- Delivery Method:
Recipient NameMr. Walter R. Heinle
- Aire-Master of America, Inc.
1821 N. State Highway CC
Nixa, MO 65714-8015
- Issuing Office:
- Division of Pharmaceutical Quality Operations III
May 23, 2022
Dear Mr. Heinle:
The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Aire-Master of America, Inc., FEI 3002764676, at 1821 N. State Highway CC, Nixa Missouri, from October 5 to October 19, 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, Aire-Master Foaming Hand Sanitizer (2 and 64 fl oz) and Aire-Master Foaming Hand Sanitizer with Aloe are unapproved new drugs introduced or delivered for introduction into interstate commerce in violation of section 505(a) of the FD&C Act, 21 U.S.C. 355(a), and are misbranded under sections 502(ee) of the FD&C Act, 21 U.S.C. 352(ee). Introduction or delivery for introduction of such products into interstate commerce is prohibited under sections 301(d) and (a) of the FD&C Act, 21 U.S.C. 331(d) and (a). These violations are described in more detail below.
We reviewed your November 4, 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 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 laboratory sampling plans and testing methods were not scientifically sound. You collected non-representative samples of your water system. Water from your water system is used in the formulation of your topical over-the-counter (OTC) drug products. Specifically, your water system monitoring procedure provided during the inspection did not discuss the number, location, or frequency of samples to collect. You told our investigator that you typically take a sample from your water system (b)(4) from a single location near the (b)(4) component. The sampling frequency and locations, which did not include sampling from any point of use, were not appropriate to provide substantive data to promptly detect system variability.
Furthermore, your microbiological testing used for water analysis was deficient. You have not shown your test methods were adequate for determining the quality of the water in view of its intended use in your drug products. Furthermore, you lacked appropriate limits, routine testing, or validated methods for detecting the presence of B. cepacia in your water system. Your microbiological testing is insufficient to assure that your water system is suitable for its intended use.
Additionally, FDA analysis of samples collected from your water system recovered too-numerous-to-count results for multiple total microbial count tests.
In response to this letter, provide the following:
- A comprehensive, independent assessment of your water system design, control, and maintenance.
- A thorough remediation plan to install and operate a suitable water system. Include a robust ongoing control, maintenance, and monitoring program to ensure the remediated system design consistently produces water adhering to (b)(4) Water, USP monograph specifications and appropriate microbial limits.
- A detailed risk assessment addressing the potential effects of the observed water system failures on the quality of all drug product lots currently in U.S. distribution or within expiry. Specify actions that you will take in response to the risk assessment, such as customer notifications and product recalls.
- 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.
- A procedure for your water system monitoring that specifies routine microbial testing of (b)(4) water to ensure its acceptability for use in each batch of drug products produced by your firm.
- A diagram of your water system and its components. Include a list of all water system point-of-uses (POUs), their locations, and frequency of testing.
- 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.
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 quality unit (QU) failed to conduct an adequate investigation into a complaint received for a “fishy” odor in your Foaming Waterless Hand Sanitizer1 lot #713588. Your investigation stated that you “checked inventory in the warehouse and noticed the smell that the customer complained of. Inventory was then taken out of stock.” You determined to rework some of the old product into a new batch “to lessen the smell of the product in question.”
Our investigator collected a certificate of analysis (COA) showing “alcohol/no fragrance” as the specification for this drug product. As this complaint described a foul odor in distributed drug product, your QU should have performed a thorough investigation into this complaint as per 21 CFR 211.198. Instead, your production management performed a very limited investigation. The resolution for this complaint was to ensure employees “purge the (b)(4) tank before filling the vat with (b)(4) water.” While the investigation indicated that the (b)(4) water was the source of the odor, you failed to address why your formulation water had a foul odor. Additionally, your investigation lacked meaningful corrective action and preventive action (CAPA) to prevent recurrence.
Inadequate investigations can lead to unidentified root causes, ineffective CAPA, and recurring problems that compromise the ability to produce safe and effective products.
