Antibiotic manufacturing standard

Minimizing risk ofdeveloping antibiotic
resistance andaquatic ecotoxicity
in the environment
resulting fromthe manufacturingof human antibiotics
JUNE 2022

Updated September 2022
Authors’ note: Case studies (C1-C4) have been updated
since the original publication date to better clarify thedata and to correct numeric errors. No material changes
in the overall outcome of any case study resulted fromthe updates.

Contents
Foreword

4

0.0

Introduction

5

1.0

Scope

7

2.0

Normative references8

3.0

Terms, definitions and abbreviations

8

4.0

Wastewater management program

11

5.0

Solids management program

17

6.0

Management of change

19

Annex A (informative) Guidance for risk minimization

20

Annex B (informative) Program auditing

23

Annex C (informative) Case study examples

25

Bibliography

30

Further Reading

31

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Foreword
Publishing information
The AMR Industry Alliance (AMRIA) engaged BSI Standards Limited to provide expert
services in relation to the development of this antibiotic manufacturing standard.
This included engaging the technical author Jessica Vestel of MSD to produce an
initial draft, editing the draft in accordance with BSI Rules for the structure and drafting of UK standards and providing an updated draft to The AMR Industry Alliance forfurther development.
This private standard is not to be regarded as a BSI publication, such as a British
Standard, a BSI PAS or a BSI Flex. Work by BSI was completed in May 2022.
www.bsigroup.com

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0.0 Introduction
0.1

Background
With the significant rise in death toll across the globe, antibiotic resistance (ABR) has
become a major global health concern that threatens to undermine the basis of modern medicine by rendering the antibiotics used to treat and prevent infectious diseaseineffective (e.g. during invasive surgery) [1].
There are several causes of ABR, including over and misuse of antibiotics in humanand animal health in the agriculture and aquaculture sectors. Human health is inextricability linked to environmental health and as such there are concerns that thepresence of antibiotics in the environment may also contribute to antibiotic resistance in humans through the development and subsequent spread of resistance inenvironmental bacteria.

0.2

Pharmaceuticals in the environment
While the major source of pharmaceuticals in the environment (PiE) is believed toresult from patient use of medicine and subsequent excretion, other sources can include industrial emissions during the manufacture of pharmaceuticals. See Figure 1.
In general, emissions of active pharmaceutical ingredients (APIs) are not regulated
globally. Some companies go beyond compliance with the basic regulatory requirements for chemical manufacturers (e.g. control of pH, biological oxygen demand,chemical oxygen demand) by establishing environmental protection goals to evaluate and reduce potential environmental risks from production of their products.
Most programs, however, focus on potential toxicity to aquatic species, inefficiencies in wastewater treatment plants or potential toxicity to humans from drinking
water consumption.
Inadequate management of pharmaceutical manufacturing discharges can lead tonegative local impacts on the environment. In the case of antibiotics, the potential
exists that elevated presence of antibiotics in the environment could increase therate of ABR selection, although the relationship and significance of environmental
reservoirs of resistance and adverse human health impacts is still under investigation. This highlights the importance of effective control of API emissions from manufacturing, both in production of the API itself and its formulation into drug products
for patient use, and science‐based receiving water targets for antibiotics discharged
from manufacturing operations.

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Manufacturing
Process

Livestock
Treatments

Treatment ofCompanion Animals
Storage ofManure andSlurryAquaculture
Treatments

Inappropriate
Disposals of Used
Containers andUnused Medicines

Wastewater
Treatment

Receiving
Water

Manure/Slurry
Spreading

Soil
SOURCE: Boxall, A. The environmental side effects of medication. 2004. European Molecular Biology Organization Reports: 5 [2].

Figure 1

Sources of antimicrobials in the environment
Figure 1 illustrates how pharmaceuticals (including antibiotics) can enter the environment fromnumerous sources.

0.3

AMR Industry Alliance (AMRIA) work
The AMRIA is committed to minimizing the risk of antibiotic resistance developing
as a result of antibiotic manufacturing waste streams that might contain antibiotic residues entering the environment. To this end, the AMRIA created and publishedthe common antibiotic manufacturing framework in 2018 [3] which describes a riskbased approach to assessing and controlling antibiotic manufacturing waste streams.
Having shared the framework broadly and having shared AMRIA members’ progress towards implementing the requirements of the framework, the AMRIA decided
to codify the framework requirements in this antibiotic manufacturing standard. In
creating this standard, the opportunity has been taken to update key requirements
based on extensive AMRIA member implementation experience, incorporation of antibiotic predicted no-effect concentrations (PNECs), and inclusion of feedback frominterested stakeholders.
NOTE

The AMRIA also intend to develop an accompanying certification scheme. Such a scheme would
enable antibiotic manufacturers to seek independent certification that the process which creates
each antibiotic product follows the requirements of the standard.

