A significant proportion of new drugs under development contain high-potency active pharmaceutical ingredients (HPAPIs), which is leading to explosive growth in demand for their production. The cytotoxicity of HPAPIs, however, presents handling challenges and requires heavy investment in specialized containment to ensure that employees and their environment are protected from exposure. This article examines the planning, equipment, and facility design of chemical and biologic HPAPIs as well as biologic–HPAPI conjugate manufacture. It also outlines the efforts made by the pharmaceutical industry to develop voluntary standards for HPAPI production and handling.
During the last decade, the demand for HPAPIs has grown rapidly, mainly as a result of advances in clinical pharmacology and oncology research. There is particular interest in HPAPI–antibody conjugate technology, which uses monoclonal antibodies to selectively deliver HPAPIs to specific cancer tumors. When conjugated to the antibody, the HPAPI targets cancer cells specifically and thereby spares nontarget cells many of the toxic effects. Wyeth's "Mylotarg" (gemtuzumab ozogamicin) is an example of such a drug. It is commercialized for treating acute myeloid leukemia, and numerous other antibody drug conjugates are in preclinical or clinical trials.
Compared with the overall growth in the pharmaceutical market of about 7% per year, HPAPIs are estimated to have an annual growth of 12% (1, 2). They account for about 12% of the total pharmaceutical market, and this share is set to rise strongly (3). Although this emerging market is attractive, it presents a significant challenge for pharmaceutical manufacturers to upgrade existing facilities that are set up to handle only nonpotent APIs—the challenge being the major cost associated with the specialized containment needed to ensure that employees and their environment are protected from exposure. Many contract manufacturers are also building new facilities that are designed specifically for the manufacture of HPAPIs, which require an investment of millions of dollars beyond typical GMP (good manufacturing practices) production facilities. This investment may include specialized facilities for HPAPI–antibody conjugations that incorporate both potent-compound handling and biologics processing capabilities.
Definition of HPAPIs
The definition of an HPAPI varies depending on the literature; however, APIs deemed to be potent may fall into the following categories (4):
1. A pharmacologically active ingredient or intermediate with biological activity at approximately 150 μg/kg of body weight or below in humans (therapeutic daily dose at or below 10 mg)
2. An active pharmaceutical ingredient or intermediate with an occupational exposure limit (OEL) at or below 10 μg/m3 of air as an 8-h time-weighted average
3. A pharmacologically active ingredient or intermediate with high selectivity (i.e., ability to bind to specific receptors or inhibit specific enzymes) and/or with the potential to cause cancer, mutations, developmental effects, or reproductive toxicity at low doses
4. Or, by default, a novel compound of unknown potency and toxicity.
The potency of pharmaceutical chemicals is often characterized by OELs in μg/m3; the lower the value, the more potent the chemical and the greater the level of containment that is required. Currently, there is a significant increase in the number of APIs going through development and clinical trials, and into the production environment with OELs well below 10 μg/m3. These processes require specialized containment to ensure that employees and their environment are protected from exposure. Figure 1 shows a facility design of a typical kilo-laboratory (using glassware) for HPAPI handling. The main features are as follows:
Figure 1 (FIGURE 1 IS COURTESY OF SAFC.)
- Room pressure differentials designed for containment (with monitoring and verification), with the main HPAPI-handling area at negative pressure to surrounding rooms
- Airlocks and vestibules around manufacturing and laboratory spaces to provide gowning and degowning areas and proper pressure differentials
- Restricted access to ensure that only the necessary trained employees enter the HPAPI-handling areas
- HVAC (heating, ventilation, and air conditioning) systems designed for single-pass air—no return, with temperature, humidity, and particulate controls
- Misting showers as part of degown and exit vestibules to rinse personal protective equipment (PPE) and gowning prior to removal
- Filtration and capture of contaminants, with safe-change filters, both point source (within the isolator, ventilated enclosure) and the general HVAC exhaust system
- Preventive maintenance and change-control procedures to ensure that equipment and systems continue to operate properly and according to design specifications.