June 15, 2009 by David Taylor


The research pharmaceutical industry is approaching environmental sustainability in two ways. Firstly by minimising its environmental footprint by increasing the efficiency with which it uses resources across all aspects of its business activities. Secondly, by reducing the environmental pressure exerted by that footprint by moving towards the use of less hazardous materials where that is possible. The objective is to minimise environmental impact whilst maintaining patient benefit.

A ‘sustainable’ business needs to satisfy three criteria: it must be economically viable, socially justified and environmentally acceptable. This article describes how the pharmaceutical industry works and how the research based companies are adopting a holistic approach to continuously reducing their environmental footprint whilst continuing to deliver benefit to the patient.

Sustainability is now the stated aim of most of the research companies. The environmental component of sustainability relates not only to manufacturing but also to product sales and distribution. Where possible, sustainability also applies to product design. Figure 1 (Clark and Summerton, 2008) shows the challenges and opportunities facing the industry. Rapid progress is now being made in most of these areas.

A costly business with high risks

The pharmaceutical industry is a very unusual one for two reasons. Firstly, the costs of new product development are extremely high when compared to the cost of manufacture. Secondly, new innovations tend to add to the overall availability of medicines rather than replacing existing products. As a consequence the industry has developed in two separate ways. A high risk/high profit innovation sector and a low risk/low profit generic supply sector.

The vast majority of new pharmaceuticals are thus developed by a small number of well known research pharmaceutical companies such as AstraZeneca and Pfizer. The bulk of existing medicinal products is supplied by a wide range of generic manufacturers, whose names are largely unknown to the public. This means that, at any point in time, the innovating research pharmaceutical companies are selling only around 10-20 percent by volume of the medicines being taken by patients. The remainder is produced by generic companies.

Product innovation is a very high risk business. It costs a very large amount of money, $500m to $800m, to take a new compound from the laboratory bench to the patient. Success rates are also extremely low. Only one or two out of every 100 compounds entering development results in a marketable product. This means that a large proportion of the research into new medicines does not lead to any subsequent income. The innovating company does have exclusive rights to sell a new product until the patent protection expires in order to recover its costs and generate profits to fund further investment. The development process is lengthy however and it can take 10-12 years between the granting of the patent and the launching the product. This leaves only 8-10 years of exclusive sales.

Although a successful pharmaceutical will eventually become well known to all doctors, this will take several years. As a consequence, research pharmaceutical companies must also engage in a large amount of marketing to ensure that the value of the new drug becomes widely known as fast as possible.

When the patent protection of a successful new pharmaceutical expires, its manufacture and sale is usually rapidly taken over by one of the many ‘generic’ pharmaceutical companies. This is a very low risk activity. In general these companies are not involved in new product development. Furthermore, since the drug is already a successful and well known product at the end of its patent life, sales and marketing needs are much less. Manufacturing costs are relatively small and thus the price of a new pharmaceutical falls dramatically after patent expiry.

This means that to survive, the research based companies need to constantly renew their product ranges. There is increasing evidence, however, that the rate of innovation is declining, (PriceWaterhouseCoopers 2007) whilst risk aversion in patients is increasing and pressure to reduce prices continues to grow. Consequently, the research companies are being driven to reduce development times, become even more innovative and use resources more efficiently.

Product Design – the key to success

In the research pharmaceutical sector, research and development is a major activity. In 2007, for example, AstraZeneca’s 13,000 researchers spent $10m every second on R&D in 17 principal centres across the world. This large scale activity has its own sustainability challenges related to the operation of the research facilities and to staff travel. In fact more energy is consumed by AstraZeneca’s research laboratories mainly in operating fume cupboards than by its factories. These issues are being addressed within the global programmes of reducing energy consumption. Most research pharmaceutical companies have set themselves targets to dramatically reduce their energy demand as well as cutting their emissions of greenhouse gases.

The objective of all this activity is to produce a regular stream of new medicines. A new drug will take from 8-12 years to develop from initial concept to marketable product and most candidates fail at one of the many hurdles along the way. At any moment a research pharmaceutical company will be undertaking research into anything from 50 to 150 potential drugs. A rigorous environmental risk assessment of all new medicines is now required as part of the EU Marketing Authorisation process (EC, 2006). Environmental evaluation is also needed to meet the requirements of other legislation, e.g. the eventual manufacturing plant will need to meet the consent conditions imposed by the local environmental regulator. This could apply to the product as well as to any waste materials involved in its manufacture.

