Column robustness case study for a liquid chromatographic method validated in compliance with ICH, VICH, and GMP guidelines.

This article presents a case study in dealing with robustness investigations and attempts by our analytical laboratory to address these issues without sacrificing valuable time in revamping the method validation prior to submission. A liquid chromatographic method is developed for the analysis of a novel triazinetrione anticoccidial product. The method effectively separates the active pharmaceutical ingredient (API), impurities, and preservatives in the API and product formulation. For much of the validation, the method holds up to the rigorous guidelines of the International Conference of Harmonization, the International Cooperation on Harmonization of Technical Requirements for Registration of Veterinary Medicinal Products, and the Good Manufacturing Practices. However, in analyzing a base-degraded sample one of the impurity peaks yields inconsistent retention times (RTs) during a series of injections. When switching the system to another analytical column from the same supplier, this impurity peak elutes at a different retention window and the remaining peaks in the chromatographic profile remain essentially the same. This RT variation of a single peak in the chromatographic profile is observed with additional columns from the same supplier and from different manufacturing lots. This suitability problem is not encountered with the columns used in the method development stage. The method no longer meets the robustness criteria established for pharmaceutical methods. An investigation is commenced and it is discovered that with the addition of tetrabutylammonium hydroxide to the mobile phases, the impurity peak gives a consistent RT in relation to the active peak. The peak shows comparable RTs relative to that of the API peak with columns of different silica lots and bond lots. All peaks, including the aforementioned impurity peak, are well-resolved under the revised high-performance liquid chromatographic conditions. This temporary solution enables continued submission work for FDA, but the robustness of this method is still a concern. After further investigation, it is determined that inhomogeneity of the active sites on the column's stationary phase is the likely culprit. Fortunately, a new column is found to be more suitable for this method and a column qualification study is initiated.

Withdrawal of life support: how the family feels, and why.

The objectives of this study were to develop an instrument to assess the satisfaction of family members with withdrawal of life support (WLS), and to determine which factors are associated with greater levels of satisfaction. To do this, we developed a self-administered questionnaire that was sent to the next-of-kin of intensive care unit (ICU) patients dying following WLS. Over a six-month period, 69 patients died following WLS in the ICU. Three letters were returned "address unknown", 33 did not respond, and 33 responded, of whom 29 agreed to participate (29/66 = 44% of those contacted). Of these, 24 (83%) strongly agreed with the patient's death being compassionate and dignified, one moderately agreed, one mildly agreed, one was neutral and two strongly disagreed. Items associated with greater satisfaction included: the process of WLS being well explained, WLS proceeding as expected, patient appearing comfortable, family/friends prepared for the decision, appropriate person initiating discussion, adequate privacy during WLS, chance to voice concerns. The study suggests factors that are important to consider in ensuring family comfort with the process of withdrawing life support.

Gas chromatographic analysis of fosfomycin in plasma for pharmacokinetic analysis.

An efficient method for gas chromatographic analysis of fosfomycin in plasma was developed for preliminary investigations of the bioavailability in poultry of 3 commercial complexes of fosfomycin: a levorotatory Ca(-) salt, a racemic Ca(+/-) salt, and a tromethamine (THAM) salt. The method was used to determine whether the less expensive racemic mixture would provide equivalent levels of fosfomycin in blood as the pure Ca(-) form and the THAM salt. The THAM salt, a more expensive product to market, was thought to have the greatest bioavailability. The assay is selective, sensitive, and applicable to pharmacokinetic analysis.

Liquid chromatographic analysis of bacitracin methylene disalicylate in feed.

Because of its peptide structure, bacitracin is not chemically distinct from many matrixes such as feeds or residue samples. Thus, bacitracin must be isolated from the matrix components or chemically altered to form a distinct component. Because of the complexity of this problem, bacitracin is still analyzed almost exclusively by microbiological methods. However, advances in solid-phase extraction has made sample isolation from the matrix much more practical. In this investigation both strong-cation exchange and C8 columns were used to isolate bacitracin for liquid chromatographic (LC) analysis. Results of both LC and microbiological analyses are compared.

The impact of musculoskeletal disorders in the population: are they just aches and pains? Findings from the 1990 Ontario Health Survey.

