Regulatory Justifications for Omission of Intermediate Condition Studies

Regulatory Justifications for Omitting Intermediate Stability Studies in Pharmaceutical Development

Intermediate condition studies—typically performed at 30°C ± 2°C / 65% RH ± 5%—are a critical element in pharmaceutical stability programs, especially when accelerated studies show significant change. However, there are scenarios where omitting intermediate condition testing is scientifically and regulatorily acceptable. With proper justification, such omissions can be incorporated into a compliant and streamlined submission. This guide explores regulatory expectations, valid scenarios, and documentation strategies for omitting intermediate studies in CTD filings.

1. Regulatory Basis for Intermediate Testing

As outlined in ICH Q1A(R2), intermediate testing is generally conducted:

When accelerated stability (40°C/75% RH) results in significant change
When a product is expected to be temperature-sensitive

However, if long-term and accelerated data demonstrate adequate stability, or if intermediate testing is not relevant to the product, the study can be omitted with sufficient justification.

ICH Language on Intermediate Testing:

“Where ‘significant change’ is not observed during accelerated testing, intermediate storage condition testing is not necessary.”

2. Valid Scenarios for Omitting Intermediate Condition Studies

A. No Significant Change in Accelerated Studies

All CQAs remain within specification at 40°C/75% RH for 6 months
No new impurities or physical changes observed

B. Short Shelf-Life Products

Product shelf life is ≤12 months, supported by real-time data
Real-time and accelerated studies completed before submission

C. Thermally Stable APIs or Formulations

Forced degradation studies show resistance to temperature and humidity
Stability profile consistent across all tested conditions

D. Products Stored in Controlled Environments

Cold chain products (e.g., 2–8°C) with validated temperature protection
Intermediate conditions are not relevant to labeled storage

3. Regulatory Expectations for Omission Justification

FDA (U.S.):

Expects clear rationale supported by accelerated and real-time data
Will question omission if accelerated shows borderline results

EMA (Europe):

Requires detailed scientific justification in CTD Module 3.2.P.8.2
May request post-approval monitoring if intermediate omitted

WHO PQ:

Generally expects intermediate testing for Zone IV markets unless fully justified
Omission must be risk-assessed and referenced in protocol deviation logs

4. CTD Submission Strategy for Omission

Module 3.2.P.8.1: Stability Summary

State conditions used for long-term and accelerated testing
Clearly mention that intermediate testing was not performed

Module 3.2.P.8.2: Justification for Shelf-Life Assignment

Include detailed rationale covering:

Stability of product at accelerated and long-term conditions
Absence of significant change during accelerated storage
Risk assessment for omitting intermediate testing
Data from forced degradation studies supporting thermal resilience

Module 3.2.P.8.3: Data Presentation

Include clear summary tables and trend plots showing no accelerated degradation
Highlight similarity in batch performance across time points

5. Scientific Justification Templates

Use a structured format to defend omission decisions:

Example Justification Structure:

Product Name: ABC 500 mg Tablet
Accelerated Results: 6 months at 40°C/75% RH – No significant change
Long-Term Data: 18 months at 25°C/60% RH – All parameters stable
Degradation Study: Forced degradation confirms thermal resistance
Conclusion: Intermediate condition (30°C/65% RH) not required per ICH Q1A(R2)

6. Real-World Case Examples

Case 1: Omission Approved by EMA

A European manufacturer submitted an antihypertensive tablet dossier without intermediate data. The product showed no significant change at 40°C/75% RH for 6 months. EMA accepted the justification and approved a 24-month shelf life.

Case 2: WHO PQ Rejection and Resubmission

A company omitted intermediate testing for a syrup intended for African markets. WHO rejected the submission due to lack of Zone IVb justification. The sponsor re-ran 30°C/65% RH studies and gained approval after 6 months.

Case 3: FDA 505(b)(2) Submission Acceptance

A reformulated product based on an existing reference was filed with long-term and accelerated data only. Intermediate conditions were omitted with justification based on prior product stability and new forced degradation studies. The FDA approved with no additional questions.

7. Tools and SOPs for Documenting Omission Justifications

Available from Pharma SOP:

Intermediate Stability Study Waiver Justification Template
Risk Assessment Matrix for Stability Study Decisions
ICH Q1A Omission Evaluation Checklist
Forced Degradation Summary and Mapping Tool

Explore related dossiers and case study walkthroughs at Stability Studies.

Conclusion

Omitting intermediate condition studies is permissible under regulatory frameworks when backed by strong scientific data and clear documentation. By understanding ICH provisions, validating product-specific behavior, and preparing risk-based justifications, pharmaceutical professionals can streamline development without compromising compliance. A proactive, evidence-driven approach ensures both regulatory alignment and efficient lifecycle management of drug products.