Surgical Therapeutic Design: Key Considerations In Formulation And Delivery

By Dalit Hazan, deputy CEO & EVP R&D, Clinical & Regulatory Affairs, PolyPid

Surgical site infections (SSIs) pose a major, yet often overlooked, clinical and economic burden on patients and health systems. They remain among the most common healthcare-associated infections, resulting in longer hospital stays, increased costs through readmissions, negative patient outcomes, and extended recovery times.

Traditional strategies for preventing SSIs have historically relied on hygiene-based procedures, centered on sterile environments and the systemic "brute force" of broad-spectrum antibiotics. However, relying on these methods and focusing on antibiotic spectrum and strength, with the goal of eliminating pathogens before infection can take hold, often misses the mark. Antibiotics can be cleared from the bloodstream or be metabolized before they reach the therapeutic concentrations required at target tissue sites, leaving the surgical site vulnerable. Even the most potent antibiotics may struggle to reach effective concentrations at the right time and place.

Successful SSI prevention hinges as much on achieving effective local exposure in the surgical environment as on the therapeutic itself. The manner in which a medication is delivered to the desired tissue, the length of time it maintains local and effective concentration, and its behavior within the surgical environment make all the difference.

Formulation and delivery strategy is therefore critical. Optimizing pharmacokinetics at the surgical site and maintaining sustained therapeutic exposure during the most vulnerable periods are essential for truly effective prophylaxis.

The Demand For A New Drug Delivery Mindset In The Surgical Environment

The surgical environment presents further unique challenges when it comes to infection prevention. Incision and tissue manipulation disrupt local blood flow, limiting drug access to the affected tissue. The standard protocol of intravenous antibiotics administered prior to incision has been somewhat effective, but systemic delivery often struggles to maintain adequate drug concentrations once the incision is made. During early wound healing, when perfusion gradually returns and tissues remain particularly susceptible to infection, antibiotic levels may already be declining. Attempts to extend systemic dosing to compensate are often constrained by safety considerations, including toxicity and other unintended systemic effects.

The real-world impact of this "perfusion gap" is significant. Traditional prophylactic antibiotics leave patients vulnerable, as infection risk can persist beyond the timeframe systemic antibiotics can reliably cover. Guidelines recommend IV prophylaxis within 60 minutes before surgery and no more than 24 hours after, yet studies show that up to 60% of surgical site infections emerge after hospital discharge. Addressing this challenge requires shifting the focus from drug potency alone to delivery strategies designed to align with surgical conditions.

Changing The Equation: Long-Acting, Controlled-Release Targeted Delivery

Delivering antibiotics directly at the surgical site while maintaining therapeutic concentrations over extended periods addresses a key limitation of conventional prophylaxis. Standard systemic doses provide strong initial exposure, but drug levels in surgical tissues decline quickly, even while patients remain in the early postoperative window when infection risk is highest. Controlled-release formulations bridge this gap by sustaining local antibiotic exposure during the period when protection is needed most.

These systems do not modify the antibiotic itself. Instead, the drug is incorporated into a reservoir-like delivery matrix that allows for gradual releases over time, creating sustained local exposure rather than a single transient peak. By maintaining higher concentrations at the surgical site while limiting systemic distribution, controlled-release delivery can extend coverage and reduce reliance on repeated dosing.

Developing these systems requires careful consideration of how drug delivery aligns with clinical practice. Beyond the mechanics of drug release, technical, clinical, manufacturing, and practical factors — including consistent release profiles, usability at surgical sites, and compliance with development and regulatory pathways — must be addressed.

Several key considerations ultimately shape how these systems are designed and implemented in practice. Above all, biocompatibility and safety are foundational and require that formulation excipients be well tolerated by the surgical tissue. This includes having established safety profiles that reduce uncertainty around local responses and streamline regulatory evaluation.

Equally important is clinical compatibility, ensuring that formulations integrate seamlessly into surgical workflows and complement existing infection-prevention bundles. This includes preoperative antibiotics, temperature and glucose control, and wound management, without interfering with wound closure or other procedural steps.

Beyond clinical integration, these systems must demonstrate reliability across the full development continuum, from bench to commercial scale, with consistent quality and performance. Finally, design must account for variability across surgical settings, recognizing that different procedures present distinct biological environments and microbial profiles, requiring delivery systems that balance site-specific needs with broader clinical applicability.

Regulatory And Development Considerations

Locally administered controlled-release therapy approaches present unique regulatory challenges that must be addressed early in development. Because these approaches often involve novel delivery strategies, there is a need to clearly demonstrate both safety and the scientific rationale for use. Careful documentation of formulation design, such as excipient selection, compatibility between ingredients, particle size, stability over time, and overall delivery strategy (including route of administration and dosage considerations), supported by structured development methodologies, is essential.

In addition, regulatory review includes:

• examining how in vitro release profiles translate to in vivo pharmacokinetics
• evaluating depot-style formulations for residual drug and component behavior in the body
• considering local tissue response, biocompatibility, and systemic safety to ensure both efficacy and minimal disruption to surrounding tissues.

Within this framework, several key areas guide regulatory evaluation of controlled-release therapies.  A central requirement is delivery approach justification, where regulators expect clear evidence that localized delivery provides advantages over systemic administration, including higher target tissue concentrations, improved pharmacokinetics, and reduced systemic exposure. This rationale must demonstrate consistency and reproducibility across development stages by showing robust formulation design documentation, alongside structured development methodologies such as design of experiments (DoE).

At the same time, release kinetics must be considered, with regulatory review focusing heavily on how in vitro release correlates with in vivo pharmacokinetics. Demonstrating an in vitro–in vivo correlation (IVIVC) or providing alternative evidence of in vivo predictability is essential to support translational confidence.

For long-acting formulations, evaluations extend to residuals after the complete drug release, as well as the behavior of formulation components in the body, and whether any need for removal or mitigation exists. In parallel, local tissue response, biocompatibility, and systemic exposure remain central to regulatory assessment, with materials required to demonstrate minimal toxicity and limited disruption to surrounding tissue while still delivering the intended therapeutic effect. Proactive engagement with regulators can further streamline development by addressing these considerations early, before entry into clinical trials, thereby increasing the likelihood of successful translation from laboratory to surgical practice.

Elevating Delivery

Preventing surgical site infections demands an approach that extends beyond drug discovery. It requires that therapies are developed from the outset with careful attention to how they are intended to be delivered. Integrating clinical insight and regulatory strategy from the start can create treatments that not only improve patient outcomes but also accelerate development. Looking ahead, embedding delivery-focused thinking into every stage of therapy design across surgical applications will be key to advancing safer, more effective interventions and high-value programs. With this mindset, we are rethinking not just what we deliver but how the next generation of prophylactic therapies can achieve stronger, more reliable infection prevention in surgical care. 

About The Author

Dalit Hazan, deputy CEO and EVP of R&D, clinical, and regulatory affairs at PolyPid, brings over 25 years of experience in pharmaceutical R&D and regulatory affairs. She has led successful submissions and interactions with global health authorities, including the FDA, EMA, and Health Canada. With a strong background in clinical development and regulatory operations, she has advanced programs from early-stage studies through to approval. Prior to PolyPid, she held senior regulatory roles at Teva Pharmaceuticals. Hazan holds an M.Sc. in physiology and pharmacology from Tel Aviv University’s Faculty of Medicine and an Executive MBA from Bar-Ilan University.