Capsules content uniformity

To use the acceptance limits proposed by CuDAL, an acceptance limit table is generated to give the upper bound on the sample RSD for various values of the sample mean. For this example, the table was constructed for capsule content uniformity using a 90% confidence level with a lower bound (LBOUND) of 95%. A portion of the acceptance limit table is as follows ... 

The CuDAL acceptance limit table for capsule content uniformity and dissolution are as follows. 

To use the tolerance interval approach, the Satterthwaite approximate degrees of freedom (d.f.) is 21.48. The 90% tolerance interval to capture 90% of the individual capsule content uniformity results is 97.50 +/- 2.112(4.356) = (88.30, 106.70). The tolerance factor was determined using linear interpolation. This would meet the criterion, since the interval is completely contained within the interval 85-115%. As mentioned in Sec. III.A, if the coverage level associated with tablets (96.7%) was used instead of the coverage level associated with capsules (90.0%), the tolerance factor would be 2.731 and the tolerance interval would be (85.60, 109.40). This would just barely meet the acceptance criterion. 

R. W. Roller, Intact Capsule Content Uniformity Feasability by NIR Solid Dose, Proc. PittCon, New Orleans, March, 2000. 

Roller, R. W. Intact capsule content uniformity feasibility by NIR solid dose. In Pittsburgh Conference of Analytical Chemistry and Applied Spectroscopy, March 2000, New Orleans, LA. 

Capsules content, uniformity of weight, content uniformity, appearance, disintegration time, dissolution rate. 

The two main online applications of hyperspectral imaging are blending endpoint determination (Figure 19) and capsule control (Figure 20). Other applications may be possible, such as content uniformity, determination of dissolution properties, and water quantification, but are not described in this chapter. 

Two of the most common tests for finished product that have acceptance criteria are content uniformity and dissolution. The United States Pharmacopeia (USP 25) requirements for content uniformity for both tablets and capsules as well as for dissolution are summarized in Tables 1-3. 

Table 2 USP 25 Content Uniformity Test Requirements for Capsules... 

CuDAL Approach. The CuDAL approach is specifically written for tablets or capsules. This approach is recommended in the PDA paper [1] for final product testing. For content uniformity, when the potency limits are not symmetrical about 100% of label claim, the USP 25 content uniformity test allows the individual results to be expressed as either a percentage of the label claim, the found mean, or the average of the upper and lower potency specifications, depending on the value of the sample mean. Acceptance limits have not been constructed for the more complicated situation in which the potency shelf life limits are not symmetric about 100%. One approach to this problem is to evaluate the content uniformity results twice. First express the sample mean as a percentage of label claim and then express the mean as a percentage of the average of the potency specifications. To pass the acceptance limits, both means must meet the acceptance criteria. To use the dissolution acceptance limit tables, the value of Q is required. 

For the tolerance interval approach, a 90% coverage is used, since capsules are being evaluated. (See Sec. III.A.) The 90% two-sided tolerance interval to capture 90% of the individual content uniformity results is 97.76 2.406 = (91.41, 104.11). Since the interval is completely contained within the 85-115% range, the criterion is met. 

The sample mean for this example is 97.76%, so the upper limit for the sample RSD is 3.68%. It is recommended that the means always be rounded to the more restrictive RSD limit so that the assurance level and lower bound specifications are still met, so in this case 97.76% is rounded to 97.7%. Therefore, since the sample RSD of 2.70% is less than the critical RSD of 3.68, the acceptance criterion is met. This means that with 90% assurance, at least 95% of samples taken from the blender would pass the USP 25 content uniformity test for capsules. As mentioned in Sec. III.A., if the USP 25 tablet criterion were evaluated instead of the capsule criterion, the upper limit for the sample RSD would be 2.98% and would also pass. 

Assume that during encapsulation a sample was taken at each of 30 locations throughout the batch. One capsule from each location was tested for content uniformity and one for dissolution, with the following results. 

A 90% tolerance interval to capture 90% of the individual content uniformity results using the Satterthwaite approximation of 21.56 d.f. is 98.20+/-2.111(2.407) = (93.12, 103.28). The tolerance interval indicates that the capsules have good content uniformity. 

Notice that in example 2, the blend failed content uniformity but the capsules passed. The approach given in the PDA paper [1] applies an analysis by synthesis as follows ... 

As part of the international harmonization of test methods, a proposed change to the USP <905> content uniformity test has been made [12]. This test is more restrictive than the current USP test, especially as the batch mean deviates from target. It is also more restrictive for capsules, since both the tablets and capsules are required to meet the same requirements. A number of USP Pharmacopeial Forum articles have been written by the Pharmaceutical Manufacturers Association (PhRMA) statistics expert team discussing the proposal and their characteristics. An approved version of the proposal is eventually expected. In anticipation of this happening, appropriate modifications to the CuDAL approach have been determined to evaluate the newly proposed test. 

The DPP technique working at pH 4.5 for peak I was selected, which exhibited adequate repeatability, reproducibility, and selectivity. The recovery was 99.97 1.5% and the detection and quantitation limits were 5.13 x 10 7 and 1.11 x 10 6 M, respectively. The method was applied successfully to the individual assay of capsules to verify the content uniformity of zaleplon. 

Rohrs BR, Amidon GE, Meury RH, Secreast PJ, King HM, Skoug CJ. 2006. Particle size limits to meet USP content uniformity criteria for tablets and capsules. J. Pharm. Sci. 95(5) 1049-1059. 

---