Role of Knowledge Management in Development and Lifecycle Management of Biopharmaceuticals

Knowledge Management (KM) is a key enabler for achieving quality in a lifecycle approach for production of biopharmaceuticals. Due to the important role that it plays towards successful implementation of Quality by Design (QbD), an analysis of KM solutions is needed. This work provides a comprehensive review of the interface between KM and QbD-driven biopharmaceutical production systems as perceived by academic as well as industrial viewpoints. A comprehensive set of 356 publications addressing the applications of KM tools to QbD-related tasks were screened and a query to gather industrial inputs from 17 major biopharmaceutical organizations was performed. Three KM tool classes were identified as having high relevance for biopharmaceutical production systems and have been further explored: knowledge indicators, ontologies, and process modeling. A proposed categorization of 16 distinct KM tool classes allowed for the identification of holistic technologies supporting QbD. In addition, the classification allowed for addressing the disparity between industrial and academic expectations regarding the application of KM methodologies. This is a first of a kind attempt and thus we think that this paper would be of considerable interest to those in academia and industry that are engaged in accelerating development and commercialization of biopharmaceuticals.     

Determinants to immunization information system implementation in independent community pharmacies

BackgroundImmunization information systems (IISs) facilitate consolidated vaccination data within each state. Many have limited pharmacy participation, especially Alabama. As pharmacists increasingly engage in delivery of vaccines recommended across the life span, it is critical to understand the barriers to IIS implementation, particularly in rural community pharmacies where access to primary care may be limited.ObjectiveThe purpose of this study was to identify barriers and facilitators to IIS implementation in rural, independent community pharmacies in Alabama.MethodsQualitative interviews with rural, independent community pharmacy personnel and IIS experts in both states with high IIS participation and Alabama (state with low IIS participation) were conducted. States with high participation were identified as those with ≥75% of adults recorded in their respective state IIS. Less than 25% of Alabama adults were recorded in the state IIS at the time of this study. Deductive coding using CFIR constructs was conducted with a second coder to ensure inter-rater reliability. CFIR Rating Rules were applied to the coded data to allow for identification of constructs that have the greatest impact on implementation.ResultsA total of twenty-five participants (16 pharmacy personnel; 9 IIS experts) were interviewed. During interviews, 32 of 39 CFIR constructs were mentioned and 11 constructs with a strong influence (+2 or ?2) were identified. These included, “adaptability”, “complexity”, “compatibility”, “available resources”, “access to knowledge and information”, “needs and resources of those served by the organization”, “peer pressure”, “external policy and initiatives”, “knowledge and beliefs about the innovation”, “engaging key stakeholders”, and “engaging innovation participants”.ConclusionsThis qualitative study explored perceived barriers and facilitators to IIS implementation in the rural, independent community pharmacy setting from the perspectives of pharmacy personnel and IIS experts. Factors identified can be used to inform the development of resources and implementation strategies to improve IIS uptake and participation.     

Improving lead generation success through integrated methods: transcending 'drug discovery by numbers'

Key methodologies such as HTS and combinatorial chemistry have allowed pharmaceutical discovery to focus on identifying promising drug candidates through the use of statistics. Thus, amassing large data sets from large-scale screening campaigns of ever-increasing corporate compound collections was expected to deliver unprecedented success for the pharmaceutical industry. This feature review explores aspects of how the reliance on using numbers to drive discovery has gone awry. Building knowledge equity from the integration of multiple parallel screening assays, workstreams and data sources provides an alternative to driving discovery through statistics. Thus, a more rational approach to creating and inventing new leads and drug opportunities may be pursued.     

我院单剂量全自动药品分包机质量与安全管理及实施体会

目的：建立单剂量全自动药品分包机的质量与安全管理模式。方法：结合我院各病区、中心药房工作要求及单剂量全自动药品分包机的特点,从药品管理、设备管理、工作流程、应急预案等方面逐步建立管理规定并组织实施。结果：确保全自动药品分包机高效、安全运行,为病人提供高质量的药学服务。     

Fine particles: from scientific uncertainty to policy strategy

Gaps in our knowledge should not be a reason for not making policy decisions. How can we define robust policy strategies, given the various uncertainties in the sources, exposure, and causes of health effects? Which uncertainties are most important? What are its policy implications? This contribution will describe policy strategies for particulate matter (PM) abatement that are consistent with certain sets of assumptions, as well as the risks that are associated with such strategies. What is an optimal strategy assuming that the fine particles (PM2.5) are the main cause of health effects? And what would be the "mistake" of such a strategy, if "in the end" PM10 or carbonaceous particles prove to be the "real" cause? How can we make the policy strategy more robust and minimise its financial risks and health risks? This contribution describes a systematic way of dealing with the knowledge gaps in the policy process.     

