WARNING LETTER
AnuMed International, LLC
MARCS-CMS 674310 —
August 20, 2024
Delivery Method:
Via Email
Product:
Drugs
Recipient:
Recipient Name
Julie R. Alcantar
Recipient Title
Owner
AnuMed International, LLC
3908 E Broadway Rd, Suite 110
Phoenix
,
AZ
85040-2995
United States
julie@anumed-intl.com
Issuing Office:
Center for Drug Evaluation and Research (CDER)
United States
WARNING LETTER
August 20, 2024
RE: 674310
Dear Julie Alcantar:
The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, AnuMed International, LLC, FEI 3010164449, at 3908 E Broadway Rd, Suite 110, Phoenix, Arizona from November 1 to 7, 2023.
FDA also reviewed your website at the Internet address https://www.anumed-intl.com/ in February and April 2024 and has observed that your website offers “Semaglutide Homeopathic Formula,” “Magnesium 50 mg Body Cream,” “AnuMed™ 25mg Per Pump PROGESTERONE CREAM,” “AnuMed™ 75mg Per Pump PROGESTERONE CREAM,” “AnuMed™ BIO-IDENTICAL BIO-EST 2.5mg PER PUMP,” “AnuMed™ BIO-IDENTICAL BIO-EST 5mg Per Pump,” “AnuMed™ 2.5 All Natural ESTRIOL CREAM,” “AnuMed™ 5.0 All Natural ESTRIOL CREAM,” “AnuMed™ Bio-Identical DHEA 20 CREAM,” “AnuMed™ Bio-Identical DHEA 50 CREAM,” “50,000 IU Vitamin D3+K2 CREAM,” “Travel Safe Drops: Advanced Intestinal Flora, Parasite Cleanser & Digestive Health Support,” “Vitamin C Booster - 2000mg,” “Immune Booster 90 Capsules,” “Vegan Vitamin D3 K2 60ct Capsules,” “B-12 – 1000 and Vitamin B12 5000mcg Drops (Methylcobalamin),” “2oz Vitamin C Booster Drops,” “2oz Anumed Zinc Drops,” and “Turmeric Curcumin Drops 775mg with Black Pepper Extract” products for sale in the United States. As described below, your above-mentioned products are unapproved new drugs introduced or delivered for introduction into interstate commerce in violation of sections 505(a) and 301(d) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), 21 U.S.C. 355(a) and 331(d). Furthermore, your “Magnesium 50 mg Body Cream,” “AnuMed™ 25mg Per Pump PROGESTERONE CREAM,” “AnuMed™ 2.5 All Natural ESTRIOL CREAM,” “AnuMed™ 5.0 All Natural ESTRIOL CREAM,” “AnuMed™ BIO-IDENTICAL BIO-EST 2.5mg PER PUMP,” “AnuMed™ BIO-IDENTICAL BIO-EST 5mg Per Pump,” “AnuMed™ Bio-Identical DHEA 50 CREAM” and “AnuMed™ Bio-Identical DHEA 20 CREAM,” “Vitamin C Booster - 2000mg,” “Immune Booster 90 Capsules,” “Vegan Vitamin D3 K2 60ct Capsules,” “B-12 – 1000 and Vitamin B12 5000mcg Drops (Methylcobalamin)” products are misbranded drugs under section 502 of the FD&C Act, 21 U.S.C. 352, introduced or delivered for introduction into interstate commerce in violation of section 301(a) of the FD&C Act, 21 U.S.C. 331(a).
In addition, 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 FD&C Act, 21 U.S.C. 351(a)(2)(B). We reviewed your November 28, 2023, response to our Form FDA 483 in detail and acknowledge receipt of your subsequent correspondence.
Unapproved New Drugs
Based on a review of your product labeling obtained during FDA’s inspection and on your website, your “Semaglutide Homeopathic Formula,” “Magnesium 50 mg Body Cream,” “AnuMed™ 25mg Per Pump PROGESTERONE CREAM,” “AnuMed™ 75mg Per Pump PROGESTERONE CREAM,” “AnuMed™ BIO-IDENTICAL BIO-EST 2.5mg PER PUMP,” “AnuMed™ BIO-IDENTICAL BIO-EST 5mg Per Pump,” “AnuMed™ 2.5 All Natural ESTRIOL CREAM,” “AnuMed™ 5.0 All Natural ESTRIOL CREAM,” “AnuMed™ Bio-Identical DHEA 20 CREAM,” “AnuMed™ Bio-Identical DHEA 50 CREAM,” “50,000 IU Vitamin D3+K2 CREAM,” “Travel Safe Drops: Advanced Intestinal Flora, Parasite Cleanser & Digestive Health Support,” “Vitamin C Booster - 2000mg,” “Immune Booster 90 Capsules,” “Vegan Vitamin D3 K2 60ct Capsules,” “B-12 – 1000 and Vitamin B12 5000mcg Drops (Methylcobalamin),” “2oz Vitamin C Booster Drops,” “2oz Anumed Zinc Drops,” and “Turmeric Curcumin Drops 775mg with Black Pepper Extract” are drugs as defined by section 201(g)(1) of the FD&C Act, 21 U.S.C. 321(g)(1), because they are intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease, and/or intended to affect the structure or any function of the body.
