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.
PhM: LIMS vendors are beginning to incorporate “green tools” (e.g., that aid in selecting benign solvents, etc.) into their products. What possibility does this open up?
B.C.: Anything that can be done to make adoption and use of green chemistry metrics user-friendlier is sure to enhance and expand their use. Moreover, by providing a pick list of green options as alternatives to a non/less green entry, the LIMS user will be assured of a greener outcome. This is why the ACS GCIPR is discussing with LIMS providers of electronic notebooks this possibility. I can see a tool like iSustain being incorporated eventually as well.
PhM: Where do biologics manufacturers stand, and do they really need a completely different set of metrics than traditional chemical drug manufacturers?
B.C.: Biological drugs (vaccines, proteins and monoclonal antibodies) have not advanced as far as small molecule drugs in establishing green metrics—water usage and energy usage are two obvious ones. A paper appeared in 2010, which represents the first attempt to do this. (See Ho, McLaughlin, Cue and Dunn, Green Chemistry, 2010, 12, 755-766.)
PhM: Where are manufacturers in term of considering the environmental impact of a product’s entire life cycle? Isn’t life cycle analysis really the key to gaining a complete picture of how a product impacts the environment?
B.C.: Yes, it is. In fact, a life cycle comparison among sertraline process options is one of the tools that led Pfizer to select the improvements that won a Presidential Green Chemistry Challenge Award in 2002. But process chemists who dominate the pharma industry are not generally well versed in LCA. The National Academies’ 2005 study of challenges to sustainability in the chemical industry highlighted LCA as an underutilized tool in part because chemists are not trained to use it as part of their academic training. Chemical engineers tend to be much better trained in the use of LCA, but are not involved early enough in API process design to have the kind of impact they could have. By the time an engineer sees a process, API for toxicology studies, clinical studies and ICH stability studies has been made, and changes to the process now could trip the ICH impurity level alarms.
PhM: Finally, how does the patient fit into the equation, especially in regards to compounds that enter the environment as waste? Do manufacturers need to consider, for example, bioavailability as a green metric?
B.C.: This is a complicated question and my answer represents at best an informed opinion of a pharmaceutical green chemist. I would recommend you seek comment from environmental toxicologists familiar with the pharmaceutical industry as well. Most drugs enter the environment by patient use and excretion. A smaller amount enters because patients or hospitals discard unwanted drugs into the wastewater treatment systems. State level take back programs are becoming more common as a way to reduce this source of environmental contamination, but it is early days.
First, detection of ppm, ppb or even ppt levels of drugs in the environment do not necessarily represent a health risk for patients or the public. The pharmaceutical industry studies the toxicity of its products far more extensively than any other industrial sector and perhaps as many as half of the drugs that start out in R&D are dropped from development and never reach the market due to toxicology issues.
But there is a growing concern among some environmental toxicologists that exposing developing fetuses to low levels of drug during certain “windows” of development could be lead to problems. And while individual drugs are studied extensively, cocktails of multiple drugs have not been studied to my knowledge.
The responsibility for the design of the API is an R&D responsibility. API selection happens in the drug discovery part of R&D and there are no design tools that would be the equivalent of the Lipinski Rule of Five to guide the medicinal chemist to select molecules that will be benign to the environment. The creation of such tools represents an opportunity for innovative R&D. In fact, green chemistry is uncovering many opportunities to invent tools for the industrial scientists to use to create greener outcomes.
Medicinal chemists do use tools like the Rule of Five to design and select molecules that are orally active, yet 40% of the drugs being developed are poorly soluble, BCS Class 2 molecules. These drugs can benefit from the use of bioavailability enhancing formulations like spray dry dispersion or hot melt extrusion, for example. Increasing bioavailability can lower the amount of API a patient needs to get a desired biological response, reducing the amount of API and metabolites that enter the environment. Lower API usage also lowers API synthesis waste-a secondary environmental benefit.
The holy grail of green drug design is a molecule that is stable during manufacture, storage and patient use, but then degrades rapidly to innocuous products when it enters the environment. The barrier to achieving this is that factors that degrade drugs during manufacture, use and storage—heat, light, oxygen, enzymes, acid or base hydrolysis—are the same processes that cause degradation in the environment.
We have not yet invented the magic switch that, depending on whether it is on or off, renders a drug inert or susceptible to these processes. Perhaps a drug delivery platform will be that switch. Klaus Kummerer states that possibly 25% of the thousands of drugs that are sold are rapidly degraded when they enter the environment and questions that if 25% can be made this way accidentally why can’t more be made this way intentionally. This is a good question and a challenge for pharmaceutical science.
But if every molecule entering R&D tomorrow were benign by design, with only 25 or so new molecular entities (NME’s) approved each year, thousands of drugs already on the market were not designed with green criteria in mind and represent a different and new challenge.
Biological drugs, one of the fastest growing classes of medicinal agents, are reported not to persist in the environment, so this is an area where their credentials are greener than small molecules.
Finally, much more research is needed into treating waste water to destroy these low levels of drugs as well as into water purification to remove them from drinking water.
A combination of increasing oral bioavailability, designing drugs that better degrade, prescription take back programs, waste water treatment and drinking water purification seems like a recipe for success.