Preclinical studies drug substance

Local clinical trial may be waived by the licensing authority in the interest of the public good, in which case data from preclinical studies are to be evaluated. TTie approval for import permission is given on Form 45 or 45A, clinical trial on Form 46 and/or 46A, and new bulk drug substance on Form 54a. 

Due to its high selectivity and potency at H3 receptors (/ )-a-methylhistamine (12) is nowadays used as the standard agonist in pharmacological assays related to this receptor. With regard to its pharmacodynamic properties, which were substantiated in preclinical studies [40], (R)-a-methylhistamine (12) meets all criteria of a potential drug substance. However, in contrast to its pharmacodynamic potential (ft)-a-methyl-histamine (12) suffers from its pharmacokinetic drawbacks which limit its use in both pharmacological and conceivable clinical studies. 

Bioburden testing is required for biologies used in pivotal preclinical studies to support clinical development and registration. Endotoxin levels are the primary concern in this regard. There are several major regulatory documents listed below (taken from Associates of Cape Cod Inc. Web site http //www. acciusa.com/) that describe how drugs, devices, dialysate, water, and other substances are to be tested for endotoxin. 

It also should be noted that FDA may request additional preclinical toxicology studies. This will depend on the degree(s) of difference(s) in the profiles, identities, and the levels of impurities in bulk drug substances produced from the pivotal intermediate made by the various routes of synthesis, and whether the finished drug is intended for short-term or chronic use. 

Dombey (1990) commented that the concept of qucility is the basis of cill drug development and creates confidence in product safety and efficacy. The drug substance has to be of sufficient quality to interpret the preclinical studies and the drug product has to be of sufficient quality to link all the human studies together and to provide confidence in the marketed product . 

The degree of purity, as well as the individual and total amounts of degradation products of the biotechnological or biological product entered into the stability studies, should be reported and documented whenever possible. Limits of acceptable degradation should be derived from the analytical profiles of batches of the drug substance and drug product used in the preclinical and clinical studies. 

Series of articles on pharmacology, kinetics, clinical studies J. CUn. Pharmacol 20, 213-424 (1980). Preclinical narcotic abuse liability evaluation J. H Woods et al, Arz-neimittei-Forsch. 33, 218 (1983). Multicenter clinical study in painful conditions C E. Steele, W, L, Jefferson, Curr. Med. Res. Opin. 8, 382 (1983). Review of pharmacology and therapeutic efficacy P. A. Morley er al. Drugs 23, 250-275 (1982). Comprehensive description M, Zinic et at in Analytical Profiles of Drug Substances vol. 15, K. Florey, Ed. (Academic Press, New York, 1986) pp 673-698,... 

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