Journal of Cleaner Production 44 (2013) 123e132

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Journal of Cleaner Production

journal homepage: www.elsevier.com/locate/jclepro

Cleaner production aspects of tablet coating process in pharmaceutical

industry: problem of VOCs emission
Zorana Boltic a, *, Nenad Ruzic a, Mica Jovanovic c, Marina Savic b, Jovan Jovanovic b, Slobodan Petrovic c
a

Hemofarm A.D., Beogradski put b.b., 26300 Vrsac, Serbia

Innovation Centre of the Faculty of Technology and Metallurgy, University of Belgrade, Karnegijeva 4, 11000 Belgrade, Serbia
c
Faculty of Technology and Metallurgy, University of Belgrade, Karnegijeva 4, 11000 Belgrade, Serbia
b

a r t i c l e i n f o

a b s t r a c t

Article history:
Received 5 April 2012
Received in revised form
1 January 2013
Accepted 3 January 2013
Available online 20 January 2013

The aim of the article is to present a case study related to implementation of cleaner production (CP)
process with the concept of minimizing emissions versus the end of pipe (EOP) approach within pharmaceutical industry. The idea is to move beyond simple pollution control by technology improvement
and prevention of organic solvents emission into the atmosphere. Furthermore, cost-effectiveness of the
suggested approach is evaluated compared to traditional concepts of polluted air treatment, ensuring
both environmentally friendly and effective production of lm coated tablets. Technological changes to
improve the impact on the environment have been applied already in many industries as well as in
pharmaceutical manufacturing. However, more effort is to be made in order to further decrease particularly VOCs emission into the atmosphere. An analysis is provided to stimulate a proactive approach in
this eld towards completely eliminating the use of organic solvents from lm-coating systems in the
production of the pharmaceutical solid dosage forms. The new way of addressing the costs actually
associated with embracing cleaner technologies, which are mostly related to regulatory aspects in
pharmaceutical industry, is aimed to promote the change in culture, as well as to be applied in the
decision making process for other pharmaceutical facilities still using organic solvents based coatings in
the manufacturing of tablets. The signicance of the small scale projects is additionally emphasized
considering the magnitude of the world generic market.
2013 Elsevier Ltd. All rights reserved.

Keywords:
Tablet coating
Pharmaceutical industry
BAT
VOCs emission

1. Introduction
The modern pharmaceutical industry is a highly competitive
industry whose origins can be traced back to the late 19th century
when most of todays major pharmaceutical companies started out
as chemical industries. These companies gradually evolved into
global players within the pharmaceutical sector witnessing major
developments in the 1970s with the introduction of tighter regulatory controls, especially regulations governing the manufacture of
generics. The global pharmaceutical market sale is expected to
grow at a 4e7% compound annual growth rate (CAGR) through
2013, which is, among other factors, driven by the changing combination of innovative and mature products (Pharmaceutical
Market Trends, 2010).

* Corresponding author. Tel.: 381 13 803 019.

E-mail addresses: Zorana.Boltic@hemofarm.com, zboltic@yahoo.com (Z. Boltic),
Nenad.Ruzic@hemofarm.com (N. Ruzic), mica@tmf.bg.ac.rs (M. Jovanovic),
msavic@tmf.bg.ac.rs (M. Savic), jovamic@eunet.rs (J. Jovanovic), sloba@tmf.bg.ac.rs
(S. Petrovic).
0959-6526/$ e see front matter 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.jclepro.2013.01.004

A generic drug product is one that is comparable to an innovator

drug product, i.e. contains the same medicinal or therapeutic ingredient(s) as the original brand name drug. Research-based
pharmaceutical companies have made enormous progress in the
treatment of many illnesses. Nevertheless, generic medicines make
up nearly 50% of all medicines dispensed in the EU, by more than
700 generic companies in Europe (including Hemofarm, member of
STADA Group) employing 130,000 staff (Research Facts Ltd, 2009).
Rising healthcare costs have resulted in an increase in generic
pharmaceutical usage with China being the largest generic market
in Asia, and second largest in the world after the US. The majority of
pharmaceuticals available in China are domestically manufactured
generics with preference over more expensive branded drugs
among poorer patients. Growing generic pharmaceutical usage in
Brazil and India is even more present with 83.2% of total pharmaceutical market sales in Brazil (2008) and generics making up to
99.8% of the prescriptions sales market in India (IMAP, Inc, 2011).
This is why cleaner production (CP) in particular is useful in
developing world, where people are facing both resource and
environmental challenges like in China, where there is still no

