biotechnological Solution:Flexible Terpenoid Production

27

Pharmaceuticals

Anti-Malaria

Biofuels Additives

Flavors / Fragrances

limonene

nootkatone

(S)-(-)-perillyl alcohol

artemisin

O

s

OH

O

O

OO

H

R

H

H


PROCESS DEVELOPMENT28


Process Development and Scale-up

• Continuous interaction between experimentation and substance production technology.

Input: chemical reactions in the lab

Outcome: production plant process

• Develop a process entails the transfer of chemical reactions from the lab up to a large plant scale in a economic way

• Expansion of equipment in small steps (scale-up) ? Empirical method and practical for some applications but not generally for continuous process.

• Alternatives with microreactors (scale-down?)

29


Chemical Product and Process Development 30

Process Development Workflow

Lab Batch Runs

Pilot Plant Test Runs

ProcessDesign

ProductionPlant

Chemical &Catalyst Design

Chemists R&D Engineers

Process Engineers

Plant Operators


Scale Up31

< 0.1 0.1-1 10-100 100-1000 > 1000

0 2 4 6 8 10 12

lab. miniplant pilot plant demonstration plant commercial plant

Years

design/constructionoperation

Conventional scale up production for bulk chemicals


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 (the reactor, does the

required separation work?)• A process flow sheet is drawn.• A small scale plant is designed (mini-plant) to evaluate performance of 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.

32


Laboratory vs. Plant Procedures

Many operations routinely performed in a laboratory :• Rotary evaporation: not done at plant scale. Stirred reactors used for

concentration• Concentration to dryness: frequently done in lab but avoided in plant

operations. Danger of product degradation. Alternative is to telescope process

• Trituration: Never done on scale• Flammable solvents: Low boiling or flammable solvents not used due to

fire and explosion.• Decanting / Siphoning: not used • Column chromatography: used only for high value products.• Drying with desiccant: Not done on scale• Addition of dangerous reagents: simpler on large scale• Extended additions: often required on scale to control exotherms or

impurities

33


Cyclic Nature of Modern Process Development34

Exploratory stage

Process conceptConceptual design

Development of individual steps

Evaluate

Preliminary plant flow sheet. Downscaling

Abandon development

Miniplant and if needed individual steps in pilots

Evaluate

Integrated pilot plant

Evaluate

Integrated pilot plant

Abandon development

Abandon development


Breakdown of Steps

Exploratory Phase

Decision taken on discovery of a new product, a new chemical synthesis route, or an improvement to a process

Focus on chemical reactions

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• toxicity of reagents, intermediates and products• safety of process and equipment

35


Breakdown of Steps

• Preliminary Flow-sheet Determine the availability and quality of raw materials (first design step would be

compare raw material costs with product value) Draw up preliminary flow-sheets and alternatives Typically under defined, so we must make assumptions. What units should be used? How will the units be connected? What T, P and flow rates 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

36


Input Information

• The reactions and reaction conditions• Desired production rate• Desired product purity (cost vs. purity)• Raw materials (also need cost vs. purity info here)• Information on rate of reaction, catalyst deactivation• Processing constraints? (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.• Preliminary risk analysis• Cost data for byproducts and wastes, equipment and utilities.

37


1. Reactor System…

1. 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

Determine the reactor materials and components

Define the more suitable reactor technology

38


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 and selectivity

7. Product separation

Often available from the literature Identify any side reactions that may take place

39


Decision 1: Batch vs. Continuous?

• Production rates Capacity ≥ 5 × 106 kg/year, usually continuous Capacity ≤ 0.5 × 106 kg/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

40


Continuous or Batch Process?

Continuous

41

Batch

Feed batch

Batch-with product removal


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

• 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? Multi-purpose plant is available?

42


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?

• It is possible itegrate the co-products or waste in other processes?

• You can recover energy from exothermic stages?

• Material storage (Reactants, products, Intermediates, solvents, catalysts, reagents, etc……)

43


Decision 3: Separation / Purification

• 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 (i.e. boiling point, solubility) • Identify possible unit operations (i.e. distillation, absorption, adsorption, solvent

extraction, etc.)• If reactor effluent is a liquid, use liquid separation system

distillation liquid extraction, etc. Avoid gas absorbers, gas absorbers.

• 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.

