Current and future trens in the quality control of pharmaceuticals and biopharmaticals : impacts on Cost of Goods Sold (COGS)

[Summary] 2. Roles of quality control in the pharmaceutical and biopharmaceutical industries. - 2.1. Pharmaceutical industry. - 2.2. Biopharmaceutical industry. - 2.3. Policy and regulatory. - 2.3.1. The US Food and Drug Administration (FDA). - 2.3.2. The European Medicine Agency (EMEA). - 2.3.3. The Japanese Ministry of Work, Labor and Welfare (MHLW). - 2.3.4. The Swiss Agency for Therapeutic Products (Swissmedic). - 2.3.5. The International Conference on Harmonization (ICH). - - 3. Types of testing. - 3.1. Microbiological purity tests. - 3.2. Physiochemical tests. - 3.3. Critical to quality steps. - 3.3.1. API starting materials and excipients. - 3.3.2. Intermediates. - 3.3.3. APIs (drug substances) and final drug product. - 3.3.4. Primary and secondary packaging materials fro drug products. - - 4. Manufacturing cost and quality control. - 4.1.1. Pharmaceutical manufacturing cost breakdown. - 4.1.2. Biopharmaceutical manufacturing cost breakdown. - 4.2. Batch failure / rejection / rework / recalls. - - 5. Future trends in the quality control of pharmaceuticals and biopharmaceuticals. - 5.1. Rapid and real time testing. - 5.1.1. Physio-chemicals testing. - 5.1.2. Rapid microbiology methods

O6-Methylguanine-DNA methyltransferase protein expression by immunohistochemistry in brain and non-brain systemic tumours: systematic review and meta-analysis of correlation with methylation-specific polymerase chain reaction

Background: The DNA repair protein O6-Methylguanine-DNA methyltransferase (MGMT) confers resistance to alkylating agents. Several methods have been applied to its analysis, with methylation-specific polymerase chain reaction (MSP) the most commonly used for promoter methylation study, while immunohistochemistry (IHC) has become the most frequently used for the detection of MGMT protein expression. Agreement on the best and most reliable technique for evaluating MGMT status remains unsettled. The aim of this study was to perform a systematic review and meta-analysis of the correlation between IHC and MSP. Methods A computer-aided search of MEDLINE (1950-October 2009), EBSCO (1966-October 2009) and EMBASE (1974-October 2009) was performed for relevant publications. Studies meeting inclusion criteria were those comparing MGMT protein expression by IHC with MGMT promoter methylation by MSP in the same cohort of patients. Methodological quality was assessed by using the QUADAS and STARD instruments. Previously published guidelines were followed for meta-analysis performance. Results Of 254 studies identified as eligible for full-text review, 52 (20.5%) met the inclusion criteria. The review showed that results of MGMT protein expression by IHC are not in close agreement with those obtained with MSP. Moreover, type of tumour (primary brain tumour vs others) was an independent covariate of accuracy estimates in the meta-regression analysis beyond the cut-off value. Conclusions Protein expression assessed by IHC alone fails to reflect the promoter methylation status of MGMT. Thus, in attempts at clinical diagnosis the two methods seem to select different groups of patients and should not be used interchangeably.

Analysis of translational errors in frame-based and frameless cranial radiosurgery using an anthropomorphic phantom

Abstract Objective: To evaluate three-dimensional translational setup errors and residual errors in image-guided radiosurgery, comparing frameless and frame-based techniques, using an anthropomorphic phantom. Materials and Methods: We initially used specific phantoms for the calibration and quality control of the image-guided system. For the hidden target test, we used an Alderson Radiation Therapy (ART)-210 anthropomorphic head phantom, into which we inserted four 5mm metal balls to simulate target treatment volumes. Computed tomography images were the taken with the head phantom properly positioned for frameless and frame-based radiosurgery. Results: For the frameless technique, the mean error magnitude was 0.22 ± 0.04 mm for setup errors and 0.14 ± 0.02 mm for residual errors, the combined uncertainty being 0.28 mm and 0.16 mm, respectively. For the frame-based technique, the mean error magnitude was 0.73 ± 0.14 mm for setup errors and 0.31 ± 0.04 mm for residual errors, the combined uncertainty being 1.15 mm and 0.63 mm, respectively. Conclusion: The mean values, standard deviations, and combined uncertainties showed no evidence of a significant differences between the two techniques when the head phantom ART-210 was used.