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1.0 ScopeThis antibiotic manufacturing standard specifies requirements to reduce the development of ABR and the risk of aquatic (surface water) ecotoxicity in the environment
resulting from antibiotic manufacturing operations.
This antibiotic manufacturing standard covers the process of commercial manufacture of antibiotics intended for human use API; and antibiotics as part of drug product formulations containing the drug substance.
A site might manufacture multiple antibiotic APIs and/or final dosage forms containing antibiotics, and each process is to follow the requirements of the antibiotic
manufacturing standard.
This antibiotic manufacturing standard also covers:a)the management of antibiotic process wastewaters discharged during manufacturing
to meet predicted no-effect concentration (PNECs);b)methods to minimize the amount and concentration of antibiotics lost to wastewater;c)handling, treatment and disposal of other antibiotic waste to minimize or eliminate
release of antibiotics into the environment; andd)processes and systems to demonstrate conformity to this antibiotic
manufacturing standard.
This antibiotic manufacturing standard excludes non-antibiotic APIs or other hazardous chemicals, products prior to commercialization (e.g. development or clinical trials), intermediate chemicals used in antibiotic manufacturing processes and patientuse of antibiotics.
This antibiotic manufacturing standard does not cover non-ABR related and non-ecotoxicity related environmental impacts that might arise from antibiotic operations,
including but not limited to:1)energy use;2)

greenhouse gas emissions;3)

volatile organic compound (VOC) emissions;4)

air emissions, such as CO2 or nitrous oxides from boilers;5)

non-antibiotic parameters typically included in aqueous permits such as biochemical
oxygen demand (BOD), chemical oxygen demand (COD), pH; and6)solid waste not containing antibiotic residues.
This antibiotic manufacturing standard is intended for use by antibiotic manufacturers.
It may also be of interest to other pharmaceutical industry manufacturers and stakeholders with an interest in antibiotic manufactures and their antibiotic suppliers, suchas non-governmental organizations, academia, investors, buyers of antibiotics, andlocal and national governments.

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2.0 Normative references
There are no normative references in this standard.1

3.0 Terms, definitions
and abbreviations
For the purposes of this standard, the following terms and definitions apply.

3.1

Terms and definitions

3.1.1

active pharmaceutical ingredientbiologically active ingredient in a pharmaceutical drug

3.1.2

antibiotic
medicine used to prevent and treat bacterial infections

3.1.3

antibiotic resistanceacquired ability of a bacterial strain to withstand antibiotic exposure better thana wild-type bacterium of the same species

3.1.4

antibiotic waste
waste (solid or liquid) that is suspected to be contaminated with antibiotic API,
regardless of concentration

3.1.5

antimicrobial resistanceacquired ability of a strain of bacteria, viruses, fungi or parasite to better withstandtreatment with antimicrobials than the corresponding wildtype organisms

3.1.6

effluent
treated or untreated wastewater that flows out of a treatment plant, sewer,
or industrial outfall

1. Documents that are referred to solely in an informative manner are listed in the Bibliography.

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3.1.7

manufacturing
processes which create medicines
NOTE

3.1.8

Including the creation of the API and drug product formulation.

minimum inhibition concentration
lowest concentration of an antibiotic that inhibits 100% of the visible growthof a given strain of bacteria after 24-hour incubation

3.1.9

pharmaceuticals in the environment
presence of pharmaceuticals in environmental compartments
NOTE

3.1.10

Such as in surface water, ground water and soils.

point of generation
initial removal of materials from the manufacturing process with the intent
of disposal

3.1.11predicted environmental concentration
calculated concentration of a chemical in the environment, typically using modelling

3.1.12predicted no-effect concentration
concentration of a chemical, below which adverse effects in the environment are notexpected to occur

3.1.13

receiving water
river, ocean, stream, or other watercourse into which wastewater or treated effluent
is discharged

3.1.14risk quotientmeasure of risk that compares the predicted environmental concentration
to the predicted no-effect concentration (RQ = PEC/PNEC)

3.1.15secure landfill
waste storage facility designed and operated to prevent release into the environment
NOTE

For example through impermeable liners and leachate collection systems.

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3.1.16solid waste
solid material containing antibiotic residue and generated from manufacturing
including, but not limited to fermentation biomass, pollution control device solids,
wastewater treatment plant sludge, contaminated packaging

3.1.17wastewater treatment plantfacility that aims to remove contaminants through a combination of processes
in order to produce effluent suitable for intended discharge
NOTE

3.1.18

Examples of processes used include physical, chemical and biological.

zero liquid discharge
wastewater management system for the maximum recovery of waterfrom wastewater
NOTE

3.2

The water is beneficially reused (e.g. in boilers and cooling towers) after treatment. In the case ofland application of treated water (e.g. landscape use), proper risk assessment and controls are to
be done. The salts and other solids removed from the wastewater are properly disposed in a manner
which does not allow release to water (e.g. incineration, contained landfill).

Abbreviations
For the purposes of this standard, the following abbreviations apply.
ABR

antibacterial resistance

AMR

antimicrobial resistanceAPI

active pharmaceutical ingredient

MIC

minimum inhibition concentration

PEC

predicted environmental concentration

PiE

pharmaceuticals in the environment

PNEC

predicted no-effect concentration

POG

point of generation

RQ

risk quotient

WWTP

wastewater treatment plant

ZLD

zero liquid discharge

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4.0 Wastewater
management program
COMMENTARY ON CLAUSE 4
The level of detail and complexity of the environmental management system varies depending
on compliance obligations and the nature of activities, including environmental aspects andassociated environmental impacts. Compliance obligations can arise from mandatory requirements, such as applicable laws and regulations, or voluntary commitments, such as organizational and industry standards, contractual relationships, codes of practice and agreements with
community groups or non-governmental organizations.

