Implementation of continuous flow manufacturing in United States industries

Continuous Flow Manufacturing (CFM) is one of the key strategies to enable the United States industries to adapt to any volume increase and rapidly changing requirements of the market place. CFM is an on-going analysis and improvement activity used to optimize the efficiency, effectiveness and flexibility of any process. The two basic goals of CFM are to reduce cycle time to less than customer order leadtime and to eliminate inefficiencies from the overall manufacturing processes. The thesis will describe reasons for the scarcity of CFM in United States industries. The methodology applied was a detailed six page questionnaire sent to over thirty-five industries in United States, using CFM as a part in their manufacturing operations. The research focused on difficulties experienced during preparation and implementation of CFM. The theoretical research and the questionnaire analysis revealed that CFM is indeed partially culture-based, difficult to understand, not easy to accept and hard enough to implement. Although the research was taken from a stratified sample of already known CFM implementors, full scale implementation fell very short. In fact, most industries in United States seemed to be engaged in preparing for CFM. Hopefully, the information presented will help the United States industries to formulate plans and strategies to implement further actions that will lead to more efficiency and effectiveness in their manufacturing operations

The Effect of Risk Return Analysis of Pharmaceutical Companies on Indian Stock Market

Each individual endeavors to stop his/her well deserved funds in different venture roads relying on his/her targets. Among the different venture options, securities exchange is viewed as a standout amongst the most compensating roads of speculation. At the point when the normal return is high, the hazard related with such return is additionally high. So before putting resources into value advertise one should come to realize the hazard return attributes of those stocks and those ventures in which he/she plans to contribute. In this viewpoint, an examination has been embraced to break down the hazard return relationship of chose organizations in pharmaceutical industry of Indian securities exchange. The pharmaceutical business of India positions third on the planet regarding volume and fourteenth as far as esteem. The business is said to be the ideal part for parcel of speculators. The financial specialists must know about the hazard and return associated with the speculation. This investigation encourages the potential financial specialists to settle on educated and reasonable venture choice. The example time of this examination is five years from 2013 to 2018. The investigation has endeavored to discover the hazard return attributes of chosen 10 pharmaceutical organizations in Indian securities exchange. The information has been gathered and examined utilizing MS exceed expectations. The examination inferred that from the chose pharmaceutical organizations Sun Pharmaceutical Industries Ltd gives exceptional yield yet the market danger of the offers is much high. So the value offers of Divi's Laboratories Ltd are increasingly great to potential speculators since it gives exceptional yield and the hazard related with those offers less

Utility of ranolazine in chronic stable angina patients

Chronic stable angina is a debilitating illness affecting at least 6.6 million US residents. Despite being optimally treated by pharmacotherapy and revascularization up to 26% of patients still experience angina. Diabetes mellitus is a common co-morbid condition in angina patients. Several new investigational medications are being tested for chronic angina. Advances in understanding of myocardial ischemia have prompted evaluation of a number of new antianginal strategies. In this review we discuss the utility of ranolazine, a recently approved novel antianginal agent and its efficacy in the diabetic patient population. In addition to its antianginal action in diabetic patients with chronic angina, ranolazine may have favorable effects on glycated hemoglobin levels

Comparison of the efficacy and safety of norethisterone vs. combined oral contraceptive pills for the management of puberty menorrhagia

Background: The most common cause of puberty menorrhagia is immaturity of the hypothalamic pituitary ovarian axis. Treatment is directed towards stabilizing the endometrium and treating the hormonal alterations. The objective of this study was to compare the efficacy and safety of norethisterone and combined oral contraceptive (COC) pills for the management of puberty menorrhagia.Methods: A total of 60 young girls from age of menarche to 19 years with menorrhagia were randomized to receive either norethisterone or COC pills. The end points included change from baseline in health-related quality-of-life parameters, estimation of blood loss and effect on hemoglobin level. Health-related quality-of-life question scores at baseline and after treatment were calculated as mean for norethisterone group and COC pills group.Results: Norethisterone and COC pills treatment groups showed mean improvement in Menorrhagia Impact Questionnaire (MIQ) scores compared to baseline. However, the total mean score was higher in norethisterone group compared to COC pills group after three treatment cycles (21 Vs 17). The treatment failure was less in norethisterone group compared to COC pills group.Conclusions: Use of norethisterone was more effective and better tolerated compared to combined oral contraceptive pills for the management of puberty menorrhagia

