Water Resources and Industry 24 (2020) 100132

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Water efficiency and safe re-use of different grades of water -

Topical issues for the pharmaceutical industry
a, b a,* c
Elina Strade , Daina Kalnina , Joanna Kulczycka
a
Riga Technical University, Faculty of Materials Science and Applied Chemistry, Institute of General Chemical Engineering, Paula Valdena iela 3/7,
Riga, LV-1048, Latvia
b
JSC “Grindeks”, Krustpils iela 53, Riga, LV-1057, Latvia
c
Mineral and Energy Economy Research Institute, J.Wybickiego 7A, Krako�w, Poland

A R T I C L E I N F O
A B S T R A C T
Keywords:
Pharmaceutical industry The pharmaceutical industry is a highly water-dependent economic sector and requires different
Safe water re-use degrees of water purity. The study presents an overview of the current water quality re-
Circular economy quirements, as well as limitations and safety considerations for water re-use in pharmaceutical
Water quality manufacturing. Several principles for implementing circular economy elements into pharma-
Resource recovery ceutical wastewater treatment procedures are described: the use of recovered solvents as an
easily degradable carbon source for the denitrification process, the use of phosphorus-containing
wastewater as a nutrient source for activated sludge microorganisms, the use of inorganic acids
and bases for pH control in wastewater treatment processes, and the use of Al3þ containing
wastewater as a coagulant. The case study indicates that specific wastewater streams can be
reused as secondary materials if the chemical composition of wastewater from pharmaceutical
batch processing is well constrained and separate collection is ensured.

1. Introduction

According to the European Union (EU) rating, the pharmaceutical and chemical industries, along with agriculture and paper
production, provide the greatest gross value sectors of the EU economy, but exhibit the highest dependency on a stable supply of water
in sufficient quantity and quality [1]. The OECD Environmental Outlook to 2050 predicts that the global water demand for
manufacturing will increase by 400% between 2000 and 2050 [2]. To ensure the sustainability of water resources, the industry should
improve water efficiency in a value chain, as well as maximise the opportunities for safe re-use of different grades of water. Moreover,
water-related industries need to focus not only on climate change and water scarcity [ 3], but also on environmental sustainability and
the sustainable use of industrial water [4], introduction of instrumentation for real-time water quality monitoring [5], water man-
agement and water-energy nexus [6] and strive for zero liquid discharge (ZLD) [7]. According to Toth et al. [8], physicochemical

Abbreviations: EU, European Union; ZLD, Zero liquid discharge; UASB/MBR, up-flow anaerobic sludge blanket/membrane bioreactors; SDG,
sustainable development goals; MBBR, moving-bed biofilm reactors; APIs, active pharmaceutical ingredients; FDFs, final dosage forms; GMP, good
manufacturing practice; EMA, European Medicines Agency; WHO, World Health Organisation; PW, purified water; RO, reverse osmosis; WFI, water
for injections; Ph. Eur., European Pharmacopoeia; USP, United States Pharmacopoeia; HVAC, heating, ventilation and air conditioning; ERA,
environmental risk assessment.
* Corresponding author.
E-mail address: [email protected] (D. Kalnina).

https://doi.org/10.1016/j.wri.2020.100132
Received 29 May 2020; Accepted 7 June 2020
Available online 11 June 2020
2212-3717/© 2020 The Authors. Published by Elsevier B.V. This is an open access article under
the CC BY license
(http://creativecommons.org/licenses/by/4.0/).
E. Strade et al. Water Resources and Industry 24 (2020)
100132

