Manufacturing

There are many opportunities for investigating greenmanufacturing strategies in the pharmaceuticalindustry. Green engineering is defined as the design,commercialisation and use of processes and productsthat are feasible and economical, while reducing therisk to human health and the environment, andminimising the generation of pollution at the source. In this article, we look at the main causes ofpharmaceutical waste and how they can be moderated,the approaches the industry can adopt to improve itsenvironmental footprint, and the ways in which thesegreen improvements can be measured.

CURRENT PRACTICES

While the pharmaceutical industry may not generate alarge volume of waste in comparison with other sectorslike steel manufacturing or petroleum refining, it hasconsistently generated one of the highest amounts ofwastes per amount of finished product. This is due to thenumerous process inefficiencies that exist from thesynthesis of intermediates to the finished drug. The

industry has traditionally used batch processes in whichnumerous organic synthesis reactions are conducted insequential steps. Each of these steps requires its ownisolation and purification train, which in turn typicallyrequires different organic solvents (1). It has beenestimated that solvent use can account for as much as 80-90 per cent of the total mass in a process, the majority ofwhich are organic solvents (2). Since solvents are not partof the reaction stoichiometry, the spent solvent is eitherdisposed of or recycled. Solvent usage and wastegeneration can thus be quite high when compared withthe final API produced. The E-factor – the amount ofwaste generated per quantity of API – can typically rangefrom 25 to over 100 kg/kg of API (3). Thus when a large volume API is produced in the 100-plus metric ton range, the variety and amount of solvents used can be significant.

The US Environmental Protection Agency (EPA)requires the pharmaceutical industry to report thedisposition of chemicals to the Toxic Release Inventory(TRI). Although this list comprises only chemicals thatmeet certain pollutant criteria, it is still a goodindicator of the waste profile. According to the TRI,the pharmaceutical industry in the US generated 128million kg of waste in 2006. This waste includedmainly organic solvents, the top three of which aremethanol, 44.8 million kg/year; dichloromethane,22.3 million kg/year; and toluene, 12.1 millionkg/year. The top 10 solvents accounted for more than80 per cent of the waste generated (see Figure 1, (4)).Over the last 10 years the industry has reduced solventuse and waste generation, but there is still a long wayto go in improving productivity. According to the TRI2006 report, the majority of solvent waste,approximately 70 per cent, was treated or recycled, and30 per cent was used for energy recovery. Only a smallpercentage was still directly released into theenvironment (4). Since solvents are costly to purchaseand dispose of, for a greener and more sustainablepharmaceutical industry it is imperative that

Green manufacturing strategies not only reduce the industry’s carbonfootprint – they also make for more efficient processes from both a rawmaterials and waste perspective, resulting in a ‘win-win’ situation for boththe environment and pharmaceutical companies.

78 Innovations in Pharmaceutical Technology

By C Stewart Slater and Mariano J Savelski at the Department ofChemical Engineering,Rowan University, US

Towards a Greener Manufacturing Environment

Figure 1: Pharmaceutical industry waste profile using US EnvironmentalProtection Agency (EPA) Toxic Release Inventory data for 2006 – primarycommercial sector category

Methanol

DichloromethaneToluene

Acetonitrile

Hydrochloric acid

Nitrate compounds

Chloroform

n-Hexane

n-Butyl alcohol

N, N-dimethylformamide

Various othersolvents

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approaches to solvent reduction, recovery andsubstitution be more widely incorporated.

GREENER PROCESSES

The pharmaceutical industry is investigating manyapproaches to improve its environmental footprint. Thegoal is to make a better process in the early stages ofclinical development when changes can more readily bemade. As a drug moves further along the developmenttimeline to final manufacturing, changes may be moredifficult to implement. Even after a drug has beenmanufactured for a number of years, improvements toprocess efficiency can be made, as long as API quality isnot affected.

A classic example of this is the award-winningimprovements made by Pfizer in the sildenafil citrateprocess. They were able to reduce the solvent use from1,540 to 5kg/kg/API as the process was improved fromthe discovery stage through successive manufacturingcampaigns. By improving the synthesis andincorporating solvent recovery methods, a significantreduction of highly hazardous solvents was achieved (5).

The optimisation of solvent use and reduction of wastegeneration have become key elements in improving theoverall environmental footprint of the pharmaceuticalindustry. Solvent selection and solvent substitutionpractices, the elimination of hazardous solvents andopportunities for purification, re-use and recycling are all being explored as a means to reduce solvent use and waste generation. Solvent substitution practices –such as the replacement of chlorinated solvents(dichloromethane) with more benign alternatives – haveyielded greener processes, while ionic liquids and

supercritical carbon dioxide have potential as reactionmedia. The ‘plant of the future’ may use a limitednumber of ‘universal’ green solvents, the properties ofwhich would also allow for easy recovery. The use ofcontinuous processes, biosynthetic routes and greenersolvents can all reduce the use of hazardous organicsolvents. Therefore, a future manufacturing schemewould not only be greener but would be optimised toenable a more agile operation. A common method usedto minimise both solvent use and waste generation canbe achieved by reducing the number of chemicaltransformations or steps (telescoping) within a process.Process chemistry optimisation is typically practiced inthe early development cycle and can yield significantimprovements when scaled up to manufacturing. Inaddition, new approaches such as solid-state chemistryand microwave reactions are being explored for theirpotential in solvent reduction.

