Drug residues, definition

The 1997 consultation addressed the topic of safety factors, which is vitally important for die protection of public health. Setting MRLs is in fact based on a series of assumptions. One assumption is that humans are at least as sensitive as the most sensitive laboratory animal to a potentially toxic residue. Another assumption is diat all the residues covered by the MRLs are as toxic as the parent substance. A third assumption is that residues free from the human gastrointestinal tract are all totally bioavailable. A fourth assumption is the safety factor used to infer an ADI from a NOEL, including the additional safety factor, generally with a value of 2, to establish a provisional ADI until further information is available to convert this into a definite ADI. Other assumptions are the overestimation of consumer exposure to drug residues and the reduction of MRL values to take account of normal conditions under which the veterinary drugs are administered. 

Microbiological or immunochemical techniques offer the advantage to screen rapidly and at low cost a large number of food samples for potential drug residues but cannot provide definitive information on the identity of the specific drug residues found. Unlike microbiological and immunochemical techniques, physicochemical techniques actually aim at the identification, quantification, and/or confirmation of the presence of violative residues in suspected samples. 

The definition of calibration function does not specify that the measurement be made in the presence of potential interferants. This serves as an introduction to a discussion of the appropriate approach to calibration in an analytical method for veterinary drug residues, such as antibiotics. Construction of a calibration curve requires a sufficient number of standard solutions to define the response in relation to concentration, where the number of standard solutions used is a function of the concentration range. In most cases, a minimum of five concentrations (plus a blank, or zero ) is considered appropriate for characterization of the calibration curve during method validation. It is also typically recommended that the curve be statistically tested and expressed, usually through linear regression analysis. However, for LC/ESI-MS analysis of residues, the function tends to be quadratic. The analytical range for the analysis is usually defined by the minimum and maximum concentrations used in establishing the calibration curve. 

The use of drugs in food-producing animals inevitably results in the appearance of drug-related residues in milk, meat, and eggs. Antimicrobial residues occur more frequently than desired violative residues occur much less frequently, but in definitely significant numbers. 

The very large G protein-coupled receptor family has provided many examples of the definition of residue roles in drug interactions. Thus, for the beta-adrenoceptor, critical interacting residues have been determined to be aspartate-113 on helix III, serine-204 and -207 on helix V and phenylalanine-290 on helix VI. Such studies have defined a homologous binding pocket on this receptor family that is shared by the cationic neurotransmitters, acetylcholine, histamine, norepinephrine etc., and related small ligands. 

Of these molecular variants, one is the desired product with the desired properties with respect to biological activity and efficacy. Some structurally related variants (referred to as product related ) exhibit similar properties to the desired product and are therefore not considered as impurities. However, there may also be structurally related variants with altered properties with respect to biological activity, efficacy and/ or safety, which must be considered as impurities. In addition to the molecular variants of the protein (or protein-like) product, additional process-related substances may be part of a biotechnological drug substance, e.g., cell culture media, host cell proteins, DNA residuals, solvents, bacteria and/or viruses. This suggests that the determination of purity of these products (which is referred to as purity estimation rather than purity determination ) is a complex analytical issue. A purity estimation consists of both the definition of the heterogeneity of the protein (or proteinlike) product, and the identification and quantitation of product- and process-re-... 

The remainder of this article will outline the major parts of the human food safety portion of the new animal drug approval process with emphasis on the important interface between drug toxicology and residue chemistry. However, before the discussion of the guideline material a brief discussion of some important historical aspects and definitions needs to be given. 

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