Examples of claims from your product labeling and website https://www.anumed-intl.com/ that provide evidence of the intended use of these products as drugs include, but may not be limited to, the following:
Semaglutide Homeopathic Formula
On the product label:
• “CRAVINGS
APPETITE
WEIGHT LOSS”
• “INDICATIONS:
It may help to temporarily reduce minor hunger pangs and control appetite to support weight loss efforts.”
• “DIRECTIONS: . . . For maximum effectiveness repeat 2 to 3 times per day until desired weight or craving control is achieved. Continue as needed if cravings arise and to help avoid weight regain.”
Magnesium 50 mg Body Cream
On the product webpage:
• “Highly Effective for Leg Cramps, Muscle Soreness, Nighttime Leg Discomfort, Inflammation Relief”
• “Magnesium is important for many processes in the body. It helps regulate muscle and nerve function, blood sugar levels, blood pressure, making protein, bone and DNA. Studies have shown that deficiency of Magnesium results in cramping and several muscular pain.”
• “Magnesium Chloride helps with the normal functioning of cells, nerves, bones, and the heart.”
• “Niacin (vitamin B3) helps support the cardiovascular system and the heart. It contributes to healthy metabolic function, supports the pancreas, and works to support brain & nerve function.”
AnuMed™ 25mg Per Pump PROGESTERONE CREAM and AnuMed™ 75mg Per Pump PROGESTERONE CREAM
On the product label:
• “75 mg Per Pump PROGESTERONE CREAM . . . Hormones / Mood / Sleep . . . Use 1 pump a day 1 to 3 minutes before a meal, or as recommended by your practitioner.”
On the product webpage:
• “
5 Benefits of Natural Progesterone Cream with ISO99:
. . . Relieves Menopause Symptoms . . . promote bone density . . . Boosts Fertility . . . preventing miscarriage. . . . Treats Fibroid Tumors . . . Helps Endometriosis . . . Balance Hormones and Relieve PMS Symptoms . . . Relieves Inflammation”
AnuMed™ BIO-IDENTICAL BIO-EST 2.5mg PER PUMP and AnuMed™ BIO-IDENTICAL BIO-EST 5mg Per Pump
On the product webpage:
• “
Natural Bio-Identical BIO-EST 2.5mg
may help with menopause symptoms. . . .
BENEFITS
. . . Lower the risk of urinary tract infections (UTIs) . . . Strengthen bones and prevent osteoporosis”
• “
Natural Bio-Identical Bio-EST 5mg
may help with menopause symptoms. . . .
BENEFITS
. . . Lower the risk of urinary tract infections (UTIs) . . . Strengthen bones and prevent osteoporosis”
AnuMed™ 2.5 All Natural ESTRIOL CREAM and AnuMed™ 5.0 All Natural ESTRIOL CREAM
On the product webpage:
• “
Natural Bioidentical Estriol Cream 2.5 with Hyaluronic Acid
. . . #1 Recommended Estriol Cream for Menopause Relief, Mood Swings, Hot Flashes, Breast soreness . . . Natural Hormone Balance”
• “
Natural Bioidentical Estriol Cream 5.0 with Hyaluronic Acid
. . . #1 Recommended Estriol Cream for Menopause Relief, Mood Swings, Hot Flashes, Breast soreness . . . Natural Hormone Balance”
AnuMed™ Bio-Identical DHEA 20 CREAM and AnuMed™ Bio-Identical DHEA 50 CREAM
From your storefront on Amazon’s webpage https://www.amazon.com/ANUMED-Bioidentical-Dehydroepiandrosterone-Hyaluronic-Essential/dp/B0BNHH4R8Q?th=1
• “ANUMED – All Natural Bioidentical DHEA 20mg Cream . . . for Hormone Balance, Mood, Immune System . . . Natural Balancing of Hormone Levels, Promotes Mood, Immune System, Anti-Aging, Energy, Metabolism.”
