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The market for formulated drugs based on highly potent active pharmaceutical ingredients (HPAPIs) is growing at a rapid pace, largely due to the development of highly targeted therapies based on antibody-drug conjugates, which can include cytotoxic small-molecule components. The manufacture of this expanding field of HPAPIs is challenging and requires specific know-how, facilities, equipment, and procedures designed to mitigate the risk associated with producing and handling potent compounds. Standards and technologies are continually changing, and HPAPI manufacturers must remain vigilant and prepared to adopt and implement the latest designs, equipment, training, and procedures to reduce the risks posed by HPAPIs.
Dealing with uncertainty
Although many challenges exist for high-containment API manufacturing, the variability and uncertainty associated with each compound present the greatest risks, according to Waldo Mossi, general manager of Helsinn Advanced Synthesis. “The importance of occupational exposure limits (OELs) is widely neglected in discovery research and early development,” he states. He explains that many companies use a one-size-fits-all approach to handling and managing the containment of bulk drug substances. Each individual process, however, offers different challenges, and no two new chemical entities (NCEs) are alike. The situation is aggravated by the lack of universally accepted definitions for various compound types, such as highly active, highly potent, and cytotoxic agents, which can lead to confusion between sponsor companies and custom-manufacturing organizations (CMOs), according to Mossi.
To manage the variation and address the uncertainty associated with new substances, Helsinn continues to strive for design of toxicology testing and safety evaluation from the early stages of process development. The company also uses a comprehensive, science-based OEL evaluation approach from the start of an HPAPI project, and works with experienced industrial hygienists to assign initially conservative OELs to each potent compound that will enter its facility. “Since a certain level of risk will always exist when working with HPAPIs, it is important to foster a strong company culture of excellence in protecting employees, products, and the environment. Our comprehensive approach to process and compound evaluation helps to clearly define the needs and objectives in handling each process step,” Mossi observes.
Fortunately, as an HPAPI project proceeds through the development lifecycle and into clinical trials, the understanding of the risks associated with the potent compound increases and risk mitigation generally becomes less difficult, according to Patrick Klipstine, director of SAFC’s Madison, WI site. “During the development process, SAFC pursues ongoing internal evaluations and works with third parties to bolster this process. As the definition of potency becomes better defined during the development cycle, our process engineers and environmental, health, and safety (EHS) representatives can make appropriate modifications to the manufacturing engineering controls,” he notes.
Manufacturing and process continuity are also crucial during scale up to ensure that risks are minimized, according to Mossi. “Laboratories and small-scale GMP equipment should be designed so that they are aligned with the large-scale equipment used for commercial production in order to ease the transition and reduce uncertainty and risk during scale up,” he says. At Helsinn, the risk associated with scale up is reduced through facility design and investigated during early design of experiment (DOE) analyses.
More than chemistry
In any chemical manufacturing plant, the protection of operators is a top priority. In facilities producing HPAPIs, providing operator protection is absolutely critical and the top priority, according to Klipstine, which means that appropriate engineering controls are in place and personal protective equipment is available. In addition, every unit operation must be considered with regard to both the chemistry and potential occupational exposure. “Chemical processing steps are evaluated on their merits with regard to sound chemical process hazard criteria, and then each process is developed to allow for the safest execution of the process within the identified equipment train, taking into consideration compatibility with materials of construction, thermal output, gas evolution, waste stream management, etc.” Klipstine notes. With these considerations taken into account, SAFC then applies engineering controls for containment to mitigate the risk for occupational exposure. Specifically, the company has adopted a risk-minimization strategy that is systematically constant, but allows for different outcomes depending on the chemistry and potency of each API.
“Each opportunity that turns into a project goes through a defined risk assessment process, with experts in our process development, EHS, and process engineering groups closely collaborating to provide a robust process from both a chemical engineering and process engineering standpoint. One of SAFC’s first principles is that all processing of powders and liquids are conducted in closed systems that have been verified to be effective for the prevention of occupational exposure. Second tier to these systems are robust training programs that have been designed for specific unit operations,” he adds.
Helsinn also emphasizes the use of fully closed systems and isolation to avoid or mitigate areas of greatest risk. The company fosters the approach of contained chemistry, which means that equipment for each individual process (e.g., balances, rotary dryers, pressure filter dryers, and slurry vessels) is installed inside an isolator that has been qualified for occupational exposure levels down to nanogram levels according to the International Society for Pharmaceutical Engineering’s (ISPE) Standardized Measurement of Equipment Particulate Airborne Concentration (SMEPAC) methodology. The use of such an approach, according to Mossi, was made possible by a clean atmosphere design supported by accurate general ventilation using double-pass, high-efficiency particulate arrestance (HEPA) filtration.
It should also be noted, according to Mossi, that in addition to variable chemistry, operational risk depends greatly on several factors, including the company culture, personnel training, proper operational execution, and the design and engineering of the facility. In general, the greatest challenges are typically associated with operations such as sampling, loading/unloading of the reactor, and transfer of the material. “Powder handling presents the highest probability for potential worker exposure, and it is important to carefully study optimal methods for minimizing and, wherever possible, removing powder handling operations from an HPAPI process,” he states. At Helsinn, if powder handling is necessary, effective and consistent safeguards are factored in with redundancies to mitigate the risk even further.
SAFC handles both liquid and powder HPAPIs under a defined set of unit operations to minimize the potential for occupational exposure. “By using one common system defined appropriately for scale to ensure containment, our chemists can be assured that the processes they are executing are appropriately identified for the defined potency,” Klipstine explains. To reduce risk, all large-scale isolation of powders is conducted in jacketed filter dryers where solids can be filtered and dried without the necessity for discharge from the drying unit operation. Once dry, the HPAPI is discharged using glove-box containment techniques directly into predefined drug-substance packaging using ILC Dover continuous liner technologies, according to Klipstine. As a best practice, Helsinn investigates each manufacturing process step for hazard and safety together with the aid of an outside industry expert as part of its DOE analysis.
Of significance to HPAPI producers is having a thorough understanding of the cleaning procedures required to meet allowable carryover limits for multipurpose equipment, according to Klipstine. “Controlling cross-over contamination mitigates any potential risk to patients,” he asserts. Mossi agrees that safety cleaning verification at each stage of a manufacturing process and GMP cleaning validation is crucial. SAFC’s philosophy is to apply a continuous improvement mentality so that its systems will exceed current industry standards. Even so, one challenge the company faces regularly as a CMO with a multipurpose facility relates to servicing customers ranging from virtual biotechnology firms to large pharmaceutical manufacturers that have a wide range of expectations regarding handling and cleaning verification.
Another challenge for CMOs that offer HPAPI manufacturing services is the continual evolution of industry standards and technologies. “Companies that want to participate in this market must adopt these newer technologies,” Klipstine asserts. SAFC, for example, had to transition to more robust analytical technologies with improved sensitivity and detection levels that allow for the determination of potential API carryover at part-per-billion levels.
On the other hand, as the industry continues to mature, consultants and innovative equipment manufacturers can help design state-of-the-art engineering controls to better suit specific facility containment requirements, according to Mossi. He notes that Helsinn’s recent facility expansion was custom-designed to support workflow, ergonomics, and safety, while containing several unit operations within only a few isolators.
About the Author
Cynthia A. Challener, PhD, is a contributing editor to Pharmaceutical Technology.
Article DetailsPharmaceutical Technology
Vol. 39, Issue 3
Citation: When referring to this article, please cite as C. Challener, “Minimizing Risk during HPAPI Manufacture,” Pharmaceutical Technology 39 (3) 2015.