- Delivery Method:
- Via Email
Recipient NameMr. Fielding R. Smith
- Yusef Manufacturing Laboratories, LLC
Freeport West, F-4, #3
PO Box 160347
Clearfield, UT 84016
- Issuing Office:
- Division of Pharmaceutical Quality Operations IV
February 8, 2022
Dear Mr. Smith:
The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Yusef Manufacturing Laboratories, LLC, FEI 3004845420, at Freeport West, F-4, #3, Clearfield, UT from September 20 to 24, 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).
We reviewed your October 12, 2021, 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 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 the components to manufacture your over-the-counter (OTC) drug products. Additionally, you relied on certificates of analysis (COAs) from unqualified suppliers for specifications such as purity, strength, and quality. By not adequately analyzing your components for identity, purity, strength, and quality, you failed to ensure your incoming components meet appropriate specifications.
For example, you accepted the ethanol active pharmaceutical ingredient (API) from your supplier based only on its color, odor, appearance, and subsequently used it to manufacture your hand sanitizer1 drug products. You did not test this ethanol for identity or methanol prior to use. You relied on your supplier’s COA and did not test for any other quality attributes. Furthermore, the COA from your ethanol supplier states, “It is not intended for use as an active ingredient in drug manufacturing nor as a medical device or disinfectant.”
In your response, you committed to performing identity testing for your API used to manufacture your sunscreens and hand sanitizers. However, the supportive documentation provided for your corrective action and preventive action (CAPA) only addresses identity testing for APIs in your sunscreen drug product(s). You did not address how you plan to establish the reliability of, and periodically validate, the test results on your suppliers’ COAs. You also did not commit to testing your reserve samples to verify the identity of your components used in your OTC drug products.
You manufacture drugs that contain ethanol. The use of ethanol contaminated with methanol has resulted in various lethal poisoning incidents in humans worldwide. See FDA’s guidance document Policy for Testing of Alcohol (Ethanol) and Isopropyl Alcohol for Methanol, Including During the Public Health Emergency (COVID-19) to help you meet the CGMP requirements when manufacturing drugs containing ethanol at https://www.fda.gov/media/145262/download.
In response to this letter, provide the following:
• Your risk assessment for using non-pharmaceutical grade ethanol that is not intended to be used as an active ingredient in drug manufacturing. Your risk assessment should include an evaluation of whether there are specific safety risks that warrant a recall of your drug product.
• 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 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 that describes this COA validation program.
• A summary of your program for qualifying and overseeing contract facilities that test the drug products you manufacture.
• A comprehensive, independent 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.
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 investigations into out-of-specification (OOS) laboratory results are incomplete, do not include scientifically supported conclusions, and lack adequate CAPA.
For example, while testing SPF30 Lip Balm Sunscreen batch (b)(4), you obtained a failing assay result of 80.1% for meradimate API and 81.9% octisalate API (release testing specification: (b)(4)% and (b)(4)% respectively). During the investigation, you confirmed the initial failing results. Then you collected fresh samples from the top, middle and bottom of three boxes with unlabeled finished product and obtained passing results. You reported the average of the passing results on your COA and released the product. Without conducting a full-scale investigation (e.g., manufacturing process), you attributed that the initial failing results to heated filling nozzles at the start of production, which is quenched when filling the first sample.
Your CAPA was to discuss with your operators “how many pieces are discarded at the beginning of the production run.” You failed to determine how you could eliminate or mitigate the effect of the heated nozzles in the future.
In your response, you stated that you were “not aware of the depth to which changes to procedures and processes needed to be documented.” Your response is inadequate because you have not addressed how you will remediate your investigation system to determine appropriate root cause, identify adequate CAPAs to prevent recurrence, and measure effectiveness of your CAPAs.
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/downloads/drugs/guidances/ucm070287.pdf.
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 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.
o 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
• A comprehensive, independent assessment of your overall system for investigating deviations, discrepancies, complaints, OOS 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 assurance unit oversight, and written procedures. Address how your firm will ensure all phases of investigations are appropriately conducted.
• A comprehensive, independent assessment of your change management system. This assessment should include, but not be limited to, your procedure(s) to ensure changes are justified, reviewed, and approved by your quality assurance unit. Your change management program should also include provisions for determining change effectiveness.
3. Your firm failed to establish laboratory controls that include scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure that components, drug product containers, closures, in-process materials, labeling, and drug products conform to appropriate standards of identity, strength, quality, and purity (21 CFR 211.160(b)).
You lacked analytical instrumentation and suitable test methods to test your ethanol-based hand sanitizer drug product for assay, identity of the active ingredient, and impurities limits (e.g., methanol) before it was released for distribution. Drug products must be tested for identity, strength, quality, and purity prior to release and distribution.
