Analysis of Highly Active and Highly Toxic Substances

Solvias AG

This is mainly the result of intensified research in the anticancer drug field, which has yielded many cytotoxic substances. But other areas in the pharmaceutical world besides oncology generate substances that are cytotoxic or toxic in some other way and that must be handled. At the same time, there has been a significant increase in safety awareness among the public and within industry. The declared goal is minimize the risk to staff from handling chemicals.

The pharmaceutical industry and service providers are thus faced with the challenge of installing new equipment and procedures for the safe handling of highly active and highly toxic substances [1]. Thanks to our experienced and specially trained staff and requisite protection measures, Solvias is now able to offer virtually comprehensive analytical services for highly hazardous substances.

Employers' risk reduction obligations

The legal situation regarding the handling of highly hazardous substances is not particularly transparent. On the one hand, there are clear laws obliging employers to minimize the risk of handling such substances, i.e. exposure to such substances must be kept as low as possible. On the other hand, there are no clear recipes as how this is to be achieved in practice.

Furthermore, the same laws and regulations apply to all fields of chemistry, including such different businesses as petrochemicals, plastics, agrochemicals, and pharmaceuticals. As a result, each company has to establish its own specific and detailed rules which of course must comply with local laws and regulations. Solvias has accordingly established Standard Operating [1] Procedures (SOPs) for handling chemical substances and preparations, including highly hazardous substances.

[1] The definition of the term highly hazardous substances used in this document is identical to the American Society of Hospital Pharmacists' definition of hazardous drugs (ASHP Technical Assistance Bulletin on Handling Cytotoxic and Hazardous Drugs. Am J Hosp Pharm 1990;47:1033-1049), endorsed by the U.S. Department of Labor's Occupational Safety & Health Administration (OSHA), namely "substances with one of the following characteristics:

  • genotoxicity
  • carcinogenicity
  • teratogenicity or fertility impairment
  • serious organ damage or other toxic manifestation at low doses in experimental animals or treated patients."

(OSHA Technical Manual Section VI, Chapter 2, 1999;
http://www.osha.gov/dts/osta/otm/otm_vi/otm_vi_2.html)

Categorisation according to hazard potential

Even if safety information is available on a substance, assessing its hazard potential in routine practice is not always straightforward. What safety precautions should realistically be deployed in such a case? To answer this question Solvias has introduced a 3 category classification system (Table 1). We thus ensure that all staff apply the same classification and hence same safety measures for any given substance.

As a service provider, Solvias must rely on the information it gets from its customers. This can be a Material Safety Data Sheet (MSDS), for example, or similar information. Even though it may sometimes come across as bugging our customers, our project managers and sales staff will insist on getting as much information as possible from our customers in order to assign a substance to its correct category. The purpose of such thoroughness is not only to ensure the safety of our staff, it also in the final analysis contributes to the success of our customers' projects.

To further simplify classification, with some of our customers we have established correlation tables which translate their hazard categories into our own. Such correlation tables can of course be established for other customers too.
We assign substances with very rudimentary or nonexistent safety information to category 2 by default. This applies in particular to compounds in an early phase of development. If we then receive further information, for example on the intended use of the substance, the resulting risk assessment can lead to the substance being reclassified: a substance designed for pain relief is probably less critical than a substance designed for use in cancer treatment.

Of course, common sense must be applied too. It makes no sense to assign caffeine, which most of us take orally on a regular basis, into category 2 just because its rat LD50 is slightly less than 200 mg/ kg. In such a case, our responsible person for safety can decide to assign the compound to a lower category.

Assigning a substance to the correct category also makes economic sense. It helps to avoid unnecessary costs. After all, only if strict safety measures are really necessary should the additional effort be made.

Safety precautions per category

Table 1 outlines the protection measures that apply based on the category to which a substance has been assigned. A zerotolerance philosophy is followed with category 3 substances.

Handling of solid substances is the most critical. The risk is that it can generate airborne dust that can be inhaled by the handler. Handling is less critical once a substance is in solution. Thus in an analytical lab the trickiest step is usually the weighing of a substance followed by preparation of the solution. For this reason, for highly hazardous substances, Solvias has set up special rooms with controlled access containing ventilated balance enclosures with special exhaust air filters (figure 1). All operations in such rooms can be performed according to GMP quality standard.

Diagram
Table 1

For studies which involve investigations of solids (e.g. polymorphism studies), special equipment and procedures have been introduced. These include the glove box and personal protection shown in figure 2. This enables Solvias to deploy almost all analytical techniques even on highly hazardous substances. One exception is particle size analysis by laser diffraction with dry dispersion. Because dry dispersion intrinsically generates large amounts of dust, Solvias does not offer it for highly hazardous substances. In this case, however, we can offer to develop a wet dispersion method for the customer, which is then also suitable for highly hazardous substances.

Scientist At Work
Figure 1) Ventilated balance enclosures with special exhaust air filters

Glove Box and Personal Protection
Figure 2) Glove box and personalprotection

At Solvias we place great emphasis not only on technical measures but also on proper staff training. All staff must be specially trained before working with category 3 substances.

Besides the measures described above, laws and regulations also require proper disposal of all hazardous waste. At least double-layer is used to pack highly hazardous waste. This largely eliminates the risk of spills. We also work with a specialized company that incinerates all hazardous waste in a special high-temperature oven. This completely destroys all critical compounds. Very similar procedures . the high-temperature oven, in particular . are used by all major pharmaceutical companies in the Basel area.

Solvias is thus ideally prepared to carry out such demanding projects from A to Z, safely and according to the regulations. We look forward to making your project possible.

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