Basic information OEL PBOELHHC for API IPI Level

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

Objective n To learn about exposure limits, particularly for Active Pharmaceutical Ingredient and Isolated Process Intermediates (APIs and IPIs) n To understand how exposure limits are derived n To know where you get the information you need and how you use it 2

Hazardous substances n Hazardous substances are substances that can have a harmful effect on health n Examples: – Chemicals – organic solvents, acids, pharmaceutical ingredients… – Dust – metal dust, wood dust, flour… – Fumes – welding, soldering… – Fibres – asbestos 3

Hazardous substances can enter the body inhalation dermal ingestion 4

Type of Health Effects Acute effects – immediate reaction Chronic effects – develop over years 5

Potency of Hazardous Substances Snake poison – < 100 mg can kill Alcohol-2000 mg gives effect ten times that amount can kill Nicotine- 2 mg gives effect 50 mg can kill 6

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 7

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) 8

OELs - caution n OELs do not provide universal protection. n Adverse effects may occur despite adherence to the OEL due to reasons such as: – Individual sensitivity – pregnancy – pre-existing illness 9

Variation of exposure with time n n n 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 10

OEL reference periods – 8 hours n 8 hour reference period – (ACGIH descriptor TLV-TWA) n 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 n 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 11

OEL reference periods – 15 minutes and ceiling n 15 minute reference period – called Short Term Exposure Limit (STEL) n Ceiling (TLV-C) – the concentration that should not be exceeded during any part of the working exposure n 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 n 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 n The ceiling limit should not be exceeded during any part of the working exposure. 12

Who assigns Occupational Exposure Limits? Who assigns OELs? For common hazardous substances 1. 2. Your national health and safety authority ACGIH (called Threshold Limit Value, TLV) For pharmaceutical ingredients 1. J&J corporate toxicologists 13

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 14

Examples of OELs set by ACGIH (values 2007) Hazardous substance Threshold Limit Value TLV 8 hour 15 minute Isopropyl alcohol 200 ppm 400 ppm Benzene 0. 5 ppm 2. 5 ppm Ammonia 25 ppm 35 ppm - C 0. 1 ppm 10 mg/m 3 - Acrolein Particles not otherwise specified Cobalt 0. 02 mg/m 3 - An instantaneous ceiling value that should not be exceeded Source: ACGIH 2007 15

Concentration Units As mass in unit volume 1 mg /m 3 is 1 mg in a cubic meter 1 m 1 μg /m 3 is 1 μg in a cubic meter 1000 μg /m 3 = 1 mg/m 3 1 m 1 m As the proportion of molecules 1 ppm is one part (molecule) in a million 1 ppb is one part in a billion 1000 ppb = 1 ppm 16

OELs for APIs and IPIs n National and international bodies do not set OELs for APIs and IPIs n 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 17

Setting an OEL – what to consider n Sources of information – Animal studies – Pharmaceutical trials These indicate the lowest active dose, or the dose where there is no observed adverse effect n Things that influence the effect on the body – – – Amount you breath in (10 m 3 per day) Body weight How long the chemical stays in the body Amount absorbed by body Any hazardous substances formed in the body 18

Setting an OEL for APIs & APIs – how it is calculated OEL (mg/m 3) = NOEL (mg/kg/day) x BW (kg) V (m 3/day) x S x UF x n n n 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 m 3/day) S = time, in days, to achieve a plasma steady state UF = uncertainty factors (alpha) = % absorbed through inhalation 19

Typical Notes given with OELs n n 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 20

Acceptable Surface Limits n 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 21

Acceptable Surface Limits Acceptable Surface Limit ASL n n 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 100 cm 2 Not as frequently used as OEL Not set by ACGIH for any substance 22

What to do with the OEL … n Compare the results from your exposure monitoring surveys with the OEL to check if the exposure is OK 23

Evaluate exposure by comparing measured TWA exposure with OEL Exposure exceeds OEL Exposure as % of OEL Exposure well below OEL 24

What to do with the OEL … n If you use Respiratory Protection Equipment, compare the calculated exposure inside the mask with the OEL to check if the effective exposure is OK n Use the protection factor of the mask to get the concentration inside the mask Conc inside mask = Conc outside mask Protection factor 25

What to do with the ASL… n Compare the measured surface concentration with the ASL to check that surface contamination levels are OK n Measure surface contamination on skin, if feasible, and compare result with ASL 26

J&J hazard classification for API & IPI n When drugs are in an early stage of development, there is not enough information available to set an OEL, but controls must be implemented n J&J uses a hazard classification system to group pharmaceutical ingredients according to their hazard called Pb. OEL-HHC (Pb. OEL- Health Hazard Categories) 27

OEL ranges of the Pb. OEL-HHCs Categories n n n 1 A 1 B 2 3 A 3 B 4 >1000 – 3000 g/m 3 >100 – <1000 g/m 3 >20 – <100 g/m 3 >5 - <20 g/m 3 >. 5 g/m 3– <5 g/m 3 <. 5 g/m 3 28

Pb. OEL-HHC versus OEL n A Pb. OEL-HHC is set at a very early stage in drug development, before there is enough information to set an OEL n Information is compiled in the Pb. OEL-HHC summary 29

Examples of OEL’s and Pb. OELs for API’s and IPI’s Substance OEL mg/m 3 Pb. OEL category 0. 2 1 B Nicotine 0. 070 2 Nebivolol hydrochloride 0. 015 3 A Risperidone 0. 0025 3 B Fentanyl 0. 0001 4 Ketoconazole Remark: These values can change - always consult the most recent global Pb. OEL-HHC OEL list for actual information! 30

OEL monographs n When corporate toxicologists assign exposure limits, they publish an OEL monograph. This document contains useful information such as: 1. Pb. OEL-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 2. 3. 4. 5. 6. 7. 31

Summary n The hazard associated with an API/IPI is quantified by a Pb. OEL-HHC, an OEL and sometimes an ASL n APIs/IPIs are assigned to one of the 6 Pb. OEL-HHCs, depending on how hazardous they are. Pb. OEL-HHC 1 A is the least hazardous, Pb. OEL-HHC 4 is the most hazardous category n An OEL is a limit for the exposure to hazardous substances by inhalation. The reference periods are 8 hours and/or 15 minutes n An ASL is a limit for the dermal exposure to hazardous substances. The reference area is typically 100 cm 2. This is only assigned if the dermal route is a significant exposure path n Pb. OEL-HHCs/OELs /ASLs for APIs/IPIs are set by J&J n The OEL monograph contains these limits and other useful information n Use these limits as the input for the risk assessment to design controls and to monitor their effectiveness 32