Meg Rivers is the former senior editor for 

Meg Rivers

How can organizations determine when to outsource vs. insource? What factors can (or should) be considered? The right outsourcing strategy has the potential to limit unnecessary costs, maintain output and turnaround times, and enable continued flexibility. In part two of this outsourcing series, Meg Rivers and Jeff Henderson, key account manager of Vetter, discuss:

What the biopharma industry currently tends to outsource

Outsourcing strategies the biopharma industry should be utilizing

Internal tasks the biopharma industry should consider outsourcing more in development and manufacturing

What the biopharma industry should reconsider outsourcing and instead perform in-house

What organizations are choosing not to outsource and why

Jeff Henderson, key account manager, Vetter:

 Henderson has served in a variety of positions as an engineer, consultant, and business development professional over the span of his 25-year career. He began his engineering and consulting role with Barry-Wehmiller Design Group in St. Louis, designing, installing, and validating filling and packaging lines for the food, beverage, and pharma industries before earning his MBA at Pepperdine University in Malibu, CA. After that, Henderson worked at Amgen where he was initially responsible for managing contract manufacturing operations at various packaging and sterile fill/finish sites in the United States. He later moved into a more strategic role in developing manufacturing strategies for clinical and commercial products in Amgen’s pipeline. In 2007, he moved to Seattle to focus on downstream efforts in automated warehousing and material handling before returning to a biotech engineering role at Medimmune’s pilot plant in Gaithersburg, MD. Following his position at MedImmune, he joined Vetter as a key account manager in 2010 and has been growing a solid business footprint over the past 12 years.

 presents the Drug Solutions podcast, where the editors will chat with industry experts from across the pharmaceutical and biopharmaceutical supply chain. Join us as experts share insights into your biggest questions—from the technologies, to strategies, to regulations related to the development and manufacture of drug products.

Listen to part one of this outsourcing series.

Podcasts

In this episode of the Drug Solutions Podcast, Meg Rivers discusses outsourcing strategies in biopharma with Jeff Henderson, key account manager of Vetter.

Drug Solutions Podcast: Outsourcing vs. Insourcing in Biopharma: Determining the Best Strategy: Part 2

In this exclusive Drug Digest video interview, Meg Rivers and Feliza Mirasol, Pharmaceutical Technology editors, discuss the benefits of automating entire workflows in analytics (laboratories) versus automating only specific pieces of equipment or only certain processes. What influence or impact would this have on workflows further downstream, such as clinical or commercial manufacturing?

They discuss additional topics, including:

Additional automation approaches and how modular approaches fit into this

Automation opportunities in pharma (i.e., small molecule) vs. biopharma (i.e., large molecule)

Whether the level of adoption of automation differs in the industry between pharma and biopharma

How this trend toward automation in laboratory workflows impacts clinical and commercial drug development and manufacturing


is the head of product at Automata, a London-based biotech company providing robotic automation solutions to the life sciences industry. He is a trained mechanical engineer and studied at Oxford University. Pattinson joined Automata to help make real, tangible change and help unlock the potential of scientists through automation in laboratories.

This episode of Drug Digest is sponsored by:

Drug Digest is a tech talk video series with the 

 editors, who interview industry experts to discuss the emerging opportunities, obstacles, and advances in the pharmaceutical and biopharmaceutical industry for the research, development, formulation, analysis, upstream and downstream processing, manufacturing, supply chain, and packaging of drug products.

Videos

Pharmaceutical Technology editors interview an automation expert from Automata on the benefits of automating entire workflows in analytics versus automating only specific pieces of equipment or only certain processes.

Drug Digest: Automation in Biopharma and the Impact on Workflows

Absorption, distribution, metabolism, and excretion (ADME) studies are a key part of drug discovery and preclinical phases, as this evaluation of pharmacological properties determines the efficacy and safety of a given drug compound. Some say this process defines the disposition of a drug. 

 dives into ADME studies in this exclusive interview with Dr. Yassen Abbas, lead scientist, CN Bio, an organ-on-a-chip (OOC) company that designs and manufactures microphysiological systems.

How would you describe the process of ADME studies? What does that typically look like?