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integrated assessment for implementing CP technologies in pharmaceutical industry (Zhi-Dong et al., 2011a, 2011b). Furthermore,
when it comes to this region where generic pharmaceuticals have
signicant impact on the total industrial value of the whole country, and although some cases of execution of CP exist showing that
the return of investment in CP is quick, frequently only limited
interest is expressed in terms of involvement in building a serious
strategy within the pharmaceutical sector and on the regional level
(Ze-hua et al., 2011; Zhi-Dong et al., 2011a).
All new drugs, both innovator and generic, must be approved by
relevant regulatory authorities before marketing. In terms of CP aspects, the product Life Cycle Assessment (LCA) is usually considered
in this process as well. Although LCA as an environmental management tool has been used in some industrial sectors since 1970s and
experienced signicant methodological development in 1990s,
especially for applications in process selection, design and optimization (Azapagic, 1999), as well as recently in production logistics
(Burchart-Korol, 2011a), very few LCA studies can be found in the
literature today concerning pharmaceutical products or processes
(Mata et al., 2012). Despite the fact that LCA has become one of the
most relevant methodologies to help organizations accomplish their
environmental and sustainability goals, such as Life Cycle Sustainable Assessment (LCSA) as one of the most comprehensive methods
to assess processes, products or technologies at every stage
(Burchart-Korol, 2011b), difculties exist in pharmaceutical industry
related to different factors like measuring inputs and outputs
(pharmaceuticals being among the most complex chemicals produced), specialized processes involved in the production itself usually organized in discreet batches varying in size, and multipurpose
plants, sharing equipment and facilities between production lines.
Nevertheless, since the life cycles of pharmaceuticals have recently
become a concern for many environmental scientists, some LCA was
performed in pharmaceutical industry, although mostly related to
Active Pharmaceutical Ingredients (API) Production. Case studies
from Pzer, Bristol-Myers Squibb and Novartis were examined
where solvent recovery and reduction techniques were integrated
into API synthesis as a pollution prevention solution (Raymond et al.,
2010), as well as Hoffmann-La Roche (Wernet et al., 2010), and Life
Cycle Inventory (LCI) performed for vancomycine hydrochloride
(Ponder and Overcash, 2010), but excluding further use of the API in
a galenic formulation (preparation of the tablet/solution), i.e. production steps of a pharmaceutical, in all cases. The production of
sertraline hydrochloride and paroxetine was also investigated previously by the same research group working on vancomycine hydrochloride, showing that solvent and energy usage have the
greatest impact on LCA. However, no detailed information is available as a full LCI of a nished pharmaceutical product, actually using
these APIs as raw materials for further processing.
On the other hand, numerous action plans and processes were
developed in order to reduce or eliminate the use or generation of
substances hazardous for the environment in different sectors such
as healthcare (Zimmer and McKinley, 2008; Allen, 2006) and industry according to the Green Chemistry concept (Manley et al.,
2008), and CP technologies implemented by the companies of
major environmental concern to reduce ecological damage
(Jovanovic et al., 2010). There is also a variety of articles dealing
with problems of stimulating technological changes to enhance
environmental preservation (Fukasaku, 2000) and reduce pollutant
emissions at the source, as well as with the role of regulations as
clean technology promoters, especially for VOCs emissions reduction (Belis-Bergouignan et al., 2004). The discussions were raised in
an attempt to answer the question why companies still do not fully
comply with the requirement to adopt clean technologies favored
by the European VOC directive and to explain the gap between
regulatory developments and actual industrial choices, i.e. to

understand the reasons why there is still preference for EOP technologies despite the regulatory factors encouraging CP.
When it comes to production processes in pharmaceutical industry, since being one of the largest users of organic solvents per
amount of the nal product (Slater et al., 2006), end of pipe (EOP)
technologies or reduced consumption of toxic and hazardous raw
materials/reduction of emissions and wastes from the process itself
may be applied. However, very few articles are dealing with actual
implementation of the practical solutions within CP in generic
pharmaceutical industry. In constant attempt to eliminate the usage of organic solvents by following other, more environmentally
friendly industries, efforts have been made in the pharmaceutical
sector to decrease their amounts in API synthesis and drug products
manufacturing (Grodowska and Parczewski, 2010).
Pharmaceutical production takes place in numerous facilities all
over the world and coated tablets are the most common pharmaceutical form comprising a mixture of active substance(s) and excipients usually pressed or compacted from a powder into a solid
dosage form. Although a large number of companies are now regularly practicing aqueous lm coating, lot of other companies still
continue to use huge quantities of VOCs in the tablet coating process as solvent systems for dispersing the polymers, plasticizers,
opaciers, lubricants and pigments. New technologies in polymers
production replaced organic solvents usage in a lm coating process almost entirely, conrming the positive contribution that
technological innovation makes in achieving environmental targets
(Fukasaku, 2000). Still, the biggest motivation for manufacturers
who continue using organic solvents is that their coating facilities
are not fully optimized for aqueous lm coating and in most
pharmaceutical companies more emphasis is given to granulation,
mostly in terms of residual solvents (Grodowska and Parczewski,
2010) and compression of tablets, while necessary steps are not
always considered for lm coating operations. Another important
issue in a highly regulated sector such as pharmacy, is that a variation needs to be submitted for all process modication which is
very often regarded as costly and time consuming, although the
newest technologies successfully avoid organic solvents in favor of
water (McGinity and Felton, 2008). Nevertheless, complete shift
from using organic solvents to a solvent-free concept raises questions about companies knowledgebase and product performances.
Consequently something needs to be done to avoid the harmful
effects of VOCs on the environment and when it comes to tablet
coating, the industry has to choose between EOP and substitution
of solvents, i.e. process changes, the category through which clean
technologies are actually assessed (Belis-Bergouignan et al., 2004).
It is essential that generic manufacturing in particular becomes
the subject of CP analysis mostly because it is based on innovators
know how after the expiry of relevant patents, but still represents
the majority of drugs used for treatment of numerous illnesses in
overall population, particularly due to lower prices. Furthermore,
generic pharmaceutical industry is a very important part of
chemical industry in Serbia due to signicant portion of the production volumes, employment, income and prots with 3.2% in
a gross domestic product of the country. To additionally support the
relevance of the articles scope for promoting the concept of CP
throughout the region, it is important to emphasize that Hemofarm
is the largest pharmaceutical industry with 47.7% compared to
another two major companies in Serbian pharmaceutical sector e
Galenika a.d. (27.3%) and Zdravlje a.d. with 13.6% (Ofcial Gazette of
the Republic of Serbia, 2009). The aim of the presented case study is
to practically evaluate the approach of process modication in the
generic pharmaceutical industry through eliminating of VOCs
against EOP technologies which deal with them, preventing pollution by adequate treatment. For that purpose, the example of
coated tablets production process using ethanol and methylene

