Storage Labeling Justifications Based on Freeze-Thaw Data: A Regulatory and Scientific Approach

Storage conditions on pharmaceutical labels—such as “Store at 2–8°C” or “Do Not Freeze”—are not arbitrary. These directives are backed by rigorous stability studies, including freeze-thaw evaluations that simulate real-world temperature stresses. Regulatory authorities demand that such labels be scientifically justified with data that demonstrates the drug’s performance under specified and stressed conditions. This expert guide explores how pharmaceutical companies can generate, interpret, and document freeze-thaw data to substantiate their storage labeling for regulatory compliance and market acceptance.

1. Importance of Freeze-Thaw Data in Labeling

Why Storage Conditions Matter:

• Ensure drug potency and safety throughout the product lifecycle
• Prevent patient harm from degraded or destabilized products
• Comply with global regulatory frameworks and inspection standards
• Support global distribution and supply chain flexibility

Impact of Inaccurate Labeling:

• Product recalls and batch rejections
• Regulatory warning letters or market withdrawal
• Loss of reputation and financial penalties

2. Regulatory Framework for Storage Labeling

ICH Q1A(R2):

• Mandates stress testing including freeze-thaw simulations
• Storage conditions must be justified by long-term and accelerated data

FDA and EMA Requirements:

• Explicit data is needed to support “Do Not Freeze” or “Stable if frozen” labels
• Excursion tolerances must be tested and documented

WHO PQ Guidelines:

• Stability data must support the product’s distribution profile in tropical and temperate zones
• “Vaccine vial monitors” and freeze indicators are often required for cold chain products

3. Freeze-Thaw Study Design for Label Support

Key Elements:

• Use final product in commercial packaging (vials, ampoules, syringes, etc.)
• Perform 3–5 cycles of freezing (–20°C to –80°C) and thawing (2–8°C or 25°C)
• Document each cycle with calibrated temperature loggers
• Compare to control samples stored under ICH long-term or accelerated conditions

Parameters to Monitor:

• Assay and related substances (HPLC/UPLC)
• pH, osmolality, appearance, and viscosity
• Aggregation or phase separation (for biologics/emulsions)
• Container closure integrity (HVLD or vacuum decay)

4. Justification for Common Labeling Statements

“Do Not Freeze”

• Supported by freeze-thaw studies showing:
  • Protein aggregation in biologics
  • Emulsion phase separation
  • Loss of preservative efficacy
  • Container deformation or leakage

“Stable When Frozen” or “May Be Frozen for Long-Term Storage”

• Supported by:
  • mRNA vaccine stability data showing preservation of activity below –20°C
  • Protein-based drugs validated for –80°C storage with SEC and potency assays

“Store Between 2–8°C”

• Requires:
  • Degradation data at 25°C showing loss of stability
  • Consistency across ICH long-term, accelerated, and freeze-thaw studies

“Protect from Freezing” (on packaging/cartons)

• Justified if even a single freeze-thaw cycle leads to:
  • Visible precipitation or pH drift
  • Loss of emulsifier function
  • Packaging integrity risk

5. CTD Filing Strategy for Labeling Justifications

Module 3.2.P.8.3: Stability Summary and Conclusion

• Include freeze-thaw data tables and charts
• Discuss how results support storage claims

Module 3.2.P.2.4: Container and Excipient Justification

• Include data supporting packaging protection under thermal stress
• Discuss impact of freezing on container materials (e.g., rubber stoppers, plastic ampoules)

Labeling Documentation:

• Product Information Leaflet (PIL)
• Summary of Product Characteristics (SmPC)
• Package Insert language based on freeze-thaw justification

6. Case Examples of Labeling Based on Freeze-Thaw Data

Case 1: Injectable Emulsion with “Do Not Freeze” Label

Freeze-thaw testing revealed irreversible oil phase separation and pH drop. Label was finalized with “Do Not Freeze” warning, supported by SEC, DLS, and visual inspection data.

Case 2: mRNA Vaccine Approved with –20°C Storage

Stability data over 6 months at –20°C and accelerated thawing showed consistent potency. EMA and FDA accepted –20°C long-term storage with “Do Not Refreeze” language after thaw.

Case 3: Ophthalmic Solution with Freeze-Tolerant Label

Three freeze-thaw cycles produced no change in clarity, pH, or assay. Label included “May be frozen and thawed up to three times” to support distribution to remote regions.

7. Best Practices for Label Justification Using Freeze-Thaw Data

• Design freeze-thaw studies during early development (phase II-III)
• Use real-time and stress data to simulate global distribution risks
• Document all justification language during stability summary creation
• Ensure QA and regulatory teams align on data-driven decisions
• Audit labeling documents against available supporting data

8. SOPs and Templates for Storage Labeling Justification

Available from Pharma SOP:

• Freeze-Thaw Stability Testing SOP
• Labeling Justification Template Based on Stability Data
• CTD Module 3.2.P.8.3 Label Support Report
• Excursion Assessment Matrix for Labeling Decisions

More guidance and case studies available at Stability Studies.

Conclusion

Storage labeling is one of the most visible and critical outputs of pharmaceutical development—and it must be backed by sound science. Freeze-thaw studies provide the foundation for justifying claims like “Do Not Freeze” or “Store at 2–8°C,” ensuring that products remain effective and safe under real-world conditions. By aligning study design, analytical methods, and regulatory filings, pharma teams can deliver accurate, defensible storage labeling that meets global standards and protects patients.