ANTIMICROBIAL RESISTANCE (AMR) PROGRAMME

Methods matter: What steps arecompanies taking to help curb AMR
by manufacturing responsibly?
AUGUST 2023

The discharge of antibiotic waste that contains active
pharmaceutical ingredients into the environment is one of thedrivers of antimicrobial resistance (AMR), which is a hugely
significant threat to global public health. By responsibly
managing and disposing of their antibiotic manufacturing
waste, pharmaceutical companies can help curb thedevelopment and spread of AMR. Some companies are alreadytaking steps to employ responsible manufacturing practices,
however, more needs to be done to make a greater impact
in the fight against AMR. This report highlights three areas
companies can focus on to boost their efforts.

AMR report on responsible manufacturing

ACKNOWLE DG E M E NTS
The Access to Medicine Foundation would like to thank the following
people and organisations for their support.
FU N D E RS

UK Foreign, Commonwealth and Development Office
The Dutch Ministry of Health, Welfare and SportAXA Investment Managers

AUTH O RS

E D ITO R IAL TE AM

E XPE RT R E VI E WE RS

Martijn van Gerven

Jana Jacobs

Joakim Larsson, University of Gothenburg;

Fatema Rafiqi

Mark Montforts, RIVM, the Dutch National Institute for
Public Health and the Environment

ACCESS TO M E D I CI N E FO U N DATI O N

The Access to Medicine Foundation is an independent non-profit organisation that seeks to transform the healthcare ecosystem by motivating
and mobilising companies to expand access to their essential healthcare
products in low- and middle-income countries.
Naritaweg 227-A
1043 CB, Amsterdam
The Netherlands
For more information about this publication, please contact
Marijn Verhoef, Director of Operations and Researchmverhoef@accesstomedicinefoundation.org+31 (0) 20 215 35 35
www.accesstomedicinefoundation.org

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AMR report on responsible manufacturing

Table of contents

About this report3This report is part of the Access to Medicine Foundation’s Antimicrobial

About this report

Resistance (AMR) Programme, which works to move pharmaceutical4	Executive summarycompanies in responding to the growing challenge of drug-resistantinfections. The AMR Programme’s publications – including both the AMR

7Current state of play

Benchmark (published in 2018, 2020 and 2021) and targeted thematic
reports such as this – focus on how pharmaceutical companies perform10

How companies can step up toin terms of taking action on identified priorities to address AMR.

manufacture responsibly
11

Employ effective methods

HOW TH IS RE PO RT WAS D EVE LO PE D

to reduce AMR risks
16

Promote compliance with discharge

The case studies, discussion and recommendations in this report have

limits across the supply chain

been drawn from research published in the 2021 AMR Benchmark, as

20

Disclose actions transparently

well as from recent interviews with selected companies. Consultations

23

Why is responsible manufacturingorganisations, investors, academia and policymakers. The report was

becoming an operational andfurther informed by sources available in the public domain, including

business priority for companies?

peer-reviewed literature, company and global health reports, policy liter-

were also held with relevant expert stakeholders, including procurement

ature and government documents. The information collected from the29	Staying ahead of the curve

sources was cross-checked to ensure accuracy, including directly withcompanies and other stakeholders, as appropriate and relevant.

32	Definitions
SCO PE O F TH E RESE ARCH
33

References
CO M PAN I ESThis report includes case studies on pharmaceuticalcompanies – including large research-based companies,
generic medicine manufacturers and business-to-businesssuppliers – that manufacture antibiotics and antifungal
medicines. It considers both a) companies’ directly operated manufacturing sites, and b) companies’ third-party
supplier sites. The following companies are specificallymentioned in the report: Abbott; Aurobindo; Centrient;
Fresenius Kabi; GSK; Pfizer; Novartis and its generics
unit, Sandoz*; Shionogi; Teva, and Viatris. Data was also
analysed from the following companies’ previous submissions to the 2021 AMR Benchmark: Alkem, Cipla, Hainan
Hailing, Johnson & Johnson, MSD, Otsuka, Sanofi and Sun
Pharma.
PRO D U C TS

This report looks at marketed antibiotic and antifungal
medicines.

*Novartis has announced that it will separate its generics
division, Sandoz, into a standalone company by way of a
100% spin-off, planned for Q4 2023.1

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AMR report on responsible manufacturing

Executive summary
Antimicrobial resistance (AMR) is a serious global health threat that already kills
millions of people worldwide each year. And the threat is growing.
Tackling this urgent issue requires comprehensive approaches that target thevarious drivers of drug resistance. While the overuse and misuse, as well as lack ofaccess to appropriate antibiotics, are among the well-known drivers of AMR, it is
becoming increasingly clear that releasing antibiotic waste into the environment
can also fuel rising drug resistance.
When antibiotics are manufactured, waste that is generated is discharged into
the environment – particularly into rivers that are used for drinking water andagriculture. If this waste contains high levels of active pharmaceutical ingredients(APIs), it poses a serious risk to the emergence and spread of AMR while also
causing environmental harm.
It is therefore vital that pharmaceutical companies engage in responsible
manufacturing practices that ensure their lifesaving medicines are produced in a
way that does not – as an unintended consequence – have a detrimental impact onhuman health and the environment.
Pharmaceutical companies play a critical role in reducing the impact ofantibiotic waste in the environment
Globally, antibiotic manufacturing supply chains are complex, involving multiple
producers that supply partners with APIs and drug products. At the same time, thesupply chains for antibiotics are also highly fragmented. There are several important upstream supply stages, with many suppliers available at some of these points,
and very few at other vital stages – with the consequence that there is often aheavy reliance on a limited number of producers of a certain API, for example.
Among the various players across antibiotic manufacturing supply chains,
pharmaceutical companies with marketing authorisations are among the largest,and can have the biggest impact on transforming the industry. Not only do theyfrequently operate their own manufacturing sites, but they also contract awide range of third-party suppliers, manufacturers, wholesalers, and retailers.
Pharmaceutical companies are therefore uniquely positioned to influence andshape responsible manufacturing practices across the supply chain – starting attheir own manufacturing sites.
However, previous research by the Access to Medicine Foundation – as partof the 2021 Antimicrobial Resistance (AMR) Benchmark – has found that many
pharmaceutical companies have not yet taken effective action to address AMR risks
in their manufacturing processes and supply chains.
To support and enable progress, the Foundation has developed this report. By

INSIGHTSThe company examples assessed in thisreport clearly illustrate that it is possible
for companies – regardless of size – totake progressive steps in implementing
responsible manufacturing practices at theirown manufacturing sites and those of their
suppliers.
Companies with ≥ 10 directly operated
manufacturing sites:• GSK reports that 100% of supplier sites
are compliant with discharge limits, while
Pfizer reports this for over 86% of its
supplier sites.
• Abbott offers support for its contracted
manufacturing suppliers in conducting
wastewater analysis more efficiently, freeof charge.
• GSK, Teva and Viatris publicly
report specific details of their waste
management practices.
Companies with < 10 directly operated
manufacturing sites:• Centrient reports that 100% of its suppliersites are compliant with discharge limits,
while Shionogi reports this for 71% of its
supplier sites.
• In consultations for this report, Shionogi
stated achieving compliance directly in
its wastewater for all five antibiotics it
manufactures: cefiderocol, flomoxef,
latamoxef, doripenem and cefcapene
pivoxil.
• Centrient implements a comprehensive
waste-treatment process to achieve endof-pipe compliance at its site in Toansa,
India.
• Centrient and Shionogi publicly
report specific details of their waste
management practices, with Shionogi
disclosing the status of compliancewith discharge limits and location of its
suppliers.

zeroing in on responsible manufacturing practices, it identifies specific areas thatcompanies need to focus on, and the steps they can take, to develop and maintainsolutions that will help them limit their antibiotic waste more effectively.

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AMR report on responsible manufacturing

Steps companies can take to ensure they manufacture responsibly
The company examples analysed in this report demonstrate the feasibility of progressing in these areas – with recommendations aimed at guiding leaders on how
to boost their efforts, and showing others what they need to do to step up.
Firstly, companies need to prioritise effective wastewater management
methods to establish, quantify and monitor discharge limits for ensuring theirwastewater safety.
A discharge limit indicates the highest concentration of APIs that can be present
in wastewater at which no resistance is expected to occur. Among the companies
evaluated in the 2021 AMR Benchmark, those that quantify APIs all carry out such
estimations after their wastewater has been released into a river or waterway.
However, this means that the estimated concentrations will be diluted. It is, rather,in undiluted wastewater where bacteria are first exposed to antibiotic waste, withthe risk of resistance already occurring here. If companies were to comply with limits before releasing their wastewater (i.e., assessing concentrations before they are
diluted in a river, for example), this could significantly reduce the risk of exposing
bacteria to APIs.
To date, no company reports actively applying discharge limits in their wastewater before releasing it. In fact, many companies are still struggling to achievecompliance with limits in rivers, let alone before releasing wastewater. However,two companies in scope of this report demonstrate clear, effective approaches tomitigating AMR risk in wastewater before releasing it into the environment. BothCentrient and Shionogi utilise extensive and comprehensive waste treatment processes to ensure wastewater safety, with Centrient also conducting regular monitoring of its wastewater by taking monthly wastewater samples and testing antibiotic concentrations each quarter.
These examples demonstrate that even though reaching full compliance ofwastewater before it is released into the environment may be a longer-term
endeavour, it is possible for companies to try and maximise their efforts to ensure
the safety of their wastewater before discharging it.
Secondly, companies can utilise their unique positions in the antibiotic supply
chain to transform the industry.
Over and above employing effective waste management practices at their own
manufacturing sites, companies can also ensure that their suppliers comply with
discharge limits, as demonstrated by four companies in scope of this report.
Centrient, GSK, Shionogi and Pfizer report that either the majority of their suppliers, or all of them, comply with discharge limits set for the receiving environment.
To hold suppliers accountable, companies can, for example, include contractual
clauses and provisions to comply with discharge limits to reduce AMR risk. Where
possible, companies can enforce such contracts with non-compliant suppliers andseek an alternative supplier, as available.
However, given that there are often limited suppliers for certain APIs and drug
products, companies consulted for this report stated that they prefer to build longterm relationships with suppliers. Notably, Abbott demonstrates this by offering
support for its contracted manufacturing suppliers in conducting wastewater
analysis more efficiently, free of charge.
If more companies take proactive steps to support their suppliers in suchpractical ways, we will see responsible manufacturing progress without jeopardisingsustainable and secure supply of antibiotics to patients.

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AMR report on responsible manufacturing

Finally, it is crucial for companies to ensure transparency and accountability
along the supply chain.
When companies take action to mitigate AMR risks through responsible manufacturing, it is critical that they provide clear information about the initiatives andprocesses that are being implemented at their own manufacturing sites, and how
they are monitoring supplier compliance. Not only will this allow for accountability
across the supply chain, but it can offer much-needed insights into the relationshipbetween wastewater management and AMR.
However, overall transparency along the supply chain is currently lacking. Whilesome companies assessed by the AMR Benchmark and this report do disclose
whether they meet discharge limits, for example, they do not provide clarification
on how they achieve this, such as details on how concentrations are quantified. This
information can, for example, be valuable in helping experts and other stakeholders
gain a better understanding of the link between AMR and manufacturing.
Centrient, GSK, Shionogi, Teva and Viatris are the only companies to publicly
report specific details on their waste management practices. However, none ofthese companies, or any others, report actual antibiotic discharge levels (at theirown or suppliers’ sites).
What’s next?
At present, the regulatory landscape is underdeveloped and – across the world –there is no regulation specifically targeting antibiotic discharge from manufacturing
sites to help limit AMR. In the absence of regulation, the onus is largely on pharmaceutical companies to take voluntary action and seize opportunities to reduce theirimpact on the environment and AMR. As this report identifies, there are a handful ofleading companies that demonstrate that this is entirely possible. However, overall
industry efforts are still not going far enough, and more companies will have to stepup.
Moreover, with AMR gaining prominence on multilateral and national agendas,
stakeholders – including governments, regulators, procurers, and investors – arefocusing more keenly on the risks of AMR from manufacturing and are increasingly
expecting companies to demonstrate responsible manufacturing practices.
Beyond taking responsibility for curbing AMR, the final section of this report
explains why companies need to proactively adopt and scale responsible
manufacturing practices from a business and operational perspective.
Procurers, for example, who can consider criteria related to the environmentand sustainability when making purchasing decisions, are increasingly expecting
companies to demonstrate comprehensive and effective practices to limit antibiotic
waste. More investors also now view AMR as a systemic risk that needs to beconsidered within environmental, social and governance (ESG) standard-setting andreporting frameworks. There are also signs that regulation aimed at reducing AMR
risk from manufacturing may be introduced, or strengthened, in several countries.
For companies that prioritise their environmental impact, and recognise theirrole in tackling global health issues, responsible manufacturing can further ensure
their sustainability within a global health landscape that is increasingly focusing on
AMR and the factors that fuel it.
By acting now and investing in responsible manufacturing, companies will not
only help curb this global health threat, but can set themselves apart in the market.

