Content-uniformity

Example 48 The result is thus CL(/4) = 7.390 0.028 mM/g, and should be either left as given or rounded to one significant digit in C1 7.39 0.03 The %-variance contributions are given in parentheses (Eq. (4.24)). Note that the analytical method with the best precision (titrimetry), because of the particular numerical constellation, here gives rise to the largest contribution (77%). 

Introduction In order to assure constant tablet quality, the following requirements apply  

Note on GMPs The assays are conducted on individual dosage units (here tablets) and not on composite samples. The CU test serves to limit the variability from one dosage unit to the next (the Dissolution Rate test is the other test that is commonly used). Under this premise, outlier tests would be scientific nonsense, because precisely these outliers contain information on the width of the distribution that one is looking for. The U.S. vs. Barr Laboratories Decision makes it illegal to apply outlier tests in connection with CU and DR tests. This does not mean that the distribution and seemingly or truly atypical results should not be carefully investigated in order to improve the production process. 

Example 49 A tablet weighing 340 mg, of which 50 mg are drug, is to be produced. It is known that the Content and Weight Uniformities, expressed as SDs, are 2.25 mg, respectively 6.15 mg. Since the weighing operation is very accurate and has an excellent repeatability in the 300 mg range (typically LSD = 0.05 mg or 0.005 mg, that is a resolution of 1 6000 or even 1 60000), the variability of the tablet weight must be wholly due to processing. The HPLC analysis is found to be fairly precise ( 0.5% or 1.7 mg, double determination). 

Question How much may the mean content and weight deviate from the nominal values and still comply with the requirements Two approaches will 

The assay is conducted on 10 randomly pulled tablets. Nine out of the ten assay results must be within 85-115% of the mean, and none may be outside the 75-125% range. (See Section (905) of the USP. ) The mean content must be within the window given shortly. 

The coefficient of variation must be 6% or less. This figure includes both the sampling and the analytical variance. 

---

Manufacturing, analytical, and quaUty control procedures are thus estabhshed. Specifications for taw and in-process materials, as well as for final products per USP/NF and in-house standards are also determined. Process and formula vaUdation assures that each technological procedure in manufacture accomplishes its purpose most efficiently, eg, blending times for powdered mixtures in tableting, and that each formula ingredient is present in optimal concentrations (12). Thus, it serves to ensure process control (qv), reproducibiUty, and content uniformity. 

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. 

Subcase b2 This case, called the paired f-test , is often done when two test procedures, such as methods A and B, are applied to the same samples, for instance when validating a proposed procedure with respect to the accepted one. In practicular, an official content uniformity" 5 assay might prescribe a photometric measurement (extract the active principle from a tablet... 

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. 

Initial Situation An experimental granulation technique is to be evaluated a sample of tablets of the hrst trial run is sent to the analytical laboratory for the standard batch analysis prescribed for this kind of product, including content uniformity (homogeneity of the drug substance on a tablet-to-tablet basis, see USP Section (905)" ), tablet dissolution, friability (abrassion resistance), hardness, and weight. The last two tests require little time and were therefore done first. (Note Hardness data is either given in [kg-force] or [N], with 1 kg = 9.81 Newton). 

Simulation Approach The numerical simulations were carried out using program SIMGAUSS, see data file TABLET C.dat for content uniformity, respectively TABLET W.dat for weight uniformity. The mean weights and contents were varied over a range covering the nominal values. 

Table 4.34. Content Uniformity of Dosage Form Resnits After Elimination of Three Outliers Are in Italics...

X) duplicate measurements in same 0.2% class, single results in (U) Content Uniformity or (R) lOx Repeatability test ( ) out-of-specification measasurement,... 

Content Uniformity Ten tablets per formulation are worked up one by one and aliquots of the so obtained solutions are injected. 

Example 60 If compound samples that were actually composed of five individual tablets had been analyzed instead of the spiked matrix, the CV would be expected to be larger than 0.5% on account of the additional manufacturing error, but by a factor Vs = 2.2 lower than the content uniformity CV. (Cf. Eq. (1.5).) Since the average CV for CU was found to be -1.76% ( 1.97, 1.28, resp. 1.95%), this would have to be in the region of about 1.76/2.2 = 0.8, which is still well within the range of accepted instrumental noise. 

The content uniformity is within the accepted range (1.93% is less than 6% CV maximum one out of ten values is outside the 85-115% range, but within the 75-125% range no value below 75 or above 125% of label claim. 

