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CGPP Report 2004/29

AT A GLANCE
Ethanol is one of the raw materials used by
the active pharmaceutical ingredients (API)
manufacturer Wexport in the production of
Tinzaparin, an anticoagulant that is used in the
treatment of deep vein thrombosis (DVT) and
pulmonary embolism. Each year, the Wexport
plant uses 227, 374 litres of ethanol during
the production process. Such usage has
substantial economic and environmental
consequences. As part of its involvement in
the Cleaner Greener Production Programme
(CGPP) Wexport undertook to carry out a
feasibility study on the replacement of highpurity ethanol with recycled ethanol
containing low-volatile impurities. The key
factor that would determine the suitability of
the recycled ethanol for use during the overall
production process would be whether it met
European Pharmacopoeia (EP) specifications
for that product. As a result of its involvement
in the project Wexport has made significant
strides in the application of recycled ethanol.
However, some further quality improvements
will be necessary. Once it meets EP
specifications, Wexport will aim to use
recycled ethanol as a replacement for highpurity ethanol across the full range of its
production processes.

WEXPORT LTD

Printed on recycled paper using water based inks

Wexport Ltd (a subsidiary of the

pharmaceuticals multinational Leo) was
established at Little Island, Cork in 1987. The
Wexport plant is one of the worlds leading
bulk producers of heparin, an anticoagulant
that is used in the treatment of deep vein
thrombosis (DVT) and pulmonary embolism.
Heparin is a naturally occurring anticoagulant
of porcine origin.
At the Wexport plant, the raw heparin is put
through a series of purification processes
including chemical and biochemical treatments,
filtration and drying.
Wexport Ltd manufactures two basic types of
heparin heparin sodium and low-molecular
weight heparin (Tinzaparin). These bulk active
pharmaceutical ingredients (API) are exported
to Leo Group subsidiaries and other
pharmaceutical production facilities around the
world. These plants then take the heparin to
the next stage of the production process final
formulation, filling and packaging.

STUDY ON THE POTENTIAL USE OF

REGENERATED ETHANOL IN THE
PRODUCTION OF TINZAPARIN
AIMS OF THIS PROJECT
The main aim of this project was to produce
a recycled ethanol of a quality and standard
that would meet European Pharmacopoeia
(EP) specifications: in this particular case the
specification required was 96% ethanol.
In order to ensure that it did not in any way
adversely impact on the quality of the endproduct (Tinzaparin), the use of recycled
ethanol in any aspect of the production
process would first require the validation of
the relevant regulatory agencies.

The CGPP project team designed a

series of experiments, which were aimed
at identifying impurities and determining
their source of origin.
The presence of acetaldehyde was the
first hypothesis considered.
Hydrogen peroxide made up one
portion of the ethanol feed to the
distillation column. Due to the elevated
temperature of the column, it was
assumed that the ethanol was oxidised
and therefore converted into
acetaldehyde (ethanal) and, possibly, to
acetic acid (ethanoic acid).

Previous tests carried out by Wexport on

ethanol that had been recovered on site
showed that it had a high acetaldehyde level
i.e. 300 parts per million (ppm). This level
was way in excess of the EP limit (10 ppm).

Figure 2: Distillation column

Figure 1: The Wexport Plant

The team analysed ethanol samples to

confirm the presence of acetaldehyde
and to determine the varying levels of
hydrogen peroxide present at the range
of temperatures that would apply
during normal distillation conditions.

PROJECT DESCRIPTION
The project was implemented in four
stages. As follows:

Stage One focused on determining what

was creating the impurities present in the
ethanol recovered on site.
Figure 3: Distillation column

BETTER BUSINESS IN A BETTER IRELAND

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Analysis of the samples confirmed that the peroxide present

during the processing operation was causing the oxidisation
of the ethanol to ethanal. The team also observed that the
chemical reaction occurred at room temperature. This was
surprising because it had been assumed that the primary
source of the oxidation was the distillation column itself.
Overall, the analysis showed that it would not be necessary
to pre-treat the ethanol feed to the distillation column in
order to neutralise the peroxide and thus prevent the
formation of acetaldehyde.
In summary, only a limited number of applications would be
required to remove impurities from the ethanol and thus
meet EP specifications.

