Discussion on chemical, pharmaceutical aspects and biological aspects

During the procedure, a number of issues were highlighted relating to: GMP status of the manufacture of the active substance and of the testing sites of the finished product for the purpose of batch release, the comparability between clinical and commercial material, and the absence of data on finished product manufactured at the commercial site.

These issues were classified as Major Objections (MOs) in order to ensure completion of the data set by the applicant at appropriate time points. Further MOs were raised regarding the potential presence of visible particles in the mRNA-loaded LNP intermediate and final product and regarding the proposed RNA purity at release and at the end of shelf life. EU GMP certificates for the manufacturing and testing sites were subsequently obtained. This MO was therefore resolved.

Data have been submitted by the applicant during the procedure in relation to the Major Objections, while a number of specific obligations (SOs) are identified as necessary in order to complete the quality documentation. Further information is provided below on the resolution of the major objections and the rational for accepting a number of open issues to be addressed as specific obligations post-marketing.

Several other issues are further highlighted as Recommendations to be addressed by the applicant post-approval.

The CTD Module 3 dossier structure currently describes the mRNA, the lipid excipients and the lipid nanoparticles in 3.2.S. During the procedure, the BWP confirmed that the mRNA (referred to by the applicant as CX-024414) should be considered as the active substance as per Directive 2001/83/EC and this was accepted by the applicant. Although the current dossier structure would require

adjustment to meet EU CTD requirements, there are no associated risks for GMP or product quality at the time of authorisation. In order to bring the current dossier structure in line with EU CTD

requirements the company should update the Module 3 CTD structure in line with the agreed active substance and finished product definitions (REC 1.1).

In addition, it should be ensured that, in accordance with Annex I of Directive 2001/83/EC and Article 16 of Regulation (EC) No 726/2004, the active substance and finished product are manufactured and controlled by means of processes and methods in compliance with the latest state of scientific and technical progress. As a consequence, the manufacturing processes and controls (including the

specifications) shall be designed to ensure product consistency and a product quality of at least shown to be safe and efficacious in clinical trials and shall introduce any subsequent changes to their

manufacturing process and controls as needed.

Active substance

The major part of the dossier is of acceptable quality. However, certain information and data

requirements remain to be provided, due to the very short time frame of product development. These data will be submitted in the closing sequence or further addressed in specific obligations and other post-approval measures (recommendations). Information on the manufacturing process and process controls for the manufacturing sites Lonza, Visp, and Rovi is provided.

Biological characterisation of the active substance was provided and certain points need to be addressed post-approval. Since these outstanding data form the basis of the determination of

comparability for scale-up and transfer of manufacturing processes for the active substance, additional data are requested as Specific Obligation 1.

Several active substance processes have been used during the development; from personalised vaccine unit to Process Scale A (clinical trial material) and initial Scale B. The major change was from PVU process to the Scale A process, including the addition of two tangential flow filtration unit

operations for the Scale A process. No changes were made to the unit operations or sequence of unit operations from Scale A to initial Scale B processes. Major Objections in relation to insufficient validation data for the active substance manufacturing process (initial scale B) resulted in Specific Obligation 2.

In the initial Rolling Review submission, PPQ data from the Scale A and initial Scale B from the US manufacturing sites was provided. In a second submission data from one batch manufactured at Lonza, Visp included. The data from the EU manufacturing batch showed a good comparability to the PPQ lots from the US sites. The complete PPQ/validation of Lonza, Visp will be provided post-approval via a Specific Obligation 2.

The proposed specification for active substance is acceptable with respect to the attributes chosen for routine release testing in the context of the pandemic situation. However, the active substance specifications acceptance limits should be re-assessed, and revised as appropriate, as further data becomes available from ongoing clinical trials and in line with manufacturing process capability.

Although the stability data were limited, the applicant has demonstrated a good understanding of the mode and rate of degradation. and the data available justify the current shelf life. To supplement the knowledge on stability, further data are requested as Specific Obligation 3.

