control banding from the pharma perspective

Control Banding from the Pharma PerspectiveStaying Ahead of the Regulations

David Eherts, PhD, CIHPurdue Pharma LPSCHC 2004

International Program on Chemical Safety

Partners

Partners in this international effort include: IPCS (International Labour Organization and World Health Organization); International Occupational Hygiene Association (IOHA); The Health and Safety Executive (HSE) in Great Britain; US National Institute for Occupational Safety and Health (NIOSH); and the German Gesellschaft für Technische Zusammenarbeit(GTZ).

Stakeholders

Stakeholders include implementers (including employers), researchers and workers/users of chemicals. Bodies that may be involved in the implementation of this Strategy include: intergovernmental and international non-governmental organizations (such as IOHA); government agencies; industry, including associations of chemical producers and suppliers; employer and employee associations; industrial hygienists; labour unions; labour inspectors; researchers; and training professionals.

Are you a partner or a stakeholder?

Overview • Control Banding

– What it is– Why the pharmaceutical industry is so far ahead– The difference between Hazard and Risk– What OELs and OEBs are

• How we apply OEBs to determine appropriate equipment and control technologies

» Understand how OELs and OEBs are calculated» Understand exposures related to typical process steps » Understand how to determine acceptable control» Understand concept of 8-hr TWA» Understand protection factors for various respiratory

protection equipment (RPE)

Definition:• Effective and efficient hazard communication is an important component

in assuring employees’ health and safety. • Use of Occupational Exposure Bands (OEB 1 – 5) provide common and

understandable ”language” to accomplish this communication.

A band describes a distinct range of OELs, grouped so that a single recommendation for exposure control technology can adequately protect employees engaged in similar tasks or process.

• The 1-5 categorizations serve as the keystone for “Safe Handling Guidelines” that communicate typical safe handling methods and degree of containment that should be achieved when handling or processing pharmaceutical actives.

Purdue’s Bands:

Extremely toxic, may be corrosive, sensitizing or genotoxic and/or extremely high pharmacological activity

< 15

Toxic, may be corrosive, sensitizing or genotoxic and/or very high pharmacological activity

1-104

Moderate toxic and/or high pharmacological activity10-1003

Harmful, may be irritant and/or moderate pharmacological activity

100-10002

Not harmful, not irritating and/or low pharmacological activity

> 10001

DescriptionRange of OEL (mcg/m3)

OEB

ABPI Bands:

Extremely toxic, may be corrosive, sensitizing or genotoxic and/or extremely high pharmacological activity

< 1

Toxic, may be corrosive, sensitizing or genotoxic and/or very high pharmacological activity

1-10D

Moderate toxic and/or high pharmacological activity10-100C

Harmful, may be irritant and/or moderate pharmacological activity

100-1000B

Not harmful, not irritating and/or low pharmacological activity

> 1000A

DescriptionRange of OEL (mcg/m3)

OEB

Company 1Company 2Company 3Company 4Company 5Company 6Company 7Company 8Company 9Company 10Company 11Company 12Company 13Company 14Company 15Company 16Company 17Company 18Company 19

Pharma Industry Bands:

Distribution of Pharma OELs:

0

100

200

300

400

500

600

1mg 10mcg 0.1mcg <10ng

OEL (LOWER LIMIT)

19981999200020012002

Distribution of Regulatory PELs

0

50

100

150

200

250

300

350

1000 10

OEL (LOWER LIMIT)

2004

Internal OELs and OEBs• Occupational Exposure Limits (OELs)

– the airborne limit concentrations of compounds that are believed to safeguard the health of employees

– the concentration for an 8-hour workday, 40-hour work week, to which nearly all workers maybe repeatedly exposed, day after day, without adverse effect

– Industrial hygienists conduct monitoring to assess employees’ exposures relative to these levels

• Occupational Exposure Bands (OEBs)– 1 through 5 based upon range of OEL

• But may be qualitatively driven also• Communicate the recommendation for appropriate ECM

– Provide everyone with a common and understandable language to accomplish effective hazard communication

