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Excipients and new processing techniques can make a real difference in the development of highly potent therapies.
New molecular entities have continued to increase in potency over the past decade as pharmaceutical and biotechnology companies seek to improve treatment options for oncology and other chronic and rare disease areas. Approximately 70–80% of drugs in the pharmaceutical pipeline exhibit low solubility and fall into the Biopharmaceutics Classification System (BCS) Class II or IV, according to a 2015 Market Study by Kline & Co., with the majority of these compounds being Class II (poor solubility, high permeability) (1).
Lonza Pharma Biotech & Nutrition reported to Pharmaceutical Technology that 20% of the current drug development pipeline is highly potent and/or requires special handling and also has solubility or permeability challenges.
While solubility and bioavailability challenges are not unique to highly potent APIs (HPAPIs) and in the small-molecule world are highly dependent upon their particular moieties and morphologies, poorly soluble HPAPIs can pose additional challenges with respect to formulation development and manufacturing. Several enabling technologies are helping drug makers and their outsourcing partners overcome these hurdles.
Any handling of HPAPIs requires care, appropriate equipment, and good practice to ensure the operator is kept safe at all times, according to Alyn McNaughton, technical director with Lonza Pharma Biotech & Nutrition. “Biopharma companies and manufacturers must be dedicated to ensuring that operators are able to do their work safely and without concern for contamination. With the technical challenges of bioavailability enhancement, additional time and dedicated experimental areas can be needed, which can make it challenging to meet development timelines,” he observes.
As one example, complex molecules designed to provide targeted activity, while minimizing side effects, also often have permeability that is limited due their larger sizes, according to McNaughton. As a consequence, the variability of absorbed dosage can be large if the product is not robustly formulated.
Even for materials where bioavailability can be readily enabled, the dosage required in the product can be incredibly low, often only a few micrograms or less, McNaughton adds. “This situation presents the secondary challenge of achieving homogeneity within the product, where an individual particle of the HPAPI may be a large portion of, or sometimes even bigger than, the specified dosage,” he says.
The particle size of APIs can strongly influence the rate of dissolution. With this approach, according to Jessica Mueller-Albers, strategic marketing director for oral drug delivery solutions at Evonik, the concentration gradient between the gut and blood vessels will be increased to facilitate drug transport and consequently absorption. However, micronized particles can be associated with increased health risks.
“The high potency of these molecules can create potential exposure concerns for workers, even at extremely small amounts. There is a need for specialized processes and expertise in the handling and containment of the drug substance, as well as intermediates resulting from particle engineering and the manufacturing of the finished drug product,” she notes.
In fact, challenges in containment can limit the technology that can be deployed for solubility enhancement, according to Adam Kujath, global senior director of manufacturing science and technology at Alcami. “Typical API approaches for solid dosage forms to improve solubility like micronization and spray drying are more difficult to outfit with appropriate containment systems. For instance, milling of solids, while not impossible to do in appropriate containment, poses a challenge since it tends to create dust in the breathing airspace for any worker. For parenteral formulations, lyophilization presents a similar challenge,” he says.
The toxicity of highly potent compounds also drives low allowable carryovers in the manufacturing equipment at change over. “Low solubility means cleaning reactors is inherently more challenging, and analytically may provide poor surface recoveries or impact the achievable cleaning method sensitivity. Furthermore, if they happen to be organometallic compounds, you have to worry about not only the active compound, but related organometallic and inorganic metallic species (such as mercury, arsenic, and platinum) as typical byproducts,” Kujath explains.
For contract drug-product manufacturers, the first hurdles can occur upon receipt of the HPAPI. Packaging systems can vary widely, and it is rare for the manufacturer of an HPAPI and the product manufacturer to use a common handling system, according to McNaughton. A suitable mechanism needs to be available for accessing the HPAPI in a safe and hygienic fashion.
An effective containment strategy should include clear, standardized processes for equipment startup, as well as defined cleaning procedures and robust decontamination procedures, according to Mueller-Albers. “It is integral to have operators who are well-trained in the operation of relevant equipment and procedures for the types of substances being handled,” she adds.
Any handling, introduction, and transfer of powder between processing steps must be conducted in a closed or isolated system, which requires more complex and specialized equipment, according to McNaughton. “Highly diligent processes are required to prevent operators and the surrounding environment from being exposed to dangerous airborne powders,” Mueller-Albers adds. She notes that in addition to closed systems for milling, containment systems for spray drying have also improved considerably over the past decade, which has created opportunities for the spraying of HPAPIs to form amorphous solid dispersions.
For some technologies, equipment may be specific to the individual process and require specialized handling protocols. “HPAPI product manufacturing is most straightforward for processes that have minimal steps, can be serially conducted, and do not require the material to be transferred to a completely different area,” adds McNaughton. “The resulting process commonly needs to be qualified to ensure the containment is sufficient for the product being manufactured so that any resulting operator contamination is significantly below the level at which the HPAPI could have a therapeutic effect,” he continues.