Z. Boltic et al. / Journal of Cleaner Production 44 (2013) 123e132

chloride is analyzed, not only in terms of environmental protection,

but also considering technical and economical aspects of CP concept implementation into the manufacturing process. Special
attention is given to toxicological properties and potential hazards
of raw materials used for the manufacturing of the selected drug
product. Process modication in this case subject to the analysis,
corresponds to the situation where overall process principle remains the same and step(s) are simply added to enable replacement of certain resources. As there is no such thing as a completely
clean technology, the idea of gradual deployment of CP, especially
through substitution and savings in inputs at the same time (BelisBergouignan et al., 2004) is challenged through implementing the
approach of starting with small-scale improvement projects and
gradually enable further embedding of CP practices in all manufacturing areas through incremental changes, also supported by an
adequate continuous improvement (CI) program. The integrated
Lean and Clean concept is not new, as from management perspective, both economic and environmental performance can be
reached by the organization that uses integrative and preventive
approaches to minimize risks and wastes of energy, materials and
reputation (Baas, 2005). There are many sources for CP opportunities, which may result from CI programs such as six sigma and
lean manufacturing (Shah, 2012), as well as positive experience in
different organizations applying lean and green production principles to achieve reduced environmental impact and save money at
the same time (Environmental Protection Agency, 2007). However,
not many practical examples of the surge of interest in lean production serving to promote CP in pharmaceutical industry can be
found in literature. Hemofarm in particular, is one of the rst
manufacturing sites within STADA Group where structured
approach to CI was established through deployment of Lean and Six
Sigma methodologies throughout the whole business.
2. Best Available Techniques (BAT) analysis
According to BAT Guidance Note on Best Available Techniques
for Pharmaceutical and Other Speciality Organic Chemicals
(Environmental Protection Agency, 2008), emissions of volatile
organic compounds is one of the key environmental issues of this

125

sector. As for the possible control techniques stipulated in this

guidance note, most of the prevention and minimization measures
related to environmental impact are focusing on the design phase
of pharmaceutical processes and/or facilities (selection of site
location, plant design and product development), not readily
applicable to the already established systems and processes within
the majority of generic industry. However, different technologies
are available for treatment of gaseous residues under Management
and Treatment of Residues in the same guidance note e BAT is to
assess individual exhaust gas volume ows from process equipment to recovery/abatement systems. Furthermore, BAT is to apply
recovery/abatement techniques for VOCs such as activated carbon
adsorption, thermal oxidation etc. Considering the BAT Hierarchy of
course, as well as the requirements of the Integrated Pollution
Prevention and Control (IPPC) Directive 96/61/EC (European
Commission, 2003), the emphasis is always placed on pollution
prevention techniques (such as the use of low-waste technology,
less hazardous substances etc) rather than the EOP treatment,
whenever applicable. Therefore, based on General Environmental,
Health and Safety (EHS) Guidelines (International Finance
Corporation, 2007), as well as EHS for Pharmaceutical and Biotechnology Manufacturing (IFC, 2007), some of the recommended
prevention and control techniques, i.e. minimization measures for
solvent and VOC emissions applicable for pharmaceutical industry
are presented in Fig. 1.
It should be noted that when it comes to EOP technologies, there
is a lack of literature specically related to BAT in pharmaceutical
industry, especially production of generic drugs and relevant processes, as well as associated investments and costs for different
options. The most suitable technique is usually selected for the individual process based on the dened criteria. Nevertheless, most
waste gas control techniques require further downstream treatment
for either waste water or waste gas generated during the treatment
process (European Commission, 2003). Waste gas treatment normally takes place directly at source, as treatment units are specically designed for a particular waste gas composition.
According to the selection of techniques by waste gas ow rate
given in the relevant reference documents on BAT (BREF) reecting
information exchange carried out under Article 16(2) of Council

Pharmaceutical production
tablet coating
VOC emissions

Prevention/change of
technology switch to aqueousbased films

Management and
treatment of waste
streams, i.e. gas (EOP)

Abatement and final

treatment techniques

Recovery techniques

Condensers

Adsorbers *
(activated carbon,
alumini, silikates etc)

* May be classified as recovery or abatement, depending on additional separation stages

Fig. 1. Alternatives for reduction of VOCs emission.