44


Decision 4 – Process Support Services/Utilities

• Steam• Cooling water• Chilled water• Other heat transfer fluids• Inert gases• Compressed air• Electricity• Demineralised water/deionised water• UP water• Distilled water• Effluent treatment

Purified water/WFI : Purified Water/WFI, Specified in pharmacopoeias, storage, Depth filter, organic traps, carbon filter, DI, Filtration (0.45 µm)/UV (254 nm), UF (0.22 µm), distillation/RO, and WFI distribution (sealed, loop, in pipe, UV)

45


Flowsheets

Flowsheets are used to describe the operating details of chemical processes. There are a number of basic types:

– Flowcharts (or block diagrams),– Process flowsheets (or Process Flow Diagram), (Layout)– Piping and Instrumentation Diagrams (PID).

Schematic representations Arrangement of equipment Interconnections Movement of material Stream connections Stream flows/quantities Stream compositions Operating conditions

46

Flowcharts

Simple flowcharts can be used to show the main material routes through the process (lines and arrows) and to depict the main operations (blocks).


P and I Diagram

• Equipment details and arrangement (item no., name, dimensions, materials of construction, rate or capacity, occupation time, T, P, materials handled, heat duty, power)

• Pipe details• Valves• Ancillary fittings• Pumps• Instrumentation and control loops• Services (utilities)• Symbols• Layout

For a large chemical plant a large number of such flowsheets will be required to specify the process. These will be grouped into individual plant operating areas.

47


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 scale-up problems on novel processes gain operational know-how determine long term effects of operation training of workers

• Typically run to 10% of the commercial plant cost.

48


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 (i.e. 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.

49


Relationships of Scale50

Production rate(kg/h)

Scale Up Factor

Industrial Plant 1000-10,000 -

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 mini-plant data (extraction, crystallization, fluidized beds) due to flow characteristics.

• See table on the side for some scale-up values.

51

G.H. Vogel, Process Development, Wiley Ed. 2005

Typical maximum scale-up values of some important process steps

a Scale-up factors of over 50000 have already been achieved.


Requirement for Pilot Plant Testing52

Rules of thumb to decide which unit operations require pilot plant testing.

Operation Pilot plant required? Comments

Distillation Usually not. Sometimes needed to determine tray effiency

Foaming may become aproblem

Fluid flow Usually not for single phase. Often for two-phase

Some I-phase polymer systems are also difficult to predict. CFDa can be an important tool

Reactors Frequently Scale-up from lab often justified for homogeneous systems and single-phase

Evaporators, reboilers, coolers,condenser, heat exchangers

Usually not unless there isa possibility of fouling

Dryers, solids, handling,crystallization

Almost always Usually done using vendorequipment

Extraction Almost always


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

53


Heterogeneous Reactors

• Examples include steam reforming, ammonia synthesis, hydrotreating, but also Pt/C hydrogenation, oxidations with O2, etc.

• 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) Exothermic reactions need to be cooled – hot spots must be controlled 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

54


Heterogeneous Reactors

• 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.

• Hydrodynamics 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 Hot spots on catalyst

55


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

56

Mechanical failure38%

Operational error26%

Unknown, miscellaneo

us12%

Process upset10%

Natural hazard

7%

Design error4%

Arson. Sabotage

3%


Flammability

• Fires and explosions• Fuel, oxidizer and ignition source

57

Characteristic DescriptionFlashpoint Lowest temperature at which a liquid will ignite from

an open flameAutoignition temperature Temperature at which a material will ignite from

spontaneously in air, without any external source of ignition (flame, spark, etc.)

Flammability limits Lowest and highest concentrations of a substance in air, at normal pressure and temperature, at which a flame will propagate through the mixture

Lower flammability limit (LFL) Below LFL mixture is too lean to burn (not enough fuel)

Upper flammability limit (UFL) Above UFL mixture is too reach to burn (not enough oxygen)


Toxicity and Flammability Characteristics of Common Liquids and Gases

58

Compound TLVa

(ppm)Flash point (K)

LFL (vol% in air)

UFL (vol% in

air)

Auto ignition temperature

(K)

Heat of combustion

(MJ/kg)Acetone 750 253 2.5 13 738 28.6Ethyne 2500b Gas 2.5 100 578 48.2Benzene 10c 262 1.3 7.9 771 40.2Butane 800 213 1.6 8.4 678 45.8Cyclohexane 300 255 1.3 8 518 43.5Ethanol 1000 286 3.3 19 636 26.8Ethene 2700b Gas 2.7 36.0 763 47.3Ethene oxide 1c 244 3.0 100 700 27.7Hydrogen 4000b Gas 4.0 75 773 120.0Methane 5000b 85 5.0 15 811 50.2Toluene 100 (skin) 278 1.2 7.1 809 31.3

a TLV = threshold limit value. b Simple asphyxiant; value shown is 10% of LFL.c Suspect carcinogen; exposure should be carefully controlled to levels as low as reasonably achievable below TLV.


