Content uniformity test

VALIDATED HPTLC DETERMINATION AND CONTENT UNIFORMITY TEST FOR ALPRAZOLAM AND MELATONINE IN TABLET DOSAGE FORM... 

Such yes/no decisions are of great importance in foodstuffs control and environmental analysis. They also play an important role in pharmacy in the form of content uniformity tests. Without suitable screening methods for rapid detection of positive samples it would scarcely be possible to carry out economic doping controls and toxicological investigations or to recognize medicament abuse. 

Since the 1993 court decision against Barr Laboratories, 5 tjjg elimination of outliers has taken on a decidedly legal aspect in the U.S. (any non-U.S. company that wishes to export pharmaceuticals or preciwsor products to the U.S. market must adhere to this decision concerning out-of-specifica-tion results, too) the relevant section states that ... An alternative means to invalidate an individual OOS result... is the (outlier test). The court placed specific restrictions on the use of this test. (1) Firms cannot frequently reject results on this basis, (2) The USP standards govern its use in specific areas, (3) The test cannot be used for chemical testing results. ... A footnote explicitly refers only to a content uniformity test, 5 but it appears that the rule must be similarly interpreted for all other forms of inherently precise physicochemical methods. For a possible interpretation, see Section 4.24. 

The number of samples to be processed for every batch produced six samples of 13 tablets each are taken at prescribed times after starting the tablet press (10 tablets are ground and well mixed (= compound sample), two average aliquots are taken, and each is extracted) the additional three tablets are used for content uniformity testing this gives a total of 6 (2 -t- 3) = 30 determinations that have to be performed. 

Example 61 The raw data, given as %-of-nominal values with one decimal place, are found in Table 4.37 For each group of 10 values the mean and the standard deviation were calculated. Using these, the t-values for the differences L - mean, with L = 75, 85, 115, resp. 125% were determined they are all above 2.9, indicating low risk. The corresponding CP-values were calculated the differences ACP75-85 and ACP 15-125 were added and multiplied by 100 to obtain the approximate risk, in %, of finding a result between the inner and the outer limits. For a content uniformity test with n = 10 tablets, a risk of 0.003872% translates into a deviant result once every 20-25 trials, or, with six CU runs per batch, every third or fourth batch. 

Sandell, D., Diener, M., Vukovinsky, K., Hofer, J., and Pazdan, J. (2006), Development of a content uniformity test suitable for large sample sizes, Drug. Info. J., 40, 337. 

The information in this chapter applies specifically to the first element sample preparation. The sample preparation steps are usually the most tedious and labor-intensive part of an analysis. By automating the sample preparation, a significant improvement in efficiency can be achieved. It is important to make sure that (1) suitable instrument qualification has been concluded successfully before initiation of automated sample preparation validation [2], (2) the operational reliability of the automated workstation is acceptable, (3) the analyte measurement procedure has been optimized (e.g., LC run conditions), and (4) appropriate training in use of the instrument has been provided to the operator(s). The equipment used to perform automated sample preparation can be purchased as off-the-shelf units that are precustomized, or it can be built by the laboratory in conjunction with a vendor (custom-designed system). Off-the-shelf workstations for fully automated dissolution testing, automated assay, and content uniformity testing are available from a variety of suppliers, such as Zymark (www.zymark.com) and Sotax (www.sotax.com). These workstations are very well represented in the pharmaceutical industry and are all based on the same functional requirements and basic principles. 

Content Uniformity Content uniformity testing of the proposed product lot should be performed as described in USP 23. 

Individual assay results from content uniformity testing... 

Content uniformity testing is not a requirement for drug substance Bl, hence no information is available about the weight of the active ingredient in individual dosage units. With so much emphasis today on demonstrating adequate control over this variable, a one-time study run concurrently with the next production should be considered. Kieffer and Torbeck suggest two statistical... 

Table 1 USP 25 Content Uniformity Test Requirements for Tablets...

Figure 1 95% contour plots for probability of passing USP 25 content uniformity test... 

By setting the future sample size m to 10, which is the stage-1 sample size for the USP 25 content uniformity test, and by requiring that the upper bound on the standard deviation of a future sample of size 10 be less than 6.0%, which is the USP 25 stage-1 RSD requirement, the SDPI approach can be tied to the USP 25 content uniformity test. The SDPI equation in Sec. II can be rearranged to obtain the following equation ... 

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. 

Simulation. One approach is to assume the sample mean and standard deviation are the true population mean and standard deviation, to provide a best estimate of the true probability of passing. This has the advantage that it can provide estimates of the probability of passing at any stage and can handle the nonsymmetric potency shelf life limits in the content uniformity test. The disadvantage is that it does not provide a bound on the probability with high assurance and is not a function of sample size. It can provide a good summary statistic of the content uniformity data, however. 

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. 

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. 

After tablet compression, content uniformity testing is recommended for each active ingredient, taken from at least three samples of the batch. If coating is included as a process step, the coated tablet would then be tested according to the normal product release testing. In effect, uniformity would not be an issue for the coated core, but it would be important to know that the final product meets its specifications. 

The construction of the electrode is simple, fast and reproducible. The electrode proved to be useful for the determination of the enan-tiopurity of S-captopril—raw material as well as for the content uniformity test of Novocaptopril tablets, by direct potentiometric method. The reliability of the analytical information is assured by the RSD values obtained in the uniformity content test. 

P. Walsh, H. Abdou, R. Barnes, and B. Cohen, Laboratory robotics for tablet content uniformity testing. In Advances in Laboratory Automation Robotics 1985 (J. R. Srimaitis and G. L. Hawk, eds.), Zymark Corp., Hopkinton, MA, 1985, p. 547. 

Another method for estimating the effect of particle size on content uniformity has been described by Yalkowsky and Bolton2 and more recently updated by Rohrs et al.4 The Yalkowsky and Bolton approach attempts to establish a particle size specification that would lead to a 99% chance of passing the USP Content Uniformity test. In this section, a comparison of their approach vs the ideal mixing model1 will be made. 

Panderi and Parissi-Poulou developed a microbore liquid chromatographic method for the simultaneous determination of benazepril hydrochloride and hydrochlorothiazide in pharmaceutical dosage forms [30]. The use of a BDS C-18 microbore analytical column was found to result in substantial reduction in solvent consumption and in increased sensitivity. The mobile phase consisted of a mixture of 25 mM sodium dihydrogen phosphate buffer (pH 4.8) and acetonitrile (11 9 v/v), pumped at a flow rate of 0.4 mL/min. Detection was effected at 250 nm using an ultraviolet absorbance detector. The intra- and inter-day relative standard deviation values were less than 1.25% (n = 5), while the relative percentage error was less than 0.9% (n = 5). The detection limits obtained according to the IUPAC definition were 0.88 and 0.58 pg/mL for benazepril hydrochloride and hydrochlorothiazide, respectively. The method was applied to the quality control of commercial tablets and content uniformity test, and proved to be suitable for rapid and reliable analysis. 

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