Content uniformity Nine out of 10 randomly picked and individually analyzed tablets must yield drug contents between 85 and 115% of label claim all 10 results must be within 75-125% of label claim. 

Figure 4.40. Content uniformity samples (10 each) taken from the beginning, middle, and end of a production run and each assayed for the compounds A and B. The results were sorted according to size both the slopes and the averages are very similar and well within the allowed range.

The content uniformity results for compounds A and B are shown in Fig. 4.40 the three data sets from the beginning, middle, and end of the manufacturing run were individually ordered by size and plotted. The results are as follows (use program MULTI and data file CU Assayl.dat see Tables 4.37 and 4.38) ... 

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. 

Table 4.37. Content Uniformity of Tablets and Determination of Risk of Noncompliance... 

Figure 4.49. Assay and content uniformity (CU) results for six batches of a tablet containing two drugs. One assay result falls completely out of line while there is general loss of component B during manufacturing.

The content uniformity values are even further reduced relative to the assays, which is probably due to the sample work-up with very small amounts of drug. 

Figure 4.52. Coefficients of variation that reflect both tablet to tablet and analytical variability. For formulation B, particularly strengths 2 and 3, the drop in CV with higher cumulative release (a - b) is marked, cf. Fig, 4.50. When the dissolution rate is high, individual differences dominate, while towards the end analytical uncertainty is all that remains. The very low CVs obtained with strength 3 of formulation A ( 0.7-0.8%, data offset by +10% for clarity) are indicative of the analytical uncertainty. Because content uniformity is harder to achieve the lower the drug-to-excipient ratio, this pattern is not unexpected.

TABLET C.dat Section 4.18 Simulated drug content uniformity measurements 10 different means, starting from 46 mg, with two samples of 10 tablets each at every weight. N = 10, M = 20. To be used with HUBER, HISTO, but also CORREL to test for spurious correlations in table of random numbers and with MSD to test for conformance with limits. 

In general, vapor pressures are not all that important in preformulation, but it should always be kept in mind that a substance may have sufficiently high vapor pressure to (a) become lost to a sufficient extent to cause apparent stability problems and content uniformity problems and (b) exhibit a potential for interaction with other compounds and adsorption onto or sorption into package components [27],... 

Content uniformity and long-term stability of a pharmaceutical product are required for a consistent and accurate dosing. Aggregation of dispersed particles and resulting instabilities such as flocculation, sedimentation (in suspensions), or creaming and coalescence (in emulsions) often represent major problems in formulating pharmaceutical disperse systems. 

Iyer et al. [50] investigated the effects of roto-granulation on the performance of hydroxypropyl methylcellulose (HPMC), gelatin, and poly(-vinylpyrrolidone) (Povidone, PVP). In this process, all three binders produced similar results. However, HPMC was preferred due to prolonged drug release profiles, smaller particle size, and better content uniformity. 

The dose uniformity of tablets can be determined by two different general approaches the weight variation between a specified number of tablets or the extent of drug content uniformity. The USP permits the latter approach in all cases. Moreover, drug content uniformity must be measured for coated tablets because... 

Content uniformity is a USP test is designed to establish the homogeneity of a batch. Ten tablets are assayed individually after which the arithmetic mean and relative standard deviation (RSD) are calculated. USP criteria are met if the content uniformity lies within 85-115% of the label claim and the RSD is not greater than 6%. Provision is included in the compendium for additional testing if one or more units fail to meet the standards. 

In-process controls, such as the checking of weights and disintegration or dissolution of tablets, satisfactory mixing, appropriate suspension preparation, or clarity of solutions must be conducted to ensure appropriate product content uniformity and performance... 

The physical characteristics should be considered (in combination as appropriate) in relation to the proposed dosage form and route of administration. Factors to be considered extend to solubility characteristics, crystal form and properties, moisture or solvent content, particle size and size distribution (which may affect bioavailability, content uniformity, suspension properties, stability, and preclinical or clinical acceptability), polymorphism, etc. 

Details of the specific types of apparatus need not normally be given except for nonstandard processes. A flow chart of the manufacturing operation and the in-process controls (and acceptance limits) is required. Proposals for alternative processes will need to be supported by appropriate data to show that the finished products resulting from these are consistent with the finished product specification. Certain manufacturing operations such as mixing may require additional information on quality parameters monitored during production and prior to batch release. Appropriate quality parameters should be included in the finished product specification regardless of the outcome of validation studies (e.g., content uniformity for solid and semi-solid products). 

---