Option 3: second-pass system to remove acetaldehyde

QVF was requested to model a solution, which would focus
on using the regenerated ethanol from the distillation
column. As hydrogen peroxide is not present in the system,
this approach should have presented fewer challenges. The
project team examined the possibility of using the distillate
output from the first column as the feed for a smaller flash
column, which would take the distilled ethanol from the
primary column and then flash distil the acetaldehyde from
the ethanol. The distillate from the flash column would
contain acetaldehyde and other impurities, while the bottom
of the flash column would contain high-purity ethanol.
A series of on-site pilot trials was carried out by QVF, the
results of which are shown in Table 1.

Stage Two focused on determining the best ways to

reduce impurities and ensure that the recycled ethanol met
EP specifications.

Table 1: Distillation results

Option 1: modifications to existing distillation column

The CGPP project team met with QVF (the original
designers of the distillation column) to discuss modifications
that would be necessary in order to enable a single-pass
system produce 96% ethanol. QVF prepared models for
several possible design modifications. However, it transpired
that each of the proposed modifications would have some
degree of negative impact on ethanol purity. Moreover, the
CGPP project team confirmed that the presence of
hydrogen peroxide would further exacerbate the problem
because acetaldehyde would continue to be formed during
the distillation process. For all of these reasons, they decided
not to proceed any further with investigations into using the
modifications to existing distillation column approach.

Option 2: pre-treatment of ethanol with a

reducing agent
This approach would involve the pre-treatment of ethanol
with a reducing agent. Specifically, sodium borohydride
would be added to cause the acetaldehyde molecules to
revert to ethanol. Normally, Venpure, a Rohm Haas sodium
borohydride, which has been stabilised with sodium
hydroxide, is used for this type of application.
It should have been possible to introduce aqueous sodium
borohydride into the distillation column to convert the
acetaldehyde into ethanol. However, the adoption of this
approach would have presented a number of engineering
challenges. For example, hydrogen would be generated
during this process; hydrogen has a low auto-ignition point,
and therefore the installation of the requisite safety controls
would be very expensive.

While the results show a significant reduction in

acetaldehyde using the flash column, the required EP limit
of <10ppm was not achieved.

Stage Three focused on testing the recycled ethanol to see

if it met EP specification during laboratory-scale production.
If those results were to prove positive, then further tests
would be carried out in a plant-scale operation to confirm
that there were no adverse effect on product quality.
It did not prove possible to achieve positive confirmation
from the laboratory tests on the recycled ethanol within the
stipulated 12-month project timeframe.

Stage Four involved submitting a proposal for a

registration change to allow the use of ethanol (96%) EP
during the Tinzaparin manufacturing process.
The CGPP project team presented a registration change
proposal to the Wexport management
team, which agreed to proceed with the requisite
modifications to plant and equipment, should the outcome
of the EP specification application process prove successful.

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ACHIEVEMENTS

LESSONS

This CGPP project clearly demonstrates that the following

economic and environmental benefits are achievable.

2. Wexport could minimise the disposal of waste as a result

of eliminating the shipment of hazardous ethanol waste
from the site.

Wexport is firmly committed to the introduction of cleaner

production processes throughout every aspect of its operation.
Future company initiatives will include an examination of the
issue of energy consumption and how to minimise it.
In the case of the ethanol recycling initiative, the problems
that the team encountered made the execution of this
project more difficult than had been envisaged initially. This
was largely due to the complex nature of the distillation
process, which required the carrying out of a much greater
number of tests than expected: this extended the timescale
of the project considerably.

