Control Banding from the Pharma Perspective Staying Ahead of the Regulations

David Eherts, PhD, CIH Purdue Pharma LP SCHC 2004 International Program on Chemical Safety Are you a partner or a stakeholder? Partners Partners in this international effort include: IPCS (International Labour Organization and World Health Organization); International 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;labourunions;labourinspectors; researchers; and training professionals. Overview •Control Banding –What it is –Why the pharmaceutical industry is so far ahead –The difference between 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:

OEB Range of OEL Description (mcg/m3) 1 > 1000 Not harmful, not irritating and/or low pharmacological activity 2 100-1000 Harmful, may be irritant and/or moderate pharmacological activity 3 10-100 Moderate toxic and/or high pharmacological activity

4 1-10 Toxic, may be corrosive, sensitizing or genotoxic and/or very high pharmacological activity

5 < 1 Extremely toxic, may be corrosive, sensitizing or genotoxic and/or extremely high pharmacological activity ABPI Bands:

OEB Range of OEL Description (mcg/m3) A > 1000 Not harmful, not irritating and/or low pharmacological activity B 100-1000 Harmful, may be irritant and/or moderate pharmacological activity C 10-100 Moderate toxic and/or high pharmacological activity

D 1-10 Toxic, may be corrosive, sensitizing or genotoxic and/or very high pharmacological activity

< 1 Extremely toxic, may be corrosive, sensitizing or genotoxic and/or extremely high pharmacological activity

Pharma Industry Bands: Company 1 Company 2 Company 3 Company 4 Company 5 Company 6 Company 7 Company 8 Company 9 Company 10 Company 11 Company 12 Company 13 Company 14 Company 15 Company 16 Company 17 Company 18 Company 19 Distribution of Pharma OELs:

1998 1999 600 2000 2001 500 2002 400

300

200

100

0 1mg 10mcg 0.1mcg <10ng

OEL (LOWER LIMIT) Distribution of Regulatory PELs

350 2004 300 250 200 150 100 50 0 1000 10

OEL (LOWER LIMIT) 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 a = OEL mg kg-dy employee 10 m3 UF b 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 a = bioavailability in test species b = bioavailability in exposed workers

Uncertainty Factors: 10X Interspecies Variation, 10X Intraspecies Variation 10X Sub-Chronic to Chronic, 10X LOEL to NOEL Setting Bands with R Phrases Relative Toxicity or Pharmacologic Activity:

OEB Range of OEL Description (mcg/m3) 1 > 1000 Not harmful, not irritating and/or low pharmacological activity 2 100-1000 Harmful, may be irritant and/or moderate pharmacological activity 3 10-100 Moderate toxic and/or high pharmacological activity

4 1-10 Toxic, may be corrosive, sensitizing or genotoxic and/or very high pharmacological activity

5 < 1 Extremely toxic, may be corrosive, sensitizing or genotoxic and/or extremely high pharmacological activity Examples of Qualitative Defaults

Effect OEB 1 OEB 2 OEB 3 OEB 4 OEB 5

Sensitization Negative Slight cutaneous Moderate / strong Prevalent allergic reactions cutaneous allergic moderate to reactions strong respiratory allergic reactions

Mutagenicity Negative Negative Positive in some in Mutagenic in most vitro assays, not relevant in vivo and confirmed in vivo in vitro assays

Carcinogenicity Negative Negative Some evidence in Confirmed in OEB5 may be animals animals and assigned based on humans relatively high potency DaRT Negative Inadequate Evidence of Evidence of strong evidence in animals moderate reprotoxic defects reprotoxic defects in animals and/or in animals (OEB 3 suspected or may be assigned proved in humans for human teratogens with relatively low potency) 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

•Particle size •Wetness Naso-pharyngeal •Vapor Pressure Region (> 10 um) •Batch size

