Green Manufacturing Problems For Pharmaceutical Manufacture 27 January 2010
Background • The funds committed by GSK and EDB towards green manufacturing (~33 million) will be used to fund green manufacturing research • Through the completion of research and development projects applied to sustainable manufacturing problems, we will increase the green manufacturing skill set in Singapore. • The program will last approximately 10 total years • GSK’s role is to serve as strong industrial sponsors, partnering with EDB to ensure goals of funding are met • Supply industry problems • Organize RFPs and assist in review of proposals • Provide contacts to assist principal investigators – guidance on problems, potentially materials, exposure of trainees to industry
Proposal Review Criteria Alignment with the strategic objectives of the Fund Strengthening the capability and training a talent pool in Singapore to meet the sustainable manufacturing challenges that local industries will face Further enhance the working relationship between universities, institutes and local companies through interdisciplinary research into sustainability Enabling Singapore to become a leader in sustainability research for pharmaceuticals and fine chemicals. Impact of the proposal to sustainable manufacturing science Potential for eventual industrialization of research outputs Originality / Novelty of Proposal
The Problems 27 January 2010
Improving Manufacturing Sustainability: An Overview IN (kg) Out (kg) Raw Material 1 PROCESS Raw Material 2 Product Raw Material 3 Raw Material 4 Raw Material 5 By-products £ LOSSES Waste Reject ££ Re-cycle Re-use Down-cycle Re-sale • Pharmaceutical manufacture typically has > 100 kg raw material consumption/kg product • Disposal costs • Infrastructure costs • Energy costs
Improving Manufacturing Sustainability: An Overview (2) Problem Statement Emphasis • Basic principles of Green Manufacturing • Maximize resource efficiency (i.e., energy and mass) • Eliminate and minimize EHS hazards • Design systems using life cycle analysis thinking
Breakdown of Sustainable Manufacturing Areas of Focus 1st RFP, 27 January 2010 GSK staff have prepared problem statements under each of these problem areas. These problem statements are a ‘snapshot’ and will continue to be developed for future proposal calls • Sustainable Manufacturing Problem Areas • Chemical Transformations • Biotransformations • Physical Transformations • Solvent Selection and Optimization • Unit Operation Selection and Optimization • Equipment and Technology Selection • Controls Selection and Optimization • Recovery and Reuse Integration • Waste Treatment and Minimization • Lifecycle Analysis • Facilities and Supply Chain
Chemical and Bio Transformations • Key green chemistry research areas - a perspective from pharmaceutical manufacturers • David J. C. Constablea, Peter J. Dunn*b, John D. Haylerc, Guy R. Humphreyd, Johnnie L. Leazer, Jr.d, Russell J. Lindermane, Kurt Lorenzf, Julie Manleyg, Bruce A. Pearlmanh, Andrew Wellsi, Aleksey Zaksh and Tony Y. Zhangf • Green Chemistry, Issue 7, No. 5, pg 411
Chemical and Bio Transformations (2) Hydride Reduction OH activation • Some specific biotransformation challenges • Ester to amide conversion • Nitrile to primary amine • Chiral epoxidation of alkenes • N-alkylation via activated alcohol Mitsunobo Reaction
Physical Transformations Problem 1 - Dematerialization The manufacture of active ingredients typically represents > 70% of the total carbon footprint of an oral tablet If through enhanced exposure the amount of active ingredient could be reduced, the reduction in total carbon footprint would be nearly proportional Bioenhancement or targeted deliver can help accomplish this objective J. Am. Chem. Soc., 2003, 125 (28), pp 8456–8457 Problem 2: Improve energy efficiency of particle forming and formulation operations Energy efficient mfg. methods are desired to produce medicines Ways of minimizing the energy of key unit operations (crystallization, particle size reduction, granulation, drying) are desired (e.g., what is optimum particle fomation and formulation method from an energy/mass perspective? Bend Research Web Site
Facilities and Supply Chain • Problem 2: Global Supply Chains • Active ingredients and tablets are often shipped to several countries for manufacture / packaging prior to getting to patients • What is the total carbon footprint of the supply chain in relation to manufacturing processes? What is the time impact? Full complexity? • Needed: optimization of current pharma supply chains Problem 1: Greener facilities • Only 10-30% of the total energy associated with a facility ends up going into a product • Function of • facility design • energy use option • What does facility of the future look like?
