Genlabs Corporation MARCS-CMS 625479 — May 12, 2022

WARNING LETTER

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• Delivery Method: VIA Electronic Mail
• Product: Drugs

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• Recipient: Joyce A. Nicola; CEO; Genlabs Corporation; 5568 Schaefer Ave.; Chino, CA 91710-9041; United States; jnicola@genlabscorp.com

• Issuing Office: Division of Pharmaceutical Quality Operations IV ; United States

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WARNING LETTER

May 12, 2022

Dear Ms. Nicola:

The U.S. Food and Drug Administration inspected your drug manufacturing facility, Genlabs Corporation, FEI 1000125638, at 5568 Schaefer Ave., Chino, from November 29 to December 1, 2021, and on December 9, 2021.

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, FIRST STREET Dishwashing Concentrate & Antimicrobial Hand Soap drug product is misbranded under section 502(c) of the FD&C Act, 21 U.S.C. 352(c). Introduction or delivery for introduction of such a product into interstate commerce is prohibited under section 301(a) of the FD&C Act, 21 U.S.C. 331(a). This violation is described in more detail below.

We reviewed your December 16, 2021 response to our Form FDA 483 in detail and acknowledge receipt of your subsequent correspondence. Your response is inadequate because it did not provide sufficient detail or evidence of corrective actions to bring your operations into compliance with CGMP.

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

1. Your firm failed to establish and follow adequate written procedures for cleaning and maintenance of equipment (21 CFR 211.67(b)).

You manufacture several over-the-counter (OTC) drug products, including Genlabs Strike Bac Antibacterial Hand Soap, under your own label, and First Street Antimicrobial Liquid Hand Soap, for your customer, (b)(4). You manufacture these drug products using the same equipment that you use to manufacture numerous non-pharmaceutical industrial products (e.g., (b)(4) brand Squeegee Off window cleaner and (b)(4) brand Ultimate Quik Wax). You lack an adequate cleaning procedure to ensure that your drug products are not cross-contaminated with your non-pharmaceutical products. This is a repeat observation from your 2017 inspection.

The Safety Data Sheet for the (b)(4) brand Squeegee Off window cleaner lists the product as “acute (immediate) health hazard”, “maybe harmful if swallowed” and “causes eye irritation”. Additionally, the ingredients in (b)(4) brand Ultimate Quik Wax are difficult to remove from manufacturing equipment and could contaminate the drug products you manufacture on this shared equipment.

It is unacceptable as a matter of CGMP to continue manufacturing drugs using the same equipment that you use to manufacture hazardous industrial-grade cleaning products or other non-pharmaceutical products due to the risk of cross-contamination.

In your response, you stated that you will create a procedure for maintaining and cleaning of laboratory equipment and you will perform cleaning validation of your shared equipment.

Your response is inadequate because you did not assess the risk of potential cross-contamination and its effect on product quality for batches of drug product manufactured on this shared equipment.

In response to this letter, provide the following:

• A risk assessment for all drugs you have previously produced on equipment shared with industrial products. For each product, assess the risk of potential contamination due to the shared equipment, and provide your plans for addressing the product quality and patient safety risks for any product still in distribution, including potential recalls or market withdrawals.

• Your plans regarding the manufacture of both pharmaceutical and nonpharmaceutical products at your facility. If you intend to continue to manufacture both pharmaceutical and non-pharmaceutical products at your facility, provide your plan to separate the areas in which you will maintain dedicated manufacturing equipment for your pharmaceutical manufacturing and industrial product manufacturing operations.

• 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 them difficult to clean
  o swabbing locations for areas that are most difficult to clean
  o maximum hold times before cleaning

In addition, describe 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.

2. Your firm failed to have, for each batch of drug product, appropriate laboratory determination of satisfactory conformance to final specifications for the drug product, including the identity and strength of each active ingredient, prior to release, and for each batch of drug product required to be free of objectionable microorganisms, appropriate laboratory testing, as necessary (21 CFR 211.165(a) and (b)). And your firm failed to establish the accuracy, sensitivity, specificity, and reproducibility of its test methods (21 CFR 211.165(e)).

Release of drug product prior to determination that products met assay specifications

Your firm released and distributed the OTC finished drug product, antibacterial hand soap (b)(4) lot#1135 without adequate final product testing prior to release. You released the finished drug product on April 6, 2020, and shipped it to the customer on April 8, 2020. However, you did not receive the microbiological analysis result until April 18, 2020, and the assay result for the active ingredient, PCMX (chloroxylenol) until May 7, 2020. This is a repeat observation from your 2017 inspection.

Inadequate Method Validation

Your firm lacked appropriate validation or verification (for United States Pharmacopeia (USP) compendial methods) of your analytical test methods used to determine acceptability of your drug product before release for distribution.

Your firm uses (b)(4) as one of your release testing criteria for Iris Antimicrobial Hand Soap lot #2236. You failed to provide documentation to show that your testing method used for determining the (b)(4) acceptance criteria range is supported by validation studies to ensure it is suitable for intended use.

