Case Study: Implementing Real-Time Stability Testing for Oral Solid Dosage Forms

Real-time stability testing is a regulatory requirement and quality assurance cornerstone in the pharmaceutical industry. This expert case study explores the end-to-end implementation of real-time stability testing for oral solid dosage forms (tablets and capsules), highlighting ICH compliance, protocol design, and actionable lessons for pharmaceutical professionals.

Background and Product Overview

This case involves a fixed-dose combination (FDC) of two antihypertensive agents in film-coated tablet form. The product was intended for global submission, including regions in Climatic Zones II, III, and IVb. The project aimed to establish a shelf life of 24 months using real-time data compliant with ICH Q1A(R2).

Formulation Details:

• Tablet form with core and film coat
• Moisture-sensitive API in one component
• PVC-Alu blister as the final container

1. Protocol Design and Objective

The protocol was designed to demonstrate long-term stability under recommended storage conditions. Objectives included shelf-life determination, regulatory support for NDAs, and formulation validation.

Key Protocol Elements:

1. Storage Conditions: 25°C ± 2°C / 60% RH ± 5% RH (Zone II); additional studies at 30°C/75% RH for Zone IVb
2. Duration: 0, 3, 6, 9, 12, 18, 24 months
3. Sample Type: Three production-scale batches
4. Testing Parameters: Assay, dissolution, related substances, water content, hardness, friability

2. Selection of Representative Batches

Three commercial-scale batches were selected, each manufactured using validated processes and packaged in final market-intended packaging. One batch incorporated the maximum theoretical impurity profile to serve as the worst-case scenario.

Batch Handling Notes:

• Batch IDs: FDC1001, FDC1002, FDC1003
• Blister-packed and sealed within 24 hours post-manufacture
• Samples split between primary and backup stability chambers

3. Stability Chamber Setup and Qualification

The real-time study was conducted in ICH-qualified chambers maintained at 25°C/60% RH and 30°C/75% RH. All chambers underwent IQ/OQ/PQ and were mapped for uniformity before sample placement.

Monitoring Parameters:

• Temperature and RH probes calibrated quarterly
• Automated deviation alerts and backup power system

4. Analytical Method Validation

All test parameters were evaluated using stability-indicating methods validated according to ICH Q2(R1).

Key Analytical Methods:

• Assay and impurities: HPLC with dual wavelength detection
• Dissolution: USP Apparatus 2, 900 mL media
• Water Content: Karl Fischer titration
• Physical tests: Hardness tester, friability drum

5. Stability Data Summary

Results from 0 to 24 months showed consistent performance across all three batches. No significant degradation was observed, and all critical parameters remained within specification.

Tabulated Data Snapshot:

6. Observations and Key Learnings

Despite the presence of a moisture-sensitive API, the film coating and PVC-Alu packaging provided excellent protection. No unexpected impurities formed, and the dissolution profile remained consistent across time points.

Lessons Learned:

• Packaging selection critically impacts moisture control
• Worst-case batch strategy is valuable in predicting long-term behavior
• Dual-chamber redundancy improves data reliability and risk mitigation

7. Regulatory Submission and Approval

The real-time stability data formed part of Module 3.2.P.8.3 of the CTD submitted to regulatory authorities. No data gaps or deficiencies were noted during the review, and a 24-month shelf life was granted without the need for additional justification.

Supporting SOPs, protocols, and validation templates are available at Pharma SOP. For more such real-time case explorations, visit Stability Studies.

Conclusion

This case study demonstrates the successful implementation of a real-time stability program for oral solid dosage forms. With careful batch selection, validated methods, and robust chamber controls, pharmaceutical professionals can generate high-quality data that support regulatory filings and ensure long-term product integrity.