Impurities and contaminants

Because the higher alcohols are made by a number of processes and from different raw materials, analytical procedures are designed to yield three kinds of information the carbon chain length distribution, or combining weight, of the alcohols present the purity of the material and the presence of minor impurities and contaminants that would interfere with subsequent use of the product. Analytical methods and characterization of alcohols have been summarized (13). 

It is essential to determine the concentration of each isomer and define limits for all isomeric components, impurities, and contaminants of the compound tested preclin-ically that is intended for use in clinical trials. The maximum level of impurities in a stereoisomeric product used in clinical studies should not exceed that in the material evaluated in nonclinical toxicity studies. This point is expanded in the ICH impurities guideline (Section 13.5.3). 

ELISAs can be used for identification and quantitation of the product as well as impurities in the various purification steps (as discussed previously). They can be used to document the removal of known impurities and contaminants, and in process validation to demonstrate batch-to-batch consistency of manufacturing. 

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. 

A-Hydroxyphthalimide 178a (NHPI Chart 4), described for the first time in 1880, is a weak acid (plfa = 7), which forms highly colored salts with alkali metals, heavy metals, ammonia or amines. More precisely, the two crystalline forms of NHPI reported in the literature display different colors, colorless (white) and yellow, with the colors depending on the solvent in which the NHPI is prepared. The variations in physical properties, including color, have been attributed to synthetic problems , such as impurities, and contamination from a fluorescent compound that could not be isolated or characterized. 

The second area addressed in the GMP revisions is a broad question of impurities and contaminants. Currently, the industry utilizes the general principles of the GMPS coupled with a series of guidelines and directives related to potential concerns over specific impurities—in API and in final product processing—that have caused concerns in the past. The new GMPs will likely address these concerns in specific and will call for enhanced carcinogenicity and related preclinical studies to examine the effects of all significant impurities. 

It is important to determine permissible maximum limits for impurities and contaminants that may be present in these products, adapting the limits according to technological advances for testing or from the continuous assessment of the effects of clinical applications. 

Table 13.1 describes the most frequent types of impurities and contaminants, indicating the most suitable detection methods as a guide. 

Safety concerns may arise from the presence of impurities or contaminants. It is preferable to rely on purification processes to remove impurities and contaminants rather than to establish a preclinical testing program for their qualification. In all cases, the product should be sufficiently characterized to allow an appropriate design of preclinical safety studies. In general, the product that is used in the definitive pharmacology and toxicology studies should be comparable to the product proposed for the initial clinical studies. (ICH S6)... 

Diffuse reflectance has also been used extensively for trace analysis. In such a case, the sample to be studied is dissolved using a volatile solvent and transferred to KBr powder, preferably in microcups. The solvent is evaporated, and the sample has coated the KBr particles. With microsampling techniques, sample loadings lower than 100 ng can give satisfactory spectra. If strict rules for avoiding impurities and contamination are observed, detection limits even at the low nanogram... 

Impurities and contaminants can also affect the lifetime of polyolefins, generally In an adverse manner. The adverse effect of copper on the long-term stability of polyolefins Is well known.(9.10) Other active metals have also been shown to accelerate the oxidation process.(11. 12)... 

However, the technological processes also contribute to the problems arising when developing a biotech product for the pharmaceutical markets. Due to the production process there are impurities and contaminants which are much more diffi-... 

Likewise, it is convenient to check the behaviour of the catalysts when working with real plastic wastes rather than simply with model polymers, in order to ascertain the effect of the various impurities and contaminants the wastes may contain on the catalyst activity and stability. 

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