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, J Chem Phys, 1934, 2, 128 (b) Badger, R M, J Chem Phys, 1935, 3, 710 (c) Gordy, W, J Chem Phys, 1946, 14, 305 92 (a) Mack H G; Christen, D; Oberhammer, H, J Mol Struct, 1988, 190, 215 (b) Christen, D; Gupta, O D; Kadel, J; Kirchmeier, R L; Mack, H G; Oberhammer, H; Shreeve, J M, J Am Chem Soc, 1991, 113, 9131 93 R ggen, I; Dahl, T, J Am Chem Soc, 1992, 114, 511, and references therein 94 David, S; Eisenstein, O; Hehre, W J; Salem, L; Ho mann, R, J Am Chem Soc, 1973, 95, 3806 95 Laube, T; Hollenstein, S, J Am Chem Soc, 1992, 114, 8812 8817, and references therein 96.





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laboratories, for example, quality control laboratory, and regulatory expectations for the successful validation of a method to be used in support of a commercial product. An example of the minimum requirement for potency assay of the drug substance and drug product is tabulated in Table 4. Note that the postponement of intermediate precision is aligned with previous discussion that the use of early phase analytical method resides mainly in one laboratory and is used only by a very limited number of analysts. Each individual company s phased method validation procedures and processes will vary, but the overall philosophy is the same. The extent of and expectations from early phase method validation are lower than the requirements in the later stages of development. The validation exercise becomes larger and more detailed and collects a larger body of data to ensure that the method is robust and appropriate for use at the commercial site. However, certain fundamental concepts of cGMPs must be applied regardless of the details of the phased appropriate method validation strategy used. Examples are (1) proper documentation, (2) change control, (3) deviations, (4) equipment and utilities quali cation, and (5) proper training. A detailed method validation report may not be necessary until submission of the nal market application. However, summary reports should be available to facilitate ef cient data retrieval and ful ll requests from regulatory agencies for the information when required.

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DR is important, but who will do it It is a program that does not generate revenue. Will the DR plan keep pace with the raw growth How much will it cost With all the push for lower headcounts, can we pull this off If the work gets too thick midway, will the DR project go to the backburner and get extinguished In operating in a DR mode, will the project-management team have enough steam They seem too stretched in normal day-to-day operations. How much DR is enough If there are multiple disasters in a wide geographical area, will there be ample capacity to address them all

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For a review of the structural consequences of hyperconjugation, see Radom, L, Prog Theor Org Chem, 1982, 3, 1 97 Zurawski, B; Ahlrichs, R; Kutzelnigg, W, Chem Phys Lett, 1973, 21, 309 98 (a) Raghavachari, K; Haddon, R C; Schleyer, P v R; Schaefer III, H F, J Am Chem Soc, 1983, 105, 5915 (b) Yoshimine, M; McLean, A D; Liu, B; DeFrees, D J; Binkley, J S, J Am Chem Soc, 1983, 105, 6185 99 (a) Hawthorne, M F, Acc Chem Res, 1968, 1, 281 (b) Lipscomb, W N, Acc Chem Res, 1973, 6, 257 100 Walsh, A D, Trans Faraday Soc, 1949, 45, 179 101 For a discussion of the bonding in cyclopropane and other molecules with ``bent'' bonds, see Wiberg, K B, Acc.

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