Where is the drug industry in its pursuit of meaningful green metrics? We asked this and related questions to green chemistry expert Berkeley “Buzz” Cue, president of BWC Pharma Consulting and a founder of the American Chemical Society Green Chemistry Institute’s Pharmaceutical Roundtable.
PhM: First, a general question: How extensive and reliable are the so-called green metrics that the average drug manufacturer uses? Do manufacturers really have a good handle on the environmental impact of their processes and operations?
B.C.: The two most common green metrics used by drug manufacturers are mass intensity (MI), sometimes called process mass intensity, and E-Factor (E). Both relate the weight (mass) of the API produced to the weight (mass) of all solvents, reagents, process aids, and, in the case of mass intensity, process water used to manufacture the API. Neither metric tracks solvent/water/cleaning agents used to clean the equipment between runs and this can be a very large number.
E-Factor has been around longer than mass intensity and they are related by E = MI-1—E-factor measures waste generated while MI measured total resource utilization. Typical E-factors or MI’s are > 100 with the industry best E/MI around 10. That means the typical API process consumes > 100 kg of materials to produce 1 kg of API. There is clearly room for improvement.
The ACS Green Chemistry Institute Pharmaceutical Roundtable members have benchmarked their MI numbers for API processes in R&D twice. These results are located on their website. Bristol Myers Squibb, not a member of the roundtable, also tracks waste metrics—E-factor, I believe. To my knowledge, smaller pharma and biopharma companies do not generally track green metrics unless the metric is required to demonstrate compliance with environmental regulations. Every company is required to track these.
Another important pharma industry sector that is largely absent from green chemistry is the generic drug industry. A notable exception is Dr. Reddys, which has been very active in the green space for some time now. Since more than 75% of all new Rx’s in 2010 were written for generic drugs and with the massive patent expiration cliff it is important that the major players in the generic drug industry get on board.
One warning on metrics like MI and E. Both are quantitative metrics, e.g., how much. Neither speaks to the qualitative metrics, e.g. how safe. A process with an E-factor of 20, which uses benzene as a solvent, is not a green process.
PhM: In your opinion, does corporate management generally support activity to develop comprehensive green metrics? Is it lip service, or are good metrics perhaps only supported in instances in which there are clear cost or regulatory benefits?
B.C.: In my opinion, for many companies, those corporate officers who live in the “C-suite” for the most part are unaware that their companies are even involved in green chemistry—let alone that metrics to measure the greenness of their products and processes are being developed. We are seeing more information about a company’s green chemistry activities on their websites and in corporate annual reports, but this is just beginning and I encourage it to continue and increase.
For comparison, Rohm and Haas in their annual reports have published graphically how many of their manufacturing processes met each of the 12-green chemistry principles coined by Anastas and Warner. S.C. Johnson developed and published its GreenList, which rates the greenness of all of its products. For this it received a U.S. EPA Presidential Green Chemistry Challenge Award, one of the highest environmental scientific recognitions there is. I am told one pharmaceutical company may disclose the E-factors for each of its commercial API manufacturing processes in 2011. If this happens it will be a huge positive step. Nothing like peer pressure.
PhM: Process Mass Intensity (PMI) is a common metric for measuring the amount of material used in a given process. How extensively is PMI used by drug manufacturers, and what improvements has the industry made in the past few years in this regard?
B.C.: It is used extensively by ACS GCI Pharma Roundtable members. Two iterations of benchmarking data seem to show a decrease in overall PMI, but we’ll need a few more cycles of benchmarking to know for sure. It’s hard to be sure how accurate your straight line is with an n of 2.
PhM: How does PMI complement or overlap with other common green chemistry metrics, such as E-factor or Atom economy? Should they all be part of a manufacturer’s toolbox for each and every process?
B.C.: Yes, I believe the toolbox should have several metrics. Atom economy is an interesting metric but I do not think it is useful as a stand-alone metric. By the way, it is defined you can have a high AE (good) but still have a high E (bad) process.
PhM: Many such common metrics focus on mass, but is it at the expense of metrics that focus on energy? You mentioned work that J&J is doing to incorporate energy more into process selection, but is this a trend that will catch on more broadly?
B.C.: I am starting to see other companies cite energy comparisons across process options, so I would say the trend it encouraging.
PhM: You also noted that the iSustain tool is popular among academics, but is just gaining popularity within the drug industry. Why is this?
B.C.: First, it is a very new tool and it has been made available for free to academia, while industry must pay a subscription fee to use it. It is not clear yet whether pharma processes will be any greener using iSustain than they are by using E or MI, energy and other process optimization strategies like QbD and right first time manufacture. I think industry wants to see the tool in use for a while so it can prove its value before it adopts it widely.