 ADME studies are performed during drug discovery and preclinical phases to optimize drug properties, support candidate selection, and subsequently inform the design of the clinical phase. Experiments are first performed 

and investigate parameters such as [the] extent of protein binding, [the] likelihood of inhibition of major drug metabolizing enzymes, and understanding of the metabolic stability of a drug. Then they are followed by animal (i.e., 

) studies, which provide more insight into a drug’s behavior in a whole organism, complete with the immune and circulatory systems. Combined, these preclinical studies enable decision-makers to make a go-no-go choice to move the drug into the late preclinical stage and clinical trials or abandon the project.

Unfortunately, the clinical translatability of data derived using standard preclinical 

approaches remain constrained by certain limitations. Where preclinical ADME predictions are inaccurate, this can result in poor efficacy or unforeseen toxicity in the clinic. Due to their simplicity

ADME assays are limited by poor physiological relevance. Animal models circumvent this but are in turn limited by a host of interspecies differences—for example, in the expression profile of cytochrome p450 enzymes, which affect their predictability. The use of complementary 

modeling to overcome these limitations remains constrained by the quality of the model’s input data.

Over the past decade, OOC technologies have been developed to bridge the gap between traditional 

tissue functionality in humans. Here, primary human cells—cultured in physiologically-relevant combinations and perfused by fluidic flow to mimic the bloodstream—form three-dimensional microtissues that function and respond to drugs in a similar way to humans. For liver-on-a-chip models, also known as liver microphysiological systems, the inclusion of fluidic flow is critical to their success, helping to maintain their metabolic competency and viability for much longer (at least two to three weeks) compared to static 

2D cultures. Amazingly, different organ models can now be connected to simulate key ADME processes, such as drug absorption by the intestine, then hepatic metabolism by the liver. Samples collected from these models can be sent for analytical chemistry analysis using liquid chromatography/mass spectrometry to determine the drug concentration over time. The data can then be fed into 

models to determine pharmacokinetic (PK) parameters, such as hepatic clearance, intestinal clearance, and intestinal permeability (1). Here, the quality of the PK parameters generated by the 

models is dependent on the ability of the biological models used to predict behavior in humans.

What can affect the outcome of an ADME study?

absorption, distribution, metabolism, and excretion (ADME) studies help predict whether potential drug candidates are likely to have the right properties in humans, according to Scott Martin, head of analytical and bioanalytical, Domainex, a preclinical contract research organization.

A small-molecule oral drug that shows promise would be expected to have good bioavailability/pharmacokinetics, free-drug exposure within the therapeutic window, and acceptable levels of accumulation on repeat dosing, Martin explains. Furthermore, a promising drug candidate would ideally exhibit low drug–drug interaction risk and demonstrate no metabolite issues under metabolite in safety testing guidance, which 

ADME preclinical and clinical studies can help to determine, he adds.

 The lack of human-relevant preclinical models is a major cause of drug failure—

models being too restrictive and lacking the complexity of a living organism whilst animals utilize non-human pathways, notably in their immunity, metabolism, and microbiome, all of which can impact their response to drugs. As such, the output quality of an early drug development ADME study generally depends on the quality of the biological model used to extrapolate key PK parameters.

The success of a study can also depend on the chemical properties of the drugs being studied. Those that have a high partition coefficient, LogP (>3), a measure of lipophilicity, exhibit poor solubility in aqueous solutions, and high-binding affinities to proteins. These drugs typically have poor intestinal permeability and low oral bioavailability. Where there is a concern, experiments are performed 

without cells but in media to quantify the free fraction of a drug. Routinely performing ADME experiments in serum-free media (to limit drug binding) is key to successfully assessing a drug’s true properties. It is also important to consider the composition of the material used for cell culture as some regularly used 2D, 3D, and OOC cell-culture materials, such as polydimethylsiloxane, have high non-specific binding properties and, therefore, can impact data accuracy.

Another contributing factor to poor data accuracy is 

cell culture media evaporation. High levels of evaporation can make the interpretation of PK data challenging, especially for low clearance compounds. To prevent evaporation, some cell culture systems have incorporated an additional well containing sterile water along the consumable plate’s edge to limit cell culture media loss.

What are early signs/red flags that an ADME study is going poorly?