3. Overall production costs could be lowered significantly as

a result of reducing purchases of certain essential raw
materials.

The project concept remains valid, and the companys

management team has committed the requisite financial
and human resources to ensure that its objectives are met

4. By re-engineering its production process Wexport could

improve its overall business efficiency.

MORE INFORMATION

1. It is possible to conserve plant resources and raw

materials by recycling a key raw material, thereby
eliminating the need to purchase at least 227,374 litres
of ethanol a year.

For more information on this project contact:

OBSERVATIONS
While the project was not completed within the anticipated
timeframe, the positive results that have been achieved so
far will ensure that work in this area will continue until the
original CGPP project objectives are met.

Martin Rea
Process Chemist
Wexport Ltd
Little Island
Cork
Tel: 021 435 4102
Fax: 021 435 4319
Email: martin.rea@leo-pharma.com
Website: www.leo.ie

Figure 4: Ethanol tank farm

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CLEANER GREENER
PRODUCTION IS
the application of integrated preventive environmental
strategies to processes, products, and services to increase
overall efficiency and reduce risks to humans and the
environment.
Production processes: conserving raw materials and
energy, eliminating toxic raw materials, and reducing the
quantity and toxicity of all emissions and wastes
Products: reducing negative impacts along the life cycle
of a product, from raw materials extraction to its
ultimate disposal.
Services: incorporating environmental concerns into
designing and delivering services.

CLEANER GREENER
PRODUCTION REQUIRES
new attitudes, better environmental management, and
evaluating available technology options. We need to take
good environmental practice to the stage where it is an
inherent part of any business operation.

HOW IS CLEANER GREENER

PRODUCTION DIFFERENT?
Much of the current thinking on environmental protection
focuses on what to do with wastes and emissions after they
have been created. The goal of cleaner, greener production
is to avoid generating pollution in the first place.
This means:

Better efficiency
Better business
Better environmental protection
Lower costs
Less waste
Less emissions
Less resource consumption

WHY IS THE CLEANER

GREENER PRODUCTION
PROGRAMME BEING RUN?

The long-term goal is to ensure that cleaner, greener production

becomes the established norm in Ireland. The programme seeks to
promote environmentally friendly business through increased
resource productivity, waste reduction, recovery of materials,
improved efficiency in a product value chain, energy management,
and a change of culture within organisations.
The programme aims are focussed on avoiding and preventing
adverse environmental impact rather than treating or cleaning up
afterwards. This approach brings better economic and
environmental efficiency.

PROGRAMME MANAGERS:
The Clean Technology Centre (CTC) at Cork Institute of
Technology was appointed to manage the programme in
association with OSullivan Public Relations Ltd, and Energy
Transport Actions Ltd, (ENTRAC).
The CTC was established in 1991 and is now nationally and
internationally regarded as a centre of excellence in cleaner
production, environmental management and eco-innovation across
a range of industrial sectors.

WHERE CAN I GET

FURTHER INFORMATION?
This case study report is one of 29 reports
available from the organisations that
participated in the first phase of the Cleaner
Greener Production Programme. A summary
of all the projects and CD containing all the reports
are also available. More information on the Programme
is available from the Environmental Protection Agency
Ms. Helen Walsh,
CGPP,
Environmental Protection Agency,
Richview, Clonskeagh Road, Dublin 14, Ireland.
Tel. 01 2680100
Website

Fax. 01 2680199

www.epa.ie

select link to cleaner production.

Email. ertdi@epa.ie
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The Irish Government, through the National Development

Plan 2000 - 2006, has allocated funds to a programme for
Environmental Research, Technological Development and
Innovation (ERTDI).

The Department of the Environment and Local Government asked

the Environmental Protection Agency (EPA) to run the CGPP as
part of the ERTDI programme. With the programme continuing to
2006 about 60 businesses will be supported to implement cleaner
greener production and to demonstrate their achievements to the
rest of Ireland.