methods are increasingly used for industrial wastewater treatment since they have a smaller footprint compared to that of biological
wastewater treatment, although the biological ones have been greatly developed and are successfully used for the treatment of
different industrial wastewaters. In the case of the pharmaceutical industry, new eco-innovative proposals in the literature focusing on
the application of up-flow anaerobic sludge blanket/membrane bioreactors (UASB/MBR) for wastewater re-use in landscape irrigation
while avoiding the hazards of introducing pharmaceutical residues into the environment [9] achieved the removal of organic halogens
from process wastewaters [8], performed catalytic oXidation processes for detoXification and improving the biodegradability of
pharmaceutical wastewater streams [10], developed nanofiltration [11], and used ionising radiation as the source of both reducing
and oXidizing radicals for water treatment [12–14].
Innovative, advanced treatment technologies are currently being developed for highly polluted water. The reviews of biological,
chemical, advanced chemical technologies, or advanced oXidation processes, and hybrid technologies for the treatment of industrial
wastewaters were presented [15–20].
Although many new technologies have been proposed, the main concept is to use hybrid approaches that combine various
treatment mechanisms to remove the full spectrum of chemicals present in pharmaceutical wastewaters.
The rapid development of the pharmaceutical industry presents conflicting challenges to water resources management. The
discharge of inadequately treated wastewaters results in the release of pharmaceutical substances into the environment, resulting in
risks to water quality and a possible adverse impact on aquatic ecosystems and public health [21].
In recent years, there has been an increasing focus on water use in those several highly water-dependent industries besides the
production of pharmaceuticals: the chemical industry [22,23] motor vehicle production [24], paper production [25,26], the steel
industry [27,28], the textile industry [29,30], as well as the food and beverage industry [31–33].
The pharmaceutical industry has a special place in this list of highly water-dependent industries. Many pharmaceutical processes
require very pure water that meets strict quality standards, simultaneously they can generate heavily polluted and toXic wastewaters
that require complex and costly multi-step treatment to meet the regulatory requirements [21]. Pharmaceutical plants typically use a
broad range of chemicals and technological processes, presenting major challenges for waste cleanup technologies and procedures.
Mineralization represents the most effective treatment, which is the ultimate goal in many areas of pollutant control and destruction.
High-purity water is an indispensable resource for the production of medicines for human and veterinary use, but at the same time
the pharmaceutical industry is one of the main polluters of local water resources [21]. Another source of high risk regarding phar-
maceuticals is very polluted waste water at hospitals and homes for the elderly; this waste water contains pharmaceuticals together
with greatly variable and hazardous microbiological pollutants, where the concentration of pharmaceutical residues could be several
times higher than in municipal wastewater [34–37] Futhermore, without any treatment, veterinary pharmaceutical residues from
aquaculture and livestock farms can enter into the water as an active parent product or biologically active metabolites [38].
The current trends of sustainable development goals (SDG) include efforts of water re-use, which is recognized as a key option
to reduce water consumption at the manufacturing facility level [39]. However, the re-use of water in pharmaceutical production is met
with caution from the regulatory agencies concerned with the quality and safety of pharmaceuticals, prompting new strategies
that may reconcile the conflicting goals of wastewater re-use and ensuring that contaminants cannot enter pharmaceutical production
via reused water. Innovative ZLD technologies make it possible to almost completely eliminate wastewater discharges, maximizing
water re-use in the industry [40–43]. Despite the high potential for water saving, the application of ZLD on an industrial scale is
currently very limited due to the high costs, energy consumption [40], and the generation of solid hazardous waste [40,41].
Although the data from certain industries point to opportunities for decreasing water consumption by up to 50% [44], implementation
of circular water management in the pharmaceutical industry is quite limited due to very strict legislative regulations and safety
considerations.
The main barriers for water re-use in the pharmaceutical industry are the unique requirements of water quality and the risks
associated with product contamination and human health [15]. With the rapid development of a circular economic strategy within the
EU member states in recent years, many incentives have been implemented, providing support for research and innovation through
different grant programmes, while promoting new legal and economic regulations. Therefore, pharmaceutical manufacturers are
currently interested in practical options for closing the ‘water loop’ in those technological processes where water does not come into
direct contact with pharmaceutical products. Moreover, manufacturers are seeking to minimise the use of water, energy, and haz-
ardous materials, to eliminate waste during the product life cycle, and to use treated wastewater for other purposes. In several
countries (Switzerland, the USA, Singapore, Australia), where wastewater after treatment is reused for agricultural irrigation or
discharged into aquifers that also serve as sources of drinking water, certain pharmaceuticals are included in the water monitoring
programs [45], while these biologically active substances are not systematically regulated at a global level. Despite evidence of the
presence of pharmaceutical residues in various aquatic environments of Latvia [46], the state has not yet implemented a long-term
strategy to reduce the risk caused by this pollution.
The purpose of this article is to point out water-related challenges facing the pharmaceutical industry. The overall water flow at the
pharmaceutical plant of JSC Grindeks is shown. The most water-intensive technological processes are identified and reusable water
streams are specified. The second objective is to show and assess the environmental benefit of the best practically implemented
pharmaceutical wastewater re-use examples on the basis of the experience gained at JSC Grindeks, a medium-sized multiproduct
pharmaceutical company.

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Fig. 1. Flow chart illustrating the water management practices at JSC Grindeks.

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2. Materials and methods

2.1. Plant description

The pharmaceutical company JSC Grindeks located in Riga, Latvia was selected for a case study in our article. The multi-
product manufacturing facility of JSC Grindeks produces both active pharmaceutical ingredients (APIs) and final dosage forms
(FDFs) belonging to the cardiovascular, central nervous system, gastroenterological, and anti-cancer therapeutic groups.
The wastewaters originating from the pharmaceutical manufacturing facilities of JSC Grindeks are polluted with a wide range of
difficult-to-degrade and toXic organic compounds, including phenols, while also containing high concentrations of organic nitrogen
compounds and inorganic salts in combination with the near absence of phosphorus compounds. The wastewaters are treated in a
system of compact moving-bed biofilm reactors (MBBRs). The technological process and main operational parameters of the WWTP
3
are detailed in a previous study by Strade et al. [47]. According to the data from year 2019, the average wastewater flow is 200 m /d,
while the incoming COD load fluctuates from 0.4 to 2.2 t per day and the total nitrogen load varies from 0.012 to 0.075 t per day. After
pre-treatment, the wastewaters are discharged into the municipal sewer system for final treatment.

2.2. Data acquisition

A comprehensive analysis of the incoming and outgoing water flows within the pharmaceutical manufacturing facilities of JSC
Grindeks was carried out, including pharmaceutical grade water, cooling water, water for the steam generation, and wastewater. The
analysis included plant-specific data about: (i) water supply sources; (ii) quality requirements of water used for industrial purposes;
(iii) water preparation (pre-treatment) processes used at the manufacturing facilities; (iv) water consumption; (v) wastewater pro-
duction: generation, composition, flows and treatments; (vi) water and wastewater reuse practices. The numerical values of water
consumption and wastewater reuse were analysed using the monitoring data from year 2019.
The relevant data were obtained from internal technical documentation and standard operating procedures, from the information
provided to local regulatory agencies, as well as through interviews with employees. The chemical and microbiological purity stan-
dards of the pharmaceutical-grade water and the defined uses during the various manufacturing stages of the APIs and FDFs were
summarized and analysed according to Good Manufacturing Practice (GMP) guidelines, Pharmacopoeia monographs, and the
guidelines from European Medicines Agency (EMA) and the World Health Organisation (WHO).

2.3. Data evaluation

On the basis of the complete water flow analysis, the overall water flow chart for the pharmaceutical manufacturing facilities of JSC
Grindeks was summarized and analysed for the first time. The information obtained was used to identify the bottlenecks in the current
water management system and to point out the opportunities to improve water usage efficiency, to implement reuse solutions, and to
“close the water loop”. Restrictions and limitations related to direct water reuse in the pharmaceutical production were emphasized
based on the sector-specific regulatory requirements and product quality and safety risks. The percentage of water savings from water
efficiency improvements and reuse actions was estimated using scientific and technical literature sources.
In order to demonstrate the dependence of pharmaceutical industry on water resources, the first part of the article provides an
overview of the diverse applications of water in pharmaceutical manufacturing processes. The sector-specific water quality re-
quirements are analysed in this part to underline the difference of pharmaceutical industry from other process industries. Considering
that the pharmaceutical sector also is one of the major polluters of water resources, the following section of this article points out the
shortcomings of the current legislation regarding the control of environmental emissions from the pharmaceutical industry. Various
possibilities for applying the principles of circular economy through the recovery of resources and the reuse of wastewater streams are
discussed at the end of this article. The application of the principles of circular economy in the management of chemically polluted
wastewater was analysed from three aspects: (i) the reuse of untreated wastewater streams as secondary resources in the biological
wastewater treatment processes (ii) the recovery of materials from concentrated wastewater streams; (ii) the possibilities and limi-
tations of wastewater reuse after the application of different treatment strategies.

