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The impact of pharmaceutical manufacturing on the environment has triggered demands for tighter environmental controls in EU and national legislations.
Controls on pharmaceuticals in the environment (PIE) look likely to be tightened up in Europe at the European Union and national levels. The industry has broadly accepted the need for stricter regulations and guidelines, but there are concerns that some of the measures being proposed may be unnecessarily restrictive. Regulatory initiatives are being taken on several fronts. The European Commission, the Brussels-based EU executive, is working on a PIE strategy due for completion in the first half of 2017, which could be followed by regulations specific to pharmaceuticals.
The European Medicines Agency (EMA), responsible for EU-wide medicines approvals, has just started consultations with stakeholders on a revision of its 10-year-old guideline on environmental risk assessments (ERAs) of new pharmaceuticals (1). There is mounting pressure for the agency’s guideline on GMPs to be extended to the environmental performance of pharmaceutical manufacturing facilities, particularly those making APIs for the European market, many of which are in India and China. This pressure comes as a result of studies (2) showing that plants making finished medicines and APIs are a much bigger source than previously thought of contamination of the environment by pharmaceuticals in comparison to that from usage and disposal.
At the national level, some EU member states are now applying environmental criteria for the procurement of medicines for public sector healthcare services. Some of these criteria require drug suppliers to ensure that emissions from plants contracted to make medicines and APIs for them, especially those outside Europe, are properly monitored. Moves to impose stricter controls on pharmaceuticals in the environment stem from the big increase in the amount of academic and other research on the issue.
Contamination from pharmaceutical plants
One of the most influential PIE research programmes has been MistraPharma, a seven-year project funded by the Swedish Foundation for Strategic Environmental Research. It published its final report in May 2016 (2) based on research carried out by a number of Swedish universities as well as one from the United Kingdom. A broad range of Swedish stakeholders were also involved in the scheme, including representatives of regulators, the pharmaceutical industry, professional associations, and healthcare providers.
Among its major findings was that contamination of the environment by pharmaceuticals is more extensive than previously estimated and that the levels of pollution from medicines and API manufacturing plants across the world are much higher than has been reported earlier. “The largest emissions of pharmaceuticals on earth do not arise from usage but from manufacturing discharges,” the report (2) says, with some of the worse culprits being antibiotics plants in India. In one Indian facility, MistraPharma researchers discovered that all the bacteria that they isolated were typically resistant to 30 out of 39 tested antibiotics while some were resistant to almost every tested antibiotic.
Recommendations on environmental controls
The MistraPharma report made 10 recommendations, one of which states that risks to the environment from emissions from manufacturing sites should be included in ERAs. Among the other recommendations is that environmental risks should be included in the risk-benefit analyses by regulators before a new medicine is given market authorization, that ERAs should be updated in the light of new information after drug approvals, and that ERAs should be carried out on medicines marketed before 2006 when the EMA’s guideline on ERAs was first published. The report also suggests that all ERAs and information about manufacturing sites should be made publicly available.
“Most stakeholders in Sweden agree with the recommendations,” Professor Christina Ruden, programme director and deputy head of Stockholm University’s environmental science and analytical chemistry department, told Pharmaceutical Technology Europe.
“We also have a decision by the Swedish Government that Sweden should work toward a better handling of environmental aspects with pharma at the EU level. Sweden is now partly a forerunner with its national initiatives, such as greener procurement of pharmaceuticals. But to have a real impact, a change at the EU-level is of course needed in the long run.”
Opposition from the industry
In line with the policy of trade associations such as the Brussels-based European Federation of Pharmaceutical Industries and Associations (EFPIA), the Swedish pharmaceutical industry is opposing MistraPharma’s proposals that ERAs should be included in risk-benefit analyses on medicines. The European industry is also concerned about the growing demands, which was not included in MistraPharma’s recommendations, for GMP to be extended to include environmental standards at production sites, particularly emissions on pollutants.
Calls for GMP to be broadened in scope have been reinforced by recent reports (3, 4) by non-governmental organizations (NGOs) such as the New York-based Sum of Us and by the Scandinavian financial group Nordea Asset Management. These reports provide evidence of extensive environmental pollution by pharmaceutical plants in India and China.
“An extended GMP can be an effective means of protecting not only the environment but also human health because plant emissions can increase antimicrobial resistance,” Adela Maghear, pharmaceuticals policy officer, at Health Care Without Harm (HCWH), Brussels, said in an interview with Pharmaceutical Technology Europe.