SOLVENT RECOVERY

Solvent recovery has increased at both pharmaceuticalmanufacturing and off-site recovery facilities.Distillation still dominates the processes used in solventrecovery operations, but this may not be perceived asbeing green by today’s standards. Energy-intensiveoperations – such as distillation – are coming undergreater scrutiny at a time of volatile oil prices.Pharmaceutical wastes typically contain multiplesolvents (in both homogenous and heterogeneousmixtures), unconverted reactants and other byproducts,requiring complex separation schemes to obtain high quality solvent for re-use. Although manymanufacturers have a centralised solvent recoveryfacility, a new approach is to integrate separationprocesses at the point of use to perform the operationmore easily. One of the challenges faced in solventrecovery is the separation of azeotropic mixtures.Traditionally, this has meant the use of entrainer-baseddistillation methods that are more energy-intensive andare associated with other environmental issues linked tothe use of entrainers. One of the greener technologiesthat avoids this use of additional chemicals, energy and

waste is membrane pervaporation.

Membrane pervaporation uses a highlyselective semi-permeable barrier tofacilitate the removal of selected chemicalsfrom a liquid feed. Unlike equilibrium-based separations – such as distillation –that rely on the relative volatilities of the

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substances to be separated, pervaporation relies onrelative membrane permeabilities of the substances toaccomplish the separation. A liquid feed is sent to the pervaporation unit, which is fitted with a hydrophilic membrane. The water selectively permeatesthe membrane leaving a retentate stream that nowcomprises the dehydrated solvent. Solvents that are goodcandidates for commercial-scale dehydration includeisopropanol, ethanol, methanol, ethyl acetate, butylacetate, acetone, acetronitrile, tetrahydrofuran, n-butanol and methylethylketone (6).

Current research shows that it is more efficient to use a hybrid process combining distillation andpervaporation to separate low water-content,azeotropic solvent waste streams (7). Distillation is

used first to increase the solvent to the azeotropicconcentration, and pervaporation is then used on thedistillate stream to purify the solvent to the desiredwater content (see Figure 2). This optimises thecapabilities of each process, since distillation istypically more effective in concentrating non-azeotropic dilute organic-water mixtures, andpervaporation is more effective in dehydrating highorganic water concentration mixtures. Pervaporation isa suitable platform technology for the pharmaceuticalindustry; it is quite scalable to any operation from pilot plant to manufacturing campaigns and can run in a continuous or batch mode. In addition, apervaporation system can have membranes changedover to optimise performance when handling differentsolvent mixtures for different drug campaigns. Currentcommercial types of membrane used in solventdehydration are polyvinyl alcohol-based polymers andceramics composed of silica or zeolites (8).

MEASURING GREEN IMPROVEMENTS

A simple process improvement metric based on wastereduced per API manufactured (E-factor) offers astraightforward analysis – but it may not necessarilyindicate the ‘greenness’ of the improvements. Thiswould be the case when, for example, more benignsolvents are reduced instead of the more toxic ones. Forthis reason, solvent-scoring indices have beendeveloped to quantify the greenness of solvents usingfactors that represent environmental health, safety andsustainability. GlaxoSmithKline (9), Pfizer (10) andBristol-Myers Squibb (11) among others havedeveloped their own methods to evaluate the greennessof solvents. The American Chemical Society (ACS)Green Chemistry Institute (GCI) PharmaceuticalRoundtable is collaborating with its membercompanies to deliver a solvent selection guide in thenear future (12). Slater and Savelski (1) have developedan approach to measure the overall greenness of amanufacturing process based on the amounts andenvironmental characteristics of the solvents used. Thismethod uses a combination of health and safetyparameters such as inhalation toxicity and ingestiontoxicity, along with sustainability parameters likeozone depletion and global warming potential.

