Eco Lips, Inc. MARCS-CMS 631629 — September 20, 2022

WARNING LETTER

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• Delivery Method: UPS
• Product: Drugs

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• Recipient: Glen A. Jasper; President and Chief Sales Officer; Eco Lips, Inc.; 6000 Huntington Ct. NE; Cedar Rapids, IA 52402; United States

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

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September 20, 2022

WARNING LETTER
WL 631629

Dear Mr. Jasper:

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Eco Lips, Inc., FEI 3004966182, at 6000 Huntington Ct. NE, Cedar Rapids from March 22 to March 24, 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).

We reviewed your April 13, 2022, response to our Form FDA 483 in detail and acknowledge receipt of your subsequent correspondence.

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

1. Your firm failed to establish an adequate written testing program designed to assess the stability characteristics of drug products and to use results of stability testing to determine appropriate storage conditions and expiration dates (21 CFR 211.166(a)).

Your firm failed to establish an adequate stability program and determine appropriate expiration dates for the over-the-counter (OTC) drug products that you manufacture. Specifically:

• You assigned a (b)(4) expiry period to all your drug products but did not provide data to demonstrate that their chemical and physical attributes will remain acceptable throughout the expiry period assigned based on your product groupings.
• Your products failed to meet specifications at various timepoints of accelerated stability testing. For example, Group (b)(4) SPF 15” product grouping failed to meet the assay specification at the Initial, (b)(4) timepoints. Additionally, at the (b)(4) timepoint, Group (b)(4) SPF 15” and Group (b)(4) SPF 30” failed to meet the color specification and Group (b)(4) 8% Zinc Tinted SPF” failed to meet the odor specification.
• The number of batches placed on stability is inadequate. Your firm placed one batch per product group in accelerated and long-term stability studies to support your (b)(4) stability claims.
• At least one batch of each product manufactured is not placed on long-term stability per year.

In your response, you described your plan to engage a third-party laboratory to begin the design and submission of additional stability studies and “to establish a written stability program for initial long-term and ongoing stability for OTC products.”

Your response is inadequate. You failed to provide stability protocols, including all relevant quality attributes and acceptance criteria, and you did not provide assurance that your test methods are stability indicating. This is a repeat observation from your 2019 and 2021 inspections.

In response to this letter, provide the following:

• A comprehensive independent 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, including but not limited to process validation batches, are added each year 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 assessment of all products in the market to determine if they conform to specifications throughout their shelf-life, including evaluating the different packaging configurations you use. Based on an analysis of this additional data, describe the impact on any batches that remain within expiry in the U.S. market.
• Remediation of your procedures governing customer, supplier, and contractor interactions to implement agreements that ensure you receive stability data, contract testing data, test method validation summaries (e.g., microbiological testing) and any other data that is associated with quality of the batches you produce in a timely fashion. Your procedures should also address the need for your quality unit to request this information and ensure your firm is accountable for promptly addressing any quality (e.g., in-process, release, stability) failures for the products you produce.

2. 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 failed to investigate out-of-specification (OOS) assay results for several batches of your OTC drug products. For example, (b)(4) product batches (b)(4) and (b)(4) were initially found to be OOS for assay.

An investigation into the initial OOS results was not conducted, however, you retested and released these batches even though all assay results for batch (b)(4) failed.

In your response you described your plan to update your OOS procedure to include “missing relevant details.” We also acknowledge that your firm has committed to voluntarily recall (b)(4) product batches (b)(4) and (b)(4).

Your response is inadequate. You failed to initiate investigations in a timely manner to determine root causes and assess the impact of the OOS results. You also failed to implement appropriate CAPAs to mitigate and prevent recurrence. Your response did not provide a retrospective review to ensure that you have fully identified and thoroughly investigated all OOS results. We also learned from your firm that your previous quality director allowed the inappropriate average of passing and failing test results to release product that failed specification.

For more information about handling failing, out-of-specification, out-of-trend, or other unexpected 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/regulatory-information/search-fda-guidance-documents/investigating-out-specification-oos-test-results-pharmaceutical-production-level-2-revision.

In response to this letter, provide the following:

• A retrospective, independent review of all invalidated OOS (including in-process and release/stability testing) results for US products for the last three years from the initial date of inspection 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 the 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 result investigation systems. The CAPA should include but not be limited to addressing the following:

    o Quality unit 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 Adequately scoping of each investigation and its CAPA
    o Revised OOS investigation procedures with these and other remediations
    o Competencies of staff who perform, oversee, and approve OOS investigations

3. Your firm failed to establish 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)).

Your firm failed to provide data to demonstrate that you have validated manufacturing processes for all your OTC sunscreen drug products. At the time of our inspection, process validation had not been completed for seven of the nine sunscreen product groups that your firm categorized based on active ingredient combinations and inactive ingredient composition.

In your response, you indicated one additional process validation study had been completed and that you intend to perform further process validation studies for all nine groups within (b)(4). You also indicated that your sunscreen drug product batches had been released, even though process validation studies had not been completed for that grouping.

Your response is inadequate. You have not demonstrated that your manufacturing processes are designed, controlled and reproducible to yield a product of uniform character and quality. Failure to validate your manufacturing processes can result in product quality attribute failure. In addition, your response did not address or otherwise include a risk assessment for any marketed drug products manufactured with unvalidated processes.

Furthermore, you failed to provide a sufficient justification for your product groupings used for validation, given the differences in formulation, equipment used, and packaging configurations. This is a repeat observation from your 2021 inspection.