Incinerators

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Z. Boltic et al. / Journal of Cleaner Production 44 (2013) 123e132

Directive 96/61/EC (European Commission, 2003), thermal oxidation (incineration) is not recommended for low gas ows. Besides
ow rate of the gas stream, other key selection issues for gas
treatment systems whose suitability has a signicant impact on the
required capital and operating costs, are contaminant concentrations as well as their nature since the treatment systems are limited
in this respect. For example, the efciency of condensation depends
on the vapor pressure of the contaminants at condensation temperature and only compounds of small molecular size can be
effectively adsorbed and desorbed. On the other hand, adsorption
systems may be very efcient as long as it is taken care to avoid
saturating the adsorbent (European Commission, 2003).
As controlling emissions at a cost-effective level requires
investigation of source reduction opportunities based on the causes
of emissions, it may be revealed that change of technology represents lower investment than the EOP treatment. The implementation of this kind of change in pharmaceutical industry
assumes the following:





product reformulation,
stability testing,
manufacturing process validation,
documentation for submission of proper variations to regulatory authorities on relevant markets, and
 revision of manufacturing and analytical instructions.

Active Pharmaceutical
Ingredient (API)

PREPARATION OF
RAW MATERIALS

GRANULATION

TABLETTING

In Process
Control (IPC)

COATING

COATING SUSPENSION
containing organic solvents

In Process
Control (IPC)

PACKAGING
Fig. 2. Film coated tablets manufacturing process ow chart.

The cost associated with each of the above suggested approaches (EOP and change of technology) may be expressed as
xed expenses needed to introduce either the new equipment at
the EOP or to switch to a new, cleaner technological process mainly
from regulatory point of view. There may be also considered expenses for equipment maintenance/organic solvents regeneration,
i.e. annual savings due to lower raw material cost by switching to
the coating process using water instead of organic solvents. Anyway, the industry may most certainly benet from this approach
gaining lower emissions with the unchanged product quality.
3. Case study e the methodology
3.1. The study area e tablet coating process problem denition
The production process of lm coated tablets consists of the
following phases: preparation of raw materials, granulation, tabletting, coating and packaging (Fig. 2).
As the model drug for this study, it was chosen generic diclofenac sodium produced by several companies and used to treat pain
and inammation seen with various types of arthritis. During its
manufacturing, organic solvents ethanol and methylene chloride
are used for coating, both in the same quantity of 15.7 kg. These
solvents evaporate on higher temperatures and the gases are
emitted in the atmosphere through ventilation of 0.67 m3/s capacity. Film coating process starts by introduction of dry tablet
cores into the drum of the coating equipment where these cores are
coated with the suspension. Capacity of the drum used for model
drug coating is 100 kg tablet cores, the duration of the coating
process is: pre-heating 900 s, coating 2e3 h, drying and cooling
900 s. From the coating equipment, the waste air is drawn into the
atmosphere through the ventilator and class F9 lter for reduction
of powder material (DIN EN 779, 2003).
Emissions were measured in 2006 by an accredited laboratory
and the measuring points within the waste gas ow were chosen
near the outlet of the uid into the atmosphere ensuring the
laminar ow. Measuring was performed as individual in order to
control the emission at the facility with mostly uniform working
conditions. According to Serbian regulations covering Emission

Limit Values (ELVs) in the waste air ow (Ofcial Gazette of the

Republic of Serbia, 1997), article 9, types and classes of organic
compounds, as well as their ELVs and mass ow thresholds are
dened and given in Table 1.
Since all measured values of mass ow of outlet gases were
below 3 kg/h (the approximate gas ow is 1650 Nm3/h), limit
emission of 150 mg/m3 could not be applied and based on the
performed measurements in the ventilation canals during the
production process (tablets coating) of the model drug, it was
concluded that the emissions of ethanol and methylene chloride do
not exceed the limit value dened in relevant regulation covering
ELVs (Ofcial Gazette of the Republic of Serbia, 1997). Nevertheless,
according to limit values for the manufacture of pharmaceutical
products in the VOC Directive (European Parliament and Council,
1999) assigned the risk phrase R40, is established as 20 mg/m3
with the threshold of 100 g/h. Furthermore, in Sweden, methylene
chloride is essentially banned for use in processes (European
Commission, 2006) and the commitment to continuous improvement in a proactive way is expected according to European regulations, besides adopting the environmental policy consistent with
regulatory compliance (Cunningham, 1995).
3.2. BAT selection
Based on the presented BAT analysis, two BAT alternatives are
selected for further analysis in terms of cost-effectiveness: a) xedbed adsorption EOP technology, as incineration is not recommended for low gas ows, while adsorption systems may be very
Table 1
ELVs of Methylene chloride and ethanol in the waste air ow.
Type of compound

Class

ELV (mg/m3)

Thresholda

Methylene Chloride
Ethanol

III
III

150
150

3 kg/h
3 kg/h

ELV applicable for mass ow above 3 kg/h.

