VERSION 1/3/99

ENVIRONMENT, HEALTH AND SAFETY COMMITTEE

NOTE ON

SAFETY ISSUES IN THE SCALE UP OF

CHEMICAL REACTIONS

Enquiries received by the Royal Society of Chemistry indicate that there is a need to
provide some basic guidance on safety issues raised by the scale up of chemical
reactions from laboratory scale to full sized commercial plant. The Society believes
that chemists should be fully aware of the safety problems associated with the scale
up of chemical processes and should contribute to the scale up procedure in order to
ensure the health and safety of all persons involved.

This Note is designed to provide guidance to members who either manage

laboratories or are employed in laboratories where the scale up of chemical reactions
is undertaken. Therefore it assumes familiarity with basic terms such as ‘risk’and
‘hazard’. The Note is not intended to be a full or definitive guide and readers are
urged to obtain more detailed information and/or expert advice if this is required.

The Note was prepared by a Working Party of the Environment, Health and Safety
Committee (EHSC) of the Royal Society of Chemistry. The Society is a registered
Charity. Its Royal Charter obliges it to serve the public interest by acting in an
independent advisory capacity. In order to meet this obligation the members of the
EHSC are drawn from a wide range of backgrounds and serve on the committee as
individual experts and not as representatives of their employers.

The EHSC is eager to receive feedback on this Note. Comments can be sent to the
Committee Secretary whose details are given on the last page.

1. INTRODUCTION

Of the chemical incidents reported to HSE each year as dangerous occurrences

under RIDDOR some 20 to 30 are exothermic runaways. There may be other
chemical incidents which are either not reported or which do not fit the legal
definition of a ‘dangerous occurrence’. It is likely that many of these are
attributable to inadequate scale up procedures.
 Chemical processes usually originate on a small scale in the laboratory and
their development is normally carried out by conducting the reactions on
successively larger scale before transferring to full size production plant. In
the early stages of process development limited quantities of chemicals are
used and full information about the reaction or side reactions is not usually
available. Risk assessment studies and the scale up procedure enable further
information to be obtained which is relevant to the final process plant design.

Failure to scale up properly and to take appropriate precautions may lead to

the loss of process control which in turn may result in a runaway exothermic
reaction and /or the generation or release of toxic materials. There have been a
number of such failures in the past which have led to multiple fatalities, severe
damage to property, environmental damage and business loss.

Other problems which have arisen from inadequate scale up procedures

include for example :

• dust and vapour explosions inside vessels due to the mishandling of reactants
and solvents
• fires due to overfilling of vessels
• failure to correctly assess electrical equipment for use in hazardous areas
identifying all possible sources of ignition
• autoignition of flammable vapours, usually resulting in a flash fire.

The first and most critical step in the scale up procedure is to undertake a risk
assessment of the proposed chemical process at the concept stage. Where
appropriate this should include a study of the thermochemistry of the proposed
reaction.

2. ASSESSMENT OF REACTION HAZARDS

The risk assessment undertaken on all new or modified reactions should be

recorded and should involve the consideration, where appropriate, of the
following:

• the physical and chemical properties of the reactants, intermediates,

products and wastes

• the possibility of hazardous reactions if there are deviations from set

parameters

• the potential for the substances in use to corrode plant

• the fire and explosion hazards

• the health hazards and associated COSHH and Personal Protective

Equipment (PPE) assessments

• the thermochemistry of both of the desired and potential undesired

reactions, in particular the rate of heat output

2
 • the rate of gas generation and the potential for vessel over-pressurisation

• scale-up problems (see below)

• plant design characteristics, including control systems, service needs (eg

cooling water, inert gas) and the adequacy and reliability of safety devices
such as pressure relief valves, bursting discs, vents, etc

• the application of hazard identification methods, such as ‘What If’studies,

Hazard and Operability Studies (HAZOPS) and quantified risk assessment
techniques;

• environmental effects;

• new or modified process instructions; and

• the training needs of operators.

The first stage in the risk assessment is data collection. This will enable
desktop screening of the hazards of the proposed reaction to be undertaken and
if possible thermochemical calculations to be carried out. In this exercise
consideration should be given to the reactive group(s) of the reactants and
comparisons should be made with analogous substances or reactions. A
number of publications are cited in the Bibliography which may be useful in
this desktop screening exercise.