4.1

General principle
Antibiotic concentration in manufacturing wastewater discharge shall not increase
the risk of antibiotic resistance (AMR) developing in bacteria in the environment.
The user shall assess wastewater discharges containing antibiotic to determine theconcentration of antibiotic(s). This predicted environmental concentration (PEC)
shall be less than the concentration believed to result in increased selection pressure on bacteria in the environment, known as the predicted no-effect concentration(PNEC). Where necessary the user shall apply controls or treatment to achieve the
PNEC, where:
PEC / PNEC = Risk Quotient (RQ)
RQ<1
Risk assessment measures shall be documented (see 4.4). Measures to control
emissions shall be in accordance with 4.4.and 4.5.

4.2

Demonstrating authorization/license/permit compliance

4.2.1

GeneralAs required by local regulation, the user shall hold an authorization/license/permit todischarge treated wastewater directly to the environment or to a downstream off-sitewastewater treatment plant (WWTP) owned and operated by a third party (i.e. a privately-owned WWTP or publicly-owned treatment works (POTW) or other seweragetreatment facility).

4.2.2

Authorization/license/permit conditions
The user shall have each condition identified and have a system in place that monitors, assesses and demonstrates compliance.

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4.2.3

Wastewater treatment and monitoring
Effective wastewater treatment shall be provided. Wastewater monitoring devices andtreatment systems shall be in good operating condition and be appropriately maintained.

4.2.4

Record keeping
Monitoring data shall be maintained and readily available, including information
required by permit(s) and the operations used to demonstrate adequate control ofwastewater discharges (e.g. WWTP operations). Equipment maintenance records
shall be maintained.

4.2.5

ReportingRoutine and deviation reporting shall occur in a timely manner and be in accordancewith permit conditions.

4.2.6

Permit deviations
Reportable deviations shall be investigated, with corrective and preventative action(CAPA) plans developed to minimize deviation re-occurrence.

4.3

Characterizing wastewater discharges
Wastewater sources from operations shall be characterized and controlled to risk
quotient (RQ<1). Supporting documents, such as water balances, process flow diagrams and criteria for allowable discharge to wastewater shall be maintained andmade readily available.

4.4

Quantifying and assessing antibiotic discharges
COMMENTARY ON 4.4
When the PEC is less than the PNEC (RQ) <1, the risk to the environment is considered low,indicating that wastewater discharges are effectively being managed. When the PEC is greaterthan the PNEC (RQ >1), there is the potential for environmental impact and wastewater discharge control practices are to be taken for adequate risk mitigation, i.e. RQ <1. Case studies
demonstrating how this works, with examples where RQ <1 which meets the standard and
RQ >1 which does not meet the standard, are illustrated in Annex C.

4.4.1

GeneralAntibiotic residue in wastewater shall be quantified and assessed against environmental protection criteria to measure risk. Risk shall be measured by the risk quotient(RQ), which is a comparison of the predicted environmental concentration (PEC) of
an API in the environment resulting from a site’s wastewater discharge to the predicted no-effect concentration (PNEC).

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4.4.2

Predicted environmental concentration (PEC)
COMMENTARY ON 4.4.2
The PEC is the concentration of antibiotic in the receiving water (i.e. river, lake, ocean) resulting from a manufacturing discharge. It is determined by quantifying API losses to wastewater
through mass balance and/or analytical testing and applying appropriate API treatability anddilution factors. These factors are often site-specific and depend on API characteristics, wastewater treatment plant technologies and the ultimate discharge point into the environment.

The user shall make available any supporting documentation, including:a)mass balances: the total mass of antibiotic(s) lost during all manufacturing campaigns is established; losses allocated to wastewater are determined through batchrecord review;

NOTE 1

Guidance on estimating actual API losses from the manufacturing process (calculation of a PEC) isavailable from the Pharmaceutical Supply Chain Initiative (PSCI) [4].

b)analytical testing: analytical testing is not required, however if testing waste streams
for antibiotic residue, testing is used to supplement the mass balance calculations
or it is used to determine the antibiotic concentration at the site end-of-pipe (EOP);c)the analytical method shall have sufficient sensitivity to be able to detect an antibiotic concentration at a limit of quantification to allow for comparison to the PNEC,
inclusive of downstream dilution factors.

NOTE 2

Sampling guidance is available from the Pharmaceutical Supply Chain Initiative (PSCI) [4] and Caldwell, et al., 2016 [5].

d)API treatability: the fate of API in wastewater treatment shall be established throughsite-specific testing and/or through relevant literature values (OECD testing, comparative treatment operations or through modelling). When no site-specific testing or
relevant literature values are available, the API treatability default shall be 0%; andNOTE 3

Assessment models are available, which can be used to refine the PEC based on the inherent properties of the antibiotic (e.g. fate in a wastewater treatment plant using assessment tools such as
SimpleTreat)e)receiving water dilution factors: where available, local dilution factors shall be derived from known flow rates or through modelling. Low flow conditions (e.g. 10th
percentile, 7Q10) or applicable mixing zone factors (e.g. chronic mixing zone for an
ocean or lake discharge) shall be applied. When low flow data is unavailable, 33%of the average flow shall be applied. If local dilution is not known, standard dilution
factors can be used (i.e. 10 for a river and 100 for an ocean discharge).

