Active pharmaceutical ingredient (APIs) manufacturing produces a lot of waste. And that’s not just a lot compared with, say, the organic food ingredients industry, that’s a lot compared with the oil refining sector.
In 1997 Roger Sheldon from Delft University of Technology in the Netherlands tallied the energy and material inputs required to make various chemicals with the amount of waste produced and assigned each process an Environmental (E) factor to rank their impact.
According to the research refined oil has an E-factor of 0.1; meaning 0.1kg or waste is produced per kilogram of product.
Most bulk chemicals have an E-factor of between 1 and 5, and fine chemicals, production of which requires more processing steps than bulk chemicals, have E-factors in the 5 to 50 range.
Active pharmaceuticals ingredients (API) have even higher E-factors with most being in the 50 to 100 range, largely due to the additional processing steps required and solvents used in their production.
Sheldon underlined the environmental impact API production has by pointing out that manufacturing final drug formulations often creates less waste than producing ingredients.
Green chemistry
The findings are often cited as a driver for drug industry interest in "green chemistry," which is an approach that aims to maximise the amount of raw material present in the final product and minimize energy usage and the amount of waste generated.
In a report published ahead of the CPhI WW tradeshow in Paris, Piramal COO Vijay Shah referenced the Sheldon E-factor figures in his prediction that the pharmaceutical market for green chemistry will be worth nearly $100bn by 2020.
"A report by Pike Research suggests that while the global chemical industry is expected to grow from $4 tr in 2011 to $5.3 tr by 2020, green chemistry represented a market opportunity of $2.8bn in 2011 with expected growth to $98.5bn by 2020."
Shah, who also forecast that green chemistry will save the industry $65bn by 2020, said: “Traditional organic chemical synthesis methods currently result in higher manufacturing costs due to the high E-factor, combined with the costs associated with disposing of waste produced.
“For an industry where the development of new drugs is expensive, time-consuming and has a falling rate of market approval, developing greener and more efficient methodologies for existing processes can help improve cost efficiencies.”
2020 vision: green or rose tinted?
But is this $100bn 2020 forecast just an optimistic projection designed for an API and drug industry audience at a tradeshow?
While many ingredient manufacturers have talked about green chemistry, to-date only a few have invested any serious money in such technology according to Mario Pagliaro from Italy’s National Research Council (CNR).
Pagliaro, whose green chemistry review was published late in 2013, called the $100bn forecast optimistic and told in-Pharmatechnologist.com “industry is reluctant to invest in any process innovation, unless it can guarantee a 10-fold return on investment in three years.”
He said industry has been slow to adopt green chemistry and in fact ingredient production is dirtier than ever, arguing that: “The 25−100 kg of waste produced per kilogram of API in 1992, at the end of the racemic era, is probably now more realistically 25−200 in the chiral era.”
“The huge academic interest [in green chemistry] is faced by limited interest of industry. Europe's leading scientific update organization has been trying to organize courses on green chemistry in this industry for the last decade,” Pagliaro said, adding that “Invariably, courses were cancelled due to lack of attendees.”
Racemic vs chiral
A racemic mixture has equal amounts of left- and right-handed enantiomers of a chiral molecule.
A chiral molecule is a type of molecule that has a non-superposable mirror image.
Left handed molecules are favoured in nature and drugmakers strive to produce them preferentially.
Industry Biocatalytic conversion?
One green chemistry area in which the drug and ingredients industry has shown some interest interest is biocatalysis, where enzymes replace metal catalysts, as evidenced by the fact that big pharma firms like Pfizer, Merck & Co and, more recently, GSK have teamed up specialists like Codexis.
This interest in biocatalyisis came about “because those return on investment and payback values were self-evident and clearly communicated” according to Pagliaro, who contrasted this with industry disinterest in nanocatalysis.
“Industry has not bought into heterogeneous nanocatalysis because 95% of those catalysts made in academic labs simply do not work when applied to real manufacturing processes” he said, adding that “This is now changing, although slowly.”
“In our recent paper in OPRD on the topic we included a section on how to communicate green chemistry to busy managers by talking their language, i.e. money.”
But, even despite these changes, Pagliaro still does not agree with Shah’s forecast telling us that: “The market for green chemistry solutions by 2020 will amount to less than $1bn.”
Green or green washing?
We asked David Santillo, a Greenpeace Research Fellow who works at Exeter University in the UK, for his take on the environmental impact of pharmaceutical manufacturing practices and the potential benefits green chemistry can offer the drug industry.
He told us: "The principles of Green Chemistry, if applied in their most rigorous form, have the potential to set industrial sectors on the pathway to more sustainable design, production and marketing of chemicals and finished products. One of the difficulties, however, is that there are many definitions of Green Chemistry, some of which are relatively weak and open to wide interpretation."
Santillo did not comment on the 2020 forecast, but did say that: "What matters in practice, whether for the pharmaceutical industry or other sectors, is that companies can demonstrate real progress in reducing or eliminating the uses of hazardous chemicals, increasing material and energy efficiency, improving the sustainability of feedstocks and minimizing waste in ways which stand up to independent scrutiny and verification.
He added that: "Without that level of auditing, and without a long-term commitment right from the product design stage onwards, 'green chemistry' is in danger of being 'green-wash'."