Analytical methods must be validated to show they are suitable for their intended use, and equivalent or better than applicable USP compendial methods. Verifying the accuracy, sensitivity, specificity, and reproducibility of your test methods is essential to determine if the drug products you manufacture meet established specifications for chemical and microbial attributes.

In your response, you stated that the above example is from older batches, and you are currently receiving all finished product assay results prior to distribution. You will update the (b)(4) test procedure and validate the test methods used in the release of drug products and acceptance criteria will be justified based on the validation.

Your response is inadequate because you did not address your failure to perform adequate release testing on your finished drug products. You also did not provide sufficient information regarding the validation or verification of your test methods for identity and strength of Chloroxylenol.

In response to this letter, provide the following:

• A list of chemical and microbial specifications, including test methods, used to analyze each batch of your drug products before batch disposition decisions.
  o An action plan and timelines for conducting full chemical and microbiological testing of retain samples to determine the quality of all batches of drug product distributed to the United States that are within expiry as of the date of this letter.
  o A summary of all results obtained from testing retain samples from each batch. If such testing reveals substandard quality drug products, take rapid corrective actions, such as notifying customers and product recalls.

• A comprehensive independent third-party assessment of your laboratory practices, procedures, methods, equipment, documentation, and analyst competencies. This assessment should include, but not be limited to, a review of method suitability criteria, and validation (or verification, for USP compendial methods) to determine whether they are fit for their intended use. Based on this review, provide a detailed plan to remediate and evaluate the effectiveness of your laboratory system.

3. Your firm failed to establish adequate 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)).

The water used to manufacture your drug products and clean your equipment comes from a system that you have not validated. You lack assurance that your water system consistently produces water suitable for pharmaceutical use that conforms to the USP monograph for (b)(4) water with appropriate microbial standards. This is a repeat observation from your 2017 inspection.

Additionally, you failed to provide data to demonstrate that the manufacturing processes for your OTC drug products have been validated. During the inspection you were unable to provide the bulk hold time studies for your antimicrobial hand soap product code 8981 that may be held at the in-process stage for up to (b)(4). You stated that you did not know if a study existed, but the process has been in place for a long time and no discrepancies have been experienced.

See the FDA’s guidance document Process Validation: General Principles and Practices for general principles and approaches that the FDA considers appropriate elements of process validation at https://www.fda.gov/media/71021/download.

In your response, you stated that your water system validation is in progress, and you will perform validation to show (b)(4) Water, USP is produced. As part of your validation plan, include testing for Burkholderia cepacia complex (BCC). BCC poses a risk of contamination in non-sterile, water-based drug products. For further information regarding the significance of BCC contamination in drug products, see the FDA’s July 7, 2021, advisory, as the FDA advises drug manufacturers that Burkholderia cepacia complex poses a contamination risk in non-sterile, water-based drug products.

Your response is inadequate because you failed to provide a comprehensive plan for ongoing control and maintenance of your water system. You failed to address why it was not adequately designed and validated. Additionally, your response lacked preventive actions in place to ensure more vigilant and timely operational oversight. Also, you did not describe any interim actions that your firm will take to ensure that the water used in the manufacture of your drug products meets its action limits.

In response to this letter, provide the following:

• A comprehensive remediation plan for the design, control, and maintenance of the water system.
  o A (b)(4) water system validation report. Also, include the summary of any improvements made to system design and to the program for ongoing control and maintenance.

• The current action/alert limits for total counts and objectionable organisms used for your (b)(4) Water system. Also, include the formulas (ingredients; percent composition) for each drug product, and state whether you will be testing batches for BCC as part of release testing. Release testing specifications should be developed based, in part, on your formulation and validated manufacturing steps to ensure your aqueous drug products are free from BCC.

• A detailed risk assessment addressing the potential effects of any observed water system failures on the quality of all drug product lots currently in U.S. distribution or within expiry. Specify actions that you will take in response to the risk assessment, such as customer notifications and product recalls. A procedure for your water system monitoring that specifies routine microbial and chemical testing of water to ensure its acceptability for use in each batch of drug products produced by your firm.

• A procedure governing your program for ongoing control, maintenance, and monitoring that ensures the system consistently produces water that meets (b)(4) Water, USP monograph specifications and appropriate microbial limits.

• 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 monitoring of both intra-batch and inter-batch variation to ensure a continuing state of control.

• A timeline for performing process performance qualification for each of your marketed drug products and completion of the validation of your water system. Include any interim measures or additional controls put in place prior to the completion of your validation activities.

4. Your firm’s quality control 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 firm lacked an adequate quality unit (QU). For example, your QU failed to establish procedures describing QU roles, responsibilities, and authorities. Also, your QU’s oversight of your drug manufacturing operations were inadequate. For example, your QU failed to:

• Approve or reject and review specifications impacting identity, strength, quality, and purity.
• Establish a change control program.
• Develop label issuance and reconciliation procedures for finished drug product.
• Perform annual product reviews.

Additionally, your firm does not have a program for qualifying suppliers, nor do you have a description of CGMP roles and responsibilities with any of your customers or suppliers.

Also, you lack an adequate stability program. The inspection found that no stability testing has been conducted since December 18, 2013.

