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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: [email protected]: 203.588.8618