Z. Boltic et al. / Journal of Cleaner Production 44 (2013) 123e132

3.2.1. Fixed-bed adsorption EOP technology

Fixed-bed adsorption processes are widely used and applicable
to control emissions from pharmaceuticals with limits and restrictions given in relevant BREF (European Commission, 2003).
The gas is fed at about 40  C to the adsorber, passes upwards and
leaves puried. To allow regeneration, adsorbers are normally
operated as multiple bed facilities, but the application as abatement
technology may be chosen in this case considering low measured
VOC concentrations in the waste gas (expenditure of energy or
material is disproportionate to the ecological benet derived, nal
treatment of the exhaust gas stream being a driving force in this
case). Achievable performance rates for VOC (Granular Activated
Carbon e GAC) depend on the adsorption characteristics of the
individual compound (European Commission, 2006), but range
from 80 to 95%, and the consumables are energy and the adsorbent
itself, as well as steam and cooling water in case of solvent regeneration. The environmental performance that could be anticipated
as a result of the application of the technique chosen for waste gas
treatment in this particular case is to be understood bearing in
mind the balance of estimated costs and known advantages.
Although the initial investment required for the selected EOP
system e adsorption, is important, the operating costs may be even
more signicant including utility consumption (xed-bed adsorption systems normally use steam for desorption), replacement of
adsorption media, cost of chemicals, operations and maintenance,
by-product disposal, pre- and post-treatment, etc. Regeneration
and/or disposal of adsorbent (cross-media effects) can also be done
by external companies. According to the economics listed in BREF
for Common Waste Water and Waste Gas Treatment/Management
Systems in the Chemical Sector, Draft 2 (European Commission,
2011), the rough indication of the magnitude of the costs
involved is as follows:

health and safety issues are considered early in the process development phase, especially when production process requires validation according to the requirements of Good Manufacturing
Practice, EU GMP (European Commission, 2001) and approval by
regulatory agencies, i.e. applicable medicine approval authorities. In
such cases, retrotting of a process causes revalidation, stability
assessment, documentation preparation and variation processes.
Nevertheless, this approach may still be more advantageous in terms
of cost-effectiveness of the selected solutions for emission control,
additionally resulting in better environmental performance, while
product quality remains unchanged e conrmed through appropriate dissolution proles e performed in two dissolution mediums
(water and phosphate buffer pH 6.8, because of insolubility of the
model drug in acid medium).
Documentation required to le the variation for switching to
aqueous instead of organic lm generally includes the following:
 studies which conrm absence of changes in dissolution prole
for one production batch with introduced change (replacement
of organic solvents with puried water) compared to at least
three batches manufactured according to the approved technology (with organic solvents) e Fig. 3;
 started stability studies at least during 3 months and more.
Guarantees should be also provided that upon nishing stability studies, the data will be immediately sent to the relevant
regulatory agency and
 process validation.

60

Water

50

Drug release, %

efcient as long as care is taken to avoid saturating the adsorbent

(European Commission, 2003) and b) process modication by new,
environmentally friendly, raw materials introduction (in this case,
replacement of organic solvents used for coating suspension
preparation with water, approximately in the same quantity e
31.54 kg may be applied).

127

40
Aueous film

30

Batch 1
Batch 2

20

Batch 3

 initial capital for GAC adsorber per 1000 Nm /h is in the range

form 10,000e50,000 EUR and
 the cost of consumables EUR 0.8e6 per kg of adsorbent
replaced (including disposal).

10

0
0

80

Phosphate buffer

70
60
50

Aqueous film

40

Batch 1

30

Batch 2
Batch 3

20
10
0
0

3.2.2. Process modication

The likelihood of successful prevention and minimization of the
environmental impact of a process increases if the environmental,

Time, h

Drug release, %

Actual cost of applying this technique will, however, depend on

the specic situation mostly regarding the technical characteristics
of the installation concerned. The costs to implement the necessary
infrastructure are not included either and the supplier equipment
costs are given relative to the waste gas stream (typically 20e30% of
the total erected cost including also engineering costs associated
with project design and supervision, relocation/modication of the
existing facilities/piping, drawings, process and instrumentation
diagrams development, is for major equipment purchase). Also, full
implications of the likely expenses incurred by a technique are not
easy to quantify, especially since equipment items will eventually
become more costly over time. Therefore, these gures may not be
used for direct comparison of costs associated with different pollution control techniques (EOP and raw materials replacement), but
may however provide the rough insight in the level of investment
needed in this case for discussion purposes.

Time, h
Fig. 3. Dissolution proles.

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Z. Boltic et al. / Journal of Cleaner Production 44 (2013) 123e132

4. Results analysis

Table 3
Testing frequencies for moderate and long term storage conditions.

4.1. Product reformulation

The elimination of organic solvents from a lm-coating system
and switch to the use of aqueous-based coating presents certain
challenges, as although aqueous lm-coating technology has
advanced to a level where it has become a matter of routine
(McGinity and Felton, 2008), there are still factors and parameters
that must be considered and controlled to obtain an optimized
nished product. As for the model drug subject to this case study,
appropriate considerations have been made relevant to potential
processing and stability problems, as presented in Table 2.
4.2. Cost analysis for the stability study
For the purpose of the stability study, samples taken from three
batches of model drug (aqueous lm) are kept under storage conditions according to ICH Q1A (International Conference on
Harmonisation, 2003) and testing frequencies are given in
Table 3. Overall cost of this stability study is presented in Table 4.
4.3. Cost analysis for the process validation
Process validation assumes the activities of documents preparation (Validation Protocol and Report) and testing performance on
three validation batches according to the protocol. The costs associated with the performance of these tests for three validation
batches (chemical testing), as well as preparation of validation
documents (based on time needed for Validation Protocol and
Report preparation and average salary per hour of an expert
involved in validation activities) are presented in Table 5.

