Ensuring Safety Health and Ensuring Safety, Health and

Ensuring Safety, Health and 

Environmental issues are addressed 

during Process Development (main focus on 

Environmental Assessment) 

AstraZeneca SHE Triggers Model 

Mark Hoyle, Process Safety, Supply Chain, Pharmaceutical 

Development, Macclesfield, UK 

t or pro oject nam me 

partmen 

Dep

The ‘Model’ 

• Flexible tool to identify when key SHE activities should be 

undertaken. Ensures SHE activities are not on the critical 

path. (Project Manager has overall responsibility - but does not carry 

out the individual activities) 

Trigger 1 Trigger 2 Trigger 3 Trigger 4 Trigger 5 

Project Start Route Evaluation Route Freeze Process Freeze Detailed Process 

Freeze / TT 

GENERAL ACTIVITIES THROUGHOUT DEVELOPMENT 

FGLPD 

~ 6 Years 

TT 

General set of fActivities iti Throughout h Development (and need reviewing i at all triggers) 

Review of Chemical Registration Requirements 

Review any Transportation Requirements 

Review any Safety Data Sheet (SDS) Requirements 

Process Risk kAssessment for Internal Manufacture 

- Review full Chemical Hazard Assessment 

- Review Operational Hazards

The Model 

• Does not cover all the direct SHE activities that need 

to be carried out on a day-to-day basis. These are 

covered by local procedures and work practices with 

support from the locally-based AZ SHE Advisers. 

• The general activities need reviewing by the Project 

Manager / project team at regular intervals as these 

could (and do) change considerably during 

development and can take significant time to 

complete.

Outline of requirements at each Trigger 

FGLPD 

~ 6 Years 

TT 

Trigger 1 

Project Start 

Trigger 2 

Route Evaluation 

Trigger 3 

Route Freeze 

Trigger 4 

Process Freeze 

Trigger 5 

Detailed Process 

Freeze / TT 

(Information gathering and initiation on safety/tox work –most work is done or initiated at this stage!) 

Obtain SHE Information from the Discovery team 

Information to Process Safety for Preliminary Assessment 

Assign HAZR&D Group to Materials 

Request HAZR&D Report 

Review Chemical Hazard Information - Decide if existing 

Information is adequate 

Submit structures for SAR assessment (starting materials and 

intermediates) 

Develop Occupational Health Hazard Evaluation Requirements 

(Tox Testing) in Conjunction with Occupational Toxicology 

Consult Occupational Toxicology to Review Route Selection with 

Respect to Health Effects


FGLPD 

~ 6 Years 

TT 

Trigger 1 

Project Start 

Trigger 2 

Route Evaluation 

Trigger 3 

Route Freeze 

Trigger 4 

Process Freeze 

Trigger 5 

Detailed Process 

Freeze / TT 

Submit New Compound in Development Form to AZ SHE (should be one that will pass 

through initial manufacture with potential for long-term use) – ensures all functions (Occupational 

Toxicology, Chemical Registration Team, Environmental Risk Assessment, Dangerous Goods 

team and Process Safety (within Pharmaceutical Development) are all aware of the compound 

and its initial route (just in case they have not been involved previously) 

Preliminary Environmental Review – regulatory review carried out by SHE group 

(Environmental Risk Assessment) 

Environmental Risk Assessment/Preliminary Environmental Assessment - the review above 

directly feeds into the risk assessment (tool) and identifies major issues. 

Aim of Environmental Assessment Process is to ideally prevent, then minimise and ultimately to 

render harmless pollution to air, water and land (from our processes)


FGLPD 

~ 6 Years 

TT 


Project Start t 

Route Evaluation Route Freeze Process Freeze Detailed Process 

Freeze / TT 

Environmental Assessment at Route Freeze 

Review Occupational Health Hazard Evaluation Requirements 

(SAR Evaluation/Tox Testing) in Consultation with AZ SHE


FGLPD 

~ 6 Years 

TT 


Project Start t 

Route Evaluation Route Freeze Process Freeze Detailed Process 

Freeze / TT 

Environmental Assessment at Process Freeze 

Review Occupational Health Hazard Evaluation Requirements 

(Tox Testing) in Consultation with AZ SHE


FGLPD 

~ 6 Years 

TT 

Trigger 1 

Trigger 2 

Trigger 3 

Trigger 4 

Trigger 5 


Freeze / TT 

Request Full Safety Data Sheets 

Final Environmental Review 

Final Chemical Registration Review 

SHE TT Report

Environmental Assessments 

• Aim to design out significant Environmental issues 

• Provide an auditable trail of E issues (through development) 