The need to tighten up guidelines on ERAs at the international level, including not just the EU but globally through bodies such as the World Health Organization (WHO), is one area where there is a broad consensus between industry, regulators, and NGOs. EMA issued a concept paper (5) on a revision of its 2006 ERA guideline in April 2016, which is now subject to a six-month consultation with stakeholders.
“Since the 2006 EMA guideline, a clear improvement and consistency of the ERA dossiers has been observed,” says a spokesperson for the agency. “Transparency of ERA data has also been improved and information is made available in more detail and more consistently in the European public assessment reports (EPAR) published at the time of [recommended approval of medicines]. Still, EMA believes that further improvements in ERAs can be made.”
In its concept paper (5), the agency pinpoints a number of aspects of environmental risk assessments that need to be reviewed. These areas include “approaches for substances with specific properties” such as persistent, bioaccumulative, toxic (PBT) compounds, endocrine disruptors, and mixtures of different chemicals that can have a combined environmental effect. There may also need to be changes to current environmental test strategies for pharmaceuticals, particularly when taking into account their pharmacodynamic and pharmacokinetic properties. Some improvements, however, such as the introduction of systems of data sharing and periodic updates of ERAs, would require changes to EU legislation, the ERA warns.
Extending the scope of GMP
Amendments to the EMA’s guidelines on GMP to extend it to environmental quality matters would be in a similar position. “The legal scope for GMP does not include inspections related to potential ERA pollution at the site of manufacture,” says the agency’s spokesperson. “Although changes in the legislation are not in the remit of the agency, if the scope is [changed], the EMA would adapt its guidelines accordingly.”
The European Commission’s proposed PIE strategy, due to be published in 2017, could lead to new legislation or amendments to existing regulations, but these proposals are likely to be related to water quality policies. The Commission is already working on improvements to water legislation including criteria for placing pharmaceuticals and other compounds on watch or priority control lists. One major difficulty confronting the Commission is how to deal with mixtures of pollutants in water, which in the area of water quality MistraPharma highlighted as being a big challenge.
Representatives of the European pharmaceutical industry have been expressing concerns about the levels and characteristics of emissions from pharmaceutical plants. But they believe that using GMP as a tool to deal with the problem would be a mistake.
“GMP should remain focused on product quality and hence patient safety,” Bengt Mattson, environment and corporate responsibility manager at the Swedish research-based pharmaceutical industry association (LIF) told Pharmaceutical Technology Europe. “If its scope was changed to include environmental standards it would divert attention from product quality.”
Pharma’s own initiatives
The industry’s opposition to ERAs being included in risk-benefit analyses of medicines for marketing approvals is based on similar concerns. “Marketing authorization decisions should be based on medical evidence and not environmental risks,” said Mattson, who is also co-chair of a PIE task force backed by the industry’s three main European associations-EFPIA, Medicines for Europe for generics, and AESGP for the European pharmaceutical wholesalers.
The industry believes that some of its recently launched voluntary schemes can do a lot to deal with the anxieties among regulators, NGOs, and the general public about the impact of pharmaceuticals on the environment. These initiatives include its Eco-Pharmaco-Stewardship (EPS) scheme, supported by the three associations. This scheme covers the management of effuents from manufacturing units on which the industry has compiled a list of best practices to minimize risks to the environment.
“Pharmaceutical companies in Europe are already carrying out audits of environmental standards in the manufacturing plants of APIs and other suppliers outside the region,” said Mattson. “Under the industry’s Pharmaceutical Supply Chain Initiative, information from these audits is being shared between companies.” The industry’s task over the next few years is to convince the regulators and politicians that it has a tight enough grip on environmental standards in its supply chains to make changes like extensions to GMP unnecessary.
1. EMA, Guideline on the Environmental Risk Assessment of Medicinal Products for Human Use (London, June 2006).
2. MistraPharma Research, “Identification and Reduction of
Environmental Risks Caused by Human Pharmaceuticals,” Final Report (Stockholm, May 2016).
3. Sum of Us, “Bad Medicine--How the pharmaceutical industry is contributing to the global rise of antibiotic-resistant superbugs” (New York, 2015).
4. Norsea Asset Management. “Impacts of Pharmaceutical Pollution on Communities and Environment in India” (Stockholm, 2015).
5. EMA, Concept paper on the revision of the ‘Guideline on the environmental risk assessment of medicinal products for human use’ (EMEA/CHMP/SWP/4447/00 corr 2) (London, 28 April 2016).