Permitted Daily Exposure Calculation

The PDE represents 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. 

Determination of a PDE involves: 

(i) hazard identification by reviewing all relevant data, 

(ii) identification of “critical effects”, 

(iii) determination of the no-observed-adverse-effect level (NOAEL) of the findings that are considered to be critical effects, and 

(iv) use of several adjustment factors to account for various uncertainties. 

Appendices 3 of the ICH Q3C and VICH GL 18 guidelines present the following equation for the derivation of the PDE:

PDE = (NOAEL x Weight Adjustment) / (F1 x F2 x F3 x F4 x F5)

 

For all critical effects identified, a NOAEL should be established. The NOAEL is the highest tested dose at which no “critical” effect is observed. If the critical effect is observed in several animal studies, the NOAEL occurring at the lowest dose should be used for calculation of the PDE value. If no NOAEL is obtained, the lowest-observed-adverse-effect level (LOAEL) may be used. A NOAEL based on clinical pharmacodynamic effects should correspond to the highest dose tested which is considered therapeutically inefficacious.

The PDE is derived by dividing the NOAEL for the critical effect by various adjustment factors (also referred to as safety-, uncertainty-, assessment- or modifying factors) to account for various uncertainties and to allow extrapolation to a reliable and robust no-effect level in the human or target animal population. F1 to F5 are addressing the following sources of uncertainty:

• F1: A factor (values between 2 and 12) to account for extrapolation between species
• F2: A factor of 10 to account for variability between individuals
• F3: A factor 10 to account for repeat-dose toxicity studies of short duration, i.e., less than 4-weeks
• F4: A factor (1-10) that may be applied in cases of severe toxicity, e.g. non-genotoxic carcinogenicity, neurotoxicity or teratogenicity
• F5: A variable factor that may be applied if the no-effect level was not established. When only an LOEL is available, a factor of up to 10 could be used depending on the severity of the toxicity.

Permitted Daily Exposures for Elemental Impurities

PDEs reported in this table (µg/day) have been established on the basis of safety data described in the guideline (ICH Q3D), and apply to new drug products. The PDEs in the monographs are not rounded. For practical purposes the PDEs in this table have been rounded to 1 or 2 significant figures.

Permitted Concentrations of Elemental Impurities for Individual Component Option 1 (based on a maximum 10-g dose)

Elements to Be Considered in the Risk Assessment

Options for Demonstrating Compliance

The results obtained from the analysis of a typical dosage unit, scaled to a maximum daily dose, are compared with the daily dose PDE.

Daily dose  PDE ≥ measured  value  (μg/g) × maximum  daily dose (g/day)

The measured amount of each impurity is not more than the daily dose PDE, unless otherwise stated in the individual monograph.

Separately, add the amounts of each elemental impurity (in µg/g) present in each of the components of the drug product:

Daily dose  PDE≥ [ΣM1 (CM×WM) ] × DD

M = each ingredient used to manufacture a dosage unit

CM = element concentration in component (drug substance or excipient) (µg/g)

WM = weight of component in a dosage unit (g/dosage unit)

DD = number of units in the maximum daily dose (unit/day)

The result of the summation of each impurity is not more than the daily dose PDE, unless otherwise stated in the individual monograph. Before products can be evaluated using this option, the manufacturer must ensure that additional elemental impurities cannot be inadvertently added through the manufacturing process or via the container–closure system over the shelf life of the product.

Related:

• Pharmaceutical Impurities Calculation
• Classification of Elemental Impurities