Regulatory considerations of pharmaceutical solid polymorphism in Abbreviated New Drug Applications (ANDAs)

A sponsor of an Abbreviated New Drug Application (ANDA) must have information to show that the proposed generic product and the innovator product are both pharmaceutically equivalent and bioequivalent, and therefore, therapeutically equivalent. Many pharmaceutical solids exist in several crystalline forms and thus exhibit polymorphism. Polymorphism may result in differences in the physico-chemical properties of the active ingredient and variations in these properties may render a generic drug product to be bioinequivalent to the innovator brand. For this reason, in ANDAs, careful attention is paid to the effect of polymorphism in the context of generic drug product equivalency. This review discusses the impact of polymorphism on drug product manufacturability, quality, and performance. Conclusions from this analysis demonstrate that pharmaceutical solid polymorphism has no relevance to the determination of drug substance "sameness" in ANDAs. Three decision trees for solid oral dosage forms or liquid suspensions are provided for evaluating when and how polymorphs of drug substances should be monitored and controlled in ANDA submissions. Case studies from ANDAs are provided which demonstrate the irrelevance of polymorphism to the determination of drug substance "sameness". These case studies also illustrate the conceptual framework from these decision trees and illustrate how their general principles are sufficient to assure both the quality and the therapeutic equivalence of marketed generic drug products.     

Analysis of purity in 19 drug product tablets containing clopidogrel: 18 copies versus the original brand

In this study, 18 copies of PLAVIX tablets containing clopidogrel hydrogensulfate were compared to the innovator drug product for uniformity of mass, impurity profile, content, dissolution properties and stability. In order to be able to separate the R-enantiomer of clopidogrel, an enantiospecific liquid chromatographic method was used to determine the impurities and to perform the assay. The paddle method was used for dissolution testing. Most of the copies were not similar compared to the original drug product: their amount of impurities was higher, the content of clopidogrel lower, the dissolution profiles different and after 3 months under stress conditions in the original packaging, the results for the samples and the reference were significantly different in most of the cases.     

cDNA isolation and functional expression of myrcene synthase from Perilla frutescens

cDNA cloning of a monoterpene synthase from Perilla frutescens whose steam-distilled oil contains 92.9% perillaketone, was performed by the PCR method using primers designed based on limonene synthase. The full-length nucleotide sequence of this cDNA consisted of 1978 bp including a 1827-bp translational region encoding a deduced protein of 608 amino acids, which was similar to that of limonene synthase from P. frutescens (85% identity). Functional expression of this clone in Escherichia coli yielded an active monoterpene synthase enzyme, which converted geranyl diphosphate into 53.8% myrcene, 20.9% sabinene, 19.8% linalool and 5.5% limonene. As for the extraction of reaction products, we performed SPME (solid phase micro extraction) as well as conventional solvent extraction, and compared these two extraction methods.     

6-phosphogluconate dehydrogenase: a target for drugs in African trypanosomes

New drugs are urgently required for Human African Trypanosomiasis (sleeping sickness), a disease which has re-emerged as a major health threat in Sub-Saharan Africa. The third enzyme of the pentose phosphate pathway, 6-phosphogluconate dehydrogenase, has been shown to be a good target for drugs. The enzyme is essential to the trypanosomes that causes sleeping sickness and structural differences when compared to its mammalian counterpart allow for selective inhibition. Three series of inhibitors have been designed, these include phosphorylated carbohydrate substrate and transition state analogues, non-carbohydrate substrate analogues and also triphenylmethane-based compounds. All have shown selective inhibition of the trypanosomal 6-phosphogluconate dehydrogenase and representatives of each have trypanocidal activity.     

360-feedback in health care management: a field study

In recent years, organizations representing all types of industries, including health care, have adopted the 360-feedback approach with the goal of strengthening leader performance. But while 360-feedback enjoys a high level of face validity, current research shows that it is not problem-free and often fails to achieve its goals without proper development and implementation. This research, conducted in a large public hospital, surveyed the top management team of 49 executives who participated in a 360-feedback project beginning in February 2001. The survey, designed to solicit opinions about the effectiveness of the 360-feedback project, resulted in several recommendations to improve the process: One, both mentors and participants (raters and those rated) should be formally trained to improve the feedback process. Two, participants--both raters and those rated--should be significantly involved in 360-feedback planning and development efforts. Three, the 360-feedback process should be linked to hospital objectives. Four, the 360-feedback process should focus not only on interpersonal issues but departmental and organizational goals as well. First and foremost, our findings show that regardless of how popular a management development program may be, no technique for improving management and organizational effectiveness, including 360-feedback, will work unless properly designed and implemented.     

Inhibition of leukotriene biosynthesis by quinolone alkaloids from the fruits of Evodia rutaecarpa

The n-hexane extract of the fruits of Evodia rutaecarpa showed a considerable inhibiting effect on leukotriene biosynthesis in human granulocytes. Bioassay-guided fractionation of the extract led to the isolation of the 5 quinolone alkaloids: 1-methyl-2-nonyl-4(1H)-quinolinone, 1-methyl-2-(6Z)-6-undecenyl-4(1H)-quinolinone, 1-methyl-2-(4Z,7Z)-4,7-tridecadienyl-4(1H)-quinolinone, evocarpine and 1-methyl-2-(6Z,9Z)-6,9-pentadecadienyl-4(1H)-quinolinone. The compounds exhibited inhibitory activity on leukotriene biosynthesis in a bioassay using human polymorphonuclear granulocytes, with IC50 values of 12.1, 10.0, 10.1, 14,6 and 12.3 microM, respectively. Structure elucidation of the compounds was achieved by 1D and 2D NMR experiments and comparison of spectral data with literature data.     

Negotiation as relationship-building in healthcare organizations: a case study exercise

A key skill needed by healthcare managers is an ability to simultaneously maintain and enhance relationships with multiple stakeholders, most notably clinical professionals, through the process of decision-making and negotiation. Additionally, healthcare managers need to be able to actively integrate various components of functional areas into their decision-making process. This article presents two exercises that serve the following purposes: (1) it can help raise students' awareness of the complexity involved in decision-making and negotiating, (2) it can create an understanding that decision-making and negotiations are embedded in a larger context involving multiple relationships between parties, and (3) it can be used as a means to measure the student's integrative ability within the traditional curriculum of an MHA program.     

Patterns of intra-cluster correlation from primary care research to inform study design and analysis

OBJECTIVE: To provide information concerning the magnitude of the intraclass correlation coefficient (ICC) for cluster-based studies set in primary care. STUDY DESIGN AND SETTING: Reanalysis of data from 31 cluster-based studies in primary care to estimate intraclass correlation coefficients from random effects models using maximum likelihood estimation. RESULTS: ICCs were estimated for 1,039 variables. The median ICC was 0.010 (interquartile range [IQR] 0 to 0.032, range 0 to 0.840). After adjusting for individual- and cluster-level characteristics, the median ICC was 0.005 (IQR 0 to 0.021). A given measure showed widely varying ICC estimates in different datasets. In six datasets, the ICCs for SF-36 physical functioning scale ranged from 0.001 to 0.055 and for SF-36 general health from 0 to 0.072. In four datasets, the ICC for systolic blood pressure ranged from 0 to 0.052 and for diastolic blood pressure from 0 to 0.108. CONCLUSION: The precise magnitude of between-cluster variation for a given measure can rarely be estimated in advance. Studies should be designed with reference to the overall distribution of ICCs and with attention to features that increase efficiency.