Towards a Greener Manufacturing Environment by dfsiopmhy6

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									IPT 29 2009    11/6/09     11:00      Page 78




                                    Manufacturing




                                    Towards a Greener
                                    Manufacturing Environment
       By C Stewart Slater          Green manufacturing strategies not only reduce the industry’s carbon
       and Mariano J Savelski       footprint – they also make for more efficient processes from both a raw
       at the Department of
       Chemical Engineering,        materials and waste perspective, resulting in a ‘win-win’ situation for both
       Rowan University, US         the environment and pharmaceutical companies.

                                    There are many opportunities for investigating green        industry has traditionally used batch processes in which
                                    manufacturing strategies in the pharmaceutical              numerous organic synthesis reactions are conducted in
                                    industry. Green engineering is defined as the design,       sequential steps. Each of these steps requires its own
                                    commercialisation and use of processes and products         isolation and purification train, which in turn typically
                                    that are feasible and economical, while reducing the        requires different organic solvents (1). It has been
                                    risk to human health and the environment, and               estimated that solvent use can account for as much as 80-
                                    minimising the generation of pollution at the source.       90 per cent of the total mass in a process, the majority of
                                    In this article, we look at the main causes of              which are organic solvents (2). Since solvents are not part
                                    pharmaceutical waste and how they can be moderated,         of the reaction stoichiometry, the spent solvent is either
                                    the approaches the industry can adopt to improve its        disposed of or recycled. Solvent usage and waste
                                    environmental footprint, and the ways in which these        generation can thus be quite high when compared with
                                    green improvements can be measured.                         the final API produced. The E-factor – the amount of
                                                                                                waste generated per quantity of API – can typically range
                                    CURRENT PRACTICES                                           from 25 to over 100 kg/kg of API (3). Thus when a
                                                                                                large volume API is produced in the 100-plus metric
                                    While the pharmaceutical industry may not generate a        ton range, the variety and amount of solvents used can
                                    large volume of waste in comparison with other sectors      be significant.
                                    like steel manufacturing or petroleum refining, it has
                                    consistently generated one of the highest amounts of        The US Environmental Protection Agency (EPA)
                                    wastes per amount of finished product. This is due to the   requires the pharmaceutical industry to report the
                                    numerous process inefficiencies that exist from the         disposition of chemicals to the Toxic Release Inventory
                                    synthesis of intermediates to the finished drug. The        (TRI). Although this list comprises only chemicals that
                                                                                                meet certain pollutant criteria, it is still a good
                  Figure 1: Pharmaceutical industry waste profile using US Environmental        indicator of the waste profile. According to the TRI,
                  Protection Agency (EPA) Toxic Release Inventory data for 2006 – primary       the pharmaceutical industry in the US generated 128
                  commercial sector category
                                                                                                million kg of waste in 2006. This waste included
                                                                                                mainly organic solvents, the top three of which are
                                           Various other
                                             solvents                                           methanol, 44.8 million kg/year; dichloromethane,
                                                                                                22.3 million kg/year; and toluene, 12.1 million
                     N, N-dimethylformamide
                                                                                                kg/year. The top 10 solvents accounted for more than
                          n-Butyl alcohol
                                                                               Methanol         80 per cent of the waste generated (see Figure 1, (4)).
                                n-Hexane
                                                                                                Over the last 10 years the industry has reduced solvent
                            Chloroform
                                                                                                use and waste generation, but there is still a long way
                    Nitrate compounds
                                                                                                to go in improving productivity. According to the TRI
                       Hydrochloric acid
                                                                                                2006 report, the majority of solvent waste,
                                                                                                approximately 70 per cent, was treated or recycled, and
                                 Acetonitrile                                                   30 per cent was used for energy recovery. Only a small
                                                                                                percentage was still directly released into the
                                                Toluene                                         environment (4). Since solvents are costly to purchase
                                                                  Dichloromethane
                                                                                                and dispose of, for a greener and more sustainable
                                                                                                pharmaceutical industry it is imperative that


