How to Avoid High Potency API Contamination
Olindo Lazzaro, Michael Gallagher, & Max Brescia
For drug manufacturers, patient safety is of the utmost concern, and efforts to prevent cross contamination of highly potent active pharmaceutical ingredient (HPAPI) are a critical part of a safe manufacturing process. Likewise, the safety of workers who make the drug products, and the environment in which they work, is also paramount, particularly when manufacturing with high containment compounds. Inadequate containment of these compounds can put patients, employees, and the environment at increased risk, while decreasing product yields. Manufacturing costs can also rise with additional requirements for personal protective equipment and medical surveillance for workers, or for pollution controls and special housekeeping for manufacturing areas.
To ensure that employee exposures are kept within accepted limits and protect the environment while containing costs, pharmaceutical companies and their contract partners who manufacture and handle high containment compounds must carefully select equipment, outline processes and procedures, and deploy appropriate containment technologies.
Applying engineering controls in the manufacturing process reduces the risk of contamination of the manufacturing environment and is the preferred method of controlling employee exposure. Occupational hygiene monitoring techniques and methods of analysis can then be used to verify the performance of the engineering controls. Separate guidelines are required for the design and construction of the facilities in which high containment compounds are handled.
Determine Exposure Potential
The first step in avoiding HPAPI environmental contamination is to identify the exposure potential. Factors to be considered include the quantity handled and the percent active, the potential for dust, and the duration of the task. Small (gram) or medium (kilogram) quantities of API with low dust potential and a short duration (minutes) would have the lowest exposure potential, while high volume (ton), high dust potential with a long duration (hours) provides the highest exposure potential.
Once the exposure potential and containment level is determined, you can select a control approach. AbbVie Contract Manufacturing uses a four-tier containment band and five containment strategies to guide its containment controls. The containment band runs from 1S, > 100 mcg.m3, to 4S, which is below 1 mcg/m3. This is tied to employee exposure limits (EEL). For example, two compounds with an EEL of 2 and 7 mcg/m3 would both fall in containment band 3 at AbbVie, and be handled in the same manner.
Containment strategies range from the least restrictive – open transfer with general ventilation – to the most restrictive, which involves glovebox isolators with rapid transit ports (RTP), split butterfly valve with extraction and/or liquid rinse, a HicoFlex transfer system, and a closed or dust-tight system with closed transfer. The containment strategy that is chosen is verified with Environmental Health and Safety (EHS) personnel prior to selection of the containment equipment and technologies to be used.
* Metal to metal clamps are not permitted.
* Use of the above containment strategies does not assume reduction in respiratory personal protective equipment until occupational hygiene exposure assessment studies are completed.
Equipment and Technology Selection
Once the exposure potential is identified and a containment strategy selected, the equipment and technologies used to manufacture the HPAPI must be selected. Factors to consider include the materials or compounds involved, the processes being used, environmental and safety considerations, and GMP requirements. A risk-based approach should be applied when selecting the type of containment strategy to use for a particular process. In general, the approach should consider the exposure limit, percent active, quantity, task duration, and material properties such as dust potential.
It should be noted that Employee Exposure Limits (EELs) are not standard, as they are established by consensus guidelines, various regulatory authorities worldwide, and individual manufacturers’ internal standards. These limits and levels apply to manufacturing facilities and pilot plants, as well as any laboratories handling certain containment levels.
Factors that can affect the worker and the environment include the physical characteristics of the highly active or highly potent compound, such as its cohesion. A granular, dense compound that is more prone to clumping may be much easier to contain than a light, fluffy one. Its form, whether liquid, solid, vapor, or gas, affects the choice of containment control strategies, equipment, and processes, as does the particulate size, adhesion, and viscosity qualities. Nanomaterials, high adhesion, and dusty materials are more difficult to contain. Other chemical characteristics to evaluate include the compounds’ flammability, combustibility, reactivity, and explosivity.
Containment strategies must consider whether the process used involves direct or indirect handling, or limited vs. repetitive handling, as well as the number of transfer steps. Processes should be designed with a minimum number of transfer points, or make/break connections, to limit operator exposure. Other considerations include such product sampling requirements as size, quantity, location, container type, and any limitations of the receiving lab. Manufactures must anticipate and account for any in-process adjustments and visibility issues, including tooling changeovers, equipment malfunctions, equipment inspections, line clearance to remove product for the next batch, and visibility to inspect material flow.
Standardization of types and sizes of valves and containers, and compatibility with upstream and downstream processes also contribute to containment strategy selection. For cleaning, determine whether a process is dedicated or not, which cleaning materials will be used for deactivation, and which cleaning methods will be used: manual, wash in place, clean in place, or a combination. Ergonomics is another factor in equipment selection, with accessibility to valves, and ability to make equipment adjustments and clean a determinant in best choice.
A Note on Environmental Protection
For Pharmaceutical in the Environment (PIE) control, the data generated from environmental risk assessments of products can provide the knowledge to make intelligent, risk-based control decisions for cost-effective manufacturing. Studies of predicted no-effect concentrations (PNECs) for the APIs involved allow manufacturers to identify water-quality control technology for the predicted environmental concentrations (PECs) in the vicinity of the manufacturing facility. Abbie’s goal is to keep our site effluents tenfold below the no-effect concentration, on top of containment measures; therefore, we have implemented effective segregation of concentrated streams and, where needed, state-of-the-art design of specific wastewater treatment for our manufacturing facilities.
Having standards in place for engineering controls is the first line of defense against harm from cross contamination or exposure to the patient, manufacturing employees, or the environment when working with HPAPIs. These standards must take into account and guide the selection of equipment, processes, and technologies used to contain HPAPIs. While such standards are not set by industry, CMO partners should have practices in place that they can share with pharmaceutical sponsors to demonstrate their ability to manufacture HPAPIs to exacting standards, without adverse effects.