Pediatric Mini-Tablets: Predicting the Hidden Risk of Fill Errors

Abstract

Compressed mini-tablets in sachets or capsules are an increasingly prevalent oral solid dosage form for pediatric products. While resembling adult tablets, additional care is required to control weight and potency (blend uniformity) variation due to their small size (≤2.5 mm average diameter). Additionally, sachet fill count errors complicate dose accuracy as they are difficult to resolve with weight-checking equipment. This study quantified the probability of failing content uniformity (CU) specifications (which results in the inability to release a batch) defined in USP <905> using a Monte Carlo computational model. Failure risk was modeled as a function of sachet fill count, mini-tablet weight, potency distribution, and fill error frequency. The model allows product developers to (1) determine appropriate fill counts based on anticipated product weight and potency relative standard deviation (RSD), (2) set fill error probability tolerances for sachet filling processes, (3) identify CU improvement opportunities, and (4) quantify the probability of CU failure informing risk management activities and risk disclosure for regulatory agencies. A representative product with weight and potency RSD no greater than 5%, fill count of 1-4 mini-tablets per sachet, and fill error probability per mini-tablet filled of 0.1% may experience CU batch failure probabilities as high as 8.23%, but only 0.283% if the fill count is increased to 5-10 mini-tablets per sachet. Generally, fill counts of less than five mini-tablets per sachet should be avoided where possible.

Keywords: content uniformity; dose uniformity; fill count; fill errors; mini-tablet; sachet.

Figure 3

The probability of failing CU requirements was found to be qualitatively proportional to the root sum of squares of bulk mini-tablet weight RSD and potency RSD (Equation (1)). The composite RSD (bold solid line) is overlaid on the simulated probability of stage 2 failure with a fill count equal to 1 and a fill count probability equal to 0%. A similar trend is observed for other fill counts as well (Figure 4).

Figure 4

Probability of stage 1 and stage 2 content uniformity batch failure and acceptance values for 0% fill error probability represented as a function of modeled bulk mini-tablet weight RSD (vertical axes), bulk mini-tablet potency RSD (horizontal axes), and sachet fill count (rows). Tabulated values may be found in Supplementary Materials Section S2.1.

Figure 1

Oral granules comprise a compressed oral solid dosage form 1.0–2.5 mm in diameter and offer a quasi-flexible dosing solution for pediatric populations by varying fill count per dosage unit. (A) schematic illustration of mini-tablet features and (B) image of a vial filled with mini-tablets 2 mm in diameter (therefore qualifying as oral granules and treated as such for content uniformity evaluation).

Figure 2

Simplified representation of USP <905> model decision matrix for CU assessment. In the Stage 1 assessment, the contents of 10 individual sachets are assayed to calculate an acceptance value (AV). If the AV is less than 15%, the batch passes CU testing. However, if the AV is greater than or equal to 15%, Stage 2 testing is required. In Stage 2 testing, the contents of additional 20 sachets are assayed, and data are aggregated with the initial ten sachets from stage 1. As in stage 1, an AV is calculated and compared to the 15% threshold. If AV is greater than 15% in Stage 2, the batch fails CU testing. If it passes, an additional criterion is required for the contents of individual sachets. Here, the contents of each sachet must be within plus/minus 25% of the target label claim. Failure to meet this criterion results in batch failure, and success results in batch passage of CU criteria. * Note, this criterion represents the case where the mean %LC is 98.5–101.5% of the target. It varies slightly if the mean %LC is outside this range and may be as low as 73.875–123.125% and as high as 76.125–126.875%.

Figure 5

The probability of stage 1 and stage 2 content uniformity batch failure and acceptance values (AV) modeled as a function of sachet fill count (horizontal axes), composite RSD of bulk mini-tablets (vertical axes), and fill error probability per mini-tablet filled (rows). Tabulated values may be found in Supplementary Materials Section S2.2.

Figure 6

The probability of stage 1 and stage 2 content uniformity batch failure and acceptance values (AV) are modeled as a function of sachet fill count (horizontal axes), fill error probability per mini-tablet filled (vertical axes), and composite RSD (rows). Tabulated values may be found in Supplementary Materials Section S2.3.

Figure 7

Probability of stage 1 or stage 2 CU failure for an example product having 2% composite RSD and 1% fill error probability, illustrating sharp probability transitions (arrows) occurring between sachet fill counts of 4 to 5 mini-tablets and 8 to 9 mini-tablets. Note these data are the same as in Figure 5 and Figure 6 but represented in two dimensions for ease of visualization.