Understanding the Tip:
Why in-use studies are essential:
In-use stability studies evaluate how a pharmaceutical product performs after it has been opened, reconstituted, or prepared for administration. This simulates real-world usage conditions—where contamination, moisture, or temperature shifts may alter the product’s stability.
Such studies are critical for multidose containers, injectables that require dilution, or powders for reconstitution, where shelf life can differ significantly from unopened products.
Impact on labeling and safety:
Without in-use data, it’s impossible to define accurate instructions such as “Use within 14 days of opening” or “Use within 6 hours of reconstitution.” Incorrect assumptions may lead to degraded or contaminated doses being administered to patients, affecting efficacy and safety.
This tip ensures stability reflects the product’s full usage lifecycle—not just its unopened condition on a warehouse shelf.
Risks of skipping in-use evaluations:
Excluding in-use studies can result in incomplete shelf life assignments and raise questions during regulatory review. It may also force last-minute label changes or impose conservative usage windows that impact usability and marketability.
Regulatory and Technical Context:
ICH and WHO expectations for in-use stability:
ICH Q1A(R2) and WHO TRS guidelines specify that in-use stability studies must be conducted if the product is reconstituted, diluted, or opened prior to full consumption. This applies to oral suspensions, parenteral solutions, ophthalmics, and inhalers.
These studies support appropriate labeling and storage guidance under conditions simulating patient handling and administration.
CTD documentation and regulatory submissions:
In-use data is typically included in CTD Module 3.2.P.8.1 (Stability Summary and Conclusions) and 3.2.P.8.3 (Stability Data). Submissions without this data for applicable formats often receive regulatory queries or post-approval conditions.
Such studies also help address global regulatory differences in allowable “use within” durations post-reconstitution.
Impact on multidose and preservative effectiveness:
For multidose containers, in-use studies verify that microbial growth does not occur between doses and that preservative systems remain effective. This is especially crucial for pediatric formulations, oral liquids, and eye drops.
Regulators assess not just microbial data but also chemical and physical parameters such as pH, color, and assay during in-use testing.
Best Practices and Implementation:
Design realistic in-use study protocols:
Simulate actual usage conditions, including reconstitution with specific diluents, repeated vial punctures, or storage at room temperature. Define time points such as 0, 6, 12, 24, and 48 hours (or longer, depending on label claim).
Use final packaging and dosage configuration during studies to replicate end-user conditions accurately.
Evaluate multiple quality attributes:
In addition to microbial testing, evaluate assay, degradation products, pH, viscosity, appearance, and particulate matter. If the product has preservatives, confirm their continued effectiveness under simulated use.
Document deviations, container-closure compatibility, and any changes in organoleptic properties during the study.
Use in-use data to inform labeling and shelf life:
Ensure your product label reflects validated “use within” periods and recommended storage after opening or preparation. Reference in-use data in your shelf-life justification reports and include any relevant risk mitigation strategies.
Update patient instructions or pharmacy dispensing guidelines as needed to reflect study findings and maintain product safety during actual use.