1. Your firm failed to maintain the buildings used in the manufacture, processing, packing, or holding of a drug product in a clean and sanitary condition and to keep them free of infestation by rodents, birds, insects, and other vermin. Trash and organic waste matter shall be held and disposed of in a timely and sanitary manner. [21 CFR 211.56(a)].
Specifically, on July 14, 2023, your Quality Assurance team observed a box of food from June 16, 2023, covered in scuttle fly pupae in the mechanical room which houses the air handling units and failed to remove the box of food until July 31, 2023. After this event, scuttle fly larvae were found in ten environmental and personnel monitoring samples collected in the cleanrooms in July 2023. Additionally, on July 26, 2023, in Suite (b)(4) Clean Room (b)(4) (Grade (b)(4)) a living scuttle fly was observed on the tube rack. Adequate control of insect infestation is needed to ensure product quality and safety.
a. Non-viable particulate monitoring is not being conducted during open manufacturing manipulations within the Grade (b)(4) utilized as the aseptic processing area for production of Humanized Anti-claudin 18.2 Autologous CAR T Cells (CT041). Non-viable particulate monitoring is critical for the detection of particulates in the manufacturing area as they pose patient harm for products administered intravenously as microorganisms can travel on particulates to contaminate the product.
b. Viable microbial active air monitoring is not being conducted during open manufacturing manipulations within the Grade (b)(4) utilized as the aseptic processing area for production of your products. Viable microbial active air monitoring is important for the detection of microorganisms in the environment surrounding the product that is exposed to the manufacturing environment.
For example, you have not validated the cleaning process for the (b)(4) used in the production of your products purported to be sterile. Your Senior Vice President of Quality stated that your firm has not conducted a cleaning validation to ascertain that your cleaning process for manufacturing your products can adequately remove contamination from your manufacturing equipment and cleanroom. Cleaning validation is used to establish cleaning conditions effective against the removal of microorganisms commonly found in your manufacturing environment that pose a contamination risk to your sterile products.
Your responses dated December 28, 2023, March 1, 2024, April 15, 2024 and May 23, 2024, are acknowledged. Your cleaning gap assessment, cleaning validation protocol and revisions to SOPs have been reviewed. While you indicate the cleaning program will assess the effective removal of bacteria and fungi from surfaces through a disinfectant efficacy study, you have failed to provide any results from this study. Without this information, it is unclear whether your disinfection process is effective for the removal of microorganisms that may contaminate your product.
4. Your firm failed to establish written procedures for production and process control designed to assure that the drug products you manufacture have the identity, strength, quality, and purity they purport or are represented to possess. [21 CFR 211.100(a)].
For example, there was no procedure for 100% visual inspection of the final drug product to ensure that it is essentially free from visible particulates, which is necessary to ensure quality and purity prior to intravascular administration.
5. Your firm failed to thoroughly investigate any unexplained discrepancy or failure of a batch or any of its components to meet any of its specifications, whether or not the batch had already been distributed. [21 CFR 211.192].
For example, there were excursions of the action limit associated with microbial monitoring of personnel in the Grade (b)(4) environment where your products are manufactured. During the investigation of these excursions, CAPAs were proposed but never implemented. Since that time, additional excursions for microbial monitoring of personnel action limit within Grade (b)(4) during manufacturing of your products have occurred. Your products have been released following these excursions. Appropriate CAPAs are to be identified and implemented in a timely manner to prevent recurrence of excursions.
It is noted in your response dated April 15, 2024, that "CARsgen RTP site Deviation and CAPA SOPs (NC-SOP-QA-0006, NC-SOP-QA-0007 respectively)" became effective on January 31, 2024. Appropriate control mechanisms have been added to the CAPA SOP to ensure both implementation of CAPAs and verification of effectiveness checks are in place." However, the updated SOPs have not been provided for review to determine suitability of the response in addressing this violation and providing for appropriate corrective action.
The nature of your above-listed violations demonstrates that you have failed to ensure that your firm manufactures drug products that meet established specifications for identity, strength, quality, and purity.
企业上述违规行为的性质表明，企业未能确保所生产的药品符合鉴别、规格、质量和纯度的既定质量标准。
We have reviewed your correspondences dated December 28, 2023, March 1, 2024, April 15, 2024, and May 23, 2024, which respond to the Form FDA-483 and set forth your corrective actions. We acknowledge you have paused manufacturing your products as of December 12, 2023, notified clinics not to administer previously released drug products to patients, and have plans for disposition of products that remain in your control. As noted above in response to specific violations, you have not provided sufficient detail to assess the adequacy of your proposed corrective actions; for all other violations, FDA may need to verify your proposed corrective actions during an inspection of your facility.
