ModularCMC^® Services

Work Package One begins with the transfer of one or more lead development candidate amino acid sequences for the development of stable CHO pool cell banks. Stable CHO pools serve as precursors for subsequent cell line development activities and enable early material generation, supporting lead Development Candidate selection; process, analytical, and formulation development, and material supply for IND-enabling non-clinical studies (e.g., dose range finding, PK/PD, and non-GLP toxicology studies).

Work Package Two utilizes stable CHO pool cell banks to perform a platform process fit assessment and to generate materials for process, analytical, and formulation development, as well as for non-clinical study material supply. This use of stable CHO pools enables rapid progression through early CMC milestones and can be performed in parallel with single cell cloning, clone selection, and clone validation activities.

Work Package Three utilizes a stable CHO pool cell substrate and partitions individual cells as clonal isolates. The single cell cloning process initiates with deposition of single clonal isolates into a single plate well and expands to sufficient quantities for generation of Development Cell Banks and for production and characterization of production and product quality attributes for selected clones, including growth kinetics, nutrient/metabolite profiles, production titer, purity, charge variation, and post-translational modifications (e.g., N-glycosylation, oxidation, deamidation, and isomerization) Wheeler employs integrated digital workflows and high-throughput analysis to ensure clonality and desired cell line and product quality attributes to serve as cell substrate for generation of a Master Cell Bank.

Work Package Four typically follows the single-cell cloning and clone selection process to generate a cGMP-compliant Master Cell Bank (MCB) intended to support clinical manufacturing activities and the subsequent generation of a Working Cell Bank (WCB). All MCB generation activities are performed in accordance with regulatory guidelines for traceability, consistency, and compliance with ICH Q5D guidance.

Work Package Five interrogates the stability of integrated expression constructs in the developed cell line. Typically performed on a Development or Master Cell Bank substrate, the Cell Line Stability assessment provides robust data for the top-selected clonal isolates in alignment with ICH Q5D guidelines. Cells are traditionally expanded through sixty (60) generations, with test cell banks made at zero (0), thirty (30), and sixty (60) generations. Following the generation of generational cell banks, a high-throughput production study is used to confirm maintenance of productivity as a readout of genetic stability.

Work Package Six provides a de-risked approach to scaling drug substance (DS) production operations by using a representative, scaled-up upstream and downstream process for the production of non-CGMP-compliant material supply. Either a stable CHO pool or a clonally derived cell line substrate can be utilized to generate. several hundred-gram quantities of manufactured drug substance to support non-clinical studies (e.g., GLP-toxicology studies, non-CGMP Drug Product (DP) operations, including stability studies).

Work Package Seven follows the completion of MCB generation and non-cGMP DS process scale-up and involves the generation of cGMP-compliant batch records, the qualification of analytical methods for DS release, and the production of kilogram quantities of DS intended for the generation of cGMP-compliant DP, to be utilized during clinical development studies. In addition, the material generated supports IND-enabling viral clearance studies, generation and characterization of a Reference Standard (RS), and DS/DP stability studies. </br> Quality Assurance issues a Certificate of Compliance (CoC) confirming that the cGMP DS batch was manufactured in accordance with cGMP requirements and approved batch records/SOPs, using qualified equipment, calibrated instruments, and approved materials. The CoC also verifies that all required in-process and release tests were completed with qualified methods, that the batch meets all identity, purity, potency, safety, and quality specifications, and that it has been formally reviewed and approved by authorized Quality personnel.

Work Package Eight provides management and oversight of cGMP-compliant Drug Product (DP) manufacturing activities (aka fill/finish) through a Drug Product (DP) partner. Subsequent DP lot release testing and stability studies are then carried out at Wheeler Bio. Through use of our DP fill/finish partner, Wheeler provides seamless gene to DP release services.

Work Package Nine supports the preparation of an electronic common technical document (eCTD) in support of IND (or equivalent) submission to ICH-aligned regulatory agencies. These services are performed in collaboration with Pharmefex consulting and can range from a standalone Module 3 section, to supporting all Modules. eCTD preparation is performed in parallel with CMC development and manufacturing activities reduce the timeframe to initiation of clinical development studies.