On the product webpage:
• “
All Natural Bioidentical DHEA 50mg Cream (Dehydroepiandrosterone) + Hyaluronic Acid . . . Hormone Balance, Mood, Energy, Immune System
. . . Natural Balancing of Hormone Levels. Promotes Mood, Immune System, Anti-Aging, Energy, Metabolism.”
50,000 IU Vitamin D3+K2 CREAM
On the product label:
• “With Hyaluronic Acid . . . May Increase Calcium Absorption . . . PSORIASIS & ECZEMA RELIEF . . . May help relieve skin flares caused by Psoriasis & Eczema. . . . Vitamin D is necessary for strong bones and teeth. . . . May Help muscle function & support immune system. . . . May help heal wounds faster such as fading bruising.”
On the product webpage:
• “Vitamin D3 50,000 IU cream is our most potent vitamin-based solution created with the intent of replenishing the lowest vitamin deficiencies and relieving the symptoms of various conditions such as psoriasis and eczema in a minimal time frame. It can help with boosting immune system.”
Travel Safe Drops: Advanced Intestinal Flora, Parasite Cleanser & Digestive Health Support
• In the name of the product – “Parasite Cleanser”
On the product webpage:
• “A proprietary blend of herbals along with zinc to help fight and eliminate parasites in the body”
• “Wormwood kills adult parasites and especially pinworms.”
• “Black Walnut which has anti-fungal and antibacterial properties and can kill intestinal parasites like roundworm and tapeworm. It helps to clean out any toxins and dangerous pathogens.”
• “Clove Bud kills the parasite eggs that may be lingering in the intestinal tract along with worms . . . Thus, helps relieve indigestion and constipation problems. . . . These compounds provide potent antiseptic and anti-inflammatory benefits.”
• “Fennel is helpful in reducing diarrhea if it is caused by bacterial infection because some components of the essential oil in fennel such as anetol and cineole have disinfectant and antibacterial properties.” • “Ginger is known as an anti-parasitic. Researchers show that it can inhibit a variety of worms and parasites..”
Vitamin C Booster - 2000mg
On the product webpage:
• “Best protection support from cold, flu [influenza], virus [viral infection]”
• “Zinc may help with wound healting [sic]”
• “L-Lysine . . . Also, may help people with the herpes simplex virus (HSV) [viral infection] and diabetes.”
• “Ultimate Defense from cold, Flu [influenza], Virus [viral infection], allergy”
Immune Booster 90 Capsules
On the product webpage:
• “Has Zinc for which . . . may help combat colds, upper respiratory infections and viruses [viral infection]. . . . This product not only boosts immune system to help make body strong in order to combat most viruses [viral infection] and infections”
Vegan Vitamin D3 K2 60ct Capsules
On the product webpage:
• “Research studies have indicated that K2 intake can decrease bone loss among those with Osteoporosis.”
• “Vitamin D deficiencies have been linked by researchers to . . . sleeping disorders.”
• “Research has indicated that vitamin D, while in combination with other bodily properties, plays a pivotal role in fortifying the antibacterial potency of the essential immune cells.”
B-12 – 1000 and Vitamin B12 5000mcg Drops (Methylcobalamin)
On the product webpage:
• “Heart Disease: Research has found that B-12 in combination with B-6 and folic acid may help regulate and decrease the levels of homocysteine in the blood system, which are known to increase the chances of cardiovascular disease.”
• “Dementia and Cognitive Abilities: . . . Research has indicated an association between low levels of B-12 and cognitive decline. As a result, the B-12 . . . solution may help support and replace the lack of the nutrient while improving cognitive function.”
• “When the body has a deficiency of the vitamin, harmful bacteria begins to grow. A consistent intake of B-12 has demonstrated that it can help remove bad bacteria . . . and potentially prevent gastrointestinal disorders.”
2oz Vitamin C Booster Drops
On the product webpage:
• “Has been recommended to try and help ease cold and flu [influenza] symptoms.”
• “Be prepared for fighting illness and germs.”
