FDA 向 Silgan Dispensing Systems 发出警告信 320-27-04，涉其 Spokane 工厂 CGMP 缺陷

Delivery Method:

VIA ELECTRONIC MAIL READ/DELIVERY RECEIPT REQUESTED

Product:

Drugs
Over-the-Counter Drugs

Recipient:

Recipient Name

Mr. Earl Lawson

Recipient Title

President

Silgan Dispensing Systems

1001 Haxall Point, Suite 701
Richmond, VA 23219
United States

(b)(4)

Issuing Office:

Center for Drug Evaluation and Research (CDER)

United States

October 5, 2026

WARNING LETTER
Reference number: 320-27-04

To Mr. Earl Lawson:

This warning letter advises you of significant violations observed during a U.S. Food and Drug Administration (FDA) inspection of your products, processes, facility and records. Promptly address the violations described herein without delay, including ensuring that appropriate resources are allocated to fully address the violations and prevent their recurrence. This is not intended to be an all-inclusive list of the violations that exist at your facility. It is your responsibility to ensure that your firm complies with all requirements of federal law, including FDA regulations. Failure to adequately address violations may result in legal action without further notice including, without limitation, seizure and injunction.

FDA Inspection and Review

Violations were observed and documented during an inspection of your drug manufacturing facility, Silgan Unicep Packaging, LLC, Facility Establishment Identifier (FEI) 3011913386, at 4122 South Grove Road, Spokane, Washington, from March 26 to April 2, 2026. This inspection was conducted under FDA’s statutory authority and public health responsibilities to protect the public from unsafe, ineffective, and poor quality drugs.

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 products are 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).

In addition, violations were identified and documented during a review of the product labeling, including the product website at the internet address (b)(4) website in July 2026. Based on our review, “(b)(4)” are unapproved new drugs under section 505(a) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), 21 U.S.C. 355(a). As explained further below, introducing or delivering these products for introduction into interstate commerce is prohibited under sections 301(d) and 505(a) of the FD&C Act, 21 U.S.C. 331(d) and 355(a).

We reviewed your April 22, 2026, response to our Form FDA 483 in detail and acknowledge receipt of your subsequent correspondence.

Violations of the Federal Food, Drug, and Cosmetic Act

The following are violations identified during our inspection and review. As a reminder, this is not an all-inclusive list of violations at your facility.

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).

Your firm contract manufactures non-sterile over-the-counter (OTC) (b)(4) drug products, including those labeled for use in (b)(4). You failed to adequately investigate out-of-specification (OOS) microbiological testing results for components used to manufacture your drug products.

For example, in November 2025, you obtained OOS microbiological results for (b)(4) lots (b)(4). You prepared (b)(4) independent samples from each lot. You tested (b)(4) of the samples for total aerobic microbial count and the (b)(4) samples for total yeast and mold count. One sample from each lot exceeded your total yeast and mold count acceptance criterion of no more than (b)(4) colony forming units per gram.

You did not perform an appropriate investigation into the OOS results. Rather, you invalidated the OOS results by averaging the (b)(4) total yeast and mold count sample results to obtain a passing result. You also revised your microbiological sampling plan to allow for averaging of test results for component testing. This practice is not in accordance with the United States Pharmacopeia <61> test method and is unacceptable as it obscures the detection of non-uniform microbiological contamination within a lot. You subsequently released (b)(4) lots and used them in the manufacture of (b)(4) Lot (b)(4), distributed in (b)(4).

Notably, on (b)(4), your customer, (b)(4), initiated a Class I recall of (b)(4) lots of (b)(4) manufactured at your facility due to potential fungal contamination in your (b)(4). The investigation associated with this recall is inadequate. For example, you implemented (b)(4) of incoming (b)(4) prior to filling to reduce bioburden, but subsequent OOS microbiological results obtained from (b)(4) lots demonstrate this corrective action was ineffective. Additionally, your change control associated with the (b)(4) process did not include ensuring appropriate validation of the process as well as evaluation of the (b)(4).

Further, you lacked cleaning procedures for the (b)(4) line, did not conduct cleaning validation of the (b)(4) line, and failed to include yeast and mold microbiological testing as part of your environmental monitoring program. Though your investigation into the potential fungal contamination documented an evaluation of the cleaning procedures and environmental monitoring, it did not identify nor appropriately follow-up on these risks related to potential mold contamination.

In your response to the OOS microbiological test results, you state that you plan to update your work instructions to prohibit averaging of results. You commit to conducting a retrospective review of all drug product OOS events over a (b)(4) period to identify inadequate investigations and initiate customer notifications where warranted. You also commit to engaging a consultant for root cause analysis and failure investigation training, as well as updating the change control with a risk assessment of the (b)(4).

