---

---

---

WARNING LETTER

July 1, 2024

Dear Ms. Vanderlaan:

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Genuine Virgin Aloe Corp, dba Triderma, FEI 3008235829, at 1395 North Manassero Street, Anaheim, CA, from January 17 to 29, 2024.

This warning letter summarizes significant violations of Current Good Manufacturing Practice (CGMP) regulations for finished pharmaceuticals. See Title 21 Code of Federal Regulations (CFR), parts 210 and 211 (21 CFR parts 210 and 211).

Because your methods, facilities, or controls for manufacturing, processing, packing, or holding do not conform to CGMP, your drug products are adulterated within the meaning of section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), 21 U.S.C. 351(a)(2)(B).

We reviewed your February 19, 2024, response to our Form FDA 483 in detail.

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

1. 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)).

Your firm manufactures over-the-counter (OTC) drug products such as skin protectant creams for eczema and diabetics. You failed to conduct adequate identity testing on incoming raw materials such as salicylic acid, allantoin, and colloidal oatmeal used in the manufacture of your OTC drug products. Furthermore, you relied on your suppliers’ certificate of analyses (COA) without establishing the reliability of your component suppliers’ test analyses at appropriate intervals.

Your firm also failed to adequately test each shipment of each lot of incoming components at high risk of diethylene glycol (DEG) or ethylene glycol (EG) contamination. These include, but are not limited to, testing of glycerin, you use in manufacturing drug products to determine its appropriate identity. Identity testing of glycerin, along with other high-risk drug components,¹ include 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 identity testing on each shipment of each glycerin lot using the USP identification test that detects these hazardous impurities, you failed to assure the acceptability of these components for use in the 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 the 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.

In your response, you commit to performing “required physical, analytical, and microbial tests specified in the COA to verify the product’s compliance with the agreed-upon specifications.”

Your response is inadequate because you failed to provide sufficient details regarding how you will ensure that at least one identity test for each lot of incoming raw materials is performed, and how you establish the reliability of your component suppliers’ COAs at appropriate intervals. You also did not address how you will assess the quality of your components used in your distributed drug products that are within expiry.

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 retains for all lots of high-risk drug components used in the manufacture of drug products. Alternatively, if a retain of a component lot is unavailable, perform retain 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 (including, but not limited to, glycerin). 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 action and preventive action (CAPA) 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 suppliers’ COA instead of testing each component lot for strength, quality, and purity, specify how you will robustly establish the reliability of your suppliers’ 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.
• A summary of your program for qualifying and overseeing contract facilities that test the incoming components and finished drug products you manufacture.

2. 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 failed to validate the processes used to manufacture your drug products. In addition, you could not provide evidence that you have qualified all of your manufacturing equipment.

In your response you state that you will conduct equipment qualification, as well as validate your manufacturing processes.

Your response is inadequate because you did not commit to ensuring prospective validation studies are completed prior to the distribution of your products, nor did you include a risk assessment for marketed drug products manufactured by unvalidated processes.

Without adequate process validation, your firm lacks basic assurance that you can consistently deliver products that meet specifications. See the FDA’s guidance document Process Validation: General Principles and Practices for general principles and approaches that the FDA considers appropriate elements of process validation at, https://www.fda.gov/media/71021/download.

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 appropriate PPQ for each of your marketed drug products. Include your process performance protocol(s), and written procedures for qualification of equipment and facilities.
• A risk assessment for the distributed drug product produced using inadequately validated process.
• Provide a detailed program for designing, validating, maintaining, controlling, and monitoring each of your manufacturing processes that includes vigilant monitoring of intra-batch and inter-batch variation to ensure an ongoing state of control. Also, include your program for qualification of your equipment and facility.

3. Your firm failed to establish an adequate written testing program designed to assess the stability characteristics of drug products and to use results of stability testing to determine appropriate storage conditions and expiration dates. (21 CFR 211.166(a)).

Your firm failed to establish an adequate stability program and determine appropriate expiration dates for the drug products that you manufacture. You assigned a three-year expiry period to many of your drug products but failed to provide data to demonstrate that their chemical and physical attributes will remain acceptable throughout the expiry period assigned.

In your response, you state that you would place drug products on accelerated stability studies to issue tentative expiration dates, and place (b)(4) commercial batches in long term stability studies to confirm tentative expiration dates. Your response fails to indicate whether you are going to use validated stability indicating methods in your stability program.

In response to this letter, provide the following:

• A comprehensive, independent assessment and CAPA plan to ensure the adequacy of your stability program. Your remediated program should include, but not be limited to:

o Stability indicating methods.
o Stability studies for each drug product in its marketed container-closure system before distribution is permitted.
o An ongoing program in which representative batches of each drug product are added each year to the program to determine if the shelf-life claim remains valid.
o Detailed definition of the specific attributes to be tested at each station (timepoint)
o All procedures that describe these and other elements of your remediated stability program.

4. 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)).

Your quality unit (QU) failed to provide adequate oversight of your CGMP records. For example, your batch record for Psoriasis Control Cream, lot (b)(4), contained incomplete information. Additionally, your QU failed to follow your procedures for conducting annual product reviews.

In your response, you indicate you have created new procedures for batch production record review and annual product reviews. Your response is inadequate because you do not assess whether you reviewed other production records for missing information and whether the incomplete or missing information in the batch records affected distributed drug products.

Significant findings in this letter demonstrate that your firm does not operate an effective quality system in accordance with CGMP. In addition to the lack of effective management oversight of your production operations, we found your QU is not enabled to exercise proper authority and/or has insufficiently implemented its responsibilities. Executive management should immediately and comprehensively assess your company’s global manufacturing operations to ensure that your systems, processes, and products conform to the FDA requirements.

See the 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.

In response to this letter, provide the following:

• 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.

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 evaluate your operations and 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 your CAPAs before you pursue resolution of your firm’s compliance status with the FDA. 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 the FDA to withhold issuance of Export Certificates. The 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.

Please send your electronic reply to ORAPHARM4_Responses@FDA.HHS.GOV or mail your reply to:

CDR Steven E. Porter, Jr.
Director, Division of Pharmaceutical Quality Operations IV
U.S. Food & Drug Administration
19701 Fairchild Road
Irvine, California 92612-2506

Please identify your responses with the unique identifier: CMS 679744.

If there is any question about the released information, please contact Yumi Hiramine, Compliance Officer at Yumi.Hiramine@fda.hhs.gov, or at (818) 226-1839.

Sincerely,
/S/

CDR Steven E. Porter, Jr.
Director, Division of Pharmaceutical Quality Operations IV

__________________

1 Components with higher risk of DEG or EG contamination compared to other drug components.