Comparison of four different multiclass, multiresidue sample preparation methods in the analysis of veterinary drugs in fish and other food matrices.

In 2018, AOAC International issued Standard Method Performance Requirements (SPMR) 2018.010 - Screening and Identification Method for Regulated Veterinary Drug Residues in Food. In response, we compared 4 different multiresidue methods of sample preparation using the same analytical method entailing ultrahigh-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). Tilapia was chosen for testing, and the analytes and monitoring levels were from SPMR 2018.010. The methods consist of efficient procedures with published validation results from the US Department of Agriculture (USDA), Food and Drug Administration (FDA), and Canadian Food Inspection Agency (CFIA), and an enhanced-matrix removal (EMR)-Lipid protocol from China. Each method was used to prepare 102 final extracts of tilapia spiked or not at different levels with the 78 targeted analytes plus metabolites. The same FDA/USDA rules of mass spectral identification were employed in all analyses to assess rates of false positives and negatives. Quantitative accuracy of the methods was also compared in terms of recoveries and reproducibility of spiked tilapia, incurred catfish, and spiked and certified reference material of bovine muscle. Each method yielded generally acceptable results for the targeted veterinary drugs, but the USDA "extract & inject" method was the fastest, simplest, and cheapest to achieve equally or more acceptable results for the widest scope of analytes for the tested food matrices.

La Regulación de los medicamentos veterinarios en España / The regulation of veterinary drugs in Spain

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Respuesta de la autora de "La regulación de los medicamentos veterinarios en España" / Answer to "The regulation of veterinary drugs in Spain"

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Validated spectrophotometric determination of maduramicin ammonium using three charge transfer complexation reactions.

Direct spectrophotometric determination of Maduramicin ammonium (MAD) represents an analytical challenge since it is a weak UV-absorbing and lacking a strong chromophore. This work represents the first spectrophotometric determination of MAD as no direct spectrophotometric or colorimetric determination methods for MAD are available in the literature. The present study illustrates the development of three simple, rapid and inexpensive colorimetric methods for the routine quality control analysis of MAD based on the formation of colored charge transfer complexes with three electron acceptors namely p-chloranilic acid (p-CA), 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) and picric acid (PA). The color products of MAD with p-CA, DDQ and PA were measured at 519, 588 and 405nm respectively. The proposed methods were validated in terms of linearity, ranges, precision, accuracy, robustness and limits of detection and quantification. MAD was effectively determined over concentration ranges of 100-1000, 25-250 and 30-150µg/mL using p-CA, DDQ and PA, respectively with good linearity as shown by the values of correlation coefficients not less than 0.9991. The developed methods were successfully implemented in the assay of MAD powder pharmaceutical formulation for veterinary use.

[The reclassification assistant: Drug reclassification made easy]. / Umwidmungs-Assistent: Arzneimittelumwidmung leicht gemacht.

INTRODUCTION: In Switzerland, just over 700 veterinary medicinal products are authorized. Nevertheless, in practice veterinarians are often confronted with extraordinary situations in which a suitable veterinary medicinal product is not authorized, unavailable or otherwise not applicable. For livestock and horses in particular, this poses a challenge for pharmacotherapy due to food safety regulations. In these cases, the reclassification assistant can be used to determine whether and how a medicinal product containing the appropriate drug can be reclassified and correctly applied in food-producing animals. The users will be guided step by step with selectable options through the online assistant. If the desired reclassification is permitted in the legal framework, information on the withdrawal periods to be observed for the chosen medicinal product will be provided. This online assistant follows an algorithm based on the reclassification cascade and applicable food safety regulations.

INTRODUCTION: En Suisse, un peu plus de 700 médicaments vétérinaires sont autorisés. Néanmoins, dans la pratique, les vétérinaires sont souvent confrontés à des situations extraordinaires dans lesquelles un médicament vétérinaire approprié n'est ni autorisé, ni disponible, ni utilisable pour d'autres raisons. En particulier pour le bétail et les chevaux, cela pose un défi pour la pharmacothérapie en raison de la réglementation sur la sécurité alimentaire. Dans ces cas, l'assistant de reconversion peut être utilisé pour déterminer si et comment un médicament contenant le principe actif approprié peut être reconverti et correctement appliqué. Les utilisateurs seront guidés pas à pas avec des options sélectionnables via l'assistant en ligne. Si la reconversion souhaitée est autorisée dans le cadre légal, des informations sur les délais d'attente à respecter pour le médicament choisi seront fournies. Cet assistant en ligne suit un algorithme basé sur la cascade de reconversion les réglementations applicables en matière de sécurité alimentaire.

Importance of antibiotic residues in animal food.

