Professional Documents
Culture Documents
FOR A
COST EFFICIENT,SUSTAINABLE
&
GREEN MANUFACTURING
Production Scale
Industries E-factor
(Tons per Year)
Source: R.A.Sheldon, Chem & Ind, 1992, 903 ; 1997, 12, IGCW 2011 2
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
Renewable
sources
Biodegradable
Fermentation
Nature’s
Catalysts
Whole Cells
Biocatalysis (Isolated Enzymes)
4
There are several benefits of using enzymes over
chemical reaction to produce APIs & Fine Chemicals
▪ Improved Productivity
− Higher Yields
− Shortened synthesis route
▪ Greater Selectivity
− High level of Stereo-, regio-, and
chemo-selectivity
▪ Simplified work-streams
− Simplified processing and purification
− Fewer byproducts, reducing impurities
5
Biocatalysis reactions adhere to green chemistry
principles
6. Performed at ambient
7. Renewable
conditions
6
Biocatalysis gets its principles from several
disciplines and applies to a number of industries
7
Based on the reaction types, enzymes are grouped into
several classes
Hydrolases are the most used enzyme class in biotransformation's followed
by oxidoreductases
Some key examples of enzyme classes and their applications
EC
Selected Reactions Enzyme Class Key Applications
No.
▪ C=O and C=C reduction
▪ Atorvastatin
▪ Reductive amination of C=O
Oxidoreductase 1 Intermediate
▪ Oxidation of C-H,C=C, C-N and C-O
▪ Montelukast
▪ Cofactor reduction/oxidation
▪ Cyclodextrin from
▪ Transfer of functional groups such as
Starch
amino,Acyl,phosphoryl, methyl, glycosyl, nitro Transferase 2
▪ Sitagliptin
& sulphur groups
▪ Diltiazem
▪ Hydrolysis of esters, amides, lactones, lactams, Intermediate
Hydrolase 3
epoxides, nitriles & reverse reactions ▪ Resolution of rac.
phenylethylamine
▪ Addition of small molecules to double bonds Lyase ▪ L-Malic acid
4
such as C=C, C=N and C=O (synthase) ▪ Statin Intermediate
▪ Isomerisations such as racemizations,
Isomerase 5 ▪ HFCS from glucose
epimerizations & rearrangement reactions
Source: 8
Biocatalysis is a proven technology for some
prominent active pharmaceutical ingredients synthesis
9
Pregabalin Biocatalytic Route
Novozymes
Lipase
Lipozyme TL
100 L
Inefficient
Resolution at
rac.pregabalin
stage
10
Flow Chart of Pregabalin Process……..
Racemisation
Pregabalin
Recycling
(R)-Diester (R)-Diester
(S)-Monoester
(S)-Diester (S)-Monoester Water
Water
Water Water Enzyme
Enzyme
Enzyme Enzyme
Biotreatment
Key Advantages of Biocatalytic Route
▪ Starting material reduction by 800 Mt
▪ Low protein Loading(0.8%) (cumulative)
▪ Resolution at first stage-wrong isomer can be recycled ▪ Drastic reduction in solvent usage
▪ High throughput ▪ Mandelic acid usage-500Mt eliminated
▪ All reactions conducted in water (Cumulative)
▪ E-factor improved from 86 to 17 ▪ Energy usage reduced by 83%
11
Pregabalin Chemoenzymatic route used >5x less inputs than
Chemical Route
Raw Material Inputs for 1000kg API Output
Inputs Chemical Route Chemoenzymatic
Reduction
Route
Kg Kg
Enzyme 0 574
So Far… the first and second wave The third wave: future outlook
Variant Smarter
Directed
Selection or Libraries of
Evolution
First wave screening Enzymes
▪ living cells applied to useful chemical
transformations
Advanced and Emerging Technologies
Second Wave
▪ DNA technology & Protein engineering
▪ Initial protein engineering techniques ▪ Bioinformatics
extended range of enzymes to allow ▪ Molecular Modelling studies-Docking of
synthesis of unusual synthetic substrate with proteins
intermediates ▪ Reaction engineering & process intensification
using biocatalysts
▪ High throughput enzyme screening
▪ Enzyme screening kits
13
The way forward……….
▪ Biocatalysis likely to be one of the most important tools for Fine Chemicals & Pharma for
− It is likely that biocatalysts would be available for all types of transformations in future
▪ More and more collaborations between fine chemicals/pharmaceutical companies & Enzyme
▪ Biocatalysis companies will likely evolve into companies providing end to end solutions from
… And Novozymes is adequately positioned and aggressively poised to help the industry
in this journey
14