OR WAIT null SECS
The European Commission is striving to tackle environmental pollution by pharmaceuticals as a means of curbing antimicrobial resistance.
The European Union is close to finalizing a new strategy on pharmaceuticals in the environment (PIE), which could include proposals for stricter controls on effluents from medicines and active ingredient plants. Its initial focus is likely to be on tackling environmental pollution by pharmaceuticals as a means of curbing antimicrobial resistance (AMR). In the longer term, measures against discharges of antimicrobial manufacturing waste will be followed by steps against emissions from plants making other pharmaceuticals of environmental concern such as endocrine disruptors.
The European Commission, the Brussels-based EU executive, adopted in June 2017 an action plan (1) on antimicrobial resistance with the objective, according to Vytenis Andriukaitis, health and food safety commissioner, of making “the EU a best practice region worthy of shaping the global agenda on AMR in this increasingly interconnected world.”
Waste from antibiotic API plants
In a roadmap issued in April 2017 to enable stakeholders to provide feedback on the planned PIE strategy, the Commission acknowledges that pharmaceutical pollution was an “emerging environmental problem” that required initiatives from the Commission, particularly on water contamination by drug substances. So far, the Commission has avoided making any specific proposals on dealing with the issue of discharges of antibiotics waste from plants manufacturing antimicrobial APIs considered by some experts to be a major source of AMR. The Commission, however, has been coming under mounting pressure to take some sort of initiative on waste from the manufacture of antibiotic APIs because of these possible links with antimicrobial resistance.
In recent years, studies, mostly by academics, have provided mounting evidence that discharges of antibiotics APIs from production plants could be causing the creation of resistant pathogens, which could ultimately be spread around the world. In one of the biggest investigations of AMR, the Review on Antimicrobial Resistance funded by the United Kingdom government and Wellcome Trust and chaired by the economist Jim O’Neill claimed (2) that in discussions of the issue the way antimicrobials were produced “had been too often neglected.” The review, published in 2016, recommended that global bodies, governments, and regulators should set evidence-based, enforceable targets for the maximum levels of discharged antimicrobial APIs in manufacturing waste. It also suggested that pharmaceutical companies should improve the monitoring of their own API manufacturing units and those of third-party suppliers.
In fact, with the assistance of the Review on Antimicrobial Resistance, the pharmaceutical industry had already been taking action on AMR. In early 2016, 96 pharmaceutical, biotechnology, and diagnostics companies and nine industry associations drew up what was called the Davos Declaration (3) under which the signatories pledged their support for a series of anti-AMR measures, including initiatives to combat environmental pollution by antibiotics. In September 2016, a group of companies within the Geneva-based International Federation of Pharmaceutical Manufacturers & Associations (IFPMA) issued a roadmap laying out a voluntary programme for controlling antibiotic discharges from pharmaceutical plants. The 13 signatories to the document included leading global players such as AstraZeneca, Roche, GlaxoSmithKline, Merck & Co., Novartis, Pfizer, and Sanofi.
Pollution from manufacturing sites in India and China
For the European Union, which works mainly through legislation adopted by its 28 member states rather than voluntary schemes, curbing antibiotic discharges is a big challenge. The vast majority of antimicrobial APIs supplied to the European market are manufactured in India and China. Studies have revealed high levels of pollution from antimicrobial APIs at manufacturing sites in both countries. In 2016, a group of German researchers working in Hyderabad in southern India, which is a hub of bulk drug manufacture, detected the antifungal fluconazole at a concentration of 236,950 micrograms per litre, which was more than 20 times greater than therapeutically desired levels in the blood (4).
“To our knowledge, this is the highest concentration of any drug ever measured in the environment,” said the scientists headed by Christoph Luebbert of Leipzig University Hospital’s infectious diseases and tropical medicine unit. “Our findings confirm those of previous studies that demonstrated a strong association between environmentally stable anti-infective residue pollution and the presence of multi-drug resistant (MDR) bacteria.”
In the face of such high concentrations of pollution and the likelihood it triggers the creation of large AMR reservoirs, the European Commission is being urged to take a strong line with non-European API suppliers in the fight against antimicrobial resistance.
“From a moral standpoint, minimizing such discharges fall within the responsibility of Europe, as we are buying and using these drugs,” said Professor Joachim Larsson, a specialist in antimicrobial resistance at Gothenburg University’s Institute of Biomedicine in Sweden. “The responsible way of acting, as buyers and consumers, would be to develop and apply demands and regulations that secures environmentally safe production, regardless if production takes place in Europe or elsewhere,” he explained in a feedback to the proposed PIE strategy (5). He warned about the global threat of inadequate controls on discharges from bulk drug plants. Because of the way that resistant pathogens evolve, theoretically an AMR-polluting incident need happen only “once at one site of our planet, then travelling and globalization takes care of the spread of these bacteria,” he said.