3. Results and discussion

3.1. Different grades of water in the pharmaceutical industry

According to the World Health Organisation, the most widely used raw material in pharmaceutical manufacturing is water
[48]. Consistent and high-quality water supply is required for the production of pharmaceutical products, rinsing and cleaning of
equipment, as well as for technical purposes like steam generation and cooling [15]. The various types of water use in
pharmaceutical manufacturing requires efficient management of both incoming and outgoing water flows. The water flows at JSC
Grindeks are depicted in Fig. 1. This scheme characterises the water sources and the applied water pre-treatment methods in various
technological processes, and also outlines the wastewater management practices at the company. A reference to this flow chart is
given in the following sections of this article to describe the specific stages of water management at JSC Grindeks.

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3.1.1. Pharmaceutical grade water

In pharmaceutical manufacturing, different grades of water are used as raw material, ingredient, and solvent in the production,
processing, and formulation of active pharmaceutical ingredients (APIs) and final dosage forms (FDFs) for human or veterinary use (Fig.
2). The grades of water used highly depend on the formulation and the route of administration of the pharmaceutical product, and as well
as on the stage in the manufacturing process at which water is used [49]. Fig. 2 summarises the minimum acceptable grade of water
used during the manufacture of APIs and FDFs.

Fig. 2. Different grades of water used in pharmaceutical production.

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Potable water may be used in chemical synthesis of all intermediates of API prior to the final isolation and purification steps.
Potable water is also used for the initial rinse of the manufacturing equipment, containers and closures in the manufacturing of APIs
and non-sterile FDFs, unless there are specific technical or quality requirements for higher grades of water [ 49]. Potable water is not
covered by a Pharmacopoeia monograph, but should, at a minimum, meet the World Health Organisation (WHO) guidelines for
drinking water quality [50]. Potable water is used as feed water for the production of pharmaceutical grade waters: purified water and
water for injections.
Purified water (PW). PW is used as an excipient for the final isolation and purification of APIs and for the preparation of nonsterile
FDFs. Additionally, PW is used in the granulation and tablet coating processes, preparation of ointments, creams and gels, as well as for
the formulation of syrups. The water content in each FDF is specified in the registration dossier. PW is the accepted grade of water for
the final rinse of equipment, containers and closures in the manufacture of non-parenteral FDFs. PW is typically prepared by ion
exchange, ultrafiltration, and reverse osmosis (RO) or distillation.
JSC Grindeks uses a siX-step purification system for obtaining PW for pharmaceutical production (Fig. 1). The purification
system provides mechanical filtration, iron removal, softening, filtration through activated carbon, a two-stage RO process, and
degassing.
The PW storage and distribution system consists of a water storage tank, a circulation pump, a UV irradiation cell and a PW circulation
loop pipeline with water outlet valves at the production sites. The average annual PW consumption of JSC Grindeks is about 6500–
3
7000 m .
Water for injections (WFI). WFI is the highest quality water used by the pharmaceutical industry. WFI is used in the manufacturing
of sterile pharmaceutical products for parenteral administration and other pharmaceutical products where endoto Xin content must be
controlled. WFI is also used for the final rinsing of primary packaging materials. WFI must be sterile and non-pyrogenic in order to
avoid the introduction of contamination and to prevent the growth of microorganisms in pharmaceutical products. Until 2017, the
European Union Good Manufacturing Practice (GMP) regulations disallowed the production of WFI by non-distillation methods
because of concerns about biofilm formation and endotoXin contamination. After recent changes in the European Pharmacopoeia, it is
now also allowed to produce WFI by reverse osmosis coupled to other suitable techniques, such as electro-deionisation, ultrafiltration
3
or nano-filtration. JSC Grindeks uses very small quantities of WFI (<1 m /year), which are purchased from external suppliers. This
type of water is used in the final production stage for the oXytocin API, due to the tight specification for microbiological purity and the
absence of endotoXins.
Water for the preparation of extracts. Water for the preparation of herbal drug extracts must comply with the requirements for
PW or water intended for human consumption of a quality equivalent to that defined in Directive 98/83/EC [49].
The chemical and microbiological purity requirements for pharmaceutical grade water are defined in the relevant pharmacopoeias.
Table 1 represents the current quality specifications for PW and WFI defined by the European Pharmacopoeia (Ph. Eur.) and the United
States Pharmacopoeia (USP). Unlike USP, Ph. Eur. specifies a limit for heavy metals in PW and a limit for nitrate concentration in PW
and WFI. Both pharmacopoeias also have different requirements for the electrical conductivity of pharmaceutical grade water. The
control of bacterial endotoXins (lipopolysaccharide cell wall components of gram-negative bacteria) in water used in the manufacture
of FDFs intended for parenteral administration is critical, as reaction to endoto Xins can lead to potentially lethal anaphylactic shock in
patients [51].
A less commonly discussed aspect is the continued quality assurance of the various water grades. Pharmaceutical water production,
storage, and distribution systems should be designed, installed, commissioned, qualified, and maintained to ensure reliable production
of water at the specified quality [48]. Failure to meet water quality requirements poses an unacceptable risk to public health, therefore,
continuous quality control of water used in the manufacturing of pharmaceutical products is of vital importance. The frequency of
quality control and the water sampling points are usually specified by the water monitoring programs. Failures in the purification
process pose critical levels of risk and the lack of proper quality water can result in manufacturing downtime or product recall.
Despite the use of validated purification systems and stringent operational controls, microbial contamination is the most chal-
lenging issue in the purification process of pharmaceutical grade water. Recent recall surveys from the USA have found that the
presence of water-borne bacteria Burkholderia cepacia represent the vast majority of microbiological contamination cases that have
triggered Food and Drug Administration (FDA) recalls of non-sterile drug products [52]. Various design features, like continual cir-
culation at a flowrate of 1–3 m/s, heating options and the inclusion of high intensity ultraviolet (UV) light lamps may be incorporated
to prevent the growth of biofilms and to control microbial contamination in pharmaceutical grade water systems [51].

