Permitted Daily Exposure - Calculation

Permitted Daily Exposure (PDE) Calculation for Cleaning Validation
Permitted Daily Exposure (PDE) is calculated on the basis of the pre-clinical data (Toxicological
studies on animals) and clinical studies data (pharmacology and adverse effects).
The acceptance criteria for cleaning validations preferably should be based on the Acceptable
Daily Exposure (ADE) or Permitted Daily Exposure (PDE) calculations whenever this data is
available.
The ADE/ PDE define limits at which a patient may be exposed every day for a lifetime with
acceptable risks related to adverse health effects.
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×Weight adjustment ÷ F 1× F 2× F 3 × F 4 × F 5
The PDE is derived preferably from a NOAEL. If no NOAEL is obtained, the LOEL may be used.
Modifying factors proposed here, for relating the data to humans, are the same kind of
"uncertainty factors" used in Environmental Health Criteria (Environmental Health Criteria
170, World Health Organization, Geneva, 1994), and "modifying factors" or "safety factors" in
Pharmacopeial Forum. The assumption of 100% systemic exposure is used in all calculations
regardless of route of administration.
Modifying Factors:
The modifying factors are as follows:
F1 = A factor to account for extrapolation between species
Species MF
Human 1
Rats 5
Mice 12
Dogs 2
Rabbits 2.5
Monkeys 3
Other 10
F2 = A factor of 10 to account for variability between individuals

A factor of 10 is generally given for all organic solvents, and 10 is used consistently in this
guideline.
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F3 = A variable factor to account for toxicity studies of short-term exposure
Species Duration MF
≥ 1 year 1
≥ 6 & < 12 months 2
≥ 3 & < 6 months 5
Rodents or Rabbits < 3 months 10
Reproductive study entire 1
period of embryogenesis is
covered
≥ 7 years 1
≥ 3.5 & < 7 years 2
≥ 2 & < 3.5 years 5
Monkeys, Dogs, Cats < 2 years 10
Reproductive study entire 1
period of embryogenesis is
covered
In all cases, the higher factor has to be used for study durations between the time points, e.g.,
a factor of 2 for a 9-month rodent study.
F4 = A factor that may be applied in cases of severe toxicity, e.g., non-genotoxic

carcinogenicity, neurotoxicity or teratogenicity.
Species MF
Soft Toxic Effects: 1
Diarrheas caused by antibiotics
Increase of the weight of organs without correlated tissular
pathology
Stress effects with modification of the volume of the thymus
Non-Lethal Toxic Effects: 5
Inhibition of a Cellular Cycle
Hypertrophy
Myelotoxicity
High Blood Pressure
Potential Lethal effects: 10
Degenerative and necrosed hurts of organs
Tumors
Stop of functioning of an organ
In studies of reproductive toxicity, the following factors are used:
Page 2 of 3
Species MF
Fetal toxicity with maternal toxicity 1
Fetal toxicity without maternal toxicity 5
Teratogenic effect with maternal toxicity 5
Teratogenic effect without maternal toxicity 10
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.
The weight adjustment assumes an arbitrary adult human body weight for either sex of 50
kg.
Selection of final PDE:
If several critical effects have been identified resulting in calculation of more than one PDE
value, a decision with respect to the most appropriate PDE to be used for the cleaning
validation process should be made with an appropriate justification. Usually, by default the
lowest PDE value will be used.
The OEL data can also be used to calculate the ADE / PDE for setting the acceptance criteria
for cleaning of equipment.
In certain cases, where availability of pharmacological or toxicological data is limited, for

example for chemicals, raw materials, starting materials, intermediates or API’s in early
phase clinical trials, cleaning limits based on fraction of clinical doses, LD50 and / or general
cleaning limits may be calculated.
References:
1. EMA Guideline on setting health based exposure limits for use in risk identification in
the manufacture of different medicinal products in shared facilities.
EMA/CHMP/CVMP/SWP/169430/2012
2. Overview of comments received on Questions and answers on implementation of risk
based prevention of cross contamination in production and ‘Guideline on setting health
based exposure limits for use in risk identification in the manufacture of different
medicinal products in shared facilities’ (EMA/CHMP/CVMP/SWP/169430/2012)
3. Active Pharmaceutical Ingredients Committee (APIC) Guidance on aspects of cleaning
validation in active pharmaceutical ingredient plants.
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Permitted Daily Exposure - Calculation

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Permitted Daily Exposure (PDE) Calculation for Cleaning Validation

F2 = A factor of 10 to account for variability between individuals

F3 = A variable factor to account for toxicity studies of short-term exposure

F4 = A factor that may be applied in cases of severe toxicity, e.g., non-genotoxic

In studies of reproductive toxicity, the following factors are used:

Selection of final PDE:

In certain cases, where availability of pharmacological or toxicological data is limited, for

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