青霉素生产工艺优化及代谢分析提高产量

青霉素作为第一个被应用的β-内酰胺类抗生素，至今仍在医疗健康领域发挥着重要作用。在产黄青霉补料分批发酵的传统工艺中，青霉素合成速率在100h左右开始快速下降。针对这一问题，本文设计了后期倒种和后期补盐两种工艺优化策略，对传统工艺加以改进。结果表明，后期倒种工艺中，发酵250h后仍具有较高的青霉素合成速率，但后期倒种使大量仍具有较强青霉素合成能力的菌体流失，造成严重浪费。后期补盐工艺中，发酵终末青霉素总产量以及产物对糖得率分别较原始工艺提高了28.46%和34.55%。对细胞代谢途径及菌体形态等的进一步探讨表明，传统工艺发酵后期包括磷源及金属离子在内的痕量营养物质的不足会影响菌体的生长，并且抑制前体氨基酸及NADPH的合成，从而造成了青霉素产率的下降，菌株自身的发酵效率潜力依旧可以挖掘。     

Workshop on trichothecenes with a focus on DON: summary report

A number of mycotoxins of the class of trichothecenes are produced by a variety of Fusarium fungi commonly found on cereals. Unfavourable weather conditions may lead to a high level of Fusarium infections in crops such as wheat and correspondingly high trichothecene contents. The ILSI Europe Natural Toxin Task Force therefore organised a workshop on trichothecenes with a special focus on deoxynivalenol (DON). A number of experts reviewed the current knowledge on trichothecenes with respect to occurrence, including aspects of mould growth, toxin formation, storage and effects of processing; prevention; analytical methodologies, including sampling; surveillance and exposure assessments; and toxicology and risk assessment. A number of recommendations were given under the headings: prevention, sampling and analytical methods, exposure assessment, and toxicology. Gaps in knowledge were also identified.     

Multidisciplinary DEprescribing review for Frail oldER adults in long-term care (DEFERAL): Implementation strategy design using behaviour science tools and stakeholder engagement

IntroductionDeprescribing is a strategy for reducing the use of potentially inappropriate medications for older adults. Limited evidence exists on the development of strategies to support healthcare professionals (HCPs) deprescribing for frail older adults in long-term care (LTC).ObjectiveTo design an implementation strategy, informed by theory, behavioural science and consensus from HCPs, which facilitates deprescribing in LTC.MethodsThis study was consisted of 3 phases. First, factors influencing deprescribing in LTC were mapped to behaviour change techniques (BCTs) using the Behaviour Change Wheel and two published BCT taxonomies. Second, a Delphi survey of purposively sampled HCPs (general practitioners, pharmacists, nurses, geriatricians and psychiatrists) was conducted to select feasible BCTs to support deprescribing. The Delphi consisted of two rounds. Using Delphi results and literature on BCTs used in effective deprescribing interventions, BCTs which could form an implementation strategy were shortlisted by the research team based on acceptability, practicability and effectiveness. Finally, a roundtable discussion was held with a purposeful, convenience sample of LTC general practitioners, pharmacists and nurses to prioritise factors influencing deprescribing and tailor the proposed strategies for LTC.ResultsFactors influencing deprescribing in LTC were mapped to 34 BCTs. The Delphi survey was completed by 16 participants. Participants reached consensus that 26 BCTs were feasible. Following the research team assessment, 21 BCTs were included in the roundtable. The roundtable discussion identified lack of resources as the primary barrier to address. The agreed implementation strategy incorporated 11 BCTs and consisted of an education-enhanced 3-monthly multidisciplinary team deprescribing review, led by a nurse, conducted at the LTC site.ConclusionThe deprescribing strategy incorporates HCPs’ experiential understanding of the nuances of LTC and thus addresses systemic barriers to deprescribing in this context. The strategy designed addresses five determinants of behaviour to best support HCPs engaging with deprescribing.     