2oz Anumed Zinc Drops
On the product webpage:
• “Ultimate Defense from Cold, Flu [influenza], Virus [viral infection], Allergy”
Turmeric Curcumin Drops 775mg with Black Pepper Extract
On the product webpage:
• “Curcumin and other chemicals in turmeric might decrease swelling (inflammation). Because of this, turmeric might be beneficial for treating conditions that involve inflammation. Has been known to help with the reduction of inflammation, pain”
Your “Semaglutide Homeopathic Formula,” “Magnesium 50 mg Body Cream,” “AnuMed™ 25mg Per Pump PROGESTERONE CREAM,” “AnuMed™ 75mg Per Pump PROGESTERONE CREAM,” “AnuMed™ BIO-IDENTICAL BIO-EST 2.5mg PER PUMP,” “AnuMed™ BIO-IDENTICAL BIO-EST 5mg Per Pump,” “AnuMed™ 2.5 All Natural ESTRIOL CREAM,” “AnuMed™ 5.0 All Natural ESTRIOL CREAM,” “AnuMed™ Bio-Identical DHEA 20 CREAM,” “AnuMed™ Bio-Identical DHEA 50 CREAM,” and “50,000 IU Vitamin D3+K2 CREAM,” “Travel Safe Drops: Advanced Intestinal Flora, Parasite Cleanser & Digestive Health Support,” “Vitamin C Booster - 2000mg,” “Immune Booster 90 Capsules,” “Vegan Vitamin D3 K2 60ct Capsules,” “B-12 – 1000 and Vitamin B12 5000mcg Drops (Methylcobalamin),” “2oz Vitamin C Booster Drops,” “2oz Anumed Zinc Drops,” and “Turmeric Curcumin Drops 775mg with Black Pepper Extract” products are not generally recognized as safe and effective (GRASE) for their 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
1
, 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 approved applications pursuant to section 505 of the FD&C Act, 21 U.S.C. 355, are in effect for these products.
2
Accordingly, the introduction or delivery for introduction into interstate commerce of these products violates sections 301(d) and 505(a) of the FD&C Act, 21 U.S.C. 331(d) and 355(a).
Misbranded Drugs
“Magnesium 50 mg Body Cream,” “AnuMed™ 25mg Per Pump PROGESTERONE CREAM,” “AnuMed™ 2.5 All Natural ESTRIOL CREAM,” “AnuMed™ 5.0 All Natural ESTRIOL CREAM,” “AnuMed™ BIO-IDENTICAL BIO-EST 2.5mg PER PUMP,” “AnuMed™ BIO-IDENTICAL BIO-EST 5mg Per Pump,” “AnuMed™ Bio-Identical DHEA 50 CREAM” and “AnuMed™ Bio-Identical DHEA 20 CREAM” are misbranded under section 502(a) of the FD&C Act, 21 U.S.C. 352(a), because the product labels and/or websites include statements that misleadingly suggest that the drug products are approved or endorsed by FDA in some way. For example, the website for Magnesium 50 mg Body Cream includes the image of a blue circle with the claim, “FDA * APPROVED * FACILITY.” Further, the product labels and/or websites for the other seven before-listed products include statements that these products are made or manufactured in an “FDA inspected and Certified Facility,” a “Certified FDA registered facility,” and/or a “FDA registered facility.” FDA’s regulations provide that “[r]egistration of an establishment or listing of a drug does not denote approval of the establishment, the drug, or other drugs of the establishment, nor does it mean that a product may be legally marketed” (21 CFR 207.77(a)). However, the general public is not likely to be familiar with the details of FDA’s regulations. The above assertions misleadingly suggest that the above-mentioned drug products are approved or endorsed by FDA in some way. Your “Magnesium 50 mg Body Cream,” “AnuMed™ 25mg Per Pump PROGESTERONE CREAM,” “AnuMed™ 2.5 All Natural ESTRIOL CREAM,” “AnuMed™ 5.0 All Natural ESTRIOL CREAM,” “AnuMed™ BIO-IDENTICAL BIO-EST 2.5mg PER PUMP,” “AnuMed™ BIO-IDENTICAL BIO-EST 5mg Per Pump,” “AnuMed™ Bio-Identical DHEA 50 CREAM” and “AnuMed™ Bio-Identical DHEA 20 CREAM” products are not the subjects of an FDA-approved application. Therefore, these products are misbranded under section 502(a) of the FD&C Act, 21 U.S.C. 352(a), because their labeling is false or misleading. 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, a drug is misbranded under section 502(f)(1) of the FD&C Act, 21 U.S.C. 352(f)(1) if the drug fails to bear adequate directions for its intended use(s). “Adequate directions for use” means directions under which a layperson can use a drug safely and for the purposes for which it is intended (21 CFR 201.5). Prescription drugs, as defined in section 503(b)(1)(A) of the Act, 21 U.S.C. 353(b)(1)(A), can only be used safely at the direction, and under the supervision, of a licensed practitioner.