• Accessibility to ALL chemists and engineers is key 

• Make it easier for non-experts to engage (with the process) making it 

more success 

To put statements t t on materials such as this (below) into an easily 

understood / usable format 

Exhibits high/moderate toxicity …. subject to a mandatory UK 

Environmental Quality Standard of 50μg l -1 (freshwater) and 40μg l -1 

(seawater). UK….discharges contributing >1% EQS considered significant. 

Risk assessment at European level …recommendation that it be added to 

the Priority Substances List of the Water Framework Directive. EU 

legislation - category 3 reprotoxin….may increase pressure from 

regulators and may result in a more stringent EU-wide EQS. Likely to be 

rapidly removed from water by volatilisation, which may pose issues during 

biotreatment….

Why do we do these assessments: 

• Integrated Pollution and Prevention Control (IPPC) Regulations 

(UK, and similar in EU) - required to demonstrate Best Available 

Technology (BAT) for the whole route (EU based regulations) 

• Regulators can ask at any time – with no warning 

• Corporate Responsibility (‘Fits’ (Fits our Corporate SHE Objectives) 

• Aim for continuous improvement in the sustainability of all our 

activities by, amongst other things, economising on the use of natural 

resources and working to eliminate pollution. 

• Train, empower and require individuals to take personal responsibility 

for safety, health and the environment. 

• Cannot outsource responsibility for SHE issues 

• Regardless of regulations, toxic materials are toxic wherever handled 

• Annual reporting - metrics provide data for reporting of waste 

• Business Drivers 

• Promotes transferable processes 

• Risk management – if we don’t do this we are at risk (of breaching 

permit to work and loss of reputation). 

ti

‘Fits’ AZ Corporate SHE Objectives 

• Objective 1 

Aim to eliminate all work-related related injuries and cases of 

ill health by providing a safe and healthy work 

environment and promoting health & wellbeing. 


Aim for continuous improvement in the sustainability 

of all our activities i i by, amongst other things, 

economising on the use of natural resources and 

working to eliminate pollution. 


Train, empower and require individuals to take 

personal responsibility for safety, health and the 

environment.

Approach based on ‘Inherent Safety 

Principles’ 

Prevent 

More 

emphasis 

throughout 

Environmental 

Assessment 

Process 

Minimise 

Render harmless 

Likelihood of success 

increases as we 

move back up the 

Development 

process

AZ (Pharm Dev) SHE Trigger Model & the 

Environmental Assessment Process 

FGLPD 

~ 6 Years 

TT 

Trigger 1 

Trigger 2 

Trigger 3 

Trigger 4 

Trigger 5 


Freeze/TT 

Environmental 

Assessment 

Submit NCID (PD) 

Complete PER (AZSHE) 

Risk Assessment / PEA (AZSHE/PD) 

Environmental 

Assessment 

Final Environmental 

Review 

Prevent 

Minimise 

Prevent Prevent 

Minimise 

Minimise 

Render 

Render 

Render 

Harmless Harmless Harmless

Environmental Risk Assessment Tool 

• Excel Interface 

• Assumptions & limits 

Assumptions & limits 

• Substance (Process) Mass intensity metric 

• Likelihood calculator 

• Actions (AZ or contractor) 

• Environmental Risk Profile

Environmental Risk Assessment Tool 

1. Consequence/Hazard Score against each material 

4 – Very High Environmental impact material (major issue, legislation will 

prevent use or severely restrict emission in short/medium term) 

3 – High environmental impact material (significant issue) 

2 – Medium Issue (e.g. UK class A VOC) 