Advances in knowledge management for pharmaceutical research and development

There are two assumptions that are taken for granted in the pharmaceutical industry today. Firstly, that we can generate an unprecedented amount of drug-related information along the research and development (R&D) pipeline, and secondly, that researchers are more connected to each other than they have ever been, owing to the internet revolution of the past 15 years or so. Both of these aspects of the modern pharmaceutical company have brought many benefits to the business. However, the pharmaceutical industry is currently under fire due to allegations of decreased productivity despite significant investments in R&D, which if left to continue at the present pace, will reach almost US 60 billion dollars by 2006. This article explores the role of knowledge in the industry and reviews recent developments and emerging opportunities in the field of knowledge management (KM) as it applies to pharmaceutical R&D. It is argued that systematic KM will be increasingly necessary to optimize the value of preceding advances in high-throughput approaches to R&D, and to fully realize the anticipated increase in productivity. The application of KM principles and practices to the business can highlight opportunities for balancing the current reliance on blockbuster drugs with a more patient-centric focus on human health, which is now becoming possible.     

Adaptive designs in clinical drug development: opportunities, challenges, and scope reflections following PhRMA's November 2006 workshop

This paper provides reflections on the opportunities, scope and challenges of adaptive design as discussed at PhRMA's workshop held in November 2006. We also provide a status report of workstreams within PhRMA's working group on adaptive designs, which were triggered by the November workshop. Rather than providing a comprehensive review of the presentations given, we limit ourselves to a selection of key statements. The authors reflect the position of PhRMA's working group on adaptive designs.     

医药生物产业专利战略研究

目的 研究当前我国医药生物产业专利现状,以期发现需要提升的方面.方法 采用文献研究法.结果与结论 该领域需要从4个方面深入实施知识产权战略：重视收集专利情报,加强分析,建立专利预警体系;加大研发力度,努力创造重量级的核心专利,提升严密的专利布局;充分挖掘已有专利技术,积极申请外围专利;避免野生种质资源流失,争夺世界级的话语权.     

医院药学经济激励的信息化管理系统研发与应用

目的:完善药学管理中的激励机制,优化人力资源管理,提高药学服务质量.方法:利用信息化手段建立操作简便、指标明确、统计功能完备的多层级经济激励管理系统,辅助落实医院药学绩效考核机制.结果:该系统的应用,使奖励分配在3～5个工作日内完成,通过图表清晰展现分配细节,完整保存管理原始数据,实现经济激励多层级管理.结论:经济激励信息化管理系统的建立作为医院药学部门规范管理、高效运转的重要部分,切实起到激励员工、提高药学服务质量的作用.     

The Impact of Product and Process Related Critical Quality Attributes on Immunogenicity and Adverse Immunological Effects of Biotherapeutics

The pharmaceutical industry has experienced great successes with protein therapeutics in the last two decades and with novel modalities, including cell therapies and gene therapies, more recently. Biotherapeutics are complex in structure and present challenges for discovery, development, regulatory, and life cycle management. Biotherapeutics can interact with the immune system that may lead to undesired immunological responses, including immunogenicity, hypersensitivity reactions (HSR), injection site reactions (ISR), and others. Many product and process related critical quality attributes (CQAs) have the potential to trigger or augment such immunological responses to the product. Tremendous efforts, both clinically and preclinically, have been invested to understand the impact of product and process related CQAs on adverse immunological effects. The information and knowledge are critical for the implementation of Quality by Design (QbD), which requires risk assessment and establishment of specifications and control strategies for CQAs. A quality target product profile (QTPP) that identifies the key CQAs through process development can help assign severity scores based on safety, immunogenicity, pharmacokinetics (PK) and pharmacodynamics (PD) of the molecule. Gaps and future directions related to biotherapeutics and emerging novel modalities are presented.     

