Appropriate Process Design Critical for Commercial Manufacture of Highly Potent APIs

The majority of highly potent APIs (HPAPIs) to date have been developed for the treatment of cancer (cytotoxics and cytostatics), particularly tyrosine kinase inhibitors and derivatives. There are, however, other therapeutics, including hormones, narcotics, and retinoids, which are also highly potent. In addition, while HPAPIs are generally thought of as small-molecule drugs, many biopharmaceuticals have occupational exposure limits  (OELs) of 10 μg/m3·8 h or less, a general guideline for classifying APIs as highly potent, according to Srinivas Achanta, regulatory affairs manager with Hetero. Of particular interest are antibody drug conjugates (ADCs), drugs that include a small molecule, cytotoxic payload, and an antibody connected with a linker. These therapies are designed to deliver the highly potent payload to targeted cells, reducing the likelihood of harm to normal cells. The number of ADCs in development has grown in recent years, and this growth is a key driver of the HPAPI market. The increasing number of ADCs and HPAPIs in general is creating challenges with respect to the prevention of cross-contamination in large manufacturing facilities with multi-use equipment and maintaining containment during larger-scale purifications.

Importance of ADCs
Because ADCs enable the targeted delivery of HPAPIs to the specific cancer cells (or other problematic cells), they have attracted significant attention, and the number of ADCs in development has increased dramatically. “The toxin that is conjugated to the antibody in ADCs has been the fastest growing segment of the HPAPI market, with demand quickly increasing in recent years,” says Dave Bormett, director of operations for SAFC. With three components to manufacture and combine together under containment conditions, the production of ADCs can be a complex process, adds Achanta. In addition, Bormett notes that certain new types of ADC compounds, which may be considered the next generation of ADCs, are considered to be even more potent than existing products and are pushing the limits on current capabilities with respect to the handling of low OEL materials.

Opportunity for single-use systems
Single-use manufacturing technologies are on the rise for small-scale highly potent products such as ADCs, according to Jeff Marcoux, technical business development manager at Novasep. “Another important trend is the widespread acceptance of portable dedicated equipment, including both single-use and permanent systems for small-scale production of very highly potent compounds such as ADC payloads, which often have OELs lower than 0.1 µg/m3·8 h,” he notes. “Dedication of equipment and the adoption of single-use technologies can play an important role in controlling cross-contamination and maximum carry-over limits after cleaning (MACO) when implemented as part of a risk-based approach,” adds Marcoux.

At SAFC, on the other hand, single-use, disposable technologies have thus far been used in certain limited applications, but they are being considered for HPAPI manufacturing where they can improve containment, particularly for larger-scale manufacturing activities, according to Bormett.

“All high-potency APIs must be produced under conditions that not only protect the operators from exposure to the compounds, but also prevent contamination and the inadvertent carryover of a different product that was previously produced or is simultaneously being manufactured. While modern HPAPI facilities are meeting today’s requirements, there is a continual need to improve these technologies going forward. To accomplish this task, we need to focus on the development of production and handling methods including single-use systems and/or new technologies that can provide increased protection of the API from cross-contamination. Such protection systems must focus on the cleaning and removal steps,” observes Achanta. “The development of such new technologies is of increasing importance as the number of multiproduct facilities, which pose the greatest risk of contamination of HPAPIs, are growing around the world in order to meet the greater demand for these products,” he adds.

The purification challenge
ADC payloads are small molecules containing complex chemical structures. As such, the purification of these molecules is challenging from a safety, health, and environmental point of view, as well as with respect to the technological aspects, according to Marcoux. “The chemical structures of the impurities obtained from chemical processes used for the synthesis of ADC payloads are often closely related to the desired HPAPI. As a result, traditional purification processes, such as crystallization or low-pressure silica gel chromatography, are often inadequate or lead to unacceptable loss levels,” he explains.  Novasep has found that HPLC purification technologies are particularly well suited for this class of compounds, ensuring robust, scalable, and reproducible purification under contained operational conditions.

Marcoux also notes that because tracking of impurities is a challenge at the ADC stage after conjugation of the payloads with the antibody, much of the purity control for ADCs occurs at the payload stage. Both conjugatable and non-conjugatable impurities are increasingly controlled at this stage of the manufacturing process.

Maintaining containment around large-scale purification steps, such as chromatography, can also be challenging, according to Bormett. “It is important, therefore, to implement appropriate facility and equipment controls to ensure that these operations are handled appropriately,” he comments.

Need for appropriate process design
Appropriate process design is in fact crucial for the entire HPAPI production operation. “Most very highly potent APIs and ADC payloads require small clinical and commercial quantities, and the production of gram-scale GMP APIs and payloads can be challenging. The control of containment using flexible and small equipment, including glass equipment, is always a challenge and requires a tailored approach for each process and each unit operation,” Marcoux says.  The appropriate process design at the development scale is also necessary to ensure that the process will fit the equipment and capabilities of the facility upon scale-up, according to Bormett. “The technical issues that must be addressed for scale-up of a manufacturing process are the same for an HPAPI or non-HPAPI. The challenge is ensuring that the proper engineering controls are in place for the process upon scale-up, and ensuring any limitations are considered when developing the process,” he notes.

One of the biggest challenges at large scale is the handling of powders and solids, according to Achanta. “Up to a scale of a few kilos, it is relatively straightforward to manage solids, because bottles with alpha-beta split butterfly valve connectors can be used for charging reactors to maintain containment. On a larger scale, however, this approach is impractical,” he explains.

Bormett also notes that appropriate cleaning methods must be implemented to achieve the required limits for residue levels in multi-use equipment. “The use of analytical methods that provide very low detection limits is necessary in order to confirm that the required residue levels have been achieved,” he says. Bormett further notes that there is certainly an interest in continually achieving lower detection limits when handling HPAPIs.

Finally, Achanta points to the ambiguity surrounding the classification of HAPAIs given that different pharmaceutical companies often use proprietary systems is an issue. In addition, he notes that because the classifications for new APIs are often unknown due to a lack of data, they must be carefully managed with appropriate process design and containment controls.

Increased investment activity
There has been an increase in investment in HPAPI capacity by both contract manufacturing organizations and large pharmaceutical companies, particularly to support ADC development and manufacturing, according to Bormett. SAFC, for example, has two major expansion projects under way to support HPAPI manufacturing. At the company’s Verona, WI facility, three HPAPI-capable GMP manufacturing areas are being added, including a plant with 400 L and 800 L reactors. In addition, Bormett says that SAFC is building a commercial antibody drug conjugation facility in St. Louis, MO to meet growing market demand beyond the current clinical-scale facility.

Novasep, meanwhile, recently invested $4 million to expand its HPAPI manufacturing capabilities at its site in Le Mans, France. In the expanded cGMP facility, which has been commissioned, the company manufactures highly potent compounds with OELs lower than 0.03 µg/m3·8 h at the kg-scale, according to Marcoux. The investment features cryogenic chemistry at -60°C in Hastelloy reactors, as well as large-scale HPLC chromatography and drying in contained areas to manufacture ADC payloads at commercial scale.

About the Author
Cynthia A. Challener is a contributing editor to Pharmaceutical Technology.