Your response is inadequate. You limit the retrospective review to documented OOS events and do not extend it to all microbiological test results to identify instances in which you inappropriately applied averaging to individual failing results to obtain overall passing results. This practice potentially resulted in the improper release of drug products. Furthermore, your response lacks an adequate plan to address product quality risks. It relies solely on procedural and documentation updates without an effectiveness verification plan and fails to address the systemic quality oversight failures that allowed these practices.

Inadequate investigations can lead to unidentified root causes, ineffective corrective action and preventive action (CAPA), and recurring problems that compromise the ability to manufacture safe and effective drug products. For more information about handling OOS and failing test results, and documentation of your investigations, see FDA’s guidance document Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production at https://www.fda.gov/media/158416/download. While this guidance addresses chemistry laboratory analyses, many of its principles are also relevant to investigating OOS microbiological results and out-of-trend results.

In response to this letter, provide:

• A retrospective, independent review of all invalidated OOS (including in-process and release/stability testing) results for US products currently in the U.S. market and within expiry as of the date of this letter and a report summarizing the findings of the analysis, including the following for each OOS: o Determine whether the scientific justification and evidence relating to the invalidated OOS result conclusively or inconclusively demonstrates causative laboratory error.
  o For investigations that conclusively establish laboratory root cause, provide rationale and ensure that all other laboratory methods vulnerable to the same or similar root cause are identified for remediation.
  o For all OOS results found by the retrospective review to have an inconclusive or no root cause identified in the laboratory, 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 manufacturing operation improvements.
• A comprehensive review and remediation plan for your OOS and out-of-limit (OOL) result investigation systems. The CAPA should include but not be limited to addressing the following:
  o Quality unit (QU) oversight of laboratory investigations
  o Identification of adverse laboratory control trends
  o Resolution of causes of laboratory variation
  o Initiation of thorough investigations of potential manufacturing causes whenever a laboratory cause cannot be conclusively identified
  o Adequate scoping of each investigation and its CAPA
  o Revised OOS investigation procedures with these and other remediations
  o A similar review and remediation of your system for handling out-of-limit findings (i.e., data that falls outside action limits)
• A comprehensive, independent assessment of your overall system for investigating deviations, discrepancies, complaints, OOS results, OOL results, and failures. 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, CAPA effectiveness, quality unit oversight, and written procedures. Address how your firm will ensure all phases of investigations are appropriately conducted.
  o Furthermore, provide your (b)(4) validation study and updated cleaning procedures that demonstrate effectiveness in cleaning mold. Also provide the updated environmental monitoring study (WI-00480 Environmental Monitoring (Microbial) of Manufacturing and Laboratory Facilities Rev. 24) referenced in your response indicating sample locations, frequency, and duration, as well as alert and action limits.
• A comprehensive, independent assessment of the design and control of your firm’s manufacturing operations with a detailed and thorough review of all microbiological hazards.
• A detailed risk assessment addressing the hazards posed by distributing drug products with potentially objectionable contamination. Specify actions you will take in response to the risk assessment, such as customer notifications and product recalls.
• Complete investigations into all batches with potential objectionable microbial contamination or an OOS microbiological result whether or not later invalidated. The investigations should detail your findings regarding the root causes of the contamination.
• A summary of results from testing retain samples of all drug product batches within expiry. You should test microbiological quality (total counts and identification of bioburden to detect any objectionable microbes) of each batch. If testing yields an OOS result, indicate the corrective actions you will take, including notifying customers and initiating recalls.

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 QU failed to adequately oversee your OTC (b)(4) drug product manufacturing operations. For example, your QU failed to:

• Validate and establish the reliability of your component supplier’s test analyses at appropriate intervals (21 CFR 211.84(d)(2)).
• Follow a written testing program designed to assess the stability characteristics of drug products (21 CFR 211.166(a)).
• Maintain written records so that the quality standards of each drug product can be evaluated at least annually to determine the need for changes in drug product specifications, manufacturing, or control procedures (21 CFR 211.180(e)).

In your response, you commit to revising your vendor evaluation and control procedure, updating your stability program master plan, and retrospectively generating stability study reports for all drug products. You also commit to updating your periodic product review procedure and completing retrospective annual product reviews for all manufactured drug products.

Your response is inadequate. You did not provide supporting documentation to verify the adequacy and effectiveness of your corrective actions, nor did you address the systemic quality oversight failure that allowed deficiencies to persist undetected for multiple years, including the absence of stability study reports since 2020 and the failure to complete annual product reviews for (b)(4) of your drug products since 2024.

