Through poor practices, the pharmaceutical industry is adding to the problem of antimicrobial resistance instead of helping to solve it.

Source: istockphoto.com

Medicines like antibiotics save countless lives and improve the safety of critical medical procedures. It is sometimes easy to forget that the oft-maligned pharmaceutical industry produces them — and should be highly regarded for this invaluable contribution to the society. However, the industry is also complicit in one of the greatest challenges to society — the threat posed by antibiotic resistance.

The major focus of public efforts is aimed at the right prescription and use of antibiotics by doctors, pharmacists and patients. Although this is important, there is a more imminent issue that producers of antibiotics must address — environmental pollution.

In 2009, Joakim Larsson of the University of Göteborg and his team found rivers near Hyderabad, one of India’s pharmaceutical centres, with concentrations of antibiotics higher than the blood of a patient undergoing treatment[1].

Most antibiotics are manufactured in China and India (India in turn relies on China for up to 90% of its raw materials and intermediates for certain drugs). Environmental legislations and regulation and enforcement are substantially different across these regions.

The threat of antibiotic resistance is well known and on the political agenda. The World Health Organization, for example, has named antimicrobial resistance (AMR) one of the top threats to mankind. UK Prime Minister David Cameron held an inquiry into the issue in 2014. In June 2014, the Dutch government held a conference on antibiotic resistance, while in the United States, Obama produced a presidential report on combatting AMR.

The European Medicines Agency (EMA) and the European Centre for Disease Prevention and Control (ECDC) estimate that about 25,000 patients die each year from an infection of multidrug-resistant bacteria[2], resulting in extra healthcare costs and productivity losses of at least €1.5bn each year in Europe. And these numbers are likely to be an underestimate. We see the same in the United States, with US Centre for Disease Prevention estimates of 23,000 deaths and additional healthcare costs of US$20bn each year[3].

This is likely to be much worse in developing countries, although only patchy data exists. It has been reported that an estimated 60,000 newborn babies die each year in India because of AMR[4].

Bad practice

There are outstanding examples of compliant manufacturers in both India and China. Unfortunately, there are also production plants that have serious compliance and quality problems with some potentially fatal consequences.

For example, in November 2014, 13 women died after receiving tainted ciprofloxacin, a commonly prescribed antibiotic in India, after undergoing sterilisation surgery, The New York Times reported[5]. Pharmaceutical product recalls and forced factory closures regularly make the news[6]. As recent as December 2014, an investigative report by CCTV, China’s state television, featured a segment on antibiotics found in the municipal water supply of Chinese cities[7],[8]. The report uncovered that two antibiotics producers had been illegally discharging waste water containing high concentrations of antibiotics, making it unsafe to drink[9]. This is the first time public focus has been drawn to the issue of antibiotics residue in the public water supply and the connection of this issue with non-compliant antibiotics producers.

There are countless examples of non-compliance, including factories using decades-old technology to produce and to treat their waste and dumping untreated waste water and antibiotics into the environment. In China, the Ministry of Environmental Protection and the provincial Environmental Protection Bureaus (EPB) do inspections and operate a website where warning letters and violations are posted online and publicly.

Right move

Despite such concerning reports that pharma is adding to the growing problem of AMR, the industry can be part of the solution. Industry needs to first improve environmental performance. It cannot allow the illegal discharge of waste water containing active antibiotics, which contributes to AMR, and other non-compliant practices. Pharmaceutical companies need to take action to prevent such reckless behaviour through, for example, adopting the highest industry standards for themselves and by insisting that suppliers adhere to the same high standards.

At DSM Sinochem Pharmaceuticals, we adhere to one manufacturing standard globally. Our plants in China use the same waste treatment technologies as in, for example, the Netherlands, Spain, Mexico and India. We have also started supplier sustainability audits together with several reputable multinational companies.

Through a combination of industry self-regulation and the right regulation from authorities, and, more importantly, effective regulatory enforcement, the right incentives can be created for pharmaceutical producers to invest in responsible manufacturing.

Recent years have seen a rising number of product recalls and even import bans initiated often by the US Food and Drug Administration (FDA) or European Directorate for the Quality of Medicines and Health Care (EDQM). This is well documented, with the FDA publishing warning letters[10] and enforcement activities[11] online, as does the EDQM[12].

China is beginning to take action. Premier Li Keqiang made it clear that environmental protection is on top of the government’s agenda[13]. Throughout 2014 and continuing now, regulators have shut down several production plants that were polluting the environment, as reported on the Chinese Ministry of Environmental Protection’s website. As recently as 1 January 2015, China introduced strict environmental legislation[14].

It is yet to be seen how India’s government will tackle this issue.

Pharmaceutical companies should, of course, ensure the quality of their own product and work with partners and suppliers that can guarantee security of supply (meaning that all orders are shipped and received in full on time and in the required quality). To take its responsibility seriously, environmental legislation and good manufacturing practice must be fully complied with. Both achievements would be helped by using quality raw materials and by setting high standards for the way medicines are manufactured, including reducing product recalls.

Proper regulation

There should be production and environmental regulation by industry regulators, ideally widely harmonised and enforced by authorities. This is an area where the antibiotics production industry can quickly and effectively make an impact and help reverse the AMR problem by preventing the active antibiotic from entering the environment during the first steps of the production chain, the manufacturing of intermediates and the production of the active pharmaceutical ingredient (API). Only a fully compliant production plant will significantly reduce the environmental impact of antibiotics production.

Regulatory authorities in originating countries and in end markets must work together to ensure compliance with the highest industry standards. Regulators must also pay increased attention to environmental compliance and take enforcement actions if necessary.

In the United States and the European Union, strict regulatory regimens govern pharmaceutical production and environmental protection, enforced by respected organisations, including the FDA, the EDQM and local environmental authorities. In the United States, the production plant and the final product must be FDA approved. Enforcement of these regulations is done by inspections by regulatory authorities and by intermediate and API customers themselves. Ultimately, regulation must attack the challenge from several sides to be successful.

Better market regulation and stopping the sale of antibiotics over the counter, as is the case in India and China, would help reduce misuse. Antibiotics should only be available on prescription from a doctor and dispensed by a pharmacist, who can give important advice on correct use and disposal.

Industry needs to promote the prudent use of antibiotics. By sharing its data on production and consumption, its knowledge on antibiotics in general, and by supporting education and knowledge sharing, the pharmaceutical industry can fulfil its broader product stewardship role. Pharma needs to be involved in the public debate around its products.

The industry also needs to start self-regulation. It is in the interest of drug manufacturers to adhere to high standards and request high standards from suppliers to make sure their medicines are of the highest quality and to protect their brands and reputation. This is a clear economic incentive.

The pharmaceutical industry has had its share of bad publicity in recent years (including the lack of transparency with clinical trial data) but it has an opportunity to make a difference by joining the fight to combat AMR, not contribute to it.