Working towards greener manufacturing

How committed is the pharmaceutical industry to green manufacturing?

The pharmaceutical industry has responded actively to the green chemistry challenge. For example, in 2005, the American Chemical Society Green Chemistry Institute (ACS GCI) established a pharmaceutical roundtable — a partnership between pharmaceutical corporations and the Institute dedicated to integrating green chemistry and green engineering into the global pharmaceutical industry. Today, nearly all major pharmaceutical research, development and manufacturing companies have joined this group. Furthermore, over the past 15 years, pharmaceutical companies have been awarded the US Environmental Protection Agency's (US EPA) Presidential Green Chemistry award multiple times. I think that shows a pretty good response to the green chemistry challenge by the industry.

(JORG GREUEL/GETTY IMAGES)

What steps should industry be taking to be green?

There are seven key recommendations that I would make to pharmaceutical companies that seek to reduce the environmental impact of their manufacturing processes:

1. Select solvents carefully: within our industry, 80% of the waste generated is solvent; careful solvent selection and minimisation is vital.

2. Minimise materials used: it is also important to minimise the use of all other materials used in manufacturing wherever possible.

3. Reduce energy consumption: this goes without saying and will be a natural consequence of reducing the use of materials and waste, and improving the efficiency of manufacturing processes.

4. Avoid highly toxic reagents and solvents: significant costs are generally associated with the containment or disposal of highly toxic materials. This is an additional cost that can be avoided with a green solvent or reagent.

5. Select an efficient catalyst: use catalytic rather than stoichiometric reagents and, in particular, wherever possible I would recommend the use biocatalysis as the preferred mode of catalysis, i.e. using nature's own chemical catalysts.

6. Recycle: Companies should aim to design a process that enables a high percentage of solvent to be recycled. The process must of course be cost-effective.

7. Use key performance indicators: At Pfizer, we assess process efficiency by looking at the E-factor, i.e. the kilos of waste per kilo of product; it is a very quick way of getting a good indication of the effectiveness of a process. The E-factor was first proposed by Professor Roger Sheldon and is calculated by dividing the total waste (kg) by the amount of product (kg) produced. The metric is very simple to understand and to use and it highlights the waste produced in the process as opposed to the reaction, thus helping those who try to fulfil one of the twelve principles of green chemistry (see sidebar) to avoid waste production.

Dr. Peter Dunn

When will revalidation be required?

Whether a process change requires revalidation or not depends on the timing of the change; if you're making the process change during phase II or III of clinical testing, then no validation is required. If you're making a major change, such as a change in synthetic route after the product has been filed and approved — what we call a second-generation filing — then you will need to both re-file the chemistry and revalidate.

Going forward, one way that validation can be minimised is if we use design space or Quality by Design (QbD) filings. However, some of the biggest environmental savings come from radical changes, i.e. second-generation filings. These changes are so radical, they are outside of the QbD scope.

In which areas of manufacturing can the pharmaceutical industry make the most significant energy savings?

In small molecule chemistry one must understand that energy use actually has a much smaller CO₂ impact than the amount of solvent used. In contrast, in the manufacture of large molecules, such as therapeutic proteins, energy use is much higher and much more critical. Therefore, I personally believe that the biggest opportunity to save energy going forward will be to improve large molecule synthesis. I think this is the single biggest area where energy savings can be made.

What steps has Pfizer taken to make manufacturing more energy efficient and what have been the main benefits?

Our basic strategy is to roll our green chemistry programme into all aspects of Pfizer work, from making the first few milligrams in the laboratory to making tons of medicines in manufacturing. Very different strategies are of course needed at each phase of the process. A great example of where we have benefited significantly from efficient energy use can be seen in the manufacture of our second biggest volume drug, pregabalin. The new enzymatic process that we have implemented uses 83% less energy than the original launch process. This change has equated to an environmental saving of more than 410 000 metric tons of CO2 emissions, that is the equivalent of taking 69 000 US cars (120 000 European cars) off the road for one year.

