A practical approach for exploration and modeling of the design space of a bacterial vaccine cultivation process.

A licensed pharmaceutical process is required to be executed within the validated ranges throughout the lifetime of product manufacturing. Changes to the process, especially for processes involving biological products, usually require the manufacturer to demonstrate that the safety and efficacy of the product remains unchanged by new or additional clinical testing. Recent changes in the regulations for pharmaceutical processing allow broader ranges of process settings to be submitted for regulatory approval, the so-called process design space, which means that a manufacturer can optimize his process within the submitted ranges after the product has entered the market, which allows flexible processes. In this article, the applicability of this concept of the process design space is investigated for the cultivation process step for a vaccine against whooping cough disease. An experimental design (DoE) is applied to investigate the ranges of critical process parameters that still result in a product that meets specifications. The on-line process data, including near infrared spectroscopy, are used to build a descriptive model of the processes used in the experimental design. Finally, the data of all processes are integrated in a multivariate batch monitoring model that represents the investigated process design space. This article demonstrates how the general principles of PAT and process design space can be applied for an undefined biological product such as a whole cell vaccine. The approach chosen for model development described here, allows on line monitoring and control of cultivation batches in order to assure in real time that a process is running within the process design space.

Clinical background of women prescribed tibolone or combined estrogen + progestogen therapies: a UK MediPlus study.

OBJECTIVES: To describe and compare the history and clinical characteristics of women who were prescribed tibolone or one of the following combined estrogen + progestogen therapies (CEPT): sequential conjugated equine estrogens (CEE)/norgestrel, sequential CEE/medroxyprogesterone acetate (MPA), continuous CEE/MPA or continuous estradiol/norethisterone acetate (NETA). METHODS: This was a descriptive study using MediPlus, a UK Primary Care database; 3762 women participated who, between July 1st, 1999 and June 30th, 2001, were prescribed either tibolone or one of the CEPT regimens mentioned above. Risk factors associated with endometrial cancer and breast cancer were assessed. RESULTS: The results of this study suggest that the clinical background of women who were prescribed tibolone differed from that of the women who were prescribed the combination products. More frequently than expected women who were most recently prescribed tibolone have a history of chronic breast disease, a personal history of breast cancer or a history of being prescribed (long-term) estrogen-only therapy. Furthermore, this group of women more frequently had hypertension and performed uterine procedures recorded in their medical records. This preferential prescribing of tibolone occurs at first-ever prescription of hormone therapy but is, in some instances, the underlying reason for switch behavior. CONCLUSION: In the UK, general practitioners seem to preferentially prescribe tibolone to women with an increased risk for breast and endometrial cancer, as compared to women being prescribed other CEPT products.

Vitamin B6 resistant primary hyperoxaluria type I. Report of 5 cases.

Primary hyperoxaluria type I (PH I) is characterized by an excessive endogenous production and excretion of oxalic and glycolic acid. Prognosis of this "inborn error of metabolism" is not favorable due to calcium-oxalate depositions in kidney and other organs. Vitamin B6 administration and/or renal transplantation can greatly improve the prognosis, as reported in literature. In this article our experience with 5 patients with vitamin B6 resistant hyperoxaluria is reported. Symptomatology and progression of the primary disease are described. The results of treatment interfering with oxalate production and calcium-oxalate crystallization are given. Three patients underwent renal replacement therapy. In these, oxalosis developed during hemodialysis and progressed following transplantation; a disabling bone disease was the most severe complication. Outcome of transplantation was disappointing. In two out of three patients, there was recurrence of the primary disease in the graft. In only one of them long-term graft function was satisfying. However, even this good function could not prevent disabling symptoms of oxalosis. Therefore, evaluation of the results of transplantation should not only include data related to graft function and survival, but also the complications due to calcium-oxalate depositions in various organs. To prevent oxalosis, kidney transplantation should be performed before end stage renal disease is achieved in patients with vitamin B6 resistant PH I.