FDA Warning Letter September 1, 2023
The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, PureChemPros LLC, FEI 3019411371, at 2141 E. Cedar Street, Suite 6, Tempe, from November 17 to November 22, 2022.
This warning letter summarizes significant violations of Current Good Manufacturing Practice (CGMP) regulations for finished pharmaceuticals. See Title 21 Code of Federal Regulations (CFR), parts 210 and 211 (21 CFR parts 210 and 211).
Because your methods, facilities, or controls for manufacturing, processing, packing, or holding do not conform to CGMP, your drug products are adulterated within the meaning of section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), 21 U.S.C. 351(a)(2)(B).
In addition, your “35% FOOD GRADE HYDROGEN PEROXIDE” and “3% FOOD GRADE HYDROGEN PEROXIDE” products 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). Introduction or delivery for introduction of such products into interstate commerce is prohibited under section 301(d) of the FD&C Act, 21 U.S.C. 331(d). Further, “35% FOOD GRADE HYDROGEN PEROXIDE” and “3% FOOD GRADE HYDROGEN PEROXIDE” are misbranded under section 502(ee) of the FD&C Act, 21 U.S.C. 352(ee). Additionally, “LIQUID HAND SANITIZER” is misbranded under sections 502(b)(1) and (x) of the FD&C Act, 21 U.S.C. 352(b)(1) and (x), and “3% FOOD GRADE HYDROGEN PEROXIDE” is misbranded under section 502(c) of the FD&C Act, 21 U.S.C. 352(c). Introduction or delivery for introduction of such products into interstate commerce is prohibited under section 301(a) of the FD&C Act, 21 U.S.C. 331(a). These violations are described in more detail below.
We acknowledge receipt of your December 29, 2022 response to our Form FDA 483. 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 investigator observed specific violations including, but not limited to, the following.
1. Your firm’s quality control unit failed to exercise its responsibility to ensure drug products manufactured are in compliance with CGMP, and meet established specifications for identity, strength, quality, and purity (21 CFR 211.22).
Your firm manufactures over-the-counter (OTC) hand rub drug products (also referred to as a consumer hand sanitizer) including PureCareRx Liquid Hand Sanitizer (0.1% benzalkonium chloride). Your firm failed to establish a quality unit (QU) to adequately oversee the manufacture of your drug products, including approximately (b)(4) gallons of PureCareRx Liquid Hand Sanitizer shipped on September 2, 2022, to an Amazon distribution center. Your firm failed to establish a QU to ensure:
- Appropriate production and process controls designed to assure drug products manufactured have the identity, strength, quality, and purity purported or represented to possess (21 CFR 211.100(a)).
- Formulation of your drug product with intent to provide no less than 100% of the labeled active ingredient (21 CFR 211.101(a)).
- Adequate cleaning and maintenance procedures for your equipment (21 CFR 211.67(b)).
- Preparation of adequate batch control and production records for your drug products (21 CFR 211.188).
- Appropriate testing for the identity and strength of the active ingredients was performed and reviewed before release for each batch of drug product (21 CFR 211.165(a)).
- Thorough investigations for out-of-specifications (OOS) results, complaints, deviations, and other discrepant results are performed per an adequate written and approved procedure (21 CFR 211.192).
- Appropriate written procedures to identify each batch of drug product with a lot or control number (21 CFR 211.130(c)).
An adequate QU overseeing all manufacturing operations is necessary to consistently ensure drug quality. See FDA’s guidance document Quality Systems Approach to Pharmaceutical CGMP Regulations for help implementing quality systems and risk management approaches to meet the requirements of CGMP regulations 21 CFR, parts 210 and 211 at https://www.fda.gov/media/71023/download.
2. Your firm failed to test samples of each component for identity and conformity with all appropriate written specifications for purity, strength, and quality. Your firm also failed to validate and establish the reliability of your component supplier’s test analyses at appropriate intervals (21 CFR 211.84(d)(1) and 211.84(d)(2)).
You failed to adequately test your incoming components, including for identity, before using the components to manufacture your drug products. Additionally, you relied on certificates of analyses (COA) 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 that your incoming components meet appropriate specifications.
In addition, your firm has not shown that the (b)(4) water that you use as a component for manufacturing drug products is suitable for aqueous-based dosage forms and, at a minimum, meets the Purified Water USP monograph and appropriate microbial limits. You failed to test your (b)(4) water, and that lacked adequate procedures regarding water specifications, testing, or handling of water.
3. Your firm failed to assure that the drug product bore an expiration date that was supported by appropriate stability testing (21 CFR 211.137(a)).
