Contents 3 Specific tests

In current industrial practice gas chromatographic analysis (glc) is used for quahty control. The impurities, mainly a small amount of water (by Kad-Fischer) and some organic trace constituents (by glc), are deterrnined quantitatively, and the balance to 100% is taken as the acetone content. Compliance to specified ranges of individual impurities can also be assured by this analysis. The gas chromatographic method is accurately correlated to any other tests specified for the assay of acetone in the product. Contract specification tests are performed on product to be shipped. Typical wet methods for the deterrnination of acetone are acidimetry (49), titration of the Hberated hydrochloric acid after treating the acetone with hydroxylamine hydrochloride and iodimetry (50), titrating the excess of iodine after treating the acetone with iodine and base (iodoform reaction). 

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 matter may be illustrated by the example of qualitative analysis. As a result of a specific test, it is stated that a constituent searched for is present in the test sample (x+) or not (x ) depending on whether a specific signal is detected (z+) or not (z ) as represented in Fig. 9.1. In Table 9.1 the different types of information contents are compiled, each for various a priori probabilities. 

Blood, stomach content, tissues Miscellaneous compounds Group tests, specific tests, particular methods Ion-exchange columns, formation of ion-pairs, SPE, LLE, continuous extraction GC-MS LC-MS... 

Part—I has three chapters that exclusively deal with General Aspects of pharmaceutical analysis. Chapter 1 focuses on the pharmaceutical chemicals and their respective purity and management. Critical information with regard to description of the finished product, sampling procedures, bioavailability, identification tests, physical constants and miscellaneous characteristics, such as ash values, loss on drying, clarity and color of solution, specific tests, limit tests of metallic and non-metallic impurities, limits of moisture content, volatile and non-volatile matter and lastly residue on ignition have also been dealt with. Each section provides adequate procedural details supported by ample typical examples from the Official Compendia. Chapter 2 embraces the theory and technique of quantitative analysis with specific emphasis on volumetric analysis, volumetric apparatus, their specifications, standardization and utility. It also includes biomedical analytical chemistry, colorimetric assays, theory and assay of biochemicals, such as urea, bilirubin, cholesterol and enzymatic assays, such as alkaline phosphatase, lactate dehydrogenase, salient features of radioimmunoassay and automated methods of chemical analysis. Chapter 3 provides special emphasis on errors in pharmaceutical analysis and their statistical validation. The first aspect is related to errors in pharmaceutical analysis and embodies classification of errors, accuracy, precision and makes... 

Several in vitro tests are currently employed to assure drug product quality. These include purity, potency, assay, content uniformity, and dissolution specifications. For a pharmaceutical product to be consistently effective, it must meet all of its quality test criteria. When used as a QC test, the in vitro dissolution test provides information for marketing authorization. The dissolution test forms the basis for setting specifications (test, methodology, acceptance criteria) to allow batch release into the market place. Dissolution tests also provides a useful check on a number of physical characteristics, including particle size distribution, crystal form, etc., which may be influenced by the manufacturing procedure. In vitro dissolution tests and QC specifications should be based on the in vitro performance of the test batches used in in vivo studies or on suitable compendial specifications. For conventional-release products, a single-point dissolution... 

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. 

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. 

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. 

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. 

Thirteen specimens of 90/10 Cu-Ni alloys, each with a specific iron content, were tested in a corrosion-wheel setup. The wheel was rotated in salt sea water at 30 ft/sec for 60 days. The corrosion was measured in weight loss in milligrams/square decimeter/day, MDD. The following data were collected ... 

The preceding pages cover the dehydration tank shown in Fig. 4.9 in considerable detail. Again note Fig. 4.11, showing the oil-phase residence time in this dehydration tank required to make a 1% or less by volume treated-oil water content specification. You should normally allow 16 h or more residence time for the oil to dehydrate. Again, the point is stressed to make laboratory tests to confirm the residence time required here. Unfortunately, however, our lab tests of the day are indeed approximate and in many cases fail to reveal reliable data. It is therefore prudent to run actual field operating tests, proving without... 

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. 

Note to Test Takers Keep this practice book until you receive your score report. The book contains important information about content specifications and scoring. 

The content and scope of each test are specified and reviewed periodically by the committee of examiners. Test questions are written by the committee and by other faculty who are also subject-matter specialists and by subject-matter specialists at ETS. All questions proposed for the test are reviewed by the committee and revised as necessary. The accepted questions are assembled into a test in accordance with the content specifications developed by the committee to ensure adequate coverage of the various aspects of the field and, at the same time, to prevent overemphasis on any single topic. The entire test is then reviewed and approved by the committee. 

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