Advances in Drug Delivery and Areas for Improvement

AdobeStock_270715752_Leigh Prather

Sometimes, to fully appreciate modern advances, taking a glance backward can show just how far an industry has come.

“Arguably the most significant advances in the history of drug delivery took place in the 18th and 19th centuries,” says Elham Blouet, head of biopharma, injectables, and specialty APIs, Roquette. “Some notable examples include Edward Jenner’s development of the first ever vaccine for smallpox in 1796, the invention of the syringe in 1853 by Charles Gabriel Pravaz and Alexander Wood, and the synthesis of the first commercially available painkiller with Felix Hoffman’s invention of aspirin in 1899.”

Blouet acknowledges in more recent years that, “pharmaceutical brands are gradually shifting their offerings towards large-molecule biologics due to their improved selectivity and efficacy. The current barrier to this transition is the fact that most therapeutic peptides and proteins must be delivered via injection, but the tide is slowly starting to turn.”

She elaborates further that: “[S]everal brands have begun developing orally-administered biologics as an alternative to traditional parenteral delivery forms, giving patients an easier, quicker, and less invasive way to receive their medication. The key to formulating successful oral biologics hinges on protecting peptide and protein molecules from the mechanical and chemical stresses of the manufacturing process.”

Blouet also stresses the importance of conducting extensive trials to ensure the API(s) can effectively permeate through the absorption barriers in the gastrointestinal tract.

“The development of complex formulations, such as nanoparticles or liposomes, also represented a major step forward in ensuring [APIs] are protected within the gastrointestinal tract so they are better able to reach the desired delivery site,” says Blouet. “We shouldn’t forget the incredible achievement that was the development of the various COVID-19 vaccines either, which have saved so many lives worldwide. This, in turn, has boosted the development of other vaccines, particularly in terms of the shift from injectables to innovative nasal vaccine delivery forms.”

In addition to innovative dosage forms and complex formulations, developments in containment systems are another advancement. In the past, patients went to hospitals or outpatient centers to receive drugs that were delivered in vials, which eventually led to the emergence of prefilled syringes and autoinjectors.

“Now we’re seeing a rise of on-body delivery systems,” says Nicolas Brandes, director of global product management, polymer prefilled system and vial containment, West Pharmaceutical Services. “There are still many drugs that need to be delivered intravenously, requiring patients to travel, and sometimes to stay in a hospital. It’s time-consuming both for patients and healthcare providers. With on-body delivery systems, the patients can take the same dose at home. They don’t have to travel or change their routine. That’s a great advantage.”

Nicholas W. Warne, vice president, pharmaceutical R&D, Pfizer, adds that, while parenteral administration with a needle and syringe is the gold standard for drug delivery, there have been several successful drug delivery approaches over the past two decades. Specifically, these technologies have allowed “a particular disease mechanism to be treated effectively, potentially via a compelling increase in convenience, which drives adherence and moves a market forward within a specific therapeutic area,” Warne explains.

According to Warne, there are multiple examples of enabling technologies, such as antibody-drug conjugates for the treatment of cancer cells and lipid nanoparticle (LNP) delivery of RNA to treat diseases, including infective diseases. Other examples include delivery devices, such as wearable pumps that allow “sustained or pulsatile delivery of medication depending on the needs of the patient and mechanism of action,” says Warne. Finally, Warne explains that vaccine adjuvants have enhanced the immunogenicity of a number of critical vaccines, enabling billions of children and adults to avoid life-threatening diseases.

Ying Tam, chief scientific officer, Acuitas Therapeutics—a biotechnology company specializing in LNP delivery technology from R&D to commercial development—also points to LNP delivery as a significant advancement in drug delivery.

“Historically, for small-molecule drugs, one of the greatest advancements was the discovery that pH gradients across the membrane structure of LNP could be used to rapidly and efficiently load many clinically important drugs into the aqueous core of LNP to extremely high concentrations. This active loading process occurs because the neutral form of the drug can diffuse into the LNP and becomes charged in the acidic interior. In addition, precipitation of the loaded drug can further contribute to very high loading efficiencies,” says Tam. “This technical breakthrough enabled the development of cost-effective manufacturing processes for several clinically approved cancer drug formulations.”

Maintaining optimal delivery: development versus manufacturing

“The transition from the development of a delivery system to manufacturing depends on product design, process development, and the overall robustness of both,” says Warne. “If we accept the premise that a delivery chemistry can be designed in a formulation lab at a scale suitable for initial clinical studies, then the challenge of scale-up, while significant, should be conquerable.”