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AMR report on responsible manufacturing

Current state of play
Antimicrobial resistance (AMR) is rising fast and, as of 2019, the World HealthOrganization (WHO) has declared it to be one of the top ten global public healththreats facing humanity.2 In 2019 alone, the deaths of 1.27 million people weredirectly attributed to antimicrobial-resistant infections, and it is the people living in
the world’s poorest countries that experience severe levels of AMR and the highest
rates of infectious disease.3
Among the drivers of AMR – which include overuse and misuse of antibiotics,
as well as lack of access to appropriate antibiotics – is antibiotic waste that isdischarged into the environment during the manufacture of antibiotics.4,5During the manufacturing of antibiotics, large quantities of concentrated waste
are generated. While solid waste is typically sent for incineration or to landfill,liquid waste from antibiotic manufacturing is discharged into the environment
via receiving waters (i.e., rivers and waterways). When this waste is not properly
treated and managed before it is released, high concentrations of active
pharmaceutical ingredients (APIs), as well as antibiotic-resistant bacteria andtheir resistance genes, are discharged into the receiving waters.6,7 Not only is thispotentially harmful to human and animal health, but there is also a serious risk it willcontribute to AMR (see Figure 1).4
It is therefore critical that companies take responsibility for, and are cautious
about, their manufacturing processes. This includes the way in which wastewater istreated before it is released into receiving waters, as well as setting and complying
with safe discharge limits on antibiotic waste.

FIGURE 1 How antibiotic waste can contribute to AMR
Exposing naturally present and typically harmless bacteria to highly concentrated antibiotics can resultin a process known as selective pressure, where the bacteria that are susceptible to the antibiotics
present in the wastewater are killed off, leaving the bacteria with evolved resistance genes to survive,
multiply and even transfer resistant genes to other bacteria through the process of horizontal genetransfer. As antibiotic resistant genes spread in the environment, they also spread to human and animal
populations resulting in antibiotic resistant infections that are hard, or impossible to treat.8,9Antibiotic waste

Resistance is naturallyHigh concentrations of active

Resistant bacteria can multiply,

Resistant bacteria can transfer

present in typicallypharmaceutical ingredients

leading to the emergence ofresistance genes to harmful bacteria,

harmless bacteria.

(APIs) kill off bacteria thatnew forms of resistance.

which can result in antibiotic-

are susceptible, leading to theresistant infections in humans.

selection of resistant bacteria.

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AMR report on responsible manufacturing

The pharmaceutical industry’s response to the issue
Currently, there are no independently developed global standards or regulations
aimed at specifically curtailing antibiotic residues in wastewater to help limit AMR.10
However, particularly since 2016, multi-organisational approaches have led to theestablishment of tools and basic guidance to support pharmaceutical companies inlimiting their antibiotic waste from manufacturing.
While these initiatives and platforms are encouraging, it is ultimately up tocompanies to take voluntary action to limit the release of antibiotic waste into
the environment. Importantly, companies can build on the minimum requirementsof these guidelines to further develop, implement, and expand their responsible
manufacturing practices to limit AMR risk more effectively.

2006

The Pharmaceutical Supply Chain Initiative establishedThe Pharmaceutical Supply Chain Initiative (PSCI) provides companies withtools to support responsible manufacturing. This industry coalition wasformed to establish and promote responsible practices across members’
supply chains and, in particular, to make supplier assessments more efficient.

2016

First-ever collaborative response from industry on AMR
The 2016 World Economic Forum (WEF) in Davos marked the first timethat the pharmaceutical industry engaged collaboratively to address therising risks of AMR, including the impact of manufacturing. Following thesigning of the “Declaration by the Pharmaceutical, Biotechnology and
Diagnostics Industries on Combating Antimicrobial Resistance’’ by morethan 80 companies and associations at WEF, 13 companies signed the“Industry Roadmap for Progress on Combating Antimicrobial Resistance”,
which set out clear commitments from companies on addressing
environmental pollution associated with antibiotic manufacturing.11,12 This
was also a catalyst for the establishment of the AMR Industry Alliance in2017, which represents a coalition of companies and associations and aims
to drive progress on AMR by the life sciences industry.

2018

AMR Industry Alliance publishes Common Antibiotic Manufacturing
Framework
In 2018, research-based and generic pharmaceutical companies in the AMR
Industry Alliance agreed on a Common Antibiotic Manufacturing Framework,
which described a risk-based approach to assessing and controlling antibiotic
waste streams from manufacturing.13 The framework provided a methodology and set of minimum requirements needed to conduct risk evaluations ofantibiotic manufacturing sites in the supply chain. In 2022, the AMR Industry
Alliance formalised the framework to become the Antibiotic Manufacturing
Standard.

2022

AMR Industry Alliance formalises Antibiotic Manufacturing Standard
In the absence of independent regulation targeting the AMR risk fromantibiotic manufacturing, the AMR Industry Alliance developed its Antibiotic
Manufacturing Standard, facilitated by BSI Standards Limited (BSI).14
This framework provides guidance and serves as a self-assessment tool
for manufacturers in the global antibiotic supply chain to encourage theresponsible manufacture of antibiotics. The goal is to minimise both theecological effects and the risks of AMR in the environment. However,the framework has been subjected to criticism regarding its scientificfoundations.15

2023

Minimised Risk of AMR Certification Programme launched
In June 2023, BSI launched the global Minimised Risk of Antimicrobial
Resistance (AMR) Certification Programme. This certification programme isopen to the entire antibiotic supply chain and was initially piloted by several

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AMR report on responsible manufacturing

companies, including Centrient, Pfizer, Roche, Sandoz (100% spin-off from
Novartis set for Q4 2023), Teva, and Viatris.1 The programme includes thethird-party verification of production waste streams containing APIs toensure they are quantified and controlled during manufacturing and meet
predicted no-effect concentrations (PNECs) in the receiving environment.
The certification process involves initial conformance evaluation against
the Antibiotic Manufacturing Standard of the AMR Industry Alliance andannual surveillance to maintain compliance, leading to a three-year validity
to the certificate for that product.16 Companies holding a valid certificate
are responsible for ensuring ongoing effective waste management andreassessing and managing risks in relation to changes in production volumes
or waste treatment technologies. While all antibiotic manufacturers are
eligible for certification, motivations to participate will depend on factors
such as company drivers to minimise antibiotic waste, cost and financial
investment drivers, procurers’ criteria for rewarding the certification,
stakeholder expectations and environmental considerations.

Why actions from pharmaceutical companies can have a significant impact
It is important to note that the pharmaceutical market for manufacturing antibiotics is sprawling and complex, with manufacturing sites worldwide varying in sizeand capacity. While some sites are large and well-structured, others are smaller andmay specialise in manufacturing a single antibiotic. At the same time, supply chainsfor antibiotics are also highly fragmented, consisting of many players at somestages and very few at other vital stages – with the consequence that there is often
a heavy reliance on a limited number of producers of a certain API that is needed to
manufacture an antibiotic, for example.17
Despite these challenges, the steps pharmaceutical companies take to develop
responsible manufacturing practices can have a broader impact across the supply
chain.
As a starting point, companies can prioritise responsible manufacturing
practices at the manufacturing sites that they operate directly. But pharmaceuticalcompanies are also uniquely positioned to influence and shape the standards of thewide range of third-party suppliers, manufacturers, wholesalers, and retailers they
contract across the supply chain. Specifically, they can extend their expectations to
suppliers and hold them to account. Where suppliers for a particular API are limited– or a smaller supplier lacks the resources to develop responsible manufacturing
practices – pharmaceutical companies can support them.
This report maps out clear actions by a handful of leading companies that are
not only taking responsibility at their own manufacturing sites, but also show how
they are promoting responsible practices at their suppliers’ sites. These examples
demonstrate that working towards developing and implementing effective,
sustainable manufacturing practices is entirely feasible – and that progress can be
made.

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AMR report on responsible manufacturing

How companies can step up to
manufacture responsibly
Over the last six years, the Foundation’s AMR Benchmark has analysed
the manufacturing practices of pharmaceutical companies, finding thatwhile some progress has been made in addressing antibiotic waste
released into the environment, significant gaps remain.18
To examine the issue more closely, and to identify potential solutions,the findings and analyses in this report zero in on positive examples ofwhat a small number of leading companies are doing to minimise theimpact of their antibiotic manufacturing on AMR and the environment.
This report sets out three key areas of focus for companies to drive
further progress:
1.

Employ effective methods to reduce AMR risksFirstly, companies need to set and adhere to safe discharge
limits and minimise the impacts associated with manufacturing
antibiotics. This section sets out the various methods that are
best suited to achieving this.

2.

Promote compliance with discharge limits across the supply
chainOver and above ensuring compliance with discharge limits attheir own manufacturing sites, companies must work with their
third-party suppliers to support them in limiting antibiotic waste.

3.

Disclose actions transparently
Publicly sharing information on the actions taken by companies
and suppliers promotes accountability, allows progress to be
tracked, and facilitates further advancements in addressing
challenges. Transparent reporting also encourages others tofollow suit, fostering ongoing progress.

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AMR report on responsible manufacturing

1. Employ effective methods to reduce
AMR risks
When releasing wastewater into the environment, companies need to ensure

The importance of differentiating PNEC riskthat the levels of antibiotic concentrations discharged are within safe limits. As
identified by the AMR Benchmark, companies generally do this by setting limits
based on the predicted no-effect concentrations (PNECs). Companies then comply
with their PNEC-based limits to ensure that the levels of antibiotic residue in theenvironment remain below concentrations that could cause harm to ecosystems
and contribute to the development of resistance (see sidebar).

It is important to note that industry currently
assesses for two distinct risks presented
by their wastewater: resistance selectionand ecological effects in the environment.
However, the current approach is to combine
these two predicted no-effect concentrations(PNECs) to form a single risk assessment

However, companies can go further and employ more robust methods tobased on the lowest PNEC. Differentiating

measure and to apply limits to maximise the effectiveness of their wastewater

these risk assessments would provide formanagement.

a more comprehensive understanding andConsidering the latest research in the field, and guidance from experts, there arethree key areas companies can address to further mitigate the risk of AMR frommanufacturing: a) where to apply limits, b) quantifying antibiotic concentrations andc) waste management strategies for intermediates.

targeted mitigation of the specific risks
involved.
• Resistance selection risk:
Should compare PNECs with exposure in

A select few companies have already taken proactive measures in these key

wastewater.

areas, setting the example of how companies can do more to ensure the safety of
their wastewater.

• Ecological effects risk:
Should compare PNECs for ecologicaleffects in the recipients of wastewaterA) Where to apply limits(such as rivers).

Among the companies evaluated in the 2021 AMR Benchmark, those thatmonitor compliance with antibiotic discharge limits typically quantify antibiotic
concentrations in the receiving waters. However, it is important to note that
this quantification reflects the diluted wastewater. It is, rather, in the undiluted
wastewater where bacteria are first exposed to antibiotic waste, including
resistance genes already present (see Figure 2).4
Additionally, applying discharge limits to antibiotics measured in the receiving
waters makes it difficult to determine the proportion of antibiotic waste originatingfrom manufacturing as opposed to other upstream sources, such as hospital effluent or agricultural runoff.
FIGURE 2 Where to apply limits for antibiotic discharge
If manufacturers apply antibiotic concentration limits to determine AMR risks, they are set in thereceiving waters (e.g., rivers), where the wastewater has already been diluted, rather than directly in thewastewater at the end of pipe. Wastewater is the first point where bacteria are exposed to antibiotic
waste and the risk of selection resistance occurs.4 Once wastewater is discharged into receiving waters,
gradual dilution occurs. Applying antibiotic concentration limits in receiving waters may not effectively
address the risks associated with resistance selection.

Factory

Applying discharge limitsCompanies apply discharge limits in

before release could be more

receiving waters, where quantification

effective in limiting AMR riskreflects gradually diluted concentrations.

