Basic information OEL & PBOEL-HHC for API & IPI Level 1 Updated December 2010 - Information provided subject to the 'Conditions for Sharing Materials and Advice' - - Information provided subject to the 'Conditions for Sharing Materials and Advice' -

Objective To learn about exposure limits, particularly for Active Pharmaceutical Ingredient and Isolated Process Intermediates (APIs and IPIs) To understand how exposure limits are derived To know where you get the information you need and how you use it

Hazardous substances Hazardous substances are substances that can have a harmful effect on health Examples: Chemicals – organic solvents, acids, pharmaceutical ingredients… Dust – metal dust, wood dust, flour… Fumes – welding, soldering… Fibres – asbestos

Hazardous substances can enter the body inhalation dermal ingestion

Acute effects – immediate reaction Type of Health Effects Acute effects – immediate reaction Chronic effects – develop over years

Potency of Hazardous Substances Snake poison – < 100mg can kill Alcohol-2000mg gives effect ten times that amount can kill Nicotine- 2mg gives effect 50mg can kill

Occupational Exposure Limit OEL Describing the hazard We need to know how much of a hazardous substance a worker can breathe without harm This is given by the Occupational Exposure Limit OEL

Occupational Exposure Limits The OEL is the concentration in the air to which nearly all workers may be repeatedly exposed day after day without adverse health effects to themselves or their children. Termed Threshold Limit Value TLV by ACGIH (ACGIH is an American organisation for industrial hygiene)

OELs do not provide universal protection. OELs - caution OELs do not provide universal protection. Adverse effects may occur despite adherence to the OEL due to reasons such as: Individual sensitivity pregnancy pre-existing illness

Variation of exposure with time Exposure patterns vary, some tasks give high exposure, others none. Some shifts give more exposure than others Shift durations vary, typically between 8 and 12 hours To compare exposures for different situations, we need a fixed reference period

OEL reference periods – 8 hours 8 hour reference period – (ACGIH descriptor TLV-TWA) This is the main reference period and is concerned with chronic effects. When the worker exposure is measured, it is calculated what concentration it would be if the exposure was constant over 8 hours – called the 8 hour Time Weighted Average, or daily exposure The 8 hour OEL is the 8 hour TWA exposure to which it is believed that nearly all workers may be repeatedly exposed, day after day, for a working lifetime, without adverse effect

OEL reference periods – 15 minutes and ceiling 15 minute reference period – called Short Term Exposure Limit (STEL) Ceiling (TLV-C) – the concentration that should not be exceeded during any part of the working exposure These are concerned with acute effects. The worker exposure is measured over the period when the exposure is greatest, and the 15 minute average or maximum level is determined. These are compared with the STEL and Ceiling limit respectively The 15 minute TWA exposure should not be exceeded at any time during a work day, even if the 8 hour TWA is within the TLV-TWA. Exposures (re. 15 mins) above the TLV-TWA but below the TLV-STEL should not occur more than 4 times a day, with 60 minutes at least between successive exposures The ceiling limit should not be exceeded during any part of the working exposure.

Who assigns Occupational Exposure Limits? Who assigns OELs? For common hazardous substances Your national health and safety authority ACGIH (called Threshold Limit Value, TLV) For pharmaceutical ingredients J&J corporate toxicologists

Order from www.acgih.org ACGIH TLVs Order from www.acgih.org The OEL set by your health and safety authority and ACGIH might be different USE THE LOWER OEL

Examples of OELs set by ACGIH (values 2007) Hazardous substance Threshold Limit Value TLV 8 hour 15 minute Isopropyl alcohol 200ppm 400ppm Benzene 0.5ppm 2.5ppm Ammonia 25ppm 35ppm Acrolein - C 0.1ppm Particles not otherwise specified 10 mg/m3 Cobalt 0.02 mg/m3 An instantaneous ceiling value that should not be exceeded Source: ACGIH 2007

As the proportion of molecules Concentration Units As mass in unit volume 1m 1 mg /m3 is 1 mg in a cubic meter 1 μg /m3 is 1 μg in a cubic meter 1000 μg /m3 = 1 mg/m3 As the proportion of molecules 1 ppm is one part (molecule) in a million 1ppb is one part in a billion 1000 ppb = 1 ppm

OELs for APIs and IPIs National and international bodies do not set OELs for APIs and IPIs OELs for APIs and IPIs are set by the company that has developed them or are manufacturing them API : Active Pharmaceutical Ingredients IPI: Isolated Process Intermediates

