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The emergence of biosimilars has highlighted the challenges involved in manufacturing large, complex biological products. How can bioequivalence or manufacturing consistency be established in complex mixtures that are not easily identified or characterized? And while human serum-derived products such as albumin and immune globulin are long established therapeutics, development, approval and manufacture of complex biologics remains a challenge for both drug developers and regulators.

Central to drug development is the requirement that every aspect of a potential drug product is defined and controlled. The product, as defined, is directly tied to clinical performance for a specified indication, established via extensive, rigorous and well-controlled clinical trials. Thus, a unique product is developed with a defined use. Once approved and marketed, established and validated production processes assure that the defined product is continuously (and identically) delivered to market.

The basic tenets and the regulatory framework of drug development have been heavily influenced by the most common pharmaceutical product developed—the small molecule. Small, well-defined active ingredients are straightforward in their characterization and control. Regulators sometimes seek to apply these “small molecule practices” to the development and regulation of complex compounds. This translation is imperfect. Small molecules are more easily defined and often have a single clinical or biological relationship. In the FDA’s words, “In contrast to most drugs that are chemically synthesized and their structure is known, most biologics are complex mixtures that are not easily identified or characterized.”

Regardless, large complex biologics are, at times, managed under regulations that are based in historical precedence rather than scientific reason. Even with current advances in the development of biosimilar regulation, complex biologics remain difficult to define and characterize. These drug substances are often large proteins with specific geometry or sometimes mixtures of active peptides. Defining complex mixtures carries additional challenges in that certain components of the mixture are critical and controlled with known biological actions related to the indication while the roles of others may be less well-established. Identity must be well established to permit clinical evaluation and consistent manufacturing.

A chemical entity is not a “drug” until it is recognized by regulatory bodies for its proven utility in the treatment of a clinical problem under an acceptable risk benefit calculus defined by established safety and efficacy. Defining product components and procedures to yield the same drug product every time it is produced is a cardinal tenet of pharmaceutical production. This controls for change in the entity which may arguably render the product inactive or shift the benefit risk ratio.

Complex biologics, however are neither simple nor easily defined. Characterizing the end product of manufacturing to the required degree of consistency is often not possible. Regulatory agencies have sought to define these complex products by placing strict controls on the production process, to ensure that every production run is identical and produces product that meet the same final specifications.

Any small modification in product or process may impact the product’s identity and trigger a requirement to demonstrate the end product carries the same efficacy and safety.

Without the ability to absolutely define the drug produced, manufacturers are bound to the established production process, making common tasks like ingredient substitution, changes in manufacturing or critical process parameter changes (often intended to optimize a product) onerous if not impossible.

A current example of a complex biologic in development is IRX Therapeutics’ lead product, IRX-2, a human derived, multi-cytokine biologic whose established identity is based upon the assay off our specific cytokines (IL-1ß, IL-2, IFN-γ, TNF-α). As IRX-2 is a naturally derived, mixed cytokine product, it is well understood and accepted by regulators that there are other biological components (cytokines, proteins) present in addition to the four release-specified cytokines.While the additional cytokines/chemokines in IRX-2 may have individual activity, it is not practical (nor arguably necessary) to have release specifications for every component present in a biologic of natural origin such as IRX-2. Rather, IRX Therapeutics established specifications for product release by selecting representative components believed to be primary contributors to IRX-2 activity, as well as surrogate markers for product quality and consistency. In a biologic mixture, it is necessary to have one cytokine selected to establish concentration to support established dosing. As this directly relates to establishing dose, the chosen principal cytokine should be one of the most biologically relevant and have a level which is readily measured. For IRX-2, IL-2 has been designated as this primary cytokine. It has been so designated as it is commonly held as a component with a key role in cell-based immunotherapy and one of the few cytokines previously licensed for this purpose.

Taken together, the four release-specified cytokines (IL-1ß, IL-2, IFN-γ, TNF-α) are believed to be important mediators of overall IRX-2 induced biological activity and act as the key representatives of activity on T-cells and antigen presenting cells (APCs). This is supported by literature documenting the potential role of these cytokines in immuno-oncology-related outcomes. These cytokines were also selected as they are known products of T-cells and monocytes, the two primary cell types utilized during IRX-2 manufacture. Thus, they serve as markers for consistent production of other cytokines, which are not specified as release criteria. TNF-α is also included as a release specification because it is highly labile and therefore serves as an indicator that the product has been handled appropriately throughout the manufacturing and filling process.

The identification and characterization of a complex product by choosing representative components that may contribute most significantly to target indication is different, but not unique. Other multi-component biologic drugs, such as immune globulin (human), stand as products characterized without specification of all components.

The increase in the number of marketed complex biologic products, growing legislation for the consideration of follow-on biosimilars, and advances in biologics characterization as well as the increasing ability to quantify complex products may be anticipated to influence the evolving regulatory review process.