Table 1
Quality specifications for different grades of water, as defined by Ph. Eur. and USP.
Parameter Purified water (PW) Water for Injection (WFI)

Ph. Eur. USP Ph. Eur. USP

TOC (μg/L) <500 <500 <500 <500
Conductivity (μS/cm) �4.3 at 20 � C �1.3 at 25 � C �1.1 at 20 � C �1.3 at 25 �C
Nitrate (mg/L) �0.2 NA �0.2 NA
Heavy metals (mg/L as Pb) �0.1 NA NA NA
Aerobic bacteria �100 CFU/mL �100 CFU/mL �10 CFU/100 mL �10 CFU/100 mL
Bacterial endotoXins (I.U./mL) NA NA �0.25 �0.25

NA – not an applicable requirement.

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The experience at JSC Grindeks shows that proper sanitation and regular maintenance procedures are essential to preventing
microbial proliferation and recontamination of the water. For example, a validated sanitization procedure of the PW distribution and
storage system in the API manufacturing facility is performed with 3% or 10% hydrogen peroXide solution: 1) at least once a year; 2) if
the PW system has been shut down for more than 14 days; 3) in cases in which the parameters of microbiological contamination do not
meet the requirements of the relevant Pharmacopoeia. Thermal sanitization (85 � C/30 min) of the PW system in the
FDF manufacturing facility is used for routine operations (twice per year) and if the TOC or total number of aerobic bacteria of
the PW
circulating in the loop exceed the maximum level or if the loop has been emptied, if reconstruction work in the loop has been per-
formed or the system has been exposed to air. Special attention is paid to the plastic tubing at PW outlet points. To avoid the intro-
duction of microbiological contamination into the PW circulation loop, they are disconnected, rinsed with 70% ethanol, and dried after
each use, as well as replaced at least every 6 months.
From a water efficiency standpoint, the preparation of pharmaceutical grade water is associated with relatively high losses of
water. The experience of JSC Grindeks confirms that due to the very high purity requirements of PW, up to 50% of the feed water
is discharged as waste from the RO modules (Fig. 1). However, this water is still of sufficiently high quality for re-use as an
alternative
onsite water source in units that do not come into a direct contact with pharmaceutical products, for example, in cooling systems. This
inefficiency has been identified as one of the bottlenecks in the water management system of JSC Grindeks where the circular economy
3
approach could be applied to partially close the water loop and to reduce the water consumption by about 7000 m annually (equal to
12% of the total amount of potable water used in production processes at JSC Grindeks).

3.1.2. Process water

In addition to direct use in pharmaceutical production where water comes into contact with pharmaceutical substances, it is also
used as a key resource for technical purposes, for example, cooling and steam generation.

3.1.2.1. Cooling water. To provide reliable pharmaceutical manufacturing process conditions, the correct process temperature must
be guaranteed at all times, which may require a cooling capacity. The main pharmaceutical manufacturing processes that require an
effective cooling system are:

●Batch processing in multipurpose reactors (for example, temperature sensitive chemical reactions, crystallization of final products)
●Cooling of creams and ointments before pouring and packaging
●Wet granulation processes for tablet production
●Moulding of gelatine capsules
●Sterilisation of liquid FDFs.

Due to its high heat capacity and low cost, water is the most common coolant. Cooling water should be pre-treated to ensure
efficient heat transfer, reduce total energy consumption, and avoid equipment failure. Pre-treatment depends on feed water quality
and usually includes iron removal, softening, the addition of corrosion and scale inhibitors, and treatment with biocides to prevent
biological fouling in the heat exchange systems [53]. It is also important to control the pH value of cooling water, as acidic envi-
ronment promotes corrosion, while alkaline pH increases scale formation [54].
The traditionally used cooling towers or once-through (single pass) cooling systems often represent the largest percentage of water
consumption in pharmaceutical manufacturing [55], and JSC Grindeks is not an exception. The once-through cooling system used
3
at JSC Grindeks consumes up to 250 000 m of water annually, which exceeds the total amount of potable water used for
pharmaceutical
manufacturing processes by a factor of about 4.2. After a single pass through heat exchangers and/or condensers, the heated water is
discharged into the storm water drainage system. The reduction of high water consumption by once-through cooling systems requires a
change towards closed-loop recirculating cooling systems that consume an order of magnitude lower volume of cooling water
compared to once-through systems [53]. It has been noted by other authors that the installation of adiabatic cooling systems allows
pharmaceutical manufacturers to reduce water consumption by up to 98% compared to the traditionally used open-loop cooling
systems [53,56]. Besides, reusing the same clean water into closed circuit also eliminates the costs associated with the treatment and
disposal of water, and also eliminates the concerns associated with Legionnaires’ disease [56].
JSC Grindeks obtains its cooling water from 2 artesian boreholes located on the territory of the plant. The natural and regulatory
limits to water extraction from an artesian aquifer prevent further expansion of production, unless more water-efficient cooling
technologies are introduced. Otherwise, the available groundwater resources may be insufficient for the required cooling capacity, and

Table 2
The types of steam used in pharmaceutical industry.
Type of steam Intended use Direct contact with pharmaceutical
products Quality requirements of feed water or condensate

Plant steam Indirect contact process

– Produced from pre-treated potable water
heating
Chemical-free Humidification (HVAC – Produced from pre-treated water (without volatile boiler
steam systems) additives)

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Pure steam Sterilisation þ 100132
Condensate meets quality characteristics of WFI

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extensive use of this resource will incur regulatory and taxation costs.