Where there is potential for an exothermic reaction, particularly a runaway

reaction, it is essential that a study of the thermochemistry of the proposed
reaction is undertaken at an early stage. It is current best practice to subject all
new processes to thermochemical investigations. Various calorimetric
techniques are available which can be used in such a study. For example
differential scanning calorimetry or Carius tube studies can be used for basic
thermal stability screening tests. Isothermal calorimetry can be used mainly to
measure reaction kinetics and heats of reaction. Adiabatic calorimetry can be
used to examine the potential for runaways. Relief vent sizing tests can also be
carried out.

As a result of the risk assessment the principles of elimination, reduction and

control should be applied. If the risks associated with the proposed reaction are
unacceptable then an alternative route to the product should be considered, if
possible using inherently safer methods. If however the reaction is to proceed
the risk assessment should specify the control measures and safety procedures
which should be adopted to ensure the safe operation at all stages of the scale-
up process.

3. SCALE-UP PROCEDURE

The design of a commercial plant can be accomplished by scaling up from

laboratory equipment using pilot plant. In some cases several pilot plants of
increasing size may be used to effect the best design for the larger plant. Risk
assessment is an evolving process as scale-up progresses. At each stage of the

3
scale up procedure the information generated should be used to review the risk
assessment to enable a decision to be made as to whether or not to proceed to
the next stage. If the process is to proceed the risk assessment should specify
the controls and operating conditions required.

The rate of a chemical reaction is fixed at any given temperature but

temperature may be influenced by mass transfer and heat transfer, which are in
turn affected by the size and design of the reactor. It is not always possible to
theoretically assess these effects on a quantitative basis and in such cases it is
usual to carry out trials with water or inert substances in the intended plant. If
this is not feasible purpose built reactor calorimeters will be required.

Laboratory experiments, carried out in test tubes, small flasks etc., produce a
required chemical or product but do not necessarily indicate side effects of the
reaction, i.e. by-products, release of gases or vapours which may be toxic or
flammable. Heat releases may be absorbed by the equipment or surroundings
and not noticed. The chemicals used may be pure materials rather than bulk
commercial chemicals, which may contain traces of impurities. Therefore in
order to overcome this problem it is essential that the apparatus, materials and
chemicals used at all stages of the scale up accurately reflect those that will be
used in the final plant. In the laboratory reactions are usually carried out in
glass vessels but the scaled up process may well be carried out in containers
made of other materials. With some reactions such changes may be important
and could result in unexpected reactions or problems including catalytic or
inhibition effects.

As scale increases the time required to carry out each operation is also likely
to increase and appropriate allowance should be made for this.

Pilot plant is used to assist in the scale up of the chemical process design
rather than the mechanical design. It provides information for economic
design, operating parameters, and safety considerations. In addition pilot
plants can be used in small scale production for evaluation and trial marketing.
Information should be obtained from pilot plant studies to confirm the
decisions made as a result of the risk assessment stage in relation to :

• operating conditions;

• design parameters;

• reactor problems, design, materials of construction;

• unit operations problems;

• materials handing and sampling problems;

• thermal instability and other decomposition;

• Phase problems;

• impurities;

• corrosion;

4
 • fouling;

• analytical problems;

• operating procedures;

• working and environment problems; and

• effluent and waste disposal problems.

Impurities in the chemicals used can cause many problems which can be
identified in pilot plant studies. Impurities can occur in the feedstock or arise
from side reactions, decompositions, polymerisations, etc. which can cause
unexpected effects. Leaks into the system may bring in unwanted materials
such as pump lubricant, seal fluids or heat transfer media, including water.
These may lead to blockages and other problems. Some impurities can
catalyse undesirable explosive reactions or may be thermally unstable
themselves.

Pilot plant studies can reveal corrosion problems. These can be associated with
minor components such as gaskets and diaphragms or with impurities in the
reactants.

Scaling up in various size plants can produce variations in reactions, and

apparently identical reactors can give slightly different products with
apparently the same feed materials and operating conditions. This is most
marked in fermentation processes.

Pilot plants should be operated by technically qualified and appropriately

trained competent personnel. The extra unknown or unforeseen hazards
associated with pilot plant should be compensated for by better
instrumentation and technical control by the operators. It must be
remembered, however, that accidents on pilot plant despite their size can still
have serious consequences.

It is important, therefore, that scale-up of chemical reactions is done correctly

so that the eventual reactions can be carried out safely in full size production
plant.