Veterinary medicines, especially antibiotics, are among the most important components related to animal feed production. Generally, the main use of antibiotics in animals is for the treatment and prevention of diseases and growth promotion. Antibiotic usage in animals may result antibiotic residues in foodstuffs such as milk, egg and meat. These residues may cause various side effects such as transfer of antibiotic resistant bacteria to humans, immunopathological effects, allergy, mutagenicity, nephropathy (gentamicin), hepatotoxicity, reproductive disorders, bone marrow toxicity (chloramphenicol) and even carcinogenicity (sulphamethazine, oxytetracycline, furazolidone). The most important adverse effect of antibiotic residues is the transfer or antibiotic resistant bacteria to the humans due to the mobile properties of resistance. Because of these undesirable effects, it is important to regulate the use of antibiotics in food animals. The individuals and the local procedures should be aware of the problem through education by authorities. In this review, antibiotic use in the foodstuffs and their effects on the human health will be discussed.

Testing the validity of reference standard materials and stock solutions of veterinary drugs using LC-MS/MS.

This paper reports a practical approach for the stability testing of 37 veterinary drugs in stock standard solutions stored at -20°C for 1-3 years and the study of expiry date extension of 7 expired reference standard materials stored at 4°C. Stored stock solutions were compared versus freshly prepared stock solutions and concentrations determined using LC-MS/MS. The validity of expired reference materials was tested by new valid reference materials. LC-MS/MS method and parameters were optimised to get the maximum signal stability of the analytes. Statistical analysis was developed and performed to evaluate the stability results according to the acceptability criteria of 10% set by the European Commission guidance document SANTE/11813/2017. The stability of most of the stock solutions of the following veterinary drug families: ß-agonists, illegal dyes, inhibitors, macrolides, penicillins, quinolones, sulfonamides and tetracyclines ranged from 12 to 36 months. ß-Agonist compounds have the maximum stability period of 36 months while penicillin's stock solution in methanol showed the least stability. The results of testing the expiry date extension of reference standard materials demonstrated that there was no any deterioration of all tested compounds after manufacturer expiry date by 4-7 years.

Web-based Korean maximum residue limit evaluation tools: an applied example of maximum residue limit evaluation for trichlorfon in fishery products.

To ensure public safety against veterinary drug residues in food products from animal sources, maximum residue limits (MRLs) should be established by scientific evidence and a transparent estimation process. The Joint Food and Agriculture Organization (FAO)/World Health Organization (WHO) Expert Committee on Food Additives (JECFA) developed an Excel workbook-based tool for MRLs evaluation in 2003. In this study, we developed a web-based tool for MRL evaluation, called Korean MRL evaluation tools (KMET). While KMET used algorithms of JECFA workbook, it added some databases (e.g., Korean food consumption database) and provided additional functions (e.g., selection of target marker residue). Web-based KMET enabled regulatory policy makers to update the database. All input data and output results related to MRL evaluation based on residue depletion and food consumption datasets were archived and provided overall processes from the initial depletion data entry to MRL establishment with user-friendly interface. Our results demonstrated the stepwise processes whereby MRL for trichlorfon in the muscle of Paralichthys olivaceus was established with functional descriptions of KMET. MRL for trichlorfon derived from KMET was proposed and notified by the Ministry of Food and Drug Safety in 2018.

Perceived Risk, Expected Benefits and Pig Farmers' Behaviors of Veterinary Drug Usage.

To guarantee the pork quality and safety and the steady development of the pig-breeding industry in China, it is important to control veterinary drugs usage in the pig farming sector. In order to develop an effective intervention that control veterinary drug usage, it is important to perform an in-depth analysis of those factors that can affect the standardized use of veterinary drugs in the pig-breeding process. In this paper, hierarchical regression analysis is used to examine how perceived risk, expected benefits, and self-efficacy influence on the standardized use of veterinary drugs. Data were collected using a multi-stage sampling method from four provinces in China. The results show that expected benefit and self-efficacy have positive impacts on the standardized use of veterinary drugs. Self-efficacy significantly moderated the positive relationships between expected benefits and the negative relationships between perceived risk and standardized use of veterinary drugs.

Licensing and Approval of Antimicrobial Agents for Use in Animals.

The importance of antimicrobial resistance and the urgent need to combat it has increased the already existent complexity of licensing and approval of antimicrobial agents for use in animals due to its possible impact on animal and public health. VICH-the International Cooperation on Harmonisation of Technical Requirements for Registration of Veterinary Medicinal Products-is the trilateral (European Union-Japan-United States) program that has the goal of harmonizing technical requirements for veterinary product registration. This article aims to describe the data requirements and testing necessary to build a registration file to obtain marketing authorization for a new antimicrobial agent for use in animals. This information is needed in the context of the risk assessment framework currently used in the approval of veterinary medicinal products containing antimicrobial substances. This framework considers the consequences of the uncontrolled quality of the antimicrobial product, the direct exposure of people to the antimicrobial product (human occupational safety and consumer safety), inadvertent exposure of organisms to the antimicrobial product (environmental safety), the antimicrobial product causing harm in the treated animals (target animal safety), and failure to achieve claims (efficacy). Approved veterinary medicines need to have a clear positive benefit associated with their use because of the risk to public health, animal health, and the environment. However, the presence of antimicrobials in the environment exerts a selective pressure for resistance genes in bacteria, and there is growing worldwide concern about the role of polluted soil and water environments in spreading antimicrobial resistance and the role of the contaminant resistome due to food-producing animal antimicrobial treatment. Additionally, the international developments regarding the categorization of critically important antimicrobials with the possible restrictions of use and the monitoring and surveillance of antimicrobial resistance in animals are reviewed.