3.1.2.2. Water for steam generation. Steam used in pharmaceutical facilities can be separated into three categories: plant steam,
chemical-free steam, and pure steam (Table 2).
Depending on the intended use of the steam, there are different requirements of feed water quality and steam generation methods.
Feed water of the plant steam boiler must be derived from water that is of drinking quality. It is treated to remove the bulk of dissolved
solids, hardness, and silica, which could cause scaling and corrosion of the steam generator and pipelines. The manufacturing facilities
3
of JSC Grindeks consume about 17–18 000 m of potable water per year for plant steam production. Boiler feed water is purified
by passing through mechanical filters, cation exchange (softening) resins and an RO system that greatly reduces the content of
scale
forming salts, improves boiler efficiency and steam purity. Chemical-free steam is typically a separate type of steam generated without
chemical boiler additives [57]. It is used for humidity control of processes and critical cleanrooms where pharmaceutical products are
directly exposed to the room atmosphere. JSC Grindeks also uses humidification to eliminate the build-up of static electricity in
manufacturing environments where flammable gases or substances are being used. Several local steam boilers are installed in the
manufacturing facilities for such purposes. Pure steam is the highest quality of steam used in pharmaceutical manufacturing. It is used
for the sterilisation of pharmaceutical products, equipment or piping. This type of steam is critical to biopharmaceutical
production and for the production of injectable solutions. Unlike plant steam, no chemical additives are permitted in the treatment of
water used in pure steam generators. As pure steam comes into direct contact with pharmaceutical products or product contact surfaces,
additional treatment of feed water should be performed, to ensure that the condensate of pure steam meets WFI requirements for
conductivity, TOC, microbial content, and endotoXins [58]. As JSC Grindeks does not produce sterile pharmaceutical products, pure
steam is not used in the manufacturing processes.
The recovery and on-site re-use of steam condensate is one of the key actions that can improve the water efficiency at
manufacturing facilities. The re-use of high purity condensate also reduces chemical use, feed-water treatment costs, and saves energy,
since after returning to the boiler the hot condensate requires much less energy to reheat for repeated steam production.
Despite the potential water savings, steam condensate is not recovered and reused as boiler feed water at JSC Grindeks. The major
obstacle here is that the boiler house is located about 500 m from the manufacturing facilities. The relatively long distance and the
initial investment that would be necessary to build a condensate return line have prevented the re-use of plant steam condensate. From
a water efficiency point of view, in instances in which the installation costs of condensate recovery equipment are too high to be
justified, factories should evaluate alternative options for re-use of condensate. Due to its inherent heat content, condensate can be
reused in various heating systems or as a source of clean, hot water for washing purposes.
There are not only financial and technical, but also product quality and safety issues that need to be considered when analysing
condensate re-use options in a pharmaceutical plant. As pure steam comes into contact with pharmaceutical products, the condensate
must not be directly returned to a pure steam generator because of contamination risk [58]. Potential microbiological contamination of
condensate from HVAC systems also is one of the risk factors that could limit condensate re-use. Scientific publications report that
HVAC condensate can be contaminated with Legionella and other airborne bacteria, therefore, the harvested condensate water must be
properly disinfected before re-use as an alternative water resource [59].
Our case study confirms the conclusions of the United Nations [60] that the industry often prioritizes production capacity over
water efficiency and conservation. A common reason for this is that investments in efficient cooling processes or water reuse systems
may have longer return on investment than short-term improvements in production capacity. Moreover, low water prices in the re-
gions with good freshwater availability also do not encourage investment in water efficiency at the plant level and the potential
benefits of water efficiency improvements in industry are often underestimated. In order to properly evaluate and provide justifications
for modifications to equipment or operating practices, the new and true value of water should be assessed, accounting not only for the
water supply costs, but also for the related treatment, pumping, storage, purification, and disposal costs [6].

3.1.3. Water recovered from drug manufacturing processes

Pharmaceutical products are typically produced in multi-stage batch processes that create highly complex waste streams with
variable chemical composition, toXicity, and volume [15]. Such variation in the quality and quantity of wastewater may cause
shock and overload to the treatment systems, which leads to malfunctioning or even failure of treatment processes, particularly
biological treatment [61].
In order to ensure effective treatment of pharmaceutical effluents, manufacturing plants must separately manage different types of
wastewater, distinguish highly toXic and concentrated streams and providing pre-treatment if necessary. Wastewater biodegradability
and toXicity as well as the concentration of specific pollutants in the individual batch streams must be taken into account for selecting
the most appropriate treatment methods. The evaluation and separation of pharmaceutical batch streams according to the nature of
the contamination is a key activity not only for finding the most appropriate treatment solution, but also for assessing the recovery or re-
use potential of materials in the effluents.
A cost effective and simple method for to Xicity screening of pharmaceutical wastewater has been implemented in laboratory
practice at the WWTP of JSC Grindeks, which is based on BOD measurements over a wide range of initial concentrations [47]. By using
a simple BOD/COD relationship for different batch loads it is possible to identify the most toXic flows and to determine safe rates
of discharge into biological wastewater treatment systems. The extensive initial concentration range used in the experiments,
which corresponds to the real amount of wastewater generated per day, while also accounting for the dilution in equalization
tank, allows determination of the toXic threshold concentration of the sample. These data are used as a basis for assessing the risks
and predicting

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the process performance in the case of production increases or changes in the presence of specific pollutants in wastewater. Primary
attention should be paid to the most toXic compounds that enter the wastewater as synthesis by-products or unreacted raw materials. If
the screening indicates that wastewaters are to Xic to activated sludge already at low concentration levels, separate collection at the
source and further research should be performed. Pre-treatment options are then evaluated or waste disposal by specialised service
providers may be required.

