By Michael Becker, PHD
Employers must establish procedures to minimize risk
Cytotoxic drugs are primarily used as anti-cancer drugs because they are toxic to cells. These drugs have been associated with human cancers at high therapeutic levels of exposure and are carcinogenic and teratogenic in many animal species. Under current work practices, cytotoxic drugs can cause elevations in sister chromatid exchanges, chromosome breakage in circulating lymphocytes, and mutagenic activity in urine. In addition, many of these drugs can have a variety of acute effects in humans, such as localized skin necrosis after surface contact with abraded skin or damage to normal skin.
In recent years, the number of cytotoxic and toxic-active substances in the pharmaceutical industry has greatly increased because of intensified research in oncology. The pharmaceutical industry also generates substances that are cytotoxic or toxic in other ways, and they must be handled carefully.
Concerns are growing about the harm these substances may have on employees, including those involved in development and production. These concerns include the potential for toxic side effects, including chromosomal changes, reproductive abnormalities, or cancer. The pharmaceutical industry and service providers must install new equipment and establish procedures for the safe handling of cytotoxic and highly toxic substances.
Categorizing Hazard Potential
High-potency active ingredients are classified by their inherent characteristics of toxicity and pharmacological potency, as well as by their occupational exposure limits (OELs). Typically, active pharmaceutical ingredients with OELs at or below 10 μg/m3 of air as an eight-hour time-weighted average are considered potent from an occupational health perspective. High-potency compounds can be categorized based on four levels of OELs (see Table 1, below), according to SafeBridge Consultants Inc. The four categories range from Category I, low-potency compounds requiring conventional safety precautions, to Category IV, which require a high degree of containment.
Unfortunately, there is no general categorization method in place. At least 16 variations are used within the pharmaceutical industry, in addition to numerous other systems developed by contract manufacturers, biotechnology companies, generic pharmaceutical companies, and service providers. Most systems are either four-category systems (similar to the SafeBridge system described below) or five-category systems, as referred to by Naumann and colleagues in their paper describing the Merck system (AIHA J. 1996;57(1):33-42). Three- and six-category systems are also known to be in practice (see Table 2, right).
The development of a number of systems is reasonable because of differences among products, facilities, equipment, and processes. And systems must be shared with other interested parties, between the drug innovator and service companies, for example. Documentation must be kept about compound categorization and handling practices. With this information, knowledgeable health and safety professionals can “translate” from one system to another.
Common sense must also be used. It makes no sense to assign caffeine, which most of us consume daily, to category 2 (see Table 2, right) just because its rat LD50 is slightly less than 200 mg/kg. Assigning a substance to the correct category also makes economic sense, helping to avoid unnecessary costs. Additional effort should only be made if strict safety measures are necessary.
Employers Obligated to Reduce Risk
The legal obligations related to the handling of highly hazardous substances are not particularly transparent. On the one hand, the law is clear that employers must minimize the risk of handling certain substances. Exposure to such substances must be kept as low as possible. On the other hand, there are no clear standards for how this should be achieved. The same laws and regulations apply to all fields of chemistry, including businesses related to petrochemicals, plastics, agrochemicals, and pharmaceuticals. Each company must establish its own specific and detailed rules that comply with local laws and regulations.
Companies like Solvias AG have standard operating procedures for handling chemical substances and preparations, including highly hazardous substances.
There are protection measures for each category. A zero-tolerance philosophy must be followed with category 3 substances in the area of laboratory analysis.
Handling of solid substances is the most critical concern because of the generation of airborne dust that the handler could inhale. Handling is less critical if the substance is in solution. In an analytical lab, the trickiest step is usually when the substance is weighed and then prepared for solution. Special rooms with controlled access, ventilated balance enclosures, and special exhaust air filters should be installed.
For studies involving the investigations of solids (e.g., polymorphism, salt, and crystallization studies), special equipment and procedures have been introduced. These include glove boxes and personal protection gear.
Regulations also require proper disposal of all hazardous waste. A double layer or higher should be used to pack highly hazardous waste, diminishing the risk of spills. A specialized company should pick up the waste, where it will be incinerated in a special high-temperature oven to destroy all critical compounds.
Based on Solvias’s long industry experience in the analysis and solid-state development of cytotoxic and highly potent drug substances, the company supports customers in the pharmaceutical and biotech industry. State-of-the-art equipment, in-place health procedures, and well-educated staff work on dozens of customer projects involving cytotoxic and highly potent compounds every year.
Dr. Becker is a product manager at Solvias AG. Reach him at firstname.lastname@example.org.
- U.S. Occupational Safety & Health Administration (OSHA) Technical Manual (www.osha.gov/dts/osta/otm/otm_toc.html), in particular Section VI, Chapter 2.
- Caltech Environment Health & Safety: Guidelines for the use of cytotoxic or chemotherapeutic drugs (http://safety.caltech.edu/documents/33-cytotoxic_ drugs_guidelines.pdf).