High concentrationsof APIs
Onsite treatment

Wastewater containing

River

APIs and resistantbacteria is discharged
into receiving waters

APIs

Bacteria

Resistant bacteria

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AMR report on responsible manufacturing

When wastewater is discharged into receiving waters, gradual dilution occurs,
which can create a variable “plume” containing APIs that often stretches along
prolonged sections of a river, for example (see Figure 3). Dilution in receiving
waters can reach high levels (up to several thousandfold), which means that
applying PNECs in receiving waters, after dilution has occurred, may not effectively
address the risks associated with resistance selection in the undiluted wastewaterat a manufacturing site.

FIGURE 3 Gradual dilution of wastewater can create a variable ‘plume’
As dilution of wastewater can occur slowly once released into receiving waters, it often leads to a
prolonged section of a river, for example, where the undiluted wastewater forms a variable ‘plume’.

Manufacturing site(including onsite
treatment)
Wastewater

Receiving waters

High concentrations of active
pharmaceutical ingredients(APIs) present in wastewatercan flow for kilometres once
released into receiving waters
before dilution occurs.

‘Plume’APIs

Moreover, a company’s wastewater is often sent to a public wastewater treatment
plant before being discharged into the environment. Wastewater treatment plants
are already recognised as hotspots of resistance selection because they receive
wastewater from municipalities, which can contain high levels of bacteria, as well as
antibiotic residue from human consumption.19,20 If wastewater containing high levelsof APIs is sent to these same wastewater treatment plants from manufacturing
sites, it only poses further risks to the emergence and spread of AMR.
Given the risks associated with only applying discharge limits in receiving waters,
it is critical to consider the dilution factors used during the release of wastewater
to determine its safety. Since bacterial selective pressure occurs rapidly, withinminutes or hours, employing default dilution factors can alleviate the burden of
accurately estimating dilution factors for each manufacturing site. However, thisapproach may result in some degree of over- or underestimation. If the PNEC forresistance selection is directly applied to the wastewater, dilution factors become
irrelevant.

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AMR report on responsible manufacturing

Applying discharge limits directly to wastewater can be more effective in
reducing AMR risk
By applying discharge limits directly to undiluted wastewater before it is released
into receiving waters, companies can minimise AMR more effectively (also see
box-out).
If all companies would apply discharge limits directly to undiluted wastewater, it
is expected that the risk of accumulating high concentrations will be reduced, particularly in cases where several antibiotic manufacturing sites are located near thesame waterway. If a single waterway is exposed to high volumes of antibiotic wastefrom various sources, the proliferation of resistant bacteria is highly likely, as is the

EU legislation around emission limits
Applying limits directly to undiluted wastewater aligns with the Industrial Emissions
Directive (IED), which is the primary piece ofexisting legislation in the EU addressing otherindustrial pollution.
The IED mandates meeting emission limit
values at the point of emission (also see p.25of this report).23

case with the Musi River in India and the Yangtze River Delta in China.21,22
Overall, reducing antibiotic concentrations to achieve compliance is challenging
and requires resource allocation and access to advanced wastewater treatment
technology. Many companies are still striving to achieve compliance with discharge
limits in receiving waters – let alone directly in wastewater.
To date, no company assessed in the AMR Benchmark, or in this report, actively
reports applying limits directly in its wastewater before releasing it into receiving
waters. However, efforts from some companies set encouraging examples of how
to mitigate AMR risk in wastewater before it is released into the environment.
Shionogi and Centrient’s approaches to ensuring safety of wastewater
Notably, while Shionogi only publicly reports compliance with discharge limits inreceiving waters (i.e., after wastewater has been released as guided by the AMR
Industry Alliance), in consultations for this report, the company stated that it does
comply with discharge limits directly in its wastewater for all five of the antibiotics it manufactures: cefiderocol, flomoxef, latamoxef, doripenem and cefcapene
pivoxil*.
To effectively manage antibiotic waste, Shionogi employ’s a two-step process
at its Kanegasaki and Tokushima sites in Japan, which handle the production of
the company’s APIs and drug products. Firstly, the antibiotic waste undergoes
inactivation through alkaline hydrolysis, followed by biological treatment (seebox-out).
Shionogi conducts regular annual monitoring of the antibiotic concentration in
actual wastewater from the plants to ensure the safety of its wastewater.24 The
company also conducts monitoring when there is a change in production volume
or manufacturing procedure. Moreover, annual supplier audits are carried out tomaintain quality control standards. For the proper disposal of solid and sludge
waste, Shionogi relies on its external waste contractor, Eco-system Akita Co., Ltd,
to incinerate the wastes.
Centrient, a business-to-business provider** of antibiotics and antifungals,
implements a comprehensive waste-treatment process to achieve end-of-pipe

Limitations of biological wastewater
treatment
It is important to note that a limitation in theuse of biological wastewater treatments is
the reliance on natural organisms, including
bacteria, to further breakdown the remaining
organic waste. This process increases the riskof exposing bacteria to antibiotics, thereby
amplifying the risk of AMR. To mitigate forthis risk, it is advisable to test the effluent
after treatment.

compliance at its site in Toansa, India.25,26
This site, which is responsible for manufacturing semi-synthetic penicillins, is notnear any waterways in which treated wastewater can be released. Instead, the site’s
waste undergoes primary, secondary and tertiary waste-treatment steps before
being recycled. The recycled wastewater is repurposed for cooling towers andhorticulture. It’s important to note that because this recycled wastewater is used
for horticulture, it is critical that PNECs are not exceeded.
In 2021, Centrient introduced a wastewater treatment option for specificstreams that employs microorganisms without oxygen to degrade organic
contaminants found in wastewater. Additionally, solid waste from packaging, whichcontains traces of intermediates and APIs, undergoes deactivation before being
sent to approved recyclers or a controlled landfill.
*Shionogi reports that the actual concentration is below the limit of detection.
However, when a worst-case scenario was applied based on the limit ofdetection, the concentration would exceed the default discharge limit of 0.05
µg/L by only 4,2 ng/L when applied at the end of the pipe. Since such a worstcase scenario likely overestimates the concentration, Shionogi expects thatcompliance at the end of the pipe is achieved.

**In 2021, Centrient facilitatedapproximately 1.386 billion patient
treatments of penicillins, cephalosporins
and nystatin.25

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AMR report on responsible manufacturing

Sandoz employs method to remove bacteria from wastewater
Although further research is required to establish the precise correlation between
the bacterial quantities in wastewater and resistance selection, it is reasonable toassume that reducing bacterial populations will decrease the AMR risk. Removing
bacteria that are present in wastewater before releasing it could thus serve as anadditional measure to mitigate the risk of resistance.
For instance, Sandoz, (100% spin-off from Novartis planned Q4 2023) has
implemented a membrane filtration process at its primary manufacturing site inKundl, Austria, to effectively remove bacteria from wastewater effluent.1,27 The
Kundl site specialises in the production of beta-lactams and cephalosporins,
covering all production steps from active pharmaceutical ingredients (API) to final
drug products.28
B) Quantifying antibiotic concentrations
When applying discharge limits, pharmaceutical companies must prioritise theimplementation of sensitive detection methods to accurately assess whether theselimits are being exceeded. Failing to do so may lead to the release of hazardous
concentrations of antibiotics, which can contribute to the selection of resistantbacteria.
The current default approach employed by the companies assessed in thisreport and in the 2021 AMR Benchmark to determine antibiotic concentrations is
the mass balance approach. This method relies on theoretical calculations basedon estimated losses during the manufacturing process, as opposed to assessing
antibiotic concentrations in wastewater samples.
The mass balance approach does offer a quick and cost-effective way to identify
potential hotspots and prioritise actions for improvements. However, it remains
unclear whether this method provides the necessary sensitivity to accurately
determine if limits are exceeded, particularly if limits are applied to undiluted
wastewater. Furthermore, it is less transparent than analyses conducted by third
parties, and it does not allow companies to determine the removal efficiency of its
wastewater treatments.
The resolution of the mass balance calculations is another importantconsideration. Specifically, when calculating the average concentrations, companies
should focus on the time elapsed after waste – and any potential active antibiotic
residue – has been discharged. Calculating over a longer timeframe raises concerns
about overlooking peaks characterised by exceptionally high concentrations. For
example, critical steps that take place at a manufacturing site that present highrisks of discharge for residual antibiotics (such as rinses of reaction tanks) may only
take a few minutes, but companies following the guidance of AMR Industry Alliance,
for example, may typically calculate the antibiotic concentrations on a daily average.
Abbott, Centrient and Shionogi’s strategies to quantify antibiotic
concentrations more accurately
In addressing the shortcomings of the mass balance approach, some companies
have implemented strategies to assess antibiotic concentrations in wastewater
samples as either a complementary method, or as part of a verification step.
Company examples include:•

Abbott’s pharmaceuticals division utilises a combination of the mass balance
approach and wastewater analysis to ensure accurate determination ofdischarge limits.

•

Centrient established a standard practice for its own sites, conducting
monthly sampling and quarterly analysis of wastewater samples.

•

Shionogi analyses the antibiotic concentration in actual wastewater to verify
the safe levels of antibiotics in the wastewater that is discharged into thenatural environment.
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AMR report on responsible manufacturing

However, it is important to note that the companies consulted for this report raised
concerns regarding the cost and availability of certified laboratories for conducting
chemical analysis of wastewater samples in a swift and accurate manner in countries like India, where a lot of antibiotic manufacturing takes place. Drawbacks ofsampling also include the retrospective nature and the difficulty in selecting theappropriate moment to collect the sample, thereby risking overlooking discharge
peaks.
As demonstrated by Abbott’s pharmaceuticals division, companies canachieve more accurate monitoring of antibiotic concentrations in wastewater byimplementing a synergistic combination of the mass balance approach and analysis
of wastewater samples.
In consultations for this report, companies also highlighted the potential needfor tailormade approaches to achieve accurate measurements. When quantifying
antibiotic concentrations in wastewater, for example, they can employ different
methods at the various manufacturing sites in their supply chains, depending on
the nature of the manufacturing operation and the type of antibiotic that is being
manufactured.

C) Waste management strategies for intermediates
Antibiotic intermediates are the precursor molecules used in the manufacturing ofantibiotics, and some intermediates can possess pharmaceutical activity, including
antibacterial properties. However, it is important to note that not all intermediates
exhibit the same spectrum of activity or potency as the final antibiotic product.
Additionally, not all antibiotics are synthesised using intermediates with antibiotic
activity. That said, the significant volume of waste generated during the productionof intermediates compared to APIs and finished drug products is a concern.29,30
There is currently a lack of industry guidance on intermediates and among the

Examples of intermediates with
antimicrobial activity 29,31
6-APA: intermediate used in the productionof penicillin derivatives such as amoxicillin andampicillin.
7-ACA and 7-ADCA: intermediates used in the
production of cephalosporins like ceftriaxone
and cefuroxime.

companies covered in this report and the 2021 AMR Benchmark, only Centrient
has taken proactive steps to establish discharge limits for intermediates. Centrient
monitors compliance with discharge limits at relevant manufacturing sites, for
6-APA and 7-ADCA.
Notably, 6-APA,7-ACA and 7-ADCA (see box-out) are intermediates wellknown for having antimicrobial activity.29,31 While the exact contribution of anintermediate’s waste to AMR is not clearly defined, it is important for companies
and their suppliers, who predominately produce the intermediates, to takea cautious approach and include intermediates into their environmental risk
management strategies.

RECO M M E N DATI ONS FOR COM PAN I ES▶

Set discharge limits and apply these limits directly in the wastewater thatleaves the manufacturing site.

▶

Set up long-term plans that aim to support supply chain compliance,
including the setting of discharge limits and where to apply them.

▶

Be transparent on concentrations of antibiotics in wastewater; if a company
only applies limits to the recipient, it must be transparent about the dilution
factors employed.

▶

Combine the mass balance approach with sampling and chemical analysis toassess antibiotic concentrations in wastewater as accurately as possible.

▶

Set limits and reach compliance for intermediates with known antimicrobialactivity.

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AMR report on responsible manufacturing

2. Promote compliance with discharge
limits across the supply chain
In employing effective methods to ensure antibiotic discharge stays below safe
limits, companies also need to ensure compliance with these limits to mitigate thedevelopment of AMR, protect human health, and preserve the effectiveness ofantibiotics. As a starting point, companies need to strive to achieve compliance attheir own manufacturing sites, following which they can hold suppliers to the same
standards.