3.2. The role of legislation in controlling the emissions of APIs from manufacturing plants

A very important issue at a global level is the role of the pharmaceutical industry in reducing the discharge of pharmaceutical
substances into the aquatic environment. Despite the recent concerns regarding the risks to human health and ecosystems posed by
pharmaceuticals, current EU legislation does not regulate the emissions of APIs at the manufacturing stage. The Industrial Emissions
Directive (2010/75/EU), which also applies to pharmaceutical manufacturing sites, does not include APIs on the list of polluting
substances and there are no threshold values established for pharmaceutical discharge. APIs that are already registered with the
European Medicines Agency (EMA) as ingredients of medicinal products for human and veterinary use are also exempt from the
REACH regulations. GMP guidelines essentially focus on pharmaceutical product quality and safety parameters and do not include any
requirements for environmental protection.
There are a number of shortcomings in the existing EMA guidance for environmental risk assessment. First, there are insufficient or
no Environmental Risk Assessment (ERA) data available for numerous widely consumed pharmaceutical products that entered the
market before the respective guidelines came into force. In the EU, ERA is a mandatory requirement for all new marketing authori-
zation applications for medicinal products intended for human and veterinary use only since 2006 and 2001, respectively [62].
Second, the risks associated with API discharges from manufacturing sites are not included in the ERAs [63]. In contrast to veterinary
products, the results of ERA for human medicinal products should not constitute a criterion for the refusal of marketing authorization
[62,63].
A recent communication of the European Commission that refers to the European Union Strategic Approach to Pharmaceuticals in
the Environment emphasizes that the pharmaceutical industry needs to reduce its environmental impact from the product lifecycle
perspective, with the greatest focus on the research and development, as well as the manufacturing stages [64]. The development of
pharmaceutical products that degrade more readily to harmless substances in WWTP and the environment and are produced by
greener manufacturing methods are identified as the future priorities of the pharmaceutical industry [64].

Fig. 3. Problems arising from re-use of biologically treated pharmaceutical wastewaters in cooling systems.

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3.3. Opportunities and limitations of treated pharmaceutical wastewater re-use in drug manufacturing processes

From the sustainability point of view, water re-use in manufacturing is essential because it could drastically reduce freshwater
requirements and enable the expansion of production capacity without exceeding water discharge limits [15]. The opportunities for
reusing treated pharmaceutical wastewaters as a secondary resource in pharmaceutical manufacturing are quite limited due to the
high risk of product contamination, which may have serious impact on patient health, and is contrary to the GMP requirements [50].
To avoid cross-contamination between products, re-use of treated wastewater for industrial purposes might be acceptable only after
complete removal of API residues during the wastewater treatment process, if the quality of reclaimed water is not inferior to drinking
water.
It should be stressed that all changes in pharmaceutical manufacturing, such as alternative sources of starting materials (including
water reuse) should be validated and accepted by the relevant regulatory authorities, as well as approved by industrial customers. This
is a time-consuming and expensive process that can seriously impact the economic viability of any changes.
Furthermore, investments in wastewater treatment for re-use should be weighed against the cost and local availability of freshwater
resources. Among the EU Member states, Latvia ranks 4th in the availability of freshwater resources, with the average of about 18 000
3
m per inhabitant per year [65]. In contrast to Latvia, the available water resources in Poland, the Czech Republic, Cyprus, and Malta
3
are below 1700 m per inhabitant per year, indicating that those countries may experience shortages of water for industrial uses. Since
chemically and energetically intensive wastewater treatment processes are needed to improve the wastewater quality according to the
specifications for re-use, in some cases water re-use may cause higher environmental impact than the water use itself [66].
The effluent from the biological WWTP of JSC Grindeks is not suitable for internal re-use purposes. The applied MBBR system
ensures pre-treatment in accordance to the local regulations in terms of COD, as well as N and P removal, however, this level of
treatment is still insufficient for subsequent re-use of the treated wastewater, for example, in cooling systems. Fig. 3 summarises
the main problematic issues that can arise from the re-use of biologically treated pharmaceutical wastewaters in cooling systems.
First, the use of biologically treated pharmaceutical wastewater streams increases the risk of scaling and corrosion due to the high
levels of dissolved salts. Second, the re-use of effluents from biological WWTP promotes higher microbiological activity and biofouling
due to the remaining dissolved nutrients. Additional fouling problems may be associated with residual suspended solids (activated
sludge). Biofilm growth and deposits on heat transfer surfaces tend to cause loss of heat transfer efficiency. Any of these problems or a
combination of them can result in costly unscheduled downtime, reduced process capacity and reliability.
Besides that, the chemical compatibility of effluent water with materials used in the cooling systems should be assessed. Direct
contact of products with wastewater is not allowed in any situation, therefore, the pipelines should be permanently monitored and
maintained to prevent any leakage into the reaction vessels and the associated product contamination risks. Fluctuations of effluent
water quality and quantity cause additional challenges and should be taken into consideration. Furthermore, pharmaceutical
wastewater after biological treatment is often too warm for cooling purposes. For example, the temperature of effluent water from the
biological WWTP of JSC Grindeks varies between 28 and 42 � C, making it unsuitable for cooling purposes. Elevated temperature is one
of the stress factors to nitrifying bacteria that may disrupt the nitrification process, therefore, a heat exchanger for wastewater cooling
is installed at the WWTP of JSC Grindeks.

