GreenGreen Manufacturing Problems Manufacturing Problems For Pharmaceutical ManufactureFor Pharmaceutical Manufacture

27 January 2010

BackgroundBackground

• 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

Timeline and Process – Year 1Timeline and Process – Year 1

Timeline Process

27 Jan 2010

Submit by15 Mar 2010

Complete byMay 2010

Jun 2010

2H 2010

RFPKick-Off

Proposal Submission

Proposal Review

AwardGrants

2nd RFP

Proposal Review CriteriaProposal 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 ProblemsThe Problems

27 January 2010

Improving Manufacturing Sustainability: Improving Manufacturing Sustainability: An OverviewAn Overview

IN (kg)

ProductPROCESSPROCESS

Raw Material 1

Raw Material 5

Raw Material 2

Raw Material 4

Raw Material 3

Out (kg)

LOSSES WasteReject

By-productsBy-products

Re-cycleRe-cycle

Re-useRe-use

Down-cycleDown-cycle

Re-saleRe-sale

££

££££

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

•Disposal costs•Infrastructure costs•Energy costs

Improving Manufacturing Sustainability: An Improving Manufacturing Sustainability: An Overview (2)Overview (2)

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

Problem Statement Emphasis

Breakdown of Sustainable Manufacturing Breakdown of Sustainable Manufacturing Areas of FocusAreas of Focus• 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

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

Chemical and Bio TransformationsChemical 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

Commonly used reactions which need improvements

Aspirational Reactions - not commonly used, need solutions

Amide formation avoiding poor atom economy reagents

C–H activation of aromatics (cross coupling reactions avoiding the preparation of haloaromatics)

OH activation for nucleophilic substitution Aldehyde or ketone + NH3 + X to give chiral amine

Reduction of amides without hydride reagents

Asymmetric hydrogenation of unfunctionalised olefins/enamines/imines

Oxidation/Epoxidation methods without the use of chlorinated solvents

New greener fluorination methods

Safer and more environmentally friendly Mitsunobu reactions

N-Centred chemistry avoiding azides, hydrazine etc

Chemical and Bio Transformations (2)Chemical and Bio Transformations (2)

N

ArCO2Me

O

R

N

Ar

R

OH

LiAlH4

+ Metal & Quench Wastes

Some specific biotransformation challenges

•Ester to amide conversion•Nitrile to primary amine•Chiral epoxidation of alkenes•N-alkylation via activated alcoholMitsunobo Reaction

Hydride Reduction

OH activation

Physical TransformationsPhysical Transformations

J. Am. Chem. Soc., 2003, 125 (28), pp 8456–8457

Problem 1 - Dematerialization1. The manufacture of active ingredients

typically represents > 70% of the total carbon footprint of an oral tablet

2. If through enhanced exposure the amount of active ingredient could be reduced, the reduction in total carbon footprint would be nearly proportional

3. Bioenhancement or targeted deliver can help accomplish this objective

Problem 2: Improve energy efficiency of particle forming and formulation operations

1. Energy efficient mfg. methods are desired to produce medicines

2. 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 ChainFacilities and Supply ChainProblem 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?

Problem 2: Global Supply ChainsActive 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

Solvent Selection and OptimizationSolvent Selection and Optimization

N O

H

N

O

N O

HHH

N

Problem 1: Intelligent solvent selection with sustainability as objective

1. Commonly used solvents are still mostly petroleum derived

2. Heavy use of chlorinated solvents3. Solvent selection performed through

screening rather than prediction4. Little use of alternative solvents (e.g., ionic

solvents)5. Need acceptable halogen replacements,

knowledge of when ionics make sense, intelligent selection of solvents to meet sustainability needs

Problem 2: Dipolar Aprotic Replacements1. Dipolar aprotic solvents synthetically

useful2. Most dipolar aprotics teratogenic (or

exhibit another type of toxicity)3. Not always readily recoverable – high

boiling, water miscible4. Substitutes needed

Unit Operation Selection and OptimizationUnit Operation Selection and Optimization

• 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

Needs1. Energy efficient alternatives to distillation for removal of solvent from product

or transfer of product from one solvent phase to another

2. Process intensification of drying to reduce energy input

3. Method for separating trace organics from high volume nitrogen streams without using activated carbon or extreme low temperatures

4. Evaluation of methods for immobilizing frequently used homogeneous catalysts; learnings from bulk chemical catalysis that can be applied to pharmaceutical mfg

Lifecycle AnalysisLifecycle Analysis

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?

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?

Equipment and TechnologyEquipment and Technology• 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

W

D

H

C

B

T

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

Controls Selection and OptimizationControls Selection and Optimization• 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

Needs1. Advanced control algorithms for common

industry control tasks which can pass regulatory scrutiny (e.g., fully validated)

• Drying endpoint• Distillation endpoint• Reaction endpoint• Crystallization

2. Data reduction techniques that address common sources of noise for instruments

Recovery and Reuse IntegrationRecovery and Reuse Integration• 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

REACT SEPPRODUCTFEED

RECYCLE

Needs1. Assessment of solvent recovery

economics for an industrial cluster versus an individual mfg site

2. Energy efficient alternatives to thermal methods for solvent recovery

3. Assessment of stream recycle economics for our industry

Waste Treatment and MinimizationWaste Treatment and Minimization

• 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

NeedsEvaluation 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

SummarySummary

• 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

CloseClose

• 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….

SubmissionSubmission

• Both soft 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

Ye WeipingGSK-Singapore Sustainability PartnershipTechnical DevelopmentGlaxoSmithKline1 Pioneer Sector 1Singapore 628413

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