Article Figures & Data
Figures
- Figure 1
Impact of storage temperature on concentration profiles of secondary packaging leachables. Example comparison of real-time and accelerated data for a unit carton leachable observed in the same lot of ODP with an LDPE primary container. In this case, the product is not encapsulated in a foil pouch. LDPE, low-density polyethylene; ODP, ophthalmic drug product; RH, relative humidity.
Tables
LLNA EC3 (μg/cm2) Potency Classification <100 Strong 100–1,000 Moderate 1,000–10,000 Weak >10,000 Extremely Weak NCa Nonsensitizer EC3, concentration expected to give a 3-fold stimulation of lymph node cell proliferation; LLNA, local lymph node assay; NC, not calculated.
↵a No positive response is obtained at any concentration tested; therefore, an EC3 value cannot be calculated. (Table from Gerberick et al. [21]).
Peak # Compound Class Concentration (ppm) Total Daily Exposure, µg/day (acute indication) Total Daily Exposure, µg/day (chronic indication) 1 Plasticizer 13 4.2 2.1 2 Antioxidant 7 2.2 1.1 3 Preservative 1.5 0.48 0.24 4 resin intermediate 22 7 3.5 5 unknown <1 ppm Not calculated Not calculated 6 unknown <1 ppm Not calculated Not calculated Compound Genetic Toxicity Ocular Irritation/Toxicity Sensitization Antioxidant No data available Minimal reversible irritancy observed at 800× concentration on eye No indication of sensitization at doses higher than leachable level Plasticizer Negative genotoxicity but listed on California Proposition 65 list of hazardous substances with a recommended safe level of 9.8 µg/day (from all sources) Nonirritant No indication of sensitization at doses higher than leachable level Resin intermediate Negative in all test systems Strongly irritating when tested neat (10 mg) on rabbit eye; no data at lower concentrations No indication of sensitization - TABLE V
Sample Assessment: Highest Concentrations Detected and Estimated Total Daily Doses
Leachablea Highest Concentration Detected x ppm Estimated Total Daily Exposure Following Topical Ocular Administration (Both Eyes Combined) ≤ y.yy μg/dayb,c ↵aRecord name of leachable or relative retention time if unidentified.
↵bGiven the administration instructions available for the product (i.e., instill 2 drops to both eyes daily; use actual drop size).
↵cppm = mg/L; leachable conc. (mg/L; μg/1000 μL) × drop size (μL/drop) × number drops/eye/day × 2 eyes = y.yy μg/day.
- TABLE VI
Example Tool to Aid in Assessment (Add or Delete Categories as Applicable). Complete for Each Leachable
NOAEL Safety Margin above Observed Leachable Concentrations (x ppm or x mg/kg)a Local Tolerance Genotoxicity/Carcinogenicity Sensitization Repeat for Leachable 2, if applicable.
NOAEL, no-observed-adverse-effect-level
↵a Calculated as the NOAEL obtained from studies or literature, divided by concentration of the leachable.
In This Issue
Jump to section
- Article
- Abstract
- Background
- Importance of Assessing Leachables in ODPs
- Current Regulatory Approaches
- Specific Considerations for Managing Leachables in ODPs
- Potential Sources and Common Classes of Leachables for ODPs
- False Negatives Observed during Extractable Testing of Secondary Packaging Components and Leachable Testing of Drug Products for Which Secondary Packaging Components Are Critical
- Experimental Design Considerations: Extraction/Simulation Studies for ODPs
- Experimental Design Considerations: Leachable Studies for ODPs
- Analytical Evaluation Threshold
- Summary of Analytical Challenges for Extractables and Leachables in ODPs
- Toxicological Considerations for Leachables in ODPs
- Safety Qualification for Leachables in ODPs
- Conclusion: Toxicological Considerations for Leachables in ODPs
- Case Study on the Safety Qualification of Leachables in an ODP
- General Sample Evaluation (with Examples of Assessment Tables)
- Conclusion: Case Study
- Conflict of Interest Declaration
- Acknowledgment
- Footnotes
- References
- Figures & Data
- References
- Info & Metrics
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