Reducing drug residuals in the environment

Although the total mass of finished product produced by the industry is small, a large proportion of this enters the sewers by excretion from patients. Not all of this is subsequently removed during wastewater treatment. Consequently, very low residues of many pharmaceuticals can now be detected in the environment.

It is generally believed that these concentrations are far too low to pose any threat to human beings (Schwab et.al. 2005) and no immediate threat to wildlife (Cunningham et.al. 2006). There is still relatively little information on long term wildlife impacts, but the emerging conclusion from a major review of the ecotoxicological data for the EU KNAPPE Project (Knowledge and Need Assessment on Pharmaceutical Products in Environmental Waters) suggests that, with one or two exceptions, significant long term wildlife effects are also likely to be minimal (Boxall, 2008).

Nevertheless, like many industrial sectors the pharmaceutical industry is continually seeking to decrease the impact of its products on the environment. Current progress in research and development should lead to subsequent generations of drugs leaving lower residues in the environment. This does not mean that the industry is simply trying to make its products biodegradable. Biodegradable medicines can have other problems related to’shelf life’ and pharmacokinetics. They will still leave residues in the environment due to their constant input from multiple point sources, unless they degrade extremely rapidly.

In addition our knowledge of chemical degradation in the environment is currently far too rudimentary to be able to predict with any confidence how a new synthetic chemical could be modified to retain its pharmacological effectiveness and safety whilst increasing its rate of environmental decay. Research continues to be carried out in this area but it is unlikely that this will lead to any significant advances in drug design in the near future. There are many other ways, however, by which environmental residues can be reduced.

Ideal medicine

The objective of pharmaceutical research is to produce the ideal human medicine: one that is completely absorbed into the body, is effective in every patient, is specific to the disease, has no side effects and is subsequently completely metabolised in the patient to produce inert residues. It is clear that these are also many of the characteristics of a ‘green pharmaceutical’ and so improvements in drug design will inexorably lead to medicines with lower environmental footprints.

All of the major research pharmaceutical companies are, for example, very interested in the emerging area of ‘biopharmaceuticals’. These compounds, which are frequently based on proteins, now comprise up to 30 percent of new compounds under development. They have the advantage of being very specific in their mode of action. They need very low doses for effective treatment and, in most cases, they will be broken down to inert substances before excretion by the patient. It is thought that environmental residues of such medicines will be many orders of magnitude lower than that of current medicines.

The necessity of quality control

The most important aspect of pharmaceutical manufacturing is quality control. When a medicine receives approval for marketing, the authorisation relates to both the medicine and to the method by which it was manufactured. Simple product sampling techniques, as used in other industries, are insufficient to ensure the quality that is needed and manufacturers are required to follow strict Good Manufacturing Practice guidelines, GMP (EC, 2003).

These involve a holistic approach to the whole manufacturing cycle. There is a requirement for extensive and rigorous qualification and validation of equipment and procedures, together with comprehensive documentation of every aspect of the process. Regulatory agencies undertake regular, often unannounced inspections and will expect to inspect any new manufacture prior to start-up.

These quality requirements are to ensure consistency between the medicine that was tested in the clinical trials and the product eventually used by the patient. In the past this often inhibited the implementation of improvements to the sustainability of manufacturing processes, as any significant changes triggered a requirement for further confirmatory clinical data. A more pragmatic approach is now being taken by the regulators, which enable improvements to the manufacturing process to continue to be made.

Manufacturing is complex …

The manufacture of pharmaceuticals represents a relatively small part of the activities and operating costs of a research pharmaceutical company. It is carried out in two stages. The first part, bulk drug production, produces the active ingredient, whilst secondary manufacture converts this active ingredient into a medicine that can be taken by the patient. The final product then needs to be packaged for subsequent sale and distribution.

Pharmaceuticals are produced in relatively small quantities, from a few kg per year for some anticancer drugs to a few hundred tonnes per year for more widely used medicines and a few thousand tonnes per year for some analgesics. This is in contrast to some bulk chemicals where 1000 tonnes per day production is common. Unlike the majority of ‘bulk’ chemicals however, most pharmaceuticals are very complex organic molecules that have to be constructed using multiple synthetic steps, often involving the isolation of intermediate products. As a consequence, process efficiency has historically been very low (Sheldon 1994).

