Recovery and Reuse Integration Problem Statement Introduction: The inclusion of Solvent recovery processes for new pharmaceutical chemical entities (NCE’s) and manufactured products occurs by exception and not by practice. The following problem statements outlines the main technical and business reasons why solvent recovery has not been successfully embedded into the manufacture of pharmaceutical products: Problem Statement 1: Solvent Recovery Distillation/Evaporation issues. The predominant solvent recovery unit operations used in the Pharma industry is distillation and evaporation. Both these unit operations are energy intensive and results in poor recovery yields for some organic streams ie. azeotropic mixtures. At manufacturing sites solvent recovery systems are designed to operate off-line rather than on-line. This results in large plant and large solvent inventories upstream and downstream of the recovery plant on site. The resulting capital cost of large recovery systems is high and spatially challenging. In addition, the recovery of solvent from waste streams containing temperature sensitive product and reagents can raise some process safety concerns if recovered by distillation. The thermal decomposition temperature of some API’s and intermediates is sometimes within the temperature operating range of a fractionation column. Extra precautions need to be taken to mitigate against the process safety risk which in some cases results in a sub-optimal recovery yield. Exemplification of Problem Solvent recovery rates at GSK manufacturing sites are poor relative to other lean industries (i.e. Jurong 18% solvent recovery rate). This results in a higher disposal cost of the waste organic solvent and a lost opportunity to increase the mass efficiency of manufactured products on site. For instance, a recent product at our manufacturing sites had methanol used in the penultimate step and an acetonitrile/water mixture used in the final step. As projected volumes of the compound are relatively small, solvent recovery is typically not prioritised, resulting in solvents being downcycled for fuel unless they can be batched with other similar site streams. In this particular case, an azeotrope exists in the acetonitrile/water system which makes recovery to a virgin specification very difficult. Solvent recovery by distillation is energy and capital intensive, and as a result payback periods for small volume products is exceptionally long. Expected Output of Research Deliver a low cost , sustainable and regulatory compliant solvent recovery technology. The technology should be industrializable across a range of scales and have demonstrated lifecycle benefits over the replacement technology. The technology must be cost viable and applicable across a range of solvents. Problem Statement #2: Recovery and Reuse in Singapore In Singapore there is a high concentration of pharmaceutical , chemical and oil & gas manufacturing industries. These industries produce large amounts of waste which are treated and disposed of according to local environmental regulations. The treatment and disposal of waste is carried out by individual companies with focus on treatment and disposal rather than re-use and recycle. Thus opportunities for reuse, recycle and downcycle are not fully exploited as a result of lack of national infrastructure and lack of commercial recycling companies to provide a national solution. Exemplification of problem A good example of this problem is in the area of solvent recovery which is done by individual pharma companies in Singapore to varying degrees. For these companies solvent recovery is not a core business function or a core area of expertise and can involve significant capital cost. Thus very often material is disposed of instead of recycled or re-used. There is no local specialist solvent recovery company in Singapore capable of working with all the pharma industry situated on the island for solvent recovery and the waste solvent disposal companies have limited heat recovery capability from incineration. Expected output of research An Economic study on the feasibility of providing cross industry solutions in Singapore to assess key recycling, re-use and downcycling opportunities. Identify the technologies and capability required to future proof Singapore sustainability ambition for the Pharmaceutical sector. Problem Statement #3: Recovery & Re-use of homogeneous and heterogeneous catalysts. Homogeneous catalysts are useful synthetically but are expensive and difficult to recover , hence they are not recovered even though precious metals are involved. This is a large cost burden for the cost of goods for API’s as the catalyst is generally disposed of as a waste stream. For heterogeneous catalysts, the catalyst is generally isolated and recycled back to the suppliers for recovery. Singapore has very limited capability of recovering expensive metals from catalysts used in industry. If the catalyst could be recovered in Singapore this would minimize the shipping requirements of waste catalyst back to suppliers in Europe for regeneration and would also have the effect of reducing the precious metal inventory of Pharma companies. Expected output of research An Economic study on the feasibility of providing catalyst recovery capability in Singapore. Identify the technologies and capability required to future proof Singapore sustainability ambition for the Pharmaceutical sector. Problem Statement 4. – Renewable Solvents Economics.. The cost base of solvent fluctuates based on the price of oil leading to a variable cost of goods of our API’s. Maximising the solvent recovery rate mitigates this pricing uncertainty and there is commercial balance to be made between solvent recovery for reuse and downcycling the solvent for energy generation / lower grade user (paint thinners , energy recovery). However , from a lifecycle perspective, moving away from using solvent derived from fossil fuels to renewable solvents will greatly enhance the footprint of our API’s (due to the poor solvent recovery rates currently experienced). One of the key business drivers for NCE’s is speed to market. If solvent recovery is not registered by first intent , an expensive technical change is required post registration to integrate the solvent recovery process into the filing. Exemplification of problem Decisions to recycle solvents in-house or to downcycle as a fuel or as a feedstock to another industry must be made based on economic viability and lifecycle impact. The lifecycle impact is a new decision criteria for Phama Manufacturing business and the tools to support this analysis still needs to be embedded in the business. Expected Outcome of research. Improve the cost viability of using renewable solvents in the Pharma industry. Identify processes for the manufacture of renewable solvents as alternatives to the suite if solvents commonly used in the synthesis of API’s. Problem Statement 5 : Dehydration of alcohols Dehydration of common alcohols is difficult by distillation , an additional dehydration step is generally required such as pervaporation to achieve the required level of dryness to re-use the solvent in the process. Pervaporation is an expensive technology , the viability of the technology depends on the expected lifespan of the membranes. Expected Outcome of research Develop a cost viable technology for dehydration of alcohols.