Kant on anatomy and the status of the life sciences.

This paper contributes to recent interest in Kant's engagement with the life sciences by focusing on one corner of those sciences that has received comparatively little attention: physical and comparative anatomy. By attending to remarks spread across Kant's writings, we gain some insight into Kant's understanding of the disciplinary limitations but also the methodological sophistication of the study of anatomy and physiology. Insofar as Kant highlights anatomy as a paradigmatic science guided by the principle of teleology in the Critique of the Power of Judgment, a more careful study of Kant's discussions of anatomy promises to illuminate some of the obscurities of that text and of his understanding of the life sciences more generally. In the end, it is argued, Kant's ambivalence with regard to anatomy gives way to a pessimistic conclusion about the possibility that anatomy, natural history, and, by extension, the life sciences more generally might one day become true natural sciences.

A harmonization effort for acceptable daily exposure application to pharmaceutical manufacturing - Operational considerations.

A European Union (EU) regulatory guideline came into effect for all new pharmaceutical products on June 1st, 2015, and for all existing pharmaceutical products on December 1st, 2015. This guideline centers around the use of the Acceptable Daily Exposure (ADE) [synonymous with the Permitted Daily Exposure (PDE)] and operational considerations associated with implementation are outlined here. The EU guidance states that all active pharmaceutical ingredients (API) require an ADE; however, other substances such as starting materials, process intermediates, and cleaning agents may benefit from an ADE. Problems in setting ADEs for these additional substances typically relate to toxicological data limitations precluding the ability to establish a formal ADE. Established methodologies such as occupational exposure limits or bands (OELs or OEBs) and the threshold of toxicological concern (TTC) can be used or adjusted for use as interim ADEs when only limited data are available and until a more formal ADE can be established. Once formal ADEs are derived, it is important that the documents are routinely updated and that these updates are communicated to appropriate stakeholders. Another key operational consideration related to data-poor substances includes the use of maximum daily dose (MDD) in setting cross-contamination limits. The MDD is an important part of the maximum allowable/safe concentration (MAC/MSC) calculation and there are important considerations for its use and definition. Finally, other considerations discussed include operational aspects of setting ADEs for pediatrics, considerations for large molecules, and risk management in shared facilities.

Issues and approaches for ensuring effective communication on acceptable daily exposure (ADE) values applied to pharmaceutical cleaning.

This manuscript centers on communication with key stakeholders of the concepts and program goals involved in the application of health-based pharmaceutical cleaning limits. Implementation of health-based cleaning limits, as distinct from other standards such as 1/1000th of the lowest clinical dose, is a concept recently introduced into regulatory domains. While there is a great deal of technical detail in the written framework underpinning the use of Acceptable Daily Exposures (ADEs) in cleaning (for example ISPE, 2010; Sargent et al., 2013), little is available to explain how to practically create a program which meets regulatory needs while also fulfilling good manufacturing practice (GMP) and other expectations. The lack of a harmonized approach for program implementation and communication across stakeholders can ultimately foster inappropriate application of these concepts. Thus, this period in time (2014-2017) could be considered transitional with respect to influencing best practice related to establishing health-based cleaning limits. Suggestions offered in this manuscript are intended to encourage full and accurate communication regarding both scientific and administrative elements of health-based ADE values used in pharmaceutical cleaning practice. This is a large and complex effort that requires: 1) clearly explaining key terms and definitions, 2) identification of stakeholders, 3) assessment of stakeholders' subject matter knowledge, 4) formulation of key messages fit to stakeholder needs, 5) identification of effective and timely means for communication, and 6) allocation of time, energy, and motivation for initiating and carrying through with communications.

An evaluation of a cultured human corneal epithelial tissue model for the determination of the ocular irritation potential of pharmaceutical process materials.