A critical point in drug discovery where red flags are identified is the transition from 

that cannot be reproduced in animal models will require further work to establish the cause.

Signs of toxicity are major red flags to look out for particularly if these are observed at, or close to, the dose required to produce the desired therapeutic effect. Subsequent work to increase bioavailability/reduce dose by optimizing the drug formulation may be required. If toxicity is identified in animals, additional studies will be required to determine if this is likely to be a species-specific response and the potential effect in humans. It may, however, prove difficult to progress to clinical trials where toxicity has been observed in animal models due to concerns over risk.

Human single- and multi-OOC models are uniquely placed to investigate these red flags in more detail. For example, it is possible to observe the toxicity of drug candidates to intestinal or liver cells using OOC ADME assays. To ensure that toxic effects are indeed caused by the administration of a drug, quality control experiments before and after drugs are added can be performed. For the liver, a drop in the cytochrome P450 3A4 (CYP3A4) activity, albumin, and a rise in lactate dehydrogenase—a marker of cytotoxicity—is indicative. In our intestinal model, we can detect the loss of cellular barrier integrity by measuring electrical resistance across cells. Where a drug is flagged as potentially toxic in our ADME assays, we investigate further by assessing its potential to cause drug-induced liver injury. Here, we report dose-dependent toxicity across multiple concentrations using a wide range of output parameters, including clinically relevant biomarkers (e.g., alanine transaminase and aspartate aminotransferase) to provide a mechanistic fingerprint.

What are signs that an ADME study is successful and a drug shows promise?

The goal of an ADME study is to understand how much of the drug is available to reach the target organ and to accurately predict ADME behavior in humans before clinical trials. A measure of success is the safe administration of a drug candidate to human volunteers based on a pre-determined dose extrapolated from ADME studies and 

modeling. The challenge for the pharmaceutical sector is how to improve the predictability of preclinical ADME studies to reduce the attrition rate of drugs that fail to make it to market. Here, the success or failure of an ADME study depends largely on the chemistry of the compound and the human relevance of the models and assays used.

What parameters do you follow for ADME studies to determine the safety and efficacy of a drug? Is there a range for what is considered acceptable?

Many parameters reported by ADME studies are used to determine the safety and efficacy of a drug. One important parameter to identify is the metabolic property of the drug. For example, drugs that don’t inhibit CYP3A4—and are not a major substrate of the CYP3A4 metabolizing enzyme—are considered a success because the risk of drug–drug interactions are reduced.

The key parameter, however, is bioavailability … Until recently, it has not been possible to measure bioavailability 

due to the limitations of standard approaches. To derive this value, a drug must be exposed to complex physiological processes, such as drug absorption through a biological barrier and first-pass metabolism. It is now, however, possible to do exactly this using an organ-on-a-chip approach. Our gut/liver multi-organ model, for example, recreates the transit of a drug that is dosed orally and intravenously to report bioavailability. These powerful new 

animal studies to identify red flags early in the process, such as drugs with low bioavailability; and because of their high human relevance, they can be used to investigate cross-species concerns where toxicity has been identified in 

, DOI:10.1039/D2LC00276K (July 14, 2022).

Meg Rivers is a former senior editor for 

Pharmaceutical Technology, Pharmaceutical Technology Europe

Articles

Experts discuss factors that can affect the outcome of an ADME study, signs that a drug compound shows promise, red flags, and key parameters to determine safety and efficacy. 

ADME Studies: Determining Promising Drug Compounds 

In today’s political climate, contraceptives are often top-of-mind for many adults in child-bearing years. NEXT Life Sciences—a company developing and distributing contraceptives—pursues the regulatory approval of a new type of contraceptive in the United States for individuals assigned male at birth. This medical device, Vasalgel, is currently in preclinical studies.

According to the NEXT Life Sciences’ website, “Vasalgel is a proprietary hydrogel injected into the vas deferens (the tube that sperm swim through). The procedure differs from a vasectomy in that the vas is not cut or cauterized. Instead, a hydrogel is injected with a microneedle, and once formed in place, the hydrogel is intended to act as a flexible filter for sperm. The ultimate goal is for the product to be easily removed by injecting with a microneedle a fluid that dissolves and flushes out the hydrogel whenever a man wishes to restore the flow of sperm” (1).

