AMR Alliance Follows Up Global Industry Standard With Responsible Manufacturing Certification

BSI Certification Is Open To Any Manufacturer, For Any Drug

This article originally appeared in Generics Bulletin.

Following the publication of the globally applicable antimicrobial resistance industry standard in June 2022, the AMR Industry Alliance, in collaboration with the British Standards Institution, has launched a new global certification designed to promote the responsible manufacturing of antibiotics. The certification, which can be adopted by any manufacturer across the global supply chain for each of its products, focuses on minimizing the risk of aquatic toxicity to the environment and controlling the spread of AMR.

The certification has been designed to encourage antibiotic manufacturers and their supply chain partners to prioritize the sustainable production of these medicines, ensuring that they are produced responsibly and minimizing the risk of releasing antibiotic waste emissions into the environment.

Developed by the BSI to support the standard published last year, the new certification will offer independent third-party verification that waste streams containing antibiotic active pharmaceutical ingredients and drug products are being appropriately controlled by the manufacturer during the production process. The program will involve an initial evaluation, followed by annual surveillance to ensure standards are still being met over time. After three years have passed, manufacturers will need to restart the process and go through recertification for their products.

The BSI took the 2022 manufacturing standard and used it to formulate a manual to govern how it could go about assessing manufacturers and the products they make, the organization’s global director of healthcare and life sciences Courtney Soulsby explained to Generics Bulletin.

“The assessment manual development was managed through a multi-stakeholder engagement process,” she said. “We ran workshops with industry and with manufacturers to understand their technical input, of which the AMR Industry Alliance was the main leading charge, as well as engaging procurers, the World Health Organization and NGOs, to gain their input into the way we assess and the output that they would want to see on a certificate as part of the deliverable of an assessment.”

The certificate applies not to manufacturers as business entities but to individual finished antibiotic drug products as well as APIs. “On the certificate,” Soulsby said, “you will have the product name, the stage and the manufacturing site the certificate is attributed to.”

All antibiotic manufacturers globally will be eligible to seek BSI’s certification, with generic and innovator companies including Centrient, Pfizer, Roche, Sandoz, Teva, Viatris and Haupt Pharma Latina already seeking independent evidence of their compliance to the industry standard after having participated in an initial pilot program to help develop the scheme.

Certification Hinges On Predicted No-Effect Concentration

The process, Soulsby explained, starts with a desktop review to understand how a product is realized, assessing the documentation used to support the controls of wastewater discharge from the manufacturing site and ultimately the batch flow process. Assessors will then arrive on-site for stage two, where they follow the product either live in production or through a simulated manufacturing process.

AMR Industry Alliance advisor Steve Brooks said: “They’re checking that the management system that is in place to produce that antibiotic and to manage the waste streams is correctly described, correctly operated and that operators understand what they have to do. In other words, that there is not only a consistent production of the antibiotic, but a consistent way in which waste is managed, controlled and minimized every time that production is run.”

Receipt of the certification hinges on whether the manufacturer can demonstrate that any waste that ends up in the environment as a result of its antibiotic manufacturing activities is under the predicted no-effect concentration for the compound.

“We have what we believe are levels of antibiotic concentrations in the receiving environment, say a river, that we believe to be unlikely to increase risk of resistance,” Brooks said. “Notionally, we’ll call them safe concentrations. They’re very small, like a sugar cube in an Olympic swimming pool, parts per billion typically.”

The PNEC can be measured by calculating mass balance, “looking at all the inputs and all the outputs from the process and understanding exactly where your antibiotic is going through the production process,” Brooks said. Some active ingredients will be lost when cleaning and sterilizing equipment, for example, or in a waste stream from the production process.

The second option, often carried out in conjunction with calculating mass balance, is to take a sample of a drug’s waste stream and analyze the concentration of antibiotic within it. PNEC levels are “the ultimate test to receive a certificate,” said Soulsby.

