Prabhakar Reddy, PhD, senior director, Pharmaceutical Science General Chapters & Complex Generics, USP discusses how complex formulations demand a new approach to quality and standardisation.
The future of medicines will be shaped by new molecules and the formulations that deliver them. From lipid nanoparticles (LNPs), liposomes, and long-acting injectables to inhaled therapies and drug-device combination products, today's most innovative medicines depend on increasingly sophisticated and innovative formulations. In these products, quality cannot simply be tested at the end of development; rather, quality must be designed into the product from the beginning, through robust characterisation, standardised analytical approaches, and a deep understanding of how formulation impacts performance.
This shift represents more than a technical challenge. It reflects a broader transformation in pharmaceutical development, where formulation science has become a strategic enabler of innovation, regulatory confidence, and patient access. As therapies become more complex, the quality framework supporting them must evolve.
The rise of complex products
For decades, pharmaceutical formulation development focused primarily on relatively straightforward dosage forms such as tablets, capsules, and simple injectable solutions. Today, however, the landscape has fundamentally changed. Drug developers are leveraging sophisticated delivery systems, including liposomes, LNPs, microspheres, long-acting injectables, inhalation products, ophthalmic suspensions, and drug-device combination products, to improve efficacy, extend dosing intervals, enhance patient convenience, and enable entirely new therapeutic modalities.
These formulations have transformed the treatment of cancer, chronic diseases, rare disorders, infectious diseases, and genetic conditions. Yet they have also introduced a new level of complexity for manufacturers, regulators, and developers seeking to bring both innovative and follow-on products to patients.
The U.S. Food and Drug Administration (FDA) now recognises a category of "complex products" that includes formulations and delivery systems that are difficult to characterise, manufacture, or replicate. What distinguishes these products from conventional dosage forms is that performance depends on more than the active pharmaceutical ingredient. Particle size distribution, morphology, release kinetics, carrier composition, excipient characteristics, device performance, and manufacturing processes all influence how these complex products perform in patients. For example, long-acting injectable formulations rely on specialised polymers, such as poly(lactic-co-glycolic acid) (PLGA), to control drug release over weeks or months. Liposomal products depend on precisely engineered lipid compositions and particle characteristics. Inhalation products must deliver reproducible doses through sophisticated devices that consistently target the appropriate region of the respiratory tract.
As a result, formulation development is no longer solely about selecting appropriate excipients or optimising stability. It requires the ability to characterise highly complex systems and demonstrate that they will perform predictably throughout their lifecycle.
Generic development remains difficult
One consequence of this growing complexity is the limited number of generic versions of many complex products approved by FDA. While conventional drugs often face generic competition soon after patent expiration, numerous complex products remain without generic alternatives, even decades after their approval. Manufacturers are interested in developing these products, but they encounter significant scientific and technical barriers that extend well beyond traditional formulation development.
Developers must often demonstrate not only pharmaceutical equivalence, but also bioequivalence and comparable clinical performance. Reverse engineering an innovator product becomes exceptionally difficult when critical quality attributes, such as particle structure, release mechanisms, or proprietary manufacturing processes, cannot be fully characterised.
The challenge is compounded by limited in vitro-in vivo correlation tools, a lack of standardised characterisation methods, few publicly available reference materials, and expensive clinical studies required to demonstrate equivalence. These factors significantly increase development costs and risk, often limiting participation to companies with extensive technical expertise and financial resources.
As advanced formulations become increasingly common across the pharmaceutical industry, reducing these scientific barriers becomes essential for expanding patient access to important therapies.
The standardisation gap
One of the greatest challenges facing the industry is the absence of harmonised scientific frameworks for evaluating complex formulations. Traditional dosage forms benefit from well-established pharmacopeial methods and reference standards that provide common approaches for assessing identity, purity, potency, and performance. For many complex products, however, equivalent tools are still emerging.
This creates uncertainty for developers attempting to characterise their products and demonstrate equivalence. Questions remain about which analytical methods should be used, how critical quality attributes should be measured, and what constitutes acceptable product performance.
Stakeholder engagement conducted by the United States Pharmacopeia (USP) has consistently identified common needs across industry, including standardised characterisation methods, dissolution and release testing approaches, physical reference standards, and improved guidance for evaluating bioequivalence. These needs are particularly evident for liposomes, microspheres, iron colloidal products, lipid nanoparticles, and other advanced formulations.
Potential solutions for these needs can extend beyond harmonising laboratory methods. Shared scientific standards create a common language that helps enable innovation, regulatory review, and manufacturing to move forward with greater confidence and efficiency. They can provide the scientific infrastructure needed to evaluate increasingly sophisticated medicines using consistent, reproducible approaches across organisations and around the world.
Building the foundation for future innovation
Advanced modalities and combination products are redefining what is possible in medicine while simultaneously raising expectations for how these products are characterised, evaluated, and controlled. Meeting these expectations requires more than developing new analytical technologies. It requires building a scientific foundation around quality that evolves alongside therapeutic innovation.
USP helps create that foundation by developing and advancing documentary standards, reference materials, analytical methodologies, and quality frameworks that enable innovation, regulatory confidence, and patient access. Rather than prescribing how products should be manufactured, these tools can provide a common scientific basis for evaluating sophisticated medicines with consistency, transparency, and scientific rigor.
Pharmaceutical innovation continues to move toward more advanced delivery platforms, driving the need for quality science to evolve in parallel. The future of formulation development will depend not only on designing novel delivery systems, but also on creating reliable, reproducible, and globally accepted approaches to characterise them.
This evolution extends beyond formulation science. The same principles are driving advances in biologics, extractables and leachables, microbial contamination control, digital quality tools, and resilient pharmaceutical supply chains. Together, these disciplines are expected to help drive the next generation of compendial science, one that enables innovation while strengthening confidence in the quality, safety, and performance of modern medicines.