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Case #:    670899

WARNING LETTER

 

Dear Mr. Hoogendoorn:

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, ARG Laboratories, Inc., FEI 3002556034, at 2639 Manana Drive, Dallas, TX from September 11 to 20, 2023.

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, “Golden Tiger Natural Pain Relieving Cream” and “Pain Wizard Natural Relief for Muscular & Arthritic Pain” products are unapproved new drugs introduced or delivered for introduction into interstate commerce in violation of sections 505(a) and 301(d) of the FD&C Act, 21 U.S.C 355(a) and 331(d). Further, “Golden Tiger Natural Pain Relieving Cream” and “Pain Wizard Natural Relief for Muscular & Arthritic Pain” are misbranded under section 502(ee) of the FD&C Act, 21 U.S.C. 352(ee). Introduction or delivery for introduction of a misbranded product 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 reviewed your October 4, 2023, response to our Form FDA 483 in detail.

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

CGMP Violations

1.    Your firm failed to establish an adequate quality unit and the responsibilities and procedures applicable to the quality control unit are not in writing and fully followed (21 CFR 211.22(a) and (d)).

You manufacture topical over-the-counter (OTC) drug products for the U.S. market. Your quality unit (QU) did not provide adequate oversight for the manufacture of your OTC drug products. For example, your QU failed to establish adequate procedures describing the roles and responsibilities of the QU, including for supplier qualification, change control, investigation of out-of-specification (OOS) results, recalls, and complaint handling. Notably, your QU released Bullfrog Amphibious SPF Lotion that failed your specification of (b)(4)% for the active ingredient octocrylene. FDA also documented multiple other drug product lots that failed your specifications but were released.

Your response states that you intend to create procedures to comply with CGMP and ensure that all active ingredients are within the “required and approved analytic ranges.”

Your response is inadequate because you failed to address the fundamental deficiencies in your QU that led to these failures. You do not provide a comprehensive corrective action and preventative action (CAPA) plan with a systematic approach to correct these oversight deficiencies.

In response to this letter, provide:

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:

•    A determination of whether procedures used by your firm are robust and appropriate.
•    Provisions for QU oversight throughout your operations to evaluate adherence to appropriate practices.
•    A complete and final review of each batch and its related information before the QU disposition decision.
•    Oversight and approval of investigations and discharging of all other QU duties to ensure identity, strength, quality, and purity of all products.

Your firm’s quality systems are inadequate. 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/regulatory- information/search-fda-guidance-documents/quality-systems-approach-pharmaceutical- current-good-manufacturing-practice-regulations.

2.    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 211.84(d)(2)).

You failed to adequately test your incoming components for identity before using the components in your OTC drug products, including propylene glycol and active pharmaceutical ingredients such as octocrylene. Additionally, you relied on the certificates of analysis (COA) from your suppliers and failed to establish the reliability of each of your suppliers’ analyses at appropriate intervals.

Further, identity testing for propylene glycol and certain other high-risk drug components1 includes a limit test in the United States Pharmacopeia (USP) to ensure that the component meets the relevant safety limits for levels of DEG or EG. Because you did not perform adequate identity testing on each shipment of each lot using the USP identification test that detects these hazardous impurities, you failed to assure the acceptability of these components for use in manufacture of your drug products.

The use of ingredients contaminated with DEG or EG has resulted in various lethal poisoning incidents in humans worldwide. See FDA’s guidance document Testing of Glycerin, Propylene Glycol, Maltitol Solution, Hydrogenated Starch Hydrolysate, Sorbitol Solution, and Other High-Risk Drug Components for Diethylene Glycol and Ethylene Glycol to help you meet the CGMP requirements when manufacturing drugs containing ingredients at high-risk for DEG or EG contamination at https://www.fda.gov/media/167974/download.

Without adequate testing, you do not have appropriate assurance that components conform to appropriate specifications prior to use in the drug products you manufacture.

Your response states that you will sample and inspect all incoming raw materials to ensure they are “identified and match the supplier COA,” and that you will validate your suppliers’ test results. Your response is inadequate because it did not include a detailed plan for how raw materials will be tested, including test methods and review of compendial requirements. Your response also lacked sufficient detail on how you plan to establish the reliability of the test results on your suppliers’ COAs at appropriate intervals. Additionally, you did not consider a retrospective review of previously distributed drug products.

In response to this letter, provide:

•    A commitment to provide DEG and EG test results, no later than 30 calendar days from the date of this letter, from testing reserve samples of all lots of high-risk drug components used in the manufacture of drug products. Alternatively, if a reserve sample of a component lot is unavailable, perform reserve sample testing of all implicated finished drug product batches for the presence of DEG and EG.