Actions of Harmonia axyridis (Coleoptera: Coccinellidae) alkaloids on vertebrate and invertebrate nicotinic acetylcholine receptors

The productivity of livestock and crops worldwide is dramatically reduced by pest organisms and pesticides are an important front-line control. Current pesticides raise environmental concerns and are threatened by the development of resistance so there is a great need for alternatives. Previous work has shown that defensive alkaloids secreted by the Harlequin ladybird beetle, Harmonia axyridis (H. axyridis), act on insect and human nicotinic acetylcholine receptors (nAChRs). Selectivity for insect nAChRs, which are proven pesticide targets, was demonstrated so the alkaloids show promise as leads for the development of novel pesticides. Our aim was to ascertain whether these alkaloids had any anthelmintic effects by examining the effects on the pharynx and body wall neuromuscular systems of the nematode worm, Caenorhabditis elegans. Subsequent analysis of mutant strains was used to identify a possible target. Following this we aimed to demonstrate the effects on different vertebrate and invertebrate nAChRs directly using the Xenopus laevis oocyte expression system. The alkaloid extract of Harmonia axyridis inhibited the rate of pharyngeal pumping after 1 h (IC50 = 1.087 mg/ml) and 24 h (IC50 = 0.406 mg/ml). Body wall movement was also affected after 2 h (IC50 = 0.64 mg/ml), 4 h (IC50 = 0.63 mg/ml) and 6 h (IC50 = 0.58 mg/ml). Examination of mutant strains revealed the alkaloids may be acting through EAT-18 and ACR-16. This was confirmed by electrophysiological recordings of ACR-16 nAChRs expressed in Xenopus oocytes (IC50 = 9.83x10-6M) but no selectivity is apparent when compared with human α7 nAChRs (IC50 = 9.09x10-6M). Selectivity does appear to exist with a hybrid Drosophila/chicken nAChR (IC50 = 3.16x10-7M). This confirms the nAChR target of the alkaloids and that the selectivity is due to action at the nAChR. The action of alkaloids on nematodes in vivo and on nematode and insect nAChRs provides the potential for the alkaloids to serve as lead compounds for novel pesticides

Actions of Harmonia axyridis (Coleoptera: Coccinellidae) alkaloids on vertebrate and invertebrate nicotinic acetylcholine receptors

The productivity of livestock and crops worldwide is dramatically reduced by pest organisms and pesticides are an important front-line control. Current pesticides raise environmental concerns and are threatened by the development of resistance so there is a great need for alternatives. Previous work has shown that defensive alkaloids secreted by the Harlequin ladybird beetle, Harmonia axyridis (H. axyridis), act on insect and human nicotinic acetylcholine receptors (nAChRs). Selectivity for insect nAChRs, which are proven pesticide targets, was demonstrated so the alkaloids show promise as leads for the development of novel pesticides. Our aim was to ascertain whether these alkaloids had any anthelmintic effects by examining the effects on the pharynx and body wall neuromuscular systems of the nematode worm, Caenorhabditis elegans. Subsequent analysis of mutant strains was used to identify a possible target. Following this we aimed to demonstrate the effects on different vertebrate and invertebrate nAChRs directly using the Xenopus laevis oocyte expression system. The alkaloid extract of Harmonia axyridis inhibited the rate of pharyngeal pumping after 1 h (IC50 = 1.087 mg/ml) and 24 h (IC50 = 0.406 mg/ml). Body wall movement was also affected after 2 h (IC50 = 0.64 mg/ml), 4 h (IC50 = 0.63 mg/ml) and 6 h (IC50 = 0.58 mg/ml). Examination of mutant strains revealed the alkaloids may be acting through EAT-18 and ACR-16. This was confirmed by electrophysiological recordings of ACR-16 nAChRs expressed in Xenopus oocytes (IC50 = 9.83x10-6M) but no selectivity is apparent when compared with human α7 nAChRs (IC50 = 9.09x10-6M). Selectivity does appear to exist with a hybrid Drosophila/chicken nAChR (IC50 = 3.16x10-7M). This confirms the nAChR target of the alkaloids and that the selectivity is due to action at the nAChR. The action of alkaloids on nematodes in vivo and on nematode and insect nAChRs provides the potential for the alkaloids to serve as lead compounds for novel pesticides