NOTE 4

Environmental models are available, which can be used to calculate the dilution of the discharged
effluent (e.g. CORMIX).

NOTE 5

Guidance for estimating dilution factors is available from the Pharmaceutical Supply Chain Initiative(PSCI) [6].

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4.4.3

Predicted no-effect concentration (PNEC)COMMENTARY ON 4.4.3
The PNEC is the API concentration in the environment where no impact is expected. For environmental toxicity, the PNEC (known as the PNEC ENV) is derived by assessing the effective
concentration where 10% effects are observed (EC10) or the no-observed effect concentrations(NOEC) measured in toxicity studies, and then applying an assessment factor (AF). The AF is asafety factor that accounts for uncertainties and variability in strength of the dataset. For antibiotics, a PNEC is additionally determined based on the minimum inhibition concentration andis referred to as the PNEC MIC (see note 2 for further details on PNEC derivation, and selectionof the appropriate PNEC).

PNECs established by the AMRIA shall be used.
NOTE

If a compound specific PNEC is not listed, the default PNEC established by the AMRIA can be usedin the absence of data. PNEC ENVs can be developed through standardized laboratory studies (e.g.
OECD) and by applying assessment factors in a manner consistent with ECHA REACH guidance [7].

NOTE 1

Compound specific and default PNECs are available from the AMR Industry Alliance (https://www.
amrindustryalliance.org/wp-content/uploads/2022/04/AMR-Table-1-Update-February-2022.pdf).

NOTE 2

Approaches to reduce AMR risk in the environment are still under development and various options
are presented in peer reviewed literature [8], [9], [10], [11]. As the science progresses, PNEC values
deemed to be protective against the spread of AMR might change.

4.5

Control of routine discharges

4.5.1

GeneralThe user shall reduce the antibiotics discharged to the environment to an RQ lessthan 1 (RQ <1) by employing good management practices and by applying a hierarchyof control.
NOTE

4.5.2

Annex A provides guidance for risk mitigation.

Good management practices
API discharges to wastewater shall be minimized through review of the applicabilityof each of the following, including use, as determined by the review:a)products shall not be directly discharged to wastewater; reject batches that cannot
be recovered or reworked shall be collected for treatment on-site or off-site;b)maximize use of closed transfers between process equipment to minimize spills;c)maximize equipment dry cleaning (vacuum, wipe) before wet cleaning; andd)collect any dry spilled material from floors and walls before washing an area down.
The review of applicability of good practices shall be documented and include
a rationale for decisions made.

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4.5.3

Hierarchy of control
Good management practices alone might not reduce API releases to an acceptablelevel. When further action is required (i.e. RQ >1), API release reduction hierarchy,in accordance with 4.5.3.1 to 4.5.3.3 shall be applied.

4.5.3.1

Reduce losses to wastewater
To reduce losses to wastewater, the user shall:
1)evaluate process changes that could increase yields and reduce losses;

2)enhance equipment dry cleaning practices; and3)

redirect high API waste streams to solvent recovery, other treatment, or incineration.

4.5.3.2

Collect wastewater at point of generation (POG)
Specific waste streams that can be collected and treated on-site or off-site shallbe identified.
Options for treating wastewater at source or POG shall be taken into account by:a)collecting and treating (e.g. oxidation or incineration) equipment cleaning rinses;b)collecting and then evaporating to reduce amount to be treated, thereby reducing
treatment costs; andc)collecting and treating to destroy or separate and then destroy API, e.g. alkalinehydrolysis, advanced treatment and oxidation processes (such as ozone, ultraviolet,hydrogen peroxide, Fenton’s, carbon adsorption, electrochemical oxidation, or combination of technologies).

4.5.3.3

Enhance existing wastewater treatment plant
Enhanced wastewater treatment shall be taken into account after all reduction
efforts have been employed and when there are multiple waste streams requiring
enhanced control. Options for enhancing wastewater treatment shall include:1)

optimizing API reduction performance through conventional operating parameter
analysis and improvement;2)

improving biological solids separation through, e.g. membrane bioreactor; and3)providing tertiary treatment (e.g. ozone, ultraviolet, hydrogen peroxide, Fenton’s, carbon adsorption, electrochemical oxidation, membrane technologies or any suitable
proven technologies).

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4.6

Control of non-routine discharges
The user shall minimize the release of non-routine antibiotic discharges to the environment, including spills, application of treated wastewater to land for irrigation andfirewater run-off containment, such as:a)spills/releases: process and storage areas (e.g. tanks, container storage areas, andprocess sewer systems) shall be designed, constructed and operated to prevent
spills or releases to the environment. Containment system design and operation records shall be readily available; andb)irrigation with treated wastewater: risk assessments shall be conducted to determine potential risk from application to land (i.e. through run-off to surface water orleaching to groundwater, as well as to soil) and risks mitigated if RQ is more than 1(RQ >1).

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5.0 Solids management
program
COMMENTARY ON CLAUSE 5
The level of detail and complexity of the environmental management system varies depending
on compliance obligations and the nature of activities, including environmental aspects andassociated environmental impacts. Compliance obligations can arise from mandatory requirements, such as applicable laws and regulations, or voluntary commitments, such as organizational and industry standards, contractual relationships, codes of practice and agreements with
community groups or non-governmental organizations.

