Toxicology batch

Ermer, for example, utilized LCQ to monitor impurity profiles of various batches of ramorelix used in toxicological studies, clinical stndies and scale-up. Ramorelix is a synthetic glycosylated decapeptide with monoisotopic of 1530.7. The toxicological batch served as the benchmark against which all other batches were compared. Molecnlar weights of impurities were determined by ESI mass spectrometry, and nsed in conjunction with UV peak area % to gauge impurities in batches nsed in clinical trials. These impurity profiles were compared to those of batches used in the toxicologically qualified batch. Eour impurities were detected with the same value. They were believed to be diastereoisomers of ramorelix, i.e., a peptide sequence with one of the amino acids in the opposite enantiomeric form. 

Levels of impurities found in the toxicology batch are usually accepted as the allowable upper limits for the IND/NDA. Levels can be as much as a percent or two, depending on the product and vagaries of the individual synthesis. High levels of impurities can be quite acceptable provided that the toxicology work to prove the safety of the API was carried out with API containing the same high level of impurities. 

The relatively free-wheeling synthesis selection phase through the END gives way to a much more controlled development phase, wherein the quality of the Toxicology Batch (and especially impurity levels) dictates the quality of the API batches to be produced, slowing process change. Analytical methodologies and specifications for the API, intermediates, and raw materials become more refined. Impurity and stability profiles are established. Process control mechanisms are developed and plant SOPs incorporate the better controls. The NDA process slowly takes shape. 

Toxicology batches (drug candidate) Meeting deadline is primary concern, to reach go/no go decision points during API development. Note that animals may be grown in advance of such studies. Invest time to determine and prepare desired final form (salt, polymorph). Prepare high-quality material, but not ultra-pure. If tox studies are conducted on material of an unrealistically high purity, subsequent tox studies will be needed to qualify batches of lower quality. 

IV.A. Considerations for Preparing the Toxicology Batch and Subsequent Batches... 

Analytical methods for assay of the toxicology formulations and cleaning validation are developed and validated in preparation for the first GLP studies. Release and stability testing of the toxicology test articles are performed to support the suitability of the materials through their anticipated period of use. Typically, short-term accelerated stability studies are performed on the toxicology batches for at least 3 months to cover the time from date of manufacture through the last dose. 

Impurity profiles for new batches and comparison to previous toxicology batches... 

Friess, SL, Jensen DJ, Tureman, JR. 1959. Toxicology of a triaryl phosphate oil. II. A quantitative study of toxicity in different production batches. Arch Ind Health 20 253-261. 

The other change that needed to be made in the synthesis of RSR 13 for in vivo administration was the method of purification. RSR 13 is used in vivo as the sodium salt. I prepared the first batch for in vivo toxicology by triturating RSR 13 sodium salt with acetone to remove any vestiges of water. However, the first industrial scale-up procedure called for crystallization of the salt from ethanol-water. The ethanol-water crystals were not as soluble as the acetone triturated method and could not be formulated at a reasonable volume. We performed the crystal structure determination of the ethanol-water crystals and found that it was a heptahydrate (Figure 17.5) [50]. The problem for large-scale production of RS R13 was solved eventually by the industrial producers of RSR 13. 

The size and quality of the batch of bulk chemical or biological material that will be formulated for the first study in man are critical to the expeditious transfer from animals to man. Required details of the drug substance are shown in Box 4.6. Wherever possible, the same batch that has been used for toxicology should be used for the human... 

R. B. Georgieva, P. K. Petrov, P. S. Dimitrov and D. L. Tsalev, Observations on toxicologically relevant arsenic in urine in adult offspring of families with Balkan endemic nephropathy and controls by batch hydride generation atomic absorption spectrometry, Int. J. Environ. Anal. Chem., 87(9), 2007, 673-685. 

Campbell T. J., Burris D. R., Roberts A. L., and Wells R. J. (1997) Trichloroethylene and tetrachloroethylene reduction in a metallic iron-water-vapor batch system. Environmental Toxicology and Chemistry 16(4), 625-630. 

Dyeing from Organic Solvents. Chlorinated hydrocarbons, in particular, have been recommended as a medium for continuous or batch dyeing of acetate and PES fibers. For continuous dyeing, dye application from either chlorinated hydrocarbons or an aqueous liquor with fixation in solvent vapor is possible. This method is disfavored for ecological and toxicological reasons [82, p. 676],... 

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