Investigating the pharmacology of ladybird alkaloids on ligand-gated ion channels

The WHO has forecasted the global population to reach 9 billion by 2050 and increased productivity of crops and livestock is crucial in order to meet the heightened demand for food. Pest organisms are a major factor in limiting this productivity and pesticides are a key tool in their control. Environmental concerns and the spread of pesticide resistance have hastened the need for new pesticides. Natural toxins targeting the nicotinic acetylcholine receptor (nAChR) have proven a valuable source of lead compounds for the development of new pesticides. Alkaloids from multiple species of ladybird beetles have been shown to target the nAChR. Recently, studies have shown that harmonine from the Harlequin ladybird Harmonia axyridis and (-)-adaline from the 2-spot ladybird Adalia bipunctata show promise as leads for new pesticides as they have demonstrated to be selective for the neuronal-type nAChRs expressed in locust neurons over mammalian muscle-type nAChRs expressed in human TE671 cells. However, mammalian neuronal-type nAChRs need to be investigated in order to confirm this selectivity. The Xenopus oocyte expression system was used to investigate the effects of (-)-adaline and whole alkaloid extract from the harlequin ladybird (HAE) on multiple mammalian neuronal-type nAChRs and the hybrid Dα2/β2 Drosophila/chick receptor using the two electrode voltage-clamp technique. This technique also allowed the expression and investigation of α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) and N-methyl-D-aspartate (NMDA) glutamate receptors. HAE was found to be selective for the insect hybrid Dα2/β2 over the other mammalian receptors investigated with an IC50 (95% CI) of 0.44 μg/ml (0.211 – 0.91). Analysis of the current-voltage (IV) relationship of HAE inhibition showed voltage-dependent block of rat α4β2 and voltage-independent block of rat α3β4 and human α7. Examination of the effect of HAE on the ACh EC50 revealed competitive block for rat α4β2 and potential non-competitive block of human α7 and rat α3β4. Selectivity for the hybrid insect/chick receptor was not demonstrated with (-)-adaline instead showing selectivity for rat α3β4 with an IC50 (95% CI) of 0.66 μM (0.24 – 1.67). (-)-adaline was found to competitively block rat α3β4 and rat α4β2 with potential non-competitive block of human α7. (-)-adaline was also found to block in all nAChRs examined in a voltage-independent manner. As HAE showed selectivity for the hybrid Dα2/β2 receptor there is promise for component(s) of HAE to serve as lead structures for the development of new pesticides. However, HAE is a mixture of various alkaloids that could have differing modes of action. This study revealed a competitive mode of action consistent with binding to the ACh binding site and voltage-dependent block consistent with open channel blocking on rat α4β2. Separation of HAE into individual components needs to be carried out for further investigation. HAE was also found to inhibit the rat GluN1-1a/2A NMDA receptor with an IC50 (95% CI) of 0.179 μg/ml (0.116 – 0.278) at Vh = -75 mV indicating a potential therapeutic use in neurodegenerative diseases associated with NMDA receptor excitotoxicity as well as pesticidal use

DIFFERENT ASPECTS INVOLVED IN PROCESS VALIDATION

ABSTRACT Validation refers to establishing documented evidence that a process or system, when operated within established parameters, can perform effectively and reproducibly to produce a medicinal product meeting its pre-determined specifications and quality attributes. Validation of the individualsteps of the processes is called the process validation. Process validation involves the collection and evaluation of data, from the process design stage throughout production, that establish scientific evidence that a process is capable of consistently delivering a quality drug substance. It is internationally recognized that validation is necessary in analyticallaboratories. The use of validated methods is important for an analyticallaboratory to show its qualification and competency.This new approach to process validation encompasses equipmentand utility qualification and is fully science and risk-based. Itprovides the pharmaceutical industry with the opportunity tore-think the whole concept of validation and ensure that theseactivities add real value to our businesses and to patients.It involves prospective validation, retrospective validation and concurrent validation.A life-cycle approach should be applied linking product and process development, validation of the commercial manufacturing process and maintenance of the process in a state of control during routine commercial production. KEYWORDS:Validation, prospective validation, concurrent validation, retrospective  validation, quality by desig