Occupational Toxicology, IH and Containment Challenges ......AIHC Pharma Forum 2015 The process of transformation directly from the solid phase to the gaseous phase without passing

AIHC Pharma Forum 2015

Occupational Toxicology, IH and Containment

Challenges associated with an API

AIHC Pharma Forum: June 3, 2015 Salt Lake City, UT

George S. Petroka CIH, CSP: Principal

IES

Barry Ballinger, CIH, Sr. Manager Environment, Health, Safety & Sustainability

Biogen

Matthew J. Meiners, CIH: Division Manager, Laboratory Services

Bureau Veritas North America, Inc.

William Hemp, CIH: Senior Industrial Hygienist,

Johnson Matthey Pharmaceutical Materials


Active ingredient in Fumaderm™ (Germany) Approved

for treatment of Psoriasis 1994.

Used historically as anti-fungal and mold inhibitor in

furniture and leather products (sachets used in

footware and furnishings)

Recognized as an allergenic sensitizer and causing

eczema at low concentrations

2

Dimethyl fumarate - Background

Numerous cases in Europe/Finland of severe dermatitis on legs, buttocks

and back linked to recent leather furniture purchase.

1998 EU ban on use of DMFu in furniture. In the US, however sofas

have been imported from China that have been treated with DMFu


Chemical Name: Dimethyl Fumarate

Trade Name: Tecfidera (Biogen) 120 mg and 240mg oral

capsules

Indication: Relapsing forms of multiple sclerosis

Pharmacological/Chemical Class: Anti-inflammatory/Nrf2

activators Claimed to reduce inflammatory responses in both peripheral and central

cells and promotes cytoprotection of the central nervous system cells

against toxic stressor, demonstrating beneficial effects on pathways know

to exacerbate multiple sclerosis pathology.

3

API - Dimethyl fumarate


Chemical/Physical Properties

Methyl ester of fumaric acid

CAS # 624-49-7

C6H8O4

MW: 144.127 g/ml

BP: 192 oC

VP: ≈ 5.8Pa at (25 oC)

Heat of sublimation: 11 oC (51 oF)

Sublimation rate <10 ug/min at 25 oC

Equilibrium concentration in drum space of raw material expected

to be about 50 ppm (295 mg/m3)

4

API - Dimethyl fumarate

http://www.google.com/url?sa=i&source=imgres&cd=&cad=rja&uact=8&docid=Zi_NpuKk372XkM&tbnid=T26qrv_K2ujB4M:&ved=0CAwQjRw&url=http://commons.wikimedia.org/wiki/File:Dimethyl_fumarate_Structural_Formulae.png&ei=sVYkVJM6hrWxBN6cgeAB&psig=AFQjCNGvsP5RHyVuV5QUdtpA3B8JYsRkJA&ust=1411754033129015


The process of transformation directly from the solid

phase to the gaseous phase without passing through

an intermediate liquid phase

Sublimation is an endothermic phase that occurs at temperatures and

pressures below a substance's triple point* in its phase diagram.

Solids that sublimate have such high vapor pressures that heating

leads to a substantial vaporization even before the melting point is

reached.

The enthalpy of sublimation (also called heat of sublimation) can be

calculated as the enthalpy of fusion plus the enthalpy of vaporization

*Triple point of a substance is the temperature and pressure at which

the three phases (gas, liquid, and solid) of that substance

coexist in thermodynamic equilibrium.

5

Sublimation


Setting OEL and ASL taking into consideration aerosol vs.

vapor phase

DMFu “Leading effects” of concern are high potency skin

irritation, skin sensitization, severe eye irritation

A definitive OEL for dermal toxicity would have to relate to

deposited skin dose from airborne exposure

Sublimation rate is temperature dependent

Exposure/containment controls for particulate may not be

effective on vapor phase of DMFu

6

Occupational Toxicology - Challenges


Company OEB or OEL ASL Notation

Biogen OEL-TWA:

1-10 μg/m3

Wipe Limit:

< 1 μg/100 cm2

Dermal Sensitizer

Revised OEL monograph,

J & J

OEL-TWA (solid):

5 μg/m3

OEL-TWA (gas/vapor): 1 ppb

Surface Target Value:

< 1 μg/100 cm2

Dermal Sensitizer and

Skin Notation

Johnson

Matthey

ECL 4

OEB: < 10 μg/m3

Surface Limits

0.04 μg/cm2

(40 ng/cm2) sensitized

personnel

0.4 μg/cm2

(400 ng/cm2)

unsensitized personnel

Dermal Sensitizer; Tissue

Damage potential.

