Disease area and mode of action as criteria to assign a default occupational exposure limit.

In the early stages of drug research and development, there are only a few or no toxicological data available for newly synthesized small molecule drug candidates (DC). Calculation of the DC's occupational exposure limit (OEL) without toxicological data is not possible. Nevertheless, an OEL is needed to indicate the level of protection required to minimize risks for laboratory researchers and technicians. For this reason, simplified guidance is required to predict possible health hazards of DCs and their corresponding safe inhalation exposure levels. Here, we evaluated 860 drug substances (DS) with OELs calculated by Novartis and grouped the DSs by disease area (DA) and then their mode of action (MoA). 28% of the evaluated DSs (n = 242) had an OEL <10 µg/m3 and 72% (n = 618) had an OEL ≥10 µg/m3. Our evaluation confirms that in the absence of any compound-specific data, the default OEL of 10 µg/m3 is a reasonably safe exposure limit for small molecule DCs. Furthermore, our analysis suggests certain DAs and MoAs as valid criteria that may be integrated into a company's specific strategy for the assessment of data-poor compounds in order to identify DCs in an early stage of their development which require a default OEL <10 µg/m3.

Determination and application of the permitted daily exposure (PDE) for topical ocular drugs in multipurpose manufacturing facilities.

Limits for the carry-over of product residues should be based on toxicological evaluation such as described in the "Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities". The toxicological evaluation should be performed also for locally administered drugs to ensure patient safety. Currently, there is no guidance on setting PDE for ocular drug substances in particular. The purpose of this investigation was to identify and describe a method for calculating a PDE value for topical ocular drugs (PDEocular). As an alternative method, extrapolation of a PDE for systemically administered drugs to a PDEocular is presented. These methods may be applied in cross-contamination risk assessments for manufacturing of topical ocular drugs. Similarly, the methods apply to systemically administered drugs, if their production precedes manufacturing of a topical ocular drug. We have examined pharmacokinetic (PK) properties of topical ocular drugs and compared them to the PK parameters of systemically administered drugs. Furthermore, we examined possible adverse effects of the carry-over in topical ocular drugs at therapeutic doses.

Cancer risk of immunosuppressants in manufacturing.

During the chemical and pharmaceutical production of active pharmaceutical substances which are intended for immunosuppressive therapy, the employees may be exposed to these substances via inhalation. Immunosuppressants are linked to development of certain types of cancers e.g., lymphoma or skin cancer in transplant patients. The development of these cancers in patients is linked to the level of immunosuppression needed for transplantation in order to avoid organ rejection. Below these levels, with the immune system functioning uninhibited, cancer is unlikely to develop. An internal workshop was conducted to compare several pharmaceutical substances with the intrinsic property to cause immunosuppression, with the attempt to define the risk of healthy employees to develop cancer due to exposure to immunosuppressive substance at work and to determine the appropriate hazard classification for regulatory purposes. Data are discussed with emphasis on cyclosporine to reason the dose-response relationship and the safe level for occupational exposure. Our review indicates that if the exposure to cyclosporine at the workplace is below the threshold necessary to induce immunosuppression, the risk to develop cancer is negligible. Non-mutagenic immunosuppressants do not contribute to malignancies in occupational setting if their air concentrations do not exceed the immunosuppressive threshold limited with occupational exposure limits (OELs), which is for cyclosporine 17.5µg/m(3).

Regulatory assessment of in vitro skin corrosion and irritation data within the European framework: Workshop recommendations.

Validated in vitro methods for skin corrosion and irritation were adopted by the OECD and by the European Union during the last decade. In the EU, Switzerland and countries adopting the EU legislation, these assays may allow the full replacement of animal testing for identifying and classifying compounds as skin corrosives, skin irritants, and non irritants. In order to develop harmonised recommendations on the use of in vitro data for regulatory assessment purposes within the European framework, a workshop was organized by the Swiss Federal Office of Public Health together with ECVAM and the BfR. It comprised stakeholders from various European countries involved in the process from in vitro testing to the regulatory assessment of in vitro data. Discussions addressed the following questions: (1) the information requirements considered useful for regulatory assessment; (2) the applicability of in vitro skin corrosion data to assign the corrosive subcategories as implemented by the EU Classification, Labelling and Packaging Regulation; (3) the applicability of testing strategies for determining skin corrosion and irritation hazards; and (4) the applicability of the adopted in vitro assays to test mixtures, preparations and dilutions. Overall, a number of agreements and recommendations were achieved in order to clarify and facilitate the assessment and use of in vitro data from regulatory accepted methods, and ultimately help regulators and scientists facing with the new in vitro approaches to evaluate skin irritation and corrosion hazards and risks without animal data.

Setting Occupational Exposure Limits for Genotoxic Substances in the Pharmaceutical Industry.

In the pharmaceutical industry, genotoxic drug substances are developed for life-threatening indications such as cancer. Healthy employees handle these substances during research, development, and manufacturing; therefore, safe handling of genotoxic substances is essential. When an adequate preclinical dataset is available, a risk-based decision related to exposure controls for manufacturing is made following a determination of safe health-based limits, such as an occupational exposure limit (OEL). OELs are calculated for substances based on a threshold dose-response once a threshold is identified. In this review, we present examples of genotoxic mechanisms where thresholds can be demonstrated and OELs can be calculated, including a holistic toxicity assessment. We also propose a novel approach for inhalation Threshold of Toxicological Concern (TTC) limit for genotoxic substances in cases where the database is not adequate to determine a threshold.