Table 2
Factors considered for aqueous coating of the model drug and full industrial scale
application.
Identied risk area
Core tablets
Hardness and friability
a

Tablet shape
Lubricationb

Processing and Equipment, Driacoater 1200

 Pan speed to achieve
satisfactory tablet mixing
during coating operation
 Drying capacityc
Drying air ow
Inlet air temperature
Coating material
Polymer solubility in water

Effect of moisture on the

stability of active ingredients
Selection of viscosity grade

Result of the analysis/applied

solution
60e100 N with friability
max 0.5%
Round, biconvex cores
3% magnesium stearate in
the formulation
3e7 rpm

0.63e0.70 m3/s
40e65  C
Hydroxypropyl methylcellulose
(HPMC) soluble in organic
solvents, but also in water
over the entire biological
pH range
No degradation during coating
observed
HPMC 3 cP was usedd

Storage condition

Testing frequency (months)

30  C/65% RH
25  C/60% RH

3, 6, 9 and 12a
0a, 3, 6, 9, 12, 18, 12, 24, 36 and 48a

a
Microbiological testing performed initially, after 12 months at intermediate
conditions and at the end of the shelf life (4 years for the product of concern).

Table 4
Overall cost.
Stability and registration documentation
Stability testing (EUR)a
Chemical testing (14 analyses  3 batches)
Microbiological testing (3 samples  3 batches)
Total cost (testing for 3 batches and documentation)

w200 EUR
w420
w315
w935 EUR

a
Chemical testing cost per sample calculated as the sum of labor, energy and
material consumption for one analysis according to the analytical procedure for the
product is approximately 10 EUR and 35 EUR for microbiological testing per sample
(also calculated based on labor, energy and material consumption).

Table 5
Cost of process validation e model drug.
Chemical testing (model drug, 3 validation batches)
Preparation of validation documents (Protocol and Report)
Total cost (testing for 3 batches and documentation)

w30 EUR
w600 EUR
w630 EUR

4.4. Health and safety issues

Another consideration that must be made when comparing EOP
against cleaner technology is the level of impact on the environment, health and industrial safety. Although implementing an
adequate EOP solution would certainly reduce the air emissions to
the atmosphere, more effort is needed to actually improve the
workers atmosphere on the manufacturing oor in terms of
reducing their health and safety risks, as well as the safety risk
imposed for the people who live next door to the factories.
Therefore, replacement of organic solvents with water in tablet
coating process might not only be benecial from the nancial and
environmental point of view, but also for overcoming serious
health and safety issues for personnel handling these solvents.
Some of the important factors to be considered especially in
terms of safety and health hazards for people directly exposed to
solvents or close to the manufacturing areas where these solvents
are used, are the ash point, vapor pressure, toxicity, exposure and
explosive limits. Relevant information (NIOSH, 2007; Engineers
Edge, 2000e2012) for ethanol, methylene chloride and water is
given in Table 6, clearly indicating the safety with the use of water
as compared to particular organic solvents subject to this study.
Flammable solvents such as ethanol are an explosion hazard
when the vapor concentration in the air is greater than the lower
explosive limit (LEL, 3.3% for ethanol). As for toxicity, all pharmacological studies indicate that organic solvents are highly toxic even
in micro doses compared to water.
4.5. WAR analysis

Sharp edges may lead to lm cracking.

Concentration of lubricants (magnesium stearate) is critical in terms of surface
wetting/lm adhesion on the core surface.
c
Most important aspect of the aqueous lm coating as the machine needs to have
provision for extra energy requirement e drying air volume is increased so that
enough energy is available for removing water from the system without the air
temperature being excessively high.
d
High-concentration polymer solution provided due to low degree of polymerization; no peeling was observed during the coating operation.
b

Evaluating the ow and generation of potential environmental

impact of wastes from a production process can be accomplished by
the waste reduction (WAR) algorithm (Young et al., 2000). WAR
algorithm was developed and initially applied by Hilaly and Skidar
(1994) and Potential Environmental Impact (PEI) indicators were
additionally included by Young and Cabezas (1999). There are
numerous scientic articles dealing with WAR application in

Z. Boltic et al. / Journal of Cleaner Production 44 (2013) 123e132

different areas (Bonet-Ruiz et al., 2010; Cabezas et al., 1999;

Cardona et al., 2004; Mata et al., 2005; Ramzan et al., 2008;
Sammons et al., 2008; Savic et al., 2011; Smith et al., 2004; Young
and Cabezas, 1999; Young et al., 2000) and impact indices may be
used to compare environmental friendliness of different processes
in the design phase, but might also be calculated in order to provide
evidence of improvement after implementing modications, such
as eliminating of raw materials producing emission of volatile
organic compounds (VOCs) from the manufacturing process.
The WAR GUI software has been developed by US Environmental Protection Agency (US EPA). This software is applied for
determining the PEI of two design alternatives of the process. The
PEI of a given quantity of material and energy can be generally
dened as the effect that this material and energy would have on
the environment if they were to be emitted into the environment
(Cardona et al., 2004). PEI of a chemical k, Jk , is the sum of eight
specic potential environmental impacts of chemical k, Jkl , as
shown in Equation (1):