The proposed initial shelf life for the active substance is 6 months at the recommended storage temperature of -20°C.

Finished product

The finished product is a multi-dose (10-dose) ready-to-use dispersion for intramuscular injection of mRNA embedded in lipid nanoparticles (LNP).

The formulation development studies of the mRNA containing lipid nanoparticles have been sufficiently described.

The development of the manufacturing process is sufficiently described, and critical process parameters are defined.

The manufacturing process includes lipid nanoparticle fabrication followed by fill and finish (at Rovi).

The processes have been acceptably described.

Comparability between the commercial finished product and the clinical finished product has been sufficiently demonstrated for a CMA for the attributes tested. Limited data on the intermediate and finished product batches manufactured at the commercial facility Lonza, Visp and Rovi (EU market) were presented, since so far only one PPQ batch of the intermediates and the final product has been produced.

Although initial information has been provided to support comparability of LNP intermediate, the applicant should provide comparability results including extended characterisation data using the full panel of characterisation methods from all PPQ batches manufactured by Lonza AG, CH demonstrating that the commercial product manufactured at the Lonza, Visp site is representative of the material used in the clinical trials. (Specific Obligation2).

For the finished product, results are available for one scale B lot manufactured at the finished product manufacturing site for the EU market (Rovi, Spain) therefore, although there is sufficient comparability information to justify approval in this pandemic, no final conclusion can be drawn with regard to Scale A to Scale B comparability. The final validation report including an assessment of comparability is therefore requested in a specific obligation (Specific Obligation 2).

Process validation (PPQ) for commercial scale batches were initiated, and a summary report from one PPQ validation batch was provided. The reported results were comparable to the PPQ batches from the US sites. Further data was requested in order to conclude on the consistency of finished product manufacturing, to assure comparability between the commercial product with the product produced at the US sites that was also used in clinical trials, and to support the claimed finished product shelf-life and storage conditions. A process validation plan for PPQ lots has been provided. A concurrent validation approach will be used due to the urgent need for this product and the pandemic situation.

The rationale for this approach has been documented.

An overall PPQ report, which also includes comparability data, will be submitted when data from three consecutive batches manufactured at Lonza, Visp and Rovi will be available. In summary, an

acceptable validation program has been established and an interim report from one PPQ validation batch was provided, therefore the information on process validation is considered acceptable subject to a specific obligation for submission of the remaining data (Specific Obligation 2).

The specification document for finished product includes a comprehensive panel of relevant tests along with corresponding acceptance criteria. Several issues in relation to the acceptance criteria in the finished product specifications were raised in the 1^st Quality data submission, i.e. the LNP size, polydispersity, RNA encapsulation, in-vitro expression. In addition, open questions regarding the regarding the clinical justification of the proposed minimum acceptable RNA purity were discussed in

an oral explanation. during the evaluation. Whilst finished product specifications were subsequently amended and overall found to be acceptable, the acceptance limits should be re-assessed, and revised as appropriate, as further data becomes available (Specific Obligation 3). In addition, the applicant should provide an updated appearance testing description for LNP and finished product including the characterisation test of potentially occurring visible particles since these have not been clinically qualified (Specific Obligation 2).

The proposed initial shelf life for the finished product of shelf life of 7 months at -20°C including a period of 30 days at 2°C - 8°C is found acceptable, but should be confirmed by further stability data from lots manufactured at the Rovi site (Specific Obligation 3).

The applicant is performing a dye ingress test for cCCI verification during the stability, in lieu of sterility testing. The applicant has committed to provide a description of this CCI test and its validation (Specific Obligation 2).

Two novel excipients are included in the LNP. Limited information is provided for both the lipid SM-102 and the PEGylated lipid PEG200-DMG. Although this is sufficiently supportive for conditional marketing authorisation, in order to assure comprehensive control throughout the lifecycle of the finished product and to ensure batch-to-batch consistency, further information needs to be submitted regarding the synthetic process and control strategy in line with raised recommendations (Specific Obligation 1).