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Cynthia A. Challener is a contributing editor to Pharmaceutical Technology.
Operator, caregiver, and patient safety are at the forefront when selecting the best options and dosage forms.
Highly potent compounds present numerous challenges with respect to process development, formulation, and delivery. “The key features at the interface of drug delivery and highly potent APIs (HPAPIs) are the ability to maintain operator safety through containment of the API during processing and to deliver a drug product in which the HPAPI is evenly dispersed, even when doses are as low as micrograms,” asserts David Lyon, a senior research fellow with Lonza.
Doing so is becoming more challenging as the molecular complexity of HPAPIs
continues to increase significantly. “These molecules are much more specific in how they interact with the body and different cellular targets,” says Brian Haney, director of technical operations for AMRI. “As a result, it makes them much more difficult to manufacture, more difficult to test, and more unstable,” he observes.
In fact, HPAPIs have largely been too fragile for traditional oral solid-dose formulation, and the majority are delivered parenterally via infusion or intravenous injection, according to Haney.
Historically, HPAPIs have been almost exclusively associated with oncology therapeutics. “Highly potent molecules for such acute indications could be delivered by intravenous infusion even if an oral drug product could not be developed,” Lyon explains.
Currently, however, HPAPIs include a growing number of classes of molecules and new chemical entities for a broader range of indications, thus covering a much wider swath of the developmental pipeline. “For many of these indications,” Lyon comments, “oral delivery is required due to the chronic or frequent dosing needed for the molecule and indication. The need for oral solutions has thus led to adaptation of existing pharmaceutical processes to enable the handling [of] HPAPIs in a safe and efficient manner,” he adds.
Examples include microdosing, liquid-filling of capsules, and wet granulation, which help balance therapeutic benefit versus risk. These processes address safety concerns for operators by properly containing the HPAPI, according to Lyon.
“Liquid-fill and wet granulation processes remove much of the concern with operator exposure because the powder risk is removed once the HPAPI is dissolved in a lipid or solvent for either filling into a capsule of spraying onto a solid support dispersible,” explains Lyon. Once the HPAPI powder is dissolved or emulsified, further processing of the liquid becomes simpler and less costly, requiring less strict containment. Lyon also notes that these processes allow for highly accurate dosing down to low API levels, helping ensure content uniformity and reproducible dosing for caregivers and patients.
Handling a highly potent compound across the oral drug development process becomes even more complex when the compound is also bioavailability-challenged. The simplest approach, according to Lyon, is to fill the micronized active ingredient into an empty capsule shell using equipment that can be deployed in a contained space (microdosing).
Many HPAPIs, however, have material properties (sticky, semisolid, liquid, too light, too fluffy) that preclude the use of conventional microdosing. The powder may also have poor flow properties or the size and shape of the HPAPI particles may be inconsistent. In some cases, Lyon observes, HPAPI compounds may be so potent that a safe containment level cannot be easily achieved or the dosage itself may simply be below the weighable range of microdosing.
In these cases, liquid-filled hard capsules (LFHCs) can effectively minimize operator exposure to the solid HPAPIs. “The liquid-filling process is straightforward, involving only four steps: dispense, mix, fill, and seal. LFHCs contain either room-temperature liquids or thermo-softening materials manufactured as molten liquids at temperatures of up to 65 °C.
Typically, sticky semisolid and liquid HPAPIs are miscible in liquid excipients, forming a homogeneous mixture, no matter how low the dosage is,” says Lyon.
In addition, the use of solubility-enhancing excipients and liquid lipid-based options such as self-emulsifying drug delivery systems (SEDDS) and self-micro emulsifying drug delivery systems (SMEDDS) is also possible. Milling and micronization of HPAPIs to produce nanoparticles is also safer when performed in an oily solvent.
Size reduction, in fact, through “top down” approaches such as micronization and “bottom up” techniques such as crystallization, expands the surface area-to-mass ratio, thereby increasing the dissolution rate of the HPAPI, according to Ilan Avni, vice president of business development with Wavelength Pharmaceuticals. Other techniques for increasing bioavailability of HPAPIs, he remarks, include spray drying and hot-melt extrusion to generate amorphous solid dispersions in polymeric matrices and the formation of cocrystals with appropriate conformers to improve physicochemical properties.
One of the challenges to formulating highly potent APIs is the fact that often only small quantities of the drug substance are required in each unit dose. Only formulation approaches that can ensure homogenous distribution throughout the product, even at extremely low doses, are therefore appropriate. These constraints also require accurate analytical methods; again, preparing liquid solutions or emulsions for further processing (encapsulation, wet granulation, then tableting) is effective.
The melt-spray-congeal (MSC) process is also now being successfully applied to advance potent oncology compounds in lipid multiparticulate (LMP) formulations, according to Lyon. “This technology is increasingly used to address controlled release, taste-masking, and/or low solubility challenges,” he says.
