How can Occupational

Toxicology support Quality: OEL

and PDE of Pharmaceuticals

Ester Lovsin Barle, Head Health Hazard Assessment CoE

MEDICHEM; 31st August – 2nd September 2016

Global HSE & BCM

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• This presentation is based on publicly available information;

• These slides are intended for educational purposes only

and for the personal use of the audience. These slides are

not intended for wider distribution outside the intended

purpose without presenter approval;

• The content of this slide deck is accurate to the best of the

presenter’s knowledge at the time of production.

• The views and opinions expressed in this presentation are

those of the author and do not necessarily reflect the official

policy or position of Novartis or any of its officers.

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Occupational Exposure Limit

• An OEL is set at a level at which, based on current

scientific knowledge, it is judged that there is minimal risk

to the health of the workforce if exposed via inhalation to

the substance day after day.

Permitted Daily Exposure

• A PDE is 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.

Definitions

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Application of PDE

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Batch size (2) Maximal

Daily Dose (2)

Safe carry over(1)

PDE(1)

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Is PDE correlated with OEL?

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OEL

Safe level for chronic

exposure, 40 years

Exposure daily

Inhalatory route

Depends on the potency

(activity) of the substance

Applied for OH

(personal monitoring)

Target population healthy

adults (70kg)

PDE

Safe level for chronic

exposure, 80 years

Exposure daily

IV, oral, other routes

Depends on the potency

(activity) of the substance

Applied for cleaning

validation (equipment)

Target population patients

(50kg)

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• Steps for determining the PDE and OEL are the same

Is PDE correlated with OEL?

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Hazard identification

• Identify all the data about the drug

Hazard assessment

• Determine the critical effect

• Adjust the safe level to the most sensitive population

• Adjust the differences and route of exposure

• Calculate the safe level

Risk assessment

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• Several approaches of

calculations are provided

• The critical and the most

relevant is selected for

three different routes of

administration

• AFs are based on

guidances, their

application depends on

– Experts involved

– Historical differences

How is the calculation done?

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• OELs in

Novartis are

being updated

since 2014

• Risk

assessments

need to be

conducted in

case a change

is significant

What are the consequences for

workers

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0.01

0.1

1

10

100

1000

10000

0 10 20 30 40 50 60

OEL (µg/m3) Previous OEL (µg/m3)

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• Comparison of EPA and WHO values

• 65 chemicals

• Slightly different time, method, data

Harmonization of the hazard

assessment

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• 30% were identical

• 60% of values were within 3-fold difference

• 9% of values within 300-fold difference

• 1 chemical 700-fold difference

• EPA values lower than WHO

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• Changes up to 3- fold are “trivial” and are generally not

significant for risk assessment

– 0.5 ug/m3 and 1.5 ug/m3 is virtually the same

– 5 ug/m3 and 15 ug/m3 is virtually the same

– 50 ug/m3 and 150 ug/m3 is virtually the same

• Proper communication is essential to assure people

their health is not in jeopardy

– Especially important for industrial hygienists and occupational medical

personnel that are in contact directly with the workers

• Challenge with banding approaches

What does this mean?

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Harmonization of the hazard

assessment in pharma

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• PDEs are good news: not only

for the quality, but also for the

occupational risk assessment

– Because we better collaborate across

the industry

– Because we put emphasis on

consistency, data and expertise

• Important to communicate the

risks appropriately

• Quality of hazard assessment

– Think about your family member: What

quality do you expect for them?

Key thoughts

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Thank you

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References ester.lovsin_barle@novartis.com

• Lovsin Barle E, Cudd AM, Looser R, Bechter R, Winkler GC (2014). Carryover and occupational exposure limits: can they be correlated? Chimica Oggi 32:18-23.

• Weideman P., Bercu J.P., Callis C., Dolan D.G., Faria E., Flueckiger A., Gould J., Hayes E.P., Jolly R., Lovsin Barle E., Luo W., Molnar L.R., Morinello E.,

Naumann B.D, Olson M., Pfister T., Sandhu R., Sargent E.V., Seaman C., Sehner C., Shipp B.K, Stanard B., Streeter A.J., Sussman R., Walsh A., Willis A.M.,

Maier A., (2015), Deriving Health-Based Exposure Limits in the Pharmaceutical Industry. Contract Pharma; 74-80.

• Crevoisier M, Lovsin Barle E, Dolan D, Flueckiger A, Walsh A (2016), Cleaning Limits: Why We Should Abandon Using the 10 ppm Criterion, Pharmaceutical

Technology, 40: 52-56

• Sargent EV, Flueckiger A, Lovsin Barle E, Luo W, Molnar L, Sandhu R, Weideman P. 2016. The Regulatory Framework for Preventing Cross-Contamination of

Pharmaceutical Products: History and Considerations for the Future. Regul Toxicol Pharmacol. 79 Suppl 1

• Sussman RG, Schatz AR, Kimmel TA, Ader A, Naumann BD. 2016a. Identifying and Assessing Highly Hazardous Drugs within Quality Risk Management

Programs. In preparation for Regulatory Toxicology and Pharmacology.

