The regulatory framework for preventing cross-contamination of pharmaceutical products: History and considerations for the future.

Cross-contamination in multi-product pharmaceutical manufacturing facilities can impact both product safety and quality. This issue has been recognized by regulators and industry for some time, leading to publication of a number of continually evolving guidelines. This manuscript provides a historical overview of the regulatory framework for managing cross-contamination in multi-product facilities to provide context for current approaches. Early guidelines focused on the types of pharmaceuticals for which dedicated facilities and control systems were needed, and stated the requirements for cleaning validation. More recent guidelines have promoted the idea of using Acceptable Daily Exposures (ADEs) to establish cleaning limits for actives and other potentially hazardous substances. The ADE approach is considered superior to previous methods for setting cleaning limits such as using a predetermined general limit (e.g., 10 ppm or a fraction of the median lethal dose (LD50) or therapeutic dose). The ADEs can be used to drive the cleaning process and as part of the overall assessment of whether dedicated production facilities are required. While great strides have been made in using the ADE approach, work remains to update good manufacturing practices (GMPs) to ensure that the approaches are clear, consistent with the state-of-the-science, and broadly applicable yet flexible enough for adaptation to unique products and situations.

Bioavailability of therapeutic proteins by inhalation--worker safety aspects.

A literature review and analysis of inhalation bioavailability data for large therapeutic proteins was conducted in order to develop a practical estimate of the inhalation bioavailability of these drugs. This value is incorporated into equations used to derive occupational exposure limits(OELs) to protect biopharmaceutical manufacturing workers from systemic effects. Descriptive statistics implies that a value of 0.05, or 5% is an accurate estimate for large therapeutic proteins (molecular weight ≥ 40kDa). This estimate is confirmed by pharmacokinetic modeling of data from a human daily repeat-dose inhalation study of immunoglobulin G. In conclusion, we recommend using 5% bioavailability by inhalation when developing OELs for large therapeutic proteins.

Chemical pollution, respiratory allergy and asthma: a perspective.

The European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC) convened a workshop in June 2005 to address the speculation that exposure to specific chemicals, and/or chemical pollutants in general, may play an important role in the increased prevalence of allergy and asthma in 'westernized' societies. This paper summarises one perspective arrived at during this workshop. It was acknowledged that certain chemicals and certain types of pollution might trigger or exacerbate asthmatic reactions in sensitised subjects. However, overall levels of pollution appear not to have had a major impact upon the prevalence of atopic allergy. Epidemiological studies suggest that pollution may in some circumstances protect from acquisition of sensitisation. Increasing exposure to household chemicals may enhance pre-existing allergies, but evidence for their causation of allergy is lacking. Other risk factors considered included societal dietary changes and exposure to endotoxins. Future research needs were identified which included epidemiological studies employing exposure and biomonitoring data, studies on domestic exposure to chemicals and their association with the incidence of allergy and asthma, and prospective birth cohort studies employing well-defined aspects of lifestyle, diet, chemical and endotoxin exposure as factors that may drive susceptibility to allergy and asthma.