Out of Specifications: How to Improve OOS Specifications Limits

Tox by Design approach to requalify out of specifications impurities (ICH Q3A/B, Pharmacopeia) is to leverage ICH M7 new regulation options to improve specification limit, in the following cases:

First case: New drug substances or drug products during clinical development or subsequent marketing application

Second case: Post approval submission of marketed products, new marketing applications for products with a drug substance that is present in a previously approved product in both cases, but only where:

• Changes to the drug substance synthesis result in new impurities or increased acceptance criteria for existing impurities.
• Changes in the formulation, composition or manufacturing process result in new degradation products or increased acceptance criteria for existing degradation products.
• Changes in indication or dosing regimen are made which significantly affect the acceptable cancer risk level.

Tox by Design Risk Assessment methodology involves:

Step 1 − Identification and Classification of the OoS from:

• bibliographic review
• in silico studies: QSAR

Step 2 − Toxicological Limits Determination: PDE, AI, TTC, LTL

Step 3 − OoS: Safety Ratio Calculation

• If the safety threshold is above the amount of impurity in the Maximum Daily Dose, then a new specification can be proposed.
• Calculation of the specification:

         Knowing the toxicological threshold and the maximum daily dose (MDD) of the drug,

         the new specification can be calculated as follows:

Case Examples

Case 1: Biotech R&D Department New Active Substance Impurities Specifications Determination

Case 2: Impurity in Finished Products

• Not mentioned in EP monograph
• Stability data showing amount above EP limit
• etc…

Problem: You have an impurity that goes out of specification during a stability study.

You need to have information on the quantity of impurities detected in the current stability study “stability threshold”, and knowing the Maximum Daily Dose (“MDD”) of the drug, compare the value of the stability threshold to the ICH Q3B limit.

• If % impurity < % ICH Q3B limit: no evaluation
• If % impurity > % ICH Q3B limit: toxicological evaluation

Specification is based on a general purpose limit, it does not take into account toxicity.

Toxicological Evaluation and Risk Analysis

Step 1 − Determination of the toxicological profile of the impurity (CMR, acute toxicity, chronic toxicity, etc...) by studying bibliographic data or using in silico models (QSAR, read-across): a NOAEL or LOAEL value will be chosen.

Step 2 − Calculation of the toxicological threshold, Permitted Daily Exposure (“PDE”)

Step 3 − Knowing the toxicological threshold (PDE) and the MDD, the new specification can be calculated as follows:

Case 3: Impurity (contaminant, etc...) in Batch Release

Problem: Your drug has an impurity above the qualification thresholds.

With the Maximum Daily Dose (“MDD”) of the drug, the amount of impurity found is compared to the ICH Q3B qualification threshold limit value:

• If % impurity < % ICH Q3B limit: no evaluation
• If % impurity > % ICH Q3B limit: toxicological evaluation

Toxicological Evaluation and Risk Analysis

Step 1 − Determination of the toxicological profile of the impurity (CMR, acute toxicity, chronic toxicity, etc...) by studying bibliographic data or using in silico models (QSAR, read-across): a NOAEL or LOAEL value will be chosen.

Step 2 − Calculation of the toxicological threshold, Permitted Daily Exposure (“PDE”)

Step 3 − Calculation of the new specification

• If the safety ratio > 1: the impurity is qualified