Toxicological Risk Assessment/ Health based Exposure Limit Assessment
When different medicinal products are produced in shared facilities, the potential for cross-contamination is a concern. Medicinal products provide a benefit to the intended patient or target animal; however, as a cross contaminant, they provide no benefit to the patient or target animal and may even pose a risk. Hence, the presence of such contaminants should be managed according to the risk posed which in turn are related to levels that can be considered safe for all populations. To this end, health-based limits through the derivation of a safe threshold value should be employed to identify the risks posed.
Permitted Daily Exposure / Acceptable Daily Exposure Limit Determination: The PDE(EMA) and ADE (FDA) 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/ ADE involves:
Hazard identification by reviewing all relevant data,
(Mechanism of Action, LD50, repeated dose toxicity, carcinogenicity, genotoxicity, reproductive toxicity, developmental toxicity)
Identification of “critical effects”,
(Clinical and Non clinical studies, Therapeutic effects, Adverse effects)
Determination of the no-observed-adverse-effect level (NOAEL) of the findings that are considered to be critical effects,
(Based on above two steps, requires toxicological expertise, calculated as mg/kg/day.)
Use of several adjustment factors to account for various uncertainties
PDE/ ADE = NOAEL x Weight Adjustment / F1 x F2 x F3 x F4 x F5
NOAEL expressed as mg/kg/day
F1: A factor (value between 2 to 12) to account extrapolation between species.
F2: A factor 10 to account variability between species.
F3: A factor (value between 2 to 5) for duration of studies.
F4: A factor (value of 1-10) that may be applied in case of severe toxicity.
F5: A variable factor that may be applied if no -effect level was not established.
Occupational Daily Exposure Limit Determination: These are regulatory values which indicate levels of exposure that are considered to be safe (health based) for a chemical substance in the air of a workplace. ELs are a measure for minimizing the worker exposure to hazardous substances in the workplace.
Maximum Allowable Carry Over, MACO: Mathematically calculated quantity of residue from a previous product when carried over into different product that can represent potential harm to the patient.
MACO = PDE × MBSnext / SF × TDD next
MBSnext – Minimum Batch Size
SF- Safety factor
TDD next – Standard Therapeutic dose (mg/day)
Genotox Evaluation
Regulatory authorities all over the world require data on the genotoxic potential of new drugs, as part of the safety evaluation process. The pre-clinical studies are generally conducted to obtain the basic toxicological profile of new chemical entities (NCE). The toxicological data are used to evaluate the safety and efficacy of NCE, which will help in predicting the drug’s likely risk/benefit assessment in New Drug Application (NDA) process.
Genotoxicity studies can be defined as various in-vitro and in-vivo tests designed to identify any substance or compounds which may induce damage to genetic material either directly or indirectly by various mechanisms. These tests should enable the identification of hazard with respect to DNA damage and fixation. Genetic change play only a part in the complex process of heritable effects and malignancy which include the fixation of the damage to the DNA by gene mutation or large-scale chromosomal damage or recombination or numerical chromosomal changes. These tests play an important role in predicting if the compound have the potential to cause genotoxicity and carcinogenicity by testing them positive.
QSAR Analysis
Biological activity (e.g., toxicity) of substances is governed by their properties, which in turn are determined by their chemical structure. The objectives of SAR are two-fold. First, to determine as accurately as possible the limits of variation in the structure of a chemical that are consistent with the production of a specific effect (e.g., can a chemical elicit a specific toxic endpoint). Second, to define the ways, which alterations in structure and thereby the overall properties of a compound influence endpoint potency.
Structure – Activity Relationship (SAR) is an approach designed to find relationships between chemical structure (or structural-related properties) and biological activity (or target property) of studied compounds. As such it is the concept of linking chemical structure to a chemical property (e.g., water solubility) or biological activity including toxicity (e.g., fish acute mortality). Qualitative SARs and quantitative SARs, collectively are referred to as (Q)SARs. Qualitative relationships are derived from non-continuous data (e.g., yes or no data), while quantitative relationships are derived for continuous data (e.g., toxic potency data).