Performance of 18F-FET versus 18F-FDG-PET for the diagnosis and grading of brain tumors: systematic review and meta-analysis.

BACKGROUND: For the past decade (18)F-fluoro-ethyl-l-tyrosine (FET) and (18)F-fluoro-deoxy-glucose (FDG) positron emission tomography (PET) have been used for the assessment of patients with brain tumor. However, direct comparison studies reported only limited numbers of patients. Our purpose was to compare the diagnostic performance of FET and FDG-PET. METHODS: We examined studies published between January 1995 and January 2015 in the PubMed database. To be included the study should: (i) use FET and FDG-PET for the assessment of patients with isolated brain lesion and (ii) use histology as the gold standard. Analysis was performed on a per patient basis. Study quality was assessed with STARD and QUADAS criteria. RESULTS: Five studies (119 patients) were included. For the diagnosis of brain tumor, FET-PET demonstrated a pooled sensitivity of 0.94 (95% CI: 0.79-0.98) and pooled specificity of 0.88 (95% CI: 0.37-0.99), with an area under the curve of 0.96 (95% CI: 0.94-0.97), a positive likelihood ratio (LR+) of 8.1 (95% CI: 0.8-80.6), and a negative likelihood ratio (LR-) of 0.07 (95% CI: 0.02-0.30), while FDG-PET demonstrated a sensitivity of 0.38 (95% CI: 0.27-0.50) and specificity of 0.86 (95% CI: 0.31-0.99), with an area under the curve of 0.40 (95% CI: 0.36-0.44), an LR+ of 2.7 (95% CI: 0.3-27.8), and an LR- of 0.72 (95% CI: 0.47-1.11). Target-to-background ratios of either FDG or FET, however, allow distinction between low- and high-grade gliomas (P > .11). CONCLUSIONS: For brain tumor diagnosis, FET-PET performed much better than FDG and should be preferred when assessing a new isolated brain tumor. For glioma grading, however, both tracers showed similar performances.

Enriching e-learning metadata through digital library usage analysis

Peer-reviewed

What leads people to keep on e-learning? An empirical analysis of users' experiences and their effects on continuance intention

User retention is a major goal for higher education institutions running their teaching and learning programmes online. This is the first investigation into how the senses of presence and flow, together with perceptions about two central elements of the virtual education environment (didactic resource quality and instructor attitude), facilitate the user¿s intention to continue e-learning. We use data collected from a large sample survey of current users in a pure e-learning environment along with objective data about their performance. The results provide support to the theoretical model. The paper further offers practical suggestions for institutions and instructors who aim to provide effective e-learning experiences.