In addition, you also failed to demonstrate that your microbiological test methods are suitable to detect microorganisms in the water used as component and in your OTC finished drug products. You also failed to conduct growth promotion testing for the lots of media used for your microbiological testing of finished drug product.
Your response stated that you were not aware of the need to test ethanol API for methanol content, and you have not yet validated your microbiological test procedures. You also wrote that the installation of analytical testing instrumentation and set up of microbiology laboratory is pending. You did not commit to testing of your reserve samples to verify the identity of your active ingredients or impurities in your OTC drug products.
We assessed your analytical method validation for method 01-146.02 for oxybenzone, octinoxate, meradimate, and octisalate in lotion provided as a correction in your response and found it inadequate. You did not follow your method validation protocol and you inappropriately set the acceptance criteria and product specification limits only after completing the validation experiments. You did not test for possible interferences from the sample matrix, degradants or impurities to show the method’s capability to quantitate each of the active ingredients with suitable accuracy and precision. Lastly, you considered the method valid for use with not only the sunscreen lotion formulation but also wax based lip balms without any additional method validation. You must establish and validate or verify analytical methods and procedures to ensure the accuracy, sensitivity, specificity, and reproducibility of testing.
See FDA’s guidance document, Analytical Procedures and Methods Validation for Drugs and Biologics, for general principles and approaches that FDA considers appropriate elements of analytical method validation at https://www.fda.gov/media/87801/download.
In response to this letter, provide the following:
• Methanol, benzene, acetal, acetaldehyde and test results for all hand sanitizer batches released and distributed.
• A comprehensive, independent 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 lot of your drug products before a lot 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.
4. 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)).
You failed to adequately validate your manufacturing processes used to manufacture your drug products and demonstrate that your processes are reproducible and controlled to consistently yield drugs of uniform character and quality.
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.
Your response stated you have “not yet attended to the process validation” of your OTC drug products. Your response is inadequate because you failed to provide your plans and timeline for completing this work.
For more information about process validation, 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/downloads/drugs/guidances/ucm070336.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 appropriate process performance qualification 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.
5. Your firm failed to follow 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 does not have adequate stability data to show that the chemical and microbiological properties of your drug products remain acceptable throughout the labeled expiry period of three years. During the inspection, you claimed that your labeled three-year expiry was supported by a stability study. However, you were unable to provide the study during the inspection. Without appropriate stability data, you cannot ensure your drug products meet established specifications and all pre-determined quality criteria throughout the drug product assigned shelf-life.
In your response, you stated that you did not have the resources to initiate validated stability tests, and that you were not aware of all the requirements for conducting stability studies for your drug products. You have committed to initiating a stability study for each of your drug products to determine appropriate expiration dates once you install a gas chromatograph and qualify your equipment. Your response is inadequate because you did not provide your plans and timeline for completing this work.
In response to this letter, provide the following:
• A comprehensive, independent assessment and 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 drug product 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.
Repeat Violations at Facility
FDA cited your firm for similar CGMP violations and observations in the warning letter DEN-17-07-WL issued in 2017, in a regulatory meeting held in January 2020, and in previous inspections conducted in September 2007, February 2011, May 2016, February 2018, and September 2019. You had committed to remediating the cited violations and observations in your responses. Repeated failures demonstrate that executive management oversight and control over the manufacture of drugs is inadequate.
CGMP Consultant Recommended
Because you failed to correct repeat violations, we strongly recommend engaging a consultant 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.
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 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.
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 621026.
If you have questions regarding the contents of this letter, please contact Bryan Galvez, Acting Compliance Officer via email at, Bryan.Galvez@fda.hhs.gov or by telephone at 949-608-2960.
Lance M. De Souza
Acting Director, Division of Pharmaceutical Quality Operations IV
1 Due to an increased demand for alcohol-based hand sanitizers during the COVID-19 pandemic, FDA published the Guidance for Industry: Temporary Policy for Preparation of Certain Alcohol-Based Hand Sanitizer Products During the Public Health Emergency (COVID-19) on March 19, 2020, and subsequently updated the guidance several times. The guidance was withdrawn effective December 31, 2021 (86 Fed Reg at 56960). This guidance communicated the Agency’s temporary policy that we did not intend to take action against firms for CGMP violations under section 501(a)(2)(B) of the FD&C Act if such firms prepared alcohol-based hand sanitizers for consumer use (or for use as a health care personnel hand rub) during the public health emergency, provided certain circumstances described in the guidance are present. These circumstances included preparation of hand sanitizer products using only the ingredients and formulas set forth in the guidance. A review of the formulations of the drug products indicates that such products are not prepared consistent with FDA’s temporary policy set forth in the guidance. Because Yusef Manufacturing’s hand sanitizer products are not consistent with the formulations described in these guidances, they do not fall within any temporary Agency policy not to take action against firms manufacturing hand sanitizer products for violations of section 505 of the FD&C Act.