Proposal on How To Conduct a Biopharmaceutical Process Failure Mode and Effect Analysis (FMEA) as a Risk Assessment Tool

With the publication of the quality guideline ICH Q9 "Quality Risk Management" by the International Conference on Harmonization, risk management has already become a standard requirement during the life cycle of a pharmaceutical product. Failure mode and effect analysis (FMEA) is a powerful risk analysis tool that has been used for decades in mechanical and electrical industries. However, the adaptation of the FMEA methodology to biopharmaceutical processes brings about some difficulties. The proposal presented here is intended to serve as a brief but nevertheless comprehensive and detailed guideline on how to conduct a biopharmaceutical process FMEA. It includes a detailed 1-to-10-scale FMEA rating table for occurrence, severity, and detectability of failures that has been especially designed for typical biopharmaceutical processes. The application for such a biopharmaceutical process FMEA is widespread. It can be useful whenever a biopharmaceutical manufacturing process is developed or scaled-up, or when it is transferred to a different manufacturing site. It may also be conducted during substantial optimization of an existing process or the development of a second-generation process. According to their resulting risk ratings, process parameters can be ranked for importance and important variables for process development, characterization, or validation can be identified. LAY ABSTRACT: Health authorities around the world ask pharmaceutical companies to manage risk during development and manufacturing of pharmaceuticals. The so-called failure mode and effect analysis (FMEA) is an established risk analysis tool that has been used for decades in mechanical and electrical industries. However, the adaptation of the FMEA methodology to pharmaceutical processes that use modern biotechnology (biopharmaceutical processes) brings about some difficulties, because those biopharmaceutical processes differ from processes in mechanical and electrical industries. The proposal presented here explains how a biopharmaceutical process FMEA can be conducted. It includes a detailed 1-to-10-scale FMEA rating table for occurrence, severity, and detectability of failures that has been especially designed for typical biopharmaceutical processes. With the help of this guideline, different details of the manufacturing process can be ranked according to their potential risks, and this can help pharmaceutical companies to identify aspects with high potential risks and to react accordingly to improve the safety of medicines.

Treatment failure in pneumonia: Impact of antibiotic treatment and cost analysis

The aim of this study was to investigate treatment failure (TF) in hospitalised community-acquired pneumonia (CAP) patients with regard to initial antibiotic treatment and economic impact. CAP patients were included in two open, prospective multicentre studies assessing the direct costs for in-patient treatment. Patients received treatment either with moxifloxacin (MFX) or a nonstandardised antibiotic therapy. Any change in antibiotic therapy after >72 h of treatment to a broadened antibiotic spectrum was considered as TF. Overall, 1,236 patients (mean ± SD age 69.6 ± 16.8 yrs, 691 (55.9%) male) were included. TF occurred in 197 (15.9%) subjects and led to longer hospital stay (15.4 ± 7.3 days versus 9.8 ± 4.2 days; p < 0.001) and increased median treatment costs (€2,206 versus €1,284; p<0.001). 596 (48.2%) patients received MFX and witnessed less TF (10.9% versus 20.6%; p < 0.001). After controlling for confounders in multivariate analysis, adjusted risk of TF was clearly reduced in MFX as compared with β-lactam monotherapy (adjusted OR for MFX 0.43, 95% CI 0.27-0.68) and was more comparable with a β-lactam plus macrolide combination (BLM) (OR 0.68, 95% CI 0.38-1.21). In hospitalised CAP, TF is frequent and leads to prolonged hospital stay and increased treatment costs. Initial treatment with MFX or BLM is a possible strategy to prevent TF, and may thus reduce treatment costs.

Effect of preventive interventions in mentally ill parents on the mental health of the offspring: systematic review and meta-analysis

Mental illness in parents affects the mental health of their children. A systematic review and a meta-analysis of the effectiveness of interventions to prevent mental disorders or psychological symptoms in the offspring were performed.

Effect of psychological interventions on depressive symptoms in long-term rehabilitation after an acquired brain injury: a systematic review and meta-analysis