Your “Vitamin C Booster - 2000mg,” “Immune Booster 90 Capsules,” “Vegan Vitamin D3 K2 60ct Capsules,” and “B-12 – 1000 and Vitamin B12 5000mcg Drops (Methylcobalamin)” are intended for prevention or treatment of one or more diseases that are not amenable to self-diagnosis, prevention, or treatment without the supervision of a licensed practitioner. Therefore, it is impossible to write adequate directions for a layperson to use these products safely for their intended purposes. Accordingly, your before-noted products fail to bear adequate directions for their intended uses and, therefore, are misbranded under section 502(f)(1) of the Act, 21 U.S.C. 352(f)(1). The introduction or delivery for introduction into interstate commerce of these misbranded drugs violates section 301(a) of the FD&C Act, 21 U.S.C. 331(a).
CGMP Violations
During our inspection, our investigator observed specific violations including, but not limited to, the following:
1. 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 failed to perform adequate identity testing, including specific identity testing as appropriate, for each shipment of each lot of components, such as glycerin and ethyl alcohol (ethanol; alcohol), used in the manufacture of your drug products. During the inspection, you indicated that you were not aware testing was required and that you rely upon your supplier’s certificate of analysis (COA) for acceptance of incoming materials.
Alcohol (Ethanol)
Identity testing for pharmaceutical alcohol (ethanol and isopropyl alcohol) includes a limit test in the United States Pharmacopeia (USP) to ensure that the component meets the relevant safety limits for levels of methanol. 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
at: https://www.fda.gov/media/173005/download.
Glycerin
Identity testing for glycerin and certain other high-risk drug components
3
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 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 risk for DEG or EG contamination, at https://www.fda.gov/media/167974/download.
In your response, you state that you are reviewing options for identity testing of raw materials. Your response is inadequate because you did not provide sufficient detail or evidence of corrective actions (e.g., assessing retain samples).
Without appropriate testing of components, you cannot ensure the quality and safety of your drug products.
In response to this letter, provide:
• 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.
• 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 commitment to provide test results for components used in the manufacture of your drug products, no later than 30 calendar days from the date of this letter, including testing retains for all lots of drug components at high-risk for DEG and EG contamination, and pharmaceutical alcohol for methanol contamination. 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, EG, and methanol.
• A full risk assessment for drug products that are within expiry which contain any ingredient at risk for DEG, EG, or methanol contamination (including, but not limited to, glycerin and ethyl alcohol). 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, EG, or methanol 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.
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)).
Lack of Process Validation
You failed to adequately validate your processes used to manufacture your drug products and demonstrate that your processes are reproducible and controlled to consistently yield drugs of uniform character and quality.
In your response, you state that your process validation procedure will be reviewed and personnel trained. However, your response is inadequate as you did not provide sufficient detail or evidence of corrective actions.
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 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.
See FDA's guidance for industry, Process Validation: General Principles and Practices for general principles and approaches that FDA considers appropriate elements of process validation at https://www.fda.gov/media/71021/download.
Inadequate Water System
Your firm uses water as a component to manufacture your drug products. You failed to adequately qualify your purified water system. You also failed to show that your water system is adequately monitored to ensure it consistently produces water that meets appropriate microbial limits. Routine monitoring of microbial counts and identity of contamination in the system is integral to ensuring oversight of ongoing state of control and suitability of water for use in manufacturing operations.
In your response, you state that your quality unit will begin conducting regular inspections to ensure the water system is adequate. However, your response is inadequate as you did not provide sufficient detail or evidence of corrective actions.
Purified water must be suitable for its intended use and routinely tested to ensure ongoing conformance with appropriate chemical and microbiological attributes.
Furthermore, you manufacture drug products (including hormones) and non-pharmaceutical products (e.g., cosmetics) using shared equipment (e.g.,
(b)(4)
tanks,
(b)(4)
, and filling lines). In your response, you state that your cleaning validation procedure will be reviewed and revised to include the necessary cleaning validation studies. Adequate cleaning procedures are required as chemical and microbial residues on equipment from previous manufacturing activities can adversely impact the purity, quality, and safety of drug products also manufactured on that equipment.
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.
• A comprehensive, independent assessment of your water system design, control, and maintenance.
• A thorough remediation plan to assure you operate a suitable water system, including any redesign. Include a robust ongoing control, maintenance, and monitoring program to ensure the system consistently produces water adhering to Purified Water, USP monograph specifications and appropriate microbial limits.