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)

59


Reactivity Hazards

• Exothermic runaway reactions

• Reactions can occur anywhere

• Unused Catalysts may mediate undesired reactions

• Have good knowledge of reaction chemistry and reaction enthalpies

• Autoxidation of orgaic molecules is a widespread problem. Use of nitrogen blanket to keep systems inert

• Store as distant as possible reactive compounds (e.g. acid/base; oxidant/reductant)

60


Process Evaluation

Evaluate at each stage of development

1. Is the process technically feasible? This is determined at the laboratory, flow-sheet design, and pilot plant

level

2. Is it economically attractive?

3. How big is the risk (economically, safety, technically)?

61


CHEMICAL DEVELOPMENT

• Innovative, but Market-led• A discipline in its own right

• Few books or journals• Few articles

Vital for commercialization of new ideas

• PAT/QdB• System analysis

• Becoming more and more complex!

• More complex products• Chirality• Purity• Crystal size, polymorphs• Registration/legislation• Effluent/environment• Quality management

• CHALLENGING AREA

62



PROCESS RESEARCH

• New Synthetic Routes

• Some Initial Optimization

• Yield Improvements

• Possibly scale-up to large laboratory equipment (up to 20L)

Optimization

• Minor change of route/intermediate

• Cheaper reagents

• Environmentally-friendly reagents

• Yield/concentration improvement

• Statistical methods FED/Simplex

63



• Unit operations

• Simplification (work-up)

• Effluent considerations

• Cost

• Scale-up - first pilot plant trials

• Transfer to manufacturing

BUT ALSO:

• Green Chemistry

• Green Engineering

• Process Intensification

• Process Analytical technology

• Biotech(nology)

64


Process Development

1. Develop a process in-house for the manufacture of the raw material, then scale up and manufacture in-house.Advantages: all information is kept in-house and secrecy preserved and no information should be lost during technology transfer.Disadvantage: usually the resources required, which could probably be better used on the later stages of a synthesis.

2. Develop quickly a lab process, then pass to a toll-manufacturers to make kg quantities. (scaled-up process is sometime required).This option minimizes resources used, but details on the scale-up and manufacture will probably not be available, so that in the long term. in-house manufacture of the raw material cannot be carried out.

3. Farm out to a contract R&D company who will develop a process and scale and manufacture, possibly sub-contracting further. Advantages: all work and all results/information is available (either for in house use if required or to sub-contract to a toll manufacturer). Disadvantage: all the R&D work naturally has to be paid.

65


Project Scale-up

Scale-up Engineering

Comprehensive technology for raising a process from the research and development scale to that of a commercial production scale plant, in a rational manner, looking from the customer's point of view.

66

Commercialization of product

Construction of a rational engineering process

Customer's Ideas

New ProductNew Process

Commercial Plant

Process scale-up

Plant scale-up

• Well-timed commercialization• Minimization of manufacturing cost• Optimum production scale• High quality product• Efficient productivity• High reliability• Achievement of safety

• Reduction of time required• Reduction of development

risk

• Refined plan• Advanced analysis

technology

ScaIe-up units comprised of Individual operations


PROCESS SUPPORT

• Further Optimization

• Fine-tuning – Yield/Throughput

• Cost Reduction

• Process Intensification

• By-product valorisation

• Waste Minimization – Recycling

• Health and safety improvements

67


Rationale to Change a Synthetic Route

• Discovery route was not chosen

to be selective to scale up easily to be cheap to be efficient

• Raw materials and reagents may not be available in bulk

• Difficult to change later on

• GET THE BEST ROUTE AT THE START!

68


Constraints on Process Development

• Usually become involved when more material needed

• Scaling up before Process R&D carried out

• Time pressure to produce

• Pressure to retain existing synthetic route!- used by discovery chemists

This MUST be resisted !!

