---

---

---

Warning Letter 320-25-95

July 18, 2025

Dear Mr. Yi:

The United States Food and Drug Administration (FDA) inspected your drug manufacturing facility, Janssen Vaccines Corp., A Johnson & Johnson Company (Janssen), FEI 3012637764, at 23, Harmony-ro 303beon-gil, Yeonsu-gu, Incheon, from November 11 to 19, 2024.

This warning letter summarizes significant violations of Current Good Manufacturing Practice (CGMP) regulations for finished pharmaceuticals. See Title 21 Code of Federal Regulations (CFR), parts 210 and 211 (21 CFR parts 210 and 211).

Because your methods, facilities, or controls for manufacturing, processing, packing, or holding do not conform to CGMP, your drug product is adulterated within the meaning of section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), 21 U.S.C. 351(a)(2)(B).

We reviewed your December 10, 2024, response to our Form FDA 483 in detail and acknowledge receipt of your subsequent correspondence.

During our inspection, our investigator observed specific violations including, but not limited to, the following.

1. 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 has already been distributed (21 CFR 211.192).

You failed to conduct adequate investigations of recurring complaints received between November 13, 2023, and November 8, 2024, for (b)(4) stopper (b)(4) associated with (b)(4) injection, (b)(4) mg/(b)(4) mL. Several complaints included reports of stopper (b)(4) events associated with two or more vials, including one complaint that reported stopper (b)(4) in four vials from the same batch.

Your investigations, which included review of batch records, did not identify any “… relevant issue recorded which might have impacted the product quality and could lead to the investigated defect…,” and you add that “The manufacturing process is in a validated state of control and is capable to consistently meet specifications.”

However, the investigations did not include a comprehensive assessment of human use, manufacturing, and stability factors that could increase the risk of stopper (b)(4) during use. In addition, you did not always sufficiently pursue collection of relevant samples of vials from complainants.

In response to the stopper (b)(4) reports, you submitted a (b)(4) that included language instructing (b)(4) to “… (b)(4)…”

Your firm had performed an assessment that identified several human use factors that may contribute to stopper (b)(4), including (b)(4). The assessment concluded “… (b)(4).”

The (b)(4) revisions also included instructions to (b)(4).”

Your response is inadequate. You did not adequately investigate other human use factors, such as the effect of (b)(4). You also lacked investigation of the potential effects of manufacturing factors including your stopper processing methods (e.g., assembly steps for the container-closure system).

We acknowledge that your firm indicates plans to undertake further risk assessment activities.

Revised (b)(4) cannot substitute for ensuring drugs products meet all required quality attributes and remain suitable for their intended use through their labeled expiry.

In response to this letter, provide:

• A comprehensive assessment of your overall system for investigating deviations, discrepancies, and complaints. Provide a detailed action plan to remediate this system. Your action plan should include, but not be limited to, significant improvements in investigation competencies, scope determination, root cause evaluation, corrective action, and preventive action (CAPA) effectiveness, quality unit (QU) oversight, and written procedures including those associated with identifying the existence of, obtaining, and evaluating relevant samples. Address how your firm will ensure all phases of investigations are appropriately conducted.
• Provide your detailed plan to further assess the repeated reports of stopper (b)(4) associated with (b)(4). The plan should explain how you will assess (b)(4) over the labeled expiry period and include, but not be limited to, the following:
  o An analysis of the comparative effect(s) of the stopper sterilization processes employed at the Janssen facility and the (b)(4) facility where the drug is manufactured.
  o An analysis of the comparative effect(s) of container closure system assembly processes ((b)(4)), including equipment and operating parameters, employed at the Janssen facility and the (b)(4) facility.
  o An analysis of the relative risk(s) of (b)(4) associated with various human use factors, including the effect of (b)(4).
  o An analysis of any other raw material, processing, or use factors that may contribute to stopper (b)(4).
• A retrospective review of all stopper (b)(4) complaints for the last 3 years and a report summarizing the review’s findings, including for each stopper (b)(4) complaint:
  o Determine whether the scientific justification and evidence relating to the identified root cause(s) of each stopper (b)(4) report were adequately documented.
  o Determine whether relevant complaint samples were available, and if insufficient attempts were made for their return to Janssen for investigation, the root cause(s) for not adequately pursuing their return.
  o For all complaint investigations found by the retrospective review to be deficient, include a thorough review of production (e.g., batch manufacturing records, adequacy of the manufacturing steps, suitability of equipment/facilities, variability of raw materials, process capability, deviation history, complaint history, batch failure history). Provide a summary of potential manufacturing root causes for each investigation and any identified CAPA.
• An independent, comprehensive review of your company’s complaint handling program that identifies any deficiencies and corresponding CAPA.