4. SAFE OPERATION

Information obtained from the risk assessment of the chemical process and the
scale-up studies will enable decisions to be made on the most appropriate
controls to ensure a safe operation. The main options which could be
considered for a safe operation are:

• inherently safer methods which use less hazardous materials or alternative

reaction routes to eliminate or reduce hazards;

• preventative measures such as process controls using sensors, trips, alarms

(temperature, pressure, stirrer, cooling water failure) and other control
systems which initiate automatic remedial action; and

5
 • protective measures such as pressure relief valves, vents, reaction
inhibition, crash cooling, drown out/quenching or secondary containment
which will limit the consequences of a runaway reaction.

There is no single best option for controls and protective measures that can be
applied in all cases. Whichever option is chosen it must cater for the worst
credible scenario and reduce the risk as far as is reasonably practicable.

The option chosen must also be supported by appropriate occupational health

and safety management systems which cover operating procedures, the
training and supervision of operators and maintenance personnel, the

maintenance of plant and equipment, the control of plant modifications,

software and emergency procedures. It is essential that there is good
communication and co-operation between the risk assessment team, the
process plant team and maintenance personnel so that everyone concerned is
fully aware of the operating parameters and limitations of the process plant.

Once the process is operational it is important to adhere to the agreed

operating parameters and procedures. If there is to be any deviation or change
in raw materials, further risk assessments should be undertaken.

5. CONCLUSION

It is essential that suitable and sufficient risk assessments are undertaken of all
new and modified reactions during the scale-up of laboratory processes to full
sized commercial plant. Appropriate process controls and protective measures
are needed to reduce the risk of a runaway exothermic reaction and/or the
generation or release of toxic materials to a level which is as low as reasonably
practicable. This not only ensures that legal requirements are complied with
but also avoids the disruption, cost, potential damage and injuries that can be
caused by the loss of control of chemical reactions.

6. BIBLIOGRAPHY

• Royal Society of Chemistry, “EHSC Note on Individual Legal

Responsibility for Health and Safety”, 1995.
• Royal Society of Chemistry, “EHSC Note on Risk Assessment at Work”,
1997.
• Health and Safety Executive [HSE] leaflet IND(G)254 “Chemical
Reaction and the Risk of Thermal Runaway”.
• Association of the British Pharmaceutical Industry [ABPI] “Guidelines for
Chemical Reaction Hazard Evaluation”, 2nd Edition.
• J G Lowenstein “The Pilot Plant”, Chemical Engineering, Dec 9/23, 1985
pp 62-76.
• HSE/Institution of Chemical Engineers [IChemE] video “Control of
Exothermic Chemical Reactions”.
• IChemE “Chemical Reaction Hazards – a guide to safety”, Ed J Barton
and R Rogers, 2nd Edition 1998.

6
 • “Bretherick’s Handbook of Reactive Chemical Hazards”, 5th Edition, Ed.
Urben, Butterworth Heinemann, 1995
• National Fire Protection Association “Manual of Hazardous Chemical
Reactions”, 4th Edition, 1971.
• A Starkie and S Rowe ‘Taking the heat’, ‘Chemistry in Britain’, February
1996.
• 'Pilot Plants and Scale-Up of Chemical Processes II', Ed. W. Hoyle, RSC,
March 1999.

This Note was prepared by a Working Party of the RSC Environment, Health and Safety Committee [EHSC].
The members of the Working Party were :
Mr G J Dickes
Mr T G R Farthing
Mr R W Hazell [Secretary]
Dr G V MacHattie [Co-chairman]
Dr R Owen
Mr D M Sanderson
Dr I Wrightson [Co-chairman]
The Working Party gratefully acknowledges the assistance of the following individuals and organisations in
the preparation of this Note, though of course the views expressed remain the responsibility of the RSC :
• The Health and Safety Executive (HSE)
• Dr J Bickerton
• Mr K D Jackson
• Dr J D Jones
• Mr P G Lambert
• Dr I M McRobbie
• Dr A J Starkie
• Dr W Hoyle

This Note is also available on the RSC website http://www.rsc.org

The Environment, Health and Safety Committee welcomes comments on this Note. Comments should
be sent to the Committee Secretary:
Mr R W Hazell
Health, Safety and Environment Officer
The Royal Society of Chemistry
Burlington House
Piccadilly
London W1V 0BN
•Direct Tel : 0171 440 3337
•Switchboard : 0171 437 8656
•Fax : 0171 437 8883
•E-mail : hazellr@rsc.org
Web Address : http://www.rsc.org or http://www.chemsoc.org

1
l:\ehscnote\Scale up of Chemical Reactions 1 March 99
7