Fine Chemicals: Development and Scale-up

Fine Chemicals: Development and Scale-up

Prof. Attilio Citterio

Dept. CMIC – Politecnico di Milano

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

PhD

IN INDUSTRIAL CHEMISTRY AND CHEMICAL ENGINEERING (CII)

1 – Introduction

overview bibliografia PhD

CHIMICA INDUSTRIALE E INGEGNERIA CHIMICA (CII)

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 Specialties Single pure chem.

substance ….

Single pure chem.

substance

Mixtures 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 Bulk

Raw 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

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 Costs¹ ¹⁷

0 10 20 30 40 50 60 70

Swiss. Italy Poland India China

Coastal China Inner K Euro/ p/y

¹Includes fringe/other benefits

*Source: A.D. Little (2014)

Transformation Costs*

18

02 46 108 1214 1618 20

Swiss Italy Poland India China

Coastal China Inner 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

19

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

20

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 Lifecycle

21

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 Sections

22

Process

Development Center

MANUFACTURING

ANALYTICAL RESEARCH &

SERVICES ENGINEERING

PROCESS ENGINEERING

CHEMICAL RESEARCH 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 Capabilities

25

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

Full

Capability

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

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

O O

H

R H H

PROCESS DEVELOPMENT

28

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

Process Design

Production Plant Chemical &

Catalyst Design

Chemists R&D Engineers

Process Engineers

Plant Operators

Scale Up

31

< 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/construction operation

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 Development

34

Exploratory stage Process concept Conceptual 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

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 Scale

50

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 Testing

52

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 a problem

Fluid flow Usually not for single phase.

Often for two-phase

Some I-phase polymer systems are also difficult to predict. CFD^a 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 is a possibility of fouling

Dryers, solids, handling, crystallization

Almost always Usually done using vendor equipment

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 failure

38%

Operational error 26%

Unknown, miscellaneo

us 12%

Process upset

10%

Natural hazard

7%

Design error 4%

Arson.

Sabotage 3%

Flammability

• Fires and explosions

• Fuel, oxidizer and ignition source

57

Characteristic Description

Flashpoint Lowest temperature at which a liquid will ignite from an open flame

Autoignition 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 TLV^a

(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 28.6

Ethyne 2500^b Gas 2.5 100 578 48.2

Benzene 10^c 262 1.3 7.9 771 40.2

Butane 800 213 1.6 8.4 678 45.8

Cyclohexane 300 255 1.3 8 518 43.5

Ethanol 1000 286 3.3 19 636 26.8

Ethene 2700^b Gas 2.7 36.0 763 47.3

Ethene oxide 1^c 244 3.0 100 700 27.7

Hydrogen 4000^b Gas 4.0 75 773 120.0

Methane 5000^b 85 5.0 15 811 50.2

Toluene 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

CHEMICAL DEVELOPMENT

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

CHEMICAL DEVELOPMENT

• 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 Product New 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

HN Ac

S Cl O HN O

Ac

S O O

NH

NH NH₂ HN

Ac

S O O H

N

N N

R HN

Ac S

O O

NH

NH NH₂ H₂N

S O O H

N

N N

R 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 plant Evaluate Step 4 in lab

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

⇒ 7th week Carry out Step 3 in full plant Evaluate 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/Wavelets Data Compression

Real-time Data

Knowledge Base Patterns Known Faults and control actions

Novel Faults Feature Extraction

Fuzzy Pattern Recognition

Database (DB)

• Physical property values

• Reaction data

• Equilibrium data

• Other engineering data

Scale-up Engineering Process

73

Development target

Identification of core phenomena/operations

Core technology

Checking by bench operation

Pilot plant construction and testing

Commercial plant design and 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 = 0 Controlling circular flow

on liquid surface

Section through x = 0 Agitation on vertical direction

Process Intensification

• Significantly enhances the transport rates

• Gives every molecule the same processing experience

74

CONCEPTS

- Match mixing/mass transfer rate to rate of desired chemical reaction

- Match heat transfer rate to exothermicity of reaction (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) 75

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

quality

Risk assessment and risk control

Product & process design and development

Quality by Design

Design Space and

Quality Control Strategy

76

Process

(or Process Step) Design

Space

Monitoring of Parameters or Attributes

Process Controls/PAT Input

Process Parameters Input

Materials

Product

(or Intermediate) Product Variability Reduced Product Variability

Process Variability

Quality Risk Management Process (Q9)

77

Process

Development

Control Strategy Development

Continual Improvement

Role of Quality Risk Management in Development & Manufacturing

78

Manufacturing Process Scale-up

& Tech Transfer

Quality Risk Management

Process Development Product

Development

Product quality control strategy

Risk Control Risk

Assessment

Process design space

Process Understanding

Excipient &

drug substance design space

Product/prior Knowledge

Risk

Assessment

Continual improvement

Process History

Risk Review

Microreactors

“Advantages”

 Decrease in linear dimensions

 Increased surface to volume ratio

 Decrease in volume

Those due to increase in number of units (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

79

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