According to Robert S. Kellar, PhD, chief science officer, NEXT Life Sciences, Vasalgel was inspired by the research of Dr. Sujoy Guha in India in the 1970s, who created this technology to address increasing resource strain due to overpopulation in India (2). In India, this technology is called RISUG (reversible inhibition of sperm under guidance).

What is the process of administration for Vasalgel? In short, with a relatively quick procedure, a liquid solution is injected by a professional and solidifies into a flexible sperm filter that creates a barrier.

“The medical procedure is intended to be minimally invasive and to be less painful than a traditional vasectomy, allowing for a faster recovery time,” explained Kellar. “The clinician will apply a local anesthetic, then expose the vas deferens from the testicular sac. The injection of Vasalgel will then occur into the lumen of the vas deferens. Vasalgel will hydrolyze from a viscous state to a hydrogel form, which creates a blockage in the lumen of the vas without cutting or burning tissue. Vasalgel will adhere to the vas deferens walls, preventing sperm cells from passing through. For the patient, the recovery time will be faster with less post-procedural swelling and discomfort compared to traditional vasectomy.”

Effectiveness, efficacy, and reversibility of Vasalgel

Aaron Tabor, PhD, chief technology officer, NEXT Life Sciences, explained that a stable polymer is created via a chemical interaction that forms a hydrogel.

“While formal stability testing is underway, preclinical studies have demonstrated blockage,” said Tabor. “Predecessors using similar formulations to RISUG have reported more than 13 years of effectiveness. Once cleared or approved for humans, it should be possible for the male to have Vasalgel implanted and removed multiple times.”

“Based on the chemistry for the hydrogel formation, an alkaline solution can dissolve the hydrogel, which allows for sperm cells to begin traveling through the vas deferens lumen. One can have the hydrogel injected with such a solution to result in [the] dissolution of the blockage,” added Tabor. Vasalgel would, therefore, be reversible.

, RISUG was introduced in successful preclinical trials starting in 1980 and achieved success in human volunteers in Phase I, II, and III clinical trials in India (2).

Development hurdles and getting FDA approval

“To date, Vasalgel has demonstrated effectiveness in many of the preclinical models. This allows NEXT Life Sciences to confidently state we have ‘proof of concept’ on the Vasalgel technology,” said Kellar. “We are now optimizing the formulation to allow for the scale up of manufacturing. This optimizedVasalgel ensures reliable safety and efficacy expectations in preclinical models and will enable working with regulatory bodies on our proposed strategy for clinical implementation.”

NEXT Life Sciences intends to use the medical device 510(k) pathway for Vasalgel technology clearance, Kellar explained, adding that regulatory focus will be on the revisability of hydrogel, including the return of sperm cells in the ejaculate.

While there has been considerable delay in bringing Vasalgel (or other devices and drugs like it) to the US market, it could be theorized that current public attention on contraceptive methods may positively impact the regulatory review, though only time will tell.

What’s next for Vasalgel, particularly as it relates to development and potential commercial manufacturing? Tabor explains that the company is presently creating its final formulation as well as vetting contract development and manufacturing organizations that can “scale manufacturing with the regulatory approval efforts.” The company is also building its medical and scientific advisory boards with experts in the field of contraception.

Vasagel’s potential for female contraception

This technology also has the potential to be used as a contraceptive for individuals assigned female at birth.

“Hypothetically, Vasalgel could be used as a female contraceptive option,” said Tabor. “This technology could be modified for female oocyte blockage—thus, preventing the ability for sperm-and-egg fertilization. While some preclinical testing has occurred, more work would need to be completed, such as further bench-top assessment, preclinical testing, and, of course, human regulatory pathways.”

Breakthroughs in male contraceptives and areas for improvement

“Outside of equality being brought to the attention of male contraceptives, the greatest breakthrough is a grouping of minimally invasive procedures that potentially prevent irreversible damage to the vas deferens. This includes occlusive technologies such as ligation clips, silicone plugs, and hydrogel technologies, such as Vasalgel. These platforms hypothetically prevent sperm from entering the female reproductive anatomy, offering reversible or removable male contraceptives,” said Kellar.

