Assuring the Safe Handling of Potent APIs, Intermediates, and Solid-Dosage Drugs

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When manufacturing cytotoxics, antibiotics, and hormonal therapies, it is crucial to ensure the safe handling of a wide range of pharmaceutical ingredients, including highly potent APIs (HPAPIs), seed, intermediates, tablets, and capsules. During API and oral solid-dosage (OSD) drug production, manufacturers all work toward the same objectives of ensuring both product quality and operator protection. Containment solutions are a crucial part of this process, utilized to protect the operator and environment from hazardous products. Establishing an effective containment infrastructure is key to any production involving HPAPIs, for employee safety and regulatory compliance.

Over the past decade, the increase in potency of products has driven the requirements for even more advanced control strategies. These approaches are not put in place only from a safety perspective; crucially, they can also ensure industry regulatory compliance, meet good manufacturing practices (GMP) and product quality requirements, and maximize yield of transferring poorly flowing and high value product. Effective containment can also facilitate respirator-free and “shirt-sleeve” manufacturing initiatives by removing costly secondary barrier containment and cumbersome personal protective equipment (PPE).

Health and safety benefits

Containment systems are primarily devices for employers to conform to health and safety regulations for their employees. Containment strategies involve isolating the product and process rather than the operator, lessening the need for PPE. As a secondary benefit, the reality of containment equipment is the prevention of cross-contamination, reduced need for cleaning, and the creation of a more ergonomic and efficient working environment, complying to United States Food and Drug Administration (FDA) regulation and GMP design. 

In 2017, the International Society of Pharmaceutical Engineering (ISPE) launched its second edition of the Risk-Based Manufacture of Pharmaceutical Products guide, which provides a process that allows manufacturers to assess risk and determine where control strategies are necessary to meet acceptable limits for cross-contamination (1). The first step in avoiding HPAPI environmental contamination is to identify the exposure potential. Once the exposure potential and containment level are determined, a control approach can be selected. 

The types of containment equipment undertaken vary greatly depending upon the process application, process equipment involved, product toxicity, and importantly the level of protection required. Market diversification has allowed more innovative technology development to safeguard drug products and the operator, including flexible and rigid barrier isolators, extraction booths, and split butterfly valves (SBVs), which are all now commonly used throughout the manufacturing process. 

Achieving containment in the modern pharmaceutical manufacturing environment is a challenge. Integrating disparate technologies provided by different suppliers into a contained production line is a highly complex task. However, valve-based engineering controls to create common interfaces between different technologies can provide a cost-efficient and flexible means of establishing a contained environment. Closed transfer valves, such as SBVs, are increasingly replacing traditional, open transfer techniques, which reduces the risk of cross-contamination and the presence of airborne dust particulate, ultimately protecting operator safety.

Efficiencies

Smart monitoring of containment solutions is crucial to understand the health status of the technology used and ensure efficiencies. Confirming all containment technologies are functioning correctly is vital for keeping employees safe, maintaining compliance with regulations, and making production as efficient as possible. Several approaches are available to monitor containment system usage levels, including traditional modeling, manual checking, and fully integrated automated assessment systems. More recently, wireless monitoring solutions offer enhanced efficiencies at lower costs. 

Wireless monitoring approaches can communicate critical usage data of multiple valve installations to health and safety, compliance, and maintenance teams to help reduce downtime from unplanned maintenance and condense losses due to product contamination. Recording usage data, such as how many times the valve has been opened and closed, allows manufacturers to understand the health status of their transfer device. It is a continuous and automatic process that facilitates maintenance planning. In addition, the modular nature of wireless monitoring technologies means that changes to manufacturing set-ups can be easily accommodated. It is also a more economic approach that provides real-time reporting and data monitoring at a lower cost when compared to manual monitoring. 

Practical considerations

The production of solid-dose pharmaceuticals is a complex, multi-stage process. Materials must be transferred from one process to the next, for example, from dispensing, to granulation, to blending, and on to compression and coating. The key difficulty is that powder transfer involves taking material from one closed system and transferring it into a separate closed system, which may or may not be compatible. Taking into consideration accessibility, batch sizes, and containment performance requirements, it is important to ensure that the design specifications of the engineering control will meet these process conditions and that the equipment materials are compatible.

Operation sequence for SBVs. Split butterfly valves are made up of a passive unit generally attached to the mobile container and an active unit attached to the processing unit. When combined during powder charging, the two units form a sealed environment that enables a contained and efficient powder transfer. In addition, SBVs are available at a range of different sizes suited for pilot-scale development through to commercial production and are compliant with a range of containment performance, down to nanogram levels.

Cleaning and washing. Decontamination and cleaning of process equipment, ranging from milling through to compression stages, also need to be carried out in a contained manner. Washing devices can be integrated with SBVs to ensure containment is maintained during this phase. The ability to effectively clean or wash the product contact and sealing areas of an SBV can be achieved with the use of specifically designed wash-in-place (WIP) devices. These devices can be static or penetrative, offering elementary local or high-level decontamination. The arrangement can be incorporated within a small-scale, bottle wash station and allow for the cleaning of the passive unit and container. Alternatively, when washing through larger intermediate bulk containers (IBCs), automated, dedicated wash active devices (fitted with cruciform discs to maximize the washing surface) can be integrated within specific IBC wash stations, providing remote opening of passive units and introduction of high integrity washing mechanisms.

Automation and handling. Lifting and docking systems can be incorporated with SBVs to ensure safe operation in hazardous or inaccessible areas or where the production scale does not permit manual handling. Users should consider whether a fully or partially automated version would best suit the application. A system that offers status information and sequence interlocking, secured with the use of pneumatic or electric proximity sensors, can be of benefit, especially if it also offers fully integrated and factory-tested control systems. Lifting and docking systems should provide repeatable and safe alignment of equipment in conjunction with lifting hoists and docking systems. 

Troubleshooting. Preventative maintenance is a crucial part of helping to safeguard the reliability of the containment solution. The identification and rectification of any damage to the device before it is used will mitigate risk. Frequent monitoring and preventative maintenance should be a key part of the process.

Conclusion

In line with the growth of drug manufacturing using HPAPIs, the containment solution market is expected to grow rapidly by 2020. In addition, with OSD forms like tablets, capsules, and sachets making up roughly 60% of the total pharmaceutical products market, there are increasing pressures and quality demands in this area that require efficient, modular, and flexible processes (2) to maintain containment integrity. Exposure to just a small quantity of a HPAPI or highly potent compound can pose significant health risks. 

Powder transfer solutions offer a high level of containment performance to ensure the safe handling of potent API, intermediates, and pharmaceutical formulations, while smart monitoring technology allows proactive management of equipment maintenance, enabling manufacturers to achieve the highest up-time by maintaining product integrity. Containment reduces risk, not only in terms of operator safety but also to ensure optimum performance with improved productivity. 

References

1. ISPE, ISPE Baseline Guide Vol. 7: Risk-Based Manufacture of Pharmaceutical Products (Risk-MaPP), Second Edition (North Bethesda, MD, July 2017).
2. F. Scholz, “A Fresh Perspective on Oral Solid Dosage Forms,” (May 31, 2018), accessed Feb. 1, 2019.

Article Details

Pharmaceutical Technology
Vol. 43, No. 3
March 2019
Pages: 30–31, 35

Citation

When referring to this article, please cite it as M. Avraam "Assuring the Safe Handling of Potent APIs, Intermediates, and Solid-Dosage Drugs," Pharmaceutical Technology 43 (3) 2019.

About the author

Michael Avraam is global product manager at ChargePoint Technology for the PharmaSafe range of products, info@thechargepoint.com.