New certification system could promote responsible antibiotic manufacturing

Workers taking water samples

Chayantorn / iStock

Editor's Note: This story was updated on June 8 with comments from Fatema Rafiqi of the Access to Medicine Foundation.

A new certification scheme launched today aims to minimize the environmental risks posed by antibiotic manufacturing.

The Minimized Risk of Antimicrobial Resistance (AMR) certification, developed by the British Standards Institution (BSI) in collaboration with the AMR Industry Alliance, provides third-party independent verification that the antibiotic waste released into the environment by companies that manufacture antibiotics and their raw ingredients is "appropriately controlled." That means the concentration of antibiotics in the waste streams need to be below a threshold that could promote AMR in the environment.

The certification will attest to the fact that pharmaceutical companies and the facilities that produce antibiotics are meeting the responsible manufacturing guidelines developed last year by BSI and AMR Industry Alliance. Representatives of the groups say they hope the certificate will encourage the industry to prioritize responsible production of antibiotics and minimize a potential source of drug-resistant pathogens.

"I think this has the potential to be a game-changer across the antibiotic supply chain," Steve Brooks, manufacturing working group chair for the AMR Industry Alliance, told CIDRAP News.

Addressing AMR in the environment

While the effort to ensure that antibiotics are being manufactured responsibly is part of a wider move to encourage sustainable drug production, it also stems from a growing concern about the environmental aspect of AMR. Overuse of antibiotics in human and animal health is considered the primary factor in the rise and spread of AMR, but there is growing concern that the release of antibiotic residues into waterways—and subsequent interaction with bacteria—contributes to the problem.

"The environment has received limited attention in tackling AMR, but evidence shows that the environment plays a key role in the development, transmission and spread of AMR," the United Nations Environment Programme said in a report published earlier this year.

Antibiotic residues are released in waterways from a variety of sources. Hospital wastewater, farms, and sewages systems—all of which can contain excreted, unmetabolized antibiotics and resistant microorganisms—are among them.

Antibiotic manufacturing sites, which release antibiotic-laced wastewater into nearby waterways, are another. According to a CIDRAP-ASP report, approximately 20,000 tons of pharmaceuticals, including antibiotics, are produced at active pharmaceutical ingredient (API) manufacturing sites in India. Research by environmental groups in India has found high levels of antibiotics and strains of multidrug-resistant pathogens in waters near some of those sites, which are largely unregulated.

I think this has the potential to be a game-changer across the antibiotic supply chain.

Brooks said that while there is currently no way to quantify the human health risk posed by pollution from these manufacturing sites, members of the AMR Industry Alliance, several of which have factories in India, felt like this was an area where they could "lay down expectations" and lead by example.

The first step was the creation of the Antibiotic Manufacturing Standard, which requires antibiotic manufacturers to have an effective environmental management and wastewater treatment system that minimizes API discharges in wastewater. The standard requires antibiotic concentration at the release point to be less than the predicted no-effect concentration, or PNEC. That's the level at which the chemical or compound in question doesn't have a toxic effect, or in this case won't promote the development of resistance.

Brooks likened the concentration allowed to a "cube of sugar in an Olympic-sized swimming pool."

"We believe our endpoint is robust and protective," he said. "That means the selective pressure on the bacteria in the environment at that point is going to be such that it wouldn't cause increased mutation of bacteria and therefore would be unlikely to lead to increased resistance."

Multi-stage assessment process

To receive certification that they are actually meeting the standard, pharmaceutical companies—and the sites where they have their antibiotics manufactured—will undergo a multi-stage assessment process conducted by BSI. The second stage will involve testing the wastewater discharge at manufacturing sites to see if the PNEC that's been determined for the manufactured antibiotic is met.

"That's the ultimate test as to whether or not the certification is going to be granted to the manufacturer," said Courtney Soulsby, global director of healthcare at BSI. The certificates will be uploaded onto a publicly available website.

BSI will certify individual antibiotics at the site of where the finished drug product is made as well as at the sites where the API is produced. So if the API for an antibiotic is made at multiple sites, all those sites will need to be certified. Soulsby added that the certification process is not a just a stop-in-time assessment but an ongoing process.

"The certificate will be valid for 3 years, and in the in-between years we will do a surveillance assessment," she explained. "Then, at the end of the 3 years, we will recertify the product with the intent of some level of continuous improvement being shown."

Soulsby said the certification scheme is targeting key antibiotic supply chain markets like India and China, and that BSI has sought input and engagement from a wide range of companies and other stakeholders to ensure that the certification process is appropriate for all types of members. She also noted that she's seeing interest from groups that want to have independent assurance that antibiotics are being produced in a way that meets environmental standards, like health system procurers and green investment companies.

Fatema Rafiqi, PhD, of the Access to Medicine Foundation, which evaluates the steps taken by pharmaceutical companies to limit antibiotic waste in its annual AMR Benchmark report, says the certification is an important step toward more responsible antibiotic manufacturing.

"To curb AMR it is critical that companies take the needed action to actively implement responsible manufacturing practices, limiting the release of antibiotic waste into the environment," she said. "The Certification to the Antibiotic Manufacturing Standard is a commendable and positive stride towards fostering responsible manufacturing across companies that manufacture antibiotics."

Several members of the AMR Industry Alliance, which includes more than 100 pharmaceutical companies, biotechs, diagnostic companies, and generic drug makers, have already participated in a pilot program to help shape the certification program. Brooks says efforts are now underway to promote to the certification scheme to other members, as well as companies outside the alliance. There will also be outreach to companies that produce veterinary and agricultural antibiotics.

"We want to have a level of awareness raised in those industries as well," Brooks said.

Brooks says the hope, ultimately, is that more companies in the industry will seek certification and help bring some trust, verification, and transparency to the antibiotic supply chain.

"Hopefully, [the certificate] will provide the assurance that you would need to a procurer, or as a stakeholder with an interest, that a company was in fact meeting the requirements," Brooks said. "I think what we're doing here goes a long way toward addressing transparency concerns."

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