Your firm failed to implement an appropriate stability testing program. Your firm also lacked scientific rationale to support the associated labeled expiry or lack thereof. For example, you noted that any labeled expiry is based on the expiration date of the bulk concentrate active ingredient (i.e., benzalkonium chloride) used to manufacture your hand sanitizer drug products.
Unapproved New Drug and Misbranding Violations
“35% FOOD GRADE HYDROGEN PEROXIDE,” “LIQUID HAND SANITIZER,” and “3% FOOD GRADE HYDROGEN PEROXIDE” are “drugs” as defined by section 201(g)(1)(B) of the FD&C Act, 21 U.S.C. 321(g)(1)(B) because they are 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 they are intended to affect the structure or any function of the body. Specifically, they are intended for use as an over-the-counter antigingivitis/antiplaque oral healthcare drug, consumer antiseptic rub, and first-aid antiseptic/antigingivitis oral healthcare drug, respectively.
At the outset, as set forth below, your website promotes hydrogen peroxide, including 35% hydrogen peroxide, as an antiplaque/antigingivitis oral healthcare drug. There are serious risks posed by the use of “35% FOOD GRADE HYDROGEN PEROXIDE” in its undiluted form if used as an oral healthcare drug. Such harm may include caustic injury to the gastrointestinal tract [esophagitis, gastritis] or development of oxygen gas emboli with resultant life-threatening cerebrovascular, pulmonary, and/or cardiac emboli if ingested.
Examples of claims from the products’ labels and labeling that provide evidence of the intended uses (as defined by 21 CFR 201.128) of these products include, but may not be limited to, the following:
“35% FOOD GRADE HYDROGEN PEROXIDE”1
- “Hydrogen Peroxide as a Gum Disease Treatment…A cause of worry is that if ‘Gingivitis,’ the early and curable form of gum disease, is not treated, it can turn into ‘Periodontitis,’ a more severe form of gum disease and can cause teeth to fall out or loosen. Hydrogen peroxide can break up plaque and kill bacteria.”2 [from the blog tab of your product website listed on the product label, www.bulkperoxide.com]
“LIQUID HAND SANITIZER”
- “Drug Facts…Uses…For hand sanitizing to decrease bacteria on the skin Recommended for repeated use” [from product label]
“3% FOOD GRADE HYDROGEN PEROXIDE”
- “First Aid Antiseptic” [from product label]
- “Hydrogen Peroxide as a Gum Disease Treatment…A cause of worry is that if ‘Gingivitis,’ the early and curable form of gum disease, is not treated, it can turn into ‘Periodontitis,’ a more severe form of gum disease and can cause teeth to fall out or loosen. Hydrogen peroxide can break up plaque and kill bacteria.” [from the blog tab of your product website listed on the product label, www.bulkperoxide.com]
Unapproved New Drug Violations
Based on the above labeling claims, “35% FOOD GRADE HYDROGEN PEROXIDE” is intended for use as an antigingivitis/antiplaque oral healthcare drug, and “3% FOOD GRADE HYDROGEN PEROXIDE” is intended for use as an OTC combination antigingivitis/antiplaque oral healthcare and first aid antiseptic drug product. As described below, these drug 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).
In general, a drug product is a “new drug” within the meaning of section 201(p) of the FD&C Act, 21 U.S.C. 321(p), if it is not generally recognized as safe and effective (GRASE) for use under the conditions prescribed, recommended, or suggested in its labeling. With limited exceptions that do not apply here, new drugs may not be introduced or delivered for introduction into interstate commerce without an application approved by FDA, as described in section 505(a) of the FD&C Act, 21 U.S.C. 355(a). No FDA-approved application is in effect for either of the two drug products identified above.
Your “35% FOOD GRADE HYDROGEN PEROXIDE” is intended for use as an antigingivitis/antiplaque oral healthcare drug based on the labeling claim identified above. Antigingivitis/antiplaque oral healthcare drug products are subject to section 505G of the FD&C Act, 21 U.S.C. 355h, which governs nonprescription drugs marketed without an approved application. Under 505G(a)(3) of the FD&C Act, drugs that were classified as Category I for safety and effectiveness in an advance notice of proposed rulemaking (ANPR) that is the most recently applicable proposal or determination issued under 21 CFR Part 330 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 ANPR, including labeling conditions, and comply with all other applicable requirements.
We note that over-the-counter (OTC) antigingivitis/antiplaque oral healthcare drug products were addressed in an ANPR entitled “Oral Health Care Drug Products for Over-the-Counter Human Use; Antigingivitis/Antiplaque Drug Products; Establishment of a Monograph,” (68 FR 32232, May 29, 2003) (hereinafter “2003 ANPR”). Under the 2003 ANPR, hydrogen peroxide is classified as Category I for safety at a concentration of up to 3% and Category III for effectiveness. Category III for effectiveness means that additional effectiveness data are needed to support a determination that a drug product containing this active ingredient would be GRASE for use as an antigingivitis/antiplaque oral healthcare product.
