Defining Specifications for Known and Unknown Impurities in Drug Substance

The ICH Q3A guideline provides a clear regulatory framework for managing impurities in drug substances. It introduces three critical thresholds that must be understood and applied during analytical method development and regulatory submission:

1. Reporting Threshold

2. Identification Threshold

3. Qualification Threshold

🔬 What Is a Reporting Threshold?

A reporting threshold is the minimum concentration of an impurity that must be quantitatively reported in analytical results, typically in documents like the Certificate of Analysis (CoA) or stability reports.

In simple terms: if any impurity exceeds this threshold, it must be accurately and precisely reported.

However, detection alone is not sufficient. Your analytical method must be robust enough to quantify the impurity at or above the threshold with acceptable precision and accuracy. This means the method’s Limit of Quantitation (LOQ) must be equal to or lower than the reporting threshold. Only then can you ensure consistent and reliable impurity data.

🎯 Why Is the Reporting Threshold Important?

ICH Q3A links the reporting threshold to the Maximum Daily Dose (MDD) of the drug substance:

Maximum Daily Dose	Reporting Threshold
≤ 2 grams/day	0.05%
> 2 grams/day	0.03%

For example:

• If your MDD is 1000 mg (≤ 2 g), your threshold is 0.05%

• If your MDD is 3000 mg (> 2 g), your threshold is 0.03%

🧪 Implication for Method Development

An analytical method must be designed to meet or exceed this threshold:

• ✅ LOQ = 0.04% → Acceptable

• ❌ LOQ = 0.07% → Not acceptable

LOQ must be less than or equal to the reporting threshold to ensure reliable quantitation. Hence, this requirement should be addressed during method development, not just during method validation.

🧰 How to Determine the Reporting Threshold?

First, identify the Maximum Daily Dose (MDD) using:

• SBOA (Summary Basis of Approval) for USFDA

• SmPC (Summary of Product Characteristics) for EU

Then, apply the ICH Q3A criteria to determine the applicable reporting threshold.

📌 Key Takeaways on Reporting Threshold:

• Defines when impurities must be quantified

• Directly tied to Maximum Daily Dose

• LOQ should be ≤ Reporting Threshold

• Must be considered at method development stage

🔍 Special Situations:

1. Higher Reporting Thresholds Must Be Justified Scientifically: If you propose a threshold higher than ICH recommendations, it must be supported by:

• Toxicological data

• Analytical capability limitations (with rationale)

• Characterization of impurity showing no risk

2. Lower Thresholds May Be Required for Toxic Impurities: For mutagenic or highly toxic impurities (e.g., nitrosamines):

• Regulatory bodies may require lower thresholds

• All thresholds may be adjusted to prioritize patient safety

🔍 What Is an Identification Threshold?

The identification threshold is the concentration above which an impurity’s chemical identity must be determined. If an impurity is present above this level, it cannot remain "unknown."

For example:

• If threshold = 0.5%, and unknown impurity = 0.3% → No identification needed

• If unknown impurity = 0.7% → Must be identified

Thus, this threshold sets the limit for unknown impurities.

💡 How to Calculate Identification Threshold:

Maximum Daily Dose	Identification Threshold
≤ 2 g/day	0.1% or 1 mg/day (whichever is lower)
> 2 g/day	0.05%

Real-world Example:

• MDD = 500 mg

• Impurity = 1 mg/day = 0.2%

• Threshold = lower of 0.1% or 1 mg → 0.1% is lower

• ✔ Identification threshold = 0.1%

🐝 What Is a Qualification Threshold?

Once an impurity is identified, the next question is: Is it safe?

The qualification threshold is the concentration above which toxicological qualification is required. If an impurity exceeds this level, you must:

• Conduct toxicity studies, or

• Provide literature-based justification for its safety

This threshold sets the limit for known impurities.

✅ Summary Table: Know Your Thresholds

Threshold Type	Purpose	Applies To
Reporting Threshold	Must be reported and quantified	All impurities
Identification Threshold	Must be structurally identified	Unknown impurities
Qualification Threshold	Must be toxicologically qualified	Known impurities

🔄 Final Thoughts

A lack of understanding or application of these thresholds can lead to:

• Incomplete method validation

• Regulatory non-compliance

• Delayed product approvals

The aim is not just impurity detection, but correct action at the right threshold. By mastering these thresholds, you ensure regulatory readiness, data integrity, and above all, patient safety.