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Lack of toxicity data and poor physicochemical properties must be overcome.
More than 25% of drugs on the market worldwide and candidates in the pharmaceutical pipeline were considered to be formulated with highly potent APIs (HPAPIs) in 2020 (1). The vast majority of these products were cancer therapeutics—approximately 60% of approved oncology treatments are based on HPAPIs. At the time, more than 115 contract manufacturing organizations had the capability to produce highly potent drugs, and many had recently invested or were in the process of implementing capacity expansions to meet growing demand for HPAPIs and products formulated with them.
In addition to specialized facilities and equipment and highly trained personnel, organizations developing and manufacturing highly potent drugs must have the requisite expertise to overcome numerous formulating challenges ranging from lack of sufficient toxicity data to managing poor solubility and bioavailability to ensuring uniform dosing of low concentrations of HPAPIs.
HPAPIs, typically defined as having an eight-hour time-weighted occupational exposure level (OEL) of10 micrograms or less, by their nature present risks to anyone handling or using them. Prior to any formulation efforts, therefore, it is essential to understand those risks so that appropriate engineering controls, appropriate personal protective equipment, and robust operator training programs are in place prior to establishing handling and containment policies, according to David Lyon, senior fellow, global R&D small molecules at Lonza. That can be difficult, says Lisa Caralli, senior director of science and technology for pharmaceutics with Catalent, because suitable toxicology data are often lacking in early development.
“These data are not only important to evaluate risks to patients, but also to
understanding how the compounds should be handled by formulators and manufacturing personnel,” Caralli observes. Without these data, she adds that by default HPAPIs are often classified as having a more conservative occupational exposure band (OEB) or OEL, which in turn may limit the outsourcing partners that can provide development and manufacturing support as well as the types of technologies that can be used in the formulation process. “Overall, this lack of crucial knowledge will certainly increase both the timelines and costs,” Caralli comments.
Experienced development and manufacturing partners, adds Caralli, will ask the correct questions regarding the existing studies and may propose a phased, risk-based approach to formulation development, as data needed for a more concrete assessment are gathered. She emphasizes that “any formulation developed must facilitate drug exposure at the intended site of action, in order to generate high quality and accurate toxicology data, which can then be used to refine the classification of the drug.”
When insufficient toxicology and safety information is available, formulators at Evonik focus on the mechanism of action (MoA) of the HPAPI (whether it is a new chemical entity [NCE] or new biological entity [NBE]), according to Kenny McCleary, senior international ESH advisor at Evonik Health Care. Information on the toxicity and safety properties of existing compounds or an existing class of compounds with the same or similar MoAs are considered along with any pieces of information specific to the new HPAPI to determine the OEL using conservative estimates.
This OEL, says McCleary, is then used to establish cleaning strategies and unit operation containment control strategies. As formulation development proceeds and as more safety and toxicology information become available, Evonik reassesses the OEL and acceptable daily exposure classifications.
“Such assessments are essential in multi-product facilities because of the challenges in preventing cross-contamination of one highly potent product into a subsequent product, as well as protecting workers while they are conducting formulation process activities,” McCleary notes. “In the end,” he stresses, “we have two safety priorities when handling highly potent compounds: the safety of the personnel handling these compounds and the safety of the patients who will be administered the drug substance.”
HPAPIs can be found across the continuum of chemical space and, as such, can have virtually any combination of chemical and physical properties, according to Lyon. Like many candidates in the pharmaceutical pipeline, HPAPIs often suffer from some level of poor solubility and/or permeability, and thus less-than-desired bioavailability. Currently there are more than 1000 highly potent small molecules in development, notes Lyon, and approximately 70–90% of these compounds are poorly soluble and thus have low bioavailability.
Highly potent compounds can also be associated with a narrower therapeutic window. “When this is the case, it is extremely important to understand how the dosage form will perform in vivo across a wide range of patient types with well-defined co-morbidities,” Caralli says. HPAPIs with low solubilities, she says, should be formulated to ensure a high fraction remains soluble in the intestine where drug absorption occurs.
