Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities Toxicological tool Sarah O Meara, PhD, MSc PharmMed Non-clinical Assessor GMP Conference 12 th November 2014
Disclaimer: Final approval is pending, but is expected soon 12th November 2014 2
Problem Statement No defined approach in deriving an acceptable limit Plethora of toxicological tools being used Lack of harmonised approach/interpretation Different production requirements Significant financial impact on manufacture Impaired quality of medicinal products Adverse effect on patient health 12th November 2014 3
Current Approach the philosophy has been to reduce the levels of residual product in each piece of equipment, such that no greater than 1/1000 th of the normal therapeutic dose or 10ppm will be present per typical dose of the next product to be run in the equipment. Available Pharmacological/Toxicological data? Possible exposure data? Too restrictive, not restrictive enough? 12th November 2014 4
Toxicological Tool Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities -- (toxicological tool) Drafted by Safety Working Party at EMA Toxicologists (non-clinical assessors) Agreed with veterinary counterparts Public consultation January to June 2013 (concurrently with Chapter 3 & 5) EMA workshop on Dedicated Facilities (September 2013) 12th November 2014 5
Determination of health based exposure limit Permitted Daily Exposure (PDE) a substance-specific dose that is unlikely to cause an adverse effect if an individual is exposed at or below this dose every day for a lifetime ICH Q3C R(4) Impurities: Guideline for Residual Solvents VICH GL 18 residual solvents in new veterinary medicinal products, active substances and excipients (Revision) 12th November 2014 6
Determination of PDE 1) Hazard identification Review all relevant data, including: non clinical pharmacodynamic data repeat dose toxicity studies carcinogenicity studies in vitro & in vivo genotoxicity studies reproductive and developmental toxicity studies clinical data (therapeutic and adverse effects) Incomplete data sets Identify gaps Impact on a reliable health based exposure limit? 12th November 2014 7
Determination of PDE 2) Critical effects Identification of critical effects the most sensitive indicator(s) of an adverse effect from non clinical toxicological studies. includes therapeutic effect / adverse effects observed in clinical use Must be relevant to humans or target animal 12th November 2014 8
Determination of PDE 3) Establishing No-observed-adverse-effect levels (NOAELs) highest tested dose at which no adverse ( critical ) effect is observed Lowest NOAEL should be employed for PDE/ADI calculation If no NOAEL established lowest-observed-adverse-effect level (LOAEL) may be used 12th November 2014 9
Determination of PDE 4) Application of adjustment factors Use of several adjustment factors to account for various uncertainties PDE = NOAEL x Weight Adjustment F1 x F2 x F3 x F4 x F5 F1: A factor for extrapolation between species F2: A factor to account for variability between individuals F3: A factor to account for repeat-dose toxicity studies of short duration F4: A factor that may be applied for cases of severe toxicity, e.g. nongenotoxic carcinogenicity, neurotoxicity or teratogenicity F5: A variable factor where LOAEL is applied instead of NOAEL Additional modifying factors can be used if scientifically justified 12th November 2014 10
Determination of PDE 5) Selection of PDE several critical effects can result in more than one PDE Decision of most appropriate PDE should be appropriately justified By default the lowest PDE value will be used 6) Alternative approaches Other approaches to determine a health based exposure limit could be considered acceptable if adequately and scientifically justified ISPE Risk-MaPP approach 12th November 2014 11
Specific considerations Active substances with a genotoxic potential If no threshold has been established then any exposure presents a risk Threshold of Toxicological Concern (TTC) of 1.5 μg/person/day (EMA guidance on limits of genotoxic impurities EMEA/CHMP/QWP/251344/2006) TTC can be applied to products where threshold has not been established If sufficient evidence of a threshold related mechanism applies, then use of PDE approach permitted 12th November 2014 12
Specific considerations Active substances with a high sensitising potential Some actives are highly sensitising No scientifically established threshold for the response in sensitive individuals Dedicated facilities required E.g. β Lactams Classification weight of evidence assessment Frequency of sensitising occurrence in humans Probability of occurrence rate based in animal or other validated tests Severity of reaction 12th November 2014 13
Specific considerations Therapeutic macromolecules & peptides Degrade and denature when exposed to ph extremes and/or heat PDE may not be required Lack of reproductive toxicity data Use of NOAEL from sub-chronic/chronic study in determining PDE Application of an additional adjustment factor (e.g. 10) Application of a read across approach from related compounds to identify potential hazard 12th November 2014 14
Specific consideration Investigational medicinal products categorisation into specific default values categories based on low/high expected pharmacological potency, low/high toxicity, genotoxicity/carcinogenicity similar to the tiered Threshold of Toxicological Concern approaches proposed by Kroes et al. (2004), Munro et al. (2008), and Dolan et al. (2005) duration of the clinical trial will also be important Health-based exposure limits should be calculated with the availability of new data 12th November 2014 15
Reporting of PDE determination strategy Source of data must be of high quality Search and results thereof must be clearly documented Discussion of critical effects and choice of that used for PDE determination Clear rationale as to choice of adjustment factors used in calculating PDE Initial page should provide summary (template provided in the annex of the guideline) 12th November 2014 16
Thank you! 12th November 2014 17