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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.
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. Pharmaceutical Technology 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.
PharmTech: What do you believe are some of the greatest advancements in drug delivery to date?
Warne: 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 in vivo 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.
PharmTech: What are the most significant differences in drug delivery of small vs. large molecules?
Warne: 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).
PharmTech: What drug delivery technologies have you seen that best address stability?
Warne: 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.
PharmTech: 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?
Warne: 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.
PharmTech: 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?)
Warne: 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.
PharmTech: How does personalized medicine fit into drug delivery (if at all)? Any trends or predictions?
Warne: 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 ex vivo 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.
PharmTech: Where is there still room for improvement in drug delivery and why?
Warne: 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 in-vivo 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.
Meg Rivers is a senior editor for Pharmaceutical Technology, Pharmaceutical Technology Europe, and BioPharm International.
Vol. 46, No. 9
When referring to this article, please cite it as M. Rivers, "The Future of Drug Delivery for Biopharmaceuticals," Pharmaceutical Technology 46 (9) 32–36 (2022).