Setting a Pharmaceutical OEL

NOEL mg x 50 kg x 1 dy x 1 x α = OEL mg kg-dy employee 10 m3 UF β m3

e.g.: if you have a NOEL of 10 mg/kg-dy in a chronic rat study, to establish the OEL:

10 mg/kg-dy x 50kg/10m3 x 1/100 = 0.5 mg/m3 or 500 mcg/m3

α = bioavailability in test species

β = bioavailability in exposed workers

Uncertainty Factors:10X Interspecies Variation, 10X Intraspecies Variation10X Sub-Chronic to Chronic, 10X LOEL to NOEL

Setting Bands with R Phrases

Relative Toxicity or Pharmacologic Activity:

Extremely toxic, may be corrosive, sensitizing or genotoxic and/or extremely high pharmacological activity

< 15

Toxic, may be corrosive, sensitizing or genotoxic and/or very high pharmacological activity

1-104

Moderate toxic and/or high pharmacological activity10-1003

Harmful, may be irritant and/or moderate pharmacological activity

100-10002

Not harmful, not irritating and/or low pharmacological activity

> 10001

DescriptionRange of OEL (mcg/m3)

OEB

Evidence of strong reprotoxic defects in animals and/or suspected or proved in humans

Evidence of moderate reprotoxic defects in animals (OEB 3 may be assigned for human teratogens with relatively low potency)

Inadequate evidence in animals

NegativeDaRT

OEB5 may be assigned based on relatively high potency

Confirmed in animals and humans

Some evidence in animals

NegativeNegativeCarcinogenicity

Mutagenic in most relevant in vivo and in vitro assays

Positive in some in vitro assays, not confirmed in vivo

NegativeNegativeMutagenicity

Prevalent moderate to

strong respiratory allergic reactions

Moderate / strong cutaneous allergic reactions

Slight cutaneous allergic reactions

NegativeSensitization

OEB 5OEB 4OEB 3OEB 2OEB 1Effect

Examples of Qualitative Defaults

Not a Bright Line!• Occupational Exposure Guidelines (OEGs) are

guidelines to be used by board certified industrial hygienists in assessing whether pharmaceutical dust is controlled satisfactorily to safeguard the health of employees.

• Industrial hygienists conduct monitoring to assess employees’ exposures relative to these guidelines but the OEG is NOT a bright line between a safe and unsafe environment.

• There are significant safety factors built into the calculation of the OEG (see the OEG Best Practice Document for further detail).

Risk• Risk = f (Hazard, Exposure)

– Hazard is inherent in the molecule• Defined by an OEL or an OEB

– Exposure is controllable

Extent of Exposure

Naso-pharyngealRegion (> 10 um)

Tracheal-bronchialRegion (3 - 10 um)

Pulmonary Region (0.5 - 3 um)

• Particle size • Wetness• Vapor Pressure• Batch size• Type of vessel• Amount of imparted

energy…• Engineering Control• PPE

To Control Risk:

• Bands simply communicate the hazard inherent in the molecule

• To control risk therefore, increasing hazard levels require increasing levels of exposure control:

R (1) = Hazard (103) x Exposure (10-3)

OEBs for Chemicals

Pharma has done the same:

Pharma Industry Collaboration:

CommunicationOccupational Toxicology

Occupational Health Industrial Hygiene andEngineering

The following slides are my opinion only i.e., best estimate of the exposure based upon specified control technology. Personal attention to detail,

experience and motivation will vary significantly!

