(M0930-08-53) Troubleshooting a Dose Proportional Tablet Formulation

Purpose: The strength of a product indicates the amount of drug(s) in a given dosage form. A new strength of a product may be required based on clinical and commercial data revealing the therapeutic needs of certain underserved populations or new indications. Different approaches can be pursued to achieve this goal. The same formulation and process can be used as a base, and the new strength is achieved through dose proportionality. Otherwise, it is necessary to develop new formulation and/or processes. This work will discuss the successful development of a lower strength of an existing commercial product following a dose proportional approach to consistently delivering the intended performance and quality of the product.

Methods: A 2 mg formulation was developed using a proportional dosing approach based on the previously validated and successfully commercialized 6 mg formula. The formulation of both product strengths is shown in Table 1. Initially, the same concentration of each material was maintained while adjusting their weight per unit to one third of the 6 mg to yield a unit weight of 50 mg/tablet for the 2 mg strength. The equipment train used as well as the manufacturing process flow are listed in Figure 1. Process parameters during the development of the 2 mg strength were adjusted as needed to ensure a well-controlled process and product quality. The final blend was analyzed for bulk and tapped density, particle size, and Blend Uniformity to assess product characteristics and quality. The target hardness value and limits were determined by calculating similar tensile strengths to those of the 6 mg tablets. Tablets were compressed on a rotary press within the hardness specification of 3.5 kp (2.0 kp - 5.0 kp) to evaluate tablet characteristics and determine optimum compression conditions.

Results: The first experimental batch was compressed using a small R&D rotary press equipped with a gravity feeder, without any problems. However, very limited compressibility of only 2.7 kp tablet hardness was reported once an engineering batch was compressed in a medium-sized GMP press equipped with a forced feeder. This batch was manufactured using the same formulation and process as the first experimental batch. The compression process was troubleshooted, but the problem could not be resolved. A successful attempt was made to compress the final blend in the small R&D press to evaluate whether the equipment was the root cause of the problem. Later, a feeder overload related to packing of the blend in the feeder was identified after continuing with the troubleshooting of the GMP press. The press was also tested with pure microcrystalline cellulose (MCC), since the product formula contains approximately 75% MCC, without any issues. It was concluded that the blend was packed and overlubricated at the feeder because of its continuous mixing action along with an extended residence time due to the small size of the tablet. This over lubrication problem is not observed in the 6 mg product, as it is three times heavier, reducing the residence time of the blend in the feeder. In addition, the engineering batch Blend Uniformity results from the samples collected after discharge the blend into drums did not meet the specification. Refer to Table 2. To mitigate these issues, the concentration of magnesium stearate was reduced to 0.21 mg per tablet (0.42 % w/w) to be within SUPAC Level 1 guidelines, while the concentration of Microcrystalline Cellulose was increased accordingly to maintain the same tablet weight. Moreover, all raw materials and the active ingredient were sifted through a #40 mesh, while the primary blending time was increased to 360 revolutions. The lubrication was maintained unchanged at 100 revolutions. These changes ensured a more effective dispersion of the materials and homogeneity of the final blend. An experimental batch was manufactured using the reduced concentration of magnesium stearate and the enhanced blending process, achieving adequate Blend Uniformity results. The tablets were successfully compressed in the medium size GMP press to low, target, and high hardness and at various turret speeds ranging from 20 - 80 RPM.  The press feeder speed was maintained at the minimum setting of 10 RPM while the turret was set to the highest possible speed during the compression process to minimize the potential of over-lubrication at the feeder.

Conclusion: A dose of 4 mg lower than an existing commercial product was successfully developed by adjusting the initial formulation and the process steps based on the evaluated physical and analytical data. The non-uniformity of the blend and the limited compressibility of the tablets due to over-lubrication were overcome by strategically reducing the lubricant concentration, improving the dispersion of the raw materials, and using a combination of high turret and the slowest feeder speeds. The evaluation of the data from an engineering batch confirmed the adequacy of the formulation as well as the process to advance towards registration and validation batches.

Table 1. Product formula

Figure 1: Manufacturing process flow

Table 2: Blend uniformity results