Over half of sites directly operated
by pharmaceutical companies arereported to be in accordance with
discharge limits in the receiving
environment

Ensuring compliance at own manufacturing sites
Recent assessments of companies within the scope of the AMR Benchmark reports

97

indicate that more pharmaceutical companies are now ensuring compliance at theirown manufacturing sites. In 2021, the AMR Benchmark assessed the complianceof 187 sites directly operated by pharmaceutical companies and found that 97
reported to be in accordance with discharge limits that they set.18
This report identifies that, to date, only five companies – namely Aurobindo,187

directly operated

Centrient*, GSK, Shionogi and Viatris – report that all their manufacturing sitesby pharmaceuticalcompanies arecomply with discharge limits set for the receiving environment.

compliantViatris and GSK highlighted that key measures they employ to achievecompliance include practices such as dry vacuum cleaning, pre-rinsing of
manufacturing equipment and collecting these concentrated streams at the pointof generation to send for appropriate disposal, such as incineration.
Notably, Centrient reports achieving compliance by implementing advanced
wastewater treatment facilities at its sites. At one site, an effluent stream posed
challenges due to detectable residual antibiotics and high levels of inorganic
salts, making conventional treatment methods ineffective. To address this issue,
Centrient’s bioprocessing laboratory devised a solution based on biocatalysis, with-

52% of sites

Sites directly operated bypharmaceutical companies analysedby the AMR Benchmark, including
93 operated by large research-based
pharmaceutical companies and
94 operated by generic medicine
manufacturers.
Source: 2021 AMR Benchmark

out the use of bacteria, to eliminate the residual antibiotics.
These approaches demonstrate how companies that have achieved complianceacross all their manufacturing sites have taken progressive steps to achieve this.
Reaching full compliance at all sites operated by a company is a work in progress,
which makes it key for companies to have environmental standards rooted in theirlong-term strategies, and to assign sufficient resources to successfully implement
them.
Supporting supplier compliance with discharge limits and providing assistanceto address challenges
By taking responsibility not only for themselves but also across their supply chain,companies can address waste management practices in a more comprehensive
and holistic manner, and effectively reduce the risks associated with the release ofantibiotic waste.
As identified over the three iterations of the AMR Benchmark reports, pharmaceutical companies have made progress on applying the discharge limits at
third-party supplier sites (suppliers). Where gaps still exist, companies can consider
various approaches – as highlighted by the company examples in this report – toincrease supplier compliance.
Notably, Centrient, GSK, Pfizer and Shionogi report that the majority of their
supplier sites are compliant (see box-out). While Centrient and Shionogi do have asmaller number of supplier sites, GSK and Pfizer demonstrate that achieving compliance on a larger scale is also possible.

Leading companies report significant
supplier compliance with discharge limits
Centrient: 100% of 5 sites
GSK: 100% of 42 sites
Pfizer: 86% of over 100 sites
Shionogi: 71% of 7 sites*Reaching compliance at the in 2021
acquired Astral SteriTech site is still inprogress and expected end of 2023.

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AMR report on responsible manufacturing

To support their suppliers, companies need to raise awareness of AMR, communicate the risks of waste produced by the manufacture of antibiotics, and provide
training so that suppliers can enhance their practices to manufacture more responsibly. The companies consulted for this report highlighted that they often provide
the necessary tools and provide support to suppliers through membership of thePharmaceutical Supply Chain Initiative (PSCI).
However, despite such support, there can be significant challenges in achieving
compliance, particularly for smaller suppliers who may lack sufficient resources
or expertise. For example, in some cases, yield improvements and proper cleaning
processes may not be sufficient to meet discharge limits. Wastewater treatment
technologies may be required, which, if expensive, can pose financial challenges forsmall manufacturers operating with slim profit margins.
Where such resources are required, collaboration between companies and public
and/or private partners can help with solutions, as envisioned by an initiative toestablish the AMR Centre of Excellence (CoE) in Hyderabad, India. The CoE, withplanned funding contributions from the Indian government and pharmaceuticalcompanies such as Dr Reddys, has been conceptualised and developed by the
Responsible Antibiotics Manufacturing Platform (RAMP)* (see sidebar).
The CoE offers an opportunity for companies to assist their suppliers in adopting
responsible waste practices, while reducing the financial burden associated with
it. This collaborative initiative is intended to provide the support required toaccelerate compliance with discharge limits throughout the entire supply chain.

AMR Centre of Excellence in India
In collaboration with local regulators,
academic research institutes andpharmaceutical companies, the Centre of
Excellence (CoE), planned to be based in
Hyderabad, India, will support manufacturers
in achieving sustainable antibiotic
manufacturing.33 The CoE is focused on four
key objectives:
1. Provide training and awareness to
professionals – including environmental,
health and safety (EHS) staff and procurers– about AMR, responsible manufacturing
and industry best practices.
2. Build capacity for monitoring technologies
and affordable testing solutions to ensure
manufacturers can analyse wastewater
samples.
3. Provide a testbed for treatment
technologies to showcase solutions that
reduce antibiotic discharges at lower costs.

While joining forces with other stakeholders will help accelerate progress in

4. Support policy research and advocacy in the

curbing AMR from manufacturing, companies must be proactive in taking steps

development of AMR action plans, national

to facilitate this, as demonstrated by an initiative undertaken by Abbott, a generic
medicine manufacturer:

guidelines, and advisory services onacademic, operational and policy issues.

Abbott supports suppliers with free wastewater analysis and logistics
assistanceAnalysing antibiotic waste concentrations where PNECs are as low as tens of nanograms per litre, requires the appropriate skills and experience. To assist its supplierswith this, Abbott’s pharmaceuticals division has established a partnership with a
specialised laboratory to develop testing methods for its molecules. Since 2022,
Abbott has been offering free analysis of wastewater samples to all supplier sitesthat exceed limits from the mass balance approach. By facilitating testing and covering costs, Abbott aims to support its contracted manufacturing suppliers in conducting water analysis more efficiently.
Additionally, Abbott aids suppliers in addressing any logistical issues that may
arise in the process. The free testing service offered by Abbott also covers any
necessary follow-up tests needed during remedial actions.
By offering this service, Abbott aims to ensure its contracted suppliers adopt
sustainable environmental practices and foster long-term relationships. Within
PSCI, a team member of Abbott in India is leading a working group dedicated toincreasing the number of certified laboratories capable of analysing wastewater
samples in the country.
Finding certified laboratories that can perform swift and accurate chemical
analyses of wastewater samples is a challenge faced worldwide. Abbott’s approachdemonstrates how companies can take the initiative to help address this. If morecompanies follow suit in supporting suppliers, this could have a significant impact
on building a sustainable supply chain of responsible players.

*The AMR Centre of Excellence project was recommended and developed by the
Responsible Antibiotics Manufacturing Platform (RAMP) project. RAMP is a collaborative
platform which engages with stakeholders to encourage more sustainably produced
antibiotics and to promote coherence between the voluntary action of companies,
government policies and regulations, standards and market incentives.32

17AMR report on responsible manufacturing

Including contractual provisions to promote suppliers’ AMR risk management
Pharmaceutical companies can elevate standards at supplier sites by incorporating
contractual provisions that mandate compliance with discharge limits. When theseprovisions are uniformly implemented, suppliers are incentivised to meet the newstandards and implement best practices. Where suppliers are non-compliant, pharmaceutical companies can hold them accountable by enforcing contracts and seeking alternative suppliers.
However, it must be noted that replacing a supplier may be a challenge or havesignificant consequences for supply chain management, especially where there
are limited suppliers of a critical drug (see box-out). As a result, companies avoid
enforcing manufacturing standards for high-risk molecules to maintain supply chain
stability. To ensure a reliable supply of antibiotics, particularly for products wheredependency on a limited number of suppliers exists, companies generally prefer toprioritise long-term partnerships and support suppliers in achieving compliance.
Prior to the AMR Benchmark 2021, no company reported the inclusion of AMRrelated risk management in its supplier contracts. However, among the companies
included in this report, Abbott, Centrient*, GSK, Sandoz, Shionogi and Pfizer
have introduced contractual provisions to address this issue. These provisions
encompass practices for managing liquid and solid waste, compliance with

Limited suppliers for critical drugs
In January 2023, a global shortage ofamoxicillin was reported amid a surge of
respiratory infections that drove an increasein demand for antibiotics. The European
Medicines Agency noted that this shortage
was compounded by manufacturing delays
and production capacity issues.34
Amoxicillin is one of the most widelyused broad-spectrum antibiotics (Browne2021). While around 17 manufacturing sites
produce the API, only seven sites worldwide
manufacture the intermediate 6-APA, withfive of them located in China.29

discharge limits, and the provision of discharge level information. Through audits,these companies assess supplier conformance with the established contracts.
Pfizer demonstrates a clear approach to how it holds third-party suppliers to its
own company standards.
Pfizer enforces supplier contracts to uphold manufacturing standards
Pfizer has evaluated its antibiotic wastewater concentrations against discharge limits at over 100 supplier sites, reporting compliance at 86% of those. Pfizer is working with the remainder as part of its strategy to help suppliers achieve published
PNECs by the end of 2025.35 The company has dedicated staff in place to engage
suppliers and support the implementation of risk management based on the guidance of the AMR Industry Alliance’s Antibiotic Manufacturing Standard.
Pfizer conducts supplier site visits to offer support and assist with calculating
mass balances while also ensuring that suppliers are abiding by contractual
provisions with Pfizer. These contractual provisions include following the Alliance’s
guidance and complying with discharge limits in the recipient (e.g., in a river orwaterway) to reduce AMR risk.
Pfizer reports that it has terminated the contracts of seven suppliers since2021 that it identified as not meeting the company’s expectations in terms ofenvironmental, health and safety (EHS) performance. While these supplier contract
terminations were not specifically due to AMR-related risks, they do demonstratethat Pfizer actively enforces contracts based on its EHS standards.
GSK develops contractual provisions with suppliers and replaces wastewater
treatment company
GSK’s contractual provisions include compliance with discharge limits for thirdparty suppliers; they are currently being integrated into existing contracts and will
be a standard requirement for future contracts. To date, GSK has not found it necessary to enforce contractual requirements to address non-compliance with thedischarge limits among our suppliers.
However, GSK did take action – although not explicitly intended to address AMRrelated risks – when a privately-owned wastewater treatment plant it contractedwith was not upholding GSK standards. A GSK manufacturing site in the Middle
East previously sent its discharge (downstream of onsite controls) to a third-party
private wastewater treatment company that employed ultimate evaporationof wastewater, with disposal of residual sludge via landfill. As this treatment*Centrient has not been assessed in thethree iterations of the Foundation’s AMR
Benchmark.

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AMR report on responsible manufacturing

technology was not compliant with GSK standards, its manufacturing site shifted
its discharge to an alternative private wastewater-treatment company that employs
multiple treatment technologies to fully recycle the treated wastewater andincinerate any residual sludge, thereby likely minimising the risk of AMR.

RECO M M E N DATI ONS FOR COM PAN I ES▶

Create awareness among suppliers on AMR risk from manufacturing.

▶

Ensure that suppliers set and comply with discharge limits.

▶

Actively share knowledge and expertise with suppliers to support them inachieving compliance with discharge limits.

▶

Share resources and analytical capability with suppliers, such as testing ofwastewater, free of charge.

▶

Include provisions and set expectations on managing AMR risk in new andexisting supplier contracts.

▶

If suppliers are non-compliant with provisions in their contracts to prevent
AMR risk, enforce contract terminations. This recommendation depends on
the availability of alternative suppliers with demonstrated commitments to
responsible manufacturing.

