Joel Bercu PhD MPH DABT

Associate Director, Occupational and Environmental Toxicology

How OELs & ADEs Develop Over the Life Cycle of a Drug

What is involved with the synthesis of a drug?

Drug

Substance

Starting

Material Intermediate

Prestarting Material

Penultimate

Reagent

Solvent

By-Product

Drug

Product

Excipient

Isolated steps of the process and the drug substance can lead to occupational exposure and GMP cross-contamination issues

OELs and ADEs

Term Definition Use

Occupational

Exposure

Limit (OEL)

An airborne concentration

not expected to result in an

adverse effect if exposed for

an 8-hour workday, 40-hour

workweek for a working

lifetime.

Worker

Safety

Acceptable

Daily

Exposure

(ADE)

A dose that is unlikely to

cause an adverse effect if an

individual is exposed, by any

route, at or below this dose

every day for a lifetime.

Effectively synonymous with

Permitted Daily Exposure.

GMPs

Background – OEL / ADE Development is part of the

overall risk assessment process

Does potential exposure

exceed the ADE / OEL?

Reduce exposure potential

Assess potential exposure

Hazard Assessment - OEL, ADE

Risk Assessment

Pharmaceutical development, filtering to the

one good molecule

From http://www.nimh.nih.gov/about/director/2012/experimental-medicine.shtml

Scale of manufacturing

Explore/Lead ID & Lead Op

Preclinical Phase 1 Phase 2 Phase 3 Commercial

Kg

Data knowledge increases in development

The certainty of your ADE / OEL calculations increase

Drug data and phases of development

• Early Development

– Mechanism of Action

– Cell-based assays

– In vitro pharmacology

– Short-term non-GLP toxicology

– Genotoxicity

• Phase 1 IND package

– 28 day toxicity study in 2 species

– Safety Pharmacology

– Genotoxicity

– Receptor screen

– Nonclinical PD and PK data

– Human dose estimation

Drug data and phases of development cont…

• Phase 2

– Repeat-dose data for a longer duration in rodents and non-

rodents

– Clinical data

• PD, PK, Safety, Efficacy

– Worker Safety Package (Variable)

• Eye Irritation

• Skin Irritation

• Skin Sensitization

Drug data and phases of development cont…

• Phase 3

– Repro / Dev Tox

– Carcinogenicity

– Worker safety testing

– More clinical data

• Phase 3 with more patients and better understanding of

sensitive populations

• Registration and Post-marketing updates

– Phase 4 data

– Post-marketing surveillance

Data on starting materials, intermediates,

reagents

• Early Research / Development (≤ Phase 1)

– Intermediates are constantly changing

– Deadlines really fast

– Usually no data, or very limited (possibly screening)

• Late Development (≥ Phase 2 - Registration)

– Commercial route being defined

– Data generation variable

• No regulatory drivers for data generation except for

mutagenicity (ICH M7)

• Testing dependent on corporate procedures and to support

GHS Safety Data Sheet labeling

• Post-Registration

– Dependent on country product registrations (e.g., REACH)

and scale (e.g. > 1 ton)

ADE / OEL Development Over the Lifecycle

• As the drug develops more work is performed on the

ADE / OEL

– With limited resources the number of molecules can be

overwhelming in early research

– Scale is small, so exposure is limited

– More data is generated

• Revise ADE / OEL

• Less uncertainty in number

• Therefore the ADE / OEL is revised over the lifecycle of

a drug

– Defaults applied in early research

– More conservative estimates early in development

– The ADE / OEL can raise as more is known about the

compound

Integrating the ADE and OEL assessments

• It is important to be well integrated into Research

Pipeline

– Approvals for research programs and compounds

– IND submissions

– IB updates

– Toxicology testing

– Updates to Core Data Sheets

• Stakeholders need to be informed of ADEs / OELs

– Industrial Hygiene, Environmental Health and Safety

– Quality

– Project teams

– Manufacturing

– CMOs

Research, prior to Phase 1

• OELs

– Drugs – typically defaulted, flags for highly hazardous

compounds

– Intermediates, starting materials, etc. – typically defaulted,

default can be different than the drug

• ADEs

– non-GMP, and lots not supporting clinical material do not

need ADEs

Phase 1 – 2, OELs – Control Banding Example

Occupational

Exposure Band

Category

Description Exposure limits

(µg/m3)

1 Relative non-toxic and non-potent and produces no

systemic effects

1,000 – 5,000

2 Low pharmacologic potency and generally have

little or no systemic toxicity

100 – 1,000

3 Short-term effects, that are generally not life

threatening and overexposures can be managed

medically.