OBJECTIVE: In light of the high frequency of symptoms of musculoskeletal (MSK) disorders in the population, our objective was to establish the impact of these disorders on morbidity and health care utilization. METHODS: Analysis of interview data from the 1990 Ontario Health Survey (sample size 45,650 from the household population age > or = 16 years) has provided one of the first opportunities to relate reported MSK morbidity to disability, illness duration, and use of health services. RESULTS: Overall, MSK disorders were reported as a cause of morbidity or health care utilization by 29% of the population aged > or = 16 years. The prevalence of chronic MSK disorders was 22%; this includes the 5% of the population who reported longterm disability due to MSK disorders. Of reported MSK disorders, 79% had a duration of over 6 months, and the median duration was 5 years. MSK disorders impact in the previous 2 weeks, defined as reduced activity or use of health care (seeing a health professional or taking prescription or nonprescription medication) specifically because of MSK disorders, was reported by 12% of the population, of whom 72% reported chronic MSK disorders. A health professional had been consulted within the previous year for 72% of the reported MSK disorders. The proportion with consultations was over 80% for durations of one year or less, and remained over 50% for disease durations > or = 10 years. CONCLUSIONS: Reported MSK disorders cannot be dismissed as minor problems not requiring ongoing care in view of their long duration, disabling impact, and continuing consumption of health care services and resources.

Relative importance of musculoskeletal disorders as a cause of chronic health problems, disability, and health care utilization: findings from the 1990 Ontario Health Survey.

OBJECTIVE: Musculoskeletal disorders (MSD) are a leading cause of morbidity in the population, yet their prominence seems to be insufficiently appreciated. We describe the ranking compared with other major body systems of the prevalence of MSD, including arthritis and rheumatism, and back/neck disorders, as a cause of chronic health problems, longterm disability, restricted activity days, consultation with health professionals, and use of both prescription and nonprescription drugs. METHODS: We analyzed data from the 1990 Ontario Health Survey, a stratified random sample of the household dwelling population in Ontario, based on 45,650 individuals aged 16 years and over. RESULTS: MSD ranked first in prevalence as the cause of chronic health problems, longterm disabilities, and consultations with a health professional and ranked 2nd for restricted activity days and use of both prescription and nonprescription drugs. No other body systems ranked invariably within the top 2 ranks for the morbidity indices examined. Even when compared to other major disease groups, arthritis and rheumatism ranked consistently in the top 3 and back/neck disorders also ranked high. MSD were mentioned as a reason for 40% of all chronic conditions, 54% of all longterm disability, 24% of restricted activity days and almost 20% of health care utilization. The impact of MSD was even greater in the 65 and over age group. CONCLUSIONS: MSD have a major role in the health profile of the population. This high burden of illness should be considered in planning health care services and setting research priorities.

Uses of barium meal examination in dyspeptic patients under 50.

No abnormality was found in 76 of 100 dyspeptic out-patients under the age of 50 who underwent barium meal examination, while various non-malignant lesions were found in the remaining 24. Only 10% of those under 30, and 10% of those with symptoms for less than a year proved to have any abnormality. Because of the radiographic results treatment was altered in only 11 patients, and most of these changes were small.

Progressive intrahepatic cholestasis of infancy and childhood. A clinicopathological study of patient surviving to the age of 18 years.

A patient who developed chronic cholestatic jaundice during the 1st year of life and eventually died of liver cell failure at the age of 18 years is described. During the terminal illness Kayser-Fleischer-like rings were observed and the serum concentrations of total copper and ceruloplasmin were elevated. At autopsy, a mixed macronodular and micronodular cirrhosis was found and cholangiography and dissection of bile ducts revealed no obstructive lesion of the biliary tract. There was no family history of hepatobiliary disease. Liver biopsies obtained at the ages of 5 and 7 years showed accumulation of bile droplets in hepatocytes, normal-appearing bile ducts, no significant fibrosis, and intact lobular architecture. Striking features of the terminal cirrhosis were the presence of Mallory bodies and a marked excess of copper in the liver (2,175 mug per g dry weight). The latter two findings, as well as the elevated serum concentrations of total copper and ceruloplasmin, may be attributable to chronic cholestasis per se. This study emphasizes the clinical and therapeutic problems posed by chronic cholestasis of unknown etiology in childhood.