The Quality of Paediatric Nursing Care - Children’s Perspective

Hoitotyön laatu - lasten näkökulma Tämän kolmivaiheisen tutkimuksen tarkoituksena oli kuvailla lasten odotuksia ja arviointeja lasten hoitotyön laadusta sekä kehittää mittari kouluikäisille sairaalassa oleville lapsille laadun arviointiin. Perimmäisenä tavoitteena oli lasten hoitotyön laadun kehittäminen sairaalassa. Ensimmäisessä vaiheessa 20 alle kouluikäistä (4-6v) sekä 20 kouluikäistä (7-11v) lasta kuvailivat odotuksiaan lasten hoitotyön laadusta. Aineisto kerättiin haastattelulla ja lasten piirustusten avulla, sekä analysoitiin sisällön analyysilla. Lasten odotukset lasten hoitotyön laadusta kohdistuivat hoitajaan, hoitotyön toimintoihin ja ympäristöön, fyysinen ympäristö korostui piirustuksissa. Ensimmäisen vaiheen tulosten, aikaisemman kirjallisuuden sekä Leino-Kilven “HYVÄ HOITO” mittarin pohjalta kehitettiin “Lasten Hoidon Laatu Sairaalassa” (LHLS) mittari ja testattiin sen psykometrisiä ominaisuuksia tutkimuksen toisessa vaiheessa. Mittaria kehitettiin ja testattiin kolmen vaiheen kautta. Aluksi asiantuntijapaneeli (n=7) arvioi mittarin sisältöä. Seuraavaksi mittari esitestattiin kahdesti kouluikäisillä sairaalassa olevilla lapsilla (n=41 ja n=16), samassa vaiheessa myös viiden lastenosaston hoitajat (n=19) yhdessä arvioivat mittarin sisältöä sekä 8 lasta. Lopuksi mittaria testattiin kouluikäisillä lapsilla (n=388) sairaalassa sekä hoitajat (n=198) arvioivat mittarin sisällön validiteettia. Mittarin kehittämisen aikana päälaatuluokkien: hoitajan ominaisuudet, hoitotyön toiminnot ja hoitotyön ympäristö Cronbachin alfa kertoimet paranivat. Pääkomponentti analyysi tuki mittarin hoitotyön toimintojen ja ympäristön alaluokkien teoreettista rakennetta. Kolmannessa vaiheessa “Lasten Hoidon Laatu Sairaalassa” (LHLS III, versio neljä) mittarilla kerättiin aineisto Suomen yliopistosairaaloiden lastenosastoilta kouluikäisiltä 7-11 -vuotiailta lapsilta (n=388). Mittarin lopussa lapsia pyydettiin lisäksi kuvailemaan kivointa ja ikävintä kokemustaan sairaalahoidon aikana lauseen täydennystehtävänä. Aineisto analysoitiin tilastollisesti sekä sisällön analyysilla. Lapset arvioivat fyysisen hoitoympäristön, hoitajien inhimillisyyden ja luotettavuuden sekä huolenpidon ja vuorovaikutustoiminnot kiitettäviksi. Lapset arvioivat hoitajien viihdyttämistoiminnot kaikkein alhaisimmiksi. Lapsen ikä ja sairaalantulotapa olivat yhteydessä lasten saamaan tiedon määrään. Lasten kivoimmat kokemukset liittyivät ihmisiin ja heidän ominaisuuksiinsa, toimintoihin, ympäristöön sekä lopputuloksiin. Ikävimmät kokemukset liittyivät potilaana oloon, tuntemuksiin sairauden oireista sekä erossaoloon, hoitotyön fyysisiin toimintoihin sekä ympäristöön. Tutkimuksen tulokset osoittavat lasten olevan kykeneviä arvioimaan omaa hoitoaan ja heidän näkökulmansa tulisi nähdä osana koko laadun kehittämisprosessia parannettaessa laatua käytännössä todella lapsilähtöisemmällä lähestymistavalla. “Lasten Hoidon Laatu Sairaalassa” (LHLS) mittari on mahdollinen väline saada tietoa lasten arvioinneista lasten hoitotyön laadusta, mutta mittarin testaamista tulisi jatkaa tulevaisuudessa

Non-Linear Journal Bearing Model for Analysis of Superharmonic Vibrations of Rotor Systems

A rotating machine usually consists of a rotor and bearings that supports it. The nonidealities in these components may excite vibration of the rotating system. The uncontrolled vibrations may lead to excessive wearing of the components of the rotating machine or reduce the process quality. Vibrations may be harmful even when amplitudes are seemingly low, as is usually the case in superharmonic vibration that takes place below the first critical speed of the rotating machine. Superharmonic vibration is excited when the rotational velocity of the machine is a fraction of the natural frequency of the system. In such a situation, a part of the machine’s rotational energy is transformed into vibration energy. The amount of vibration energy should be minimised in the design of rotating machines. The superharmonic vibration phenomena can be studied by analysing the coupled rotor-bearing system employing a multibody simulation approach. This research is focused on the modelling of hydrodynamic journal bearings and rotorbearing systems supported by journal bearings. In particular, the non-idealities affecting the rotor-bearing system and their effect on the superharmonic vibration of the rotating system are analysed. A comparison of computationally efficient journal bearing models is carried out in order to validate one model for further development. The selected bearing model is improved in order to take the waviness of the shaft journal into account. The improved model is implemented and analyzed in a multibody simulation code. A rotor-bearing system that consists of a flexible tube roll, two journal bearings and a supporting structure is analysed employing the multibody simulation technique. The modelled non-idealities are the shell thickness variation in the tube roll and the waviness of the shaft journal in the bearing assembly. Both modelled non-idealities may cause subharmonic resonance in the system. In multibody simulation, the coupled effect of the non-idealities can be captured in the analysis. Additionally one non-ideality is presented that does not excite the vibrations itself but affects the response of the rotorbearing system, namely the waviness of the bearing bushing which is the non-rotating part of the bearing system. The modelled system is verified with measurements performed on a test rig. In the measurements the waviness of bearing bushing was not measured and therefore it’s affect on the response was not verified. In conclusion, the selected modelling approach is an appropriate method when analysing the response of the rotor-bearing system. When comparing the simulated results to the measured ones, the overall agreement between the results is concluded to be good.