* ASL sensitized status

**ASL un-sensitized

status

7

Dimethyl fumarate – OEL/OEBs and ASLs


Potential for particulate and/or vapor phases

Retention of captured material during air sampling

Addressed by Hybrid sampler (OVSS)

Analysis of front and back sections for vapor as well as particulate

analysis

Migration and losses of DMFu following sampling, pending analysis

Addressed using sample extraction with ACN in the field

8

Industrial Hygiene Sampling - Challenges


Field extraction adds it own challenges

Loss of lab control

Cross contamination

Shipping complications

Method sensitivity vs changing health limits

HPLC method LOQ is 0.54 mcg/sample

LC/MS/MS has calibration issues

Addressed with GC/ECD – 0.03 mcg/sample

9

Industrial Hygiene Sampling - Challenges


Portable “ultrafast” GC

Surface Acoustic Wave detector

ppt sensitivity??

VOCs within C4-C25 range

Results in under 30 seconds

Technology is currently being developed in house to detect

DMF to facilitate IH assessments. Anticipated benefits:

Go/No-Go decisions

Identify contamination

Reduce likelihood of employee skin reactions

Save money on PPE

10

DMFu Direct Reading Instrumentation


Particulate and vapor phase emissions

Particulate exposure control methods may not be effective for vapor

phase emissions

Containment Equipment

Facility Containment

PPE

Decontamination/de-activation using 10% NaOH/ 45% IPA/ 45%water

HEPA filtration ineffective for vapor

Control for non-manufacturing tasks – Maintenance, Filter Change,

HVAC servicing

Dust explosivity concerns:

MIE 3-5 mJ

Kst = 308 bar▪m/sec

11

Exposure Control - Challenges

AIHC Pharma Forum 2015 12

Exposure Control - Challenges

Jet-Milling – Cleanroom Run 1 Run 2 - AM Run 2 - PM Run 3 - AM Run 3 - PM

Controls-Drum DCS through PTS then continuous liner off discharge mill

Breathing Zone Personal sample on

operator

Filter: 1.5 g/m3

Filter: 3.6 g/m3

Filter: 0.5 g/m3

Filter: 0.7 g/m3

Filter: 1.2 g/m3

Vapor Front: 0.0359 ppm (212 g/m3)

Vapor Front: 0.0138 ppm (81.3 g/m3)

Vapor Front: 0.018 ppm

(106.1 g/m3)


(107.3 g/m3)


(7,722.2 g/m3)

Vapor Back: 0.0000303 ppm

(0.2 g/m3)


(1.9 g/m3)


(0.3 g/m3)


(1.2 g/m3)

Vapor Back: 0.00144 ppm (8.5 g/m3)

Total:

213.7 g/m3

Total:

86.8 g/m3

Total:

106.9 g/m3

Total:

109.2 g/m3

Total:

7,731.9g/m3

Area Sample Inside Cleanroom in

center of room

Filter: 1.3 g/m3

Filter: 0.4 g/m3

Filter: 2.5 g/m3

Filter: 0.3 g/m3

Filter: 0.7 g/m3



(199.2 g/m3)


(170.9 g/m3)



(1.3 g/m3)


(0.1 g/m3)


(0.3 g/m3)


(0.1 g/m3)


(0.3 g/m3)


(0.7 g/m3)

Total: 29.9 g/m3

Total: 199.9 g/m3

Total: 173.5 g/m3

Total: 15.2 g/m3

Total: 2.7 g/m3


Particulate more readily controlled than vapor

May need to supplement with LEV and PPE

Process redesign – wet milling vs. dry milling

Laboratory Controls and Containment

Containment Systems

Contained process equipment systems

Hardwall Systems − Door seals

− Glove ports

− Transfer ports - RTPs

Softwall − Static vs. negative

− Continuous Liners Systems

− Migration through flexible material

− Crimping

13

Containment Equipment - Challenges


Exhibits typical risks associated with an energetic API

Static electricity

Dust collection

Inerting

14

Combustible Dust- Challenges


Immediate cleaning of any powder “spills” and containment

breach (prevent sublimation)

Gowning and Degowning to prevent all skin contact

Preventing skin and gowning contact with wet solutions

(mist showers)

Storage of containers (regular drums versus airtight

containers)

15

Procedural Control Considerations


Respiratory Protection Airline vs. Air purifying

OVAG/HEPA PAPRs

Coveralls Level B

Pressurized vs. Tychem coveralls

Honeywell - Mururoa

Protection of all seam areas/glove suit interface

16

PPE- Challenges


Collaboration across disciplines and groups

Occupational Toxicology & Clinical Tox

Industrial Hygiene

Analytical Laboratory

Process Chemistry

Process Safety Management

CMO partners

Particulate more readily controlled than vapor

Decontamination/de-activation effective with high pH

Combined Control Strategies regarding vapor phase, skin

protection, combustible dust and sublimation awareness

17

Conclusions

Documents

Occupational Toxicology, IH and Containment Challenges ......AIHC Pharma Forum 2015 The process of transformation directly from the solid phase to the gaseous phase without passing