The Benefits Of Voluntary Certification

Ultimately, the process for managing antibiotic emissions is “no different from what we do with other environmental emissions,” Teva environmental compliance lead Michael Mahoney said.

“We have internal standards, that go beyond regulation, that apply to all our facilities globally,” he continued. “They establish minimum requirements for having a management system and for assuring that the emissions of any pollutants from the site are understood, in terms of magnitude and amount. We then have an expectation that the impact of those releases is evaluated, not only within the fence line and the potential impacts to colleagues but at the fence line so we don’t have an adverse impact on the community.”

The Alliance’s new certification is open not just to its members but to any antibiotic manufacturer, anywhere in the world, across the entire global supply chain. While the new certification is a voluntary one, and no manufacturer is under any obligation to undertake it, there’s an argument to be made for the superiority of voluntary schemes like this one compared to national regulations.

“AMR regulations,” Mahoney notes, “for the most part, haven’t kept pace with the science. We feel as a responsible pharmaceutical company that we have an obligation to address this even if the regulations don’t require us to address it.”

Voluntary commitments like the certification all require additional resources and costs to undertake. In some situations the assessment will reveal that further measures need to be taken during the antibiotic manufacturing process to minimize AMR impact, which will inevitably add to a company’s cost of goods.

“We’re doing it because we know it’s the right thing to do,” said Mahoney. “We have a cost disadvantage because of that, in effect, so we’re really excited about the certification because it brings more recognition to why this is important.”

This cost disadvantage can be particularly acute for a generics firm where margins are lower, he explained, meaning adding to cost of goods can be a bigger risk in a market which is highly competitive on price.

But while there is a cost sacrifice involved in meeting voluntary, above-regulation standards for AMR prevention, the practice can still give a pharmaceutical firm a competitive edge. “Buyers of antibiotics, we hope, will recognize through the certification that we’re manufacturing our antibiotics in a responsible fashion,” Mahoney said. “I think it will cause them to look at the other antibiotics they buy and ask questions.”

He continued: “I think what will happen is that those companies will recognize that for them to continue to be able to sell into that market they need to step up their game and come along and meet the standard and eventually get certification. We’re really hoping that the end result is that this effort will bring the supply chain into a uniform, responsible manufacturing approach using the standard and the certification.”

In the absence of existing regulation on a specific topic, voluntary standards and certification can sometimes be what is best suited to an industry. “It’s a way for proving good practice ahead of regulation, but also standards can inform the shaping of the future of regulation as well,” said Soulsby. Referencing industry standards, she explained, can be a useful way for regulators to shape new laws.

Expanding to India

Brooks also noted that the ideal regulatory conditions for one market may not be suitable for another. “Most of the folk calling for regulation are in the northern and western hemispheres, as it were,” he said. “Most of the people and most of the places they would like to regulate are on the opposite sides of the globe. What we have is a global solution. Just to use Mike as an example, Mike is exerting influence around the globe through his Teva sites and their supply chain, and that’s replicated across all our members in the Alliance. We truly hope that with certification and BSI’s help, we’ll be able to drive this across even more supply chains globally.”

The BSI and the Alliance are planning a dedicated launch of the certification specifically for the Indian market, which contributes 57% of the WHO’s pre-qualified list of APIs.  “There is a sensitivity,” said Brooks, “that the western world is pointing at places like India and saying ‘hey, you’re the problem’. The issue applies around the globe, in the US and in Europe, there’s just much more manufacturing in India because the magnitude of the issue is bigger.”

“In India, on the ground, I have had experience on a project trying to encourage Indian suppliers who don’t have any kind of regulatory requirement to do this kind of assessment and evaluation, and to be fair it really is hard work. They don’t necessarily understand why they need to do it and they’re concerned about cost.”

“None of that goes away with this approach to certification, but I think as it begins to get a value in the marketplace, that is what’s going to change the game.”