Quality control programmes for veterinary antimicrobial medicines.

The health benefits of the antimicrobial's use is inherently associated to the risk of antimicrobial resistance (AMR), an ever-increasing multifactorial problem, closely related with injudicious use of antimicrobials, and the lack of new antimicrobial medicines on the market, particularly for veterinary use. Currently, an increasing number of regulatory "One Health" action plans on AMR are running worldwide, already based on monitoring and surveillance systems for resistance and antimicrobials consumption. Such plans are still not mandatory in the European Union member States (EU-MS), but post marketing annual programmes for quality controls of medicines are, to verify and ensure full compliance with the marketing authorizations. The European "risk level" sampling is not based on the conventional risk-ranking process of severity factors vs the probability of occurrence, but instead, on the conviction that in the European Union (EU) all medicines are produced under good manufacturer practices (GMP) and rigorously controlled for quality by the marketing authorization holders (MAH). The present paper links poor-quality antimicrobials and AMR, highlighting examples of regulatory initiatives on this subject outside the EU, particularly those resulting from the World Health Organization (WHO) recommendations. It also intends to trigger a discussion on the role of such quality control programmes, particularly for antimicrobials, beyond the control at any stage of the quality parameters of a marketed medicine, to reflect whether or not it might be relevant to other regulatory coordinated actions against AMR.

Recommendations for Clinical Pathology Data Generation, Interpretation, and Reporting in Target Animal Safety Studies for Veterinary Drug Development.

Clinical pathology testing is routinely performed in target animal safety studies in order to identify potential toxicity associated with administration of an investigational veterinary pharmaceutical product. Regulatory and other testing guidelines that address such studies provide recommendations for clinical pathology testing but occasionally contain outdated analytes and do not take into account interspecies physiologic differences that affect the practical selection of appropriate clinical pathology tests. Additionally, strong emphasis is often placed on statistical analysis and use of reference intervals for interpretation of test article-related clinical pathology changes, with limited attention given to the critical scientific review of clinically, toxicologically, or biologically relevant changes. The purpose of this communication from the Regulatory Affairs Committee of the American Society for Veterinary Clinical Pathology is to provide current recommendations for clinical pathology testing and data interpretation in target animal safety studies and thereby enhance the value of clinical pathology testing in these studies.

National post-market surveillance assessment of veterinary medicines in Korea during the past decade.

BACKGROUND: Veterinary medicines have been widely used for the prevention and treatment of diseases, growth promotion, and to promote feeding efficacy in livestock. As the veterinary medicine industry has steadily grown, it is crucial to set up a baseline for the quality of medicine as well as the insufficiency or excessiveness of the active ingredients in drug products to ensure the compliance, safety and efficacy of these medicines. Thus, the 10 years data of post-marketing quality control study was summarized to determine the rate and extent of non-compliance of these medicines and to establish baseline data for future quality control measures of veterinary medicine. RESULTS: In this study, 1650 drugs for veterinary use were collected per year from each city and province in Korea and analysed for the quantity of active ingredients according to the "national post-market surveillance (NPMS) system" over the past decade. The NPMS assessment was performed using liquid and gas chromatography, titration, UV/Vis spectrophotometry, and bioassays. A total of 358 cases were deemed noncompliant, with the average noncompliance rate for all medicine types being 2.0%. The average noncompliance rates for antibiotics, biologics and other chemical drugs except antibiotics (OCD) were 1.1%, 1.2%, and 3.0%, respectively. The first leading cause for noncompliant products was insufficient quantity of major ingredients (283 cases), and the second leading cause was the existence of excess amount of active ingredients (60 cases). Tylosin, spiramycin, ampicillin, tetracyclines and penicillins were most frequently found to be noncompliant among antibiotics. Among the OCD, the noncompliance was found commonly in vitamin A. CONCLUSION: The overall trend presented gradually decreasing violation rates, suggesting that the quality of veterinary medicines has improved. Consistent application of the NPMS assessment and the establishment of the Korea Veterinary Good Manufacturing Practice (KVGMP) will help to maintain the good quality of medicine.

