Development roadmap for subcutaneous delivery of high dose biologics – high concentration formulation, analytical comparability and patient preference considerations for large volume devices

Abstract

High dose biologic drug products (DPs) have become a common trend for the treatment of chronic diseases across a wide range of therapeutic areas. While the expectation is to deliver these DPs via subcutaneous (SC) self-administration due to patient and healthcare provider preference, there are unique challenges that make the product development highly complex. Critical aspects that need to be considered while designing the development roadmap include high concentration formulation development, drug-device combination product design to deliver large volumes, assessment of pharmacokinetic (PK) bridging risk, user preferences, patient tolerability, etc. Such challenges can be overcome by robust formulation development strategies, analytical characterization to ensure product comparability, and well-designed patient preference and human factors studies to identify appropriate patient friendly delivery device technology. This review discusses novel formulation and processing technologies associated with patient tolerability and in-vitro/-vivo studies to minimize the risk of clinical bridging. The review also presents multiple case studies to understand user and patient preferences for defining the quality target product profile (QTPP) for selecting an appropriate device approach, dosing frequency, and overall development road map from first-in-human (FIH) to product launch. The opinions summarized in this review can be used as guidance for the development of high-dose biologic drug products (DPs).

Introduction

Recently, the pharmaceutical industry has experienced tremendous therapeutic and commercial success with biologics. Monoclonal antibodies (mAbs) have achieved significant commercial success, with 4 out of 10 of the highest-selling medications globally being mAbs therapies. Currently, more than 4,000 mAbs are being developed in the pre-clinical or clinical phase. Moreover, there is an increased trend with high dose mAbs in various disease areas, such as immunology, cardiology, respiratory, neurology, and infectious disease. One possible reason for the significant number of high-concentration antibody products (HCAPs) being commercialized and prescribed in therapeutic areas such as immunology could be the need for a higher drug dose to achieve target engagement and the required clinical efficacy for treating immunological diseases such as psoriasis, rheumatoid arthritis (RA), and psoriatic arthritis. Also, substantial growth of high-dose mAbs has been observed in neurology due to the chronic symptoms related to neurologic conditions (e.g., Alzheimer’s disease, Parkinson’s disease, etc.) and the complexity of permeating this class of molecules across the Blood Brain Barrier (BBB). Furthermore, the use of SC drug delivery is becoming more popular as compared to intramuscular (IM) injection or intravenous (IV) infusions that involve time-consuming and invasive procedures. Due to the need for long-term therapy of chronic diseases, self-administration, or at-home administration by caregivers via the SC route will soon be considered the desired standard of care. In addition to patient compliance, the SC route of administration brings additional benefits over IV delivery by cutting down on healthcare costs related to hospital administration and special arrangements with infusion set, pump, etc.  Also, slow IV infusions of large volume administered over large time periods is inconvenient for patients due to long infusion chair times5 and high health care costs. Although IM route of administration is less immunogenic than the SC route, IM injections have limitations with injectable volume and a higher risk with regard to patient tolerability The volume of medication that can be administered via IM injection is limited by the muscle tissue’s ability to absorb it. For adults, no more than 3-4 mL of medication should be administered in a single IM injection because the muscle tissue cannot absorb larger volumes well. Therefore, when compared to SC administration, IV or IM may not be the preferred approach for delivering high-dose mAbs therapies.

As SC administration becomes increasingly popular in the development of biologic DP for the treatment of chronic diseases, developing an SC delivery system capable of delivering a high dose presents significant challenges for the pharmaceutical and biotech industries. These challenges include complexities related to formulation development, identification of a suitable device, PK bridging risks, patient tolerance, and other factors encountered during clinical studies and commercialization. In addition, the unknown risk associated with the dose and relative bioavailability (rBA) of SC compared to IV administration makes product design more complex, particularly when factoring in the additional development efforts required for the delivery device and the significant resource investment during the early phases of development. Finally, the selection of primary fill finish container and compatibility with the delivery device components require serious consideration during development to minimize regulatory risk and launch delays. Moreover, with the uncertainties of dose-volume during early clinical development, it is very important to adopt the right strategies and development plan for the delivery device using a multifaceted options analysis. A proper risk-benefit analysis is also needed to assess the impact of development decisions on the final product profile to provide the highest quality product while balancing the overall risk. For example, investing resources on formulation technologies that enable high protein concentrations versus the investment in large volume delivery device development. Furthermore, since patient acceptability and adherence to the commercial product are the ultimate goals, it is important to invest and plan for phase-appropriate patient preference and human factor studies. These studies help to identify and iteratively mitigate risks associated with choosing the most appropriate, user-friendly delivery system. Cross functional collaboration with key stakeholders, such as Drug Substance (DS), Formulation, Analytical, Device, Bio-pharm, Commercial, Clinical and Regulatory functions should be employed to identify the critical parameters for success and to ensure the development of a successful combination product.

In this review, we have highlighted the development roadmap of high-dose biologic DPs from preclinical to commercialization phases. The article summarizes detailed aspects of formulation development for high protein concentrations, ongoing research and collaboration opportunities with ultra-high concentration technology, considerations of patient preferences, and acceptance of a combination DP with a large volume delivery device, all while carefully managing injection site reactions (ISRs) and tolerability. Specifically, the risk of drug leakage at the injection site and increase of pain may be a major obstacle with higher solution volumes and viscosities.

At high concentrations, proteins might aggregate and negatively impact the product quality and patient safety due to changes in efficacy and adverse effects. The presence of particles can be a major issue in the formulation, considering the immunogenicity risk with the SC route of administration. While developing formulations with high protein concentration, robust analytical characterization to detect both proteinaceous and non-proteinaceous particles is needed at product release and during the shelf life of the product. This review provides a comprehensive summary of analytical methods for characterization of critical product attributes and analytical comparability approaches for comparability assessment. Additionally, this article briefly delves into the process development-related changes to manufacture high high-concentration DP. Various analytical tests and techniques that can be utilized to characterize different aspects of high-concentration antibody formulations are discussed, along with the forced degradation studies, protein–protein interaction-related changes, and analytical testing considerations for these studies.

The article also discusses the importance of well-designed biopharmaceutical studies to minimize clinical risk associated with PK comparability due to changes in key product attributes, such as upstream cell line and process parameters for DS, changes in protein concentration, formulation components and technology, delivery device selection, injection volume and rate, and other related factors. Although the BA of mAbs is unpredictable, it must be assessed at the early phase of clinical development to understand the impact on dose-volume and overall development strategy. If the SC bioavailability is low, it increases the amount of protein required, which can negatively impact the overall cost of the product.

Finally, an overview of various large volume delivery device technologies is included with particular focus on the steps required to administer the injection in the context of the intended user of the product (i.e., patient or healthcare professional). The delivery device technologies typically fall into four categories, ranging from a traditional vial and syringe presentation to novel and innovative on-body delivery systems (OBDS). The selection of the optimal delivery system based on the intended use, user, and use environment should incorporate considerations of user and patient preferences, usability, and tolerability to optimize the product such that it is well accepted by patients. Development strategies for integrating user and patient perspectives with case studies are discussed herein.

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Development roadmap for subcutaneous delivery of high dose biologics – high concentration formulation, analytical comparability and patient preference considerations for large volume devices,
Ghosh, Indrajit et al.,
Journal of Pharmaceutical Sciences, Volume 114, Issue 9, 103914