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  1. Warning Letters

WARNING LETTER

Mr. Lulu LLC MARCS-CMS 650772 —

Delivery Method:
VIA EMAIL CONFIRMED DELIVERY
Product:
Drugs
Recipient:
Recipient Name
Mr. Roi Chairat
Recipient Title
Owner
Mr. Lulu LLC

815 West 10th Street
Claremont, CA 91711-3617
United States

Issuing Office:
Division of Pharmaceutical Quality Operations IV

United States

WARNING LETTER

June 1, 2023

Dear Mr. Chairat:

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Mr. Lulu, LLC, FEI 3021858471, at 815 West 10th Street, Claremont, from November 30 to December 9, 2022.

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 13, 2022, response to our Form FDA 483 in detail. 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 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 (21 CFR 211.165(a)).

You failed to perform adequate release testing for each batch of your drug product prior to distribution. Your firm released multiple batches of over the counter (OTC) Mr. Lulu Sunscreen Drops SPF32 to the U.S. market without adequate testing of zinc oxide and titanium dioxide content, the active ingredients in your finished drug products.

You stated that your firm does not perform assay testing on OTC finished drug products prior to release. You evaluate your drug products for scent, appearance, and texture before you release a batch for distribution. Additionally, these testing results are not documented and there are no written procedures for the review and release of finished drug products.

Drug product batches must be tested for identity, strength, quality, and purity prior to release. Testing is an essential part of ensuring the drug products that you manufacture conform to all predetermined quality attributes, including microbiological specifications and are appropriate for their intended use. Without adequate testing, you lack basic data to support that each drug product batch conforms to appropriate specifications before release and distribution.

Your response is inadequate.

In response to this letter, provide the following:

  • A comprehensive assessment of your laboratory practices, procedures, methods, equipment, documentation, and analyst competencies. Based on this review, provide a detailed plan to remediate and evaluate the effectiveness of your laboratory system.
  • A list of chemical and microbial specifications, including test methods, used to analyze each batch of your drug products before a batch disposition decision.

    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.

2. Your firm failed to conduct at least one test to verify the identity of each component of a drug product. Your firm also failed to validate and establish the reliability of your component supplier’s test analyses at appropriate intervals (21 CFR 211.84(d)(1) and (2)).

You failed to adequately test your incoming components for identity before using them to manufacture your drug products. Identity testing for each component lot used in drug product manufacturing is required, and you may only rely on certificates of analysis (COA) for other component attributes by validating the suppliers’ test results at appropriate intervals. You could not provide a written procedure for your supplier qualification process. You described your process as simply selecting manufacturers within the United States and speculated these firms may be audited, following regulations, and ensuring raw material quality.

Additionally, you used food-grade titanium dioxide to manufacture Mr. Lulu Sunscreen Drops SPF32. You did not ensure that the titanium dioxide, you used as a drug component conforms to United States Pharmacopeia (USP) specifications, as required under section 501(b) of the act.

Your response is inadequate.

In response to this letter, provide the following:

  • 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.
  • The chemical and microbiological quality control specifications you use to test and release each incoming lot of components for use in manufacturing.
  • A description of how you will test each component lot for conformity with all appropriate specifications for identity, strength, quality, and purity. If you intend to accept any results from your supplier’s COA instead of testing each component lot for strength, quality, and purity, specify how you will robustly establish the reliability of your supplier’s results through initial validation as well as periodic revalidation. In addition, include a commitment to always conduct at least one specific identity test for each incoming component lot.
  • A summary of results obtained from testing all components to evaluate the reliability of the COA from each component manufacturer. Include your standard operating procedure (SOP) that describes this COA validation program.
  • A summary of your program for qualifying and overseeing contract facilities that test the drug products you manufacture.

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. Your firm also failed to prepare batch production and control records with complete information relating to the production and control of each batch of drug product produced (21 CFR 211.100 (a) and 21 CFR 211.188)

Process Validation

You failed to validate your manufacturing processes for your OTC drug products and failed to provide assurance that you are capable of consistently manufacturing a drug product with defined quality attributes.

Your firm lacks a process validation program and data to support fundamental process parameters such as mixing speed, time, and temperature. Process validation evaluates the soundness of design and state of control of a process throughout its lifecycle. Each significant stage of a manufacturing process must be designed appropriately to assure the quality of raw material inputs, in-process materials, and finished drugs. Process qualification studies determine whether an initial state of control has been established.

Successful process qualification studies are necessary before commercial distribution. Thereafter, ongoing vigilant oversight of process performance and product quality is necessary to ensure you maintain a stable manufacturing operation throughout the product lifecycle.

See the FDA's guidance for industry, 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.

Equipment Qualification and Cleaning Validation

You did not perform equipment qualification or cleaning validation of your drug product manufacturing equipment.

For example, you used a (b)(4) mixer to manufacture Mr. Lulu Sunscreen Drops SPF32. You acknowledged that your mixer is also used for your personal use in your kitchen. You have not established evidence that this equipment functions and operates as expected or that your cleaning processes for this equipment prevents product contamination.

Batch Production Records

Your firm manufactured and released the drug product, Mr. Lulu Sunscreen Drops SPF32 in March 2022, and November 2022. However, your firm lacked executed batch records for each batch of Mr. Lulu Sunscreen Drops SPF32. This documentation is necessary to establish that manufacturing processes are consistently followed and are reproducible.

Your response is inadequate.

In response to this letter, provide the following:

  • 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 (PPQ), and ongoing monitoring of both intra-batch and inter-batch variation to ensure a continuing state of control.
  • A timeline for performing appropriate PPQ for each of your marketed drug products.
  • Include your process performance protocol(s), and written procedures for qualification of equipment and facilities.
  • Provide a detailed program for designing, validating, maintaining, controlling and monitoring each of your manufacturing processes that includes vigilant monitoring of intra-batch and inter-batch variation to ensure an ongoing state of control. Also, include your program for qualification of your equipment and facility.
  • Your master production and control records for your drug products, to demonstrate that they fully document each significant and validated manufacturing step.
  • Procedures you have implemented to ensure production records are completed as required and reviewed by your quality unit (QU) before release of products for distribution.
  • 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.

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 lacks a QU and approved written procedures defining QU responsibilities and controls. You failed to establish procedures describing critical oversight responsibilities including, but not limited to, deviations and investigations, complaint handling, and recalls. You also lack a stability program and stability data.

In addition, your finished drug products lack traceability because you did not issue batch numbers for any finished dosage units of Mr. Lulu Sunscreen Drops SPF32.

An adequate QU overseeing all manufacturing operations is necessary to consistently ensure drug quality. Your firm’s quality systems are inadequate. See the FDA’s guidance document Quality Systems Approach to Pharmaceutical CGMP Regulations for help in 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

Your response is inadequate.

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.

Quality Systems

Your firm’s quality systems are inadequate. See the 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.

CGMP Consultant 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.

Drug Production Ceased

We acknowledge your commitment to cease production of drugs at this facility. In response to this letter, clarify whether you intend to resume manufacturing any drugs at this facility in the future. If you plan to resume manufacturing drugs for the U.S. market, notify this office before resuming your operations.

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.

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 send your electronic reply to ORAPHARM4_Responses@FDA.HHS.GOV or mail your reply to:

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

Please identify your responses with the unique identifier: CMS 650772.

If there are any questions about the released information, please contact Yumi Hiramine, compliance officer, at Yumi.Hiramine@fda.hhs.gov or at 818-226-1839.

Sincerely,
/S/

Lance De Souza
Acting Director, Division of Pharmaceutical Quality Operations IV

 
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