Similar to Warne, Blouet emphasizes the importance of planning and establishing strategies upfront for the development phase. This approach then impacts the transition from development to manufacturing and general scale-up.

“Strategies to maintain optimal drug delivery are usually defined alongside the development of a product’s quality target profile,” says Blouet, adding that typical considerations for the quality target product profile include the intended use in clinical settings; the administration route; the dosage form and delivery system; the strength of the dose; and the container closure system. Other considerations include the release of the therapeutic moiety and the factors affecting the drug’s pharmacokinetic characteristics (e.g., dissolution, aerodynamic performance, etc.) and the drug’s quality criteria (e.g., sterility, purity, stability, and drug release) appropriate to the intended market for the product.

With these factors in mind, the critical quality attributes of both the final product and each raw material are assessed based on their impact on the formulation and the manufacturing process, Blouet explains. Due to the complexity of producing biological drugs, processing parameters must also be defined “to allow a safe and reproducible scale-up of activities from lab tests to pilot products and commercial rollout,” adds Blouet.

Warne provides an example of maintaining optimal drug delivery when transitioning from development to manufacturing, specifically for unmodified parenterals.

“For unmodified parenterals, this [scale-up] should be more straightforward as the process should be able to be scaled through upstream cell culture, downstream purification, and drug product manufacture,” says Warne. “For more advanced chemical delivery systems, it can be more of a challenge as specific technologies (i.e., LNPs) may require approaches that cannot be scaled linearly and may need to take a scale-up/scale-out approach. This scale-out approach speaks to the need, at times, to manufacture with multiple parallel unit operations to ensure consistent product characteristics.”

Meanwhile, for delivery devices, transitioning from development to manufacturing can also be challenging but not for the same reasons.

“The component parts of a pre-filled pen, for example, must be manufactured with extremely narrow tolerances to ensure proper assembly and functionality,” says Warne. “The design and manufacture of each component must be critically controlled to ensure a high success rate of drug delivery, especially under life-saving conditions (i.e., epinephrine). Success in this space depends on the critical partnership between the pen and component designer, manufacturer, the consistency of the pen assembly process, and the design of the drug-containing cartridge of the syringe into the device.”

Also from a medical device perspective, Ori Ben-David, PhD, vice president of R&D, pharmaceutical solutions, Eitan Medical—a company that provides drug delivery and infusion solutions, specifically smart infusion pumps and wearable injectors—emphasizes the importance of keeping internal and external stakeholders involved from the beginning.

“External stakeholders include the pharma partner (through the joint definition of product requirements) and patients (through wearability and usability studies throughout development); while internal stakeholders include regulatory representatives (defining applicable standards to adhere to throughout the project, and supporting the submission at the end point of development), manufacturing representatives (not only ensuring design for manufacturing, but also thinking forward to automation for high-volumes), quality representatives (ensuring the device is developed and manufactured according to the company’s quality management system), and others,” says Ben-David.

Whereas John D. Lewis, CEO, Entos Pharmaceuticals—a clinical-stage biotechnology company developing non-toxic and redosable genetic medicines—believes that when it comes to transitioning these therapeutics from development to manufacturing, “the product is the process.”

“For nucleic acid therapeutics, improvements to the instrumentation, component processing, and real-time quality analysis methods used to manufacture them, are important advances towards rapid upscaling,” says Lewis. “To manufacture a large number of doses to meet the needs of patients requires improved flexibility and scalability with high quality and increased throughput.”

Yet another perspective, provided by Raj Khakari, vice president of R&D, Kindeva Drug Delivery—a contract research, development, and manufacturing organization (CRDMO)—is to consider staying with the same outsourcing partner during the scale-up process.

“The easiest way to transition from development to manufacturing is when you can stay with the same CRDMO, as this eliminates external handovers and can greatly smooth the transition from the internal development team to the internal manufacturing team,” says Khakari. “When you hand off from a formulation company to a manufacturing CDMO [contract development and manufacturing organization], the best-case scenario is it will cost you time. In the worst-case scenario, not only can time and resources be negatively impacted, but the hand-off between CRDMO and CDMO can be complicated by different processes, teams, and equipment.”

Room for improvement

Although many advancements have been made in drug delivery, there is always room for improvement. According to Michael Earl, director, pharmaceutical services, Owen Mumford, sustainability is one such area.

