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
Timeline and Process – Year 1
Timeline Process
RFP
27 Jan 2010
Kick-Off
Submit by
Proposal
15 Mar 2010
Submission
Proposal
Complete by Review
May 2010
Award
Jun 2010 Grants
2nd
2H 2010
RFP
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
Pharmaceutical manufacture typically has > 100 kg raw
material consumption/kg product
• Disposal costs
• Infrastructure costs
• Energy costs
IN (kg)
Out (kg)
Raw Material 1
Raw Material 2 Product
PROCESS
Raw Material 3
Raw Material 4
Raw Material 5 By-products
£
LOSSES Reject Waste
££
Re-cycle Down-cycle
Re-use Re-sale
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
• Sustainable Manufacturing Problem Areas
– Chemical Transformations
– Biotransformations 1st RFP, 27 January 2010
– 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
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 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 Aspirational Reactions - not
which need improvements commonly used, need
solutions
Amide formation avoiding poor atom C–H activation of aromatics (cross coupling
economy reagents 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 Asymmetric hydrogenation of
reagents unfunctionalised olefins/enamines/imines
Oxidation/Epoxidation methods without the New greener fluorination methods
use of chlorinated solvents
Safer and more environmentally friendly N-Centred chemistry avoiding azides,
Mitsunobu reactions hydrazine etc
Chemical and Bio Transformations (2)
Ar Ar
CO2 Me
OH
N O N + Metal & Quench
LiAlH4 Wastes
R R
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
1. 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
J. Am. Chem. Soc., 2003, 125 (28), pp 8456–8457 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
Bend Research Web Site
energy/mass perspective?
Facilities and Supply Chain
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?
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
Solvent Selection and Optimization
14
Problem 1: Intelligent solvent selection
% Usage (top 10
12 with sustainability as objective
10
1. Commonly used solvents are still mostly
solvents)
8
6
4 petroleum derived
2 2. Heavy use of chlorinated solvents
0
3. Solvent selection performed through
screening rather than prediction
4. 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
H O
Problem 2: Dipolar Aprotic Replacements
1. Dipolar aprotic solvents synthetically N
useful N O
2. Most dipolar aprotics teratogenic (or H H
exhibit another type of toxicity) H
3. Not always readily recoverable – high O
N N
boiling, water miscible
4. Substitutes needed
Unit 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
Needs
1. 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 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 Technology
• Most pharmaceutical processing is performed in
batch reactors
• Batch reactors can be limiting for chemical
transformations B
– Highly exothermic reactions may be unsafe
– A relatively high amount of solvent is required simply
H
to agitate the contents sufficiently
– Selectivity suffers from long quench times /cooling W
D C
rates
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 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
Needs
1. 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 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
Needs
1. Assessment of solvent recovery
economics for an industrial cluster FEED PRODUCT
REACT SEP
versus an individual mfg site
2. Energy efficient alternatives to thermal
methods for solvent recovery RECYCLE
3. Assessment of stream recycle
economics for our industry
Waste 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
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
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
• Both soft copy and hard copy of the proposal are required.
• Send soft copy to: GSK-EDB-GSM@gsk.com
• Send hard copy to:
Ye Weiping
GSK-Singapore Sustainability Partnership
Technical Development
GlaxoSmithKline
1 Pioneer Sector 1
Singapore 628413
• Timeline: before 15 March 2010
Do more,
feel better,
live longer