Purpose: To ensure quality and equivalence determination, it is imperative that drug products deliver a controlled amount of drug (per dose) that is consistent with the labeled strength between batches as well as throughout its lifespan and usage. This evaluation is more challenging for complex multi-dose products, such as ophthalmic suspensions, as drug concentration should be consistent throughout the expected patient use of the product (e.g., beginning (Zone 1), middle (Zone 2) and end (Zone 3) use) (Figure 1A). Consistent dosing is compromised by caking, flocculation, or poor redispersibility of the drug product suspension, all of which may not be fully captured by particle size measurements and/or other stability tests. Herein, we demonstrate methods to assess the dose concentration of a representative ophthalmic suspension product to ensure dose content uniformity across its usage lifespan.
Methods: For comparison of consistent drug concentration across the representative usage zones, 50 µL of 15% sodium dodecyl sulfate (SDS) salt was added to Bausch & Lomb Tobramycin Dexamethasone Ophthalmic Suspension to flocculate the formulation. The drug concentration of the original and flocculated ophthalmic suspensions was determined by drop to drop comparison from the three usage zones (Zone 1, Zone 2, Zone 3) of a 5mL bottle (Figure 1A). For each zone, the bottle was shaken to ensure homogeneous distribution and then ten individual drops (doses) were collected. The concentration of dexamethasone (DEX) per drop mass was analyzed using high performance liquid chromatography. Differences in the dose content uniformity of the original and flocculated suspensions were then statically compared using the population bioequivalence (PBE)procedure.
Results: Figure 1B showed the morphology of the original sample and Figure 1C showed the flocculated sample, as caused by addition of SDS. A recovery yielding approximately 100% of the dose concentration of DEX in the original Bausch & Lomb Tobramycin Dexamethasone Ophthalmic Suspension (1 mg/mL of DEX) was consistent in each zone. The average concentration of ten measurements were: 1.012 ± 0.018 mg/mL (Zone 1); 1.015 ± 0.015 mg/mL (Zone 2); and 1.002 ± 0.013 mg/mL (Zone 3) (Figure 2).
In contrast, the dose concentration of DEX in the bottle flocculated with SDS was 0.842 ± 0.051 mg/mL (Zone 1F, 84% recovery); 0.825 ± 0.040 mg/mL (Zone 2F, 82.5% recovery); and 0.314 ± 0.017 mg/mL (Zone 3F, 31.4% recovery) (Figure 2). In addition to the DEX concentration in the flocculated bottle being lower than the original bottle it also decreased to less than 1/3 the labeled concentration by Zone 3.
The PBE test using 95% upper confidence bound confirmed the dose concentration delivered in the original bottle and the flocculated bottle were not equivalent.
Conclusion: Our findings demonstrated that the dose content uniformity concentration test sampled from the representative beginning, middle, and end use of a multi-dose ophthalmic suspension product is a potential sensitive measure that can be used to ensure drug product quality and equivalence.
Soumyarwit Manna– ORISE Fellow, US Food and Drug Administration, Silver Spring, Maryland
Peter Petrochenko– Senior Staff Fellow, US Food and Drug Administration
Yong Wu– ORISE Fellow, US Food and Drug Administration
Bin Qin– Staff Fellow, United States Food and Drug Administration
Darby Kozak– Chemist (Lead), Untied States Food and Drug Administration, White Oak, Maryland
Jiwen Zheng– Chemist, US Food and Drug Administration