From vials to pre-filled syringes, the success factors in the development of subcutaneous injection formulations compared to intravenous injections.

By transitioning from IV administration based on vials to subcutaneous administration based on PFS, the burden and risk of medical errors for healthcare professionals can be reduced, while improving patients’ quality of life. However, there are still many challenges in transitioning from vials to PFS and from infusion to subcutaneous injections.

From Intravenous to Subcutaneous Injection

Intravenous administration involves delivering drugs directly into the patient’s bloodstream and is the default and fastest method of injection. For certain drugs, intravenous administration remains the primary route of administration. However, subcutaneous administration offers a healthier and more cost-effective injection option, benefiting patient safety and comfort.

For instance, in hospitals or clinics, intravenous drug administration often requires healthcare resources and time, as well as leads to drug wastage due to overfilling. Additionally, intravenous administration adds inconvenience to patients, requiring long infusion times and travel to healthcare facilities. Switching to subcutaneous injection can simplify complex therapies as it offers faster administration, a relatively easier administration method, and potential for self-administration. These factors make subcutaneous administration more favorable compared to intravenous administration in many aspects, including compliance and quality of life, as patients experience more convenience, fewer visits, and less pain.

Advantages of Pre-filled Syringes (PFS)

Over the past two decades, there has been a growing adoption of pre-filled syringes (PFS) for approved drugs. In fact, many biopharmaceuticals, especially monoclonal antibodies, tend to use PFS for drug administration. The general consensus from clinical experience is that switching to pre-filled syringes helps reduce the steps required for preparation, potentially lowering the risk of medical errors and microbial contamination by healthcare professionals.

Furthermore, the use of PFS allows better patient adherence to treatment, particularly for chronic diseases like rheumatoid arthritis and multiple sclerosis, while also helping to reduce overall treatment costs. PFS ensures accurate drug doses for individual patients, avoiding drug loss and wastage, which is crucial for cost control of expensive medications and increasing the yield of PFS units per batch of raw materials.

Another significant reason for the increasing demand for PFS packaging is its compatibility with autoinjectors, enabling patients to have more control over their treatment independently of healthcare professionals. Additionally, new smart autoinjector devices can monitor patient compliance with treatment plans. Other promising patient-centered subcutaneous biopharmaceutical injection methods include microneedles, microneedle patches, jet/no-needle injections, and subcutaneous implants.

Challenges of Transitioning to PFS Formulations

Switching to PFS and subcutaneous formulations comes with its challenges, and the following statements highlight some of the issues in the subcutaneous injection industry.

Categories and Challenges

1. Concentration and Dosage

The volume of subcutaneous injection with PFS is generally 1-2ml, and currently, the volume of auto-injection pens can reach 2.25ml. For example, a typical intravenous injection of a monoclonal antibody may contain 400 to 750 milligrams of the drug, diluted in several hundred milliliters of solution. However, PFSs used for subcutaneous injection are usually limited to a few milliliters. Therefore, switching from intravenous to subcutaneous administration requires delivering the same dose in a much smaller volume. Reducing the volume requires increasing the drug concentration, which can make some biologics highly viscous, affecting not only the stability and administration of the drug but also its manufacturability.

2. Bioavailability

The bioavailability of biologics is unpredictable and variable, and there is a gap in finding a clinically predictive preclinical model for determining the bioavailability of subcutaneous products under development.

3. Immunogenicity

There is a lack of consistency in the industry regarding the understanding of subcutaneous immunogenicity, related test methods, and corresponding quality attributes. Therefore, quality attributes, which define the product characteristics that must be controlled to ensure high-quality products, are affected.

4. Clinical Trial Strategy

There is a lack of clarity on the optimal timing for conducting costly clinical trials for candidate drugs. Some believe that subcutaneous injections should be done as early as possible in clinical trials, while others think it should be initiated after the drug’s effectiveness has been determined.

When developing pre-filled formulations for biopharmaceuticals, factors related to the molecule’s inherent characteristics (e.g., solubility), device components, and manufacturing processes need to be considered. These factors can limit protein concentration or lead to protein degradation, aggregation, or visible particle formation.

During the transition to PFS, changes in formulation composition and drug concentration significantly impact critical process parameters for fluid mixing (transfer, mixing) and delivery (filtration, filling). Additionally, other formulation factors such as viscosity, osmolarity, and excipients may affect subcutaneous absorption and storage stability of biopharmaceuticals.

PFS biopharmaceuticals can pose long-term stability issues related to interactions between active molecules and components of the closed container system. The risk of decreased stability is higher when drug molecules are exposed to additional materials, such as polymers and silicone oil, compared to using vials. The presence of extractables and leachables (E&L) can also adversely affect the safety of medications.

Transitioning to PFS requires additional research, which prolongs development time and increases costs. Additionally, complex regulatory requirements for combination products of drugs and devices can further increase the development time and costs of PFS projects.

Overcoming Transition Challenges

Successful conversion from vials to PFS depends on several key factors, taking into account the ease of PFS transition and changes in drug formulations.

Ease of Conversion from Vials to PFS

Simple conversion:

1. Liquid to liquid
2. No change in concentration (dose, volume remains the same)
3. No change in formulation, only the packaging container changes

High concentration conversion:

1. Liquid to liquid
2. Increase in concentration and dose, with volume remaining the same
3. Changes in formulation, packaging container changes

High concentration and drug form conversion:

1. Lyophilized to liquid
2. Increase in concentration, dose, and volume remaining the same
3. Changes in formulation, packaging container changes

First, understanding the physicochemical characteristics of the biopharmaceutical is necessary. Screening pH/buffer solutions and excipients to determine the most suitable formulation for the biopharmaceutical, measuring conformation and colloid stability, and subjecting candidate formulations to stress such as heating, agitation, and freeze-thaw cycles are essential steps. Typically, the process will identify one or two candidate formulations that will be further optimized for the final dose-specific formulation combination. Secondly, evaluating various container closure systems is needed. This includes sensitivity measurements of the final combination to silicone oil and tungsten used in the container closure system and examining the functionality of the selected PFS device in terms of “injectability” and dose accuracy.

In recent years, enzyme-mediated delivery methods, such as using hyaluronidase to modify injection sites, have facilitated the transition to higher concentrations and volumes, increasing the absorption of drugs by subcutaneous tissue. Hyaluronidase is a naturally occurring glycosaminoglycan present throughout the body that creates resistance to fluid flow in the extracellular matrix, limiting the delivery of large volumes of subcutaneous drugs. Hyaluronidase, by degrading hyaluronic acid at the local injection site, enables the extensive flow of subcutaneous drugs and promotes the administration of large volumes of subcutaneous drugs. Currently, many biopharmaceuticals are utilizing this technique to develop the next generation of drugs.

Controlling the viscosity and osmolarity of biopharmaceuticals at an appropriate level, using recognized safe excipients, and avoiding buffering solutions that cause pain and excessive surfactants can prevent common subcutaneous development issues.