- Delivery Method:
- Via Email
Recipient NameMr. Adam Pogue
Recipient TitleOwner and Chief Executive Officer
- Froggy’s Fog LLC
1536 North Main Street
Mount Pleasant, TN 38474
- Issuing Office:
- Office of Pharmaceutical Quality Operations, Division II
DATE April 14, 2022
Case # 623283
Dear Mr. Pogue:
The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Froggy’s Fog LLC, 3013443567, at 1536 N. Main Street, on September 15, 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, SIMPLY 70 HAND SANITIZER GEL (70% Alcohol) is misbranded under section 502(a) of the FD&C Act, 21 U.S.C. 355(a). Introduction or delivery for introduction of these products 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 October 6, 2021 response to our Form FDA 483 in detail and acknowledge receipt of your subsequent correspondence.
During our inspection, our investigator observed specific violations including, but not limited to, the following.
1. 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 was unable to provide adequate process validation and water system validation protocols or studies during our inspection of your facility. In addition, your batch records did not include any process parameters or in-process specifications to demonstrate control in the manufacture of your over-the-counter (OTC) hand sanitizer1 drug products.
In your response, you stated that you initiated a plan to address these items and that you were developing validation protocols.
Your response is inadequate because it is incomplete. You have not adequately demonstrated that your manufacturing processes are reproducible and controlled to yield a product of uniform character and quality. Failure to validate your manufacturing processes can result in product quality attribute failures. In addition, your response did not address or otherwise include a risk assessment for any drug products manufactured on equipment shared with non-pharmaceutical products.
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.
- 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.
- 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.
- A procedure governing your program for ongoing control, maintenance, and monitoring that ensures the system consistently produces water that meets (b)(4), USP monograph specifications and appropriate microbial limits.
2. Your firm failed to perform, 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 21 CFR 211.165(b)).
Your firm failed to adequately test your OTC drugs prior to release for distribution. For example, your batch records and certificates of analysis for your hand sanitizer drug products did not include microbiological testing or testing for impurities. You also informed our investigator that you only used a density meter to perform finished product strength testing of your hand sanitizer drug products. This method is unsuitable for the testing of finished hand sanitizers that contain materials other than ethanol and water in their matrix. Furthermore, FDA laboratory testing of a batch of your SIMPLY 70 70% Alcohol Antiseptic HAND SANITIZER GEL Topical Solution drug product found that the product contained an average of 61% ethanol v/v, or only 87% of the label claim.
Your response included the corrective actions of purchasing new hydrometers to test drug product in parallel with current equipment, contacting vendors to pursue testing that aligns with compendial methods, and pursuing vendors and equipment to perform microbial testing.
Your response is inadequate. You did not provide a detailed plan to implement complete testing for all required specifications of the drug products you manufacture.
In response to this letter, provide the following:
- A list of chemical and microbial specifications, including test methods, used to analyze each lot of your drug products before a lot disposition decision.
- 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.
- 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.
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)).
Your analytical test methods were not adequately validated, including those for the active ingredient ethanol, which is used to manufacture your alcohol-based hand sanitizers. Data must be available to establish that the analytical procedures used in testing meet proper standards of accuracy, sensitivity, specificity, and reproducibility and are suitable for their intended purpose.
Your response included the corrective actions of purchasing new hydrometers to test drug product in parallel with current equipment and contacting vendors to pursue testing that aligns with compendial methods, including validation by a third party.
Your response is inadequate because it did not include an assessment of drug products that you analyzed using the deficient methods.
In your response to this letter, provide the following:
- 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.
- An independent assessment of all test methods and data review procedures used by your firm to ensure they have appropriate instructions, method suitability criteria, and validation to determine whether they are fit for intended purposes.
- Your test results, using an adequately validated test method, of retains for all finished drug products within expiry. You should test all appropriate quality attributes of each batch that you distributed into U.S. commerce to ensure that your drug products conform to appropriate standards of identity, strength, quality, and purity. If testing yields an out-of-specification (OOS) result, indicate the corrective actions you will take, including notifying customers and initiating recalls.