Some approaches to increasing solubility are better than others, however. If a high dose is used to overcome low bioavailability versus an enabling formulation that improves overall bioavailability, for instance, there is an increased risk of drug overexposure, Caralli observes. Toxic exposure levels can be reached if the drug exhibits factors such as a food effect (i.e., the drug is more soluble in the presence of food) or pH effect (where solubility is impacted by small differences in pH within the gastrointestinal tract). APIs that are CYP450 substrates can also be at risk for variable exposure as the result of genetic variability or drug-to-drug interactions that can lead to the inhibition or induction of CYP450 enzymes at different levels.
A number of different enabling technologies can be used to enhance the absorption of HPAPIs, even if the formulated doses are relatively low due to their high potency. Lyon points to amorphous solid dispersions (ASDs) as being essential for delivering poorly-soluble and highly potent compounds, and particularly spray drying, because it can somewhat mitigate the apparent potency of powdered HPAPIs through dilution in an appropriate excipient system.
HPAPIs, Lyon explains, are most potent in powder form. Therefore, the handling of the powder form must be carefully controlled. In spray drying, once the powder is introduced into a spray solution tank and dissolved in the desired spray solvent, the potency and concentration of the HPAPI are considerably reduced. Similarly, when the solution is dried, even though the API has been returned to powder form, it has been diluted by introducing a polymer or other excipient.
Liquid HPAPIs, meanwhile, are amenable to handling in a contained system and then formulated in a liquid or self-emulsifying lipid system, according to Lyon. “This approach is quite beneficial with respect to HPAPI handling because the API is dissolved throughout the processing equipment train and exposure risk can be effectively minimized,” he comments.
Overall, Caralli observes that using tools such as physiologically-based pharmacokinetic modeling is essential to assess which physicochemical parameters are associated with the highest risk. “The information that is obtained from these studies can be directly applied to the development of effective formulation strategies to ensure both safety and efficacy,” she contends.
The development of ASD formulations takes time, but drug manufacturers today face tremendous pressure to get into first-in-man studies as quickly as possible. One solution for the formulation of powdered HPAPIs during early development that is finding increasing use today is microdosing.
Microdosing, explains Lyon, is the precision-weighing and dispensing of powders directly into capsules or bottles using various specialized equipment platforms or techniques. “API-in-capsule or -bottle studies start with API characterization, from which an understanding of the API morphology, solubility, and other key attributes define the drug-product design and decision-flow diagram.”
Depending on the material’s physical attributes, API doses as low as 100 µg can be encapsulated with minimal variance in weight. That is important for HPAPIs, because these compounds provide therapeutic (and potentially toxic) effects already at very low doses. For instance, potent treatments delivered to the lung are often therapeutic in the 100s of microgram range, if not less, according to Lyon.
Microdosing of an undiluted HPAPI into a capsule using robust engineering controls can be an attractive alternative to other formulation approaches. “Using a drug-in-capsule approach for high potent drugs can be a good way to eliminate issues with blend uniformity that are associated with formulated capsules and tablets,” Caralli says. There are some limitations, however. The HPAPI must be sufficiently soluble and not require bioavailability enhancing strategies. In addition, it must have suitable flow characteristics to allow for accurate capsule filling, she observes. In vitro studies should also be performed to confirm the drug-release profile and explore the potential for undesirable drug-capsule interactions.
Microdosing, Caralli indicates, can accelerate entry to the clinic, because the HPAPI can be well contained, both during production and in the final capsule dosage form. It is not a good long-term dose-design strategy, however, as it is not suitable for scaling up for larger clinical trials or commercial applications.
For oral highly potent formulations, the use of liquid-filled capsules, either hard-shell or softgel, is an excellent approach. As is the case with ASDs, the solubilization of HPAPIs prior to filling reduces the exposure risks to formulators and manufacturing operators, Caralli notes. It also has the benefit of eliminating dose-content-uniformity issues that are associated with dry blends, and the process is directly scalable from early phase to commercial-scale batch sizes, which lowers overall program risks.