How to transport veterinary drugs in insulated boxes to avoid thermal damage by heating or freezing.

BACKGROUND: The transport of veterinary drugs must comply with the general standards for drug storage. Although many vehicles are equipped with active heating and/or cooling devices assuring recommended storage conditions, simple insulated transport boxes are also often used. In this study, measurements for typical transport boxes were performed under laboratory conditions by the use of a climate chamber for a temperature of -20 °C and 45 °C to investigate the impact of box size, insulation material, liquid vs. dry filling products, filling degree and other parameters on the thermal performance of insulated boxes. Model calculations and instructions are presented to predict the retention time of recommended drug storage temperatures. RESULTS: The measurements and the model calculations showed that the loading of the transport boxes with additional water bottles to increase the heat capacity is appropriate to prolong the retention time of the recommended temperature range of the drugs. Insulated transport boxes are not suitable to store drugs over a period of more than approximately 12 h. For practical use a recipe is presented to measure the thermal properties of a transport box and the related retention time for which the recommended storage temperatures can be assured. CONCLUSIONS: The following principles for drug transportation in vehicles are recommended: (1) Before transfer into boxes, drugs should always be thermally preconditioned (2) Increase the filling degree of the boxes with thermally preconditioned water bottles or re-usable thermal packs will increase the heat capacity. Do not deep-freeze the bottles or packs below 0 °C to avoid drug freezing due to contact. (3) Open the lid of the boxes only to uncase drugs that are immediately needed. (4) The bigger the box and the higher the filling degree, the longer the retention time of the transport box. (5) Wherever possible, place the drug box at a cool site inside the vehicle. (6) The monitoring of the inside temperature of the transport boxes is recommended. By the proper use of such transport boxes the recommended temperatures can be maintained over one working day.

When to Compound Medications for Veterinary Patients.

This article serves as a brief discussion about some of the restrictions applicable to compounding medications for veterinary patients based on U. S. Food and Drug Administration compliance policy guidelines and provides a brief summary of when it is appropriate to compound medications for veterinary patients.

Requirements for Foreign and Domestic Establishment Registration and Listing for Human Drugs, Including Drugs That Are Regulated Under a Biologics License Application, and Animal Drugs. Final rule.

The Food and Drug Administration (FDA) is amending its regulations governing drug establishment registration and drug listing. These amendments reorganize, modify, and clarify current regulations concerning who must register establishments and list human drugs, human drugs that are also biological products, and animal drugs. The final rule requires electronic submission, unless waived in certain circumstances, of registration and listing information. This rulemaking pertains to finished drug products and to active pharmaceutical ingredients (APIs) alone or together with one or more other ingredients. The final rule describes how and when owners or operators of establishments at which drugs are manufactured or processed must register their establishments with FDA and list the drugs they manufacture or process. In addition, the rule makes certain changes to the National Drug Code (NDC) system. We are taking this action to improve management of drug establishment registration and drug listing requirements and make these processes more efficient and effective for industry and for us. This action also supports implementation of the electronic prescribing provisions of the Medicare Prescription Drug, Improvement, and Modernization Act of 2003 (MMA) and the availability of current drug labeling information through DailyMed, a computerized repository of drug information maintained by the National Library of Medicine.

Agricultural Applications for Antimicrobials. A Danger to Human Health: An Official Position Statement of the Society of Infectious Diseases Pharmacists.

The use of antibiotics in agriculture, particularly in food-producing animals, is pervasive and represents the overwhelming majority of antibiotic use worldwide. The link between antibiotic use in animals and antibiotic resistance in humans is unequivocal. Transmission can occur by ingesting undercooked meats harboring resistant bacteria, by direct contact of animals by animal handlers, and by various other means. Antibiotics used in aquaculture and antifungals used in horticulture are also an evolving threat to human health. Regulations aimed at decreasing the amount of antibiotics used in food production to limit the development of antibiotic resistance have recently been implemented. However, further action is needed to minimize antibiotic use in agriculture. This article describes the extent of this current problem and serves as the official position of the Society of Infectious Diseases Pharmacists on this urgent threat to human health.

Nonmedical Uses of Antibiotics: Time to Restrict Their Use?

The global crisis of antibiotic resistance has reached a point where, if action is not taken, human medicine will enter a postantibiotic world and simple injuries could once again be life threatening. New antibiotics are needed urgently, but better use of existing agents is just as important. More appropriate use of antibiotics in medicine is vital, but the extensive use of antibiotics outside medical settings is often overlooked. Antibiotics are commonly used in animal husbandry, bee-keeping, fish farming and other forms of aquaculture, ethanol production, horticulture, antifouling paints, food preservation, and domestically. This provides multiple opportunities for the selection and spread of antibiotic-resistant bacteria. Given the current crisis, it is vital that the nonmedical use of antibiotics is critically examined and that any nonessential use halted.