Antimicrobial resistance (AMR) is at the first points of attention in all political agendas world-wide, as the lack of innovative antibiotics and the resurgence of many bacterial diseases, like tuberculosis. Also in Western countries represent worrying hazards for the health of people and animals and for the environmental sustainability. The causes at the base of AMR are usually identified in the misuse of antibiotics in humans and agriculture, but far less attention is paid to the possible role played by the manufacturing of this widely used class of medicines.

There are approx. 200 antibiotic production facilities world-wide, mainly located in India and China, which release an estimated 30,000-70,000 tons of waste in the environment per year. More than 95% of the antibiotic manufacturing waste is in liquid form and represents a possible leading cause of reservoirs of antibiotic resistance in the environment. The ‘Industry Roadmap to combat AMR’ was presented and signed on September 2016, ahead of the United Nations General Assembly (UNGA) High-Level Meeting on Antimicrobial Resistance (AMR) (“The Industry Roadmap on antimicrobial resistance”). A key role in the genesis of the Roadmap was played by DSM Sinochem Pharmaceuticals (DSP), whose ‘Sustainable Antibiotics’ programme also won the 2016 CEFIC European Responsible Care Award. (“The Sustainable Antibiotics programme”) «We started this programme in 2014 because we think it is our responsibility to manufacture our antibiotics responsibly – tells Lucas Wiarda, DSP’s Global marketing director and Head of the Sustainable Antibiotics programme –. We are on the business to fight bacterial infections, so we don’t want to make bacteria stronger. It also helps us in differentiate ourselves as a responsible manufacturer and as responsibility leader in an industry which is in its current state, unfortunately, not sustainable».

The beginning as an in-house project

More or less at the same time DSP started working at the Sustainable Antibiotics programme, UK Prime Minister David Cameron commissioned to economist Jim O’Neill the independent ‘Review on Antimicrobial Resistance’ (AMR), whose final results were published on May 2016 (“The independent AMR Review”). «At that moment, we had not a clear view on what our role in the whole issue of AMR was. In 2014 we identified AMR as a risk for our business continuity and we defined the solutions that we think are necessary to keep our products effective», further explains Mr Wiarda.

At the beginning DSP’s programme focused on the company’s own production plants, with the target to further assess the environmental impact of our antibiotic manufacturing activities, and more specifically our effluent that could drive AMR as a consequence of antibiotic pollution. DSP internally defined three basic requirements to make antibiotics responsibly and sustainably and at the first instance applied them to in-house activities. «The first one is that we use the enzymatic technology, which is considered the cleanest in the industry. The second requirement is that every manufacturing site should own its dedicated waste water treatment plant and this plant works 24 hours per day, 365 days per year as an integral part of the process – adds the Head of the programme –. If you imagine that in some cases antibiotic manufacturers are located quite close to each other while making different types of antibiotics, then untreated waste can leave a cocktail of antibiotics in the direct environment of these plants. And this cocktail of antibiotics forms a driver for antibiotic resistance. Therefore it is very important that the pollution and the antimicrobial activity in the effluent are managed before the effluent is discharged into the environment». Equally harmful it could be if different manufacturing plants send their effluents to the same municipal treatment plant. In such an instance, many different antibiotics are coming together, with the result that the surviving bacteria become multiple drug resistant.
«Every manufacturer needs to take its responsibility on managing and cleaning its own waste of antibiotics – says Mr Wiarda –. The third requirement is, of course, proving that the effluent is free of antibiotic activity». DSP has developed a single test that detects a broad range of antibiotics, with a sensitivity up to 50 parts per billion (ppb) and then applied them to check if its effluent was clean.
«Of course there could be discussions whether 50 ppb can be considered clean or not. But the legislation is still lacking, thus we have defined the 50 ppb as a first standard. If science ultimately defines that stricter discharge levels are necessary, then of course we have to change our tests and our change management practices and systems», further adds Wiarda.