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                                approaches to solvent reduction, recovery and               supercritical carbon dioxide have potential as reaction
                                substitution be more widely incorporated.                   media. The ‘plant of the future’ may use a limited
                                                                                            number of ‘universal’ green solvents, the properties of
                                GREENER PROCESSES                                           which would also allow for easy recovery. The use of
                                                                                            continuous processes, biosynthetic routes and greener
                                The pharmaceutical industry is investigating many           solvents can all reduce the use of hazardous organic
                                approaches to improve its environmental footprint. The      solvents. Therefore, a future manufacturing scheme
                                goal is to make a better process in the early stages of     would not only be greener but would be optimised to
                                clinical development when changes can more readily be       enable a more agile operation. A common method used
                                made. As a drug moves further along the development         to minimise both solvent use and waste generation can
                                timeline to final manufacturing, changes may be more        be achieved by reducing the number of chemical
                                difficult to implement. Even after a drug has been          transformations or steps (telescoping) within a process.
                                manufactured for a number of years, improvements to         Process chemistry optimisation is typically practiced in
                                process efficiency can be made, as long as API quality is   the early development cycle and can yield significant
                                not affected.                                               improvements when scaled up to manufacturing. In
                                                                                            addition, new approaches such as solid-state chemistry
                                A classic example of this is the award-winning              and microwave reactions are being explored for their
                                improvements made by Pfizer in the sildenafil citrate       potential in solvent reduction.
                                process. They were able to reduce the solvent use from
                                1,540 to 5kg/kg/API as the process was improved from        SOLVENT RECOVERY
                                the discovery stage through successive manufacturing
                                campaigns. By improving the synthesis and                   Solvent recovery has increased at both pharmaceutical
                                incorporating solvent recovery methods, a significant       manufacturing and off-site recovery facilities.
                                reduction of highly hazardous solvents was achieved (5).    Distillation still dominates the processes used in solvent
                                                                                            recovery operations, but this may not be perceived as
                                The optimisation of solvent use and reduction of waste      being green by today’s standards. Energy-intensive
                                generation have become key elements in improving the        operations – such as distillation – are coming under
                                overall environmental footprint of the pharmaceutical       greater scrutiny at a time of volatile oil prices.
                                industry. Solvent selection and solvent substitution        Pharmaceutical wastes typically contain multiple
                                practices, the elimination of hazardous solvents and        solvents (in both homogenous and heterogeneous
                                opportunities for purification, re-use and recycling are    mixtures), unconverted reactants and other byproducts,
                                all being explored as a means to reduce solvent use         requiring complex separation schemes to obtain
                                and waste generation. Solvent substitution practices –      high quality solvent for re-use. Although many
                                such as the replacement of chlorinated solvents             manufacturers have a centralised solvent recovery
                                (dichloromethane) with more benign alternatives – have      facility, a new approach is to integrate separation
                                yielded greener processes, while ionic liquids and          processes at the point of use to perform the operation
                                                                                            more easily. One of the challenges faced in solvent
                                                                                            recovery is the separation of azeotropic mixtures.
                                                                                            Traditionally, this has meant the use of entrainer-based
                                                                                            distillation methods that are more energy-intensive and
                                                                                            are associated with other environmental issues linked to
                                                                                            the use of entrainers. One of the greener technologies
                                                                                            that avoids this use of additional chemicals, energy and
                                                                                              waste is membrane pervaporation.

