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.

Design, conduct, and analysis of a multicenter, pharmacogenomic, biomarker study in matched patients with severe sepsis treated with or without drotrecogin Alfa (activated)

A genomic biomarker identifying patients likely to benefit from drotrecogin alfa (activated) (DAA) may be clinically useful as a companion diagnostic. This trial was designed to validate biomarkers (improved response polymorphisms (IRPs)). Each IRP (A and B) contains two single nucleotide polymorphisms that were associated with a differential DAA treatment effect.

Better conduct of clinical trials: the control group in critical care trials

OBJECTIVE: To review trial design issues related to control groups. DESIGN: Review of the literature with specific reference to critical care trials. MAIN RESULTS AND CONCLUSIONS: Performing randomized controlled trials in the critical care setting presents specific problems: studies include patients with rapidly lethal conditions, the majority of intensive care patients suffer from syndromes rather than from well-definable diseases, the severity of such syndromes cannot be precisely assessed, and the treatment consists of interacting therapies. Interactions between physiology, pathophysiology, and therapies are at best marginally understood and may have a major impact on study design and interpretation of results. Selection of the right control group is crucial for the interpretation and clinical implementation of results. Studies comparing new interventions with current ones or different levels of current treatments have the problem of the necessity of defining "usual care." Usual care controls without any constraints typically include substantial heterogeneity. Constraints in the usual therapy may help to reduce some variation. Inclusion of unrestricted usual care groups may help to enhance safety. Practice misalignment is a novel problem in which patients receive a treatment that is the direct opposite of usual care, and occurs when fixed-dose interventions are used in situations where care is normally titrated. Practice misalignment should be considered in the design and interpretation of studies on titrated therapies.

Refinement of experimental design and conduct in laboratory animal research.

The scientific literature of laboratory animal research is replete with papers reporting poor reproducibility of results as well as failure to translate results to clinical trials in humans. This may stem in part from poor experimental design and conduct of animal experiments. Despite widespread recognition of these problems and implementation of guidelines to attenuate them, a review of the literature suggests that experimental design and conduct of laboratory animal research are still in need of refinement. This paper will review and discuss possible sources of biases, highlight advantages and limitations of strategies proposed to alleviate them, and provide a conceptual framework for improving the reproducibility of laboratory animal research.

RELATIONSHIP OF ANTISOCIAL PERSONALITY SYNDROME IN BOYS TO PARENTAL ALCOHOL/DRUG DEPENDENCY

The study focused on the relationship between antisocial personality syndrome in boys ages 8-15 and parental alcohol/drug dependency. The population studied was case records of 101 boys coming to a private psychiatrist from 1966 through 1979. The boys were predominantly white and from middle to upper income families.^ A boy was determined to have antisocial personality syndrome if he exhibited antisocial behaviors in four or five major categories, did not exhibit a brain syndrome, and did not exhibit a thought disorder. The five major behavior categories were: (1) self-control (i.e., temper tantrums or hyperactivity), (2) behavior at home (i.e., disobedience or lying), (3) behavior at school (i.e., truancy or cheating), (4) behavior toward peers (i.e., bullying, fighting, or tattling), and (5) behavior against property (i.e., destructiveness or stealing). A boy was determined to be a control if he exhibited antisocial behaviors in two or less behavior categories.^ A parent was determined to have alcohol/drug dependency if s/he exhibited a score above the established threshold (1) for the MacAndrew Alcoholism Scale (28 or above), and (2) for the Holmes Alcoholism Scale (35 or above) which are used with the MMPI. A parent was classified not alcohol/drug dependent if s/he had scores below set thresholds (22 on the MacAndrew Alcoholism Scale and 28 on the Holmes Alcoholism Scale).^ For the final sample (N = 10), there was no reason to believe a relationship exists between antisocial personality syndrome in boys ages 8-15 and parental alcohol/drug dependency (Fisher's Exact Test {FET} P = 1.0). The small sample size primarily occurred as a result of 88.12% of the parents being classified in a questionable category in terms of alcohol/drug dependency.^ The sample was suggestive of a relationship between the fathers' Psychopathic Deviate (Pd) Scale scores as a measure of antisocial tendencies and the boy having antisocial personality syndrome (N = 75; P = .12). There was no evidence of such a relationship for mothers (N = 75; P = .97). ^

Regime survival strategies and the conduct of foreign policy in Egypt

エジプトではムバーラク大統領の国内政策と域内におけるエジプトの影響力低迷が引き金となって、2011年1月25日に抗議運動起こった。抗議運動はエジプト全土に拡がり、18日間の民衆的な反体制運動によってムバーラクは軍に見捨てられ、失脚に追い込まれた。この民衆蜂起によって警察は街頭から撤退し、シナイ半島の警察署は焼き放たれ、ムバーラクが率いていた国民民主党の建物や国内治安機関の本部は襲撃され、国家機関が数ヶ月にもわたって機能不全となり、ムバーラク体制の崩壊は国内的な混乱を招くこととなった。振り返れば、エジプトでの政治的大変動は社会的な革命へと展開することはできなかった。その理由は独裁体制からの移行を先導できる組織化された反体制勢力が存在しなかったためである。民衆による抗議運動は一時的に体制を転覆できても旧体制のエリートを分裂させることはできず、軍の影響下にある体制の復活を防ぐこともできなかった。2011年以降のエジプトは現在まで混乱状態に陥ったままであるが、1カ月に及ぶエジプト軍最高評議会(SCAF)の暫定統治、エジプト史上初の自由な大統領選挙によって選出された文民大統領のムルスィーによる一年余りの統治、そして2013年7月の軍事クーデターによって権力の座に就いたスィースィーの統治といった過程で、民衆蜂起がエジプトの外交関係に及ぼした影響はごく僅かであった。本稿は、現在のエジプトの外交政策が2011年の革命にほとんど影響を受けていないのはなぜか、またエジプトの統治者たちが政権の正統性、体制の強化および政治的な安定性を確保し、国内的な課題に対処するための戦略をいかに策定しているのかを説明することを試みる。本稿での主張は、ムバーラク以降のエジプトが体制の強化と保全のために外交政策を進めており、国内的な混乱によって地域内アクターへの依存度が高まっていることである。