See FDA’s guidance document Process Validation: General Principles and Practices for general principles and approaches that FDA considers appropriate elements of process validation at https://www.fda.gov/files/drugs/published/Process-Validation--General-Principles-and-Practices.pdf.

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 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. Your process performance protocols should be updated to include, but not be limited to, addressing differences in formulation, component suppliers, batch sizes, equipment used, packaging configuration, and other critical variables for each drug product. In addition, specify the number of PPQ batches required for each formulation.
• 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.
• An assessment of each drug product process to ensure that there is a data-driven and scientifically sound program that identifies and controls all sources of variability, such that your production processes will consistently meet appropriate specifications and manufacturing standards. This includes, but is not limited to, evaluating suitability of equipment for its intended use, sufficiency of detectability in your monitoring and testing systems, quality of input materials, and reliability of each manufacturing process step and control.
• A commitment to not release drug products until validation activities, including supporting stability data, have been reviewed and approved by your Quality Unit.

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

You did not validate the cleaning processes used for cleaning non-dedicated manufacturing equipment, such as your kettle tanks, which are used for different human drug products. You also did not perform testing to ensure that residues of your cleaning agent are adequately removed. In addition, you lacked adequate solution stability data to support the length of time your active residue cleaning validation samples were kept in solvent prior to testing.

Inadequate removal of residues from the product contact surfaces of manufacturing equipment during cleaning can lead to contamination of drug products subsequently manufactured on non-dedicated equipment.

Furthermore, your equipment dedication policy for OTC sunscreen drug products collected during the inspection indicated that they can only be batched in two kettles. However, your executed batch records demonstrated the use of at least (b)(4) for the manufacture of your OTC sunscreen drug products.

In your response, you described your plan to compile additional results to complete cleaning validation protocols, including determining cleaning agent residue removal studies and a risk assessment regarding the length of time dedicated parts can sit between uses.

Your response is inadequate. You failed to provide updated cleaning procedures, adequate solution stability data for swab samples collected and maintained for up to (b)(4) and quantification of potential carryover of cleaning agent. This is a repeat observation from your 2019 and 2021 inspections.

In response to this letter, provide the following:

• A CAPA plan, based on the retrospective assessment of your cleaning and disinfection program, that includes appropriate remediations to your cleaning and disinfection processes and practices, and timelines for completion. Provide a detailed summary of vulnerabilities in your process for lifecycle management of equipment cleaning and disinfection. Describe improvements to your cleaning and disinfection program, including enhancements to cleaning effectiveness; improved ongoing verification of proper cleaning and disinfection execution for all products and equipment; and all other needed remediations.
• 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
    o scientific justification for the groupings used to demonstrate your cleaning methods adequately cover your drug products.
    o solution stability hold times (e.g., for swab samples)
    o copy of the methods utilized for cleaning validation and summary validation reports

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.

5. Your firm failed to 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)).

You failed to conduct annual product reviews (APR) covering all the human drug products you manufacture, despite having a written and established procedure requiring them. During the inspection, an APR for only one of your nine OTC sunscreen drug product groupings had been completed.

Manufacturers are required to conduct periodic evaluation of the quality standards for each drug product. Failure to perform product reviews, at least annually, of each of your individual drug products compromises your ability to evaluate the adequacy of the state of control of manufacturing and adherence to appropriate quality standards for each of your drug products

In your response you stated that you intended to initiate the process of completing the annual product reviews.

Your response is inadequate. You did not provide a retrospective review of your manufacturing and quality data, to determine whether adverse finding would require changes to manufacturing, control procedures or specifications. Failure to conduct annual product reviews is a repeat observation from your 2019 and 2021 inspections.

In response to this letter, provide the following:

• An assessment of manufacturing and quality data associated with each drug product you manufacture. Include remediated procedures and retrospective trending to identify any adverse findings and determine the need for changes to manufacturing processes or equipment, controls, or specifications.
• Describe improvements you intend to implement to your APR program and how you intend to monitor effectiveness.

Lastly, if any of the assessments performed to address the violations listed in this letter indicate substandard quality of drug product you manufacture, specify actions that you will take in response to the assessments, such as customer notifications and product recalls.

Repeat Violations and Observations at Facility

In previous inspections, dated September 2019 and May 2021, FDA cited similar CGMP violations and observations. You proposed specific remediation for these violations and observations in your responses. Repeated failures demonstrate that executive management oversight and control over the manufacture of drugs is inadequate.

Contractor’s Responsibilities

Your firm acts as a contract manufacturer for drug products.

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

CGMP Consultant Recommended

We acknowledge you engaged a consultant to assist your firm in meeting CGMP requirements. You are responsible for ensuring consultants you use are qualified as set forth in 21 CFR 211.34 to assist your firm in meeting CGMP requirements and to correct repeat violations. 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. 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 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.

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 address your reply via email to: ORAPHARM3_RESPONSES@fda.hhs.gov

Attention: Brian D. Garthwaite, Ph. D.
Compliance Officer
U.S. Food and Drug Administration
Division of Pharmaceutical Quality Operations III

Your written notification should refer to the Warning Letter Case Number above (#631629). If you have questions regarding the contents of this letter, please contact Dr. Garthwaite at (612) 758-7132.

Sincerely,
/S/

CDR Jeffrey Meng
Program Division Director
Division of Pharmaceutical Quality Operations III