Setting an OEL – what to consider Sources of information Animal studies Pharmaceutical trials These indicate the lowest active dose, or the dose where there is no observed adverse effect Things that influence the effect on the body Amount you breath in (10 m3 per day) Body weight How long the chemical stays in the body Amount absorbed by body Any hazardous substances formed in the body

Setting an OEL for APIs & APIs – how it is calculated OEL (mg/m3) = NOEL (mg/kg/day) x BW (kg) V (m3/day) x S x UF x    NOEL = the no-observable-effect-level (mg/kg/day) BW = average human body weight (50 kg) V = volume of air breathed in an 8-hr work day (10 m3/day) S = time, in days, to achieve a plasma steady state UF = uncertainty factors  (alpha) = % absorbed through inhalation

Typical Notes given with OELs If carcinogenic, mutagenic or reproductive toxin Skin: Substances which have the capacity to penetrate intact skin Sensitization: where skin or respiratory sensitization could occur (that is, where intense response occurs to low concentrations after a person has become sensitised) BEI: if a biological exposure index has been recommended for the substance

Acceptable Surface Limits A surface limit is sometimes set. It is helpful : if there might be significant exposure through the skin if potent substances might be re-suspended and inhaled to indicate contamination of surfaces

Acceptable Surface Limits ASL The ASL is the acceptable mass on a specified surface area (typically 10 x 10 cm, the area of palms of hand) Often set at 10 times the OEL for an area of 100cm2 Not as frequently used as OEL Not set by ACGIH for any substance

What to do with the OEL … Compare the results from your exposure monitoring surveys with the OEL to check if the exposure is OK

Evaluate exposure by comparing measured TWA exposure with OEL Exposure exceeds OEL Exposure as % of OEL Exposure well below OEL

What to do with the OEL … Conc outside mask Conc inside mask = If you use Respiratory Protection Equipment, compare the calculated exposure inside the mask with the OEL to check if the effective exposure is OK Use the protection factor of the mask to get the concentration inside the mask Conc inside mask = Conc outside mask Protection factor

What to do with the ASL… Compare the measured surface concentration with the ASL to check that surface contamination levels are OK Measure surface contamination on skin, if feasible, and compare result with ASL

J&J hazard classification for API & IPI When drugs are in an early stage of development, there is not enough information available to set an OEL, but controls must be implemented J&J uses a hazard classification system to group pharmaceutical ingredients according to their hazard called PbOEL-HHC (PbOEL- Health Hazard Categories)

OEL ranges of the PbOEL-HHCs Categories 1A >1000 – 3000 g/m3 1B >100 – <1000 g/m3  2 >20 – <100 g/m3 3A >5 - <20 g/m3 3B >.5 g/m3– <5 g/m3 4 < .5 g/m3

PbOEL-HHC versus OEL A PbOEL-HHC is set at a very early stage in drug development, before there is enough information to set an OEL Information is compiled in the PbOEL-HHC summary

Examples of OEL’s and PbOELs for API’s and IPI’s Substance OEL mg/m3 PbOEL category Ketoconazole 0.2 1B Nicotine 0.070 2 Nebivolol hydrochloride 0.015 3A Risperidone 0.0025 3B Fentanyl 0.0001 4 Remark: These values can change - always consult the most recent global PbOEL-HHC OEL list for actual information!

OEL monographs When corporate toxicologists assign exposure limits, they publish an OEL monograph. This document contains useful information such as: PbOEL-HHC / OEL / ASL / notations (e.g. sensitizer) Description of substance Toxicology of substance How the substance acts in the body Relevant data from laboratory tests, field trials or epidemiological studies How the OEL was derived References

Summary The hazard associated with an API/IPI is quantified by a PbOEL-HHC, an OEL and sometimes an ASL APIs/IPIs are assigned to one of the 6 PbOEL-HHCs, depending on how hazardous they are. PbOEL-HHC 1A is the least hazardous, PbOEL-HHC 4 is the most hazardous category An OEL is a limit for the exposure to hazardous substances by inhalation. The reference periods are 8 hours and/or 15 minutes An ASL is a limit for the dermal exposure to hazardous substances. The reference area is typically 100cm2. This is only assigned if the dermal route is a significant exposure path PbOEL-HHCs/OELs /ASLs for APIs/IPIs are set by J&J The OEL monograph contains these limits and other useful information Use these limits as the input for the risk assessment to design controls and to monitor their effectiveness