… but is getting greener

Driven by cost and sustainability issues, the research pharmaceutical companies have in recent years become industry leaders in the introduction of green chemistry & technology techniques into their process design. Companies have developed sophisticated systems to ensure that potential environmental consequences, as well as health and safety considerations, are taken into account in the selection of reagents and solvents. Sustainability metrics are routinely used to compare alternative process routes (Curzons et.al. 1999). This has led to major improvements in efficiency in these complex syntheses and pharmaceutical companies regularly win US Presidential Green Challenge Awards (EPA, 2008). The major companies are also now collaborating at the American Chemical Society Green Chemistry Roundtable and sponsoring research that should lead to even more sustainable synthesis routes (Crow, 2008).

Solvents comprise the largest part of the waste produced in pharmaceutical manufacture and extensive recycling and reuse of solvents is undertaken to minimise resource consumption. Solvents that cannot be reused or further recycled are incinerated, usually in installations which can recover the energy.

Smart formulation and packaging

Once the active ingredient has been produced it must then be formulated into the final medicine, e.g. turned into a tablet, a cream or an inhaler before being packed and distributed. Since this increases both the weight of the finished product and its packaging, secondary manufacture is frequently undertaken close to the point of sale. This improves the ability to quickly react to changes in demand whilst also reducing the need to transport material over long distances. This brings benefits in terms of security as well as reducing transport related emissions.

Although the formulation aspects of manufacture do not involve chemical synthesis, they can generate significant waste streams, mainly associated with the cleaning of equipment to avoid cross contamination. These wastes are however readily treatable using modern technologies, such as reverse osmosis and activated carbon.

Minimising packaging has also been the focus of much effort in the industry, although this has sometimes been impeded by other, often desirable, legislative requirements; e.g. loose tablets now have to be encapsulated in blister packs and pharmaceutical labels must now include information in Braille (EC, 2004). Both these laudable pieces of regulation have unfortunately resulted in increased amounts of packaging.

As discussed above, the pharmaceutical industry is now beginning to explore the new area of biopharmaceuticals. Few of these have yet reached the patient and their manufacture at full scale will provide new sustainability challenges. The active ingredients, often protein based, are too large and complex to be synthesised by conventional chemical techniques. As a result, current biopharmaceuticals tend to be manufactured in cell cultures using fermentation methods which can produce very large volumes of very low concentration effluents

Outsourcing

In recent years there has been an increasing tendency for more and more of the manufacturing operations in research pharmaceutical companies to be contracted to third parties. One aim of outsourcing is to increase sustainability by improving operational efficiency and save costs.

The larger research pharmaceutical companies were originally largely self sufficient, carrying out their own R&D, Manufacture, Sales and Distribution. But outsourcing has always played a part in the industry. In some cases a company might not have had the technical capabilities to undertake part of the synthesis of the active ingredient and would have had this step undertaken by a contractor. In other cases third party contractors would have been used to provide alternative sources of supply to provide security in the event of an interruption in production at the main manufacturing site. As cost pressures have increased on the industry over the last ten years, ‘outsourcing’ has been recognised as a method to decrease costs whilst potentially improving operational efficiency.

Most drugs have a relatively short useable patent life, usually of less than 10 years. In order to get a new drug onto the market as soon as possible, the manufacturing plant needs to be established before the product has received approval from the regulators. If the product is extremely successful, this manufacturing plant may not then be big enough to cope with demand. But if the product fails to gain approval from the regulator the plant will not be needed at all, nor will it be useful after patent expiry. It is thus a more sustainable practice to contract the manufacturing of the product to a number of external suppliers, who can be expanded to cope with any unexpected demand.

In the last ten years, the contract fine chemical manufacturing sector has become very experienced, highly competent, cost efficient and successful. Since contract manufacturers are focussed on chemical manufacture, they can be more efficient in their use of energy and resources than their pharmaceutical customers. Contractors in the newly industrialised countries (NICs) such as Brazil, China and India currently have a major competitive advantage as a result of very low (although increasing) wage costs. Concerns often remain, however, about quality, security of intellectual property and health, safety & environmental issues. Recent investigations showing very high concentrations of active pharmaceutical ingredients in the effluent from a wastewater treatment plant serving drug manufacturers in Patancheru in India (Larsson et al 2007) and similar findings in China (Li et al 2008) have highlighted the potential problems. This reinforces the need for pharmaceutical companies to take great care both in their selection and particularly in their continued performance monitoring of contractors At present most pharmaceutical outsourcing remains with contractors in the developed world.