Solvent Selection and Optimization Problem 1: Intelligent solvent selection with sustainability as objective Commonly used solvents are still mostly petroleum derived Heavy use of chlorinated solvents Solvent selection performed through screening rather than prediction Little use of alternative solvents (e.g., ionic solvents) Need acceptable halogen replacements, knowledge of when ionics make sense, intelligent selection of solvents to meet sustainability needs Problem 2: Dipolar Aprotic Replacements Dipolar aprotic solvents synthetically useful Most dipolar aprotics teratogenic (or exhibit another type of toxicity) Not always readily recoverable – high boiling, water miscible Substitutes needed
Unit Operation Selection and Optimization Needs Energy efficient alternatives to distillation for removal of solvent from product or transfer of product from one solvent phase to another Process intensification of drying to reduce energy input Method for separating trace organics from high volume nitrogen streams without using activated carbon or extreme low temperatures Evaluation of methods for immobilizing frequently used homogeneous catalysts; learnings from bulk chemical catalysis that can be applied to pharmaceutical mfg The most energy intensive unit operations in pharmaceutical manufacturing are distillation and drying Inerting is one of the most frequent unit operations used, and contributes significantly to VoC emission to atmosphere Crystallization is a critical unit operation to control and deliver the correct physical attributes for active ingredients Catalysts are frequently homogeneous and are almost always used only once and disposed of
Lifecycle Analysis Inhaled Device Problem Products like Advair for asthma or other respiratory conditions, often use complex devices to deliver microgram quantity doses Each device is typically disposed of after use What is the footprint of the device versus the drug? Can a device be made that is inherently recycleable while meeting patient safety requirements? Blister Pack Problem • Many tablets are packaged using blister packs which are constructed of aluminum and polyvinyl chloride • The blister pack is not made from a sustainable source, and adds an additional carbon burden to our products • Are there alternative but equally performing materials which have a better ecological profile?
Equipment and Technology • Needs • What can continuous reaction modes offer pharmaceutical manufacture? • New chemistry? • Improved volumetric efficiency of known chemistry? • Improved selectivity of known chemistry? • What is the true cost savings of having a continuous process • Most pharmaceutical processing is performed in batch reactors • Batch reactors can be limiting for chemical transformations • Highly exothermic reactions may be unsafe • A relatively high amount of solvent is required simply to agitate the contents sufficiently • Selectivity suffers from long quench times /cooling rates
Controls Selection and Optimization • Needs • Advanced control algorithms for common industry control tasks which can pass regulatory scrutiny (e.g., fully validated) • Drying endpoint • Distillation endpoint • Reaction endpoint • Crystallization • Data reduction techniques that address common sources of noise for instruments • Most pharmaceutical manufacturing control schemes are ‘simple’ with a high manual component • Control of key attributes (e.g., purity) through sampling, offline analysis, report back result, manually move control system to next step in recipe • This results in processes with significant wait and hold periods, which consumes facility time and thus energy • In addition, real-time alerts to operations staff not available • As a result of US FDA’s Quality by Design and Process Analytical Technologies Initiatives, companies have invested heavily in on-line instrumentation • Benefits have yet to be fully realized
Recovery and Reuse Integration • Needs • Assessment of solvent recovery economics for an industrial cluster versus an individual mfg site • Energy efficient alternatives to thermal methods for solvent recovery • Assessment of stream recycle economics for our industry • Solvents consist of 85% of the mass used in active ingredient manufacture • Pharmaceuticals recycle less streams / solvents back to processes than other industries (e.g., bulk chemicals or petrochemicals) Causes • Production volumes generally low, wide variety of products; recovery cost can often be high • Regulatory and product purity concerns associated with recycle
Waste Treatment and Minimization Needs Evaluation of treatment alternatives for high COD waste streams – what is best from a sustainability perspective (e.g., concentration and burning, dilution and biotreatment, etc..) Separation solutions (e.g., membranes) for ketone and alcohol laden wastes for either solvent removal or waste concentration Common solvents in aqueous wastes include simple alcohols and ketones Integrated, efficient treatment solutions for high inorganic, high organic wastes Pharmaceuticals have relatively small volume individual waste streams which are often too concentrated (e.g., high COD) to treat biologically but too dilute to incinerate cost effectively Many of our compounds are environmentally refractory- v. slow degradation in the environment Common solvents in aqueous wastes include simple alcohols and ketones In addition to organics, pharmaceutical wastes often have high inorganic loads
Summary • An example of common pharmaceutical problems has been provided. The first RFP will be for chemical, bio, and physical transformations • There are many more problems! This list will change. We are open to additional views • Many solutions will likely benefit from multidisciplinary research, e.g. • Can a continuous reactor affect the way a transformation is discovered? • How are solvents selected to meet both an ecological and synthetic objective? • How do bio-enhanced formulations perform in animal models? • We look forward to collaborating with you and to your contribution in making Singapore a leader in green manufacturing
Close • Please contact us should you have any questions or problems during the proposal process AND • We ask for your cooperation and patience. This effort is one of the first of its kind for GSK. We are learning….
Submission • Ye Weiping • GSK-Singapore Sustainability Partnership • Technical Development • GlaxoSmithKline • 1 Pioneer Sector 1 • Singapore 628413 • Bothsoft copy and hard copy of the proposal are required. • Send soft copy to: GSK-EDB-GSM@gsk.com • Send hard copy to: • Timeline: before 15 March 2010
Do more, feel better, live longer