This client was experiencing a critical shortage of drug product to supply ongoing clinical trials and were about to run out of clinical material. A number of contributing variables were at play. First, the client had recently changed the CDMO that was manufacturing the LNP component of their drug product (DP), while additionally modifying its manufacturing process so that a tech transfer was not feasible. Secondly, drug product stability issues were being investigated. Thirdly, relationships with multiple drug substance (DS), critical component, and DP manufacturers were broken. Lastly, several lots of DP had failed to meet acceptance criteria and were therefore unusable to resupply the clinical inventory. The loss of these DP lots compounded the already tense relationship between leadership and the CMC/MSAT groups and brought the client perilously close to reaching the end of product shelf life and product availability for the current inventory. With only a few months of clinical supply remaining, and a 3-4 month manufacturing process timeline, the client reached out to DHC for help with CMC issues, repair of their CDMO relationships, and ultimately clinical resupply.
DHC sped-up and improved the client’s manufacturing process, generating material suitable for drug product manufacture to successfully release clinical GMP drug product with little to no impact on the clinical supply. This allowed patients currently enrolled to continue with treatment as well as the enrollment of additional subjects. DHC also established a manufacturing forecast to ensure that future clinical supply would continue to be met; additionally, DHC identified, prioritized, and implemented further manufacturing improvements and analytical strategy for support as the client transitions to later stage clinical trials.
DHC accepted the challenge and provided interim leadership, overseeing CMC, clinical manufacturing, and CDMO activities throughout resolution of the crisis. This allowed the client to fill critical personnel gaps in addition to giving DHC the opportunity to have an immediate direct impact on remediating the problems.
Bringing in CMC leadership, technical expertise, and project management SMEs, DHC led the implementation of an improved and scaled-up LNP process at the new CDMO, addressed stability issues, and put plans in place to better monitor drug supply chain in future. In parallel, DHC began the delicate journey of repairing relationships with the CDMOs through leadership changes, technical expertise, and by implementing project management best practices to track and address issues, improve communication, drive accountability, and establish a more consistent process for meetings, agendas, and program oversight.
One of the largest challenges DHC faced was a change to the LNP manufacturer along with the implementation of new and scaled-up process. The scale-up involved the implementation of a new, industrial-scale piece of manufacturing equipment. As a technical transfer was not feasible due to the process changes, the DHC team established strategies for qualifying the process as suitable for clinical drug product manufacturing, requiring multiple on-site visits at the CDMO to observe the installation and qualification of the equipment as well as meeting and guiding key staff during the engineering run.
Scale up of the process yielded a number of additional questions (e.g., what is the potential impact on the polydispersity? how has the diameter of the LNP changed?, etc.), all of which culminated in the need to identify the potential impact of these changes to the DP, and to identify the appropriate CQAs for the LNP, DS, and DP.
To further complicate the issue, LNP-based drug products have a unique set of analytical considerations which need to be addressed for characterization and release testing. A common problem is utilizing a test method that doesn’t sufficiently characterize the drug product based on related regulatory guidance. In this instance, DHC worked alongside the client’s analytical leadership to establish appropriate analytical testing panels to support both early-stage and late-stage trials. Leveraging an evolving DP analytical testing strategy early on, and bolstering that strategy throughout clinical trials, provided data to support late phase comparability, bridging, and validation activities that may need to occur as the client approaches commercialization.
The scope of DHC responsibilities and involvement with the client has continued to expand and now additionally includes managing production forecasting, oversight of all CMC manufacturing activities, strategic planning, and authorship/revision of regulatory documents.
