1. Risk-Based Scientific Justification
A solid scientific rationale is the foundation of any justification.
a. Toxicological Evaluation
- Use non-clinical toxicology data (acute, subchronic, chronic toxicity, genotoxicity, carcinogenicity, reproductive toxicity).
- Reference No Observed Adverse Effect Level (NOAEL) and calculate a Margin of Safety
b. Published Data and Historical Use
- Reference approved drugs or published clinical trials that used similar or higher levels of the excipient.
- Use FDA Inactive Ingredient Database (IID) or European Database on Excipients.
- Mention GRAS (Generally Recognized as Safe) status if applicable.
c. In Silico Toxicology Modeling
- If limited empirical data are available, support your justification with QSAR or DEREK predictions for genotoxicity or organ toxicity.
2. Regulatory Precedents and Guidelines
Reference acceptable limits in:
- ICH Q3A/B: Impurity limits for drug substances/products.
- ICH M7: Assessment of mutagenic impurities.
- FDA/EMA guidances for excipients, impurities, and investigational products.
Refer to:
- Past INDs, CTAs, NDAs where similar levels were accepted.
- Responses from scientific advice meetings or pre-IND consultations.
3. Clinical Justification
a. Exposure Comparison
- Compare the actual or projected human exposure to:
- Daily allowable intake (e.g., for solvents – ICH Q3C)
- Acceptable daily intake (ADI) or tolerable daily intake (TDI) values from WHO or JECFA.
b. Duration and Population
- Emphasize that the exposure is short-term or single dose (for early-phase trials).
- If target population is terminal, rare disease, or high unmet need, argue for benefit-risk balance.
4. Manufacturing and Formulation Controls
- Discuss control strategies to minimize the excipient/impurity level in future batches.
- Offer tighter in-process controls, release specifications, or stability monitoring.
- Justify if the overage is technically unavoidable due to formulation or manufacturing constraints.
5. Bridging, Mitigation, and Commitments
Propose:
- Bridging toxicology studies (e.g., repeat-dose in animals).
- Reduction of excipient level in future formulations.
- Reformulation plans if the product moves into Phase III.
Offer a risk management plan to monitor adverse events possibly linked to the excipient.
6. Documentation and Format (Regulatory Filing)
Include a structured justification in:
- Module 2.3 & 2.4 of the CTD (Quality and Nonclinical Overviews)
- Module 3.2.P.5.6 (Justification of Specification)
- Investigator’s Brochure (IB) or Clinical Protocol section on formulation and safety.
Optional Enhancements
- Comparative impurity profiling with reference listed drug (if applicable).
- Degradation pathway analysis to confirm the impurity is not from API breakdown.
- Stability data showing no increase of impurity/excipient over shelf-life.
Read also:
- FDA Inactive Ingredient Database (IID) | A Hidden Asset in Generic Drug Development
- Maximum Daily Dose Database (MDD)
Resource Person: Moinuddin syed. Ph.D, PMP®