Industry Experience - Sampling

Engineering Control Measure OEB Exposure (mcg/m3)

No ECM 3 10-100

LEV with well-designed hood 4 1-10

Downdraft laminar flow booth 4 1-10

Isolator 5 < 1

Industry Experience - Weighing

Engineering Control Measure OEB Exposure (mcg/m3)

No ECM 1 1000-10,000

Downdraft laminar flow booth 2 100-1000

Downdraft laminar flow booth with special workstation

4 1-10

Isolator 5 < 1

Industry Experience - Reactor ChargingBy scooping into the manway

Engineering Control Measure OEB Exposure (mcg/m3)

No ECM > 10,000

LEV 1 1000-10,000

LEV with ventilated charge hopper 2 100-1000

Horizontal laminar flow booth 2 100-1000

Downdraft laminar flow booth 3 10-100

Industry Experience - Reactor ChargingBy direct tipping within containment

Engineering Control Measure OEB Exposure (mcg/m3)

No ECM > 10,000

Horizontal laminar flow booth 2 100-1000

Glove bags 3 10-100

Downdraft laminar flow booth 3 10-100

Ventilated hopper with drum cone 2 10-100

Industry Experience - Reactor ChargingAutomated drum tipping system

Engineering Control Measure OEB Exposure(mcg/m3)

No ECM > 10,000

Horizontal laminar flow booth 3 10-100

Downdraft laminar flow booth 4 1-10

Glove box isolator 5 < 1

Industry Experience - Reactor ChargingVacuum Transfer

Engineering Control Measure OEB Exposure(mcg/m3)

No ECM 1 1000-10,000

Downdraft laminar flow booth 3 10-100

Industry Experience - Product IsolationDischarging a filter or centrifuge

Activity ECM OEB Exposure (mcg/m3)

Scooping No ECM or LEV only 1 1000-10,000

Into an attached sack No ECM or LEV only 1 1000-10,000

Glove bag No additional 3 10-100

Via an inflatable packing-off head

Laminar flow booth 3 10-100

Via an inflatable packing-off head with continuous liner

Laminar flow booth 4 1-10

Industry Experience - DryingCharging a tray dryer with damp powder

Activity ECM OEB Exposure (mcg/m3)

Charging trays by scooping No ECM 3 10-100

LEV 4 1-10

Laminar downflow booth

4 1-10

Industry Experience - DryingDischarging a tray dryer

Activity ECM OEB Exposure (mcg/m3)

Scooping from trays or trays tipped directly into sack

No ECM > 10,000

LEV >10,000

LEV with well-designed hood

>10,000

Laminar downflow booth

2 100-1000

Laminar downflow booth with special workstation

3 10-100

Industry Experience - DryingDischarging a fluid bed dryer

Activity ECM OEB Exposure(mcg/m3)

Manual No ECM > 10,000

LEV >10,000

By vacuum No ECM >10,000

LEV 1 1000-10,000

Laminar downflow booth 3 10-100

By contained tipping ofthe dryer bowl

No ECM 3 10-100

LEV 4 1-10

Industry Experience - DischargeFilter-dryer, mixer or blender

Engineering Control Measure OEB Exposure(mcg/m3)

No ECM > 10,000

LEV > 10,000

LEV with well-designed hood > 10,000

Inflatable seal 2 100-1000

Inflatable seal and laminar downflow booth 3 10-100

Inflatable seal, laminar downflow booth andcontinuous liner

4 1-10

Industry Experience - Discharge of IBC

Engineering Control Measure OEB Exposure(mcg/m3)

Simple butterfly valve with no ECM 1 1000-10,000

Simple butterfly valve with LEV 2 100-1000

Split butterfly or cone valve 4 1-10

Industry Experience - MillingBasic Mill

ECM OEB Exposure(mcg/m3)

No ECM >10,000

LEV >10,000

Downward laminar flow booth 3 10-100

Downward laminar flow with specialdesign workstation

4 1-10

Industry Experience - MillingContained charging, sealed discharge

ECM OEB Exposure(mcg/m3)

LEV with well-designed hood 2 100-1000

Split butterfly valve 4 1-10

Isolator 5 < 1

Industry Experience - Miconization

ECM OEB Exposure (mcg/m3)