1 – (relatively) Low Issue 

1 2 3 4 

Acetone 

Ethanolamine 

Diisopropylamine 

2-Methyltetrahydrofuran 

Acetic Acid 

1,4-Dioxane 

Diethyl ether 

Acetonitrile 

Thionyl Chloride 

N-Methyl pyrrolidone 

1,5-Cyclooctadiene 

Methyl Iodide 

Dichloromethane 

Ethyl Bromoacetate 

Copper 

1,3-Chloro-2-propanol 

Diglyme 

Dimethyl Sulphate 

Dimethylacetamide 

Epichlorohydrin 

Benzyl Mercaptan 

Butane 

Isopropyl chloride 

Isopropyl Ether 

Allyl Alcohol 

Butyl Cyanide 

Butyronitrile 

Isobutyl chloroformate 

Iodoethane 

Nitrobenzene 

Phosphorus 

Pentachloride 

Acrylonitrile 

Benzyl Chloride 

Freon 22 

Isopropyl Bromide 

n-Butyl acetate Methane Trichlorotriazene N,N-Dimethylformamide

Environmental Risk Assessment 

Tool 

2. Likelihood Score against each material: 

Mass of 

material 

used in Stage (Kg) 

Likelihood = 

× 

Mass of API (Kg) 

Projected 

TPA of 

API 

• Ranking 

Low < 100 

Medium < 1000 

High > 1000 

•Risk = Consequence x Likelihood

Environmental Risk Assessment

Environmental Risk Assessment 

Spreadsheet entry of Consequence Score and Likelihood 

(H/M/L – from Stage Mass Intensity x API tonnage calc)

Calculating Likelihood Scores 

(Excel Spreadsheet – for ease)

Risk Profile 

Environmental Risk Profile 

AZDXXXX 

Risk Matrix 

Plot Risks 

Likelihood 

al API 

dicted Annua 

nes) 

kg API) x Pred 

irement (tonn 

substance/k 

requi 

eg (kg 

>10 3 H 11, 29, 30, 31, 34 12, 33 

>10 2 M 

1, 4, 5, 6, 7, 8, 9, 

13, 15, 16, 18, 20, 

21, 22 

3, 17, 23, 24, 27 2, 10, 14, 19, 25 26 

Updated Assessment

Risk Profile 

Environmental lRi Risk Profile 

AZDXXXX 

Risk Matrix 

Plot Risks 

Likelihood 

eg (kg 

substance/k 

kg API) x Pred 

dicted Annua 

al API 

irement (tonn 

nes) 

requ 

>10 3 H 11, 29, 30, 31, 34 12, 33 

>10 2 M 

1, 4, 5, 6, 7, 8, 9, 

13, 15, 16, 18, 20, 

3, 3, 17, 17, 23, 29, 24, 3027 2, 2, 10, 14, 14, 19, 19, 3225 26 

27, 28, 21, 31, 22 33 

Further in-house Tools (to help make decisions 

based on the Risk Assessment (quickly and with relative ease) 

• Solvent Selection Guide + ‘light’ version for 

Discovery 

• Lifecycle impact added (cradle to gate) 

• Acid and Base Selection Guide 

• Substance Avoidance Database 

• Alkylating Agent Selection Guide 

• Amide Formation Reagent Selection Guide 

• API Removal Tool

Successes 

• Linear 7 step sequence convergent 3 step sequence 

• solvent 300 to 50 kg/kg API 

• water 85 to 25 kg/kg API 

• reagents 35 to 10 kg/kg API 

• 80% cost reduction 

• Eliminated use of 1,2-dimethoxyethane 

• EU VOC Directive 

• Between critical clinical deliveries, post route freeze 

• Process Mass Intensity targets have now been included in the 

Process Mass Intensity targets have now been included in the 

Environmental Assessment protocol.

Benefits 

• Efficient process (re-appraisal of the ‘model’ in 2008 streamlined it 

somewhat and incorporated the ‘risk management’ approach to 

Environmental assessment) 

• Simple visual guide for development teams 

• Easily updated through development (and beyond) 

• Promotes interaction between AZ SHE, Pharmaceutical 

Development and outsourcing partners 

• Differentiates relative project risk 

Oncology hundreds kg 

Cardiovascular, neuroscience hundreds tonnes 

, 

• Allows appropriate resource allocation

Conclusions 

• Considered d to be an improved framework for the 

continuing implementation of Green Chemistry 

• Easier interpretation & clearer focus for chemists, 

engineers and outsourcing partners.

Co-authors 

Magnus Bergqvist 

Stephen Evans 

Dan Horner 

James Baird 

Acknowledgements 

Vyv Coombe 

Caireen Hargreaves 

Andy Wells 

Wesley White

Ensuring Safety Health and Ensuring Safety, Health and

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