However, the industry still has improvements to be made in order to ensure that safe contraceptives for males are readily available. Kellar identifies a few key areas, some of which relate specifically to Vasalgel:

. How will men learn about contraceptive options? There isn’t currently a standard in the US for this education as there is for women, who are educated on contraceptive options by a gynecologist (pending access to medical care).

. At present, whether Vasalgel will be covered by insurance is yet to be determined. Meanwhile, some contraceptives for women are currently covered by medical insurance plans.

Technologies such as Vasalgel and RISUG could usher a new generation of contraceptives available to individuals of child-bearing years and provide more family-planning options. The legal, political, and cultural climate suggests alternatives to traditional approaches may find ready acceptance for this unmet medical need.

One company reaches beyond traditionally-conceived male contraceptives with Vasalgel, a reversible hydrogel injectable. 

The Next Generation of Male Contraceptives

Drug delivery has grown in leaps and bounds in recent decades, including growth in administration methods, therapeutic formulation, and delivery systems. David Bunka, chief technical officer, Aptamer Group, joins Meg Rivers, senior editor, for a deep dive into Optimers (optimized aptamers). Bunka discusses some of the key differences between Optimer-drug conjugates and antibody-drug conjugates (ADCs), such as their properties, how they are created, and potential immune responses. He also shares how Optimers can target malignant cells withoutprior knowledge of specific biomarkers, the scalability capabilities of Optimers due to their chemistry/being synthetically manufactured, and what long-term safety could look like.

David Bunka, chief technical officer and co-founder of Aptamer Group

, holds a PhD in molecular biology and has spent nearly 20 years developing nucleic acid aptamers against a wide variety of targets including small molecules (i.e., antibiotics, food contaminants, chemotherapeutics), disease-associated proteins, several cancer-associated cell-lines, viruses, and tissue biopsies. This work has been facilitated using high-throughput, automated aptamer selection methods. Bunka has built up an established international reputation in the field and has authored several peer-reviewed research articles, invited review articles, and a book chapter on aptamer-based therapeutics. He has also given many guest seminars covering aptamer-based applications at top universities and international conferences.

An expert from Aptamer Group reveals the potential of Optimers (a type of aptamer) in the realm of drug delivery, including its targeting capabilities, scalability, and key differences between Optimers and antibody-drug conjugates. 

Drug Solutions Podcast: Drug Delivery Systems: Optimer’s Therapeutic Targeting and Scaling Capabilities vs. ADCs

While parenteral administration continues to be the gold standard for drug delivery, many advancements have been made in this space—impacting drug formulation, delivery devices, as well as the method of delivery. 

interviewed Nicholas W. Warne, vice president, pharmaceutical R&D, Pfizer, about drug delivery advancements, the differences in the delivery of small versus large molecules, drug delivery technologies that best address stability, the future of drug delivery methods for biologics (beyond intravenous, intramuscular, and subcutaneous injections), and how personalized medicine fits into drug delivery.

What do you believe are some of the greatest advancements in drug delivery to date?

: Foundationally, we need to recognize the advances in aseptic manufacturing of biotechnology products and vaccines that we have enjoyed over the past several decades. The ability to manufacture these fragile products, establish their sterility in the absence of terminal sterilization, and retain their safety and effectiveness while often refrigerated is remarkable. Further, we have come a long way in the development of disposable and effective delivery devices (i.e., syringes, needles, and intravenous setups), which safely and accurately deliver nearly all biotechnology products and vaccines to billions of patients annually.

Regarding modes of delivery, parenteral administration with a needle and syringe is the gold standard for drug delivery. A healthcare professional can hold a drug-filled syringe prior to injection and, after administration and holding an empty syringe, be confident that the complete dose has been delivered to the patient. The same confidence should apply to intravenous administration. This is important in that we need to have this confidence when we deliver, for example, preventative vaccines or disease-managing therapeutics that the correct dose is administered every time.

There have been a number of successful drug delivery approaches that have been implemented over the past two decades. These are notable for two reasons that benefit patients: either they are enabling technologies that allow a particular disease mechanism to be treated effectively, or they provide a compelling increase in convenience, which drives adherence and moves a market forward within a specific therapeutic area.