5.1

GeneralSolid waste containing antibiotic residues shall be managed on-site and off-site.
NOTE

5.2

Solid waste includes process waste, fermentation biomass and wastewater treatment sludge
or solid residues generated from other pollution control measures.

On-site management
The user shall demonstrate and check controls are in place for effective and safe
handling, movement, storage, recycling, reuse and disposal of antibiotic waste.
The user shall have systems in place to prevent and mitigate accidental spills andreleases to the environment. In the case of unpermitted or accidental release of antibiotic waste in the environment, remedial measures shall be in place to prevent
reoccurrence and address associated environmental impacts.
Waste shall be stored such that discharges and unsafe conditions are prevented, andin accordance with applicable regulatory requirements:a)waste containers shall be labelled with contents, hazard characteristics (e.g. flammable, biological), and closed once waste is placed in the container;b)material shall be stored in quantities not exceeding the capacity of spill containmentand shall be sheltered from weather/elements;c)spill containment integrity shall be inspected, documented and maintained in a satisfactory condition to prevent the discharge of waste materials into the environment;d)solid wastes shall be stored to prevent discharge as a result of rain/storm water run off;e)biomass from fermentation shall be managed to prevent environmental pollution;

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f)waste containers shall be in good condition and compatible with the materials being
stored (e.g. free from corrosion, dents, bulges or other impairment that would impact
adequate containment) and remain closed except during filling and emptying operations; andg)materials shall be stored to prevent events resulting from undesired reactions,incompatibilities, decomposition and/or self-ignition.

NOTE

5.3

Attention is drawn to regulatory requirements with regard to storage of waste.

Off-site disposal
The user shall incinerate or dispose of solid waste containing antibiotic residue toa secure landfill site.
The user shall require the operator to confirm the landfill site is secure, designed andoperated to prevent release into the environment.
NOTELand application of treatment plant sludges generated on-site is not preferred, however it can beused if the user demonstrates that the risk to soil and groundwater from leaching, and the risk tosurface water from run-off is acceptable (RQ <1).

The user shall verify documentation from each waste disposal contractor that:1)waste disposal contractors possess authorizations/certifications from regulatory
authorities to manage specific waste streams in accordance with local regulations;2)

any accidental spills and releases are reported to applicable authorities in accordance with regulatory and/or permit requirements; and3)

records (e.g. waste/classification determinations, including analytical results, lettersfrom waste contractors, and certificates of destruction) are maintained.

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6.0 Managementof change
Previous risk evaluation(s) shall be reviewed and updated when significant changes
to operations are planned to determine whether the change impacts prioritization or
mitigation strategies.
Significant changes shall include new antibiotics processed in the facility and modifications to existing processes (i.e. increase or decrease in use or discharge of antibiotics from operations), as well as changes to a relevant PNEC.
NOTE

Annex B provides guidance for auditing.

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Annex A
Guidance for risk
minimization(INFORMATIVE)

A.1

Risk reduction
Risks should be prioritized and potential mitigation options for those identified to be
most significant should be implemented.

A.2

Process improvements
Process improvements to increase and/or optimize the overall yield, such as modernization of the process should be monitored to prevent or minimize the upstream
antibiotic load. Process improvements should not be made if they conflict with good
manufacturing practice (GMP) requirements.

A.3

Minimize API loss
Cleaning procedures should be optimized to reduce the antibiotic loading and to lower disposal costs by performing a thorough initial dry cleaning and by reducing thevolume of high strength rinses being generated. An additional separate cleaning step
(pre-rinsing) should be undertaken to remove large portions of APIs from large volume wash waters. The high load pre rinse streams can be separated and addressed
subsequently by a selective technology or incineration/thermal oxidation.
NOTE

A.4

If dry cleaning is performed, workplace safety should be carefully monitored. Dry cleaning should not
be an option if cleaning in place (CIP) is mandatory, according to the company’s standard operatingprocedure (SOP).

Segregate/collection waste
Mass balances can also aid in identifying wastewater stream(s) that should be segregated for disposal at an off-site facility, waste streams suitable for effective on-site
treatment prior to disposal, and waste streams that require specific pre-treatment
prior to disposal to a wastewater treatment system.
Analyses should be conducted to determine whether any residuals pose a risk either
to a subsequent WWTP (e.g. inhibition or interference) or to a receiving environment(i.e. lake, river, or ocean) after discharge. To avoid high loads of antibiotics enteringa site’s wastewater influent, the user should retain good knowledge of the content
of antibiotics in waste streams. Waste stream analysis can allow manufacturers
to potentially optimize and implement the most effective pollution prevention andcontrol measures.

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A.5

Assess alternatives to discharging
Antibiotic removal is compound specific and should be addressed on a case-by-casebasis. Mass transfer processes (antibiotics trapping) can be employed to remove
antibiotics from solution into the solid phase, thereby concentrating the volume ofwaste for treatment.
NOTE 1

Activated carbon adsorption, chemical precipitation or flocculation, membrane separation or thermal processes (evaporation) generate either concentrated liquids or solids (for incineration).