OBJECTIVE To summarize empirical studies on the effectiveness of psychological interventions in long-term rehabilitation after an acquired brain injury (ABI) in reducing depressive symptoms. DATA SOURCES A systematic literature search was conducted on MEDLINE, PsycINFO, Embase, and CINAHL to identify articles published between January 1990 and October 2011. Search terms included the 3 concepts (1) "brain injur*" or "stroke," (2) "psychotherap*" or "therapy" or "intervention" or "rehabilitation," and (3) "depress*." STUDY SELECTION Studies evaluating psychological interventions in patients after ABI were included. Time since injury was on average more than 1 year. Trials reported data on validated depression questionnaires before and after the psychological intervention. DATA EXTRACTION Two independent reviewers extracted information from the sample, the intervention, and the outcome of the included studies and calculated effect sizes (ESs) from depression questionnaires. Thirteen studies were included in a pre-post analysis. Seven studies were eligible for a meta-analysis of ESs in active interventions and control conditions. DATA SYNTHESIS Pre-post ESs were significant in 4 of 13 studies. The overall ES of .69 (95% confidence interval [CI], .29-1.09) suggests a medium effectiveness of psychological interventions on depressive symptoms compared with control conditions. Moderator analysis of the number of sessions and adequate randomization procedure did not show significant ES differences between strata. Studies with adequate randomization did not, however, suggest the effectiveness of psychological interventions on depressive symptoms after ABI. CONCLUSIONS Psychological interventions are a promising treatment option for depressive symptoms in long-term rehabilitation after ABI. Since only a few adequately randomized controlled trials (RCTs) exist, more RCTs are required to confirm this initial finding.

Time-order errors and standard-position effects in duration discrimination: An experimental study and an analysis by the sensation-weighting model

Studies have shown that the discriminability of successive time intervals depends on the presentation order of the standard (St) and the comparison (Co) stimuli. Also, this order affects the point of subjective equality. The first effect is here called the standard-position effect (SPE); the latter is known as the time-order error. In the present study, we investigated how these two effects vary across interval types and standard durations, using Hellström’s sensation-weighting model to describe the results and relate them to stimulus comparison mechanisms. In Experiment 1, four modes of interval presentation were used, factorially combining interval type (filled, empty) and sensory modality (auditory, visual). For each mode, two presentation orders (St–Co, Co–St) and two standard durations (100 ms, 1,000 ms) were used; half of the participants received correctness feedback, and half of them did not. The interstimulus interval was 900 ms. The SPEs were negative (i.e., a smaller difference limen for St–Co than for Co–St), except for the filled-auditory and empty-visual 100-ms standards, for which a positive effect was obtained. In Experiment 2, duration discrimination was investigated for filled auditory intervals with four standards between 100 and 1,000 ms, an interstimulus interval of 900 ms, and no feedback. Standard duration interacted with presentation order, here yielding SPEs that were negative for standards of 100 and 1,000 ms, but positive for 215 and 464 ms. Our findings indicate that the SPE can be positive as well as negative, depending on the interval type and standard duration, reflecting the relative weighting of the stimulus information, as is described by the sensation-weighting model.

Push-out bond strength of CAD/CAM-ceramic luted to dentin with self-adhesive resin cements

OBJECTIVES: This study evaluated the initial and the artificially aged push-out bond strength between ceramic and dentin produced by one of five resin cements. METHODS: Two-hundred direct ceramic restorations (IPS Empress CAD) were luted to standardized Class I cavities in extracted human molars using one of four self-adhesive cements (SpeedCEM, RelyX Unicem Aplicap, SmartCem2 and iCEM) or a reference etch-and-rinse resin cement (Syntac/Variolink II) (n=40/cement). Push-out bond strength (PBS) was measured (1) after 24h water storage (non-aged group; n=20/cement) or (2) after artificial ageing with 5000 thermal cycles followed by 6 months humid storage (aged group; n=20/cement). Nonparametrical ANOVA and pairwise Wilcoxon rank-sum tests with Bonferroni-Holm adjustment were applied for statistical analysis. The significance level was set at alpha=0.05. In addition, failure mode and fracture pattern were analyzed by stereomicroscope and scanning electron microscopy. RESULTS: Whereas no statistically significant effect of storage condition was found (p=0.441), there was a significant effect of resin cement (p<0.0001): RelyX Unicem showed significantly higher PBS than the other cements. Syntac/Variolink II showed significantly higher PBS than SmartCEM2 (p<0.001). No significant differences were found between SpeedCEM, SmartCem2, and iCEM. The predominant failure mode was adhesive failure of cements at the dentin interface except for RelyX Unicem which in most cases showed cohesive failure in ceramic. SIGNIFICANCE: The resin cements showed marked differences in push-out bond strength when used for luting ceramic restorations to dentin. Variolink II with the etch-and-rinse adhesive Syntac did not perform better than three of the four self-adhesive resin cements tested.

Exercise training in heart failure: from theory to practice. A consensus document of the Heart Failure Association and the European Association for Cardiovascular Prevention and Rehabilitation

The European Society of Cardiology heart failure guidelines firmly recommend regular physical activity and structured exercise training (ET), but this recommendation is still poorly implemented in daily clinical practice outside specialized centres and in the real world of heart failure clinics. In reality, exercise intolerance can be successfully tackled by applying ET. We need to encourage the mindset that breathlessness may be evidence of signalling between the periphery and central haemodynamic performance and regular physical activity may ultimately bring about favourable changes in myocardial function, symptoms, functional capacity, and increased hospitalization-free life span and probably survival. In this position paper, we provide practical advice for the application of exercise in heart failure and how to overcome traditional barriers, based on the current scientific and clinical knowledge supporting the beneficial effect of this intervention.