Jk

al Jkl

(1)

where al represents the relative weighting factor of impact category l (Young and Cabezas, 1999).
Weighting factor is dimensionless number which is used to
emphasize the particular areas of concern. In this analysis, all
weights were set to unity since every area has the same importance
(Moretz-Sohn Monteiro et al., 2009). Main individual potential
environmental impact categories can be divided into two groups:
local toxicological and global atmospheric. The four local toxicological impact categories include human toxicity potential by
ingestion (HTPI), human toxicity potential by either inhalation or
dermal exposure (HTPE), aquatic toxicity potential (ATP), and terrestrial toxicity potential (TTP). The four global atmospheric impact
categories include global warming potential (GWP), ozone depletion potential (ODP), acidication or acid-rain potential (AP), and
photochemical oxidation or smog formation potential (PCOP)
(Ramzan et al., 2008; Mata et al., 2005). PEI index e Iout shows
potential environmental impact from industrial process related to
external environmental efciency of the process plant, while PEI
index e Igen shows potential environmental impact from industrial
process related to internal environmental efciency of the process
plant (Cabezas et al., 1999).
Toxicological properties and potential hazards of the existing
process vs. deployment of raw materials replacement technique
(Rydbergt, 1994) in order to minimize emissions from the coating
phase of the manufacturing process were evaluated using WAR.
WAR analysis covered two cases: Case I e process using organic
solvents and Case II e process with puried water as a solvent
within the coating suspension. In Table 7 total output rates of PEI
for 3 different analyses are shown: 1) Non-product analysis
(product stream was not included in the calculation), 2) Product

129

Table 7
Total output rate of PEI.
Case

I
II

Iout PEI/hr

Iout PEI/kg

1627
3193

0
1566

180300
181900

47.39
93.01

0
45.62

5252
5297

stream and energy consumption were not included in the calculation and 3) Product analysis (product stream and energy consumption were included in the calculation).
Based on data presented in Table 7, product analysis resulted in
highest PEI values, which is expected since the product itself is
biologically active. In analysis 3, the PEI obtained in both cases are
very similar, i.e. the differences between cases I and II are negligible
due to the fact that the inuence of the solution replacement
within the technological process on the environment is signicantly lower compared to product PEI. Assuming that energy
consumption is approximately the same in both cases, it is concluded that the analysis in which product stream and energy consumption were not included in the calculation is most relevant.
Results obtained in this analysis are shown in Table 8.
4.6. The role of the CI program in fostering environmental strategies
to support CP approach
Improvement initiatives started in the manufacturing area to
support performance indicators related to downtime reduction,
efciency and yield increase. Besides working on individual projects, training programs were established with the aim to build an
infrastructure within the company to create different levels of
expertise among the employees (both management and hands-onthe job people) in applying relevant improvement tools and
techniques.
Within these training programs, environmental aspects are
regarded as an important motivating factor to trigger innovation
towards both safety and cost-effectiveness. As a result, the natural
alignment is developed between the environmental goals and
improvement projects selected to increase productivity, obtain
higher process yields, achieve material savings and reduce handling or waste treatment costs. The CP concept becomes an inherent part of the overall strategy to increase environmental
performance and productive efciency using a single concept of
lean manufacturing.
5. Discussion
Data presented in this article indicate that the key differences
between EOP technologies and CP approach are in that EOP requires investment in treatment facility (common for all products
manufactured using the particular equipment) and expenses related to replacement of the adsorbent, while for implementing the CP

Table 6
Comparison of solvents characteristics.
Vapor pressure kPa at 20  Ca

Solvent

Flash point

Ethanol

16.6 C

Methylene Chloride

None

72

Water

None

a
b

2.4

Exposure limits OEL (ppm)b

Summary of health effects

1000

Irritation of the eyes, skin and nose; headache; drowsiness,

dizziness; weakness and exhaustion; cough; liver damage;
anemia; reproductive and teratogenic effects
Irritation of the eyes and skin; weakness and exhaustion;
drowsiness; dizziness; numbness; tingling limbs; nausea
None

50
None

A high vapor pressure indicates a higher concentration in the air and the increased likelihood of breathing by people present close to the substance/solvent.
OEL: Alberta 8-h Occupational Exposure Limit.

130

Z. Boltic et al. / Journal of Cleaner Production 44 (2013) 123e132

Table 8
Total potential environmental impact for each impact categories.
PEI/hr outputa

Environmental
impact categories

PEI/kg product
leavingb

PEI/hr generationc

PEI/kg product generatedd

Case

II

II

II

II

HTPI
HTPE
TTP
ATP
GWP
ODP
PCOP
AP
Total

0
0
0
0
0
0
0
0
0

0.452
4.93E-3
0.452
2.17E-3
4.20E-3
0
0.65
0
1.57

0
0
0
0
0
0
0
0
0

1.32E-2
1.44E-4
1.32E-2
6.33E-5
1.22E-4
0
1.89E-2
0
0.0456

89.0
0.987
89.0
8.5E-6
0
0
0
0
179

89.9
0.996
89.9
4.50E-3
8.61E-3
0
1.88
0
183

2.59
2.88E-2
2.59
2.5E-2
0
0
0
0
5.22

2.62
2.90E-2
2.62
1.31E-4
2.51E-4
0
5.48E-2
0
5.32

a
b
c
d

Total
Total
Total
Total

output rate of PEI.

