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  1. Warning Letters

WARNING LETTER

Cosmetic Science Laboratories LLC MARCS-CMS 645558 —


Delivery Method:
Via Email
Product:
Drugs

Recipient:
Recipient Name
Mr. Claudio A. Neustadt
Recipient Title
President/Chemist
Cosmetic Science Laboratories LLC

2908 Oregon Court, Suite I-6
Torrance, CA 90503-2637
United States

Issuing Office:
Division of Pharmaceutical Quality Operations IV

United States


WARNING LETTER

March 10, 2023

Dear Mr. Neustadt:

The U.S. Food and Drug Administration inspected your drug manufacturing facility, Cosmetic Science Laboratories LLC, FEI 3001697625, at 2908 Oregon Court, in Torrance, California, from September 6 to September 20, 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 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, under section 510 of the Food Drug and Cosmetics Act (FD&C Act) and under part 207 of Title 21 of the Code of Federal Regulations (CFR), owners or operators of drug manufacturing establishments are required to register their establishments with the FDA. Registrants are also required to list each drug manufactured at their establishment(s) intended for commercial distribution and to submit updated drug listing information to the FDA twice each year, in June and December, notifying the FDA if this information has changed.

Upon the mentioned inspection, it was determined that your firm has been manufacturing 4-IN-1 Broad Spectrum SPF 50 Sunscreen (NDC 73561-001-01), Daily Protect Sunscreen Moisturizer Broad Spectrum SPF 30 (NDC 73561-100-01), Oil Daily Protect Sunscreen Moisturizer Broad Spectrum SPF 30 (NDC 73561-101-01), and SPF-30 (b)(4). To date, the FDA has not received updated registration submission from Cosmetic Science Laboratories LLC, nor has it received a drug listing submission for the above-mentioned product SPF-30 (b)(4).

We reviewed your October 5, 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 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 211.84(d)(2)).

You failed to test your incoming active pharmaceutical ingredients (APIs) for identity prior to manufacturing your bulk over-the-counter (OTC) drug products, including SPF-50 (b)(4) Sunscreen. Additionally, you relied on certificates of analysis (COAs) from your suppliers to use incoming APIs without establishing the reliability of the specifications and characteristics of each supplier’s COAs.

Your response is inadequate.

Identity testing for each component lot used in drug product manufacturing is required, and you may only rely on certificates of analysis (COAs) for other component attributes by validating the suppliers’ test results at appropriate intervals.

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 component 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 Certificates of Analysis (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 re-validation. 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.

2. 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 CFR211.188).

Process Validation

Your firm did not provide process validation documents for your contract manufactured over-the-counter (OTC) bulk drug products. During the inspection, you failed to provide your protocols, reports, or data to support that each OTC drug product met predetermined quality requirements consistently and reliably.

You also failed to provide detailed process performance qualification (PPQ) protocols for the validation of your different OTC drug product manufacturing processes.

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 and 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 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.

Batch Production Records

Your firm lacked adequate batch records. You did not include specific information such as equipment identification and process parameters that demonstrate control in the manufacture of your bulk drug products.

Cleaning Validation

During the inspection, your firm could not provide investigators with evidence that you have performed cleaning validation and equipment qualification.

You manufacture drug products using the same equipment that you use to manufacture nonpharmaceutical products such as cosmetics. Chemical and microbiological residues on equipment from previous manufacturing activities can adversely impact the purity, quality, and safety of drug products also manufactured on that equipment.

Additionally, you lacked cleaning logs and usage logs for kettles and mixers used in compounding your bulk drug products.

(b)(4) Water System

Your firm uses (b)(4) Water as a component to manufacture your drug products that are released for distribution to U.S. consumers. You did not establish that the (b)(4) Water system you use to manufacture your drug product is adequately designed, controlled, maintained, and monitored to ensure that it consistently produces water suitable for its intended use.

(b)(4) water must be suitable for its intended use and routinely tested to ensure ongoing conformance with appropriate chemical and microbiological attributes.

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, and ongoing monitoring of both intra-batch and inter-batch variation to ensure a continuing state of control.
  • A timeline for performing appropriate process performance qualification (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.
  • A complete assessment of documentation systems used throughout your manufacturing operations, to determine where documentation practices are insufficient. Include a detailed corrective action and preventive action (CAPA) plan that comprehensively remediates your firm’s documentation practices, to ensure you retain attributable, legible, complete, original, accurate, and contemporaneous records throughout your operation.
  • 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

  • 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.
  • A procedure for your water system monitoring that specifies routine microbial testing of water to ensure its acceptability for use in each batch of drug products produced by your firm.
  • The current action/alert limits for total counts and objectionable organisms used for your (b)(4) water system. Ensure that the total count limits for your (b)(4) water are appropriately stringent in view of the intended use of each of the products produced by your firm.
  • A procedure governing your program for ongoing control, maintenance, and monitoring that ensures the remediated system consistently produces water that meets (b)(4) water, USP monograph specifications and appropriate microbial limits.