NOTE 2

Removal efficiencies of different treatments vary with different antibiotics, depending on the suitability of the treatment for the antibiotics and on the specific wastewater composition in each case (e.g.
salinity, turbidity, organic load).

A.6

WWTP modifications/improvements
COMMENTARY ON CLAUSE A.6
Many facilities in API production and final dosage production in the pharmaceutical industry rely on the use of neutralization, equalization, and physical/biological (primarily activatedsludge) treatment technologies for their wastewater treatment. However, many antibiotics are
only partially removed in conventional biological treatment because of their physical and chemical characteristics.

More advanced technologies, such as ozonation or electrochemical oxidation (e.g.
Fenton’s reagent) can be applied at manufacturing sites to remove specific compounds for which conventional treatment approaches do not work.
NOTE

A.7

End-of-pipe treatment is an alternative, although this option is not preferred due to higher volumes,
mixing with other chemicals, and lower concentrations of the compound to be treated.

Pre-treatment options
In certain cases, wastewaters could be investigated in more detail for the possibilityof physico-chemical pre-treatment. In order to verify the destruction or removal of
antibiotics, such investigations should encompass physical removal through precipitation, flocculation or adsorption to activated charcoal or other substrates, possibly
furthering hydrolysis through raising or lowering the pH, with or without additionallyheating the wastewater, or ozonation. Additionally, treatment with UV radiation, or
advanced oxidation processes (AOPs) using UV with photosensitisers or oxidizers
could be tested.
Best Available Techniques (BAT) Reference Documents (BREFs) can be consulted forpre treatment options for wastewaters from the chemical sector [12], [13]. Pre-treatment options and case studies are also found in the literature [12], [14], [15], [16], [17].

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NOTE

Examples for pre-treatment options were also presented by the Pharmaceutical Supply Chain
Initiative (PSCI), including:a. in the course of a PSCI sponsored webinar on how to manage APIs in manufacturing effluent(Part 3) which took place on 25th October 2016 (https://pscinitiative.org/resource?resource=297);
b. in the course of the PiE/AMR Deep Dive training seminar held on 17th September 2019 in
Hyderabad, India (https://pscinitiative.org/resource?resource=482).

The user should be aware that any kind of pre-treatment will generate additionalcosts, including environmental costs (e.g. increased energy consumption, additionalraw materials consumed, more CO2 produced, or other kinds of wastes generated).
Wastewater incineration should be the last option, as an inordinate amount of energy
is needed to evaporate water, often constituting well over 98% of a wastewater, toeventually combust the minor residues of recalcitrant or (eco)toxic organics.

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Annex B
Program auditing(INFORMATIVE)

To check that internal and external antibiotics manufacturing facilities within the supply chain minimize the risk of ABR developing through the release (intentional or accidental) of antibiotics into the environment, on-site internal EHS audits and audits ofexternal suppliers should be performed.
Audit antibiotic suppliers at least once every five years or when significant changes
to operations or production volume are planned/occur in order to confirm adherence
to this antibiotic manufacturing standard. Audits could be performed more frequently based on result of previous audits or discovery of heightened risk at the facility.
Focus should be on areas for environmental management, including water management, solid waste management, such as fermentation residues, spill prevention andresponse, chemical storage and handling, and employee training.
Audits should include a review of applicable regulatory requirements and permit conditions, the facility’s environmental risk assessment of antibiotic discharges (quantified by mass balance or measurement, including validation documents following
records retention) and assessed against PNECs.
Maintenance plans (for critical equipment and environmental controls) and incident
investigation logs [corrective and preventative actions plan (CAPA)] for relevant incidents should be reported and included in the audit, as well as evaluating supplier practices for evaluating their own supply chain, waste and wastewater disposal records.
Audits should include evaluation of any antibiotic mass balance performed, local dilution factors selected and/or any sampling and analysis methodology used to verify
adherence to the PNEC.
Facility tours should assess operating conditions to verify practices are in place andare being followed, as required (while in-person facility tours are preferred over remote auditing, certain circumstances may mean carefully planned, virtual auditing
may be necessary).
The facility tour should include:a)antibiotic manufacturing areas;b)

storm water collection and retention practices and/or systems;c)on-site wastewater treatment plant(s) (WWTP);d)waste storage areas, process and domestic wastewater collection and treatment;e)deep wells, underground and above-ground storage tanks with associated visible piping;f)fuel storage locations;

PAGE 24 | AMR INDUSTRY ALLIANCE ANTIBIOTIC MANUFACTURING STANDARD

g)solvent storage and recovery;h)warehouses other physical storage sheds/locationsi)external tours of the facility including discharge locations (where safely accesible);j)pollution control devices; andk)receiving stream identification and observation, and fire water retention.
Audit reports should identify any non-conformity to the standard, and highlight any
gaps, deficiencies, or deviations (e.g. from generally accepted industry practices and/or contractual commitments and communicated expectations related to antibiotics
discharges).

NOTE

Audit reports remain confidential between the company and the supplier or manufacturing site, subject
to the audit unless the supplier or manufacturing site agree otherwise). Companies could opt to publicly report, for example, aggregate audit information as part of their overall EHS program reporting.