Significant findings in this letter demonstrate that your firm does not operate an effective quality system in accord with CGMP. In addition to the lack of effective management oversight of your production and laboratory operations, we found your quality unit is not enabled to exercise proper authority and/or has insufficiently implemented its responsibilities. Executive management should immediately and comprehensively assess your company’s global manufacturing operations to ensure that your systems, processes, and products conform to FDA requirements.

Your firm’s quality systems are inadequate. See FDA’s guidance documents ICH Q10 Pharmaceutical Quality System, at https://www.fda.gov/media/71553/download, and Quality Systems Approach to Pharmaceutical CGMP Regulations, at https://www.fda.gov/media/71023/download, for help implementing quality systems and risk management approaches to meet the requirements of CGMP regulations 21 CFR, parts 210 and 211.

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

Also describe how top management supports quality assurance and reliable operations, including but not limited to timely provision of resources to proactively address emerging manufacturing/quality issues and to assure a continuing state of control.

Unapproved New Drug Violations

Based on a review of the product labeling, “(b)(4)” are drugs under section 201(g)(1) of the FD&C Act, 21 U.S.C. 321(g)(1), because they are intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease, and/or intended to affect the structure or any function of the body. Examples from product labeling, including the product website (b)(4), that provide evidence of the intended uses (as defined in 21 CFR 201.128) of these products as a drug include, but may not be limited to, the following:

(b)(4)

Based on the above labeling evidence, (b)(4) intended for use as (b)(4) drug product. As such, these drug products are “new drugs” under section 201(p) of the FD&C Act, 21 U.S.C. 321(p), because they are not generally recognized as safe and effective (GRASE) for use under the conditions prescribed, recommended, or suggested in their labeling. With certain exceptions not applicable here,¹ a new drug may not be introduced or delivered for introduction into interstate commerce without an approved application from FDA in effect, as described in section 505(a) of the FD&C Act, 21 U.S.C. 355(a). No approved applications pursuant to section 505 of the FD&C Act, 21 U.S.C. 355, are in effect for these products. Accordingly, these products are unapproved new drugs. The introduction or delivery for introduction into interstate commerce of these unapproved new drug products violates sections 301(d) and 505(a) of the FD&C Act, 21 U.S.C. 331(d) and 355(a).

Drug Recall

On July 22, 2026, FDA held a teleconference with you, recommending that you recall drug products manufactured with (b)(4) lots (b)(4) currently in distribution from the U.S. market. On (b)(4), your customer, (b)(4), initiated a voluntary recall of (b)(4) lots (b)(4) currently distributed within the U.S. market. The recall was posted to the FDA’s Enforcement Report website at (b)(4)

Drug Production Suspended

We acknowledge your commitment to suspend production of all drugs at this facility.

If you plan to resume any manufacturing operations regulated under the FD&C Act, notify this office before resuming your drug manufacturing operations. If you resume CGMP activities, you are responsible for resolving all deficiencies and systemic
flaws to ensure your firm is capable of ongoing CGMP compliance. In addition, based upon the nature of the violations we identified at your firm, you should engage a consultant qualified as set forth in 21 CFR 211.34 to assist your firm in meeting CGMP requirements. The qualified consultant should also perform a comprehensive six-system audit of your entire operation for CGMP compliance and evaluate the completion and efficacy of all corrective action and preventive action, before you pursue resolution of your firm’s compliance status with FDA.

In your notification to the Agency, provide a summary of your remediations to demonstrate that you have appropriately completed all CAPA.

Conclusion

You are responsible for investigating and determining the root causes of any violations and implementing corrective and preventative measures to ensure future and sustained compliance so that these violations and any others do not occur.

Unresolved violations may prevent other Federal agencies from awarding contracts. Failure to address violations may also cause FDA to withhold issuance of Export Certificates. 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 address any violations.

Send your written response to [email protected] within fifteen (15) business days of receipt of this letter. Identify your written response with FEI 3011913386 and ATTN: Renee A. Marcsisin, Ph.D. in the subject line of the email.

If you have information that you believe demonstrates that your products are not in violation of the FD&C Act and FDA regulations, include that information for our consideration.

FDA posts warning letters to www.FDA.gov.

Sincerely,
/S/

Francis Godwin
Director
Office of Manufacturing Quality
Office of Compliance
Center for Drug Evaluation and Research
U.S. Food and Drug Administration

/S/

Tina Smith, M.S.
Captain, U.S. Public Health Service
Director
Office of Unapproved Drugs & Labeling Compliance
Office of Compliance
Center for Drug Evaluation and Research
U.S. Food and Drug Administration

cc: (b)(4)

__________________________

1 (b)(4)