1 – 100

4 Produce life-threating effects, with symptoms that

may be incapacitating and require immediate

medical intervention.

< 1

5 Extremely potent and/or toxic, life threatening Case-by-case

Adapted from Naumann et al., AIHA Journal. 1996; 57:33-42

Phase 1-2 Defaulted ADEs

Category ADE

Compounds that are not likely to

be potent, highly toxic or

carcinogenic

100 µg/day

Compounds that may be potent or

highly toxic

10 µg/day

Compounds that are mutagenic or

may be carcinogenic

1 µg/day

Adapted from Dolan et al., 2005. A 10-fold higher limit may be justified for material just used in Phase 1 (Bercu et al., 2013)

Phase 2 – Market: OEL / ADE Derivation

• Identify the critical effect

– Most sensitive effect relevant to human exposure

– Clinically relevant pharmacology is considered adverse

– Some effects may be observed in animals but not in

humans

• Derive the Point of Departure

– No-observed adverse effect level (NOAEL)

– Lowest-observed adverse effect level (LOAEL)

– Benchmark dose (BMD)

• Determine the adjustment factor

– Chemical specific factors may be used in lieu of data

Similarities / differences between OELs and

ADEs

• Similarities

– Similar equation

– Similar POD and adjustment factors

• Differences

– Populations – OELs for healthy workers, ADEs for patients

– Route of administration – OELs for inhalation, ADEs for all

routes including parenteral

– Body Weight – 50 kg for ADEs to cover a spectrum of

patients and OELs 70 kg based on worker weights

– OEL assumes an 8-hour day, can be adjusted for shorter

term tasks

– ADE can be adjusted based on route, patient population,

duration

OEL Derivation

Factor Description

F1 Inter-species

F2 Human variability

F3 Sub-chronic to Chronic

F4 LOAEL to NOAEL

F5 Severity of Effects or Database Completeness

α Bioavailability

ADE Derivation

Factor Description

F1 Inter-species

F2 Human variability

F3 Sub-chronic to Chronic

F4 LOAEL to NOAEL

F5 Severity of Effects or Database Completeness

α Bioavailability

Does ADE = OEL x 10? Maybe, but be mindful of the differences and details of the OEL calculation.

Post-market: OEL / ADE development

• Monitor development of a drug and see how it impacts

the OEL / ADE

– Don’t recreate a new OEL / ADE every time you look at it

• A company may inherit existing drugs

– Look for existing Safety Data Sheets from innovator

companies

– Look at data in the literature, package label, or regulatory

review documents (i.e., Summary Basis for Approval)

ADEs / OELs for intermediates, starting

materials etc.

• Intermediates, starting materials, etc. mostly have less

data than for drugs

• OELs – Control banding or default approaches is

typically what is done for intermediates / starting

materials

• ADEs – Defaulting (i.e., Dolan et al., 2005 or 10 ppm) is

typically done for intermediates / starting materials

• Intermediates, starting materials, etc. may get a good

data package if they are produced in large quantities

– High volume registrations for China, Korea, etc.

– Use data for OELs and ADEs

Cross-functional review committee

• Technical and Stakeholders

– Occupational Toxicologist

– Occupational Physician

– EHS

– Manufacturing

– CMO reps

– Project - Team Lead, Toxicologist, Clinical (case by case),

drug metabolism (case by case)

• Documentation

– Controlled documents

– Show scientific rationale and derivation of ADEs / OELs

– Should be made available to CMOs