PEI leaving the system per mass of products.
generation rate of PEI.
PEI generated within a system per mass of products.

approach there is an one-off cost of variation for each product, but

substantial annual savings related to purchasing of organic solvents
as well. Overall costs of raw materials replacement in terms of
regulatory compliance for one drug product were calculated as the
sum of stability and validation costs for model drug leading to the
cost of approximately 1 565 EUR. Nevertheless, in order to discuss
the choice between the suggested EOP technology (xed bed
adsorption without solvents regeneration) and raw materials
replacement, the analysis was extended to other products manufactured using the same coating equipment as the model drug
chosen for calculation of costs and environmental impact. Based on
data from the information system (year 2006e2010), an average
amount of 36,256 kg of coated tablets (model drug) and 4961 kg of
coated tablets (second product manufactured using the same
coating equipment, for which the replacement of raw materials is
also suggested) is produced annually. The cost of stability and
validation is approximately the same for both drugs therefore
leading to the total sum of 3130 EUR expenses needed for raw
material replacement in the manufacturing processes involving the
coating equipment subject to this analysis. As noted before, the
obtained value can not be directly compared to the initial capital for
GAC adsorber (10e50 000 EUR per 1000 Nm3/h of the waste gas),
but may however indicate that the switch to this environmentally
friendly manufacturing process is most certainly benecial from
the nancial point of view. Furthermore, introduction of aqueous
lm for these two products additionally leads to annual savings
based on lower overall consumption of ethylene alcohol and
methylene chloride, as shown in Table 9, in contrast to additional
cost of consumables per tonne GAC in case of implementing the
suggested EOP technology.
As for the WAR results, when water is used as the solvent within
suspension, environmental impact categories for total output rate
of PEI are equal to zero, as expected. In that case, outlet stream is
composed only from air and water vapor and therefore can not be
harmful for the environment. In case II, PCOP have the highest
Table 9
Annual savings due to replacement of raw materials for two analyzed products.
Product

kg/year

kg solvents
(1:1)/100 kg
product

t solvents/year

Annual
savingsa (EUR)

Product 1
(model drug)
Product 2
Total savings

36,256

30.62

11.1

11,877

4961

37.90

1.9

2033
13,910 EUR

a
The price of ethylene alcohol is approximately 0.97 EUR/kg and 1.17 EUR/kg for
methylene chloride.

values due to the fact that ethanol has a high PCOP. Second most
important category is represented by HTPI and TTP. Drug active
component and titanium dioxide used as an excipient are the most
signicant contributors to HTPI and TTP. As for total generation rate
of PEI for case I, it is obvious that inlet streams contribute only to
generation of local toxicological impact categories. Negative values
indicate that generated products are less harmful than the raw
materials introduced in the manufacturing process. Total generation rates of HTPI, HTPE and TTP have similar values in both cases,
all values of ODP and AP being equal to zero. As for other effects of
cleaner production activities (besides reductions in ecological
damage and different elements related to operating costs) lower
VOC emissions from the coating processes may certainly be utilized
for improving the image of the company within local pharmaceutical sector and creating an ambient of positive public reactions
in the area.
6. Conclusion
Considering the importance of introducing CP into generic
pharmaceutical processes, preferably through small scale
improvement projects, a case study for tablet coating of the model
drug was selected as a very common process, widely used in
pharmaceutical industry in general. Two possible approaches that
may be applied in order to manage pollution caused by tablet
coating were analyzed e EOP and CP approach. The technical solution for pollution control (EOP) was suggested based on the
known criteria dened in literature and its cost-effectiveness discussed in relation to pollution prevention through process modication by the replacement of raw materials. Furthermore, health
and safety risks were addressed for the workers on the manufacturing oor, as well as for people next to the factories and the
algorithm for estimating the human health and environmental
impact of two different processes (WAR) was employed to
emphasize hazards for relevant applications by using process
simulators to determine the impact indexes. The results of this
analysis revealed that, when it comes to tablet coating in pharmaceutical industry, the option of pollution preventing by modifying the design of the process represents a general approach that
provides huge benets both in terms of cost-effectiveness and
waste/environmental impact minimization. It also substantially
improves the impact on people directly involved in the manufacturing process from the health and safety point of view and,
considering the fact that based on literature review all the
necessary expertise, materials and machines are available in
a marketplace, only strong will is needed to completely switch from

Z. Boltic et al. / Journal of Cleaner Production 44 (2013) 123e132

organic solvents to aqueous coating systems in the pharmaceutical

industry. Although the expenses of raw materials replacement in
terms of regulatory compliance (calculated as 3130 EUR) may not
be directly compared to the initial capital for introduction of the
selected EOP technology (10e50 000 EUR per 1000 Nm3/h of the
waste gas), the nancial benet is obvious both from these gures
and the 13 910 EUR annual savings based on lower consumption of
organic solvents, while additional cost of consumables per tonne
GAC is connected to the waste gas treatment. Furthermore, the
overall analysis of the WAR results conrmed that the replacement
of organic solvents with water is completely justied in terms of
calculated potential environmental impact of the tablet coating
process. Although CP aspects related to liability issues and companys image were not subject to this analysis, positive effects are
expected in these areas as well, especially in terms of public reactions, but also considering compliance with EU regulations covering implementation of environmental measures and release of
polluting substances.
The contribution of this work may also be considered signicant
from the dimension of the world generic market perspective, that is
50% in Europe (more thane 700 companies) and even more in
China, Brazil and India with generics making up to 99.8% of the
prescriptions sales market. As the generic market is huge, even
small-scale projects like the case study described in this article
could generate signicant results in terms of CP, when applied by
the generic companies, facilities manufacturing lm coated tablets
as the most common pharmaceutical form, worldwide.
Acknowledgments
The authors are grateful to Hemofarm A.D., Serbia, STADA,
Germany and the Ministry of Science and Technological Development of the Republic of Serbia for the support (project TR 34009).
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