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AMR report on responsible manufacturing

3. Disclose actions transparently
When companies take action to mitigate AMR risks through responsible manufacturing, it is critical that they provide clear information about the initiatives andprocesses that are being implemented at their own manufacturing sites, and how
they are monitoring supplier compliance. Not only will this allow for accountability
across the supply chain, but it can offer much-needed insights into the relationshipbetween wastewater management and AMR.
Why disclosing details on manufacturing practices is important
It is good practice for companies to publish audit results from their own sites, aswell as from audits conducted at supplier sites, including actual discharge levels,
monitoring methods and dilution factors used (if any). This information can help
stakeholders (such as experts in the field) to study the relationship between wastewater management and AMR.
Moreover, providing clear information about waste management practices,
including mass balance calculations and dilution factors, will facilitate theindependent evaluation of a company’s performance. This has clear benefits interms of responsible procurement. When such detailed disclosure is made public,
procurers can assess the AMR risks associated with a company’s manufacturing
practices and make informed purchasing decisions (see p.25). For example, when
procuring antibiotics, governments and hospitals can also use this information toensure these medicines have been produced to standard.36
Public disclosure of the names and locations (city or district) of their
manufacturing sites and those of their suppliers can also facilitate the identificationof potential hotspots and risk areas for AMR and local environmental pollution. Thiscan enable independent third parties, such as global health organisations, academic
experts, and government institutions, to better understand the global health impactof antibiotic manufacturing. Greater transparency across the complex and fragile
antibiotic supply chain also supports governments in identifying pressure points,
allowing them to anticipate shortages and implementing appropriate mitigation
measures.36
Very few companies publicly disclose information on responsible
manufacturing practices
To date, the AMR Benchmark has found that companies fall short on transparency when it comes to disclosing information on how they address AMR throughtheir manufacturing practices. None of the 17 companies evaluated in the 2020
Benchmark reported publishing audit results or the identities of third-party suppliers, for example. The 2021 Benchmark identified that very few companies publicly
report on the number of manufacturing sites audited, or on compliance with safe
levels.
Companies also do not publicly disclose the actual levels of antibiotic residue
entering local soil and water. This is in line with observed findings in the animal
pharmaceutical sector identified by FAIRR, an investor network that raises awareness on environmental, social and governance (ESG) risks in the agriculture andfood value chains. FAIRR’s research, including an assessment of seven major animal
pharmaceutical companies’ actions to address AMR, revealed that none of themcurrently disclose information on how antibiotic waste within their supply chains ismanaged.37
Some of the companies in scope of the Benchmark reports cite confidentiality
and contractual agreements and restrictions as reasons for not publicly disclosing
such information. Competitive concerns and risks to credibility have also been indicated as factors that discourage disclosure.
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AMR report on responsible manufacturing

Five companies assessed in this report – Centrient, GSK, Shionogi, Teva and Viatris– do, however, publicly report on their waste management practices (see tablebelow). While they disclose different degrees of information, these companies aretaking steps in the right direction and demonstrate that it is possible for companies
to make details of their practices public.
Shionogi, in particular, serves as an example of how a company can provide
clarity on its responsible manufacturing practices across its antibacterial
manufacturing supply chain. Notably, the company discloses the country-level
location of each of its suppliers and the name of its external waste-management
treatment plant.
However, none of these companies, or any of the others assessed by the
AMR Benchmark, report on the actual levels of antibacterial residue entering
local soil and water, or the dilution factors applied, and no company publishes its
audit results. Until companies provide more clarity, it will remain difficult to truly
assess risks to the environment and the spread of AMR – and to hold companies
accountable.
Companies that publicly disclose their waste management practices

Company

Compliance

Location

Shionogi serves as a positive

Shares the names of the antibacterials in its portfolio

Discloses location of suppliers at country level (Japan,

example of a company

and maps the manufacturing of these products to its

Italy and India).

that provides clarity on its

own sites and suppliers’ sites, reporting the level ofantibacterial manufacturing

compliance with PNECs for each.

supply chain.24

Discloses name of external waste-treatment plant(Eco-system Akita Co., Ltd)

Centrient publicly discloses

Provides detail on methods and technologies andPublicly discloses the exact locations of each of its

details on how it manages the

how it collaborates with suppliers.

manufacturing sites for the products it produces and

AMR risk of its antibiotics andPublished a white paper setting out how it reaches

antifungals from manufacturing.

PNEC compliance in the full supply chain.28

Teva publicly reports on the

In its 2022 ESG Report, Teva indicated that itcompliance of its own sites withsuccessfully achieved its target of assessing 100%

discharge limits, and that it isof the 33 Teva sites that handle antimicrobial drug

taking remedial action whensubstances and products in 2021.

discharge limits are exceeded.

on compliance to PNEC.25

Teva also reported 20 sites discharge to be
below PNEC. For sites with at least one antibiotic
above PNEC, Teva indicated it provided technicalsupport aimed at reducing discharges – including theimplementation of corrective and preventive actions
to address findings and ensure proper governanceand oversight.39

GSK publicly shares summaries

In its 2022 ESG Report, GSK indicated that 100% ofof some of its environmental risk

its own sites and 98% of its supplier sites achieved

assessments on its website, suchcompliance with PNECs.41

as summaries for amoxicillin andcefuroxime.40
Viatris publicly discloses details

Viatris reports, in its Sustainability Report 2022, thaton its progress in limiting AMR

all manufacturing sites with antibiotic manufacturing

via responsible manufacturing

are compliant with PNECs, as calculated by massbalance.
In addition, it is disclosed that Viatris carried out
15 supplier risk assessments in 2022 to assess adherence with the Antibiotic Manufacturing Standard with
non-compliant suppliers developing and implementing corrective actions.42

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AMR report on responsible manufacturing

New Zealand example demonstrates that public disclosure of supply chains bycompanies is feasible
The New Zealand Medicines and Medical Devices Safety Authority mandates public
disclosure from companies in their supply chains (see Figure 4).43 Information on
the full supply chain of each marketed product in New Zealand is collated in a publicly available database and includes details on the manufacturing, packaging, andrelease of products, the suppliers (including names and locations) that supply eachactive ingredient, as well as the product sponsors.
This transparent approach enables New Zealand’s government and otherstakeholders to identify supply chain bottlenecks and anticipate potential
shortages. Additionally, the public availability of this information enables thegovernment to gain better insights into potential sources and locations of pollution
within the supply chain and enables procurers to prioritise the procurement ofantibiotics that have been manufactured without contributing to AMR.6,7,44
FIGURE 4 Public disclosure on global supply chains shows where potential AMR risks frommanufacturing are located - New Zealand case study on ciprofloxacin
This map shows the global supply chains for all actively marketed formulations of ciprofloxacin in New
Zealand. Ciprofloxacin is a commonly prescribed antibiotic in the treatment of Gram-negative bacterial
infections associated with urinary, respiratory, and gastrointestinal infections. Being chemicallysynthesised, ciprofloxacin is relatively stable compared to other antibiotics and difficult to degrade.
Consequently, ciprofloxacin is frequently detected in high concentrations in the environment, raisingconcerns about its impact on AMR.6,7,44

RECO M M E N DATI ONS FOR COM PAN I ES▶

Publicly disclose audit results, including discharge levels and dilution factors.
Existing collaborative platforms, such as the AMR Industry Alliance or the
PSCI, can also be used to coordinate public disclosure of audit results.

▶

Companies can renegotiate contracts to facilitate the publication of resultsof supplier audits.

▶

Disclose the manufacturer and location for each manufacturing step in the
supply chain.

▶

Report on AMR risk from manufacturing in requests and questionnaires
from ESG data providers and rating agencies.
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AMR report on responsible manufacturing

Why is responsible manufacturing
becoming an operational and businesspriority for companies?
Manufacturing antibiotics responsibly is not only a moral imperative, but it is also a
critical operational and business priority, particularly in the pharmaceutical industry.
Antibiotics are essential healthcare products that directly impact patient
health and safety. By maintaining high standards for manufacturing and waste
management, companies can protect the environment, safeguard public health andensure the long-term availability of effective antibiotics.
The benefits of responsible manufacturing overwhelmingly outweigh theperceived challenges. For example, responsible and sustainable manufacturing andwaste management practices can:•Support quality assurance;•

Mitigate risks to public health and the environment;•

Ensure adherence to regulations;•

Align with corporate social responsibilities; and•Enhance a company’s reputation, leading to increased trust and business
opportunities.

Since 2016, AMR risk from manufacturing has gained increasing attention –with international action resulting in notable progress over the last few years.
Additionally, the World Health Organization (WHO) is currently in the process ofdeveloping an independent guidance on waste and wastewater management for
antibiotic manufacturing (see sidebar).
In line with this global focus, several stakeholders – including governments,
regulators, procurers, global health organisations and investors – are increasingly
expecting responsible manufacturing practices from pharmaceutical companies.
Procurers, for example, who can consider criteria related to the environmentand sustainability when making purchasing decisions, are increasingly expecting
companies to demonstrate comprehensive and effective practices to limit antibiotic
waste. More investors also now view AMR as a systemic risk that needs to beconsidered within environmental, social and governance (ESG) standard-setting
and reporting frameworks. There are also signs that regulation aimed at reducing

The World Health Organization is developing
guidance for pharmaceutical manufacturing.
To address the environmental dimensionof AMR resulting from the pharmaceuticalproduction of antibacterials, the World
Health Organization (WHO) is in the processof developing an independent guidanceon waste and wastewater management inpharmaceutical manufacturing with a focus
on antimicrobials.
This document – of which the release dateis to be determined – will use good manufacturing practice (GMP) risk management
principles and the water safety frameworkcommon across all WHO water safety guidance as a point of departure.

AMR risk from manufacturing, which is currently lacking, may be introduced, or
strengthened, in several countries.
The examples set out in this section of the report demonstrate why companies
should be proactive in developing and implementing responsible manufacturing
practices. By acting now and investing in responsible manufacturing, companies will
not only help minimise the propagation of AMR, but can set themselves apart in themarket. Moreover, by building a reputation for quality and reliability, companies are
setting a foundation for long-term success.

STAYI NG AH EAD OF EVOLVI NG REGU L ATIONSAt present, there is a lack of internationally agreed actions or measures to control
or limit the release of antimicrobials and antimicrobial resistant bacteria and genes(ARB/ARGs) into the environment. However, some governing bodies and governments are taking steps to control antibiotic residue levels in the environment, andhave introduced incentives to encourage responsible manufacturing practices bycompanies.

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AMR report on responsible manufacturing

European Union
The EU has identified AMR as one of the top three health threats that its constituent countries are facing.45 Accordingly, in April 2023, the European Commission
proposed new and more stringent legislation. Under this proposal, pharmaceuticalcompanies seeking to market their medicines in the EU are required to conduct
an environmental risk assessment (ERA) of medicines to evaluate the potential
adverse impacts of medicines on the environment and public health. This includes
the risk of AMR from the manufacturing of antibiotics. Failure to comply may now
lead to the refusal of marketing authorisation. This legislative change will requirecompanies to implement measures, such as proper disposal protocols and wastewater treatment to limit the impact of their products.46
Furthermore, the Extended Producer Responsibility scheme under the Urban
Wastewater Directive makes pharmaceutical producers financially responsible
for the removal of pharmaceuticals, including antibiotics, by public wastewater
treatment plants. This shift aligns with the principle of ‘’polluter pays’’ and highlights
the industry’s role in keeping water clean of pharmaceutical residues.47
Additionally, indirect measures are in place to address industrial pollution. The
Industrial Emissions Directive (IED) mandates compliance with emissions limit
values, ensuring companies adhere to specified thresholds. The Registration,
Evaluation, Authorisation and Restriction of Chemicals (REACH) legislation
establishes specific dilution factors for discharging substances into water bodies,
further safeguarding the environment.23
These changes, currently considered by the European Parliament and theCouncil in the standard legislative procedure, are intended to combat AMR, protect
the environment, and promote responsible pharmaceutical manufacturing andwaste management practices in the EU.
China and India
Antibacterial production involves numerous manufacturing sites worldwide, witha high proportion of them based in China and India. China accounted for morethan 40% of global antibiotics exports by value in 2021.48 In both countries, concerns around rising AMR and its impact on the environment are gaining increased
attention.
In China, the government has implemented a range of strategies to combat AMR
and reduce environmental and safety risks. In 2018, tax legislation was introduced
to incentivise high polluting industries, including the pharmaceutical industry, toadopt more sustainable practices.49 However, it is important to note that, as yet,this legislation does not target the discharge of active pharmaceutical ingredients(APIs) during antibiotic manufacturing.
China’s National Action Plan on AMR (NAP) 2022-2025 recognises theenvironmental impact of AMR and includes measures to strengthen control
over antimicrobial pollution discharge and to monitor antimicrobials in water
environments.50 In 2021, China issued the “Notice on the Reform Implementation
Plan for Hazardous Waste Management Supervision and Utilization Capacity” toimprove the management and supervision of hazardous wastes. This hazardous
waste list includes solid waste from antibiotics, indicating regulations for managing
some pharmaceutical waste.51
India is increasingly prioritising responsible manufacturing practices and placing
more emphasis on requirements for companies. All API bulk-drug manufacturing
sites are classified as "grossly polluting industries" and are required to adhere to
zero liquid discharge (ZLD) standards.52 For example, Abbott reports that the useof ZLD technology is mandated by Himachal Pradesh’s Pollution Control Board(PCB). This state’s PCB has started collecting monthly wastewater samples atmanufacturing sites to analyse antimicrobial residues and found that a third ofmonitored antibiotic manufacturers were exceeding discharge limits.53

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AMR report on responsible manufacturing

With India holding the 2023 G20 presidency, the G20 Summit taking place in the
country in September 2023 provides an opportunity for countries to call for further
actions from pharmaceutical companies to limit AMR.
To further reinforce the implementation of existing regulations, the National
Green Tribunal (NGT), a specialised federal body dealing with environmental
protection, is taking assertive measures where there is adverse impact on publichealth and environment due to non-compliance.54 In an attempt to put regulation inplace, the Indian government proposed legislation in 2019 that included discharge
limits on antibiotics in wastewater discharged from manufacturing sites into
receiving waterways.55 Although the final published legislation in 2021 did notinclude such discharge limits, the NGT has ordered its implementation in an ongoinglegal case.56
As China and India increase oversight and tightening of regulations, companies
would be well-served to proactively prioritise responsible manufacturing practices
and measures in these manufacturing hubs.

