Formulation And Delivery Considerations For Cell And Gene Therapies

By Paolo Siciliano, Gloria Lam, Geoffrey Uhl, and Tim Barrow-Williams, PA Consulting

Across the world, a surge of new cell and gene therapies (CGTs) are reaching commercial approval.

Achieving a successful CGT involves integrating delivery technologies with modular manufacturing platforms and rigorous quality control systems to ensure safety, efficacy, and scalability. But more needs to be done for CGTs to become widely accessible and have an even greater long-lasting impact on the healthcare ecosystem. The right combination of three interconnected, dependent pillars is key to ensuring revolutionary treatments deliver their therapeutic effect in an efficient, safe way: therapy formulation, preparation, and bespoke delivery.

Formulation

Formulation in CGTs underpins the success of advanced therapeutic modalities. As the field matures, the formulation process has become increasingly specialized, reflecting the complexity of biologically active components such as cells and nucleic acids. Formulation strategies now accommodate both ex vivo and in vivo therapies. For gene therapies, delivery systems range from viral vectors (e.g., lentiviral vectors) to non-viral platforms like lipid nanoparticles, which gained prominence during COVID-19. 

The importance of formulation lies in its role as a bridge between development and clinical application. It ensures that therapeutic agents maintain their biological activity, are protected from degradation, and reach intended targets. Poor formulation can compromise therapeutic outcomes, increase immunogenic risks, and hinder regulatory approval. Formulation also impacts manufacturing scalability, cost efficiency, and patient access, making it a cornerstone of commercially viable CGTs. 

Therapy developers can work alongside technology providers to tailor systems to the payload type and target tissue, with considerations for immunogenicity, stability, and bioavailability — ensuring the preservation of cell viability and function throughout processing, transport, and administration.

Understanding the behavior of components in real physiological conditions is critical. AI models could help to predict how therapies will interact within the patient’s body, cutting the time and cost of development by reducing the number of in vivo studies required. Additionally, understanding how approved therapies will be manufactured at the early stages of formulation will support GMP compliance and cost-effective scale-up. Regulatory bodies demand thorough characterization of product quality attributes such as potency, purity, and stability. Formulation must support consistent manufacturing and facilitate robust chemistry, manufacturing, and controls (CMC) documentation. 

“Last mile” preparation before infusion in patients is a complex step. As cell therapies require cold chain logistics, in most cases the addition of cryoprotectants (e.g., DMSO) is necessary to preserve cell viability during storage and transportation. Cryoprotectants are removed prior to infusion into patients due to their toxic effect, adding an extra burden to healthcare providers that increases the risk of human error and the loss of therapeutic material. Identifying alternatives to cryoprotectants can reduce these risks. 

Therapy developers also need to consider how the choice of delivery system (e.g., viral or non-viral) affects targeting precision, immune response, and scalability. Aligning delivery systems, therapeutic goals, and patient profiles will reduce risk for patients while increasing targeted delivery to specific sites. 

Formulation isn’t just a technical step, it’s a strategic enabler of successful CGTs that relies on the holistic balance of scientific innovation, regulatory rigor, and operational feasibility.

Preparation

The last mile refers to the final steps in delivering complex, ultra-sensitive CGTs to patients, typically within hospitals or specialized clinical settings. This phase involves the transition from manufacturing and logistics to clinical administration. Despite advancements in supply chain coordination, digital tracking, and specialized training for healthcare providers, the last mile remains one of the most challenging aspects of CGT delivery.

CGTs require specialized infrastructure and trained personnel, which aren’t universally available across geographies. This creates access barriers for patients, especially those in rural or underserved areas. Even with the right infrastructure, equipment, and skills, healthcare professionals (including physicians, nurses, and hospital personnel) need to prepare final doses using specific equipment, coordinating patient-specific logistics and ensuring compliance with strict handling protocols. This puts additional pressure on professionals in resource-constrained, high-stress clinical environments. And getting it wrong comes with a heavy financial and human cost.

To address these challenges, therapy developers and technology providers can take a proactive and collaborative approach to design therapies with the end user in mind; considering not just efficacy but also ease of preparation, administration, and storage. Simplifying handling requirements or extending shelf life can significantly reduce the burden on clinical teams. Innovators such as Cellular Vehicles are developing a platform to standardize and automate preparation of cell therapy doses at the clinical site, easing the process that specialized nurses and healthcare professionals follow before infusion to patients. Another example is Barkey’s automatic thawing device, Plasmatherm, which avoids contamination risks from water baths. Similarly, the ViaThaw system from Cytiva provides automated, dry thawing of cryopreserved drug components, ensuring precise temperature control and delivering consistent, traceable results for safer preparation.

Therapy developers can further support preparation by investing in robust training and support systems for healthcare providers, including clear protocols, digital tracking and documentation, and real-time technical assistance. Tech providers and therapy developers can also provide integrated platforms to manage scheduling, logistics, and compliance across the therapy life cycle and beyond. Providing this additional support to healthcare providers in the last mile of the CGT journey will increase the wider delivery and adoption of CGTs.