4. Your firm failed to conduct (b)(4) 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 have not demonstrated that you adequately test all incoming raw materials used in the manufacture of your drug products, including identity testing on each lot of incoming raw material. For example, your procedure did not ensure adequate identity testing on each lot of incoming ethanol, the active pharmaceutical ingredient in your hand sanitizer products. Additionally, your active pharmaceutical ingredient, ethanol, is not tested for methanol content, and your procedures did not ensure that you test glycerin for presence of diethylene glycol. Your standard operating procedure (SOP) for supplier approval indicated your firm verifies the conformity of incoming materials. However, your supplier approval SOP did not adequately describe how you establish the reliability of your suppliers’ certificates of analysis (COAs).
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 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 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.
5. Your firm failed to establish and follow adequate written procedures for cleaning and maintenance of equipment (21 CFR 211.67(b)).
Your firm did not validate your cleaning processes used for cleaning non-dedicated manufacturing equipment. Inadequate removal of residues from the product contact surfaces of manufacturing equipment during cleaning can contaminate drug products subsequently manufactured on non-dedicated equipment.
In your response, you stated that you initiated a plan to address these items and that you were developing a cleaning validation program.
Your response is inadequate because you failed to provide sufficient details of your cleaning validation program along with a detailed timeline for completion. In addition, your response did not address or otherwise include a risk assessment for any drug products manufactured on equipment shared with non-pharmaceutical products.
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
Products Containing Ethanol
You manufacture multiple 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/regulatory-information/search-fda-guidance-documents/policy-testing-alcohol-ethanol-and-isopropyl-alcohol-methanol-including-during-public-health.
Products Contain Glycerin
You manufacture products that contain glycerin. The use of glycerin contaminated with diethylene glycol (DEG) has resulted in various lethal poisoning incidents in humans worldwide.
See FDA’s guidance document Testing of Glycerin for Diethylene Glycol to help you meet the CGMP requirements when manufacturing drugs containing glycerin at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/testing-glycerin-diethylene-glycol.
SIMPLY 70 HAND SANITIZER GEL (70% Alcohol) 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, this product is intended as a consumer topical antiseptic.
Examples of claims observed on the SIMPLY 70 HAND SANITIZER GEL (70% Alcohol) product label 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:
“HAND SANITIZER. . . Drug Facts. . . Antiseptic . . . Uses: Hand sanitizer to help reduce bacteria that can potentially cause disease. For use when soap and water are not available.”
This hand sanitizer is misbranded under section 502(a) of the FD&C Act, 21 U.S.C 352(a), because its labeling is false or misleading. SIMPLY 70 HAND SANITIZER GEL (70% Alcohol) is misbranded under section 502(a) of the FD&C Act, 21 U.S.C. 352(a), because according to the product label, SIMPLY 70 HAND SANITIZER GEL (70% Alcohol) contains the active ingredient ethyl alcohol 70% v/v. However, FDA laboratory analyses of this product demonstrate that SIMPLY 70 HAND SANITIZER GEL (70% Alcohol) contains ethyl alcohol in an average concentration of ethanol 60% v/v. Thus, the misleading representation of the concentration of the active ingredient ethyl alcohol in the product, cause SIMPLY 70 HAND SANITIZER GEL (70% Alcohol) to be misbranded under section 502(a) of the FD&C Act, 21 U.S.C. 352(a).
The introduction or delivery for introduction of a misbranded drug into interstate commerce is prohibited under section 301(a) of the FD&C Act, 21 U.S.C. 331(a).
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.
Your written notification should refer to Case # 623283
Please electronically submit your reply on company letterhead to Mark W. Rivero, Compliance Officer, at ORAPHARM2_RESPONSES@fda.hhs.gov. In addition, please submit a signed copy of your response to Mr. Rivero at email@example.com.
If you have questions regarding the contents of this letter, you may contact Mr. Rivero via (504) 846-6103 or firstname.lastname@example.org.
Monica R. Maxwell
Program Division Director
Office of Pharmaceutical Quality Operations,
Adams Rodgers, D.Ph.
Tennessee Department of Health
Health Related Boards
Tennessee Board of Pharmacy
665 Mainstream Drive
Nashville, TN 37243
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 were not prepared consistent with FDA’s temporary policy set forth in the guidance. Because Froggy’s Fog hand sanitizer drug products were not consistent with the formulations described in these guidances, they did not fall within any temporary Agency policy not to take action against firms manufacturing hand sanitizer drug products for violations of section 505 of the FD&C Act.