Introducing a green sales force

At first sight Sales & Distribution may appear to have little relevance to sustainability. But there are significant challenges in this area. Research companies need to ensure that any new medicine is brought rapidly to the attention of as many doctors as possible. This has traditionally been done by using sales representatives that call personally on doctors to provide them with information.

A major company will usually have a large sales force whose only efficient means of transport will be the motor car. In 2007 AstraZeneca reported that business travel by car amounted to 730 million kilometres, 90 percent of which was associated with sales and marketing. This distance is equivalent to 18,300 times around the world and produced 150,000 tonnes of greenhouse gas emissions (AstraZeneca, 2008b).

Companies are tackling this in two ways. The immediate objective is to improve the efficiency of road travel by using more efficient vehicles and extending driver training to include eco-driving techniques. In the longer term e-commerce techniques may dramatically reduce the need for direct contact between the sales force and the individual doctor.

AstraZeneca is introducing both ‘hybrid vehicles’ and ‘flex fuel’ vehicles into its sales fleet. In Brazil, where ethanol fuels are widely available, more than 96 percent of the cars in the Marketing & Sales fleet can be powered by either ethanol or petrol. The company also provides its drivers with training in ‘eco-driving’ techniques, which encourages them to think ahead, planning acceleration and deceleration, anticipating traffic flow and maintaining a steady speed to improve fuel efficiency as well as safety. The company has set ambitious targets which are being realised, e.g. the US Fleet Services are on track to achieving their goal to reduce greenhouse gas emissions from vehicles by 12 percent by 2010.

Right amount at the right place and time

To fulfil demand, the product has to be distributed from the factory to the pharmacy. This inevitably leads to the emission of greenhouse gases, even if distribution is not a major emitter. As an example, only 10 percent of AstraZeneca’s total greenhouse gas emissions come from freight transport. But improvements are nevertheless being made. Bulk transport with final packing of products at the marketing companies has reduced demand for freight whilst efforts have simultaneously been made to use more environmentally friendly packaging options.

For example, volumes can be reduced significantly by using slip-sheet techniques in air freight rather than conventional pallet. Furthermore, reusable blankets have replaced polystyrene boxes for temperature-controlled transport wherever possible. Selection criteria for road hauliers and airlines take into account both age and type of fleet as a matter of course. Trials are also underway into the use of container ships to replace some road and airfreight. This has the potential to reduce greenhouse gas emissions whilst simultaneously increasing security and providing more consistent storage conditions.

Finally, considerable efforts are going into the elimination of wastage in the distribution system. This is much more complicated than it sounds. Unlike most other commodities, it is essential for patient care that their medicine is always available from the pharmacy whenever they need it. Demand for a particular medicine, however, is variable and difficult to predict since the requests come from a very large number of pharmacies.

In the past, this problem was dealt with by ensuring that sufficient stocks were held by the manufacturer, distributer and pharmacy to meet all requirements. Most pharmaceuticals, however, have a limited shelf life and this policy has resulted in very significant amounts of out-of-date medicines being continually returned to the manufacturer for destruction. This is both wasteful and very costly and serious attempts are now being made, using more sophisticated ‘lean’ engineering and’just-in-time’ delivery systems, to eliminate unnecessary stocks in the supply chain. This will reduce overall wastage whilst ensuring continuity of supply to the patient.

Making information available

Until recently, information on the environmental impact of individual pharmaceuticals was not available to either health professionals or patients. In 2005 however, Stockholm County Council introduced and made publicly available, an environmental hazard classification scheme that covered approximately 30 percent of the medicines used in Stockholm (Wennmalm & Gunnarsson, 2005) This has since been updated annually.

At the same time the Swedish Association of the Pharmaceutical Industry, LIF, took the initiative to develop a voluntary environmental classification system for pharmaceuticals used in the whole of Sweden. The system was developed by LIF and a number of Swedish stakeholders, in conjunction with expert representatives from international pharmaceutical companies (Mattson et.al. 2007). The information is made available on the website of the Swedish Doctors Prescribing Guide (www.FASS.se). There is currently interest in extending coverage across the European Union.

