Rational design of lyophilized high concentration protein formulations-mitigating the challenge of slow reconstitution with multidisciplinary strategies

Characterization of the Physical Stability of a Lyophilized IgG1 mAb after Accelerated Shipping-Like Stress

“…These differences in reconstitution time did not change, however, when the samples were reconstituted at different rates and with different diluents. While this lyophilized protein formulation had a relatively short reconstitution time, for other lyophilized protein samples in which the reconstitution time is longer and may be problematic during clinical administration, techniques mentioned by Cao et al could be beneficial. For example, reconstituting under vacuum, adding wetting agents, and/or using low diluent volumes were observed to be methods that can decrease reconstitution times in a high concentration lyophilized formulation of a Fc‐fusion protein .…”

“…Protein instability is also possible during secondary drying, during which the non‐frozen water bound to the protein or excipients is removed. The composition of the reconstitution medium and its rate of addition may also affect the stability of a lyophilized protein upon reconstitution back into the liquid state . For example, if the reconstitution medium is added too rapidly, the dried protein may not be given sufficient time to rehydrate and assume its native conformation, and the presence of this improperly rehydrated protein may lead to aggregation .…”

An Impedance-Based Method to Determine Reconstitution Time for Freeze-Dried Pharmaceuticals

“…This includes activities in early‐ and late‐stage formulation and process research and development (e.g., formulation development, lyophilization process development, and testing or robustness and consistency). As changes in cake morphology, specific surface area, and formulation (e.g., crystallinity, wettability) can significantly impact reconstitution time, the measurement of reconstitution time and behavior can be helpful when assessing changes of freeze‐dried product manufacturing processes, sites or equipment, and quality control (e.g., release testing) …”

Stability of buffer-free freeze-dried formulations: A feasibility study of a monoclonal antibody at high protein concentrations

“…82 There is consequently a certain need for understanding 83 development of highly concentrated freeze-dried formulations 84 (HC-FDF). 85 The main HC-FDF development challenge is balancing perfor- 86 mance factors-e.g., maintaining stability, reconstitution times, 87 and even the pharmaceutical elegance of the lyophilized cake 88 within specified limits [4,7,8]. 89 For example, reconstitution time of freeze-dried products 90 increases, over a range from minutes to hours, as a function of pro-91 tein concentration.…”

“…89 For example, reconstitution time of freeze-dried products 90 increases, over a range from minutes to hours, as a function of pro-91 tein concentration. Very long reconstitution times might seriously 92 impair the potency or usability of a lyophilized product [6,7,9,10]. 93 It is therefore necessary to examine ways of reducing reconstitution 94 time (by controlling ice nucleation, for example) [11][12][13].…”