Anti-C5 Antibody Formulation Stability
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Solution Overview
Problem
Therapeutic antibodies, such as anti-C5 antibodies, face challenges in maintaining stability during storage and administration due to degradation, aggregation, and chemical modifications in aqueous solutions, particularly for patients with complement-associated disorders like PNH or aHUS, where current formulations require careful handling and are prone to microbial contamination.
Innovation Solution
Development of stable, highly-concentrated aqueous solutions of anti-C5 antibodies like ravulizumab, formulated with stabilizing agents and without lyophilization, providing physical and functional stability, ease of administration, and reduced risk of microbial contamination, along with manufacturing cost savings and extended shelf-life.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of operation
If therapeutic antibodies are formulated in aqueous solution, then they can be administered to patients, but they are prone to degradation, aggregation, or undesired chemical modifications
Solution Approach 1:
The patent applies parameter changes by optimizing the concentration of excipients (sugars at 1-10%, amino acids at 0.1-5%, surfactants at 0.01-1%, salts at 0.1-5%) and adjusting pH (6.0-8.0) and ionic strength to achieve a formulation that maintains antibody stability in aqueous solution while enabling convenient administration. This resolves the contradiction by finding optimal parameter ranges that simultaneously satisfy both stability and ease of administration requirements.
2Reliability
If lyophilization is used to maintain stability, then storage stability is improved, but reconstitution is required which increases opportunity for microbial contamination and requires considerable care
Solution Approach 1:
The patent inverts the conventional approach by formulating antibodies as stable aqueous solutions that do not require lyophilization. Instead of drying the antibody to improve stability and then reconstituting it, the invention maintains the antibody in liquid form with optimized excipients that prevent degradation, aggregation, and chemical modifications. This eliminates the reconstitution step entirely, reducing microbial contamination risk and simplifying administration while maintaining storage stability.
3Quantity of substance
If high concentration formulations are used, then therapeutic efficacy is improved for small volume administration, but viscosity and visual quality must be carefully controlled
Solution Approach 1:
The patent applies parameter changes by optimizing the concentration of excipients and their interactions to achieve high antibody concentrations (e.g., 50-100 mg/mL) while maintaining acceptable viscosity and visual quality. The balanced combination of sugars, amino acids, surfactants, and salts at specifically optimized concentrations prevents aggregation and maintains solubility, resolving the contradiction between high concentration and formulation complexity.
4Productivity
If stable aqueous solutions are formulated, then manufacturing cost savings are achieved by decreasing bulk storage space, but the formulation must remain stable during storage and subsequent use
Solution Approach 1:
The patent applies parameter changes by optimizing the formulation composition (excipient types and concentrations, pH, ionic strength) to enable stable storage of high-concentration aqueous antibody solutions. The balanced excipient system prevents degradation and aggregation over extended storage periods, allowing bulk storage space reduction and manufacturing efficiency improvements without compromising stability.
Data Source
AI summary
The present disclosure relates to stable aqueous solutions comprising a high concentration of an anti-C5 antibody (e.g., ravulizumab) and methods for preparing the solutions. The disclosure also provides methods for treating or preventing complement-associated disorders, such as paroxysmal nocturnal hemoglobinuria (PNH) and thrombotic microangiopathy (TMA), including atypical hemolytic uremic syndrome (aHUS) using the solutions. Also featured are therapeutic kits containing one or more of the solutions.