Many other people participating in the consultation exercise earlier in 2017 on the Commission’s planned PIE strategy also wanted action taken against polluting plants. The vast majority of stakeholders in the consultation, representing industry, non-governmental organizations (NGOs), healthcare providers, and other public and private sector organizations, backed more surveillance and collection of data on discharges and the application of minimum manufacturing standards to prevent pharmaceutical waste causing resistance.
Even regulators supported tougher controls on emissions. EU legislation should be tightened up with greater transparency and traceability in the manufacturing chain to prevent the environmental consequences of API production, said the Norwegian Medicines Agency in its feedback (6). Norway is a non-EU state but a member of the EU single market.
Extension of GMP
One option being put forward by backers of a more robust European approach is for good manufacturing practice (GMP) standards to be extended to cover control of emissions. This would be fiercely opposed by industry, which wants GMP to remain firmly focused on product quality and safety.
“GMP is not about environmental standards,” Bengt Mattson, environment and corporate responsibility manager at the Swedish research-based pharmaceutical industry association (LIF), told Pharmaceutical Technology Europe. “If the EU tries to impose environmental standards through GMP, it will risk getting into trade conflicts,” added Mattson, who is also co-chair of a PIE task force backed by the industry’s three main European associations-the European Federation of Pharmaceutical Industries and Associations (EFPIA), Medicines for Europe (previously the European Generics Medicines Association [EGA]), and the Association of European Self-Medication Industry (AESGP) for the European pharmaceutical wholesalers.
An extension of GMP would also be at odds with the EU’s own system of pollution controls in manufacturing which are applied through plant operating permits. “India and China have their own, similar environmental legislation,” said Mattson. “The difference is in the way it is enforced.”
An alternative would be for the EU to take a more decentralized approach under which India and Chinese plants would be given “quality marks” for pollution controls. Then individual European governments, national procurement agencies, or healthcare providers would decide for themselves whether to buy from low-ranking suppliers.
The roadmap signatories within IFPMA are moving towards a system based upon limits on AMR-threatening discharges at individual sites, which with the help of expert advisors, would be set by the industry. The participants in the roadmap scheme will establish in 2018 a common framework of good practice for controlling discharges of antibiotics into the environment in their supply chains.
By 2020 science-driven, risk-based limits on concentrations of discharges of antibiotics waste will be introduced with good practice methods being applied to reduce the environmental impacts of these emissions. The roadmap group stresses that any system of limits on discharges will need to be funded with the help of higher margins on antibiotics and other antimicrobials.
“There are enormous price pressures at the moment,” said Mattson. “Some antibiotics are currently as cheap as sticks of candy. This is one reason why some producers have been taking short cuts with their control of emissions. Society has to be prepared to pay for the costs of good quality environmental standards.”
Low prices are considered to be a factor behind shortages of antibiotics in Europe as a result of poor profitability leading to reductions in production capacity. “This downward price pressure on essential antibiotics has jeopardized their continued availability,” a spokesman for Medicines for Europe told Pharmaceutical Technology Europe. “In most European countries, the price level of antibiotics is close to marginal cost, and sometimes even below that-for example in Denmark and Portugal. As a result of these unsustainable price levels and drastic cost-containment measures, the number of antibiotic manufacturers in Europe has gone down.”
Medicines for Europe has been urging the EU countries to adopt pricing and procurement policies for antibiotics, which would help boost investment in production capacity in Europe. To be consistent with what is likely to be an EU strategy on PIE aimed at preventing manufacturing discharges causing antimicrobial resistance, such pricing policies will also have to be aimed at generating funds for building state-of-the art waste treatment plants.
1. European Commission, A European One Health Action Plan against Antimicrobial Resistance (Brussels, 29 June 2017).
2. The Review on Antimicrobial Resistance, chaired by Jim O’Neill. Tackling Drug-Resistant Infections Globally: Final Report and Recommendations (London, May 2016).
3. Declaration by the Pharmaceutical, Biotechnology and Diagnostics Industries on Combating Antimicrobial Resistance (Davos, 21 Jan. 2016).
4. C. Lübbert et al., Infection 45, 479–491 (2017).
5. J. Larsson, European Commission’s Strategic Approach to Pharmaceuticals in the Environment, Feedback reference-F1756 (Brussels, May 2017).
6. Norwegian Medicines Agency, European Commission’s Strategic Approach to Pharmaceuticals in the Environment, Feedback reference-F1787 (Brussels, May 2017).
Article DetailsPharmaceutical Technology Europe
Vol. 29, No. 10
When referring to this article, please cite it as S. Milmo, “Pharmaceutical Environmental Pollution and Antimicrobial Resistance,”Pharmaceutical Technology Europe 29 (10) 6–8 (2017).