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In addition to ADCs, other types of highly potent biologics require specialized manufacturing skills.
Highly potent compounds are typically associated with small-molecule APIs, except perhaps antibody-drug conjugates (ADCs) that include a cytotoxic chemical API linked to an antibody. ADCs have received significant attention due to their ability to provide targeted delivery of their cytotoxic payloads, affording higher efficacy with dramatically reduced side effects. There are, however, several other types of biologic drugs that are potent and require specialized facilities and equipment and highly trained operators to ensure protection of personnel and the environment.
Highly potent drug substances—and drug products—are generally considered to have occupational exposure limits (OELs) of <10 µg/m3 and require a low dose to generate a pharmaceutical effect, according to Iwan Bertholjotti, director of commercial development for bioconjugates at Lonza. “While the majority of these drugs are based on small molecules, some biologics fall into this class due to their potential to be sensitizers, including monoclonal antibodies (mAbs) and ADCs as well as non-oncology drugs such as hormones, narcotics, and retinoids,” he says.
Meinhard Hasslacher, director of CMC for SOTIO, adds that some highly potent conjugates are derived from mAbs, such as antibody fragments, diabodies, and single-chain variable fragments, while additional non-antibody scaffolds include affibodies (from Staphylococcus Protein A) and fibronectin Type III.
Other types of bioconjugates may also be highly potent, notes Gregory A. Sacha, senior research scientist with Baxter BioPharma Solutions. He points to peptide drug conjugates (PDCs) in development for cancer therapy. “These modalities are attracting attention given their potential to provide improved homogeneity of conjugation and more predictable pharmacokinetics than ADCs, combined with the possibility of designing PDCs with the ability to cross the blood brain barrier,” he explains.
It is important to keep in mind, notes Hasslacher, that highly potent does not necessarily mean toxic. “A protein that is active at the milligram or microgram level in a body—like hormones, insulin, clotting factors, or even some vitamins—are highly potent. High potency in combination with a toxic compound adds another level of complexity, which is what we see with ADCs,” he observes.
As with highly potent small molecules, it is important to assess the potency of new biologic compounds with the potential to be classified as highly potent, which can be challenging for new drug substances with little available toxicity data. “Potency is assessed considering the indicated dose and pharmacological and toxicological aspects,” comments Bertholjotti.
Baxter BioPharma Solutions, according to Sacha, uses information provided by its clients, including safety data sheets and OELs, to evaluate the exposure control category.“In addition,” he says, “risk evaluations are conducted prior to the introduction of a new product to ensure there is no risk of cross contamination.”
The risk assessment of both potent substances and their production processes ultimately defines how those substances will be handled to protect operators and the environment. Waste management is also an important topic and needs to be appropriately defined, Bertholjotti adds. “Based on experience and similar substances handled in the past, it is possible to identify a catalog of standard protection measures,” he states.
Once preclinical animal data are available, SOTIO uses this information to determine values for the lowest observed adverse effect level and no observed adverse effect level, says Hasslacher. With this information in hand, it is possible to calculate the permitted daily exposure. In combination with pharmacokinetic data, an OEL and ultimately appropriate occupational exposure bands can be calculated.
Accurate determination of potency is crucial for establishing the appropriate level of containment that will protect personnel during manufacturing and subsequent product handling, waste management, and equipment cleaning. “Once the risk assessment described above is completed, required measures are implemented according to company policy, local legal requirements, and other potential considerations,” Hasslacher says.
The handling of highly potent drugs requires defined concepts to protect operators and the environment, agrees Bertholjotti. It also necessitates the proper safety culture, he asserts, which can present a challenge that is essential for companies to overcome before they introduce highly potent processing into their facilities. “To establish a safety culture, time and investment in people and infrastructure are both required,” he explains.
Once the containment concept is defined, operators must then be trained. In some cases, Lonza also conducts surrogate studies to confirm that the containment approach delivers the level of protection expected. At that point, there is assurance that highly potent drugs can be handled safely, Bertholjotti says.