3.4. Processing of pharmaceutical waste streams for resource recovery and re-use

For a typical batch chemical process in the pharmaceutical industry, solvents can constitute up to 80–90% of the non-aqueous mass
[67]. Due to their high proportion in process miXtures, spent solvents also represent a major part of the waste generated by the
pharmaceutical industry. The minimisation of solvent use, substitution of hazardous solvents, as well as solvent recovery and re-use are
becoming key priorities for the purposes of greener manufacturing [68–70].
In practice, about 50% of waste solvents are recovered and reused in the batch chemical processes at JSC Grindeks, while the
remaining part is either disposed through incineration or biologically degraded as dilute aqueous solutions during wastewater
treatment in the post denitrification process (see more details in Section 3.5.4). The main barriers to solvent recovery, especially in the
manufacturing of low volume APIs, include the technical difficulty and cost of recovery, purity requirements equal to those for fresh
solvents, and the time-consuming analytical and administrative procedures necessary to verify the quality and to approve solvent re-
use in the manufacturing. Although many pharmaceutical manufacturers have centralised solvent recovery facilities, the distillation
equipment at JSC Grindeks is integrated at separate production sites. Such an approach allows better optimisation of the solvent
recovery processes and eliminates the risks of cross-contamination between pharmaceutical products by using shared equipment for
solvent recovery.
Transition metal catalysts play an important role in the pharmaceutical industry and are extensively used for the development
of new drug candidates and large-scale synthesis of APIs [71]. Wastewater containing transition metals may not be discharged
into biological WWTP, as these metals tend to accumulate in the sludge, causing toXic effects on microorganisms and having an
effect on further processing of sludge [72,73]. In accordance with Latvian legislation, elevated content of heavy metals in the
sludge is a basic criterion for their classification as hazardous waste [74]. Due to the efforts to prevent heavy metal emissions in
the pharmaceutical wastewater stream, the sludge generated at the WWTP of JSC Grindeks typically corresponds to Class 1 or 2 (Class 5
is considered to be hazardous waste), which allows use of the sludge for soil fertilisation and re-cultivation of degraded areas.
Spent catalysts and/or contaminated wastewater streams from metal-catalysed chemical synthesis steps could be utilised as a resource
for the recovery of toXic heavy metals [75]. Due to the relatively small volumes of heavy metal-containing wastewater and the
need for specific pro- cessing, JSC Grindeks does not carry out on-site recovery of heavy metals from wastewater streams. Spent
Pd and Ni catalysts along
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with concentrated metal-containing wastewaters from chemical synthesis are collected separately and sent to specialised organisations
for processing, while copper ions are precipitated and removed from the wastewater in the form of insoluble hydro Xide prior to the
discharge into the biological WWTP.
There are several other wastewater streams arising from pharmaceutical manufacturing processes that can be directly reused as
resources and secondary raw materials, such as alkaline streams, effluents containing nutrients, such as phosphates, and metals.
Practical examples focusing on the re-use of these flows are detailed in Section 3.5. The successful use of such wastes as valuable
materials serves as an example of the circular economy approach, providing a motivation for improved waste stream management at
the chemical plant level and/or enhanced cooperation both with other companies i.e. to develop industrial symbiosis and with
universities.

3.5. Implementing circular economy elements into pharmaceutical wastewater treatment procedures

The practical experience at the WWTP of JSC Grindeks shows that there are several possible ways for reusing contaminated
wastewater streams from batch chemical synthesis operations as raw materials in the biological WWTP. To identify and manage
the possible ways of wastewater re-use, each batch process should be analysed separately and effective communication between
pro- duction sites and wastewater treatment plant should be facilitated to share information that is relevant for the WWTP. Obviously,
such

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Fig. 4. Scenarios for the use of selected pharmaceutical wastewater batch streams as raw materials in a biological WWTP.

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commitment also requires technical possibilities for collecting the individual wastewater streams in separate containers for temporary
storage, which might be a limiting factor in some cases.
The examples of reusing untreated pharmaceutical wastewater batch streams as raw materials in the biological WWTP of JSC
Grindeks are given in Fig. 4. Practical implementation is demonstrated for metal-containing wastewater streams, alkaline solutions,
and nutrient-containing effluents. The given examples indicate that certain pharmaceutical wastewater batch streams should be
considered not as a waste but rather as a valuable resource to be handled according to the principles of circular economy. The
implementation of circular economy elements through pharmaceutical wastewater re-use allows reduction of the chemical con-
sumption and operational costs of WWTP.

3.5.1. The use of Al3þ containing wastewater as coagulant in sludge removal processes
3þ
Aluminium chloride is used as a Lewis acid in the synthesis of Milnacipran Hydrochloride API [76]. An acidic aqueous Al solution
is generated as a synthesis by-product. Aluminium acts as a to Xic agent to aquatic organisms, including fish, invertebrates, and plants
[77]. To avoid the disruption of the activated sludge process, it is crucial to assess the toXicity risks of such waste streams to biological
water treatment plants before large-scale production and the biocenosis from the particular WWTP must be employed in the to Xicity
3þ
tests [78]. In the performed toXicity tests, Al containing wastewater showed highly toXic effects on the activated sludge microor-
ganisms at the WWTP of JSC Grindeks [47]. In a separate pilot study, it was found that this type of wastewater is suitable for re-use as a
coagulant in the sludge removal process and excess phosphorus precipitation at full-scale WWTP. For the best process performance the
optimum pH range and dosage should be adjusted depending on case-specific effluent characteristics. In many situations the pH drop
upon the addition of aluminium salts needs to be counteracted by the addition of an alkaline solution. pH control is important also to
maintain minimum levels of dissolved residual aluminium in treated wastewater [79].
3 3þ
At the current production capacity, about 15 m of Al containing wastewater is generated each year, and 100% of this wastewater
is reused in the sludge removal process at the on-site WWTP of JSC Grindeks. The implementation of such circular economy elements
3þ
as the introduction of Al containing wastewater to the sludge removal process allows for replacement of the traditionally used
commercial aqueous 40% FeCl3 solution.

3.5.2. The use of inorganic acids or bases for pH control in moving-bed biofilm reactors (MBBRs)
The pH values of pharmaceutical wastewater from different batch processes can vary greatly, ranging from highly acidic to
alkaline. If high amounts of acids or bases are discharged into wastewaters, considerable amounts of chemicals are required to return
the pH value to a neutral level that is optimal for activated sludge microorganisms, especially if the buffer capacity of wastewater is
low.
The pH of the wastewater received at the WWTP of JSC Grindeks is adjusted by adding 50% H2SO4 or 30% NaOH solutions ac-
cording to necessity. In general, the wastewaters of JSC Grindeks are highly alkaline (pH ~ 10 in the equalizing tank). Due to
biodegradation processes, the pH value in the first MBBRs drops down to a neutral level, therefore, the addition of H 2SO4 is usually not
necessary. Higher volumes of NaOH solution are consumed for pH control at the nitrification stage.
To avoid extreme pH fluctuations, a large volume equalizing tank is required. Alternatively, concentrated water solutions of
inorganic acids or bases, if available as by-products from the manufacturing processes, can be collected in separate containers and
subsequently reused for pH control in the biological treatment reactors. If alkaline aqueous solutions from manufacturing are intended
for pH control during the nitrification process, they must not contain biodegradable organic compounds that would directly promote
the growth of heterotrophic bacteria. The oXygen affinity and growth rate of nitrifying bacteria is low in comparison to heterotrophic
bacteria, therefore, an increase in heterotrophic bacteria may adversely affect the nitrifying bacteria by competing for space, oXygen,
and other nutrients, resulting in the inhibition of nitrification [80]. A strongly alkaline NaOH solution (Fig. 4) can also be used as a
precipitant to remove copper from wastewaters generated during other batch processes.