In your response, you committed to update the procedures with clear responsibilities assigned and write a procedure for finished drug product labels. Also, you will create and implement a change control procedure and review all drug production records.

Your response is inadequate because you did not address the fundamental failure of the QU to perform its function and identify the root cause(s). Additionally, it lacks a retrospective review and a risk assessment of all products in the market within expiration and any actions taken because of this evaluation.

In response to this letter, provide the following:

• 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.

• A comprehensive assessment and corrective action and preventive action (CAPA) plan to ensure the adequacy of your stability program. Your remediated program should include, but not be limited to:
  o Stability indicating methods.
  o Stability studies for each drug product in its marketed container-closure system before distribution is permitted.
  o An ongoing program in which representative batches of each product are (b)(4) to the program to determine if the shelf-life claim remains valid.
  o Detailed definition of the specific attributes to be tested at each station (timepoint).

• All procedures that describe these and other elements of your remediated stability program.

• A comprehensive review of your material system to determine whether all suppliers of components, containers, and closures, are each qualified and the materials are assigned appropriate expiration or retest dates. The review should also determine whether incoming material controls are adequate to prevent use of unsuitable components, containers, and closures.

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.

Misbranding Violation

FIRST STREET Dishwashing Concentrate & Antimicrobial Hand Soap is a “drug” as defined by section 201(g)(1)(B) of the FD&C Act, 21 U.S.C. 321(g)(1)(B), because it is intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease, and/or under section 201(g)(1)(C) of the FD&C Act, 21 U.S.C. 321(g)(1)(C), because it is intended to affect the structure or any function of the body. Specifically, FIRST STREET Dishwashing Concentrate & Antimicrobial Hand Soap is intended for use as a consumer topical antiseptic.

Examples of claims observed on the FIRST STREET Dishwashing Concentrate & Antimicrobial Hand Soap product label and labeling that provide evidence of the intended use (as defined in 21 CFR 201.128) of the product include, but may not be limited to, the following:

“Drug Facts . . . Active Ingredient . . . Chloroxylenol 0.3% w/w . . . Purpose . . . Antimicrobial. . . Uses . . . antimicrobial hand soap . . . Directions . . . To Wash Hands ⋅ wet hands · dispense a small amount of soap into the palm of the hand · work up lather · adding water as needed · rinse. . . Other information . . . recommended for use on dishes, glassware, pots, metal surfaces, walls, painted woodwork”

FIRST STREET Dishwashing Concentrate & Antimicrobial Hand Soap is misbranded under section 502(c) of the FD&C Act, 21 U.S.C. 352(c), because the product’s Drug Facts panel contains extraneous information that goes beyond the required warnings described in the final rule. Specifically, 21 CFR 201.66(d)(7) states that additional information not described in the content requirements for OTC drug products should not appear in the Drug Facts panel. Specifically, the Uses and Directions sections of your Drug Facts panel contain extraneous statements such as “Uses: Dishwashing . . . Directions: For Dishwashing . . . Other information: recommended for use on dishes, glassware, pots, metal surfaces, walls, painted woodwork.” Accordingly, your product’s Drug Facts panel does not conform with section 502(c) of the FD&C Act, 21 U.S.C. 352(c).

Introduction or delivery for introduction of such product into interstate commerce is prohibited under section 301(a) of the FD&C Act, 21 U.S.C. 331(a).

Repeat Observations at Facility

In a previous inspection, dated July 20 to 21, 2017, the FDA cited similar CGMP observations. You proposed specific remediation for these observations in your response. Repeated failures demonstrate that executive management oversight and control over the manufacture of drugs is inadequate.

CGMP Consult Recommended

Based upon the nature of the violations we identified at your firm, we strongly recommend engaging a consultant qualified as set forth in 21 CFR 211.34 to assist your firm in meeting CGMP requirements. Your use of a consultant does not relieve your firm’s obligation to comply with CGMP. Your firm’s executive management remains responsible for resolving all deficiencies and systemic flaws to ensure ongoing CGMP compliance.

Conclusion

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

Correct any violations promptly. Failure to promptly and adequately address this matter may result in regulatory or legal action without further notice including, without limitation, seizure, and injunction. Unresolved violations may also prevent other Federal agencies from awarding contracts.

Failure to address violations may also cause the FDA to withhold issuance of Export Certificates. The 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.

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.

Please identify your response with the unique identifier: CMS# 625479.

Send your electronic response to ORAPHARM4_Responses@FDA.HHS.GOV with ATTN: CDR Steven E. Porter, Jr. or mail your written response to:

CDR Steven E. Porter, Jr.
Director, Division of Pharmaceutical Quality Operations IV
U.S. Food & Drug Administration
19701 Fairchild Road
Irvine, California 92612-2506

If you have questions regarding this letter, please contact LCDR Rumany Penn, Compliance Officer, at (949) 608-4409, or by email at Rumany.Penn@fda.hhs.gov.

Sincerely,
/S/

CDR Steven E. Porter, Jr.
Director, Division of Pharmaceutical Quality Operations IV