                                                                                                          Membrane pervaporation uses a highly
                                                                                                          selective semi-permeable barrier to
                                                                                                          facilitate the removal of selected chemicals
                                                                                                          from a liquid feed. Unlike equilibrium-
                                                                                                          based separations – such as distillation –
                                                                                                          that rely on the relative volatilities of the
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              Figure 2: Integration of pervaporation                                                        used first to increase the solvent to the azeotropic
              and distillation in a solvent dehydration
              and recovery process
                                                                                                            concentration, and pervaporation is then used on the
                                                                                                            distillate stream to purify the solvent to the desired
                                                                            Dehydrated solvent for re-use
                                                                                                            water content (see Figure 2). This optimises the
                                    Solvent-water                                                           capabilities of each process, since distillation is
                                  azeotropic mixture
                                                                   Pervaporation                            typically more effective in concentrating non-
                                                                                                            azeotropic dilute organic-water mixtures, and
                                                                                                            pervaporation is more effective in dehydrating high
                                                                                                            organic water concentration mixtures. Pervaporation is
                                                                                                            a suitable platform technology for the pharmaceutical
              Solvent-water                                                                                 industry; it is quite scalable to any operation from
              waste stream                                                                                  pilot plant to manufacturing campaigns and can run
                                                                                                            in a continuous or batch mode. In addition, a
                                                          Low flow rate                                     pervaporation system can have membranes changed
                                                       stream: water with
                                                          some solvent                                      over to optimise performance when handling different
                                                                                                            solvent mixtures for different drug campaigns. Current
                                                                                                            commercial types of membrane used in solvent
                                        substances to be separated, pervaporation relies on                 dehydration are polyvinyl alcohol-based polymers and
                                        relative membrane permeabilities of the substances to               ceramics composed of silica or zeolites (8).
                                        accomplish the separation. A liquid feed is sent to
                                        the pervaporation unit, which is fitted with a                      MEASURING GREEN IMPROVEMENTS
                                        hydrophilic membrane. The water selectively permeates
                                        the membrane leaving a retentate stream that now                    A simple process improvement metric based on waste
                                        comprises the dehydrated solvent. Solvents that are good            reduced per API manufactured (E-factor) offers a
                                        candidates for commercial-scale dehydration include                 straightforward analysis – but it may not necessarily
                                        isopropanol, ethanol, methanol, ethyl acetate, butyl                indicate the ‘greenness’ of the improvements. This
                                        acetate, acetone, acetronitrile, tetrahydrofuran, n-                would be the case when, for example, more benign
                                        butanol and methylethylketone (6).                                  solvents are reduced instead of the more toxic ones. For
                                                                                                            this reason, solvent-scoring indices have been
                                        Current research shows that it is more efficient to                 developed to quantify the greenness of solvents using
                                        use a hybrid process combining distillation and                     factors that represent environmental health, safety and
                                        pervaporation to separate low water-content,                        sustainability. GlaxoSmithKline (9), Pfizer (10) and
                                        azeotropic solvent waste streams (7). Distillation is               Bristol-Myers Squibb (11) among others have
                                                                                                            developed their own methods to evaluate the greenness
                                                                                                            of solvents. The American Chemical Society (ACS)
              Figure 3: Life cycle assessment (LCA)                                                         Green Chemistry Institute (GCI) Pharmaceutical
              system boundary for the solvent used in
              an API manufacturing process                                                                  Roundtable is collaborating with its member
                                                                                                            companies to deliver a solvent selection guide in the
                                                                                                            near future (12). Slater and Savelski (1) have developed
                                  Emissions                                                                 an approach to measure the overall greenness of a
                                                                                                            manufacturing process based on the amounts and
                                                                                                            environmental characteristics of the solvents used. This
                  Emissions           Solvent                                               Emissions       method uses a combination of health and safety
                                    manufacture
                                                                                                            parameters such as inhalation toxicity and ingestion
                                                                                                            toxicity, along with sustainability parameters like
                  Raw materials
                                                               API                           Waste          ozone depletion and global warming potential.
                                                            manufacture                   incineration

                                                                                                            A thorough life-cycle inventory/assessment is the best
                                       Utilities
                                                                                                            approach when evaluating the greenness of a process as
                                                                                                            a whole. This can consider all of the inputs and
                                                                                                            outputs from a drug manufacturing process, or just
                                                                                                            focus on a particular step or alternative chemical used.
                                       Emissions
                                                                                                            The example in Figure 3 illustrates the environmental