• Olson M, Faria E, Hayes EP, Jolley R, Lovsin Barle E, Molnar L, Naumann BD, Pecquet AM, Shipp B, Sussman R, Weideman P. 2016. A Harmonization Effort for

Acceptable Exposure Methodology Applied to Pharmaceutical Cleaning Validation -- Communication with External Stakeholders. Regul Toxicol Pharmacol. 79

Suppl 1

• Hayes EP, Faria E, Jolly R, Lovsin Barle E, Molnar L, Naumann B, Olson M, Pecquet AM, Shipp B, Sussman R, Weideman P. 2016. A Harmonization Effort for

Acceptable Exposure Methodology Applied to Pharmaceutical Cleaning Validation -- Operational Aspects. Regul Toxicol Pharmacol. 79 Suppl 1.

• Faria EC, Bercu J, Dolan DG, Morinello E, Pecquet AM, Seaman C, Sehner C, Weideman, P. 2016. Using Default Methodologies to Derive an Acceptable Daily

Exposure (ADE). Regul Toxicol Pharmacol. 79 Suppl 1

• Bercu J, Morinello E, Sehner C, Shipp B, Weideman P. 2016. Point of Departure (PoD) Selection for the Derivation of Acceptable Daily Exposures (ADEs) for

Active Pharmaceutical Ingredients (APIs). Regul Toxicol Pharmacol. 79 Suppl 1

• Sussman R, Naumann B, Pfister T, Sehner C, Seaman C, Weideman P. 2016b. A Harmonization Effort for Exposure Methodology – Considerations for

Application of Adjustment Factors. Regul Toxicol Pharmacol. 79 Suppl 1

• Reichard JF, Maier MA, Naumann BD, Pecquet AM, Pfister T, Sandhu R, Sargent EV, Streeter AJ, Weideman P. 2016. Pharmacokinetic and Pharmacodynamic

Considerations when Deriving Health-Based Exposure Limits for Pharmaceuticals. Regul Toxicol Pharmacol. 79 Suppl 1

• Gould J, Callis C, Dolan DG, Stanard B, Weideman P. 2016. Special Endpoint and Product Specific Considerations in Pharmaceutical ADE Derivation. Regul

Toxicol Pharmacol. 79 Suppl 1

• Barle EL, Looser R, Cerne M, Bechter R. The value of acute toxicity testing of pharmaceuticals for estimation of human response. Regul Toxicol Pharmacol. 2012

Apr;62(3):412-8. Epub 2012 Jan 28.

• Pfister T, Dolan D, Bercu J; Gould J, Wang B, Bechter R, Barle EL, Pfannkuch F, Flueckiger A. (2014). Bioavailability of Therapeutic Proteins by Inhalation - Worker Safety

Aspects. Annals of Occupational Hygiene 58(7):899-911

• Lovsin Barle E, Winkler GC, Ulrich P, Perino C, Kuster M, Probst A, Thielen S, Bechter R (2014), Cancer risk of immunosuppressants in manufacturing. Regulatory

Toxicology and Pharmacology 70: 122–124.

• Winkler GC, Lovsin Barle E, Galati G, Kluwe WK (2014), Functional differentiation of cytotoxic cancer drugs and targeted cancer therapeutics. Regulatory Toxicology and

Pharmacology 70: 46–53

• Lovsin Barle E, Araya S, Fröhlicher M. (2015), Integrated testing strategy of pharmaceutical intermediates for occupational health. New Horizons in Translational Medicine

2: 70.

• Araya S, Lovsin Barle E, Glowienke S (2015), Mutagenicity assessment strategy for pharmaceutical intermediates to aid limit setting for occupational exposure. Regul

Toxicol Pharmacol. 73: 515-520

• Winkler GC, Perino C, Araya SH, Bechter R, Kuster M, Lovsin Barle E. (2015), Classification of dermal sensitizers in pharmaceutical manufacturing. Regul Toxicol

Pharmacol. 2015 May 29;72(3):501-505.

• Pletz, Weers, Winkler, Lovsin Barle (2015) Inhalation bioavailability of low molecular-weight peptide and protein drugs Toxicol Lett 238S (2015) p.134 P03-138

• Winkler GW, Glogovac M, Prause M, Lovsin Barle E. (2015) Writing Cytotoxicity Assessments for Targeted Cancer Therapeutics Toxicol Lett 238S (2015) p.56 P01-002

• Winkler GW., Mirwald J., Gromek K., Lovsin Barle E., (2016), Tiered testing strategy and assignment of occupational exposure limits for pharmaceutical intermediates.

Chimica oggi. 34: 48-52

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