In response to this letter, provide the following:
- A comprehensive, independent assessment of your overall system for investigating deviations, discrepancies, complaints, out-of-specification (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 unit oversight, and written procedures. Address how your firm will ensure all phases of investigations are appropriately conducted.
- An independent assessment and remediation plan for your CAPA program. Provide a report that evaluates whether the program includes effective root cause analysis, ensures CAPA effectiveness, analyzes investigations trends, improves the CAPA program when needed, implements final quality unit decisions, and is fully supported by executive management.
- 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
3. Your firm failed to conduct, for each batch of drug product, appropriate laboratory testing, as necessary, required to be free of objectionable microorganisms (21 CFR 211.165(b)).
Your firm released finished drug products without adequate testing for critical microbial attributes (e.g., total count, absence of objectionable microorganisms). Without testing each batch prior to release, you did not have scientific evidence that all drug product batches were free of microbial contamination that is objectionable in view of its intended use.
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.
- 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.
4. Your firm failed to clean, maintain, and, as appropriate for the nature of the drug, sanitize and/or sterilize equipment and utensils at appropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements (21 CFR 211.67(a)).
You failed to demonstrate that your cleaning and disinfection practices are adequate to remove contaminants from shared equipment used to manufacture household cleaners as well as your topical OTC drug products. Although you did not validate your equipment cleaning methods, you continued to manufacture your topical OTC drug products using the same equipment that you use to manufacture numerous cleaners in your facility, including (b)(4) Bathroom Cleaner.
This cleaner is labeled as, “CAUTION: IRRITANT” and “For Sensitive skin, please wear household rubber gloves.”
It is unacceptable as a matter of CGMP to continue manufacturing drugs using the same equipment that you use to manufacture industrial-grade cleaning products. Moreover, the potential toxicity of these products increases the hazard if a cross-contamination or material mixup deviation occurs.
In response to this letter, provide the following:
- A comprehensive, independent retrospective assessment of your cleaning effectiveness to evaluate the scope of cross-contamination hazards. Include the identity of residues, other manufacturing equipment that may have been improperly cleaned, and an assessment whether cross-contaminated products may have been released for distribution. The assessment should identify any inadequacies of cleaning procedures and practices, and encompass each piece of manufacturing equipment used to manufacture more than one product.
- 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; segregation of pharmaceutical from non-pharmaceutical manufacturing; 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
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 standard operating procedure (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 conduct at least one test to verify the identity of each component of a drug product (21 CFR 211.84(d)(1)).
You lacked appropriate identity testing for your incoming components used to manufacture your drug products. For example, your firm did not ensure that at least one specific identity test was conducted for each lot of your drug product components citric acid and carbomer. Additionally, your identity test methods for glycerin, and ethyl alcohol components are insufficient as they were not adequate to detect the toxic chemicals diethylene glycol and methanol, respectively.
By not adequately analyzing each incoming lot of components for identity, you failed to ensure your incoming components are of appropriate quality to use in the manufacture of drug products.
You manufacture multiple drugs that contain glycerin. The use of glycerin contaminated with 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.
You also 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.
In response to this letter, provide the following:
- 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 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 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.
- Results of tests for diethylene glycol (DEG) and ethylene glycol (EG) in retain samples of all glycerin lots used to manufacture your drug products.
- A full risk assessment for drug products that contain glycerin and are within expiry in the U.S. market. Take prompt corrective actions and preventive actions, and detail your future actions to ensure appropriate selection of your suppliers, ongoing scrutiny of their supply chain, and appropriate incoming lot controls.
