Impurity testing methods, method

Figure 9.8. HPLC chromatogram of a system suitability solution (SSS) tor a challenging impurity testing method for a drug product containing two APIs. This SSS contains both APIs and several key degradants and impurities at their expected concentrations (as retention time markers). One of the component DGA1 present at 0.10% level also serves as a sensitivity check and must meet the acceptance criterion of having S/N > 10.

Figure 10.15. Chromatograms illustrating gradient shift problems at 230 nm encountered during method development of an impurity test method for a drug substance (Section 8.8.2). The UV spectrum of 0.05% TFA vs. water is shown in the inset, showing considerable absorbance at...

TABLE 9.2 Impurity Testing Methods Used for Macromolecule Therapeutics... 

The pubHcations detailing standards (5—8) generally include both specifications and methods of analysis for the substances. The estabHshment of standards of quaHty for chemicals of any kind presupposes the abiHty to set numerical limits on physical properties, allowable impurities, and strength, and to provide the test methods by which conformity to the requirements may be demonstrated. Tests are considered appHcable only to the specific requirements for which they were written. Modification of a requirement, especially if the change is toward a higher level of purity, often necessitates revision of the test to ensure the test s vaHdity. 

The Standard-Setting Process. The committee has three main lines of endeavor the improvement of existing limits for impurities, the improvement of present test methods, and the development of specifications and testing methods for additional compounds. 

The ACS committee has a general rule if two producers meet a given specification, the specification is normally so defined. Usually the methods are checked by several laboratories using samples from various sources. Because of the many different matrices in which impurities are deterrnined, even the simplest impurity tests need to be checked for accuracy in the laboratory. 

Analytical and Test Methods. Measurement of the sohdification point using a highly sensitive thermometer and of APHA color by comparison of molten samples to APHA standards is straightforward. Specific impurities are measured by gas chromatography. A nonaqueous titration is used to determine phthahc acid content. 

Analytical and Test Methods. The acid number of terephthahc acid discussed above is a titration of a sample dissolved in pyridine, using a sodium or potassium hydroxide titrant. However, specifications on certain impurities are so strict that this test caimot, as a practical matter, be failed. Its use has been discontinued by some manufacturers. 

Apart from added stabilizers, commercial grades of trichloroethylene should not contain mote than the following amounts of impurities water 100 ppm acidity, ie, HCl, 5 ppm insoluble residue, 10 ppm. Free chlorine should not be detectable. Test methods have been estabUshed by ASTM to determine the following characteristics of trichloroethylene acid acceptance, acidity or alkalinity, color, corrosivity on metals, nonvolatile-matter content. 

The same is true if another situation is considered if in a batch process a sample is taken before and after the operation under scrutiny, say, impurity elimination by recrystallization, and both samples are subjected to the same test method, the results from, say, 10 batch processes can be analyzed pairwise. If the investigated operation has a strictly additive effect on the measured parameter, this will be seen in the t-test in all other cases both the difference Axmean and the standard deviation will be affected. 

For pharmacopeial materials scientific data are not normally required in the application provided that the method of production is such that uncontrolled impurities will not be present in the material. Otherwise the impurities concerned should be declared and appropriate specifications and test methods put forward. 

CNTs tested Production method and impurities content Cellular model Cytotoxic effect Ref. 

For non-compendial procedures, the performance parameters that should be determined in validation studies include specificity/selectivity, linearity, accuracy, precision (repeatability and intermediate precision), detection limit (DL), quantitation limit (QL), range, ruggedness, and robustness [6]. Other method validation information, such as the stability of analytical sample preparations, degradation/ stress studies, legible reproductions of representative instrumental output, identification and characterization of possible impurities, should be included [7], The parameters that are required to be validated depend on the type of analyses, so therefore different test methods require different validation schemes. 