3.5.3. The use of phosphorus containing wastewater as a nutrient source for activated sludge microorganisms
A characteristic feature for pharmaceutical wastewater treatment plants is the situation that influent wastewater can be deficient in
some nutrients and rich in others. In general, the industrial wastewaters of JSC Grindeks are rich in carbon and nitrogen, while
deficient in phosphorus. The median COD and nitrogen concentration of the influent water are 5500 mg/L and 160 mg/L, respectively,
yet the median phosphorus concentration in the inlet water is only 3 mg/L. To ensure optimal phosphorus levels at the biological
treatment stages at the WWTP of JSC Grindeks, H 3PO4 is added as a phosphorus source in the first MBBR, and the level of inorganic
phosphates is monitored in the first and last MBBRs, because low phosphorus availability strongly affects the biodegradation efficiency
and favours the growth of filamentous bacteria [81].
The only production process giving high amounts of phosphates (C ¼ 10 g/L PO4–P) in the wastewaters of JSC Grindeks is the batch
synthesis of Ipidacrine API, which performed in campaigns lasting only several weeks every year. In order to avoid extreme peak
3
loadings and overdose of phosphorus at these times, about 10 m of wastewater from this batch process is collected separately and
reused as a phosphorus source during the periods when its concentration is low in the influent wastewater. The substitution of H3PO4
with phosphorus-rich wastewater allows reduction of the consumption of phosphorus as a critical nutrient and lowers the operational
costs of WWTP, leading to improved plant efficiency.

3.5.4. The use of recovered solvents as easily degradable carbon source for the denitrification processes
Spent solvents that after several recovery cycles are no longer suitable for the manufacturing of pharmaceutical products, represent
a large proportion of the liquid waste generated by the pharmaceutical industry (see more details in Section 3.4). In most cases,

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elevated water content is the reason why spent solvents are no longer suitable for re-use in chemical synthesis. Solvents in general are
toXic and inhibit the enzymatic activity of activated sludge microorganisms [82], however, controlled addition of some solvents to
wastewater streams may be beneficial for the activated sludge microorganisms.
At the biological WWTP of JSC Grindeks, about 9.5 tons of water-miscible spent solvents per year are utilised as external carbon
sources in the post-denitrification process. Due to its relatively low toXicity, highly biodegradable nature, and chemical compatibility
with the dosing line materials, ethanol has been selected as the most suitable spent solvent for this purpose. The addition of a carbon
— —
source is based on an experimentally determined optimal C:N ratio of 4:1, where C is COD and N refers to both NO 3 -N and NO 2 -N. The
spent ethanol is diluted with water to a concentration of about 50% in order to reduce its flammability and to mitigate explosion risks
at the WWTP.
Although the current re-use rate of spent solvents in the denitrification process represents only about 3.5% of the total amount of
spent solvents generated at JSC Grindeks, there are opportunities to also utilise these solvents at municipal WWTPs. As the
denitri- fication efficiency at municipal WWTPs is often limited by insufficient carbon content in the untreated wastewater [83], spent
solvents can be potentially introduced as external carbon sources at municipal WWTPs. Considering that spent solvents are recovered
sepa- rately from each batch process at JSC Grindeks, it is possible to accurately determine the presence of pharmaceutical residues in
such solvents. Additionally, it allows to choose solvents from the production of those APIs that show comparatively better
biodegradability at WWTPs and does not represent therapeutic classes that have significant adverse effects on the ecosystem [84]. The
implementation of such practices allows reduction of operating costs of the WWTPs, an increase in nitrogen removal efficiency,
and general improvement of pharmaceutical waste management.

4. Conclusions

Comprehensive analysis of various water flows and their quality requirements allows identification of opportunities and limitations
for water reuse at the manufacturing plant level. Concerns about product contamination, the strict chemical and microbiological purity
requirements and current GMP regulations restrict the use of reclaimed water in direct contact with pharmaceutical products. Water
steam condensate and reject water re-use from RO systems, and a transition to water-efficient closed-loop cooling systems were
recognized as necessary actions to reduce water consumption in a particular pharmaceutical factory. Due to extreme variability of
pharmaceutical wastewater in a multiproduct factory, treatability studies and toXicity screening should be conducted for individual
batch streams to distinguish highly toXic and concentrated streams and provide pre-treatment if necessary. Our case study highlights a
synergy between manufacturing facilities and on-site WWTP that provides a logical path for implementing the elements of circular
economy in the pharmaceutical factory. As a result, specific wastewater streams from pharmaceutical batch processes can be reused as
sources of nutrients, coagulants or a pH control agent in a biological WWTP, providing both environmental and economic benefits.

Funding

This work was funded by the Polish National Agency for Academic E Xchange as the part of the project “International Cooperation
for Rational Use of Raw Materials and Circular Economy (COOPMIN) which is conducted in the division of Strategic Research in the
MEERI PAS (2019–2020), project no.PPI/APM/2018/1/00003.
ES research/publication was supported by Riga Technical University’s Doctoral grant programme.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to
influence the work reported in this paper.

Acknowledgments

The authors would like to express their gratitude for the continuous support and valuable comments from the colleagues at JSC
Grindeks who were involved in this study. The authors especially thank to Dr.Chem. Juris Gulbis for useful discussions during the early
stages of this work.

Appendix A. Supplementary data

Supplementary data to this article can be found online at https://doi.org/10.1016/j.wri.2020.100132.

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