Unapproved New Drug and Misbranding Violations
Examples of claims observed on the Aire-Master Foaming Hand Sanitizer (2 and 64 fl oz) and AireMaster Foaming Hand Sanitizer with Aloe labels that provide evidence of the intended uses2 (as defined in 21 CFR 201.128) of the product include, but may not be limited to, the following:
“Drug Facts . . . Active Ingredient . . . Ethanol 62% . . . Purpose . . . Antiseptic. . . Uses . . . Handwash to help reduce bacteria that potentially can cause disease. . . Directions . . . Dispense an adequate amount in your palm to cover all surfaces of hands completely · Rub hands together until dry · Does not require rinsing. . .” [from your Aire-Master Foaming Hand Sanitizer label]
“Drug Facts . . . Active Ingredient . . . Ethanol 62% . . . Purpose . . . Antiseptic. . . Uses . . . Handwash to help reduce bacteria that potentially can cause disease. . . Directions . . . Dispense an adequate amount in your palm to cover all surfaces of hands completely · Rub hands together until dry · Does not require rinsing. . .” [from your Aire-Master Foaming Hand Sanitizer with Aloe label]
These topical antiseptic products are “new drugs” within the meaning of section 201(p) of the FD&C Act, 21 U.S.C. 321(p), because they are not generally recognized as safe and effective (GRASE) for use under the conditions prescribed, recommended, or suggested in their labeling. New drugs may not be introduced or delivered for introduction into interstate commerce without prior approval from FDA, as described in section 505(a) of the FD&C Act, 21 U.S.C. 355(a), unless they are lawfully marketed under section 505G of the FD&C Act (which is not the case for this product, as further described below) or other exceptions not applicable here. No FDA-approved application pursuant to section 505 of the FD&C Act, 21 U.S.C. 355, is in effect for these drug products, nor are we aware of any adequate and well-controlled clinical studies in the published literature that support a determination that your AireMaster Foaming Hand Sanitizer (2 and 64 fl oz) and Aire-Master Foaming Hand Sanitizer with Aloe products are GRASE for use under the conditions suggested, recommended, or prescribed in their labeling. Accordingly, these products are unapproved new drugs marketed in violation of sections 505(a) and 301(d) of the FD&C Act, 21 U.S.C 355(a) and 331(d).
We note that over-the-counter (OTC) topical antiseptic products had been the subject of rulemaking under the Agency’s OTC Drug Review. In particular, such products were addressed in a tentative final monograph (TFM) entitled “Topical Antimicrobial Drug Products for Over-the-Counter Human Use; Tentative Final Monograph for Health-Care Antiseptic Drug Products,” Proposed Rule, 59 FR 31402 (June 17, 1994) (1994 TFM), as further amended by “Safety and Effectiveness of Consumer Antiseptics; Topical Antimicrobial Drug Products for Over-the-Counter Human Use; Proposed Amendment of the Tentative Final Monograph; Reopening of Administrative Record,” Proposed Rule, 81 FR 42912 (June 30, 2016)(Consumer Antiseptic Rubs Proposed Rule). Over the course of these rulemakings, three active ingredients (benzalkonium chloride, ethyl alcohol (ethanol), and isopropyl alcohol) were classified as Category III for use in consumer antiseptic rub products, meaning that additional safety and effectiveness data are needed to support a determination that a drug product containing one of these active ingredients would be GRASE for use as a consumer antiseptic rub. Additionally, OTC consumer antiseptic washes were addressed in “Safety and Effectiveness of Consumer Antiseptics; Topical Antimicrobial Drug Products for Over-the-Counter Human Use,” Proposed Rule, 78 FR 76444 (December 17, 2013) (Consumer Antiseptic Washes Proposed Rule) and “OTC Safety and Effectiveness of Topical Antimicrobial Drug Products for Over-the-Counter Human Use,” Final Rule, 81 FR 61106 (September 6, 2016). We note that ethyl alcohol is not one of the active ingredients that was classified as Category III for use as an active ingredient in a consumer antiseptic wash. Under the Consumer Antiseptic Washes rulemaking, ethyl alcohol was determined to be ineligible for evaluation under the OTC Drug Review for use as an active ingredient in consumer antiseptic washes.