The most common types of analyses are the identification test, the quantitative determination of active ingredients or major component, and the determination of impurities. The identification test provides data on the identity of the compound or compounds present in a sample. A negative result signifies that the concentration of the compound(s) in sample is below the DL of the analyte(s). The quantitative method for the major component provides data of the exact quantity of the major component (or active ingredients) in the sample, and a reported concentration of the major component must be higher than the QL. In a Determination of impurities test, one obtains data regarding the impurity profile of a sample, and can be divided into a limit test or quantitative reporting of impurities (see Table 1, which has been modified from Refs. [1] and [8]). 

Selection of a suitable analytical method can be made once the reason for carrying out the analysis is well understood. Analytical methods may be (a) qualitative or (b) quantitative or semi-quantitative. The former usually pose few problems if only an indication is required as to whether a particular analyte is present or not - certainly not how much with a value having a small uncertainty. If a negative result is required (i.e. confirmation of absence from the product), then one has only to worry about the limit of detection of the test used. Many tests to confirm the absence of impurities in pharmaceutical products fall into this category. Equally, rapid tests for positive confirmation are often made on unknown substances. These may subsequently be confirmed by other, quantitative tests. Quantitative methods are used in a variety of situations and a variety of different methods can be employed. What you must always remember is that the method used must be fit for the purpose. 

Analytical methods for determining traces of various other impurities, such as chlorides (ASTM D2384), are known to be in use. The presence of acetylenes in rehnery gases, although unlikely, must still be considered. Acetylenes can be determined using a chemical test method, while carbonyls are determined by the classical hydroxylamine hydrochloride reaction (ASTM D1089). 

Chloride-containing impurities are determined by various test methods (ASTM D5194, D5808, D6069) that have sensitivity to 1 mg/kg, reflecting the needs of industry to determine very low levels of these contaminants. 

ISO 580 1990 Injection-moulded unplasticized poly(vinyl chloride) (PVC-U) fittings -Oven test - Test method and basic specifications ISO 727-1 2002 Fittings made from unplasticized poly(vinyl chloride) (PVC-U), chlorinated poly (vinyl chloride) (PVC-C) or acrylonitrile/butadiene/styrene (ABS) with plain sockets for pipes under pressure - Part 1 Metric series ISO 727-2 2002 Fittings made from unplasticized poly(vinyl chloride) (PVC-U), chlorinated poly (vinyl chloride) (PVC-C) or acrylonitrile/butadiene/styrene (ABS) with plain sockets for pipes under pressure - Part 2 Inch-based series ISO 1163-1 1995 Plastics - Unplasticized poly(vinyl chloride) (PVC-U) moulding and extrusion materials - Part 1 Designation system and basis for specifications ISO 1163-2 1995 Plastics - Unplasticized poly(vinyl chloride) (PVC-U) moulding and extrusion materials - Part 2 Preparation of test specimens and determination of properties ISO 1265 1979 Plastics - Polyvinyl chloride resins - Determination of number of impurities and foreign particles... 

Sample preparation (SP) is generally not given adequate attention in discussions of pharmaceutical analysis even though its proper execution is of paramount importance in achieving fast and accurate quantification (see Chapter 5). Non-robust SP procedures, poor techniques, or incomplete extraction are the major causes of out-of-trend and out-of-specification results. The common SP techniques have been reviewed with a strong focus on tablets or capsules, as they are the primary products of the pharmaceutical industry. Detailed descriptions of SP methods for assays and impurity testing are provided with selected case studies of single- and multi-component products. 

Impurity testing is pivotal in pharmaceutical development for establishing drug safety and quality. In this chapter, an overview of impnrity evaluations of drug substances and products by HPLC is presented from both the laboratory and regulatory standpoints. Concepts from the development of impurity profiles to the final establishment of public specifications are described. Useful strategies in the identification and quantification of impurities and degradation products are summarized with practical examples to illustrate impurity method development. 

A PDA detector provides UV spectra of eluting peaks in addition to monitoring the absorbance of the HPLC eluent like the UVA is absorbance detector. It is the preferred detector for testing impurities and for method development. PDA facilitates peak identification during methods development and peak purity evaluation during method validation. Detector sensitivity was an issue in earlier models but has improved significantly (more than ten-fold) in recent years. ... 

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