69


By-products.Synthesis of Sulphamethazine

70

HNAc

SCl

OOHN

Ac

SO

ONH

NH

NH2HNAc

SO

O HN

N

NR

HNAc

SO

ONH

NH

NH2H2N

SO

O HN

N

NR

H2N

ClSO3H

guanidine

acetylacetone

acetylacetone

sulphamethazine (R = Me)

Impurity: R = Et


How to make 1 Tonne in 8 Weeks

⇒ 1st week Literature survey, order raw materials⇒ 2nd week Evaluate Step 1 in lab⇒ 3rd week Evaluate Step2 in lab⇒ 4th week Evaluate Step1 in pilot plant

Evaluate Step 3 in Lab⇒ 5th week Carry out Step 1 in full plant

Evaluate Step 2 in pilot plantEvaluate Step 4 in lab

⇒ 6th week Carry out Step 2 in full plantEvaluate Step 3 in pilot plant

⇒ 7th week Carry out Step 3 in full plantEvaluate Step 4 in pilot plant

⇒ 8th week Carry out Step 4 in full plant

71


Manufacturing Science

Sensors Hardware integration Model Integration Real-time Process Management Integrated Design Costs!!

72

B-Splines/WaveletsData Compression

Real-time Data

Knowledge Base Patterns Known Faults and control actions

Novel Faults

Feature ExtractionFuzzy Pattern Recognition


Database (DB)• Physical propertyvalues

• Reaction data• Equilibrium data• Other engineeringdata

Scale-up Engineering Process73

Development target

Identification of corephenomena/operations

Core technology

Checking by bench operation

Pilot plant constructionand testing

Commercial plant designand construction

Conversion to model

Scale-up/optimization

Tools• Analysis model• Process simulation• Dynamic simulation• Flow analysis• Equipment design tools• Negative technology• Risk analysis• Economic assessment

Customer provided DB+Global DB +Other DB

Scaled-up equipment(3000 Litter)

Model test equipment(1 Litter)

Section through x = 0Controlling circular flow

on liquid surface

Section through x = 0Agitation on

vertical direction


Process Intensification

• Significantly enhances the transport rates

• Gives every molecule the same processing experience

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CONCEPTS

- Match mixing/mass transfer rate to rate ofdesired chemical reaction

- Match heat transfer rate to exothermicity ofreaction (remove heat as it is produced)

- Match flow behaviour (eg plug flow, backmixed)to reaction scheme

- Match residence time to desired reaction time


Quality by Design (QbD) and its Elements

• Systematic approach to development• Begins with predefined objectives • Emphasizes product and process understanding and process control• Based on sound science and quality risk management

from ICH Q8(R1)

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Define desired product performance upfront;identify product CQAs

Design formulation and process to meet product

CQAs

Understand impact of material attributes and process parameters on

product CQAs

Identify and control sources of variability in material and process

Continually monitor and update process to assure consistent

qualityRisk assessment and risk control

Product & process design and developmentQuality

byDesign


Design Space and Quality Control Strategy

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Process (or Process Step)

Design Space

Monitoring ofParametersor Attributes

Process Controls/PAT

InputProcess

Parameters

Input Materials

Product (or Intermediate)

ProductVariability

ReducedProductVariability

ProcessVariability


Quality Risk Management Process (Q9)77

ProcessDevelopment

Control StrategyDevelopment

Continual Improvement


Role of Quality Risk Management inDevelopment & Manufacturing

78

ManufacturingProcess Scale-up & Tech Transfer

Quality Risk Management

Process Development

Product Development

Product qualitycontrol strategy

RiskControl

RiskAssessment

Process design space

ProcessUnderstanding

Excipient & drug substance design space

Product/prior Knowledge

RiskAssessment

Continualimprovement

ProcessHistory

RiskReview


Microreactors

“Advantages” Decrease in linear dimensions Increased surface to volume ratio Decrease in volume

Those due to increase in number ofunits (e.g. parallel/series operation) High throughput screening Production flexibility

Strategy: numbering-up versus scale-up Kinetics analysis “on a chip” Replacing a batch process by a continuous one Intensification of processing Safety Change of product properties Distribution

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from Microreactors: New Technology for Modern Chemistry, Ehrfeld et. al editors, Wiley 2000


References and Books

• G.H. Vogel, “Process Development” Wiley Ed. 2005• N Anderson “Practical Process Research and Development – A guide for

Organic Chemists”, 2nd Edition, Academic Press, 2012.• Mark McLaughlin et al. Org. Process Res. Dev., 2012.• Madjackfrost, Pharmaceutical Process Scale-Up 2nd Ed., 2009

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