Impurities/degradants

Specificity is the ability to assess unequivocally the analyte in the presence of components, which may be expected to be present. Typically these might include impurities, degradants, matrix, etc. 

Selective differential UV spectrophotometric method was presented for the determination of niclosamide in bulk and in its pharmaceuticals [43]. The method was based on measuring niclosamide in alkaline solutions against their neutral ethanolic solutions as blanks. The proposed method was sensitive, highly specific, and advantageous over the conventional UV assays, since the interference of the excipients, impurities, degradation products, or other accompanying drugs was nullified. 

In the common vernacular, the terms specificity and selectivity are often interchangeably used. More properly, a method is said to be specific if it provides a response for only a single analyte, while the term selective means that the method provides responses for a number of chemical entities that may be distinguished from each other. Selectivity also implies the ability to separate the analyte from degradation products, metabolites, and coadministrated drugs [12]. USP 28 [1] defines specificity as the ability to assess the analyte unequivocally in the presence of other components such as impurities, degradation products, and the matrix. IUPAC and AOAC have preferred the use of the term selectivity than specificity for methods that are completely selective, while USP, ICH, and FDA used the term specificity . Due to the very number of limited methods that respond to only one analyte, the term selectivity is usually more suitable, and this usage will be used in this work. 

In chromatography techniques, selectivity can be proved by the existence of good separation between the analyte and the other components (such as the matrix, impurities, degradation product(s), and metabolites). A consequence of this requirement is that the resolution of the analyte from the other components should be more than 1.5-2.0. In order to detect the possibility of coelution of other substance(s), the purity of the analyte peak should also be determined. For instance, the UV-Vis spectrum of the analyte peak/spot can be used to determine 4the purity of the analyte peak/spot, in this case the correlation coefficient V (this term is used by the software of DAD System Manager Hitachi, and CATS from Camag). With the same meaning and mathematical equation, other terms are used, such as Match... 

FIGURE 19 HPLC separation of the same stability sample shown in Figure 18 under gradient conditions showing better resolution and increased sensitivity of trace impurities, degradants (DG), and excipients (Exc). Reprinted with permission from Reference 19. 

During early phase development there is limited knowledge about the chemistry of the new chemical entity (NCE) with respect to synthetic impurities and degradation pathways and kinetics. It is, therefore, desirable to develop an array of methods that show applicability to a broad range of potential impurities, degradation products, and excipients. The methods are intended to provide the information necessary to guide the improvement of a synthesis route or a new drug formulation. 

Inappropriate response factors may have been used for quantitation of impurities/degradation products (i.e., molar extinction coefficients of degradation products are less than those of the API). 

The outcome of planning should include the generation of a method definition requirement document (MDRD) in which all stake holders agree, prior to method development, on the critical attributes of the method. Considerations such as what impurities/degradation products should be monitored, requisite reporting thresholds, the need for an MS-compatible method, if identical methods for DP and DS are required, etc., should be clearly decided and agreed upon by all stakeholders. 

It is generally required that all methods allow for the monitoring of API and impurities/degradation products in the same chromatographic run, that run times per sample should not be too long, and that for precise and robust quantitative analyses, the separation of the peaks of interest should have target resolutions of >2.0. To allow for easy transfer, the detector response for the nominal concentration of the API (100%, w/w) should be about 75% of the qualified linear dynamic range of the detector. Methods should be temperature controlled (e.g., at 35°C,... 

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... 

Once a database is established, it is made available to other laboratories through the company s secured intranet, so that the information therein can be updated, retrieved and reviewed. The resulting structural library can be referenced throughout the lifetime of the drug for rapid identification of impurities, degradants, and metabolites. 

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. 

In this chapter, we give an overview on how the API techniques work and which factors have an important influence on the performance. Examples are presented mostly from published work to demonstrate how LC-MS, LC-MS-MS, collision-induced dissociations (CIDs), accurate mass measurements and hydro-gen/deuterium exchange have been systematically and successfully applied in the structural elucidation of impurities, degradation products and metabolites. In addition, these also illustrate how mass spectrometry has offered a third dimension to chromatographic method development and validation. 

Validation parameter Confirmation of the identity of pure substances Determination of identity of unknown substances Amount single pure substance Amount active substance Limit test (semi- quantitiative) Amount impurities/ degradation products (quantitative) Dissolution speed of substances Bioequivalence studies... 

Selectivity is often referred to as the specificity of an analytical method and is a measure of the discriminating ability of the technique. The general requirement for specificity is that the method should be capable of unambiguously determining the compounds of interest in the presence of impurities, degradation products and other sample matrix components. A specificity study often involves accelerated degradation studies to ensure all degradation products will not interfere and the collection of likely process impurities. Often a placebo sample is assayed to check for interference fi om the sample matrix. 

The selectivity of an analytical method is determined by comparing test results from the analysis of samples containing impurities (related compound), degradation products (originated from samples submitted to stress conditions), or placebo ingredients with those obtained from the analysis of samples without impurities, degradation product, or placebo ingredients. 

Failed USP dissolution test requirements Microbial contamination of non-sterile products Lack of efficacy Impurities/degradation products Lack of assurance of sterility Lack of product stability Labeling Label error on declared strength Misbranded Promotional literature with unapproved therapeutic claims... 

The entire inventory of munitions at the PCD contains mustard agent. Most projectiles contain agent HD, which is distilled P,P -dichloroethyl sulfide. Some contain HT, a 60 40 eutectic mixture of HD and bis[2-(2-chloroethylthio)-ethyl] ether. All munitions may contain manufacturing byproducts or impurities, degradation products, and inorganic residues. 

Typical testing for stability studies includes appearance, potency, chiral assay, and related substances (impurities, degradation products, and contaminants) by HPLC assay, water content by Karl Fischer, identification by NIR or NMR, melting point by DSC, plus microbial testing. 

Ahuja S, Aisante KM, eds. Handbook of Isolation and Characterization of Impurities in Pharmaceuticals. Vol. 5. Separation Science and Technology Alsante KM, Hatajik TD, Lohr LL, Santafianos D, Sharp TR. Solving Impurity/Degradation Problems Case Studies. Chapter 14. San Diego, CA Academic Press 2003 361-400. 

Preclinical development IND/CTA filing Evaluation Impurity, degradant, and metabolite identification. 

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