Unlike many small-molecule processes, which require the use of organic solvents, highly potent biologics are often processed in aqueous solutions at neutral pH and room temperature. For these reasons, Hasslacher notes that containment requirements tend to be less onerous than those required for small molecules.
High-molecular-weight highly potent biologics such as ADCs may pose less risk to operators than highly potent small molecules because they are less bioavailable via absorption and inhalation, according to Sacha. Both, he adds, can be manufactured in dedicated or disposable direct product contact equipment.
Lyophilization, Sacha notes, which is not often required for small-molecule drugs, is often necessary for biologics and presents different containment requirements. “Although they represent indirect equipment and do not come in direct contact with the product, lyophilizers must be included in a robust equipment cleaning validation program,” he comments.
Many of the manufacturing challenges faced by highly potent biologics are the same as those for any biologic drug substance/drug product. For instance, microbial contamination, sterility, and endotoxin issues are similar, notes Hasslacher.
There is a possibility of forming aggregates if the molecule is sensitive to interfacial interactions such as the formation of foam during mixing or interacting with container surfaces. Most of these can be prevented by using stabilizing agents or surfactants, according to Sacha.
In addition, a highly potent biological drug must, like other drugs, be stable for several days up to several weeks in the human body at 37 °C once administered, observes Hasslacher. Stability studies must also be performed to determine storage conditions, such as the container type and whether the product must be freeze-dried or can remain in the liquid state and whether light protection is required.
“For cryopreservation, the primary package needs to be clean, tight, and suitable for use with highly potent biologic,” Bertholjotti comments. Proper processes also need to be defined and implemented also for drug product manufacturing processes.
The added challenges posed by highly potent biologic molecules relates to the need to prepare the formulation in an isolator, agrees Sacha. “There is often less space for work in an isolator and all materials needed for manufacturing must be either sterilized during sterilization of the isolator or transferred into the isolator using transfer ports,” he explains.
In addition to these containment measures, cleaning of multipurpose facilities represents a further challenge when working with highly potent biologics. “The mindset that a biotechnology process is bio and not highly potent while a chemistry process always is hazardous can be misleading,” states Bertholjotti. He concludes that the combination of biosafety, occupational hygiene, and good manufacturing practice requirements create challenges not faced by non-
Advances in various types of equipment are helping manufacturers of highly potent biologics overcome some of these challenges. Sacha points to new types of equipment that are fully contained, where preparation of the formulation and filling into containers occur all in the same space, such as the Vanrx system, acquired by Cytiva in February 2021, and the Vers-A-Tech system from the Bausch Group.
“Containment in the last decade has been influenced by the recognition that it is not possible to sufficiently protect workers using only personal protective equipment anymore; additional technical solutions are needed to contain the increasingly highly potent drug substances and ensure adequate protection of operators and the environment,”
Bertholjotti points to single-use systems available today that enable the implementation of single-use process concepts for closed manufacturing.
Despite the manufacturing challenges associated with the production of highly potent biologics, pursuit of their development and commercialization is important to the advance of new therapies. “Highly potent drugs tackle various life-threatening diseases, and the necessary capacity must be available to prevent drug shortages,” assert Bertholjotti.
“The manufacturing of these drugs requires knowledge, experience, and special attention to ensure operators and the environment are protected to deliver these drugs safely and sustainably to patients,” Bertholjotti continues. Fortunately, much progress has been made in our understanding of the best practices for highly potent biologics manufacturing. In addition, both drug developers and contract manufacturers are committed to advancing technologies to achieve ongoing improvement of existing solutions.
Cynthia A. Challener, PhD, is a contributing editor to Pharmaceutical Technology.
Vol. 45, No. 6
When referring to this article, please cite it as C. Challener, “Assessing Risk and Production of Potent Substances,” Pharmaceutical Technology 45 (6) 2021.