2. Your firm’s quality unit failed to exercise its responsibility to ensure drug products manufactured are in compliance with CGMP, and meet established specifications for identity, strength, quality, and purity (21 CFR 211.22).

Your quality unit does not consistently follow your procedures for the submission of regulatory notification of product quality defects. For example, your procedure for the preparation of “Advisory Notice” documents, including Biological Product Deviation Reports (BPDRs), includes instructions for your quality unit to “[e]scalate and/or report quality and compliance issues that may require Regulatory Body notification to Segment Management and ensure that quality issue management process is followed for decisions regarding issues that have potential to lead to an Advisory Notice.”

You received two or more stopper (b)(4) complaints for each of (b)(4) batches of (b)(4), between November 13, 2023, and November 8, 2024. Responsible officials did not adequately discharge their duties to ensure escalation and sufficient action on these complaints in accordance with your procedure.

Timely submission of BPDRs to regulatory authorities facilitates awareness and evaluation of potentially hazardous product defects. Notably, your comparable procedure for Field Alert Reports (FARs) requires the submission of a FAR upon receipt of “[t]wo or more complaints with the same confirmed defect… with or without a signal.” Additionally, your procedure “Advisory Notice US FDA Form 3911 (Drug Notification and Health Authority (HA) Communication-Reportable Events Procedure” requires the submission of a BPDR “… as soon as possible, but no more than (b)(4) from the date that information is acquired reasonably suggesting that a reportable incident occurred.”

We acknowledge that your firm ultimately submitted a BPDR for the stopper (b)(4) complaints, dated December 10, 2024, and your subsequent updates of that BDPR. We also acknowledge your commitment to update procedures associated with the submission of BPDRs.

Your response is inadequate. You identified a root cause for failing to submit a BPDR in accordance with your procedures as “…the recurring complaints were not considered reportable under the current procedure… because the definition of confirmed is related only to cases where the product quality is determined not meeting manufacturing standards or specifications.” Although you proposed multiple CAPA to address this root cause and to assess other products in your corporate portfolio for stopper (b)(4) complaints, you did not propose a retrospective review of complaints implicating marketed product quality to identify additional instances in which a BPDR should have been submitted.

In response to this letter, provide:

• A retrospective review of product quality complaints received within the last 3 years for all Janssen products to identify any circumstances in which your firm did not submit a FAR or BPDR, as applicable, when such a report should have been submitted.
• 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

Conclusion

The violations cited in this letter are not intended to be an all-inclusive list of violations that exist at your facility. You are responsible for investigating and determining the causes of any violations and for preventing their recurrence or the occurrence of other violations.

If you are considering an action that is likely to lead to a disruption in the supply of drugs produced at your facility, FDA requests that you contact CDER’s Drug Shortages Staff immediately, at drugshortages@fda.hhs.gov, so that FDA can work with you on the most effective way to bring your operations into compliance with the law. Contacting the Drug Shortages Staff also allows you to meet any obligations you may have to report discontinuances or interruptions in your drug manufacture under 21 U.S.C. 356C(b). This also allows FDA to consider, as soon as possible, what actions, if any, may be needed to avoid shortages and protect the health of patients who depend on your products.

Correct any violations promptly. FDA may withhold approval of new applications or supplements listing your firm as a drug manufacturer until any violations are completely addressed and we confirm your compliance with CGMP. We may re-inspect to verify that you have completed corrective actions to any violations.

Failure to address any violations may also result in the FDA refusing admission of articles manufactured at Janssen Vaccines Corp., A Johnson & Johnson Company, 23, Harmony-ro 303beon-gil, Yeonsu-gu, Incheon, into the United States under section 801(a)(3) of the FD&C Act, 21 U.S.C. 381(a)(3). Articles under this authority that appear to be adulterated may be detained or refused admission, in that the methods and controls used in their manufacture do not appear to conform to CGMP within the meaning of section 501(a)(2)(B) of the FD&C Act, 21 U.S.C. 351(a)(2)(B).

This letter notifies you of our findings and provides you an opportunity to address the above deficiencies. After you receive this letter, respond to this office in writing within 15 working days. Specify what you have done to address any violations and to prevent their recurrence. In response to this letter, you may provide additional information for our consideration as we continue to assess your activities and practices. If you cannot complete corrective actions within 15 working days, state your reasons for delay and your schedule for completion.

Send your electronic reply to CDER-OC-OMQ-Communications@fda.hhs.gov. Identify your response with FEI 3012637764 and ATTN: Jason F. Chancey.

Sincerely,
/S/

Francis Godwin Director
Office of Manufacturing Quality Office of Compliance
Center for Drug Evaluation and Research

Cc: Christopher Milano, Vice President, Supply Chain Quality Johnson & Johnson Innovative Medicines