•Type of vessel Tracheal-bronchial Region (3 -10 um) •Amount of imparted energy… Pulmonary •Engineering Control Region (0.5 -3 um) •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:

Communication

Occupational Toxicology

Occupational Health Industrial Hygiene and Engineering 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 4 1-10 special workstation Isolator 5 < 1

Industry Experience -Reactor Charging By 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 Charging By 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 Charging Automated 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 Charging Vacuum Transfer

Engineering Control Measure OEB Exposure (mcg/m3)

No ECM 1 1000-10,000

Downdraft laminar flow booth 3 10-100 Industry Experience -Product Isolation Discharging 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 Laminar flow booth 3 10-100 head Via an inflatable packing-off Laminar flow booth 4 1-10 head with continuous liner

Industry Experience -Drying Charging 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 4 1-10 booth

Industry Experience -Drying Discharging a tray dryer

Activity ECM OEB Exposure (mcg/m3) Scooping from trays or No ECM > 10,000 trays tipped directly into sack LEV >10,000

LEV with well-designed >10,000 hood Laminar downflow 2 100-1000 booth Laminar downflow 3 10-100 booth with special workstation

Industry Experience -Drying Discharging 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 of No ECM 3 10-100 the dryer bowl LEV 4 1-10 Industry Experience -Discharge Filter-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 and 4 1-10 continuous liner 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 -Milling Basic Mill

ECM OEB Exposure (mcg/m3) No ECM >10,000

LEV >10,000

Downward laminar flow booth 3 10-100

Downward laminar flow with special 4 1-10 design workstation Industry Experience -Milling Contained 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 -Sieving Activity ECM OEB Exposure (mcg/m3) Basic sieve No ECM >10,000

LEV with well-designed hood >10,000

Contained Laminar downflow booth 3 10-100 sieve Laminar downflow booth with 4 1-10 specially designed workstation Oscillating No ECM >10,000 sieve LEV >10,000

Laminar flow booth 2 100-1000 Industry Experience -Packaging

Activity 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 with 3 10-100 special design workstation Isolator 5 < 1 Industry Experience -Packaging

Activity ECM OEB Exposure (mcg/m3) Big bag with LEV 2 100-1000 inflatable seal

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 tipping LEV >10,000 sacks or drums 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 Cone No ECM >10,000 Blender

LEV >10,000

LEV and well- 1 1000-10,000 designed hood LEV and 2 100-1000 inflatable seal Industry Experience -Granulation

Activity ECM OEB Exposure (mcg/m3) Dry charging from sacks or No ECM >10,000 drums or by scooping

LEV >10,000

Charging damp powder by No ECM >10,000 scooping

LEV 1 1000-10,000 Industry Experience -Granulation

Activity ECM OEB Exposure (mcg/m3) Discharge by vacuum No ECM 1 1000-10,000 transfer (dry powder)

LEV 2 100-1000

Discharge by automated No ECM 1 1000-10,000 and contained tipping of the bowl LEV 2 100-1000 Industry Experience -Compressing

Activity 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 LEV 3 10-100 conveying Direct charging from No ECM 2 100-1000 container/IBC LEV 3 10-100

Industry Experience -Capsule Filling

Activity ECM OEB Exposure (mcg/m3) Charging by No ECM >10,000 scooping LEV >10,000

Horizontal laminar flow booth 3 10-100

Charging by vacuum LEV >10,000 transfer Horizontal laminar flow booth 2 100-1000

Direct feed from No ECM 2 100-1000 container/IBC 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 No ECM >10,000 scooping LEV 1 1000-10,000

Glove bag 2 100-1000

Vacuum transfer LEV 2 100-1000 from drums Vacuum transfer LEV 4 1-10

from IBC

Industry Experience -Liquid Filling

Activity ECM OEB Exposure (mcg/m3) Vial, bottle or No ECM 5 < 1 ampule filling Stopper and No ECM 5 < 1 capping 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 Eherts email: [email protected] phone: 203.588.8618