Delivery 

A well-formulated, well-prepared drug is far more likely to reach the intended area in the body. However, the delivery of CGTs presents specific challenges. Many drugs struggle to distinguish between diseased and healthy tissues, leading to off-target effects and toxicity. Therapies can also suffer from low absorption, rapid degradation, and restrictive structures such as mucosal membranes. Unlike therapies that are delivered orally or via injection or infusion, many CGT products must be delivered to a specific location within the body. Often, these sites are hard to reach, such as the brain, heart, spine, pancreas, or eyes. Not only that, but CGT products are generally composed of large biological molecules and particles that are sensitive to mechanical stress. Fluid shearing forces in delivery can deform and degrade particles and induce changes to native structures, potentially reducing efficacy. Some CGTs are also highly viscous solutions, making them difficult to administer through conventional delivery systems.

Therapy developers (in collaboration with technology developers) can work together to increase the chances of success. This includes co-creating and adopting new technologies and strategies, such as inhalable gene therapies that improve lung disease in people with cystic fibrosis. For example, at the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, pediatric physician-scientists are developing an inhalable mist to treat cystic fibrosis.

Another major move forward in this space is mass photometry, which enables single-particle analysis of adeno-associated viruses (AAV) that deliver genetic material to target sites. The U.S. Pharmacopeia recognizes mass photometry as a key method for quality control and standardized delivery.

The Whole Picture

Imagine the impact: A 22-year-old with cystic fibrosis inhales a mist tailored to their genetics. Lipid nanoparticles deliver mRNA directly to damaged cells. Clinicians track the movement of the therapy in real time, check progress against a predictive AI model, and adjust dosage as needed. Suddenly, the 22-year-old is breathing freely for the first time – just one of thousands of people finally receiving therapies that reach the right place at the right time. 

Formulation, preparation, and delivery are not isolated steps. They’re interdependent pillars of therapeutic success. A breakthrough formulation might promise enhanced targeting or reduced toxicity, but without precise preparation, its potential can be lost in translation. For instance, a cell therapy formulated with nontoxic cryoprotectants may preserve viability, but if clinical staff have to manually thaw, wash, and dose it, cell loss and human error will compromise outcomes. Conversely, automated preparation platforms and prefilled devices reduce burden and risk but rely on formulations that are compatible with those systems. Materials used in formulation must be designed with preparation workflows in mind, from syringe compatibility to encapsulation stability. 

Delivery is where all upstream efforts are tested. Even the most advanced formulation and preparation mean little if the therapy can’t reach its target site effectively. Biological barriers, degradation, and off-target effects can undo months of development unless delivery devices and tracking technologies are integrated from the start. Whether it’s inhalable mRNA mist or injectable gene therapy, success depends on how well the formulation interacts with the delivery route and how preparation supports interaction. By designing these three elements in concert, developers can ensure therapies are truly transformative for patients. Importantly, this means working with regulatory and technical experts across all stages, adjusting as necessary to ensure scalability.

Reaching The Full Potential Of Advanced Therapies

By drawing on emerging technologies and deep scientific knowledge, developers can help advanced therapies scale to their full potential. From materials science to data platforms, technology offers a launchpad for organizations to rethink formulations, standardize dose preparation, and enhance targeted delivery — boosting the potential of advanced therapies across different healthcare settings and modalities.   

Aligning development across formulation, preparation, and delivery, with the help of AI, will expand the possible use cases for advanced therapies, from long-term condition management all the way through to reconstructing damaged tissue. Ultimately, advanced therapies could even be administered in more accessible settings, such as community hospitals and outpatient clinics, opening up additional market opportunities while supporting people to live healthier, better lives.

About The Authors

Paolo Siciliano is an associate partner and life sciences expert at PA Consulting, and he leads PA Consulting’s work in cell and gene therapies globally. He has years of experience in supporting major pharma, biotech, and medtech companies to identify, develop, and leverage new technologies, as well as to improve their innovation and product development processes. His main areas of expertise range from technology and commercial strategy to technology development, across a number of therapeutic areas. He holds a Ph.D. in molecular biology and has worked as a senior research scientist in biotech companies in the U.K.

Gloria Lam is a cell and gene therapy expert at PA Consulting. She has a strong academic background in bioprocessing and more than seven years of international industry experience in developing growth strategies in cell and gene therapies and commercialising regenerative medicine products. Gloria holds a Doctor of Philosophy in biomedical engineering and has published articles on impact of fast-track designations, decision life cycle, supply chains, and capacity planning decisions on CGT.

Tim Barrow-Williams, C.Eng., is the head of drug delivery at PA Consulting.

Geoffrey Uhl is head of partnerships, cell and gene therapy, at PA Consulting.