Examples of enabling technologies include antibody-drug conjugates in which a targeting antibody—typically designed to bind to a ligand on the surface of a specific cancer cell—effectively delivers a toxin to the cancer cell, which is absorbed and results in highly specific cell death. In the absence of the covalently linked targeting antibody, the toxicity levels of an effective dose of the systemic toxin would prohibit its use via systemic administration. A second example would be lipid nanoparticle (LNP) delivery of messenger RNA (mRNA) for the treatment of several diseases—most notably, infective diseases. Delivery of mRNA to cells, intended to be a template for antigen expression, would not be possible without the LNP, which protects the mRNA from degradation as well as serves to deliver the mRNA through the cell membrane.

We should recognize the contribution of delivery devices, such as wearable pumps, which allow sustained or pulsatile delivery of medication, depending on the needs of the patient and the mechanism of action. In the absence of these technologies, these medicines might not have been successfully developed. Finally, we should recognize the significant role that vaccine adjuvants have had in enhancing the immunogenicity of critical vaccines, therefore, enabling billions of children and adults to avoid life-threatening diseases. These relatively simple adjuvants are cost-effective, safe, and highly effective depending on the antigen and disease area.

Convenience, which helps to drive adherence as well as market preference, is a significant area of competitive interest. Multi-dose auto-injectors and single-use pre-filled pens have revolutionized the convenience in several therapeutic areas—most notably, inflammation, rare disease, and diabetes. The driver for convenience has made self-administration increasingly feasible, which enables patients to manage their own health much more effectively and reduces the frequency of visits to hospitals and clinics. In addition to medical devices, there has been significant progress in extending the 

half-life of select therapies, resulting in a decrease in the frequency of injection. This has been achieved by a variety of approaches, including pegylation, the development of antibody and fusion-protein technologies, as well as depot delivery systems. This push for convenience has had a significant impact on the marketability and acceptance of several biotechnology products to the point where if medicine is inconvenient, it will not be successful.

What are the most significant differences in drug delivery of small vs. large molecules?

: Experience has taught us that the differences between small-molecule and large-molecule injectables in terms of their manufacturing, handling, and stability carry over to their drug delivery. Small molecules, in general, appear to be more pharmaceutically robust to a wider variety of solvents, which enable the application of depot delivery systems. In contrast, large molecules generally need to be formulated and managed in aqueous solutions and near-neutral pH, which is a narrower formulation design space. Both can have significant stability concerns, which need to be accounted for in the design of a delivery approach. One under-appreciated aspect to be assessed is dose and solubility. Small-molecule injectables have many more years of experience in molecular design and drug solubilization with which to enhance solubility to achieve high doses if required. Conversely, biotechnology products, such as antibodies, are now wrestling with the goal of achieving high doses (often 300+ mg) and yet maintaining a convenient route of administration (i.e., subcutaneous injection).

: What drug delivery technologies have you seen that best address stability?

 The stability of biotechnology products is critical to their safety and efficacy. That said, the drive for convenient delivery and storage often pushes the formulator to have to balance stability with patient acceptance. In brief, this can drive the balance between convenient liquid dosage forms and suspensions versus stable and robust lyophilized powders.

If a drug is unstable, often the first approach to seek to stabilize the product is lyophilization, often referred to as freeze-drying. This well-established process requires a keen balance of formulation development, process design, and facility capability and has been leveraged successfully for biotechnology products and vaccines. With this advantage, the resultant products are somewhat inconvenient in that they need to be reconstituted prior to administration. This inconvenience is less of a concern for infrequently administered drugs often delivered by a healthcare professional. For drugs that are to be self-administered, however, this is a significant inconvenience. While this has been managed by training in select indications (i.e., hemophilia), in general, patients will strongly prefer fewer steps and increased convenience.

: Intravenous, intramuscular, and subcutaneous injections are currently the most common methods to deliver biologics. Do you foresee any other methods of drug delivery coming into prominence in the future for biologics?

 Parenteral injection is the gold standard of drug delivery. The advantage of direct injection or infusion is that the healthcare provider and patient are confident that the drug has been administered properly at the right dose at the right time. Any deviation from this approach raises the question of how effectively a drug can be delivered by an alternate route of administration and how this compares to a parenteral injection.