Reconstruction and analysis of surface variation using photometric stereo

In many industrial applications, accurate and fast surface reconstruction is essential for quality control. Variation in surface finishing parameters, such as surface roughness, can reflect defects in a manufacturing process, non-optimal product operational efficiency, and reduced life expectancy of the product. This thesis considers reconstruction and analysis of high-frequency variation, that is roughness, on planar surfaces. Standard roughness measures in industry are calculated from surface topography. A fast and non-contact method to obtain surface topography is to apply photometric stereo in the estimation of surface gradients and to reconstruct the surface by integrating the gradient fields. Alternatively, visual methods, such as statistical measures, fractal dimension and distance transforms, can be used to characterize surface roughness directly from gray-scale images. In this thesis, the accuracy of distance transforms, statistical measures, and fractal dimension are evaluated in the estimation of surface roughness from gray-scale images and topographies. The results are contrasted to standard industry roughness measures. In distance transforms, the key idea is that distance values calculated along a highly varying surface are greater than distances calculated along a smoother surface. Statistical measures and fractal dimension are common surface roughness measures. In the experiments, skewness and variance of brightness distribution, fractal dimension, and distance transforms exhibited strong linear correlations to standard industry roughness measures. One of the key strengths of photometric stereo method is the acquisition of higher frequency variation of surfaces. In this thesis, the reconstruction of planar high-frequency varying surfaces is studied in the presence of imaging noise and blur. Two Wiener filterbased methods are proposed of which one is optimal in the sense of surface power spectral density given the spectral properties of the imaging noise and blur. Experiments show that the proposed methods preserve the inherent high-frequency variation in the reconstructed surfaces, whereas traditional reconstruction methods typically handle incorrect measurements by smoothing, which dampens the high-frequency variation.

EMQAL: Erasmus Mundus Master in Quality in Analytical Laboratories

The Erasmus Mundus Master in Quality in Analytical Laboratories (EMQAL) is a two-year Joint Master Degree. The course is funded by the European Commission through the Erasmus Mundus Programme, providing a number of attractive scholarships for European and non-European students. EMQAL prepares professionals for analytical laboratories, focusing on laboratory management and quality systems, along with complementing their technical knowledge. The EMQAL aims at training students in the most relevant issues concerning quality systems and management in analytical laboratories, and to become an expert in: Quality management, Analytical methods and Data Analysis. EMQAL promotes mobility. The students will attend one academic year of lectures in one of the European universities of the EMQAL consortium, and a 12 months master thesis at other European university, with the possibility to spend three-months in one of the non-EU partners. The language of instruction and examination is English. Further information is available at www.emqal.org.

Reliability analysis of medium voltage feeder

Distribution companies are facing numerous challenges in the near future. Regulation defines correlation between power quality and revenue cap. Companies have to take measures for reliability increase to successfully compete in modern conditions. Most of the failures seen by customers originate in medium voltage networks. Implementation of network automation is the very effective measure to reduce duration and number of outages, and consequently, outage costs. Topic of this diploma work is study of automation investments effect on outage costs and other reliability indices. Calculation model have been made to perform needed reliability calculations. Theoretical study of different automation scenarios has been done. Case feeder from actual distribution company has been studied and various renovation plans have been suggested. Network automation proved to be effective measure for increasing medium voltage network reliability.

Dimensioning DC-voltage capacitor for a DC-distribution system and dynamic analysis

Technical analysis of Low Voltage Direct Current (LVDC) distribution systems shows that in LVDC transmission the customer voltage quality is higher. One of the problems in LVDC distribution networks that converters both ends of the DC line are required. Because of the converters produce not pure DC voltage, but some fluctuations as well, the huge electrolytic capacitors are required to reduce voltage distortions in the DC-side. This thesis master’s thesis is focused on calculating required DC-link capacitance for LVDC transmission and estimation of the influence of different parameters on the voltage quality. The goal is to investigate the methods of the DC-link capacitance estimation and location in the transmission line.

