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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

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Green manufacturing problems for pharmaceutical manufacture l.jpg

Green Manufacturing Problems For Pharmaceutical Manufacture

27 January 2010

Background l.jpg

  • 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

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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

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The Problems

27 January 2010

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Improving Manufacturing Sustainability: An Overview

IN (kg)

Out (kg)

Raw Material 1


Raw Material 2


Raw Material 3

Raw Material 4

Raw Material 5











  • Pharmaceutical manufacture typically has > 100 kg raw material consumption/kg product

    • Disposal costs

    • Infrastructure costs

    • Energy costs

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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

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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

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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

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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

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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

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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?

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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

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Unit Operation Selection and Optimization


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

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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?

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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

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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

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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)


    • Production volumes generally low, wide variety of products; recovery cost can often be high

    • Regulatory and product purity concerns associated with recycle

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Waste Treatment and Minimization


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

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  • 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

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  • 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….

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  • 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: [email protected]

  • Send hard copy to:

  • Timeline: before 15 March 2010

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