Users should also follow up with the supplier (facility) to develop acceptable actionplans for recommendations from the audit. The supplier’s performance should bemonitored to confirm progress of actions, including subsequent remedial action closure consistent with specified timelines. Results and ongoing appropriateness of
suppliers should be monitored.

PAGE 25 | AMR INDUSTRY ALLIANCE ANTIBIOTIC MANUFACTURING STANDARD

ANNEX C
Case study examples(INFORMATIVE)

C.1

CASE STUDY:
Manufacturing of Trimethoprim (without on-site
treatment/controls) losses are too highFigure C.1 illustrates industry contribution of 20 kg is too high for the surface water
concentration to be below PNEC RQ = 59.7, and therefore this example would notconform to the standard.
The manufacturer shall reduce losses to meet PNEC so the RQ is less than 1 (RQ<1).

Figure C.1

Manufacturing of Trimethoprim (without on-site treatment/controls) losses are too high

Building A
200 kg API

Building B
0 kg API

0 g API
40,000 L
wastewaterin Stream B

75.8% yield =48.4 kg loss

0 g API
40,000 L
wastewaterin Stream C

90% total yield =20 kg loss

20,000 g
20,000 L wastewaterin Stream A

Combined
Waste Stream
from Site
Building C
0 kg APIHot flushes/rinses
performed and re-charged
to capture residual

Site API:
20,000 g
20,000 L
manufacturing
effluent

API:
21.264 g(combined)API:
1,264 g369,000,000 L
residential
wastewater [3]Large town
wastewater
treatment plant
WWTP [1]6,379 g removed(typically 30%
removal [4])API:
14,885 g
369,100,000 L
wastewater

Surface Water(Flow = 100ML)API:
14,885 g
469,100,000 L
water

PEC = 31.7 µg/L
Trimethoprim PNEC =0.5µg/L
RQ (All sources) = 63.4
RQ (Industry) = 59.6
RQ (Patient Use) = 3.8

Dose of Trimethoprim = 200 mg/day
Fpen* = 0.01 (1%) per EMA Guidelines [2]
WWTP services 790,000 inhabitants [3]-80% Trimethoprim excreted [4]Estimated loading to WWTP from patients use = 1216 g**

Industry Contribution = 94%
Patient Use Contribution = 6%

PAGE 26 | AMR INDUSTRY ALLIANCE ANTIBIOTIC MANUFACTURING STANDARDNOTE 1Mass losses and waste water volumes are on a daily basis.

NOTE 2

How to read this diagram:
1. Building A: 200 kg typical batchsize;
2. 75.8% yield following first processing steps:
a. remaining antibiotic as residual in filter dryers, equipment, etc.
3. Hot rinses/flushes are done of the equipment in an attempt to capture remaining antibiotic
and increase overall yield:
a. after flushes, yield increases to approximately 90%; andb. estimated loss of 20 kg (high but from an actual scenario) Building A effluent;
4. Antibiotic in the waste scream is combined from all buildings and whole manufacturing
effluent sent for off-site treatment:a. combined with municipal waste (e.g. patient use);
5. For trimethoprim, studies have shown an average of 30% removal in standard
wastewater treatment (4).
6. Treated effluent discharged into surface water.

NOTE 3

1. The article provides evidence for selection of multi-resistant E. coli from hospital
effluent-ScienceDirect
2. ERA: http://ema.europa.eu/en/documents/scientific-guideline-environmental-riskassessment-medicinal-products-human-use-first-version_en.pdf
3. A complete mass balance for plastics in a wastewater treatment plant—
Macroplastics contributes more than microplastics—ScienceDirect.
4. An Environmental Risk Assessment for Human-Use Trimethoprim in European
Surface Waters—PubMed (nih.gov).

* Fpen = Fraction of population receiving drug** Patient Use (g) = [Dose (mg/day) * # inhab *Fpen * % excretion] / 1 000 g.

PAGE 27 | AMR INDUSTRY ALLIANCE ANTIBIOTIC MANUFACTURING STANDARD

C.2

CASE STUDY:
Manufacturing of Trimethoprim(on-site treatment/controls)
Figure C.2 provides an example where an industry loss of 20kg is acceptable because waste stream treatment and dilution results in a concentration in the receiving
body (surface water) below the PNEC.

Figure C.2

Manufacturing of Trimethoprim(on-site treatment/controls)

Building A
200 kg API

Building B
0 kg API

0 g API
40,000 L
wastewaterin Stream B

75.8% yield =48.4 kg loss

0 g API
40,000 L
wastewaterin Stream C

90% total yield =20 kg loss

20,000 g
20,000 L wastewaterin Stream A

On site treatment

Building C
0 kg APIHot flushes/rinses
performed and re-charged
to capture residual

19.8 kg removed(99% reduction;
known via
treatability studies)

Site API:200 g
100,000 L
manufacturing
effluent

API:
1,464 g(combined)API:
1,264 g369,000,000 L
municipal
wastewater [3]Large town
wastewater
treatment plant
WWTP

439 g removed(typically 30%
removal [4])API:
1,025 g369,100,000 L
wastewater

Surface Water(Flow = 100ML)API:
1,025 g469,100,000 L
water

PEC = 2.2 µg/L
Trimethoprim PNEC = 0.5µg/L
RQ (All sources) = 4.4
RQ (Industry) = 0.6
RQ (Patient Use) = 3.8

Dose of Trimethoprim = 200 mg/day
Fpen* = 0.01 (1%) per EMA Guidelines [2]
WWTP services 790,000 inhabitants [3]-80% Trimethoprim excreted [4]Estimated loading to WWTP from patients use = 1216 g**

Industry Contribution = 14%
Patient Use Contribution = 86%

PAGE 28 | AMR INDUSTRY ALLIANCE ANTIBIOTIC MANUFACTURING STANDARD

C.3

CASE STUDY:
Manufacturing of Trimethoprim(direct discharge: on-site treatment/controls)
Figure C.3 provides an example where an industry loss of 20kg is acceptable because waste stream treatment and dilution results in a concentration in the receiving
body (surface water) below the PNEC.