Irritation and other forms of local toxicity following contact with eyes is a potentially serious problem arising from occupational exposure to chemicals. Traditionally, evaluation of the irritant potential of novel chemicals has relied on the use of in vivo studies with rabbits. Concerns about the predictive potential of in vivo methods for human hazard and demand for economical and rapid screening of chemicals has stimulated a great deal of work to investigate in vitro alternatives for evaluating ocular irritation potential. This publication describes a screening study to assess a reconstituted corneal epithelial culture system, as an alternative for testing for ocular irritation with pharmaceutical process materials, extending the chemical domain with which this system has been tested. A total of 21 test chemicals were applied to commercially supplied reconstituted human corneal epithelial (HCE) cultures and effects on tissue viability (MTT reduction assay), tissue histology and IL-alpha expression were assessed. Positive controls (0.5% and 1% SDS) showed dose- and time-related adverse effects on tissues, consistent with known irritant effects. Negative controls showed no histological changes and retained high viability throughout the time-course of the experiment. Concordance was excellent with accuracy at each sampling time point of over 80% when viability (MTT reduction) was compared with existing EU classification of the test articles for ocular irritation (classification based on results of in vivo evaluation). Tissue viability as estimated by MTT reduction appears most useful as the primary means of assessing the irritation potential of the chemicals. Histopathological examination generally agreed with the results of the MTT assay. However, the use of cytokine analysis will need further consideration as results for this parameter showed no relationship with known irritation potential. These results infer that HCE cultures, alone or as a part of a tiered hazard screening programme, have promise for use in reducing reliance on live subject tests and contribute to generation of an appropriate hazard classification and label advice.

Human health risk assessment from the presence of human pharmaceuticals in the aquatic environment.

Assessments for potential impact to human health from environmental exposures were carried out for 44 active pharmaceutical ingredients (APIs) marketed by GlaxoSmithKline (GSK), representing approximately 22 general pharmacological classes exhibiting a broad spectrum of therapeutic activities. These assessments use the considerable amount of information available on the human pharmacology and toxicology of the APIs to develop acceptable daily intakes (ADIs) which are believed to be without pharmacological or toxicological effect. With the exception of the anti-cancer drugs and some antibiotics, the minimum dose producing the intended therapeutic effect was typically used as the point of departure for calculation of ADIs. The ADI values were used to generate predicted no effect concentrations from environmental exposure for human health (PNEC(HH)s) from drinking water or fish consumption. These PNECs were compared to predicted environmental concentrations (PECs) calculated using the regional assessment models PhATE for North America and GREAT-ER for Europe. Risk was characterized by calculating the ratio of the 90th percentile PECs to the PNEC(HH)s. For the APIs reported here, these ratios are less than one for all of the compounds, varying from 7x10(-2) to 6x10(-11), indicating that based upon currently available data, these compounds do not appear to pose an appreciable risk to human health from potential environmental exposure from drinking water and fish consumption.

Reliability and validity of the Stanford Presenteeism Scale.

OBJECTIVE: This study reports the reliability and validity of the 13-item Stanford Presenteeism Scale (SPS). The SPS differs from similar scales by focusing on knowledge-based and production-based workers. METHODS: Data were obtained from administrative and medical claims databases and from a survey that incorporated the SPS, SF-36, and the Work Limitations Questionnaire. RESULTS: Sixty-three percent (7797) of employees responded. Cronbach's alpha (0.83) indicates adequate reliability. Factor analysis identified two underlying factors, "completing work" and "avoiding distraction." Knowledge-based workers load on "completing work" (alpha = 0.97), whereas production-based workers load on "avoiding distraction" (alpha = 0.98). There were significant and positive relationships between the SPS, SF-36, and Work Limitations Questionnaire. CONCLUSIONS: The SPS demonstrates a high degree of reliability and validity and may be ideal for employers who seek a single scale to measure health-related productivity in a diverse employee population.

Security issues arising in establishing a regional health information infrastructure.

A regional health information infrastructure is being developed in an internally self-governing country which is a dependent territory of the British Crown, is not part of the United Kingdom but is a member of the British Commonwealth. This country of about 70000 inhabitants (and significant numbers of visitors) within the British Isles shares many functions with the United Kingdom-from the perspective of this paper the key shared functions relate to the infrastructure of the departments of social security, social services, central registry, all health care services and national insurance systems. Although it remains independent in various other respects, for the most part it endeavours to achieve an harmonious legislative relationship with the UK, and with the EU. One primary goal of the information infrastructure development project is to provide links between community, primary and secondary healthcare services and thereby to ensure integrity of information as it refers to each individual receiving care services. A second goal has been to integrate this environment with various other government functions including the issuing and checking of NHS ID numbers and of national insurance ID numbers, the payment of social welfare benefits, and perhaps with other functions where access to a common list of names and addresses is a significant factor. This paper outlines some of the issues that have arisen in endeavouring to meet the often conflicting wishes and needs of different groups as regards a health information infrastructure within a general public sector information service.