Efficacy of communication skills training courses in oncology: a systematic review and meta-analysis

Objective: Group training in communication skills [communication skills training (CST)] has become partly mandatory for oncology staff. However, so far, a comprehensive meta-analysis on the efficacy is lacking. Design: Included studies either compare the efficacy of a specific training with a control group or look at the additional effect of booster sessions on communication behaviour, attitudes or patient outcomes. Methods: Four electronic databases were searched up to July 2008 without language restriction, and reference lists of earlier reviews were screened. Effect sizes (ESs) were extracted and pooled in random effects meta-analyses. Results: We included 13 trials (three non-randomised), 10 with no specific intervention in the control group. Meta-analysis showed a moderate effect of CST on communication behaviour ES = 0.54. Three trials compared basic training courses with more extensive training courses and showed a small additional effect on communication skills ES = 0.37. Trials investigating participants' attitudes ES = 0.35 and patient outcomes ES = 0.13 (trend) confirmed this effect. Conclusions: Training health professionals by CST is a promising approach to change communication behaviour and attitudes. Patients might also benefit from specifically trained health professionals but strong studies are lacking. However, feasibility and economic aspects have to be kept in mind when considering providing a training of optimal length.

Association between variants of the leptin receptor gene (LEPR) and overweight: a systematic review and an analysis of the CoLaus study

Background Three non-synonymous single nucleotide polymorphisms (Q223R, K109R and K656N) of the leptin receptor gene (LEPR) have been tested for association with obesity-related outcomes in multiple studies, showing inconclusive results. We performed a systematic review and meta-analysis on the association of the three LEPR variants with BMI. In addition, we analysed 15 SNPs within the LEPR gene in the CoLaus study, assessing the interaction of the variants with sex. Methodology/Principal Findings We searched electronic databases, including population-based studies that investigated the association between LEPR variants Q223R, K109R and K656N and obesity- related phenotypes in healthy, unrelated subjects. We furthermore performed meta-analyses of the genotype and allele frequencies in case-control studies. Results were stratified by SNP and by potential effect modifiers. CoLaus data were analysed by logistic and linear regressions and tested for interaction with sex. The meta-analysis of published data did not show an overall association between any of the tested LEPR variants and overweight. However, the choice of a BMI cut-off value to distinguish cases from controls was crucial to explain heterogeneity in Q223R. Differences in allele frequencies across ethnic groups are compatible with natural selection of derived alleles in Q223R and K109R and of the ancient allele in K656N in Asians. In CoLaus, the rs10128072, rs3790438 and rs3790437 variants showed interaction with sex for their association with overweight, waist circumference and fat mass in linear regressions. Conclusions Our systematic review and analysis of primary data from the CoLaus study did not show an overall association between LEPR SNPs and overweight. Most studies were underpowered to detect small effect sizes. A potential effect modification by sex, population stratification, as well as the role of natural selection should be addressed in future genetic association studies.

Role of hepatitis C virus genotype 3 in liver fibrosis progression - a systematic review and meta-analysis

The progression of liver fibrosis in chronic hepatitis C has long been considered to be independent from viral genotypes. However, recent studies suggest an association between Hepatitis C virus (HCV) genotype 3 and accelerated liver disease progression. We completed a systematic review and meta-analysis of studies evaluating the association between HCV genotypes and fibrosis progression. PubMed, Embase and ISI Web of Knowledge databases were searched for cohort, cross-sectional and case-control studies on treatment-naïve HCV-infected adults in which liver fibrosis progression rate (FPR) was assessed by the ratio of fibrosis stage in one single biopsy to the duration of infection (single-biopsy studies) or from the change in fibrosis stage between two biopsies (paired biopsies studies). A random effect model was used to derive FPR among different HCV genotypes. Eight single-biopsy studies (3182 patients, mean/median duration of infection ranging from 9 to 21 years) and eight paired biopsies studies (mean interval between biopsies 2-12 years) met the selection criteria. The odds ratio for the association of genotype 3 with accelerated fibrosis progression was 1.52 (95% CI 1.12-2.07, P = 0.007) in single-biopsy studies and 1.37 (95% CI 0.87-2.17, P = 0.17) in paired biopsy studies. In conclusion, viral genotype 3 was associated with faster fibrosis progression in single-biopsy studies. This observation may have important consequences on the clinical management of genotype 3-infected patients. The association was not significant in paired biopsies studies, although the latter may be limited by important indication bias, short observation time and small sample size.