Figure C.3

Manufacturing of Trimethoprim (direct discharge: on-site treatment/controls)

Building A
200 kg API

80% yield =40 kg loss

Hot flushes/rinses
performed and re-charged
to capture residual

90% total yield =20 kg loss

20,000 g
600,000 L wastewaterfrom total site

On site treatment(high alkali pH
12.4 - 12.5
destruction)

19.9 kg removed(99.94% reduction;
known via
treatability studies)

Site API:12 g
600,000 L
manufacturing
effluent

Surface Water(Flow = 100ML)
API:
12 g
100,600,000 L
water

PEC = 0.1 µg/L
Trimethoprim PNEC = 0.5µg/L
RQ (Industry) = 0.2

PAGE 29 | AMR INDUSTRY ALLIANCE ANTIBIOTIC MANUFACTURING STANDARD

C.4

CASE STUDY:
Tableting of Trimethoprim
Figure C.4 provides an example where an industry loss of 20 kg is acceptable because waste stream treatment and dilution results in a concentration in the receiving
body (surface water) below the PNEC.

Figure C.4

Tableting of Trimethoprim

Building B
0 kg API

0 g API
40,000 L
wastewaterin Stream B

0 g API
40,000 L
wastewaterin Stream C

Loss to water (0.2 kg)

200 g
20,000 L wastewaterin Stream A

On site WWTP

Building C
0 kg API

Losses not to water, e.g.,
dust collector (1.8 kg)

198kg API out(in productformulations)

Building A
200 kg API

60 g removed(typically 30%
removal [4])Site API:140 g
100,000 L
manufacturing
effluent

API:
1,404 g(combined)API:
1,264 g369,000,000 L
municipal
wastewater [3]Large town
wastewater
treatment plant
WWTP

421 g removed(typically 30%
removal [4])Surface Water(Flow = 100ML)

API:
983 g
369,100,000 L
wastewater

API:
983 g
469,100,000 L
water

PEC = 2.1 µg/L
Trimethoprim PNEC = 0.5µg/L
RQ (All sources) = 4.2
RQ (Industry) = 0.4
RQ (Patient Use) = 3.8

Dose of Trimethoprim = 200 mg/day
Fpen* = 0.01 (1%) per EMA Guidelines [2]
WWTP services 790,000 inhabitants [3]-80% Trimethoprim excreted [4]Estimated loading to WWTP from patients use = 1216 g**

NOTE

Industry Contribution = 10%
Patient Use Contribution = 90%

1. This article provides evidence for selection of multi-resistant E. coli by hospital
effluent—ScienceDirect
2. Environmental Risk Assessment: http://ema.europa.eu/en/documents/scientific-guideline-environmental-risk-assessment-medicinal-products-human-use-first-version_en.pdf
3. A complete mass balance for plastics in a wastewater treatment plant—Macroplastics contributes more than microplastics—ScienceDirect
4. An Environmental Risk Assessment for Human-Use Trimethoprim in European Surface Waters
PubMed (nih.gov)* Fpen = Fraction of population receiving drug** Patient Use (g) = [Dose (mg/day) * # inhab *Fpen * % excretion] / 1000 g

PAGE 30 | AMR INDUSTRY ALLIANCE ANTIBIOTIC MANUFACTURING STANDARD

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[11] GULLBERG, E., et al., Selection of resistantbacteria at very low antibiotic concentrations. PLoS Pathog, 2011, 7 (7): e1002158.
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Further reading
AGA, D.S., Advances in the Analysis of Pharmaceuticals in the Aquatic Environment, in Fateof Pharmaceuticals in the Environment and in
Water Treatment Systems. Boca Raton, FL.: CRC
Press, 2007.

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Water Framework Directive (2000/60/EC). Final
draft revised guidance document no. 27 technical guidance for deriving environmental quality
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2017: 347–366.

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Clin Infect Dis, 2013, 57 (5): 704–710.

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LARSSON, D.G.J., Environmental factors influencing the development and spread of antibiotic
resistance. FEMS Microbiol Rev, 2018, 42 (1).

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About The AMR Industry Alliance
The AMR Industry Alliance is a coalition of over 100 biotechnology,
diagnostic, generics and research-based biopharmaceutical companies and trade associations that was formed to drive and measureindustry progress to curb antimicrobial resistance. As the largest
life-sciences coalition of its kind, the Alliance aims to provide sustainable solutions in the fight against AMR through broad industry
momentum, public-private collaboration and multi-sectoral action.
amrindustryalliance.org