In the MSC process, the API is suspended or dissolved in a molten lipid formulation at elevated temperatures (70–90 °C) and then pumped to a spinning disk where the solution/suspension is atomized and then congealed, forming a multiparticle of 100–300 microns. Notably, Lyon says, these lipid multiparticles can contain from as little as a few percent API to 50% API, making them an effective vehicle for diluting HPAPIs.
Meeting sustained-release demands
Particularly for targeted oncology therapies, it takes time to deliver the HPAPI to the specific cancer cells of interest. “Sustained- or modified-release formulation makes it possible for the active substance to stay in the body longer as it travels to where it needs to go,” says Haney.
To achieve this goal, newer delivery approaches include conjugation of the HPAPI via a chemical linkage to another inert molecule that has an affinity toward the target cells. “Antibody-drug conjugates (ADCs) are an ever-growing class of drugs in this category. The HPAPI is conjugated to a monoclonal antibody that carries it to the target cells, where it is released for targeted action,” Haney explains.
AMRI, Haney adds, has been seeing other conjugation approaches as well, such as linkage of HPAPIs to polyethylene glycol (PEG) resins. “These PEG polymers, often 5000–20,000 Daltons in size, are slowly degraded by the body. The conjugated system consequently remains intact for much longer than the inherently unstable HPAPI would by itself, providing sustained release,” he comments.
Similarly, extended-release parenteral formulations based on bioabsorbable poly(lactide-co-glycolide) (PLG) microparticles can improve therapeutic efficacy and increase patient compliance. In some cases, HPAPIs can be delivered from PLG microparticles for weeks and months following a single administration.
Other approaches can also be used. For instance, if a simple modified release profile—such as delivery of the API to the duodenum—is required, a simple fill of either the solid or dissolved API into an enteric capsule may provide the desired release profile with minimal handling, according to Lyon.
Other release profiles, however, such as a zero-order release profile, will likely require a wet granulation step to obtain a homogeneous drug product intermediate prior to the final tableting step, Lyon notes. “Of course, each of these unit operations must be appropriately contained and validated for the required occupational exposure levels for the operators,” he adds.
Because many highly potent drug products are low-dose, small-volume drugs, it is important to understand and manage development of the formulation process, according to Iain MacGilp, director of GMP manufacturing at AMRI. During final formulation, for instance, aseptic filtration can potentially lead to loss of costly drug product via adsorption, which is not acceptable for complex HPAPIs.
With respect to delivery techniques for parenteral HPAPIs, MacGilp adds that it is important to understand and minimize interactions between the drug product and the delivery device while also keeping in mind the volume requirements during different phases of drug development.
There is also significant effort focused on further removing operators from the process to minimize risk, both for operator protection and product assurance, according to MacGilp. That has translated, for example, into the development of robotic systems for product filling. “While these systems can be costly, highly potent drugs often address unmet therapeutic needs and there is a drive to implement advanced formulation filling and delivery technologies to enhance specific safety requirements,” MacGilp observes.
Lyon adds that the biggest recent advances are, in fact, largely around containment. “As HPAPIs become increasingly potent, the need for containment during processing becomes increasingly rigorous,” he states. It is important to remember, he points out, that contained processing is required across HPAPI development and manufacturing, including any particle engineering and other processing required to generate a finished dosage form. “Each of the technologies used is able to be contained to different levels based on its footprint and the need for powder handling,” Lyon adds.
One of the ways to reduce risk during the manufacture and formulation of HPAPIs, at least for liquid HPAPI solutions, is to employ single-use containment systems. “Disposable solutions can be designed to be much more specific for a particular process and are just as safe in terms of band 5 containment, but significantly less expensive than traditional barrier isolation systems,” Haney explains. In particular, disposable solutions are ideal for early-phase products for which it is undesirable to dedicate manufacturing capacity and suites.
At its multiproduct sites, AMRI has implemented a single-use philosophy because it reduces risk of cross-contamination, which is a key issue for HPAPIs. “Anything that is used for our formulation process or the pathway for delivery into the vial is one-use and then disposed of,” MacGilp says. In fact, the company has moved the upstream formulation process to a single-use isolator that can contain any compound below 0.1 µg/m³. The system has been fully qualified by SafeBridge and is used as a single-use system on a routine basis.
“We are excited to blend the manufacturing controls of traditional barrier isolators and hard-sided containment with new opportunities that are more flexible and single use,” concludes Haney.
Cynthia A. Challener, PhD, is a contributing editor to Pharmaceutical Technology.
Vol. 44, No. 12
Pages: 20–22, 46
When referring to this article, please cite it as C. Challener, “HPAPI Complexity Prompts New Delivery Mechanisms,” Pharmaceutical Technology 44 (12) 2020.