M E ETI NG G ROWI NG STAKE HOLDE R EXPECTATIONS
Some countries, regional bodies and organisations have taken leading steps toimprove responsible manufacturing. While some of these examples showcase
growing expectations from procurers in high-income countries, oftentimes they
will procure antibiotics that are manufactured in low- and middle-income countries(LMICs), such as China and India. As a result, procurement decisions can have an
impact on responsible manufacturing practices in these countries.
However, going forward, greater global harmonisation and the adoption ofsimilar practices in countries across the globe will need to be prioritised in order tohave a substantial global impact on responsible manufacturing (see sidebar).

RAMP Framework guides stakeholders withharmonised manufacturing criteria
In July 2023, the Responsible Antibiotics
Manufacturing Platform (RAMP) published aframework that provides a set of guidelines
and independent criteria to evaluate andverify a company's manufacturing practices in
reducing the risks of antimicrobial resistance(AMR).52 The framework harmonises existing
criteria by industry, academia, procurers
and regulators and makes these accessible
for voluntary implementation. This aims tospur cross-sectoral collaboration between

Norway’s sustainable procurement pilot
The Norwegian Hospital Procurement Agency initiated a sustainable procurement
pilot in 2019, covering all anti-infectives necessary in Norwegian hospitals. The
pilot included non-price tender criteria, promoting the procurement of the best

stakeholders and provides them theopportunity to adopt similar practices that go
beyond the current voluntary commitmentsof pharmaceutical companies.

possible product, rather than the cheapest. The criteria focused on environmental
considerations, security of supply and other product characteristics that were considered important by healthcare professionals. The environmental considerations –weighted at 30% of the allocation criteria – specifically addressed whether companies have environmentally friendly production in place and reduce the risk of AMR.57
After years of decreasing competition, the programme resulted in a significant
increase in the number of companies submitting tender offers, thereby enabling
more competition. Notably, three companies in the scope of this report – Fresenius
Kabi, Sandoz (100% spin-off from Novartis planned Q4 2023) and Viatris – wereawarded with tenders partly for achieving the highest score on environmental
criteria compared with other participating companies (see Figure 5). These
companies demonstrate that embracing responsible manufacturing practices
helped to position them favourably in the market.

FIGURE 5 Three companies in scope awarded with tenders

Company

Ceftazidime

due to responsible manufacturing
As part of the Norwegian Hospital Procurement Agency’s 2019sustainable procurement pilot, three companies in scope of thisreport were awarded with tenders, partly for achieving thehighest score on environmental criteria that specificallyaddressed whether companies have environmentally friendly
production in place and reduce the risk of AMR.

Product

Fresenius Kabi

Ceftriaxone
Cefuroxime
Linezolid (infusion)

Sandoz*ViatrisLinezolid (tablet)
Clindamycin
Cloxacillin*Sandoz is the generics division of Novartis (100%spin-off planned Q4 2023).

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AMR report on responsible manufacturing

The success of the pilot has led to plans to optimise and streamline the criteria
for the most critical aspects of AMR risk reduction. Going forward, more stringent
requirements regarding compliance with discharge limits across the supply chain,
as well as transparency, will be implemented. For example, competing companies
will need to disclose the names and locations of suppliers, which will help the
Norwegian government to better reward companies that engage in responsible
manufacturing across the supply chain. This will also provide the necessary clarity
to ensure that tender-winning companies do not only depend on one supplier toproduce the API (also see “Disclose actions transparently” on p.21-23).
Sweden’s AMR risk criteria in procurement
In Sweden, AMR risk criteria are integrated into regional tenders for hospital procurement. Although the adoption of environmental criteria by the 21 Swedish
regions is not mandatory, there has been a notable upswing in their implementation. For example, in the densely populated region of Västra Götaland, environmental criteria now account for approximately 25% of the tender while the number ofcompanies participating in the tenders remained constant.
Additionally, the Swedish Medical Products Agency, Dental and Pharmaceutical
Benefits Agency, and E-Health Agency are collaborating to pilot, between 2025
and 2028, the implementation of an environmental premium for antibiotics sold in
pharmacies. The stringent criteria of the proposed premium will only consider companies that comply with PNECs directly in wastewater, rather than in the receiving
waters (also see “Employ effective methods to reduce AMR risks” on p.11-16).58
UK’s NHS Commitment to responsible antimicrobial procurement
In the UK, the National Health Service (NHS) emphasises responsible antimicrobial
procurement through contracts that promote good stewardship, manufacturing,and environmental practices; monitor for emerging resistance; and ensure a reliable supply. Informed by the AMR Benchmark Report of the Access to Medicine
Foundation – the NHS has set up evaluation criteria that manufacturers mustmeet to qualify for a procurement contract. The evaluation criteria are equallyapplicable to contract requirements of the recently introduced delinked and subscription-based contracts for two antibiotics: Shionogi’s cefiderocol and Pfizer’s
ceftazidime/avibactam.59
The NHS mandates companies’ adherence to good antimicrobial manufacturing practices and environmental standards throughout the supply chain – at thecompany’s own and/or its suppliers’ manufacturing sites, as well as its external
wastewater treatment plants – including compliance with discharge limits (also see"Promote compliance with discharge limits across the supply chain" on p.17-20).60,61
Additionally, the NHS requires companies to be signatories of the AMR Industry
Alliance Declaration and comply with the AMR Industry Alliance antibiotic manufacturing standard.
Health insurer AOK demonstrates how other stakeholders can promoteresponsible manufacturing
AOK, a German health insurer, has incorporated criteria related to PNEC compliance in tendering processes to promote and reward responsible manufacturing.25
AOK’s inclusion of PNEC criteria underscores another key stakeholder, in this casea health insurer, promoting responsible manufacturing in response to, among otherthings, the economic implications of AMR.
GARDP’s selection of responsible manufacturers
The Global AMR Research & Development Partnership (GARDP) selects manufacturers for its sublicense agreements based on their commitment to meetinghigh standards in areas such as environmental sustainability, quality assurance andresponsible production.
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AMR report on responsible manufacturing

GARDP was granted the right to develop, manufacture, and commercialise the antibiotic cefiderocol through sub-licensees in 135 countries. When selecting a manufacturer, GARDP, with the support of Clinton Health Access Initiative (CHAI), incorporated environmental criteria into its Request for Proposals (RFP), particularly
focusing on waste management practices to limit AMR. This included a requirement
for the manufacturer to have the ability to reach compliance with discharge limits(also see" Employ effective methods to reduce AMR risks" on p.11-16).62
To ensure the selected manufacturer (the name of the manufacturer has not
yet been disclosed) adheres to these criteria, GARDP has conducted an intensive
audit of the manufacturer’s practices, including evaluations of Good Manufacturing
Practices (GMP), financial aspects, and Environmental Health and Safety (EHS)
measures. In addition, a stipulation on compliance with discharge limits is includedin the draft sublicence contract with the manufacturer. By integrating the environmental criteria and conducting thorough audits, GARDP strives to ensure that the
manufacturer adheres to stringent environmental standards.
Investors are expecting action on AMR
In efforts to help curb AMR, and to mitigate the systemic risks it poses from a business perspective, investors are working to formally integrate AMR risks as part oftheir decision making – with the launch of the Investor Action on AMR initiativein 2020 serving as an example. This coalition between the Access to Medicine
Foundation, the FAIRR initiative, the Principles for Responsible Investment and the
UK Government of Health and Social Care seeks to galvanise investor efforts toaddress AMR globally.63 With investors focusing on this issue, their expectationsof pharmaceutical companies will increase – and transparency and accountability
around their manufacturing practices, for instance, will become crucial.
By including responsible manufacturing practices as part of their environmental, social and governance (ESG) strategies, companies can respond to investors’
existing sustainability expectations, as well as proactively meet future interest frominvestors.
For example, Amundi, a major asset manager in France, is actively engaging withleading ESG data providers and standard setters to include AMR metrics in company evaluations and standards. Notably, Institutional Shareholder Services (ISS), an
ESG corporate rating provider, has already integrated metrics on environmental risk
management strategies related to AMR risks and publicly discloses its findings.64
This trend further emphasises the importance of companies disclosing their AMR
risk management efforts and committing to responsible manufacturing.

SE I ZI NG BUSI N ESS OPPORTU N ITI ES AS AFRICAN U N IONPROMOTES LOCAL MAN U FACTU RI NG
People living in sub-Saharan Africa face a high mortality rate due to AMR.3 Local
production is a critical step for several reasons, including ensuring reliable supply,
promoting health security, reducing costs over the long term, improving regulatory oversight, and driving economic growth. Initiatives like the Pharmaceutical
Manufacturing Plan for Africa (PMPA) by the African Union and Africa CDC are
actively promoting increased local manufacturing. This can present an immense
opportunity for growth on the continent, particularly if companies embrace robust
and responsible manufacturing practices from the outset.
In many African countries, wastewater is often used in the production of drinking
water and beverages, with the consequences of inadequately treated wastewater
extending beyond the contamination of the receiving environment.8,65-67 By prioritising responsible manufacturing, companies can also contribute to socioeconomic
development by addressing issues such as inadequate effluent treatment, poorly
designed wastewater treatment plants, and water contamination.

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AMR report on responsible manufacturing

Going forward
Collaborative efforts are vital in addressing the risks posed by pharmaceuticalmanufacturing. However, as demonstrated by some of the global trends around
AMR and the environment, companies will need to take proactive action of theirown accord. Those that take responsibility for their manufacturing practices will
ensure their compliance with regulators, governments and procurers can makea substantial impact on curbing AMR and safeguarding the environment, while
enjoying growth, sustainability and a positive reputation.