Section 505G of the FD&C Act addresses nonprescription drugs marketed without an approved application. Under section 505G(a)(3) of the FD&C Act, drugs that were classified as Category III for safety or effectiveness in a TFM that is the most recently applicable proposal or determination for such drug issued under 21 CFR Part 330 – and that were not classified as Category II for safety or effectiveness – are not required to have an approved application under section 505 in order to be marketed, as long as they are in conformity with the relevant conditions of use outlined in the applicable TFM, including the active ingredient, and comply with all other applicable requirements.
However, Aire-Master Foaming Hand Sanitizer (2 and 64 fl oz) and Aire-Master Foaming Hand Sanitizer with Aloe do not conform to the 1994 TFM, as further amended by the 2016 Consumer Antiseptic Rubs Proposed Rule [and the 2013 Consumer Antiseptic Washes Proposed Rule], nor any other TFM, proposed rule, or final rule, and do not meet the conditions under section 505G(a)(3) of the FD&C Act for marketing without an approved application under section 505.
As previously noted, statements on each of the product labels for Aire-Master Foaming Hand Sanitizer (2 and 64 fl oz) and Aire-Master Foaming Hand Sanitizer with Aloe suggest that these products are intended to be both consumer antiseptic washes and consumer antiseptic rubs. However, ethyl alcohol (in any concentration) is not an active ingredient permitted for use in consumer antiseptic hand washes under the 1994 TFM.
Lastly, these products are misbranded under section 502(ee) of the FD&C Act, 21 U.S.C. 352(ee), because Aire-Master Foaming Hand Sanitizer (2 and 64 fl oz) and Aire-Master Foaming Hand Sanitizer with Aloe are nonprescription drug(s) subject to section 505G of the FD&C Act, 21 U.S.C. 355h, but do not comply with the requirements for marketing under that section and are not the subject of an application approved under section 505 of the FD&C Act, 21 U.S.C. 355.
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).
Additionally, we note that under 21 CFR 201.61(a), “[t]he principal display panel of an over-the-counter drug in package form shall bear as one of its principal features, a statement of identity of the commodity.” Under section 505G(a)(3) of the FD&C Act and the 1994 TFM, the statement of identity for health-care antiseptic drug products, a category that included consumer antiseptic rub drug products, must contain “the established name of the drug, if any” (59 FR 31442). Currently, there is no established name for consumer antiseptic rub drug products that have the active ingredient ethyl alcohol and are formulated as a gel. However, we recommend that you include the active ingredient’s name, such as “alcohol gel,” as appropriate, as part of the statement of identity that appears on the principal display panel for all of your product labels.
CGMP Consultant Recommended
Based upon the nature of the violations we identified at your firm, we strongly recommend engaging a consultant 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.
For further information regarding the significance of B. cepacia complex and other objectionable contamination of non-sterile, water-based drug products, see FDA’s advisory notice posted on July 7, 2021, at https://www.fda.gov/Drugs/DrugSafety/ucm559508.htm.
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 the Warning Letter Number above (622546). Please address your reply via email to: ORAPHARM3_RESPONSES@fda.hhs.gov
Attention: Nicholas F. Lyons, Director of Compliance
U.S. Food and Drug Administration
Division of Pharmaceutical Quality Operations III
If you have questions regarding the contents of this letter, please contact Nicholas F. Lyons, Director of Compliance at (312) 596-4220.
Jeffrey D. Meng
Program Division Director
Division of Pharmaceutical Quality Operations III
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 Aire-Master of America’s 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.
2 We note that your Aire-Master Foaming Hand Sanitizer Foaming Hand Sanitizer (2 and 64 fl oz) and Aire-Master Foaming Hand Sanitizer with Aloe, drug products’ labeling contains conflicting information regarding whether they should be used as consumer antiseptic rub/consumer antiseptic wash or consumer antiseptic rub. The term “hand sanitizer” generally refers to consumer antiseptic rubs, and the Drug Facts Label of your product both indicates that the product is to be used for handwashing (presumably with water) and suggests that it should be used without water (i.e., “[a]pply liberal amount into hand” and “rub to dryness with attention to area around nails and between fingers”). These products, however, do not conform to the requirements for either a consumer antiseptic rub or a consumer antiseptic wash, as further described below.