3. 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 CFR211.22).

Your quality unit (QU) did not provide adequate oversight for the manufacture of your OTC drug products. In an affidavit dated September 20, 2022, you stated that you could not provide documents related to several CGMP activities such as, out-of-specification (OOS) results, non-conformances, deviations and investigations, annual product review, and CGMP training.

In addition, you used (b)(4) hold-time studies to support a (b)(4) expiration date for bulk drug products, such as your SPF-30 Daily Protect Sunscreen. These (b)(4) hold-time studies do not support a (b)(4) hold time for bulk drug products. You have not determined the impact these inadequate hold-time studies may have had on the stability and quality attributes of your bulk drug products. Additionally, customers may rely on these claims to establish (b)(4) expiration dates on finished drug products.

An adequate QU overseeing all manufacturing operations is necessary to consistently ensure drug quality. Your firm’s quality systems are inadequate. See 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:

  • 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

Registration and listing violations:

Your firm has been manufacturing 4-IN-1 Broad Spectrum SPF 50 Sunscreen (NDC 73561-001-01), Daily Protect Sunscreen Moisturizer Broad Spectrum SPF 30 (NDC 73561-100-01), Oil Daily Protect Sunscreen Moisturizer Broad Spectrum SPF 30 (NDC 73561-101-01), and SPF-30 (b)(4).

Under section 510(i)(1) of the FD&C Act (21 U.S.C. 360(i)(1)) Cosmetic Science Laboratories LLC is required to submit registration information annually by electronic means for each establishment it owns or operates that is engaged in the manufacture, preparation, propagation, compounding, or processing of a drug that is in commercial distribution in the United States. Under section 510 of the FD&C Act as amended and 21 CFR (21 U.S.C. 360(j)(1), 21 CFR 207.17 and 207.41), all drugs manufactured, prepared, propagated, compounded, or processed for U.S. commercial distribution must be listed with the FDA. You have failed to fulfill your establishment registration obligations as required under section 510 of the FD&C Act, which is prohibited under section 301(p), 21 U.S.C 360 and 331(p). In addition, your firm, Cosmetic Science Laboratories LLC, failed to fulfill its listing obligations under section 510(j) of the FD&C Act, which is a prohibited act under section 301(p), 21 U.S.C. 360(j) and 331(p). Failure to properly list a drug with the FDA also renders it misbranded under section 502(o) of the FD&C Act, and in violation of section 301(a) of the FD&C Act, 21 U.S.C. 352(o) and 331(a).

As a result, the drugs 4-IN-1 Broad Spectrum SPF 50 Sunscreen (NDC 73561-001-01), Daily Protect Sunscreen Moisturizer Broad Spectrum SPF 30 (NDC 73561-100-01), Oil Daily Protect Sunscreen Moisturizer Broad Spectrum SPF 30 (NDC 73561-101-01), and SPF-30 (b)(4), are misbranded under section 502(o) of the FD&C Act, 21 U.S.C. 352(o).

Drug Production Ceased

We acknowledge your commitment to cease production of drugs at this facility and that you deregistered your facility as a drug manufacturer. As of March 7, 2023, your firm’s website, https://www.cosmeticsciencelabs.com/our-services/, continues to advertise your services as a drug contract manufacturer. 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, notify this office before resuming your operations.

CGMP Consultant Recommended

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 if your firm intends to resume manufacturing drugs for the U.S. market. The qualified consultant should also perform a comprehensive audit of your entire operation for CGMP compliance and evaluates the completion and efficacy of your corrective actions and preventive actions before you pursue resolution of your firm’s compliance status with the FDA. 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.

Responsibilities as a Contractor

Drugs must be manufactured in conformance with CGMP. The FDA is aware that many drug manufacturers use independent contractors such as production facilities, testing laboratories, packagers, and labelers. The FDA regards contractors as extensions of the manufacturer.

You are responsible for the quality of drugs you produce as a contract facility regardless of agreements in place with product owners. You are required to ensure that drugs are made in accordance with section 501(a)(2)(B) of the FD&C Act for safety, identity, strength, quality, and purity. See FDA’s guidance document Contract Manufacturing Arrangements for Drugs: Quality Agreements at https://www.fda.gov/media/86193/download.

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

Please identify your responses with the unique identifier: CMS 645558

If you have questions regarding the contents of this letter, please contact Andrew Haack, compliance officer by telephone at 206-340-8212 or email at Andrew.Haack@fda.hhs.gov.

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

 
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