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AMR report on responsible manufacturing

Staying ahead of the curve
Addressing the global health and environmental risks posed by antimicrobial resistance (AMR) will require unwavering commitment and decisive action. To help curb
this global health threat, pharmaceutical companies must acknowledge the impact

IN BRIEF

of their manufacturing practices and take measures to manage antibiotic waste• Poor waste management in the manufac-

across the manufacturing supply chain.
This report has mapped out clear actions by a handful of leading companies thatare already working towards developing and implementing manufacturing practices
that are effective and sustainable – showing that progress is entirely possible.
Looking to these standout examples, and by focusing on the areas of action set out
in this report, more companies can adopt responsible manufacturing practices toreduce AMR risk.
Methods matter
While employing the tools provided by the AMR Industry Alliance and thePharmaceutical supply Chain Initiative (PSCI) is certainly a positive step, especiallysince doing this is entirely voluntary, companies can go beyond the guidance thesetools provide.
Specifically, to minimise AMR risk more effectively, companies can develop
and implement comprehensive methods to ensure the safety of their wastewater
before it is released into the environment.
Companies can apply discharge limits directly to their wastewater, instead ofturing of antibiotics contributes to AMR.
• Pharmaceutical companies occupy a central
position in the antibiotic manufacturing
supply chain and need to do more to limit
antibiotic waste, starting at their own
manufacturing sites.
• Developing long-term, close relationships
with suppliers can promote responsible
manufacturing across the supply chain,
which can lead to a substantial impact.
• By being transparent about the actions they
are taking to reduce AMR risk from manufacturing, companies can proactively meet
future expectations from stakeholders.
• Positive examples from companies inscope of this report show that it is entirely
possible to go further in developing
responsible manufacturing practices tomore effectively limit antibiotic waste tohelp curb AMR.

applying limits before releasing it into the environment. Notably, in consultations
for this report, Shionogi stated that it complies with discharge limits directly in its
wastewater for all five of the antibiotics it manufactures. If more companies wereto strive to achieve this for more products, the risk of AMR from manufacturing
waste would be significantly reduced.
To more accurately determine whether discharge limits are being met, companies can implement a synergistic combination of the mass balance approach andanalysis of wastewater samples, as demonstrated by Abbott.
Companies can also be proactive in further limiting AMR risk in their wastewater by removing bacteria from it. Sandoz (100% spin-off from Novartis planned Q42023) does this at its main antibiotic manufacturing site in Kundl, Austria, through amembrane filtration process.
In developing their waste management practices, companies can consider intermediates – the precursor molecules used in the manufacturing of antibiotics. Whilethe link between an intermediate’s waste and AMR is not clearly defined, companies
and their suppliers need to take a cautious approach. Currently, only Centrient has
taken proactive steps to establish discharge limits for intermediates. The company
monitors compliance with discharge limits at relevant manufacturing sites forthe intermediates 6-APA and 7-ADCA, both well-known for having antimicrobialactivity.29,31
As demonstrated by these examples, companies can take practical steps to limit
AMR risks in their wastewater at their own manufacturing sites as effectively as
possible. However, it is important to note that companies will need to tailor theirapproaches to consider, for example, the nature of the manufacturing operation,
the type of antibiotic that is being manufactured, as well as the resources and costs
involved.
Compliance with discharge limits across the supply chain is key
Beyond employing effective methods at their own manufacturing sites to ensure
discharge limits are compliant with safe levels, Centrient, GSK, Pfizer and Shionogi,
have also been able to achieve compliance at the majority of their supplier sites.
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AMR report on responsible manufacturing

By leveraging their central position in the supply chain, companies can hold their
third-party suppliers to account and support them where needed. Collaborative
approaches that combine incentives and contractual provisions have shown promise in improving compliance along the supply chain. As demonstrated by GSK and
Pfizer, companies can include provisions and set expectations on managing AMR
risk in new and existing supplier contracts.
If a supplier is non-compliant and needs to be replaced, companies can ensure
they consult and engage alternative suppliers with demonstrated commitment to
responsible manufacturing. However, the fragility of the supply chain – especiallythe fact that for some critical drugs, there are only a few producers – cannot beignored. Replacing a supplier may be a challenge or have significant consequences
for supply chain management and access to antibiotics. For this reason, companies
avoid enforcing manufacturing standards for high-risk molecules. Instead, as notedin this report, companies generally prefer to build long-term partnerships with
suppliers to ensure a reliable supply of antibiotics, particularly for products wheredependency on a limited number of suppliers exists.
With this in mind, companies can create awareness among their suppliers on
AMR risk from manufacturing and actively share knowledge, resources, expertiseand analytical capabilities to support them in achieving compliance with discharge
limits. As demonstrated by Abbott, providing suppliers with wastewater sample
analysis, free of charge, is a practical way of doing this. Specifically, where smaller
suppliers lack resources, providing them with such tangible support is critical toensuring sustainability of a responsible manufacturing supply chain.
Taking transparent, proactive action to ensure sustainability
It is one thing to engage in efforts to manage waste, but without public disclosure
there is no way to hold companies accountable or to tap into the practices that areyielding positive results.
By providing information about their methods (such as how they quantify
concentrations) and compliance (including actual discharge levels), companies allow
for accountability and offer much-needed insights into the relationship between
wastewater management and AMR.
While Shionogi leads the way in providing clarity across its antibacterial supply
chain, no company assessed in the AMR Benchmark, or this report, provides
details of actual discharge levels – even though disclosing such information isstraightforward. Apart from Shionogi, only Centrient, GSK, Teva and Viatris disclose
more specific details about their manufacturing practices.
Over and above the need for accountability that transparency affords, global
health stakeholders are looking to companies that demonstrate a commitment
to sustainability – including through their manufacturing practices. Procurers, forexample, who can consider criteria related to the environment and sustainability
when making purchasing decisions, are increasingly expecting companies todemonstrate comprehensive and effective practices to limit antibiotic waste. Bybeing clear about their efforts to manufacture responsibly, companies can position
themselves favourably within the market.
Notably, three companies in scope of this report – Fresenius Kabi, Sandoz
and Viatris – were awarded with tenders as part of the Norwegian Hospital
Procurement Agency’s 2019 sustainable pilot procurement programme. The
companies received the tenders partly for achieving the highest score on
environmental criteria, which specifically considered whether companies hadenvironmentally friendly production in place to reduce the risk of AMR.
By following the recommendations included in this report and integrating robust
responsible manufacturing practices into their business operations, companies canensure they drive meaningful progress in addressing AMR while proactively preparing to meet growing expectations.

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AMR report on responsible manufacturing

Contributing to a sustainable future
The antibiotic manufacturing supply chain is complex and includes a wide rangeof players, but actions from pharmaceutical companies are especially vital in moving the needle. While collective initiatives within the pharmaceutical industry areencouraging, individual companies need to make sure they play their part and continually work towards strengthening and improving their practices. As set out in thisreport, there are companies that are already proactively and voluntarily strengthening their AMR mitigation efforts. More companies now need to seize opportunities
for progress by ensuring they develop and scale responsible manufacturing practices – and extend expectations to suppliers.
Inaction will not only be detrimental to the fight against AMR, but can haveconsequences for companies that are not at the forefront of a global healthlandscape that is focusing on the drivers that fuel drug resistance – including
antibiotic waste from manufacturing.

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AMR report on responsible manufacturing

D E FI N ITI O NS
• Active pharmaceutical ingredient (API): The

minimise risks such as unexpected contamina-

resistance, antibiotics cause a selective pressure

active pharmaceutical ingredient (API) is thetion, incorrect labelling or incorrect dose of theby killing susceptible bacteria, allowing

active pharmaceutical component of a medicine

active ingredient. GMP covers all aspects ofantibiotic-resistant bacteria to survive, developthat carries out its intended effects. Some

pharmaceutical production (e.g., startingand multiply.

medicines, such as combination therapies, havematerials, premises, equipment, training andmultiple active ingredients that target multiple

personal hygiene of staff) and includes

disease pathways and/or symptoms. The

processes that provide documented proof that

may contain antibiotic residues and is released

inactive ingredients of a medicine are referredcorrect procedures are consistently followed atfrom manufacturing facilities, hospitals, or otherto as excipients.

each step of the manufacturing process. GMP

sources where antibiotics may be used or

guidelines are established and overseen by

produced. Wastewater is often referred to as

regulatory agencies in individual countries or

effluent and is considered safe when PNECs are

regions, as well as the WHO.

met (see PNEC).

• Antibacterial medicine: Antimicrobial medicine
used to treat bacterial infections by directly• Wastewater: Wastewater or liquid waste thattargeting the bacteria that causes the infection• Mass Balance Approach: A method used to• Zero liquid discharge (ZLD) technology: This

the symptoms of the infection). Biocides are

estimate the amount of antibacterial ingredi-

is a treatment process in which the site does

not considered antibacterial medicines. See also

ents lost during the production process thatnot discharge any water into the environment

antibiotics

subsequently could be present in waste. It

as this will be reused and recycled, while solid

consists of estimating the how much of theresidue is incinerated or sent to landfill after

antibacterial ingredient is lost in the production

treatment. (Ranade 2014)or the disease process (as opposed to targeting• Antibiotics: Equivalent to Antibacterial
medicine. The term “antibiotic” is often used

process and will end up in waste, i.e., the mass

inconsistently in literature to denote either abalance, applying the removal efficiency of

drug that targets any type of microorganism inantibacterial residue through on-site treatment

the body or, alternatively, a drug that targets

and other treatment plants and applying

bacteria specificallydilution factors resulting from water flows fromtreatment plants and rivers. This approach• Antimicrobial resistance (AMR): Antimicrobial

allows companies to estimate the final

resistance is the ability of microbes such asconcentration of antibacterials in the receiving

bacteria, viruses, fungi and parasites (protozoa

environment without directly measuring themor helminths) to grow in the presence of anin the wastewater samples.

antimicrobial substance (e.g., a medicine) thatwould normally kill them or limit their growth.

• Pharmaceutical Supply Chain Initiative (PSCI):

Resistance is a consequence of evolution via

Pharmaceutical Supply Chain Initiative is anatural or artificial selection.

membership body driving action for safety,
environmental, and social outcomes across the• Corrective and preventive action (CAPA):

global pharma & healthcare supply chain.

A set of actions or improvements which can be
implemented by a company in order to tackle• Predicted No Effect Concentration (PNEC):

non-compliance, and to make sure these issues

i.e., the highest estimated concentration at

do not occur in future.

which no effects of concern are expected tooccur in an ecosystem, such as the opportunity• End of pipe: An approach to pollution control
which concentrates upon effluent treatment or

for resistance selection or harm to aquatic life.
Typically referred to as discharge limits.

filtration prior to discharge into the environment via receiving waters, as opposed to• Recipient: The receiving environment in whichmaking changes in the process giving rise to theantibiotic waste from manufacturing sites iswastes.

discharged into. Typically, this includes
waterways such as rivers, streams, lakes and• Good Manufacturing Practices (GMP): Goodoceans.

manufacturing practice (GMP) is a system
employed to ensure that products are• Selection Pressure: The influence exerted byconsistently produced and controlled accordingsome factor (such as an antibiotic) on natural

to appropriate quality standards. Within

selection to promote one group of organisms

pharmaceutical production this serves toover another. In the case of antibiotic

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AMR report on responsible manufacturing

RE FE RE NCES
1

Novartis raises 2023 forecast, maps out
Sandoz spin-off | Reuters. Accessed
July 20, 2023. https://www.reuters.
com/business/healthcare-pharmaceuticals/novartis-raises-full-yearoutlook-launches-new-share-buybackscheme-2023-07-18/

2WHO. Ten threats to global
health in 2019. Accessed January
18, 2023. https://www.who.
int/news-room/spotlight/
ten-threats-to-global-health-in-20193

Murray CJ, Ikuta KS, Sharara F, et al.
Global burden of bacterial antimicrobial
resistance in 2019: a systematic analysis. Lancet. 2022;399(10325):629-655.
doi:10.1016/S0140-6736(21)02724-0

4

Larsson J, Flach C-F. Antibiotic
resistance in the environment. Nat
Rev Microbiol. 2022;20(5):257-269.
doi:10.1038/s41579-021-00649-x

5

UNEP. Bracing for Superbugs:
Strengthening Environmental Actionin the One Health Response to
Antimicrobial Resistance | UNEP - UN
Environment Programme.; 2023.
Accessed February 7, 2023. https://www.unep.org/resources/superbugs/
environmental-action

6

Booth A, Aga DS, Wester AL.
Retrospective analysis of the global
antibiotic residues that exceed thepredicted no effect concentration
for antimicrobial resistance in various
environmental matrices. Environ
Int. 2020;141:105796. doi:10.1016/j.
envint.2020.105796

7

Wilkinson JL, Boxall ABA, Kolpin
DW, et al. Pharmaceutical pollutionof the world’s rivers. Proc Natl Acad
Sci U S A. 2022;119(8). doi:10.1073/
PNAS.2113947119

8

Mutuku C, Gazdag Z, Melegh S.
Occurrence of antibiotics and bacterial
resistance genes in wastewater: resistance mechanisms and antimicrobial
resistance control approaches. World J
Microbiol Biotechnol. 2022;38(9):1-27.
doi:10.1007/s11274-022-03334-0

9Baym M, Stone LK, Kishony R.
Multidrug evolutionary strategies toreverse antibiotic resistance. Science(80- ). 2016;351(6268). doi:10.1126/
science.aad3292

10 Miettinen M, Khan SA. Pharmaceuticalpollution: A weakly regulated global
environmental risk. Rev Eur CompInt Environ Law. 2022;31(1):75-88.
doi:10.1111/reel.12422
11

Davos. Declaration by the
Pharmaceutical, Biotechnology and
Diagnostics Industries on Combating
Antimicrobial Resistance.; 2016.

