Process impurities

These include inorganic impurities, organic impurities, and residual solvents. 

Residual solvents are considered a subset of organic impurities. Solvents used to create a solution or suspension during the manufacturing process may not be completely eliminated in the course of manufacture. Solvents used later in the synthesis are more likely to be present in the drug substance, although solvents that have low volatility may persist from earlier steps. 

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According to the free energy change associated with the pertinent reaction, nickel will form nickel tetracarbonyl at low temperatures, and this carbonyl will become unstable and revert back to nickel and carbon monoxide at moderate temperatures. The Mond process for refining nickel is based on these features. In this process, impure nickel is exposed to carbon monoxide gas at 50 °C, whereby volatile nickel tetracarbonyl (Ni(CO)4) forms. No impurity present in the crude nickel reacts with carbon monoxide. Since formation of the... 

Many of the properties of a polymer depend upon the presence or absence of crystallites. The factors that determine whether crystallinity occurs are known (see Chapter 2) and depend on the chemical structure of the polymer chain, e.g., chain mobility, tacticity, regularity and side-chain volume. Although polymers may satisfy the above requirements, other factors determine the morphology and size of crystallites. These include the rate of cooling from the melt to solid, stress and orientation applied during processing, impurities (catalyst and solvent residues), latent crystallites which have not melted (this is called self-nucleation). 

Demonstrate that process impurities that build up in the anolyte circuit can be effectively managed over prolonged operational periods. 

For DS Methods should separate the API, synthetic process impurities, and DS degradation products. Methods should be able to detect impurities and degradation products present at levels greater than 0.05% relative to the API. Impurities and degradation products present at levels greater than 0.1% should be identified and specifications should be placed on limits. 

Injecting solutions of known process impurities, degradation products, intermediates, homologues, dimers, etc. further challenges the specificity of a method. Identification of these compounds may require an extensive search in order to identify all possible species that may be... 

If reference materials of the suspected impurities are available, the drug substance or finished drug product should be spiked at an appropriate level to demonstrate that the result is unaffected by the addition of the impurity. Figure 2 shows examples of individual chromatograms of the API and three known process impurities. As shown here, none of the three process impurities interfere with the API peak, although peaks for impurities A and C appear to overlap and could co-elute if both were present in the sample. This specificity may be acceptable if the method was designated as an assay method for the quantitation of the API. For a method intended to quantitate process impurities, the overlap of these two components would in most cases be unacceptable due to the inability of the method to accurately measure the two individual components. 

For a drug substance, the accuracy experiment should demonstrate that the method is free from the interference of process impurities and... 

Upon identification of a new source for API, or in the event that the current API supplier makes any significant change to the approved synthetic process, revalidation should be considered. At a minimum, specificity of the method should be re-evaluated to ensure that any new process impurities and/or synthetic intermediates, precursors, etc. do not interfere with the analyte of interest. Revalidation is complete if the specificity study demonstrates that the change to the API has no adverse affect on the performance of the method. If the method is affected and changes are required, revalidation should proceed according to an original plan. 

FIGURE 6 (a) Intermediate prepared via the originai process. Impurities meet... 

Starting materials can be defined as the raw materials that form the basis of a chemical reaction as a part of the synthesis of an intermediate in the production of a drug substance. Catalysts typically include any material added to a mixture to accelerate, control, or otherwise modify a chemical reaction. Intermediates are those products of a synthesis scheme that will undergo further reaction. By-products are the side-products of a chemical reaction, and may include conjugates, dimers, enantiomers, unintended salts or free-bases, over-substitution, others. These types of impurities are usually considered to be process impurities and are not expected to increase in concentration over time. 

The calibration models needed to be insensitive to variations in the levels of minor additives (<1 wt%) or process impurities. This was achieved by including samples from different production lines, containing varying concentrations (including zero) of different spinning additives, in the designed experiment sample set. 

Chen Y, BriU GM, Benz NJ, Leanna MR, Dhaon MK, Rasmussen M, Zhou CC, Bruzek JA, Bellettini JR. (2007) Normal phase and reverse phase HPLC-UV-MS analysis of process impurities for rapamycin analog... 

Impurities generally fall into three main categories process impurities, degradation impurities, and contaminant impurities. Additionally, enantiomers and polymorphs may be considered impurities under some circumstances. 

Figure 1.2 illustrates the different process impurities present in a sample of erythromycin [11]. A polymeric column was used. 

Solid-phase microextraction (SPME) is effectively a miniamrised version of SPE. Instead of using a packed cartridge, a rod is typically used, which is coated with the stationary phase. This is dipped into a solution of the analyte and allowed to extract for a pre-determined period of time. After this incubation period, the rod is removed from the solution and may be inserted directly into the injection system of the GC or HPLC. All of these operations can be automated on an autosampler. Clearly, the success of this technique depends intimately on the affinity of the analyte for the stationary phase. Frost, Hussain and Raghani [34] used SPME with GC-FID to measure benzyl chloride and chloroethylmethyl ether (amongst other process impurities) in pharmaceutical preparations. 

R. P. Frost, M. S. Hussain and A. R. Raghani, Determination of pharmaceutical process impurities by solid phase microextraction gas chromatography. Journal of Separation Science, 2003, 26(12-13), 1097-1103. 

A third type of process impurity can arise when a synthetic route to a molecule involves a cyclization reaction and there are two pathways along which the cyclization can proceed. In this case an isobaric impurity may be formed with a chemical skeleton that differs from the target pharmaceutical agent. A very similar situation arises when a reaction can lead to major and minor epimers. There are numerous other examples that could be cited, but those that have been mentioned at least give the reader a glimpse of the diverse nature of impurities that can be encountered during the drug-development process. 

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