In theory, this information can be used by the doctor and patient to ensure that the patient receives the most effective medication that produces the least environmental risk. In practice, after taking both efficacy and cost into account, further choices are however likely to be very limited and in many cases the environmental profiles are likely to be similar. The data emerging from the LIF Classification scheme also shows that currently very few ‘less than two percent ‘ of existing pharmaceuticals fall into the highest risk category. Consequently, classification schemes of this type provide a welcome improvement in transparency, but their environmental benefit is likely to be modest.

Disposing of unused medicines

Most pharmaceutical residues in the environment result from excretion of the medicine by the patient and this is difficult to avoid. Another potential source of pharmaceutical residues is unused and out-of-date medicines. In the past, patients were encouraged to dispose of these medicines into the household toilet, since this would ensure that they would not be available to children. This is, of course, no longer an acceptable practice since it leads to pharmaceuticals being directly released to the environment. Unused medicines should, where possible, always be returned to a pharmacy which can ensure that such material is destroyed.

Doctors also have a role to play in minimising the amount of unused medicines. Needless to say, patients should only be prescribed pharmaceuticals when necessary and in appropriate amounts. In situations where the patient is likely to need long term therapy, the efficacy of the relevant medicine should be established by using short term prescriptions (7-14d). When the efficacy has been established, the patient can be provided with longer term supplies (28d).

The desire to minimise unused medicines needs to be balanced by the much more important requirement to encourage the patient to adhere to their treatment. For example, requiring patients on long term hypertension therapy to request a new prescription on a weekly basis would help to minimise the amount of unused medicines but would probably reduce the likelihood that the patient would take their medication continuously.

References

AstraZeneca (2008b). Responsibility Climate Change. AstraZeneca, Sweden, www.astrazeneca.com.

Boxall A (2008). Personal communication.

Clark J.H and Summerton L (2008). Greener Pharmaceuticals: Applying green chemistry across the lifecycle of pharmaceuticals. Industrial Pharmacy March, 15-19.

Crow J M (2008). Pharma goes green to cut costs. Chemistry World July, 2008.

Cunningham V. L, Buzby M, Hutchinson T H, Mastrocco F, Parke N, Roden N (2006). Effects of human pharmaceuticals on Aquatic Life: Next Steps. Env. Sc. Tech. 3457-3462.

Curzons A D, Constable D C, Cunningham V L. (1999). Solvent selection guide: a guide to the integration of environmental, health and safety criteria into the selection of solvents. Clean Products and Processes 1, 82-90.

EC (2003). Commission Directive 2003/94/EC of 8 October 2003 laying down the principles and guidelines of good manufacturing practice in respect of medicinal products for human use and investigational medicinal products for human use. Official Journal L 262, 14/10/2003, 22-26.

EC (2004). Directive 2004/27/EC of the European Parliament and of the Council of 31 March 2004 amending Directive 2001/83/EC on the Community code relating to medicinal products for human use. Official Journal L 136, 30/04/2004, 34-57.

EC (2006). Guideline on the environmental risk assessment of medicinal products for human use. EMEA/CHMP/SWP/4447/00, London.

EPA (2008). Presidential Green Chemistry Challenge. www.epa.gov/gcc/pubs/pgcc/presgcc.html.

Larsson DGJ, de Pedro C, Paxeus N. 2007. Effluent from drug manufactures contains extremely high levels of pharmaceuticals. Journal of Hazardous Materials 148:751-755.

Li D, Yang M, Hu J, Ren L, Zhang Y, Li K. 2008. Determination and fate of oxytetracycline and related compounds in oxytetracycline production wastewater and the receiving river. Environmental Toxicology and Chemistry 27:80-86

Mattson B, Nasman I, Strom J. (2007). Sweden’s voluntary environmental drug classification system. RAJ Pharma March, 153-158.

Price Waterhouse Coopers (2007). Pharma 2020: The vision Which path will you take? Price Waterhouse Coopers, London.

Schwab, B. W. et al. (2005). Human Pharmaceuticals in U.S. Surface Water: A Human Health Risk Assessment. Regul. Toxicol. Pharmacol. 42, 296-312.

Sheldon R A (1994). Consider the Environmental Quotient. Chemtech, 24, 38-47.

Wennmalm A, Gunnarsson B (2005). Public health care management of water pollution with pharmaceuticals: Environmental classification and analysis of pharmaceutical residues in sewage water. Drug Inform. J. 39(3), 291-297.