A thorough life-cycle inventory/assessment is the bestapproach when evaluating the greenness of a process asa whole. This can consider all of the inputs andoutputs from a drug manufacturing process, or justfocus on a particular step or alternative chemical used.The example in Figure 3 illustrates the environmental

82 Innovations in Pharmaceutical Technology

Figure 3: Life cycle assessment (LCA)system boundary for the solvent used inan API manufacturing process

Solvent-water waste stream

Solvent-waterazeotropic mixture

Low flow ratestream: water with

some solvent

Pervaporation

Dehydrated solvent for re-use

Solventmanufacture

APImanufacture

Wasteincineration

Utilities

Raw materials

Emissions

Emissions

Emissions

Emissions

Figure 2: Integration of pervaporation and distillation in a solvent dehydrationand recovery process

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impact of reducing solvent in an API manufacturingfacility (see Figure 3). If the solvent used is eitherreduced or recycled, then fresh solvent does not needto be manufactured, and energy and raw materials aresaved. This view beyond the plant boundary can alsoshow the reduction in greenhouse gas emissions fromthe energy saved.

A typical life-cycle inventory can be generated usingenvironmental software such as SimaPro (PRéConsultants). For example, to manufacture 1kg of IPAsolvent requires 0.89kg raw materials and 61.9 MJ-Eqcumulative energy demand, and generates 2.19kg ofemissions (including 1.63kg CO2). This represents the‘cradle’ of the solvent’s life cycle and the ‘grave’ wouldbe its disposal. For waste disposal by thermal oxidation(incineration), the emissions produced can also beestimated with software such as EcoSolvent. Makingthe process greener, by reducing and recycling spentsolvent, can lead to a significant reduction in emissionsproduced in the manufacture of virgin solvent and inthe incineration process. Of course the cost, energyand emissions associated with the solvent recoveryprocess must now be taken into account, but recentstudies have shown that these are small whencompared with overall solvent life-cycle emissions (7).

CONCLUSION

There are significant benefits that transcend carbonfootprint reduction for the pharmaceutical industry toimplement green design strategies. In general, agreener process is a more efficient process from both araw materials and waste perspective. Energy and costreductions will result from these design enhancementsand the overall operation can be made moresustainable. The greener a process is, the better theprocess – resulting in a win-win situation for both thedrug manufacturer and the environment.

Acknowledgement

The authors gratefully acknowledge the support

of the US Environmental Protection Agency

through a pollution prevention research grant,

NP97257006-0.

References

1. Slater CS and Savelski M, J Environ Sci

Health 42, pp1,595-1,605, 2007

2. Constable DJC, Jimenez-Gonzalez C and

Henderson RK, Org Process R&D 11,

pp133-137, 2007

3. Sheldon RA, Chem Ind, 1, pp12-15, 1997

4. Lopez N, Toxic Release Inventory, US

Environmental Protection Agency,

Washington, DC, 2006

5. Dunn PJ, Galvin S and Hettenbach K,

Green Chem 6, pp43-48, 2004

6. Sulzer mass transfer technology pervaporation

systems, www.sulzerchemtech.com, last

accessed 1st April, 2009

7. Slater CS, Savelski MJ, Hounsell G et al,

Paper 290b, Proc 2008 Meeting Amer

Inst Chem Eng, Philadelphia, PA,

November 2008

8. McGinness CA, Slater CS and Savelski MJ,

J Environ Sci and Health 43, pp1,673-1,684,

2008

9. Jimenez-Gonzalez C, Curzons AD, Constable DJC

and Cunningham VL, Clean Tech Environ Policy

7, pp42-50, 2005

10. Alfonsi K, Colberg J, Dunn PJ et al, Green

Chem 10, pp31-36, 2008

11. Taylor S, Paper 4b, Proc EPA Conf Opportun

Green Chem Green Eng Pharm Indus, New York,

NY, September 2007

12. Hargreaves CR and Manley JB, Collaboration

to deliver a solvent selection guide for the

pharmaceutical industry, ACS GCI Pharmaceutical

Roundtable, Washington, DC, 2008

83Innovations in Pharmaceutical Technology

C Stewart Slater is Professor of ChemicalEngineering and Founding Chair of the ChemicalEngineering Department at Rowan University(Glassboro, New Jersey). He has an extensiveresearch and teaching background in separationprocess technology with a particular focus onmembrane separation process research,

development and design for pollution prevention, manufacturingsustainability and green engineering. He received PhD, MS and BSdegrees in chemical and biochemical engineering from RutgersUniversity (New Jersey, US). Prior to joining Rowan University he was a professor at Manhattan College (Riverdale, New Jersey, US).Email: slater@rowan.edu

Mariano J Savelski is Associate Professor in theChemical Engineering Department at RowanUniversity (Glassboro, New Jersey). He has sevenyears of industrial experience in the area of designand optimisation of chemical plants. His researchand teaching interests are in optimising processesfor water and energy reduction; lean manufacturing

in food, consumer products and pharmaceuticals; and developingrenewable fuels from biomass. Mariano received a PhD in chemicalengineering from the University of Oklahoma (Norman, OK, US), anME in chemical engineering from the University of Tulsa (OK, US)and a BS in chemical engineering from the University of BuenosAires (Argentina). Email: savelski@rowan.edu

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