AmWiner & Raphe Holdings, LLC dba rapheGenerics Corp

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, AmWiner & Raphe Holdings LLC, FEI 3009569638, at 11601 Plano Road Suite 104, Dallas, Texas 75243, from June 20 to August 7, 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).

In addition, “MEN’S LIFECELL HAIR RESTORATION SOLUTION HAIR REGROWTH TREATMENT EXTRA STRENGTH” and “WOMENS LIFECELL 2% MINOXIDIL TOPICAL SOLUTION USP HAIR REGROWTH TREATMENT” drug products are unapproved new drugs introduced or delivered for introduction into interstate commerce in violation of section 505(a) and 301(d) of the FD&C Act, 21 U.S.C. 355(a) and 331(d). These violations are described in more detail below.

We reviewed your August 21, 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 have, 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 (21 CFR 211.165(a)).

Your firm manufactures topical over-the-counter (OTC) drug products, including drug products that contain the active ingredient minoxidil. You failed to establish adequate release testing procedures or specifications for your OTC drug products, and accordingly released batches of drug products for distribution without conducting adequate testing to confirm critical quality attributes.

In your response, you state that your finished product testing will be performed by a contract laboratory. Your response is inadequate. You did not describe how you will ensure that your finished products meet appropriate quality standards prior to release. You also did not consider a detailed risk assessment addressing the potential effects of releasing drug product to the market without established specifications to ensure their identity, strength, quality, and purity.

Full release testing, including strength and identity testing of the active ingredient, must be performed before drug product release and distribution. Without adequate testing, you do not have adequate scientific evidence to assure that your drug products conform to appropriate specifications before release.

In response to this letter, provide:

A list of chemical and microbial specifications, including test methods, used to analyze each lot of your drug products before a batch disposition decision.o 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.o 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.

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, and your firm’s quality control unit did not review and approve those procedures, including any changes (21 CFR 211.100(a)).

Your firm failed to complete equipment and process performance qualification (PPQ) prior to releasing your OTC drug products. Likewise, you lacked appropriate documentation, qualification, maintenance, and monitoring of your purified water system, which is used in the manufacture of your OTC drug products.

In your response, you state that procedures have been established to monitor and validate the performance of your manufacturing processes including qualifying all manufacturing equipment. You also commit to testing your purified water before it used in any manufacturing process.

Your response is inadequate as you did not provide sufficient information (such as validation protocols, reports, or timelines) to establish that your equipment and processes are adequately qualified and validated. Further, information, such as sampling procedures, testing procedures, method validation, or routine monitoring results, were not provided to support that your purified water system is adequately monitored and maintained.

In response to this letter, provide:

A remediation plan that better assures ongoing management oversight throughout the manufacturing lifecycle of all drug products. Provide a more data-driven and scientifically sound program that identifies sources of process variability, and assures that manufacturing (including both production and packaging) operations meet appropriate parameters and quality standards. This includes, but is not limited to, evaluating suitability of equipment for its intended use, ensuring quality of input materials, determining the capability and reliability of each manufacturing process step and its controls, and vigilant ongoing monitoring of process performance and product quality.

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 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.

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 comprehensive remediation plan for the design, control, and maintenance of the water system.o A purified 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 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 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.

The current action/alert limits for total counts and objectionable organisms used for your purified water system. Ensure that the total count limits for your purified water are appropriately stringent in view of the intended use of each of the 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 Purified Water, USP monograph specifications and appropriate microbial limits.

3. 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, including propylene glycol and active ingredients such as minoxidil, for identity before using them in the manufacture of your OTC drug products. Additionally, you relied on your suppliers’ certificates of analysis (COAs) without establishing the reliability of each of your suppliers’ analyses at appropriate intervals.

Propylene Glycol

You failed to adequately test each shipment of each lot of propylene glycol for identity, components at higher risk for diethylene glycol (DEG) and ethylene glycol (EG) contamination. Identity testing for glycerin, 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 product.

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.

In your response, you state that “full compendial” testing of raw materials will be performed by a contract laboratory. You also state that propylene glycol will be tested for DEG impurities before use in manufacturing, and that your firm will no longer depend on the manufacturer's COA for propylene glycol and minoxidil. Your response is inadequate. You did not provide a detailed plan for how components will be tested, including test methods and review of compendial requirements, or a timeline for implementing the corrective actions proposed. Additionally, you did not describe how you plan to establish the reliability of the test results on your suppliers’ COAs at appropriate intervals. Further, you did not consider testing retains of raw materials or a retrospective review of previously distributed OTC drug products.

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

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 lots 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, propylene glycol). 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 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 microbiology quality control specifications you use to test each incoming lot of each incoming lot of components, including, high-risk drug components to determine acceptability 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 results obtained from testing all components to evaluate the reliability of the COA from each component manufacturer. Include your standard operating procedure that describes this COA validation program.

A summary of your program for qualifying and overseeing contract facilities that test the drug products you manufacture.

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/media/71023/download.