Cleaning of processes involving HPAPIs must also be conducted in a closed system and is often the time where there is the greatest risk of exposure for the operator, according to McNaughton. A key challenge for HPAPIs is the fact that cleaning must be conducted to a level at which there is no risk of contamination of subsequent products-a level at which residual HPAPIs are often difficult to detect. When detection cannot be achieved, dedicated equipment or even facilities are often required for a single product to ensure no cross-contamination with other products is possible.
Even though risks are believed to be controlled or removed, McNaughton stresses that it is important to ensure plans, systems, and training are established so that in a worst-case scenario, such as an accidental release, there is no risk of contaminating the environment and a mechanism is in place to clean the area back to a safe standard without any risk to the operators.
Excipients that are helpful in any low solubility drug are generally applicable to an HPAPI with low solubility. Solubilizers and disintegrants are two examples, according to Kujath. Excipient selection should be based on a combination of the chemical and physical properties of the HPAPI and the target product profile, according to McNaughton. “Meeting a target product profile for a poorly soluble API requires both the correct technology selection and the appropriate science-led formulation development,” he comments.
While there are no specific excipients that are suited to highly potent materials, there are certain aspects of some technologies that offer advantages if they are also the correct technology for the product, McNaughton adds. “Under certain permeability-limited situations or biological obstacles, there are specific lipidic excipients that can provide some permeability enhancement, others that inhibit efflux, and others that could avoid first pass metabolism through utilization of the lymphatic system,” he says.
The use of polymer-based excipients is widely appreciated in the formulation of poorly soluble HPAPIs, according to Mueller-Albers. They play a key role in the formation of solid solutions, stabilizing the amorphous HPAPI in the solid state to prevent recrystallization, and also helping to maintain HPAPI supersaturation in physiological media, she explains. Polymeric excipients are also used in formulations prepared via granulation using high-shear mixing or fluid-bed spraying, which can under certain conditions be applicable for poorly soluble HPAPIs.
The first HPAPIs were often formulated as liquids and then filled into capsules to reduce safety risks such as dust formation. Liquids, however, present challenges when solubility is an issue, according to Kujath. “While micronization and spray drying of the HPAPI can be helpful for oral solid formulations, these techniques to drive initial dissolution for liquid formulations can present stability challenges, such as crystallization of an initially dissolved amorphous HPAPI from the vehicle or ripening in a micronized dispersion,” he explains. Thermocycling during terminal sterilization can also cause ripening or recrystallization or break complexes formed by solubilizers such as (2-hydroxypropyl) beta-cyclodextrin.
As the number of HPAPIs in development has increased, however, manufacturers have aggressively examined new processing techniques suitable for oral solid-dosage forms, according to Mueller-Albers. Particle-size reduction, or particle-size design, amorphous dispersions, and lipid-based formulations are all suitable techniques for improving the bioavailability for solubility-limited HPAPI, according to McNaughton
“Particle size reduction is likely to lead to an increase in the rate of solubility for an API and may provide some supersaturation effects, but is unlikely to result in the same level of potential increase that can be achieved by amorphous dispersions or lipid-based formulations,” he says. Lipids also offer a further advantage for low-dose HPAPIs where these can be fully solubilized because the potential for poor homogeneity is eliminated and accurate dosing can be provided, even for the lowest possible dose. “Achieving such formulations may be impossible in the solid state, so a lipid/liquid approach can be enabling for the molecule to be advanced,” McNaughton states.
Kujath notes, though, that while lipid-based solubilizers and the formation of nanoemulsions can be an effective way to deliver an HPAPI of low solubility, these techniques should generally be combined with the use of a low-energy means of sterilization.
If the API is not “greasy” (logP < 3), lipids are unlikely to provide the same improvements that amorphous dispersions can, according to McNaughton. In addition, processing to achieve particle-size reduction can be simpler than developing an amorphous or lipid formulation.
“Every day the industry is improving containment solutions, making it easier to leverage HPAPI handling technologies that previously may have been less accessible,” says Kujath. He also notes that more and more focus has been placed on not just patient safety, but on worker safety. There are always new and improved excipients being developed, new approaches, and better understanding of how to use them, agrees McNaughton. He adds that improved technologies to remove the vulnerable operator from harm include more hygienic valves, in-line testing to minimize operator interaction with potent molecules, and increased automation that completely removes the operator from the vicinity of these process.
However, it is important, according to Kujath, to remember that the issue of low solubility is not unique to HPAPIs and can be vastly improved in the active molecule design process. For instance, he points to technologies such as antibody-drug conjugates, which are useful for targeted delivery of small-molecule HPAPIs, but also offer a means to chemically modify a pharmacologically active compound so it can be more effectively delivered if poorly soluble.
“In the small-molecule world, time spent during molecular selection for not only potency but solubility and bioavailability should be a focus in good drug design. That would reduce the need for exotic formulations to compensate. Understanding the active sites of drugs and what can be potentially modified allows for better structural designs or the creation of pro-drug analogs to increase solubility and bioavailability,” he concludes.
1. Kline & Co., “Solubility Enhancement in Pharmaceutical Oral Solid Dosage Forms: Global Market Analysis and Opportunities,” Report, March 2015.
Vol. 43, No. 6
When referring to this article, please cite it as C. Challener, “Enabling Technologies Advance Poorly Soluble Highly Potent APIs,” Pharmaceutical Technology 43 (6) 2019.