Cooking and Active Leisure TAS Program, Spain: A Program Impact Pathways (PIP) analysis

Background. The “Cooking and Active Leisure” Tu y Alícia por la Salud (CAL-TAS) Program is a schoolbased pilot that addresses healthy lifestyle needs of Spanish secondary school students with initiatives that research has proven to improve dietary and physical activity behaviors. Objective. The objectives were to perform a Program Impact Pathways (PIP) analysis to describe key activities and processes of the CAL-TAS Program, identify Critical Quality Control Points (CCPs), and identify a suite of common indicators of healthy lifestyles to be applied across participant schools. Methods. The CAL-TAS Program designers and implementation team developed this PIP analysis through an iterative process and presented the results for feedback at the seven-country Healthy Lifestyles Program Evaluation Workshop held in Granada, Spain, 13–14 September 2013, under the auspices of the Mondelēz International Foundation. Results. The team identified three PIP CCPs: teachers’ motivation and training, changes in students’ knowledge of healthy lifestyles, and changes in students’ healthy lifestyle behavior. The selected indicators of the program’s impact on healthy lifestyles are adequacy of food intake, level of knowledge of healthy lifestyles gained, and adequacy of physical activity level according to World Health Organization recommendations. A clear definition of impact indicators, as well as collection of accurate data on healthy lifestyle behaviors and knowledge, is essential to understanding the effectiveness of this program before it can be scaled up. Conclusions. CAL-TAS is an effective secondary school-based program encouraging healthy lifestyles. The PIP analysis was instrumental in identifying CCPs to sustain and improve the quality of the program. The team hopes to sustain and improve the program through these program evaluation recommendations.

Computational Techniques for Spectral Image Analysis

Multispectral images are becoming more common in the field of remote sensing, computer vision, and industrial applications. Due to the high accuracy of the multispectral information, it can be used as an important quality factor in the inspection of industrial products. Recently, the development on multispectral imaging systems and the computational analysis on the multispectral images have been the focus of a growing interest. In this thesis, three areas of multispectral image analysis are considered. First, a method for analyzing multispectral textured images was developed. The method is based on a spectral cooccurrence matrix, which contains information of the joint distribution of spectral classes in a spectral domain. Next, a procedure for estimating the illumination spectrum of the color images was developed. Proposed method can be used, for example, in color constancy, color correction, and in the content based search from color image databases. Finally, color filters for the optical pattern recognition were designed, and a prototype of a spectral vision system was constructed. The spectral vision system can be used to acquire a low dimensional component image set for the two dimensional spectral image reconstruction. The data obtained by the spectral vision system is small and therefore convenient for storing and transmitting a spectral image.

Validation of an instrument to evaluate quality of life in the aging population: WHOQOL-AGE.

BACKGROUND: There is a need for short, specific instruments that assess quality of life (QOL) adequately in the older adult population. The aims of the present study were to obtain evidence on the validity of the inferences that could be drawn from an instrument to measure QOL in the aging population (people 50+ years old), and to test its psychometric properties. METHODS: The instrument, WHOQOL-AGE, comprised 13 positive items, assessed on a five-point rating scale, and was administered to nationally representative samples (n = 9987) from Finland, Poland, and Spain. Cronbach's alpha was employed to assess internal consistency reliability, whereas the validity of the questionnaire was assessed by means of factor analysis, graded response model, Pearson's correlation coefficient and unpaired t-test. Normative values were calculated across countries and for different age groups. RESULTS: The satisfactory goodness-of-fit indices confirmed that the factorial structure of WHOQOL-AGE comprises two first-order factors. Cronbach's alpha was 0.88 for factor 1, and 0.84 for factor 2. Evidence supporting a global score was found with a second-order factor model, according to the goodness-of-fit indices: CFI = 0.93, TLI = 0.91, RMSEA = 0.073. Convergent validity was estimated at r = 0.75 and adequate discriminant validity was also found. Significant differences were found between healthy individuals (74.19 ± 13.21) and individuals with at least one chronic condition (64.29 ± 16.29), supporting adequate known-groups validity. CONCLUSIONS: WHOQOL-AGE has shown good psychometric properties in Finland, Poland, and Spain. Therefore, considerable support is provided to using the WHOQOL-AGE to measure QOL in older adults in these countries, and to compare the QOL of older and younger adults.