Simple micronizer, No ECM >10,000

Contained micronizer 1 1000-10,000

Industry Experience - SievingActivity ECM OEB Exposure

(mcg/m3)Basic sieve No ECM >10,000

LEV with well-designed hood >10,000

Containedsieve

Laminar downflow booth 3 10-100

Laminar downflow booth withspecially designedworkstation

4 1-10

Oscillatingsieve

No ECM >10,000

LEV >10,000

Laminar flow booth 2 100-1000

Industry Experience - PackagingActivity ECM OEB Exposure

(mcg/m3)Small quantities No ECM 2 100-1000

Laminar downflow booth 3 10-100

Drum No ECM >10,000

Laminar downflow booth 2 100-1000

Laminar downflow booth withspecial design workstation

3 10-100

Isolator 5 < 1

Industry Experience - Packaging

Activity ECM OEB Exposure(mcg/m3)

Big bag withinflatable seal

LEV 2 100-1000

IBC containers LEV 1 1000-10,000

Industry Experience - Mixing and Blending

Activity ECM OEB Exposure(mcg/m3)

Charging by scooping LEV >10,000

Charging by tippingsacks or drums

LEV >10,000

Charging by vacuum No ECM 1 1000-10,000

LEV 2 100-1000

Industry Experience - Mixing and Blending

Activity ECM OEB Exposure(mcg/m3)

Charging a V ConeBlender

No ECM >10,000

LEV >10,000

LEV and well-designed hood

1 1000-10,000

LEV andinflatable seal

2 100-1000

Industry Experience - Granulation

Activity ECM OEB Exposure(mcg/m3)

Dry charging from sacks ordrums or by scooping

No ECM >10,000

LEV >10,000

Charging damp powder byscooping

No ECM >10,000

LEV 1 1000-10,000

Industry Experience - Granulation

Activity ECM OEB Exposure(mcg/m3)

Discharge by vacuumtransfer (dry powder)

No ECM 1 1000-10,000

LEV 2 100-1000

Discharge by automatedand contained tipping of thebowl

No ECM 1 1000-10,000

LEV 2 100-1000

Industry Experience - CompressingActivity ECM OEB Exposure

(mcg/m3)

Charging by scooping No ECM 1 1000-10,000

LEV 2 100-1000

Horizontal laminar flow booth 3 10-100

Contained feed – glove bag 3 10-100

Charging by vacuum conveying

LEV 3 10-100

Direct charging from container/IBC

No ECM 2 100-1000

LEV 3 10-100

Industry Experience - Capsule FillingActivity ECM OEB Exposure

(mcg/m3) Charging by scooping

No ECM >10,000

LEV >10,000

Horizontal laminar flow booth 3 10-100

Charging by vacuum transfer

LEV >10,000

Horizontal laminar flow booth 2 100-1000

Direct feed from container/IBC

No ECM 2 100-1000

LEV 3 10-100

Industry Experience - Blister Packing

Activity ECM OEB Exposure(mcg/m3)

Uncoated tablets No ECM 2 100-1000

LEV 3 10-100

Coated tablets No ECM 4 1-10

LEV 5 < 1

Industry Experience - Add to Compounding Vessel

Activity ECM OEB Exposure (mcg/m3)

Charging by scooping

No ECM >10,000

LEV 1 1000-10,000

Glove bag 2 100-1000

Vacuum transfer from drums

LEV 2 100-1000

Vacuum transfer from IBC

LEV 4 1-10

Industry Experience - Liquid Filling

Activity ECM OEB Exposure(mcg/m3)

Vial, bottle orampule filling

No ECM 5 < 1

Stopper andcapping

No ECM 5 < 1

Sterilization No ECM 5 < 1

But it’s not that simple• Depends on the duration of the task

– and the plans for the rest of the shift• Depends on the quantity of dust generated

– this depends on the strength of the formulation– and the batch quantity– and the polydispersal aerosol characteristics– and the quality of the operator

• The quality of the operator depends upon:– training– supervision– motivation…

Therefore, it’s necessary to do case-by-case quantitative analysis for confirmation!

Review• OELs and OEBs communicate the relative

hazard• OEBs can be used to recommend

engineering, administrative controls and PPE based upon task and relative quantity/potency

• Not always possible to generalize so sampling and communication with toxicologist and physician are important

For further information or a copy of the presentation:

David Ehertsemail: david.eherts@pharma.comphone: 203.588.8618