Withholding period

Complete, detailed proposed use patterns for the product, including dose rate, regimen, and proposed withholding period data showing the nature, level and safety of residues and metabolites in livestock and poultry... 

These studies should, if conducted properly, show the residues depletion profile of the formulation under study and will reveal for example any re-emergence of residues because of entero-hepatic recirculation. The time taken for the residues to be depleted to below the MRL for each of the tissues of interest is then usually chosen as the withdrawal period or withholding period (or times) for that formulation. Usually the studies must be conducted in each of the indicated species although simpler and cheaper bioequivalence studies where pharmacokinetic profiles are examined and compared, may be used to evaluate the withdrawal period in other food-producing species. 

A solution to this difficulty would be to define the depletion profile in clinical subjects or in disease models that closely simulate clinical disease. No attempt is made to meet this ideal for a range of ethical, economic, and scientific reasons. Instead, reliance is placed on conducting residue (like pharmacokinetic) studies in healthy animals. This is justified by the series of conservative assumptions made in establishing withholding periods (see Section... 

Tissue Days Post-treatment (withholding period) Marbofloxacin (flg/g) N -Desmethylmarbofloxacin (flg/g)... 

An important element of safety assessment comprises a series of studies designed to ensure that, when products are administered to food-producing species, a withholding period is established, which ensures that food from treated... 

There are differences between regulatory authorities in procedures used to set milk withholding periods. USFDA/CVM requires use of at least 20 animals and analysis of milk samples for the marker residue in triplicate.If the product is authorized for mastitis treatment, it is assumed that no more than one-third of the milk is derived from treated cows. A regression line is fitted to the log residue concentration data for each cow, and then fitted lines are used to estimate the distribution of log residue concentrations at each sampling time. Between-animal variance and measurement error variability are estimated and used to calculate a tolerance limit at each time. The WhT is set as the first time at which the upper 95% confidence limit of the 99th percentile of residue concentrations is equal to or less than the MRL. 

In setting withholding periods for AMDs in milk, regulatory authorities allow the assumption that milk from a treated cow will be admixed with milk from untreated animals that is, MRLs for milk are based on bulk tank concentrations, prompting the comment that the solution to pollution is dilution. This is not unreasonable, as the human consumption of milk from a single animal will be a relatively rare event, at least in developed countries. An increased somatic cell count (SCC) of bulk milk is an indicator of the prevalence of mastitis in a dairy herd. Such infections are widespread and are therefore widely and routinely treated by AMDs administered by intramammary infusion (most countries) or systemically (Scandinavian countries). Cases of peracute mastitis will almost always be treated systemically in all countries. There is an expectation that a non-compliant residue is more likely to occur in milk from herds with a high SCC. The US Pasteurized Milk... 

Generally have much longer withholding periods than rapidly absorbed formulations, discouraging innovative developments and field use... 

Burden for farmers required to adhere to prolonged withholding period... 

Greater risk for consumers through possible non-adherence to prolonged withholding periods... 

Problems for regulatory authorities in setting withholding periods based on slow depletion from injection sites... 

In some countries, recommended practices for minimizing residue and MRL concerns in exported foods have been developed for farmers and exporters. For example, it has been the practice of the Chilean Exporters Association jointly with the University of Chile to develop an information system for growers based on supervised trials to determine withholding periods (i.e., preharvest intervals) to meet the MRL standards recognized by the authorities in major export markets... 

Animals antiparasitic activity classes maximum residue limits mode of action poisonings pyrethrins pyrethroids uses withdrawal/withholding periods... 

Maximum Residue Limits and Drug Withdrawal/ Withholding Periods... 

When monitoring the patient taking epoetin, the nurse reportsany increase in the hematocrit of 4 points within any 2-week period because an exacerbation of hypertension is associated with an excessive rise of hematocrit. Hematocrit is decreased by decreasing or withholding the epoetin alfa dose. 

Continuous Stirred Tanks with Biomass Recycle. When the desired product is excreted, closing the system with respect to biomass offers a substantial reduction in the cost of nutrients. The idea is to force the cells into a sustained stationary or maintenance period where there is relatively little substrate used to grow biomass and where production of the desired product is maximized. One approach is to withhold some key nutrient so that cell growth is restricted, but to supply a carbon source and other components needed for the desired product. It is sometimes possible to maintain this state for weeks or months and to achieve high-volumetric productivities. There will be spontaneous cell loss (i.e., kd > 0), and true steady-state operation requires continuous purging and makeup. The purge can be achieved by incomplete separation and recycle... 

Fig. 11. Bulk soil water content and root ABA content in consecutive 10 cm soil layers on days 3, 9,12 and 18 after withholding water (A) from maize plants growing in 1 m deep soil columns. Well-watered plants (A) received water daily throughout the experimental period. Points are means of five measurements. Modified from Zhang Davies (1989).

During the period for review of a proposed publication referred to in clause 8.2 above, the Sponsor shall be entitled to make a reasoned request to the NHS Trust that publication be delayed for a period of up to six (6) months from the date of first submission to the Sponsor in order to enable the Sponsor to take steps to protect its proprietary information and the NHS Trust shall not unreasonably withhold its consent to such a request. 

Monitoring Exercise caution to withhold iron administration in the presence of evidence of tissue iron overload. Periodically monitor hematologic and hematinic parameters (hemoglobin, hematocrit, serum ferritin, and transferrin saturation). Withhold iron therapy in patients with evidence of iron overload. Transferrin saturation values increase rapidly after IV administration of iron sucrose thus, serum iron values may be reliably obtained 48 hours after IV dosing. 

Do not increase dose more frequently than once a month. If the hemoglobin is increasing and approaching 12 g/dL, reduce the dose by approximately 25%. If the hemoglobin continues to increase, temporarily withhold the dose until the hemoglobin begins to decrease, then resume therapy at that point at a dose approximately 25% below the previous dose. If the hemoglobin increases by more than 1 g/dL in a 2-week period, decrease the dose by approximately 25%. 

One might be fortunate if a smog attack of a single day s duration should coincide with a period when the field is dry, but the damage caused by withholding water in anticipation of a smog attack could be as injurious to the crop as the air pollutant. 

It is recommended that in an effort to prevent recalls, firms periodically evaluate manufacturing deviation trends within the context of their unique product lines, circumstances, and environments, with the aim of establishing criteria (other than product failure) that would justify not releasing product into market or withholding until further assessment. 

Water system qualification and requalification data, along with periodic water testing, will reveal any critical excursions and alert QA to the need to withhold product from the market. Establishing alert and action limits for this crucial raw material, particularly since it is used pervasively, can go a long way in supporting QA in recall prevention. 

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