The expansion of the programme ended up with the UNGA Industry Roadmap on AMR

The AMR issue was further acknowledged by the entire industrial sector – not only the pharmaceutical one – by the signature, in January 2016, of the Davos Declaration, where more than 100 companies and trade associations called for a “collective action to create a sustainable and predictable market for antibiotics, vaccines and diagnostics”. Another target established by the Declaration was the “coordinated action to improve prevention of infections, hygiene, stewardship and conservation measures”. «Since there were not deliverables or measurable actions defined in this industry declaration. We took the final document of the independent AMR Review conducted by Jim O’Neill as a leading document», explains Lucas Wiarda. On this basis, DSP gradually became a driving motor of a network of pharmaceutical companies sharing the same vision about the management of the antimicrobial resistance issue, an action that ended up in September 2016 with the signature of the UNGA Industry Roadmap on AMR by thirteen large pharmaceutical companies, including also two Indian manufactures like Cipla.
«One of the main challenges was to create the awareness on the environmental impact of antibiotic manufacturing. We did that first of all by approaching GSK: with its help we reached out to a number of other companies that we hoped we could convince that this is an issue we needed to tackle collectively. On top of this there are other stakeholders that continuously increase pressure and ask attention for this issue», tells the Head of Sustainable Antibiotics programme. An example of stakeholder activity is the publication, on October 19th, of the Changing Markets’ report ‘Superbugs in the Supply Chain’, showing the occurrence of drug-resistant bacteria in water streams surrounding pharmaceutical manufacturing sites in India (“The ‘Superbugs in the supply chain’ report”).
Among the more difficult actions to be addressed was the need to involve different levels of management, from executives and officers to environmental, health and safety specialists. The dozen of companies who signed the roadmap also had to find an agreement on the measurements target and on how to address their respective suppliers. «We were talking with companies that are much bigger than we are and that have to deal with different dynamics. We had to agree on achievable commitments for all. Even though we have some strategic suppliers on key intermediates, they are much smaller in number that the ones of big pharmaceutical companies».
According to the roadmap, targets to be tackled include the involvement of suppliers in building sustainability, the definition of manufacturing standards and science-based tolerance levels and the setting up of a mechanism to implement the entire process along the supply chain.
«We also had to find a platform willing to support us in the communication of the roadmap. We were extremely pleased the International federation of pharmaceutical manufacturers & associations (IFPMA) did this», says Lucas Wiarda. The Global marketing director also tells NCF that discussions are still continuing about how the adhering companies may put the principles of the roadmap into practice. «The companies do not want to have these initiatives as being a vehicle for clean washing operations. We are very serious about this topic. This is now the big challenge: how we can include and engage all the companies who want to show responsibility and ownership?».
The roadmap group of pharmaceutical companies is also working to engage process experts from the academia in order to better define the acceptable levels for discharge concentrations of antibiotics into waste waters.«The question is how we do connect with them, together with the other companies, to leverage the knowledge we all have and turn it into standards that are practical, feasible and safe», adds Lucas Wiarda.

The Pharmaceutical Supply Chain Initiative

A step further towards influencing and combine forces in the industry to establish industry-wide guidelines that reach into the entire value chain to ensure that antibiotics are produced responsibly, DSP joined the ‘Pharmaceutical supply chain initiative’ (PSCI) (BOX 4). «We consider PSCI to be an important initiative and platform. Twenty-four companies signed already for the Initiative, which has a dialogue with its members and will support projects to educate suppliers towards the sustainable standards we wish to implement in the global supply chain. It helps us auditing our suppliers along a number of agreed sustainability principles: doing so, we qualify them according to the PSCI principles and share the information with other PSCI members. Also DSP, is joining a monthly teleconference with the environmental, health and safety specialists to discuss our environmental management systems and how we can define a mechanism to increase the standards in the supply chain».

The approach chosen by the company to involve its suppliers is based on its industrial integrated strategy, which allows to serve different markets starting from glucose to the active pharmaceutical ingredients and pharmaceutical formulation ones. The company goal is to maintain dialogues with strategic suppliers of its key antibiotics intermediates in order to have them applying the same standards as DSP does. Not an easy task to be achieved in some cases, according to Lucas Wiarda: «We also had few cases were we decided tp blacklist suppliers. We are no longer buying from them. Companies that are sensitive to our concerns, we continue to source from. We have dialogues with them on our concerns and try to convince them to improve».

Other important stakeholders for the implementation process are represented by “peers”, such as competitors and customers. In this case too, maintaining dialogue is fundamental to share the respective best practices and the principles each company find important to make antibiotics responsibly. «We also started to assess partnership with peers to see if we can help them in tackling the antimicrobial activity levels in their effluents, using the tools we have developed – tells Lucas Wiarda –. We are working to establish this kind of partnerships in China and India, but also in Europe. We have a number of customers who highly appreciated our efforts and also wish to apply or to assess the same principles in their formulation manufacturing. We are very happy to see increased awareness also from the political perspective. Chinese authorities took some very serious environmental measures and stopped the manufacturing of a number of polluting pharmaceutical companies».

The next step might be a new legislation

The current (pharmaceutical) legislation is not addressing the issue of discharge concentrations of antibiotics into effluent waters coming from manufacturing plants. According to the Head of the Sustainable Antibiotics programme, there are two possible ways to handle this issue at a more regulated level. The first way could be self-regulation, triggered by issues like the roadmap and supported by initiatives like the PSCI.
«We also believe that in a way this needs to be followed by a formal legislation: there are various frameworks that can consider to establish these environmental criteria, such as Reach or GMP. It is also important that local authorities and national governments, especially in India and China, address the environmental angle of AMR in the National Actionplans on AMR, and define maximum discharge levels for antibiotic manufacturers», tells Mr Wiarda to NCF. The Global marketing director of DSP also suggests that a simple and convenient solution would see the implementation of a system where the pharmaceutical industry would be incentivized to make antibiotics responsibly, or punished in case it does not. Such mechanism could be supported by the  introduction of a new quality mark or industry label for responsible antibiotics. «If environmental criteria would be included into buying decision, this would be an incentive to the industry for making antibiotics responsibly», suggest the responsible of the programme, suggesting also the already existing examples of the Forest Stewardship Council (FSC) industry label for responsibly made paper or the UTZ certification for coffee and chocolate. 