•    A full risk assessment for drug products that are within expiry which contain any ingredient at risk for DEG or EG contamination. Take prompt and appropriate actions to determine the safety of all lots of the component(s) and any related drug product that could contain DEG or EG, including customer notifications and product recalls for any contaminated lots. Identify additional appropriate corrective actions and preventive actions (CAPAs) that secure supply chains in the future, including, but not limited to, ensuring that all incoming raw material lots are from fully qualified manufacturers and free from unsafe impurities. Detail these actions in your response to this letter.

•    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. In the case of glycerin, propylene glycol, and certain additional high-risk components we note that this includes the performance of parts A, B, and C of the USP monograph.

•    The chemical and microbiological quality control specifications you use to test and release each incoming lot of component for use in manufacturing.

•    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.

3.    Your firm failed to establish adequate 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 production and process controls. During the inspection, you acknowledged that you did not conduct process validation studies and cleaning validation studies for your non-dedicated equipment. You also failed to validate your (b)(4) water system, which supplies water as a component used in your OTC drug products. When requested to provide water quality test results, you failed to provide any test results.

Your response states that validation will be conducted on kettles used in OTC drug product manufacturing, and that the cleaning processes and water system would be validated. Your response is inadequate because it lacks sufficient detail and did not include a risk assessment or identify corrective actions to address drug products manufactured without a validated process currently in distribution.

In response to this letter, provide:

•    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 (PPQ), and ongoing monitoring of both intra-batch and inter-batch variation to ensure a continuing state of control.

•    A timeline for performing PPQ for each of your marketed drug products. Include your process performance protocol(s), and written procedures for qualification of equipment and facilities.

•    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.
 
•    A (b)(4) water system validation report. Also include the summary of any improvements made to system design and to the program for ongoing control and maintenance.

•    A procedure governing your program for ongoing control, maintenance, and monitoring that ensures the (b)(4) water system consistently produces water that meets (b)(4) monograph specifications and appropriate microbial limits.

Your firm lacks an adequate process validation program. 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 include intensive monitoring and testing throughout each significant process stage to characterize intra-batch variation and evaluate batches to 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.

4.    Your firm failed to follow a 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)).

You failed to follow your written stability procedures for your OTC drug products. During the inspection you stated that you used expiration dates provided by your clients but were unable to provide documentation to support those dates.

In your response, you state that you will place process validation batches on stability and assign appropriate expiration dates, unless the stability data is provided by your clients. Your response is inadequate because you did not address the lack of stability data to support the expiration dates for your drug products that are currently on the market.

In response to this letter, provide:

•    A comprehensive 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 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

Unapproved New Drug and Misbranding Violations

“Golden Tiger Natural Pain Relieving Cream” and “Pain Wizard Natural Relief for Muscular & Arthritic Pain,” 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.

Examples from the products’ labeling that provide evidence of the intended uses (as defined by 21 CFR 201.128) of the products as drugs include, but may not be limited to, the following:

“Golden Tiger Natural Pain Relieving Cream”

•    “DRUG FACTS…Uses: Temporarily relieves the minor aches and pains of muscles and joints associated with: ■ simple backache ■ arthritis ■ sprains ■ bruises ■ strains” [from the product label]
•    “NATURAL PAIN RELIEVING CREAM…Enriched with Capsaicin, Aloe Vera, Willow Bark & MSM” [from the product label]
•    “Golden Tiger’s Pain Relief Cream is an ideal remedy for inflammation and pain. With natural botanicals like willow, menthol, capsaicin, and ginger, relief is on the way as soon as you apply it… Golden Tiger Pain Relief Cream offers fast and effective relief from pain and inflammation from arthritis, bursitis, neck aches, headaches, cramps, backaches, bruises, muscle strains and sprains, fibromyalgia, muscle soreness, joint pain, sports injuries, and tendonitis.” [from the product website www.goldentigerusa.com listed on the product label]
•    “Other botanicals – ginger, willow, and curcumin – then penetrate and go to work reducing inflammation and relieving pain. . . ”[from the product website www.goldentigerusa.com listed on the product label]
•    “. . .ginger and curcumin fight inflammation, willow eases pain, and capsaicin loosens and warms.” [from the product website www.goldentigerusa.com listed on the product label]
•    “Golden Tiger Pain Relief Cream works quickly and effectively to relieve pain and inflammation with the power of natural botanicals like ginger, willow, and curcumin, and capsaicin.” [from the product website www.goldentigerusa.com listed on the product label]
 
“Pain Wizard Natural Relief for Muscular & Arthritic Pain”
•    “DRUG FACTS…Uses: Temporarily relieves the minor aches and pains of muscles and joints associated with: ■ simple backache ■ arthritis ■ sprains ■ bruises ■ strains” [from your product label]
•    Natural Relief for Muscular & Arthritic Pain…Enriched with Capsaicin, Camphor, Menthol & MSM” [from the product label]
•    [T]he anti-inflammatory Bromelain, an enzyme found in pineapples; from India came the anti-inflammatory Boswellia, found in the bark of the boswellia tree; from China came the anti-inflammatory, Green Tea Extract, from the leaves of the green tea plant; from Germany came the anti- inflammatory and pain reliever, Arnica, derived from the arnica montana flower; . . . Methyl Sulfonyl Methane (MSM) was added to help deliver these fine ingredients deeper into the tissues. [from the product website painwizard.com listed on your product label]

Unapproved New Drug Violations

Based on the above labeling, “Golden Tiger Natural Pain Relieving Cream” and “Pain Wizard Natural Relief for Muscular & Arthritic Pain” are intended for use as counterirritant external analgesic drug products. 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).

