Discussion forum for Pharma Quality events, Regulatory Actions

Warning letters, 483s, Recalls, Import Alerts, Audit observations

Updated on April 21, 2026

The USFDA has issued a draft guidance for Establishing Impurity Specifications for Antibiotics in April 2026. This guidance is applicable for antibiotics manufactured by fermentation and semi-synthesis processes. The guidance essentially clarifies that for listing impurities and setting specifications (identifying, qualifying and controlling impurities) in antibiotics, the same framework of ICH guidance’s shall apply

  • ICH Q3A (R2): Impurities in New Drug Substances
  • ICH Q3B (R2): Impurities in New Drug Products

The guidance acknowledges that antibiotics produced by fermentation or semisynthetic processes are complex, and can introduce a wider variety of impurities compared to chemical synthesis. In these antibiotics active ingredient is generally not a single molecular entity but a collection of structurally related, biologically active analogues.

The qualification thresholds for the impurities in the antibiotics produced by fermentation or semi-synthetic process shall be same as that defined by the ICH Q3(R) guidance’s. For new impurities that exceed these qualification thresholds, justification should be provided based on repeat dose toxicity studies of 14-90 days duration.

If the impurity has structural alerts for mutagenicity, risk assessment as per ICH M7(R2): Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk should be performed and  impurities controlled as per the recommendations of the guidance.

The guidance applies only to related organic impurities. It does not apply to extraneous contaminants, microbiological controls, residual solvents, leachables, or cell substrate-derived impurities.

Listing of Impurities and Degradation Products in Specifications of Drug Substances and Drug Products (ICH Q3A, Q3B & Q6A)
Drug Substance Drug Product
Each specified identified impurity Each specified identified degradation product
Each specified unidentified impurity Each specified unidentified degradation product
Any unspecified impurity with an acceptance criterion that does not exceed (i.e., ≤) the identification threshold Any unspecified degradation product with an acceptance criterion that does not exceed (i.e., ≤) the identification threshold
Total impurities Total degradation products

 

ICH Q3A Thresholds (TH) for Impurities in Drug Substances
Maximum Daily Dosage (MDD) Reporting TH Identification TH Qualification TH
≤ 2 g 0.05% 0.10% (or 1 mg*) 0.15% (or 1 mg*)
> 2 g 0.03% 0.05% 0.05%

 

ICH Q3B Thresholds (TH) for Degradation Products in Drug Products
Maximum Daily Dosage (MDD) Reporting TH Identification TH Qualification TH
< 1mg 0.1% 1% (or 5 µg*) 1% (or 50 µg*)
>1–10 mg 0.1% 0.5% (or 20 µg*) 1% (or 50 µg*)
10 mg 0.1% 0.5% (or 20 µg*) 0.5% (or 200 µg*)
>10–100 mg 0.1% 0.2% (or 2 mg*) 0.5% (or 200 µg*)
>100 mg–1 g 0.1% 0.2% (or 2 mg*) 0.2% (or 3 mg*)
>1–2 g 0.05% 0.2% (or 2 mg*) 0.2% (or 3 mg*)
> 2 g 0.05% 0.10% 0.15%


(*): Total Daily Intake (if it is lower)

Reporting TH: Levels above which an impurity / degradation product should be reported

Identification TH: Levels above which an impurity / degradation product should be identified, structurally characterised

Qualification TH: Levels above which biological safety of an impurity / degradation product should be established.

References:

 

Tags : , , ,

Leave a Comment