12 AMR Industry Alliance. Industry
Roadmap for Progress on Combating
Antimicrobial Resistance. Published
online 2016:3 p. Accessed May 26,
2023. https://www.amrindustryalliance.org/industry-roadmap-for-progress-on-combating-antimicrobial-resistance/
13 AMR Industry Alliance. COMMON
ANTIBIOTIC MANUFACTURING
FRAMEWORK.; 2018. doi:10.1002/
etc.3163/pdf

14 AMR Industry Alliance. AMR Industry
Alliance Launches Antibiotic
Manufacturing Standard to Help
Mitigate the Impacts of Antimicrobial
Resistance - AMR Industry Alliance.
Accessed January 16, 2023. https://www.amrindustryalliance.org/
mediaroom/amr-industry-alliance-launches-antibiotic-manufacturing-standard-to-help-mitigate-the-impacts-of-antimicrobial-resistance/
15 Larsson J. “The industry sets standards for emissions on its own terms”- LäkemedelsVärlden.https://www.
lakemedelsvarlden.se/antibiotikaindustrins-egen-utslappsstandard-pa-deras-villkor/. Published June 14, 2022.
Accessed January 16, 2023.
16 BSI Group. New certification facilitatedby BSI for the AMR Industry Alliance |BSI. Accessed July 20, 2023. https://www.bsigroup.com/en-GB/about-bsi/
media-centre/press-releases/2023/
june/new-certification-aims-to-mitigate-antimicrobial-resistance-risk-in-antibiotic-manufacturing/
17 Access to Medicine Foundation.
Shortages, stockouts and scarcity: theissues facing the security of antibiotic
supply and the role for pharmaceuticalcompanies. Amsterdam. Published May
31, 2018. Accessed March 31, 2022.
https://accesstomedicinefoundation.
org/publications/shortages-stockouts-and-scarcity-the-issues-facing-the-security-of-antibiotic-supply-and-the-role-for-pharmaceutical-companies
18 Access to Medicine Foundation.
Progress on limiting release of antibiotic waste into environment, but
gaps remain. Accessed July 20, 2023.
https://accesstomedicinefoundation.
org/resource/progress-on-limiting-release-of-antibiotic-waste-into-environment-but-gaps-remain
19 Zieliński W, Korzeniewska E, Harnisz
M, Drzymała J, Felis E, Bajkacz S.
Wastewater treatment plants as a reservoir of integrase and antibiotic resistance genes – An epidemiological threat
to workers and environment. Environ
Int. 2021;156:106641. doi:10.1016/J.
ENVINT.2021.106641
20 Osińska A, Korzeniewska E, Harnisz
M, et al. Small-scale wastewater
treatment plants as a source of thedissemination of antibiotic resistancegenes in the aquatic environment. J
Hazard Mater. 2020;381. doi:10.1016/j.
jhazmat.2019.121221
21 Gothwal R, Thatikonda S. Role ofenvironmental pollution in prevalenceof antibiotic resistant bacteria inaquatic environment of river: case ofMusi river, South India. Water Environ
J. 2017;31(4):456-462. doi:10.1111/
WEJ.12263
22 Wu Q, Li Y, Wu Y, Li F, Zhong S. The
spatial spillover effect of environmental
regulation on the total factor productivity of pharmaceutical manufacturingindustry in China. Sci Rep. 2022;12(1).
doi:10.1038/s41598-022-15614-8
23 Council of the European Union.
Proposal for a Directive of theEuropean Parliament and of theCouncil amending Directive 2010/75/
EU of the European Parliament and of
the Council of 24 November 2010 onindustrial emissions. Published 2023.
https://data.consilium.europa.eu/doc/
document/ST-7310-2023-INIT/en/pdf
24 Shionogi. Environmental Report 2022.
Published online 2023. https://www.
shionogi.com/content/dam/shionogi/
global/investors/ir-library/annual-report-integrated-report/pdf/environment Report_2022_e.pdf
25 Centrient. ESG Report 2021. Published
online 2022:1-117.
26 Centrient. Centrient’s Toansa
Manufacturing Site in India Leads the
Way in Wastewater Management.
Accessed May 26, 2023. https://www.centrient.com/media/centrients-toansa-manufacturing-site-india-leads-way-wastewater-management
27 Novartis. Sustainability Report 2022
for Novartis Austria. Published2022. https://www.sandoz.at/sites/www.sandoz.at/files/2022_
Nachhaltigkeitsbericht2022_ENG_
FINAL.pdf
28 Sandoz. Anti-Infectives. Accessed May
24, 2023. https://www.sandoz.com/
products-services/disease-areas/anti-infectives
29 Boston Consulting Group andWellcome Trust. Understanding the
Antibiotic Manufacturing Ecosystem:
A View of Global Supply Chains,
Pressure Points, and Implications for
Antimicrobial Resistance Response.;
2022. Accessed May 26, 2023. https://cms.wellcome.org/sites/default/
files/2022-04/understanding-the-antibiotic-manufacturing-ecosystem-2022.
pdf
30 Han Z, Feng H, Luan X, et al. ThreeYear Consecutive Field Application ofErythromycin Fermentation Residue
Following Hydrothermal Treatment:
Cumulative Effect on Soil Antibiotic
Resistance Genes. Engineering.
2022;15:78-88. doi:10.1016/j.
eng.2022.05.011
31 Sawant AM, Sunder AV, Vamkudoth
KR, Ramasamy S, Pundle A. Process
Development for 6-Aminopenicillanic
Acid Production Using LentikatsEncapsulated Escherichia coli Cells
Expressing Penicillin v Acylase. ACS
Omega. 2020;5(45):28972-28976.
doi:10.1021/ACSOMEGA.0C02813/
SUPPL_FILE/AO0C02813_SI_001.PDF
32 Stockholm International Water
Institute (SIWI). Responsible Antibiotics
Manufacturing Platform (RAMP).
Accessed July 24, 2023. https://siwi.
org/amr-ramp/
33 SIWI. Webinar: Sustainable Antibiotic
Manufacturing Practices in India YouTube. Published 2022. Accessed
July 24, 2023. https://www.youtube.
com/watch?v=32yL0amKvbg&t=3936s
34 EMA update on shortages of antibiotics in the EU | European Medicines
Agency. Accessed July 24, 2023.
https://www.ema.europa.eu/en/news/
ema-update-shortages-antibiotics-eu

35 CDP Water Security 2022 - Pfizer.
Accessed July 24, 2023. https://www.cdp.net/en/responses?per_page=10&queries%5Bname%5D=pfizer&sort_by=project_year&sort_dir=desc
36 Årdal C, Baraldi E, Beyer P, et al. Supply
chain transparency and the availabilityof essential medicines. Bull World
Health Organ. 2021;99(4):319-320.
doi:10.2471/BLT.20.267724
37 FAIRR. Antimicrobial Resistance andAntibiotic Stewardship in the Animal
Pharmaceutical Industry Animal
Pharmaceuticals Engagement 2022 /23. 2023;(May).
38 Centrient. Manufacturing sustainableantibiotics for the future Achieving a
PNEC-compliant supply chain Reaching
our goal of a clean antibiotics supply
chain. Published online 2022.
39 Teva. ESG Progress Report 2022.;2022. https://www.tevapharm.com/
our-impact/esg-progress-report/
40 GSK - ERA List. Accessed July 24,
2023. https://www.msds-gsk.com/
ERAList.aspx
41 GSK. ESG Perfomance Report 2022.
Published online 2022.
42 Viatris. Sustainability Report 2022.
Published online 2022.
43 MEDSAFE: New Zealand Medicines
and Medical Devices Safety Authority.
Accessed October 20, 2021. https://www.medsafe.govt.nz/regulatory/
DbSearch.asp
44 Hanna N, Tamhankar AJ, Lundborg
CS. The development of an integrated
environment–human risk approachfor the prioritisation of antibiotics forpolicy decisions. Sci Total Environ.
2023;880:163301. doi:10.1016/J.
SCITOTENV.2023.163301
45 European Commission. EU Action on
Antimicrobial Resistance.
46 A pharmaceutical strategy for Europe.
Accessed July 24, 2023. https://health.
ec.europa.eu/medicinal-products/
pharmaceutical-strategy-europe_en
47 European Commission. DIRECTIVE OF
THE EUROPEAN PARLIAMENT AND
OF THE COUNCIL concerning urban
wastewater treatment. 2022;0345.
48 China Dominates the Antibiotics Market| Statista. Published 2022. Accessed
July 24, 2023. https://www.statista.
com/chart/27709/distribution-of-global-antibiotics-export-value-by-country/
49 The Impact of China’s Environmental
Law on the Procurement of API and
Excipients. Published 2019. Accessed
January 5, 2023. https://www.beroeinc.
com/whitepaper/the-impact-chinas-environmental-law-on-procurement-of-api-and-excipients/
50 National Health Commission of thePeople’s Republic of China. National
Action Plan to Contain Antimicrobial
Resistance (2022-2025). Accessed
January 5, 2023. http://www.nhc.gov.
cn/yzygj/s7659/202210/2875ad7e2b2e46a2a672240ed9ee750f.shtml
51 Zhang Y, Walsh TR, Wang Y, ShenJ, Yang M. Minimizing Risks of33

AMR report on responsible manufacturing
Antimicrobial Resistance Developmentin the Environment from a Public One
Health Perspective. China CDC Wkly.
2022;4(49):1105-1109. doi:10.46234/
ccdcw2022.224
52 Panorel I., Schaaf N., Verma, N., Shaw
B., Salin, K. and Prakash S. 2023.
Responsible Antibiotics Manufacturing
Platform (RAMP) Framework,
Stockholm International Water
Institute.
53 Antibiotic residue in river, 37 Himachal
Pradesh firms in dock : The Tribune
India. Accessed July 11, 2023. https://www.tribuneindia.com/news/himachal/antibiotic-residue-in-river-37-himachalpradesh-firms-in-dock-370468

66 Nantaba F, Wasswa J, Kylin H, Palm WU,
Bouwman H, Kümmerer K. Occurrence,
distribution, and ecotoxicologicalrisk assessment of selected pharmaceutical compounds in water from
Lake Victoria, Uganda. Chemosphere.
2020;239:124642. doi:10.1016/J.
CHEMOSPHERE.2019.124642
67 Ogunbanwo OM, Kay P, Boxall
AB, et al. High Concentrations ofPharmaceuticals in a Nigerian River
Catchment. Environ Toxicol Chem.
2022;41(3):551-558. doi:10.1002/
ETC.4879

54 National Green Tribunal. Accessed July24, 2023. https://www.greentribunal.
gov.in/methodology-ngt
55 CIDRAP-ASP Report The Limit ofLimits: India’s Hurdles in Regulating
Antimicrobial Pollution.
56 National Green Tribunal. Case
No. 136/2020 ENVIRONMENT(PROTECTION) ACT, 1986.
Published 2022. https://greentribunal.gov.in/caseDetails/
DELHI/0701102008582020
57 Norwegian Hospital Procurement
Trust (Sykehusinnkjøp HF). Experience
Report – Environmental Requirements
for Pharmaceutical Procurements
2020-2022. Accessed February 16,
2023. www.sykehusinnkjop.no
58 Swedish Medical Products Agency.
Trial operation for an environmental
premium in the benefits system Interim
report (Miljöpremie och försäkringsskydd i läkemedelsförmånerna).
2022;04129. www.tlv.se
59 National Institute for Health and Care
Excellence (NICE). Models for theevaluation and purchase of antimicrobials. Accessed April 17, 2023. https://www.nice.org.uk/about/what-we-do/
life-sciences/scientific-advice/models-for-the-evaluation-and-purchase-of-antimicrobials
60 NHS England. Annex 1 : Selection
Questionnaire ( SQ ) Evaluation Criteria(new antimicrobials ). Published online
2020:1-16.
61 NHS England. Annex 3: Award questions and criteria. Published online
2021. https://www.nice.org.uk/Media/
Default/About/what-we-do/Lifesciences/award-questions-criteria-annex3.pdf
62 GARDP, CHAI, Shionogi. Request for
Proposal for Cefiderocol Access andStewardship Project. :1-24.
63 IAAMR. Investor Action on
Antimicrobial Resistance Investor
efforts , achievements and opportunities ahead. Published online 2022.
64 ISS. The Looming Antimicrobial
Resistance (AMR) Pandemic:
Implications For Investors. Accessed
April 4, 2023. https://insights.issgovernance.com/posts/the-looming-antimicrobial-resistance-amr-pandemic-implications-for-investors/
65 Angiro C, Abila PPO, Omara T. Effects
of industrial effluents on the qualityof water in Namanve stream, Kampala
Industrial and Business Park, Uganda.
BMC Res Notes. 2020;13(1):1-6.
doi:10.1186/S13104-020-05061-X/
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