Exploring individual and contextual factors contributing to tobacco cessation intervention implementation

BackgroundPrevious research suggests that smoking cessation interventions are poorly implemented. This study reports the development and testing of a questionnaire including knowledge, attitude, behavioral, and organizational (KABO) factors affecting the implementation of smoking cessation practices in hospitals by health care providers and organizations.MethodsAn initial pool of 44 items was developed to assess the individual knowledge, attitudes, and beliefs of health professionals towards smoking cessation practices according to the 5 A's intervention model, as well as organizational barriers and opportunities for its implementation. Items were measured in a scale from 0=“Not at all/Never” to 10 = “Completely/Always”. Data were collected from health workers (n = 702) in Catalonia. The validity of the instrument was measured by: (a) analyzing the items, (b) assessing the internal structure, (c) estimating the internal consistency, and (d) analyzing the relationship between this tool and the 5 A's intervention model.ResultsSeven domains were extracted: individual skills, positive organizational support, attitudes and beliefs, individual commitment, organizational resources, beliefs about patient desire/readiness to quit, and organizational endorsement. These domains explained 69.7% of the variance, and allowed for the development of a refined 26-item version of the questionnaire. Both the seven domains and the total scale showed adequate internal consistency.ConclusionsPsychometric testing indicates that the KABO questionnaire is a reliable and valid instrument for assessing the main barriers and facilitators to smoking cessation intervention implementation. Individual factors better explained the implementation of smoking cessation interventions in hospitals, and the seven identified domains can be used for further investigations into how the implementation of evidence-based practices impacts smoking cessation performance.     

Measurement of Michaelis constants for cytochrome P450-mediated biotransformation reactions using a substrate depletion approach.

The Michaelis constant (KM) for cytochrome P450-mediated drug biotransformation reactions can be an important parameter in understanding the potential for a drug to exhibit saturable metabolism in vivo and nonlinear dose-exposure relationships. KM values were measured for several drug biotransformation reactions using recombinant heterologously expressed human enzymes. These determinations were made using an approach of monitoring substrate loss ("in vitro t1/2" method) at multiple substrate concentrations, with the objective of comparing KM values determined by this approach with KM values determined using the conventional approach of measuring product formation rates at several substrate concentrations. The reactions examined were CYP2C9-catalyzed diclofenac 4'-hydroxylation, CYP2D6-catalyzed dextromethorphan O-demethylation and thioridazine S-oxidation, CYP2C19-catalyzed imipramine N-demethylation, CYP3A4-catalyzed midazolam 1'-hydroxylation, and CYP1A2-catalyzed tacrine 1-hydroxylation. KM values spanned an 80-fold range from 0.12 microM (CYP2D6-catalyzed thioridazine S-oxidation) to 9.8 microM (CYP2C19-catalyzed imipramine N-demethylation). On average, KM values determined by the substrate depletion approach were within 1.54-fold of those determined by measuring product formation. Thus, KM values can be determined for drug metabolism reactions without requiring knowledge of metabolite structures or requiring authentic standards of metabolites for use in construction of standard curves for quantitative bioanalysis. The in vitro t1/2 approach of determining KM values should be useful in early drug discovery efforts to identify those compounds with low KM values and, hence, a greater probability of exhibiting supraproportional dose-exposure relationships.     

Using nominal group technique among clinical providers to identify barriers and prioritize solutions to scaling up opioid agonist therapies in Ukraine

BackgroundOpioid agonist therapies (OAT) like methadone and buprenorphine maintenance treatment remain markedly under-scaled in Ukraine despite adequate funding. Clinicians and administrators were assembled as part of an implementation science strategy to scale-up OAT using the Network for Improvement of Addiction Treatment (NIATx) approach.MethodsNominal Group Technique (NGT), a key ingredient of the NIATx toolkit, was directed by three trained coaches within a learning collaborative of 18 OAT clinicians and administrators to identify barriers to increase OAT capacity at the regional “oblast” level, develop solutions, and prioritize local change projects. NGT findings were supplemented from detailed notes collected during the NGT discussion.ResultsThe top three identified barriers included: (1) Strict regulations and inflexible policies dictating distribution and dispensing of OAT; (2) No systematic approach to assessing OAT needs on regional or local level; and (3) Limited funding and financing mechanisms combined with a lack of local/regional control over funding for OAT treatment services.ConclusionsNGT provides a rapid strategy for individuals at multiple levels to work collaboratively to identify and address structural barriers to OAT scale-up. This technique creates a transparent process to address and prioritize complex issues. Targeting these priorities allowed leaders at the regional and national level to advocate collectively for approaches to minimize obstacles and create policies to improve OAT services.