These hazardous chemical agents require extraordinary care throughout the manufacturing pipeline.
Chemical hazards in the pharmaceutical industry carry elevated risks, since active pharmaceutical ingredients (APIs) are specifically designed to target chemical pathways in the human body. For this reason, the US Occupational Safety and Health Administration (OSHA) provides strict guidance for the handling of hazardous pharmaceuticals; particularly highly potent APIs (HPAPIs).
As OSHA specifies, the risks of handling HPAPIs require a variety of heightened protective measures throughout the handling, processing, packaging, transportation and storage stages. The end-to-end HPAPI supply chain must be managed with extreme care, and monitored and reviewed on an ongoing basis, in order to minimize risk to personnel.
This article provides a summary of the definition of HPAPIs, along with a set of basic guidelines for managing their handling and processing in the manufacturing pipeline.
HPAPIs are defined according to a range of interrelated attributes.
Researchers have defined HPAPIs in a variety of ways, but certain criteria have proven useful for pharma manufacturers. An HPAPI may be a pharmacologically active ingredient that becomes biologically active at 150 μg/kg in humans. But this concentration is only one attribute.
In addition, an API with an occupational exposure limit (OEL) at or below 10 μg/m3 of air, averaged over eight hours, also qualifies as an HPAPI; as does an API that selectively binds to receptors, or inhibits biochemical pathways, that can result in toxicity, cancer, or mutations. In fact, any novel compound with potentially high toxicity may fit into the HPAPI category.
A significant number of APIs currently under development have OELs below 10 μg/m3, and more compounds with low OEL values are entering the development stage each year. APIs with these characteristics demand specialized containment practices, equipment, and handling procedures, as well as facilities designed to minimize risks of infection.
An HPAPI facility must be designed and organized to safeguard staff health.
Responsibility for operating a safe HPAPI processing facility rests with the staff, from the managerial level down. A board of experts should be put in place to train all employees in the handling of HPAPIs, and the organization’s policies should include guidelines for evaluating, organizing, labeling and handling these compounds.
For example, all employees working with HPAPIs must be made aware of regulatory and safety issues around the compounds they handle, and should be monitored at all times to ensure they wear protective equipment, follow all guidelines for safe handling, and clean the lab before and after processing the product.
Furthermore, each HPAPI must be assessed in terms of toxicity, potency, and risk of hazard, in order to ensure compliance with all safe handling standards set out by OSHA. While OSHA does not provide any guidelines specific to HPAPIs, its guidelines do require that all work environments provide maximum health and safety for employees. Thus, many pharmaceutical manufacturers who handle HPAPIs have implemented tiered safety programs to mitigate risks of contact.
Such a tiered safety program typically organizes compounds into four categories: low potency chemicals with minimal chronic health risks, moderately toxic chemicals with reversible health effects, chemicals with moderate acute and chronic toxicity that may be irreversible, and toxic chemicals with high potency and rapid absorption rates. These tiers enable manufacturers to implement performance-based exposure protocols, providing engineering containment measures in accordance with each compound’s risk level.
Measures or containment of HPAPIs may include single-pass heating, ventilation, and air conditioning (HVAC) systems, restricted access airlocks, closed-system glassware, misting showers in degowning chambers, and change-control procedures designed to minimize direct contact with air and other elements that may contain trace amounts of the HPAPI. In addition, all equipment used in the processing of HPAPIs should be selected on the basis of its cleanability and flexibility.
HPAPIs must be monitored and reviewed consistently throughout the pipeline.
A new HPAPI may be introduced into a manufacturer’s pipeline via direct discovery, licensure, patent acquisition, or a number of additional channels. Regardless of its source, that compound’s hazard level must be proactively and exhaustively assessed at the moment it becomes part of the organization’s manufacturing process.
After the compound’s risk level has been determined by trained toxicology experts, the next step is to select a set of engineering procedures designed to minimize exposure, while maintaining a streamlined processing pipeline. These selections must be made by individuals with significant experience in handling and working with HPAPIs, in order to safeguard all employees against unnecessary contact with the hazardous compound.
Over time, new pre-clinical studies and trials will reveal novel insights about an HPAPI’s properties and risk level. Thus, experts must continually review the literature for any information that might further enhance the pipeline’s safety profile, or provide more robust control measures to be included in the organization’s training procedures. In other words, investment in HPAPI safety is not a one-time effort, but an ongoing process of improvement.
Ongoing review and adaptation provides other benefits as well. For example, improved dust detection systems systems can often result in more efficient processing pipelines, reducing wastage, heightening worker productivity, and delivering greater return on investment (ROI). Aligning the power of powered air-purifying respirator (PAPR) equipment to the compound’s actual OEL value can also provide the necessary level of cleanroom safety without creating resource inefficiencies.
Every new HPAPI manufacturing pipeline represents an investment; not only in the compound itself, but in the cleanroom design, equipment, safety measures, staff training, assessment and review procedures and other measures necessary to provide an OSHA-compliant working environment. Pharma manufacturers that invest in working partnerships with contract manufacturing organizations (CMOs) experienced in HPAPI handling are much more likely to prevent unnecessary workplace risk, and bring HPAPI formulations to market in an efficient, regulatory-compliant manner.