Two areas of exploration over the past 30 years include pulmonary (and nasal) and intradermal (and trans-dermal) administration. Both approaches have seen progress in preclinical models and limited clinical studies, but neither has enjoyed commercial success. For pulmonary and nasal delivery, many of the concerns have been related to effective dosing either systemically or to the lung. Whether nasal delivery of vaccines, dry powder, or nebulized delivery to the lung, there is a trade-off between the convenience of avoiding an injection versus the risk of a partial dose in comparison to an injection. A similar concern exists with intradermal (and transdermal) delivery systems. Whether a drug is delivered by a patch, microneedles, or transdermal injection device, often there is some drug remaining on the skin surface which does not reach the dermis. One should evaluate whether this variability is acceptable and, further, whether the dermis is the appropriate target tissue.

Beyond these approaches, it continues to be challenging to consider alternate routes of administration for systemic delivery that do not involve a needle.

: Delivering large volumes of biologics beyond the capacity of a syringe or autoinjector is a challenge. How has this challenge been addressed? (Through formulation tweaks? Changing the drug delivery device? Increasing the number of doses needed?)

 Over the past decade, there have been a number of biotechnology products that have established the effectiveness of a 2mL injection to the subcutaneous space. This 2mL injection, for a well-behaved monoclonal antibody, could enable doses of 300 mg with either a prefilled syringe or prefilled pen. This is a significant advance.

To go beyond 2 mL will require one of several options. Multiple injections during a single administration session may be acceptable depending on the disease and patient population. Two doses therefore could deliver 600 mg.

A second approach is the use of an on-body delivery system which contains a drug reservoir, a pumping mechanism, and a needle or catheter that infuses 2–50 mL subcutaneously over a specific timeframe. These are still early in development but show great promise in the next decade.

The use of enzymes that degrade hyaluronic acid in the subcutaneous space has been introduced commercially and enables larger volumes to be administered. The enzyme is co-administered with the drug of interest; therefore, it must be compatible and provides a non-mechanical option.

Finally, one approach which has been effective for many years is intravenous injection. While often not recommended for self-administration (except for hemophilia), this does provide a convenient option for intravenous infusions at an infusion center. If a suitable safety profile has been established for the drug and patient, an intravenous injection often takes minutes in comparison to an intravenous infusion which can take hours at an infusion center.

: How does personalized medicine fit into drug delivery (if at all)? Any trends or predictions?

 To date, this continues to be an area of thoughtful exploration albeit for a very narrow patient population. The development of personalized medicine will be driven by the disease, often oncology, and the technologies available. Autologous CAR-T (chimeric antigen receptor T cell) technologies are being explored which utilize patients’ T-cells that are modified 

and infused back into patients. While encouraging, this process will be slow and expensive. Re-administration of the modified T-cells via catheter is not particularly novel but is an enabling technology.

The development of patient- and tumor-specific therapies is being approached by harvesting specific tumor cells, characterizing specific surface proteins, and devising means to elicit an immune response against the surface proteins and eventually the cancer cell. Depending on the technology approach (i.e., mRNA-LNPs), delivery may be critical to this personalized medicine approach.

: Where is there still room for improvement in drug delivery and why?

 Drug delivery approaches must continue to be explored in a patient-focused, enabling manner. We need to continue to examine what we can do to make dosing increasingly convenient, and both encourage and enable patients so that they will be adherent and take their medication. The patient must be the center of the discussion when considering drug administration.

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. Further development of prefilled pens that are connected, environmentally sustainable, and convenient must be developed in all therapeutic areas. Further, for volumes greater than 2 mL, the same priorities must be applied to on-body systems to enable patients to better manage their disease.

Beyond medical devices, we must continue to invest in enabling delivery chemistries. Advances must continue to be made in terms of 

stability 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.


Vol. 46, No. 9
October 2022
Pages: 32–36

When referring to this article, please cite it as M. Rivers, "The Future of Drug Delivery for Biopharmaceuticals," 

Some of the greatest advancements in drug delivery are related to disposable delivery devices, vaccine adjuvants, and wearable pumps, according to Nicholas W. Warne of Pfizer.