“MEN’S LIFECELL HAIR RESTORATION SOLUTION HAIR REGROWTH TREATMENT EXTRA STRENGTH” and “WOMENS LIFECELL 2% MINOXIDIL TOPICAL SOLUTION USP HAIR REGROWTH TREATMENT” 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 “MEN’S LIFECELL HAIR RESTORATION SOLUTION HAIR REGROWTH TREATMENT EXTRA STRENGTH” and “WOMENS LIFECELL 2% MINOXIDIL TOPICAL SOLUTION USP HAIR REGROWTH TREATMENT” product labeling that provide evidence of the intended uses (as defined in 21 CFR 201.128) of the products as drugs include, but may not be limited to, the following:

“MEN’S LIFECELL HAIR RESTORATION SOLUTION HAIR REGROWTH TREATMENT EXTRA STRENGTH”

“HAIR REGROWTH TREATMENT EXTRA STRENGTH” [from the product label]

“Uses · Relieves scalp itching, irritation, redness, flaking and scaling due to seborrheic dermatitis · Helps eliminate recurrence of seborrheic dermatitis” [from the product label]

“Help hair loss and regrow fuller hair with LifeCell Extra Strength Hair Regrowth Treatment. This fast-working hair loss treatment is clinically proven to regrow up to 25% more hair. Unlike hair loss shampoos and hair thickening products that temporarily plump hair from the outside, LifeCell penetrates the scalp to reactivate shrunken hair follicles. The Minoxidil formula works to boost hair follicle activity and hair protein production, allowing for regrowth of hair. This hair thinning treatment comes in a topical solution that is easy to use: Simply apply 1 milliliter directly to your scalp twice daily and massage it through your hair.” [from the product website https://www.lifecellskin.com/]

“WOMENS LIFECELL 2% MINOXIDIL TOPICAL SOLUTION USP HAIR REGROWTH TREATMENT”

“HAIR REGROWTH TREATMENT” [from the product label]

“Reactivates Hair Follicles To Stimulate Regrowth” [from the product label]

“Uses · Relieves scalp itching, irritation, redness, flaking and scaling due to seborrheic dermatitis · Helps eliminate recurrence of seborrheic dermatitis” [from the product label]

“Help hair loss and regrow fuller hair with LifeCell Extra Strength Hair Regrowth Treatment. This fast-working hair loss treatment is clinically proven to regrow up to 25% more hair. Unlike hair loss shampoos and hair thickening products that temporarily plump hair from the outside, LifeCell penetrates the scalp to reactivate shrunken hair follicles. The Minoxidil formula works to boost hair follicle activity and hair protein production, allowing for regrowth of hair. This hair thinning treatment comes in a topical solution that is easy to use: Simply apply 1 milliliter directly to your scalp twice daily and massage it through your hair.” [from the product website https://www.lifecellskin.com/]

Based on the above labeling evidence, “MEN’S LIFECELL HAIR RESTORATION SOLUTION HAIR REGROWTH TREATMENT EXTRA STRENGTH” and “WOMENS LIFECELL 2% MINOXIDIL TOPICAL SOLUTION USP HAIR REGROWTH TREATMENT” are intended for use as OTC hair grower drug products, among other intended uses.2 As described below, these drugs 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).

As stated above, “MEN’S LIFECELL HAIR RESTORATION SOLUTION HAIR REGROWTH TREATMENT EXTRA STRENGTH” and “WOMENS LIFECELL 2% MINOXIDIL TOPICAL SOLUTION USP HAIR REGROWTH TREATMENT” are OTC hair grower drug products. According to 21 CFR 310.527(b), any OTC drug product that is labeled, represented, or promoted for external use as a hair grower or for hair loss prevention is regarded as a new drug within the meaning of section 201(p) of the FD&C Act, for which an approved new drug application under section 505 of the FD&C Act is required for marketing.

“MEN’S LIFECELL HAIR RESTORATION SOLUTION HAIR REGROWTH TREATMENT EXTRA STRENGTH” and “WOMENS LIFECELL 2% MINOXIDIL TOPICAL SOLUTION USP HAIR REGROWTH TREATMENT” are not generally recognized as safe and effective (GRASE) for its above referenced uses and, therefore, are “new drugs” under section 201(p) of the FD&C Act, 21 U.S.C. 321(p). Subject to 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 sections 301(d) and 505(a) of the FD&C Act, 21 U.S.C. 331(d) and 355(a). No FDA-approved applications pursuant to section 505 of the FD&C Act, 21 U.S.C. 355 are in effect for these products.

Accordingly, “MEN’S LIFECELL HAIR RESTORATION SOLUTION HAIR REGROWTH TREATMENT EXTRA STRENGTH” and “WOMENS LIFECELL 2% MINOXIDIL TOPICAL SOLUTION USP HAIR REGROWTH TREATMENT” 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 these products into interstate commerce violates section 301(d) of the FD&C Act, 21 U.S.C.331(d).

The violations cited in this letter are not intended to be an all-inclusive list of violations that exist in connection with your products. 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.

Send your electronic reply to CDER-OC-OMQ-Communications@fda.hhs.gov. Identify your response with FEI 3009569638 and ATTN: Christina Capacci-Daniel.