Thrombophilia and outcomes of assisted reproduction technologies: a systematic review and meta-analysis

Thrombophilia has been associated with pregnancy complications and recurrent miscarriage. The aim of this systematic review was to evaluate the controversial association between thrombophilia and failures of assisted reproduction technology (ART). A systematic search of the literature for studies reporting on thrombophilia in women undergoing ART up to April 2011 yielded 33 studies (23 evaluating anti-phospholipid antibodies, 5 inherited thrombophilia, and 5 both) involving 6092 patients. Overall, methodologic quality of the studies was poor. Combined results from case-control studies showed that factor V Leiden was significantly more prevalent among women with ART failure compared with fertile parous women or those achieving pregnancy after ART (odds ratio = 3.08; 95% confidence interval, 1.77-5.36). The prothrombin mutation, methylenetetrahydrofolate reductase mutation, deficiency of protein S, protein C, or anti-thrombin were all not associated with ART failure. Women with ART failure tested more frequently positive for anti-phospholipids antibodies (odds ratio = 3.33; 95% confidence interval, 1.77-6.26) with evidence of high degree of between-study heterogeneity (I(2) = 75%; P < .00001). Prospective cohort studies did not show significant associations between thrombophilia and ART outcomes. Although case-control studies suggest that women experiencing ART failures are more frequently positive for factor V Leiden and anti-phospholipid antibodies, the evidence is inconclusive and not supported by cohort studies.

Self-etch primers and conventional acid-etch technique for orthodontic bonding: a systematic review and meta-analysis

The use of self-etch primers has increased steadily because of their time savings and greater simplicity; however, overall benefits and potential disadvantages and harms have not been assessed systematically. In this study, we reviewed randomized controlled trials to assess the risk of attachment failure, bonding time, and demineralization adjacent to attachments between 1-stage (self-etch) and 2-stage (acid etch) bonding in orthodontic patients over a minimum follow-up period of 12 months.

Anthracyclines during induction therapy in acute myeloid leukaemia: a systematic review and meta-analysis

This systematic review and meta-analysis compared the efficacy of different anthracyclines and anthracycline dosing schedules for induction therapy in acute myeloid leukaemia in children and adults younger than 60 years of age. Twenty-nine randomized controlled trials were eligible for inclusion in the review. Idarubicin (IDA), in comparison to daunorubicin (DNR), reduced remission failure rates (risk ratio (RR) 0·81; 95% confidence interval (CI), 0·66-0·99; P = 0·04), but did not alter rates of early death or overall mortality. Superiority of IDA for remission induction was limited to studies with a DNR/IDA dose ratio <5 (ratio <5: RR 0·65; 95% CI, 0·51-0·81; P < 0·001; ratio ≥5: RR 1·03; 95% CI, 0·91-1·16; P = 0·63). Higher-dose DNR, compared to lower-dose DNR, was associated with reduced rates for remission failure (RR 0·75; 95% CI, 0·60-0·94; P = 0·003) and overall mortality (RR 0·83; 95% CI, 0·75-0·93; P < 0·001), but not for early death. Comparisons of several other anthracycline derivates did not reveal significant differences in outcomes. Survival estimates in adults suggest that both high-dose DNR (90 mg/m(2) daily × 3 or 50 mg/m(2) daily × 5) and IDA (12 mg/m(2) daily × 3) can achieve 5-year survival rates of between 40 and 50 percent.

Hylan versus hyaluronic acid for osteoarthritis of the knee: a systematic review and meta-analysis

OBJECTIVE: To compare the effectiveness and safety of intraarticular high-molecular hylan with standard preparations of hyaluronic acids in osteoarthritis of the knee. METHODS: We performed a systematic review and meta-analysis of randomized controlled trials comparing hylan with a hyaluronic acid in patients with knee osteoarthritis. Trials were identified by systematic searches of Central, Medline, EMBase, Cinahl, the Food and Drug Administration, and Science Citation Index supplemented by hand searches of conference proceedings and reference lists (last update November 2006). Literature screening and data extraction were performed in duplicate. Effect sizes were calculated from differences in means of pain-related outcomes between treatment and control groups at the end of the trial, divided by the pooled standard deviation. Trials were combined using random-effects meta-analysis. RESULTS: Thirteen trials with a pooled total of 2,085 patients contributed to the meta-analysis. The pooled effect size was -0.27 (95% confidence interval [95% CI] -0.55, 0.01), favoring hylan, but between-trial heterogeneity was high (I(2) = 88%). Trials with blinded patients, adequate concealment of allocation, and an intent-to-treat analysis had pooled effect sizes near null. The meta-analyses on safety revealed an increased risk associated with hylan for any local adverse events (relative risk [RR] 1.91; 95% CI 1.04, 3.49; I(2) = 28%) and for flares (RR 2.04; 95% CI 1.18, 3.53; I(2) = 0%). CONCLUSION: Given the likely lack of a superior effectiveness of hylan over hyaluronic acids and the increased risk of local adverse events associated with hylan, we discourage the use of intraarticular hylan in patients with knee osteoarthritis in clinical research or practice.