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          impact of reducing solvent in an API manufacturing
                                                                                             C Stewart Slater is Professor of Chemical
          facility (see Figure 3). If the solvent used is either
                                                                                             Engineering and Founding Chair of the Chemical
          reduced or recycled, then fresh solvent does not need                              Engineering Department at Rowan University
          to be manufactured, and energy and raw materials are                               (Glassboro, New Jersey). He has an extensive
          saved. This view beyond the plant boundary can also                                research and teaching background in separation
          show the reduction in greenhouse gas emissions from                                process technology with a particular focus on
          the energy saved.                                                                  membrane separation process research,
                                                                            development and design for pollution prevention, manufacturing
                                                                            sustainability and green engineering. He received PhD, MS and BS
          A typical life-cycle inventory can be generated using             degrees in chemical and biochemical engineering from Rutgers
          environmental software such as SimaPro (PRé                       University (New Jersey, US). Prior to joining Rowan University he
          Consultants). For example, to manufacture 1kg of IPA              was a professor at Manhattan College (Riverdale, New Jersey, US).
          solvent requires 0.89kg raw materials and 61.9 MJ-Eq              Email: slater@rowan.edu
          cumulative energy demand, and generates 2.19kg of
                                                                                            Mariano J Savelski is Associate Professor in the
          emissions (including 1.63kg CO2). This represents the                             Chemical Engineering Department at Rowan
          ‘cradle’ of the solvent’s life cycle and the ‘grave’ would                        University (Glassboro, New Jersey). He has seven
          be its disposal. For waste disposal by thermal oxidation                          years of industrial experience in the area of design
          (incineration), the emissions produced can also be                                and optimisation of chemical plants. His research
                                                                                            and teaching interests are in optimising processes
          estimated with software such as EcoSolvent. Making
                                                                                            for water and energy reduction; lean manufacturing
          the process greener, by reducing and recycling spent              in food, consumer products and pharmaceuticals; and developing
          solvent, can lead to a significant reduction in emissions         renewable fuels from biomass. Mariano received a PhD in chemical
          produced in the manufacture of virgin solvent and in              engineering from the University of Oklahoma (Norman, OK, US), an
          the incineration process. Of course the cost, energy              ME in chemical engineering from the University of Tulsa (OK, US)
                                                                            and a BS in chemical engineering from the University of Buenos
          and emissions associated with the solvent recovery
                                                                            Aires (Argentina). Email: savelski@rowan.edu
          process must now be taken into account, but recent
          studies have shown that these are small when
          compared with overall solvent life-cycle emissions (7).      3.     Sheldon RA, Chem Ind, 1, pp12-15, 1997
                                                                       4.     Lopez N, Toxic Release Inventory, US
          CONCLUSION                                                          Environmental Protection Agency,
                                                                              Washington, DC, 2006
          There are significant benefits that transcend carbon         5.     Dunn PJ, Galvin S and Hettenbach K,
          footprint reduction for the pharmaceutical industry to              Green Chem 6, pp43-48, 2004
          implement green design strategies. In general, a             6.     Sulzer mass transfer technology pervaporation
          greener process is a more efficient process from both a             systems, www.sulzerchemtech.com, last
          raw materials and waste perspective. Energy and cost                accessed 1st April, 2009
          reductions will result from these design enhancements        7.     Slater CS, Savelski MJ, Hounsell G et al,
          and the overall operation can be made more                          Paper 290b, Proc 2008 Meeting Amer
          sustainable. The greener a process is, the better the               Inst Chem Eng, Philadelphia, PA,
          process – resulting in a win-win situation for both the             November 2008
          drug manufacturer and the environment.                       8.     McGinness CA, Slater CS and Savelski MJ,
                                                                              J Environ Sci and Health 43, pp1,673-1,684,
              Acknowledgement                                                 2008
              The authors gratefully acknowledge the support           9.     Jimenez-Gonzalez C, Curzons AD, Constable DJC
              of the US Environmental Protection Agency                       and Cunningham VL, Clean Tech Environ Policy
              through a pollution prevention research grant,                  7, pp42-50, 2005
              NP97257006-0.                                            10. Alfonsi K, Colberg J, Dunn PJ et al, Green
                                                                              Chem 10, pp31-36, 2008
          References                                                   11. Taylor S, Paper 4b, Proc EPA Conf Opportun
                                                                              Green Chem Green Eng Pharm Indus, New York,
          1.     Slater CS and Savelski M, J Environ Sci                      NY, September 2007
                 Health 42, pp1,595-1,605, 2007                        12. Hargreaves CR and Manley JB, Collaboration
          2.     Constable DJC, Jimenez-Gonzalez C and                        to deliver a solvent selection guide for the
                 Henderson RK, Org Process R&D 11,                            pharmaceutical industry, ACS GCI Pharmaceutical
                 pp133-137, 2007                                              Roundtable, Washington, DC, 2008



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