Because hydrogen peroxide, the active ingredient in your “35% FOOD GRADE HYDROGEN PEROXIDE” antigingivitis/antiplaque oral healthcare drug product, is not classified as Category I for both safety and effectiveness, section 505G does not exempt this product from the requirement to have an approved application under section 505 of the FD&C Act.
Furthermore, your “3% FOOD GRADE HYDROGEN PEROXIDE” is intended for use as a both an antigingivitis/antiplaque oral healthcare and first aid antiseptic drug, based on the labeling claims identified above. Neither the 2003 ANPR, the Over-the-Counter Monograph M003: First Aid Antiseptic Drug Products for Over-the-Counter Human Use (hereinafter “M003”),3 nor any other monograph addresses the combination of an antigingivitis/antiplaque oral healthcare and first aid antiseptic drug product. Therefore, section 505G does not exempt your “3% FOOD GRADE HYDROGEN PEROXIDE” drug product from the requirement to have an approved application under section 505 to be legally marketed as a drug. In addition, even if your product were intended for use solely as an antigingivitis/antiplaque oral healthcare drug, as stated previously, the 2003 ANPR classifies hydrogen peroxide as Category I for safety at a concentration of 3% and Category III for effectiveness.
In addition, we are not aware of any adequate and well-controlled clinical studies in the published literature that support a determination that “35% FOOD GRADE HYDROGEN PEROXIDE” and “3% FOOD GRADE HYDROGEN PEROXIDE” are GRASE for use under the conditions prescribed, recommended, or suggested in its labeling. Moreover, there is no evident basis under the FD&C Act under which these products would be legally marketed without an approved application. No FDA-approved application pursuant to section 505 of the FD&C Act, 21 U.S.C. 355, is in effect for your products.
Accordingly, your products are unapproved new drugs marketed in violation of section 505(a) of the FD&C Act, 21 U.S.C 355(a).
Introduction or delivery for introduction of such products into interstate commerce is prohibited under sections 301(d) of the FD&C Act, 21 U.S.C. 331(d).
Misbranded Drug Violations
Additionally, “35% FOOD GRADE HYDROGEN PEROXIDE” and “3% FOOD GRADE HYDROGEN PEROXIDE” are misbranded under section 502(ee) of the FD&C Act, 21 U.S.C. 352(ee), because these products are nonprescription drugs 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.
“LIQUID HAND SANITIZER” is misbranded under section 502(b)(1) of the FD&C Act, 21 U.S.C. 352(b)(1) because the product label does not contain the place of business of the manufacturer, packer, or distributor. Although the label contains the name of the manufacturer, “PureChemPros,” it does not include the place of business of the manufacturer.
Additionally, “LIQUID HAND SANITIZER” is misbranded under section 502(x) of the FD&C Act, 21 U.S.C. 352(x) because the product label fails to include a domestic address or domestic telephone number through which the responsible person may receive a report of a serious adverse event with such drug.
Lastly, “3% FOOD GRADE HYDROGEN PEROXIDE” is also misbranded under section 502(c) of the FD&C Act, 21 U.S.C. 352(c), because the information that is required to appear on the labeling is not prominently placed thereon with such conspicuousness and in such terms as to render it likely to be read and understood by the ordinary individual under customary conditions of purchase and use. Specifically, the product label fails to include a Drug Facts panel as required under 21 CFR 201.66.
Introduction or delivery for introduction of such products into interstate commerce is prohibited under section 301(a) of the FD&C Act, 21 U.S.C. 331(a).
Systemic Remediation
In response to this letter, confirm whether you intend to continue manufacturing any drugs at this facility or any other facility in the future. If you plan to continue CGMP activities, you are responsible for resolving all deficiencies and systemic flaws to ensure your firm is capable of ongoing CGMP compliance.
Based upon the nature of the violations we identified at your firm, you should engage a consultant qualified as set forth in 21 CFR 211.34 to assist your firm in meeting CGMP requirements. The qualified consultant should also perform a comprehensive six-system audit of your entire operation for CGMP compliance and evaluate the completion and efficacy of all corrective action and preventive action (CAPA) before you pursue resolution of your firm’s compliance status (i.e., Quality System, Facilities & Equipment System, Materials System, Production System, Packaging & Labeling System, and Laboratory Control System) per FDA’s guidance document Quality Systems Approach to Pharmaceutical CGMP Regulations.
Once these actions are complete, provide a report verifying implementation and adequacy of your corrective and preventive actions.
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.