The Industry Roadmap on antimicrobial resistance
The main points of the Industry Roadmap signed by 13 pharmaceutical companies (Allergan, AstraZeneca, Cipla, DSM Sinochem Pharmaceuticals, F. Hoffman-La Roche, GSK, Johnson & Johnson, Merck & Co., Novartis, Pfizer, Sanofi, Shionogi and Wockhardt) include:

• Reduction of the environmental impact from the production of antibiotics and work with stakeholders to establish a common framework for assessing and managing antibiotic discharge;
• Helping ensure antibiotics are used only by patients who need them, recognizing this requires concerted efforts from many stakeholders, an examination of the companies’ promotional activities, sharing of surveillance data with public health bodies and healthcare professionals, and collaboration to reduce uncontrolled antibiotic purchase;
• Improving the access to current and future antibiotics, vaccines, and diagnostics, including the strengthening of global health systems and removal of access bottlenecks; establishing new business models that balance access needs, appropriate antibiotic use, expanded vaccine coverage and adequate return to companies; reduce the prevalence of substandard/counterfeit antibiotics in high-risk markets;
• Explore new opportunities for open collaborations between industry and the public sector to address challenges in the research and development.
  (source: IFPMA)

The Sustainable Antibiotics programme
As per point n.1 of the roadmap, the respective actions set forward by the DSP’s Sustainable Antibiotics programme include:

• Environmental criteria for the manufacturing of antibiotics to be included in existing legislation/mechanisms. Targets should be science driven and risk based while covering discharge concentrations and good practice methods to reduce environmental impact of antibiotics manufacturing;
• Use the best technology available with the lowest environmental impact throughout the supply chain;
• Operate dedicated wastewater treatment plants 24/7/365 at every antibiotic manufacturing site
• Apply antimicrobial activity tests to ensure disposed water is clean;
• Manufactures to drive higher standards and mechanisms to improve transparency through their supply chain by establishing a common framework for antibiotic discharge via e.g. PSCI and/or via a “Quality Mark” or “Industry Label.
  (Source: DSM Sinochem Pharmaceuticals)

The independent AMR Review
According to the final document resuming the results of the AMR Review commissioned by the UK Government and the Wellcome Trust, by 2050 more than 10 million lives a year and a cumulative $ 100 trillion of economic output are at risk due to the rise of drug-resistant infections. The report identifies ten priority actions in order to slow down the rise of drug resistance and to reduce the demand for antimicrobials:

• A massive global public awareness campaign;
• Improve hygiene and prevent the spread of infection;
• Reduce unnecessary use of antimicrobials in agriculture and their dissemination into the environment;
• Improve global surveillance of drug resistance and antimicrobial consumption in humans and animals;
• Promote new, rapid diagnostics to cut unnecessary use of antibiotics;
• Promote development and use of vaccines and alternatives;
• Improve the numbers, pay and recognition of people working in infectious disease;
• Establish a Global Innovation Fund for early-stage and non-commercial research;
• Better incentives to promote investment for new drugs and improving existing ones;
• Build a global coalition for real action – via the G20 and the UN.
  (source: AMR Review, “Tackling drug-resistant infections globally: Final report and recommendations”, May 2016)

The Pharmaceutical Supply Chain Initiative
The Pharmaceutical Supply Chain Initiative (PSCI) has been established by group of pharmaceutical and healthcare companies who wish to share a common vision, knowledge and expertise to drive complex, global change more effectively. The website of the Initiative provides materials and tools to guide responsible supply chain, including:
Abbreviated PSCI SAQ & Audit Report template for service providers and general manufacturers;

• Abbreviated PSCI SAQ & Audit Report template for service providers and general manufacturers;
• Data sharing agreement;
• Full PSCI SAQ & Audit Report template for core suppliers, external manufacturers, component and materials suppliers;
• Pre-Audit document request list;
• PSCI Audit guidance;
• PSCI Shared audit program brochure.
• Based on the program, suppliers can share audits with more than one PSCI member via a web-based platform, so to reduce the number of audits for each supplier and to increase the efficiency gains for PSCI members.
  (source: PSCI)

The ‘Superbugs in the supply chain’ report
The first of its kind report was the result of a on-ground investigation by Changing Markets and the investigative agency Ecostorm that took place in June 2016 on a total of 34 Indian manufacturing sites. Bacteria resistant to antibiotics were found in sixteen cases, according to water analysis run under the supervision of Dr Mark Holmes from the University of Cambridge. The sites close to the cities of Hyderabad, New Delhi and Chennai were found to be the most exposed to high levels of resistant bacteria, Resistance to three major classes of antibiotics – cephalosporins, carbapenems and the uoroquinolones – was detected in four plants, resistance to cephalosporins or uoroquinolones in eight cases, resistance to either cephalosporins or uoroquinolones in other four cases.
(source: ‘Superbugs in the Supply Chain: How pollution from antibiotics factories in India and China is fuelling the global rise of drug-resistant infections’, Changing Markets and Ecostorm, October 2016)