“One of the big questions in drug delivery is how it can be made more sustainable and help achieve the environmental goals many companies are actively pursuing. With many drug delivery devices being single-use and predominantly made of plastic, there is growing concern about their environmental impact, especially given the growth in their use in recent years,” says Earl. “As companies work towards net zero emissions, there is now more focus on reusable drug delivery devices as well as on the materials and methods of disposal, including the potential introduction of circular model ‘take back’ schemes. Already, many device companies are conducting a lifecycle analysis on their products to truly understand the environmental impact of the devices, their manufacturing processes, and the supply chain.”

Other potential areas for improvement include making smaller volumes of drug products, new procurement strategies, and streamlining production, adds Brandes.

“To support the shift to personalized medicine, the industry needs to pivot from making large volumes of drug products—tens of millions of units at a time—to much smaller volumes. Manufacturers need procurement strategies that tactically fit their supply-chain needs, which is tough to do under the old model of being locked into massive production volumes,” says Brandes. “And the industry needs to get better at streamlining production. During COVID, vaccine producers were struggling to secure primary packaging materials. There was an increased demand for vials, elastomeric stoppers, and seals. This should be seen as an opportunity to rethink drug delivery, to look at different approaches and materials so that the pharma industry will be better prepared for crisis situations.”

In addition to better drug delivery via potency and safety, Tam explains that for LNP delivery of mRNA to improve, the development of delivery systems that can target tissues and cells outside of the liver must be realized.

“Currently, LNP efficiently targets hepatocytes following intravenous delivery through association with endogenous apolipoprotein E (ApoE); thus, specifically targeting hepatocytes through ApoE receptors,” says Tam. “In the future, minimizing hepatocyte uptake by minimizing ApoE association and adding targeting information to the surface of LNP that redirects the delivery systems to non-liver tissues and cell types will further expand the clinical utility of this type of drug delivery technology.”

David Bunka, chief technical officer, Aptamer Group—a biotechnology company specializing in aptamers—also speaks to improvements for specific treatments and disease states, specifically for cancer treatment.

“Targeted drug delivery has shown promise in cancer treatment using previously developed antibody ligands. Beyond this, the conjugation of N-Acetylgalactosamine (GalNAc) to gene therapy payloads has proven effective in targeting hepatic tissue, showing increases of approximately 10-fold in liver targeting over the use of antisense oligonucleotides alone (1),” says Bunka. “Though targeted drug delivery systems continue to expand clinical pipelines, the ability to deliver to alternative tissues or organs, such as renal, bone, cardiometabolic, and muscle, remains highly challenging. This means there is room for improvement and the development of GalNAc-like targeting systems for these other tissues.”

Another focus, according to Bunka, is delivering drugs across the blood-brain barrier to treat the central nervous system.

“With an increasingly aging population and the rise of neurodegeneration, targeting the brain will become increasingly important,” says Bunka. “Some molecules, such as the transferrin receptor, have shown promise as targets that facilitate passage across the blood-brain barrier, but more research is required to demonstrate the validity of this target and any potential drug delivery system targeting this.”

Ben-David points out three key areas for improvement for drug delivery devices, specifically:

1. Integration for drug delivery devices with standard primary containers. This integration can reduce time to market by multiple years with device manufacturers adapting to the primary container of the pharma partner's choice and avoiding the development of a proprietary primary container, allowing lifesaving medications to reach the market faster.
2. Connectivity. Integrating full connectivity must take into account privacy, cyber security concerns, and usability.
3. Overcome supply chain issues. Whether it relates to medication or device components, the supply chain shortcomings may result from the COVID-19 pandemic, market turbulences, and international conflict. This requires forethought and supply risk mitigation strategies.

“Looking forward, I believe that parenteral administration will continue to be the gold standard for biotechnology products and vaccines. It works, it’s safe, it’s predictable, and it’s fast. If we accept this premise, then making parenteral administration more convenient is critical to future success,” says Warne. “Beyond medical devices, we must continue to invest in enabling delivery chemistries. Advances must continue to be made in terms of in vivostability to reduce the frequency of administration as well as reduce possible dose-related toxicities due to excess systemic drugs. Further, tissue targeting will become increasingly important for reasons of safety and effectiveness. We should expect to see significant advances in this area over the next decade.”

Reference

1. T.P. Prakash et al., Nucleic Acids Res., 42 (13) 8796–8807 (2014).

About the author

Meg Rivers is a senior editor for Pharmaceutical Technology, Pharmaceutical Technology Europe, and BioPharm International.

Article details

BioPharm International
Vol. 35, No. 9
September 2022
Pages: 10–13

Citation

When referring to this article, please cite it as M. Rivers, "Advances in Drug Delivery and Areas for Improvement," BioPharm International 35 (9) 10–13 (2022).