We have experienced similar savings with some of our other high-volume products, e.g. atorvastatin, celecoxib, sildenafil and sertraline. Sildenafil, celecoxib and pregabalin each have E-factors below 10, compared with an industry average of 25–200.

Overall, we have taken a two-pronged approach to our green chemistry programme: 1) tackle large volume product processes first to realise significant benefits and, 2) tackle new processes so that all new drugs will be green.

Between 2000 and 2007, Pfizer reduced its greenhouse gas emissions from energy use by 20%. Between 2008 and 2012 the goal is a further 20% reduction.

Personally, I would like to see the amount of waste produced in manufacturing per kg of active medicine reduced by half compared with industry norms of 10 years ago. I certainly believe this is achievable within the next 10–20 years.

How do you think Pfizer's achievements in green manufacturing compare with those of its peers?

We have won the US EPA Presidential green chemistry award for sertraline and we've also won a number of European awards for pregabalin and sildenafil. In 2009, we won the BCE environmental leadership award in the UK for our green chemistry programme. So I think we do pretty well.

In general, our peers in industry do many of the things that we do in our green chemistry programme. However, I think there are three areas where we are differentiated from our peers: 1) we've been very successful in helping our medicinal chemistry groups to understand and embrace green chemistry; 2) our approach to second-generation chemistry is really quite unusual in this industry because, once a process is filed, most companies at that point tend to sit back and see the regulatory hurdle as too great to re-file a more efficient, cheaper and greener synthesis. In contrast, at Pfizer, we pursue green chemistry improvements throughout the lifetime of the product. I really think it makes basic environmental sense to do this. We put a major effort into having the very best technology for the launch of a product but over a 15–20 year period, there are going to be new technologies that become available; why wouldn't you take advantage of those new technologies? So I think that is a difference; we are not frightened to re-file chemistry and that is unusual in this industry; 3) our outreach programme is very good, e.g. Pfizer sponsors the development of a green chemistry training programme for schools and this is now being used by more than 200 schools, primarily in the US.

From an operations perspective, our manufacturing facilities have substantially reduced energy consumption and waste through the aforementioned efforts. The US EPA Climate Leaders, The Carbon Disclosure Project, and a number of international agencies have recognised Pfizer for these and other sustainability efforts.

How will the industry further improve its processes in the future?

There has been a revolution in biocatalysis and we've not yet reached the end of it. The biocatalysis revolution has been mainly driven by two technology breakthroughs: 1) the ability to screen hundreds of enzymes quickly and on a small scale to identify the lead enzyme rapidly and, 2) forced enzyme evolution by changing the DNA that makes the protein.

In my opinion, biocatalysis has an even greater role to play in pharmaceutical manufacturing; I think there will be more innovation but I also think it's under-utilised by the industry. Just to give a very specific example of where it could be used more — a number of precious metals, such as rhodium and iridium, are very scarce but they are very useful for performing chemical reactions. If some of those reactions can be performed using biocatalysis, which is a fully sustainable methodology, that would be very good for the environment and for business; companies will not be subjected to the big price changes that accompany the use of these precious metals and it is also good for the environment.

Furthermore, I personally believe that the large molecule area is ripe for improvement. The science in this area is developing incredibly quickly at the moment and I'm sure it will yield huge improvements.

We are on a journey and we'll be continuing on that journey over the years ahead.

To read this interview in full, please go to www.pharmtech.com/dunn

Reference

1. P.T. Anastas & J.C. Warner. Green Chemistry: Theory and Practice (Oxford University Press: New York, USA, 1998) p.30.

Sidebar: Twelve principles of green chemistry ¹

1. Prevention

2. Atom economy

3. Less hazardous chemical syntheses

4. Designing safer chemicals

5. Safer solvents and auxiliaries

6. Design for energy efficiency

7. Use of renewable feedstocks

8. Reduce derivatives

9. Catalysis

10. Design for degradation

11. Real-time analysis for pollution prevention

12 Inherently safer chemistry for accident prevention