Lipid-based formulations, meanwhile, have the potential to offer even more advantages, as they can be used to enhance bioavailability through improved solubility, permeability, and for some APIs, may reduce metabolic loss through lymphatic transport, according to Caralli. The specific encapsulation approach, she says, is dictated by the fill solution properties and drug compatibility with the shell components.
While formulation of HPAPIs is most often associated with oral administration, they can be optimal for formulation as parenteral products. “The development of HPAPIs should always be performed with the compound’s target product profile in mind,” Lyon observes. For a compound developed to target lung disease, a locally acting, inhaled formulation would likely be best. Where possible, oral presentation is often more acceptable based on patient preference.
“Parenteral delivery, however, while more complicated due to the need for sterility and a delivery device (e.g., a pre-filled sterile solution in a syringe), can aid in patient compliance and assure that 100% of the dose is administered, particularly when stomach pH, presence of food in the stomach, or age may complicate oral administration,” comments Lyon. He also notes that parenteral administration can be useful in a clinical or hospital setting where the patient may not be able to take oral medications.
There are other benefits to parenteral delivery for HPAPIs with certain physicochemical properties. For instance, when working with hazardous APIs such as some chemotherapeutic agents, where localized tissue damage can occur, the injectable route of administration is clearly the preferred option, Caralli says. Drugs with a narrow therapeutic window that exhibit high first-pass loss or metabolic variability should be considered for injection as well.
Beyond these factors, the need for injectable delivery should be assessed as with non-highly potent drugs, according to Caralli. “Bioavailability challenges, patient dosing (e.g., hospitalized patients), and the onset of action should all be evaluated when considering the injectable route of administration,” she comments.
When sustained delivery is desired, formulation of HPAPIs as long-acting injectables (LAIs), such as bioresorbable microparticles and implants, is also highly attractive, according to Tom Tice, senior director of global technical marketing for Evonik Health Care. “In fact,” he states, “the most important criterion for LAIs is their potency, which translates to API mass.”
That is because API mass as well as excipient mass and injection vehicle mass contribute to the total injection volume, which is limited for parenteral formulations: from 1 to 2 mL for intramuscular/subcutaneous and 100 µL for intravitreal injections. “Many LAIs on the market deliver small-molecule and peptide HPAPIs for anywhere from one to four weeks and as long as six months following a single administration. Bottom line: HPAPIs are desirable candidates for long-acting injectables because of their potency, low dose, and small mass,” Tice concludes.
It is important to remember, according to Tice, that the concentration of API in the formulation, the physical form of the API, and the other excipients and carriers present do not change the inherent pharmacological properties of the compound. As such, all APIs must be managed based on their inherent toxicological properties, because whether they are potent or highly potent, the dosage and formulation of API material can impact the risk assessments, controls, and cleaning practices needed. When formulating HPAPIs in particular, Caralli emphasizes that the safety of both patients and drug development scientists are of equally high priority. “Performing the correct non-clinical studies at the right stage of development is critical to ensure the appropriate containment strategies are applied,” she says. Key to those studies, Caralli adds, is using drug formulation and delivery strategies that ensure appropriate exposure and result in high-quality data. “Because of the dangers inherent to HPAPIs, it is important to let the science drive the development strategy,” she asserts.
Given that HPAPIs will have a continuing strong presence in pharmaceutical pipelines, that potency is increasing, and that many HPAPIs have low solubility and/or low bioavailability, Lyon believes that there will be an ongoing need to further develop and refine current engineering controls, procedures, and use of personal protective equipment to ensure HPAPIs are handled in a robust manner while being formulated using increasingly effective enabling technologies.
1. V. Rees, “Research Finds 25 Percent of Drugs Contain Highly Potent Compounds,” Eur. Pharm. Rev., Sept. 25, 2020.
Cynthia A. Challener, PhD, is contributing editor to Pharmaceutical Technology.
Vol. 46, No. 7
When referring to this article, please cite it as C. Challener, “Challenges to Formulation Development for Highly Potent APIs,” Pharmaceutical Technology 46 (7) (2022).