Work Overloads Approximation on a Moving Assembly Line Workstation using Markov Chain

Moving mixed-model assembly lines are used by many companies to assemble multiple model types of a particular product. A moving assembly line consists of a material movement system that moves jobs at a constant velocity across a series of workstations. The variation in the work content of jobs at workstations may result in workstation inefficiencies if the jobs are processed through the line in random order. This gives rise to the job sequencing problem, which is to determine a job launching order, (i.e., the job sequence) that minimizes operational inefficiencies such as work overloads. Work overloads occur when a job cannot be processed within the limits of a workstation. When determining the workstation parameters on a moving assembly line they should ideally be set so that the workstation is the minimum length for a given assembly line throughput, and zero operational inefficiencies occur when job sequencing is performed. Estimating the operational inefficiencies without having to solve a sequencing problem is the topic of this research. This research establishes a discrete state Markov chain model to estimate the expected number, and the probability distribution of work overloads for a set of jobs launched in random order. The models have been tested on a variety of different job sets, and the results indicate that the model can accurately estimate the probability of work overloads as a function of workstation parameters, and whether job sequencing reduces work overloads to zero

Clarithromycin: overview and its current clinical utility in the treatment of respiratory tract infections

Upper respiratory tract infection (URTI) is a common reason for medical consultation all over the world. Streptococcus A (Strep A) and other infections can cause sore throat as well as pharyngitis or tonsillitis. It may also result in post-infection sequelae, including acute post-streptococcal glomerulonephritis, acute rheumatic fever, and rheumatic heart disease.  As a result, there is a need for an antibiotic that is effective, easy to administer, has a favorable sensitivity pattern, and preferably has some additional pharmacodynamic properties that complement the basic antibacterial profile. Clarithromycin is a macrolide antibacterial agent with broad-spectrum activity against respiratory pathogens. It is especially active against atypical Chlamydia pneumoniae, Mycoplasma pneumoniae, and Legionella spp. It is well absorbed and stable at gastric pH. It is metabolized by the cytochrome P450 enzymes and forms 14-hydroxy clarithromycin, which is more active than the parent compound, especially against Hemophilus influenzae. It acts by preventing protein synthesis by binding to the 50S subunit of bacterial ribosomes. In dosages of 500 to 1000 mg/day for 5 to 14 days, clarithromycin is effective in the treatment of community-acquired upper and lower respiratory tract infections in hospital and community settings. It exerts significant anti-inflammatory, immunomodulatory, and post-antibiotic effects. It provides a viable option for the treatment of community-acquired respiratory tract infections, in both children and adults.  

DEVELOPMENT OF A MULTI-DOSE FORMULATION FOR PREVNAR 13™

Streptococcus pneumoniae causes up to a million cases per year of invasive disease in young children and infants, most occurring in developing countries. Pfizer is partnering with WHO and the GAVI alliance to support the developing world on immunization against pneumococcal disease. Prevnar 13™ is currently approved for the prevention of invasive pneumococcal disease in twenty seven countries. If used widely, this pneumococcal conjugate vaccine could prevent hundreds of thousands of additional cases of child mortality each year. Use of single-dose preservative-free vaccine formulations will raise the overall cost of vaccination programs and may jeopardize the effectiveness of immunization programs in developing countries. Multi-dose vials lower the cost for each vaccination but typically need to include a preservative to prevent contamination that might be introduced during the withdrawal of vaccine doses from such vials. To develop a multi-dose formulation of Prevnar 13™ for the developing world, a preservative effective in meeting antimicrobial efficacy test requirements, that would maintain vaccine stability, and have an established safety record in infants was required. Multiple preservatives which include phenol, 2-phenoxyethanol (2-PE), meta-cresol, methylparaben and propyl paraben and thimerosal (as a control) were evaluated as potential candidates for a multi-dose formulation of Prevenar 13 based on preservative effectiveness and product stability. 2-PE showed superior antimicrobial effectiveness in Prevnar 13 formulations as per European Pharmacopoeia (EP) requirements and in multiple challenge studies with various organisms, as per WHO Open Vial Policy, to mimic worst case inadvertent microbial contamination that might occur during immunization of subjects when the formulation is presented in multi-dose vials. Prevnar 13 in the presence of 5mg dose of 2-PE is stable for over two years and meets the preservative effectiveness standards based on the EP 5.1.3 as well as WHO multi-organism challenge test. The data support the use of 2-PE as a more effective preservative with the potential to replace thimerosal, the most commonly used preservative in multi-dose vaccine formulations

Studies of the Effect of Cyclosporine in Psoriasis In Vivo: Combined Effects on Activated T Lymphocytes and Epidermal Regenerative Maturation

Cyclosporine (CSA) decreases lymphokine synthesis and keratinocyte proliferation in vitro, but its in vivo mechanism of action in treating recalcitrant psoriasis is incompletely understood. Ten psoriasis patients were treated with CSA (2–7.5mg/kg/d) with clinical improvement in nine of 10 patients. Skin biopsies before and after1–3 months of CSA treatment were studied for evidence of immune and keratinocyte activation using immunoperoxidase and Northern blotting analysis. The number of activated, IL-2 receptor+ T cells in plaques after CSA treatment was reduced in all patients by a mean of 60%. Seven of 10 patients showed a decrease in keratinocyte HLA-DR expression; five of seven showed a decrease in gamma-IP-10 immunoreactivity, suggesting decline in gamma interferon levels in plaques after CSA therapy. We studied the effect of CSA treatment in vivo on TGFα IL-6 and keratin K16 expression, three markers of keratinocyte growth activation. Expression of keratinocyte TGFα and IL-6,which are elevated in active psoriatic epidermis,did not change in these patients after CSA treatment. The majority of patients (five of eight) continued to express the suggest that the predominant direct mechanism of action of Cyclosporine in vivo is a diminution of T-cell activation in plaques, with attendant decreased lymphokine production

Evaluation of Critical Quality Attributes of a Pentavalent (A, C, Y, W, X) Meningococcal Conjugate Vaccine for Global Use

Towards achieving the goal of eliminating epidemic outbreaks of meningococcal disease in the African meningitis belt, a pentavalent glycoconjugate vaccine (NmCV-5) has been developed to protect against Neisseria meningitidis serogroups A, C, Y, W and X. MenA and X polysaccharides are conjugated to tetanus toxoid (TT) while MenC, Y and W polysaccharides are conjugated to recombinant cross reactive material 197 (rCRM197), a non-toxic genetic variant of diphtheria toxin. This study describes quality control testing performed by the manufacturer, Serum Institute of India Private Limited (SIIPL), and the independent control laboratory of the U.K. (NIBSC) on seven clinical lots of the vaccine to ensure its potency, purity, safety and consistency of its manufacturing. In addition to monitoring upstream-manufactured components, samples of drug substance, final drug product and stability samples were evaluated. This paper focuses on the comparison of the vaccine’s critical quality attributes and reviews key indicators of its stability and immunogenicity. Comparable results were obtained by the two laboratories demonstrating sufficient levels of polysaccharide O-acetylation, consistency in size of the bulk conjugate molecules, integrity of the conjugated saccharides in the drug substance and drug product, and acceptable endotoxin content in the final drug product. The freeze-dried vaccine in 5-dose vials was stable based on molecular sizing and free saccharide assays. Lot-to-lot manufacturing consistency was also demonstrated in preclinical studies for polysaccharide-specific IgG and complement-dependent serum bactericidal activity for each serogroup. This study demonstrates the high quality and stability of NmCV-5, which is now undergoing Phase 3 clinical trials in Africa and India