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 certain exceptions not applicable here, a new drug may not be introduced or delivered for introduction into interstate commerce without an approved application from FDA in effect, as described in section 505(a) of the FD&C Act, 21 U.S.C. 355(a). No FDA- approved application pursuant to section 505 of the FD&C Act, 21 U.S.C. 355, is in effect for the drug products identified above.

Under section 505G of the FD&C Act, certain nonprescription drugs marketed without an approved application —commonly referred to as "OTC monograph drugs"—may be legally marketed if they meet applicable requirements. With respect to nonprescription counterirritant external analgesic drug products, in order to be GRASE and not new drugs, the product must, among other things, conform to the conditions of use in the applicable OTC monograph, here the Over-the-Counter Monograph M017: External Analgesic Drug Products for Over-the-Counter Human Use (hereafter “M017”).2 However, “Golden Tiger Natural Pain Relieving Cream” and “Pain Wizard Natural Relief for Muscular & Arthritic Pain” do not conform to conditions specified in M017 for the reasons described below.

The product labeling for “Golden Tiger Natural Pain Relieving Cream” and “Pain Wizard Natural Relief for Muscular & Arthritic Pain” promote several ingredients as “active ingredients” that are not permitted by M017.3 For example, the product website for “Golden Tiger Natural Pain Relieving Cream” promotes several ingredients as providing pain relieving benefits, e.g., “botanicals like willow, menthol, and ginger, relief is on the way” and “ginger, willow, and curcumin – then penetrate and go to work reducing inflammation and relieving pain.” In addition, we note that the principal display panel of the product, prominently features willow bark. Similarly, the labeling for the “Pain Wizard Natural Relief for Muscular & Arthritic Pain” product makes several statements about the product’s ingredients, including “. . . (MSM) was added to help deliver these fine ingredients deeper into the tissues,” along with promoting MSM prominently on the principal display panel of the product. While your products are formulated to contain camphor and menthol as active ingredients, which are permitted by M017 to be active ingredients in counterirritant external analgesics, curcumin, willow bark, ginger, and MSM—in combination or as sole ingredients—are not permitted as active ingredients in M017.4 Although the Drug Facts Panels do not specifically list these ingredients as active ingredients, the website’s statements describing the pharmacological activity of ingredients along with the prominence of these specific ingredients demonstrate that they are each an “active ingredient” as defined in 21 CFR 201.66(b)(2) because they are intended to furnish pharmacological activity.5

Furthermore, “Golden Tiger Natural Pain Relieving Cream” includes indications that are not consistent with the permitted indications in M017. For example, claims that the product can be used for “relief from...inflammation…fibromyalgia…and tendonitis” do not conform with M017.50(b).

Therefore, “Golden Tiger Natural Pain Relieving Cream” and “Pain Wizard Natural Relief for Muscular & Arthritic Pain” drug products do not comply with the applicable conditions set forth in M017 and have not otherwise been found GRASE.6 Accordingly, these products are new drugs within the meaning of section 201(p) of the FD&C Act, 21 U.S.C. 321(p), and there is no basis under which section 505G of the FD&C Act under which these products would be legally marketed without an approved application. Because there are no approved applications in effect for these products, these products are unapproved new drugs. The introduction or delivery for introduction into interstate commerce of this unapproved new drugs violates sections 505(a) and 301(d) of the FD&C Act, 21 U.S.C 355(a) and 331(d).

Misbranded Drug Violations

Additionally, “Golden Tiger Natural Pain Relieving Cream” and “Pain Wizard Natural Relief for Muscular & Arthritic Pain” 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 neither one is 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 such products into interstate commerce is prohibited under section 301(a) of the FD&C Act, 21 U.S.C. 331(a).

CGMP Consultant Recommended

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.

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.

Your written notification should refer to case # 670899.

Please electronically submit your reply, on company letterhead, to Rebecca Asente, Compliance Officer, at ORAPHARM2_RESPONSES@fda.hhs.gov, and copy Ronda Loyd-Jones, Director, Compliance Branch at Ronda.Loyd- Jones@fda.hhs.gov.

If you have questions regarding the contents of this letter, you may contact Rebecca Asente via (504) 846-6104 or Rebecca.Asente@fda.hhs.gov.

 
Sincerely,
/S/
Monica R. Maxwell Program Division Director
Office of Pharmaceutical Quality Operations, Division II