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6 Pharmaceutical Technology ® Bio/Pharma Outsourcing Innovation eBook February 2024 PharmTech.com Development Case-study 1: development of combination products for subcutaneous administration In recent years, the pharmaceutical industry has wit- nessed a growing interest in developing combination products for SC administration. This shift is driven by the need for more patient-friendly drug delivery op- tions, and particularly enabled by the development of high-concentration formulations or formulations containing recombinant human hyaluronidase, an en- zyme that transiently cleaves hyaluronic acid in the SC space, facilitating injection. The hyaluronidase has been employed to reduce tissue backpressure for SC injection volumes exceeding the few milliliters range. The development of SC combination products comes with its own set of challenges, including formulation stability, compatibility with manufacturing material and primary packaging components, and formulation viscosity linked to challenges in manufacturability and usability/administration. Development of high-concentration formulations, in particular, poses significant stability challenges, as the increased drug concentration can lead to instabil- ities (e.g., aggregation, particle formation), affecting the product's shelf life and also effective delivery. Ad- dressing these challenges requires a careful approach to formulation and packaging selection, ensuring the product maintains its efficacy and safety throughout its intended shelf life. The selection of primary pack- aging components as well as their associated device component requires thorough characterization to prevent or minimize interactions that could compro- mise drug stability or safety. In addition, analyzing the impact of packaging residuals on the drug prod- uct as well as of residuals from manufacturing ma- terial is crucial for securing the overall quality of the combination product. As drug concentration rises, viscosity increases (ex- ponentially with protein concentration) impacting the f low characteristics of the formulation. Viscos- ity is also dependent on temperature, and the type of API in combination with formulation excipients impact whether the formulation shows Newtonian or Non-Newtonian f low behavior. As a result of the for- mulation's viscoelastic behavior, the design of manu- facturing operations including sterile filtration, and the filling technology for accurate filling (depending on the fill volume) needs careful selection. In addition, a higher viscosity leads to higher injections forces, which is majorly defined by the inner needle diameter (to the power of four) according to Hagen-Poiseuille's law. Interestingly, the inner diameter of needles is not harmonized in detail amongst suppliers. In any case, injection forces as part of functionality testing needs to be carefully monitored over the shelf life of a product and verified if acceptable in human factor studies. If not adequate for the intended user population, over- coming this hurdle involves optimizing formulation components (viscosity reducing agents) and leverag- ing innovative device designs to facilitate smooth and reliable injections, injection performance, and patient experience. User-friendliness is paramount in SC com- bination products, emphasizing the need for intuitive and easy-to-use devices. Design considerations, such as ergonomic features and user interface enhancements, play a crucial role in overcoming usability challenges. Selecting the appropriate device is pivotal in the success of SC combination products, and the market is trending higher toward injection volumes for the SC space exceeding 2 mL, and even surpassing 10 mL or 20 mL (also without hyaluronidase). The choice be- tween syringes, autoinjectors, or more recent on-body injectors (OBIs) depends on factors like the end-user, the dosing regimen, patient convenience, and the spe- cific therapeutic area. Most recently, options including reusable and recyclable devices are advancing. Besides device selection and optimization for the target user group, the selection of the suitable primary packaging components is crucial; a vial is no longer the standard in these developments. Choosing the right primary packaging material is critical for maintaining product integrity. In addition, compatibility with the drug for- mulation, durability, and barrier properties are essen- tial factors in the selection process. Rigorous material characterization ensures the packaging aligns with regulatory requirements and product specifications. Thinking beyond traditional limitations, which may possibly arise from urban myths (e.g., what a maximum SC injection volumes would be), will be key to driving innovation in the field. By carefully navigating these challenges and limitations, the in- dustry can unlock the full potential of SC administra- tion for high-concentration formulations, ultimately improving patient outcomes and adherence. Case-study 2: development and manufacturing of intravitreal products The development and manufacturing of IVT products represents a specialized and growing segment of the pharmaceutical industry. IVT products are designed Selecting the appropriate device is pivotal in the success of SC combination products.