US FDA Documentation and records findings

The batch production and control records are deficient in that they do not include documentation of the accomplishment of each significant step in processing and packing.

The written MDR procedure does not include documentation and recordkeeping requirements for all information that was evaluated to determine if an event was reportable.

Batch production and control records do not include complete information relating to the production and control of each batch.

Your firm failed to determine actual yield and percentages of theoretical yield at the conclusion of each appropriate phase of manufacturing, processing, packaging, or holding of the drug product [21 CFR 211.103]. Specifically, in addition to the deficiencies noted in the visual inspection reject rate calculations, our review of the data collected during the inspection revealed that the acceptable yield range established in your batch records permits yields as low as (b)(4) , allowing up to (b)(4) of a batch to be rejected without triggering an investigation, yet the batch can still be released for distribution. Furthermore, although (b)(4) meets the definition of particulate matter as “mobile undissolved particles, other than air bubbles, unintentionally present in solutions” in SOP-061 (Visual Inspection Finished Product, Rev. 23), it was classified as a “minor” defect in ISSUE-2025-0011, without scientific justification or a clear procedural basis in SOP-061. By classifying (b)(4) as a minor defect rather than as particulate matter, (b)(4) rejects are counted only as part of the minor reject rate limit, bypassing both the major defect category trigger and the separate particulate category trigger entirely. Additionally, certain “cosmetic” defects are allowed to be returned to the batch, despite SOP-061 containing no definition, criteria, or examples of what constitutes a “cosmetic” defect, nor does it specify which cosmetic defect may be returned to the batch and which must be rejected.

Batch production and control records do not include in-process results for each batch of drug product produced.

Your firm failed to establish adequate written responsibilities and procedures applicable to the quality control unit (21 CFR 211.22(d)). Your QU did not provide adequate oversight for the manufacture of your drug products. For example, your QU failed to ensure: Documentation of all interventions during filling of sterile drug products. Our investigators observed multiple batch records in which operators failed to document most aseptic interventions. For example, the batch record for (b)(4) injection (b)(4) mg/ (b)(4) ml, on February 6, 2026, documented that 12 interventions had occurred during filling. However, records indicated approximately 200 interventions were conducted. Notably, critical interventions, including but not limited to removing vials from the filling zone and removing fallen vials from (b)(4) , were not documented. (21 CFR 211.188) Performance of adequate disinfectant efficacy studies. You failed to adequately evaluate your environmental isolates for inclusion in your disinfectant efficacy studies. Studies failed to adequately represent the full spectrum of microbes in your facility. (21 CFR 211.42(c)(10)(v)) Reproducible manufacturing processes in the production of sterile (b)(4) drug products. You did not perform a process validation study after implementing a new production step nor provide stability data within your response. (21 CFR 211.100(a)). In your response, you state you will ensure the QU has a role in verifying intervention documentation in batch records and establish a procedure to periodically evaluate disinfectant efficacy. Your response is inadequate because you fail to provide sufficient details on how interventions in your aseptic process simulations will be captured, simulated, and verified. You also do not describe the QU's oversight of the disinfection practices or identify the environmental isolates to be challenged in the disinfection efficacy studies. Complete and accurate batch production and control records are necessary to ensure that manufacturing processes are consistently followed and are reproducible. Additionally, incomplete manufacturing records fundamentally compromise your ability to reliably conduct batch record review, to adequately investigate deviations and batch failures, and to ensure a continued state of control. Your firm’s quality systems are inadequate. You may refer to FDA’s guidance document Quality Systems Approach to Pharmaceutical CGMP Regulations for help implementing quality systems and risk management approaches to meet the requirements of CGMP regulations 21 CFR, parts 210 and 211 at https://www.fda.gov/media/71023/download. In response to this letter, provide: A comprehensive assessment and remediation plan to ensure your QU is given the authority and resources to effectively function. The assessment should also include, but not be limited to: o A determination of whether procedures used by your firm are robust and appropriate o Provisions for QU oversight throughout your operations to evaluate adherence to appropriate practices o A complete and final review of each batch and its related information before the QU disposition decision o Oversight and approval of investigations and discharging of all other QU duties to ensure identity, strength, quality, and purity of all products A CAPA plan, based on the retrospective assessment of your disinfection program, that includes appropriate remediations to your disinfection processes and practices, and timelines for completion. Include the following as part of the assessment and CAPA plan: o a detailed summary of vulnerabilities in your process for lifecycle management of equipment disinfection o a list of improvements, with an explanation how each will enhance disinfection effectiveness o improved ongoing verification of proper disinfection execution for all products and equipment o and, any other needed remediations. A detailed summary of your validation program for ensuring a state of control throughout the product lifecycle, along with associated procedures. Describe your program for process performance qualification, and ongoing vigilant monitoring of both intra-batch and inter-batch variation to ensure a continuing state of control. Also, describe your equipment and facility qualification program. A timeline for performing appropriate process performance qualification for each of your marketed drug products. Also provide a risk assessment and any follow up actions to be taken for the distributed drug products produced prior to performing any process validation studies. A comprehensive review of your complaints received for (b)(4) injection, including a retrospective review of all complaints for the last three years from the initial date of the inspection, with an assessment that includes but is not limited to evaluating and comparing the (b)(4) complaints received before and after the (b)(4) step. Appropriate improvements to your cleaning validation program, with special emphasis on incorporating conditions identified as worst-case in your drug manufacturing operation. This should include but not be limited to identification and evaluation of all worst-case: o drugs with higher toxicities o drugs with higher drug potencies o drugs of lower solubility in their cleaning solvents o drugs with characteristics that make their manufacturing equipment difficult to clean o swabbing locations for areas that are most difficult to clean o maximum hold times before cleaning A description of the steps that must be taken in your change management system before introduction of new manufacturing equipment or a new product. A summary of updated SOPs that ensure an appropriate program is in place for verification and validation of cleaning procedures for products, processes, and equipment.