Ensuring Safety Health and Ensuring Safety, Health and

process.safety.lab.com

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


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

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)


Outline of requirements at each Trigger

FGLPD

~ 6 Years

TT

Trigger 1 Trigger 2 Trigger 3 Trigger 4 Trigger 5

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


Outline of requirements at each Trigger

FGLPD

~ 6 Years

TT

Trigger 1 Trigger 2 Trigger 3 Trigger 4 Trigger 5

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


Outline of requirements at each Trigger

FGLPD

~ 6 Years

TT

Trigger 1

Trigger 2

Trigger 3

Trigger 4

Trigger 5

Project Start Route Evaluation Route Freeze Process Freeze Detailed Process

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.

• Objective 2

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.

• Objective 3

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

Project Start Route Evaluation Route Freeze Process Freeze Detailed Process

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

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