• Regarding the latter, ensure that your total microbial count limit for water is appropriate in view of the intended use of the products produced by your firm.
• 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.
3. 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)).
You failed to validate your non-compendial microbial methods used to test drug products and assure the methods were equivalent to or better than USP methods. For example, you use
(b)(4)
to analyze total count and yeast and mold in finished product. Additionally, you failed to follow the instructions for use and the investigator observed the use of expired
(b)(4)
test materials for finished product testing.
In your response, you indicate that you ceased use of the
(b)(4)
non-compendial tests. Your response is inadequate as you did not provide sufficient detail or evidence of corrective actions, including validation or verification of appropriate microbial methods for drug product testing by your contract laboratory or your internal laboratory, and to demonstrate that the methods used are equivalent to or better than USP methods. You also did not commit to conducting retrospective review of products tested using your non-compendial, non-validated tests.
In response to this letter, provide:
• 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.
• A list of chemical and microbial specifications, including test methods, used to analyze each lot of your drug products before a lot disposition decision. Include specifications for drug products within expiration that are already distributed within the United States and specifications for future drug products.
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.
• Chemical and microbial test method verification or validation reports and supporting data for internal and contracted testing of your components and drug products.
4. 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 quality unit (QU) did not provide adequate oversight for the manufacture of your drug products. For example, your QU failed to ensure the following:
• An adequate system for retention of production, control, or distribution records associated for all batches of drug product (21 CFR 211.180(a)).
• Batch production and control records include documentation of the accomplishment of each significant step in the manufacture and processing for each batch of drug product (21 CFR 211.188(b)).
• Performance of periodic (i.e., at least annually) product reviews (21 CFR 211.180(e)).
• Adequate training for employees engaged in the manufacture, processing, packing, or holding of drug products (21 CFR 211.25(a)).
Significant findings in this letter demonstrate that your firm does not operate an effective quality system in accord with CGMP. The QU must be accountable for implementing all the controls and reviewing the results of manufacture to ensure that product quality standards have been met. In smaller firms, it is recommended that another qualified individual, not involved in the production operation, conduct an additional, periodic review of QU activities. 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.
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:
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.
Repeat Observations at Facility
In a previous inspection ending December 13, 2017, FDA cited similar CGMP observations. You proposed specific remediation for these observations in your response. Repeated failures demonstrate that executive management oversight and control over the manufacture of drugs is inadequate.
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 CAPA before you pursue resolution of your firm’s compliance status with 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 may 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. It is your responsibility to ensure that your firm complies with all requirements of federal law, including FDA regulations.
This letter notifies you of our concerns and provides you an opportunity to address them. Failure to adequately address this matter may result in legal action including, without limitation, seizure, and injunction.
Please notify FDA in writing, within 15 working days of receipt of this letter, of the specific steps you have taken to address any violations. Include an explanation of each step being taken to prevent the recurrence of violations, as well as copies of related documentation. If you believe that your products are not in violation of the FD&C Act, include your reasoning and any supporting information for our consideration. If you cannot complete corrective action within 15 working days, state the reason for the delay and the time within which you will complete the correction. Your response should be sent to U.S. Food and Drug Administration, CDER/OC/Office of Unapproved Drugs and Labeling Compliance by email to FDAAdvisory@fda.hhs.gov and include your firm name in the subject line of your email.
Sincerely,
/S/
Jill Furman
Director
Office of Compliance
Center for Drug Evaluation and Research
Food and Drug Administration
_________________
1
Your AnuMed™ 25mg Per Pump PROGESTERONE CREAM,” “AnuMed™ 75mg Per Pump PROGESTERONE CREAM,” “AnuMed™ BIO-IDENTICAL BIO-EST 2.5mg PER PUMP,” “AnuMed™ BIO-IDENTICAL BIO-EST 5mg Per Pump,” “AnuMed™ 2.5 All Natural ESTRIOL CREAM,” “AnuMed™ 5.0 All Natural ESTRIOL CREAM, “AnuMed™ Bio-Identical DHEA 20 CREAM” and “AnuMed™ Bio-Identical DHEA 50 CREAM” drugs are hormone containing products that are deemed to be new drugs under a final determination issued under 21 CFR part 330, as published in the Federal Register on September 9, 1993 (see 58 FR 47610). There, the Agency has determined that any OTC drug product other than hydrocortisone that is labeled, represented, or promoted as a topically applied hormone-containing product for drug use are not generally recognized as safe and effective under section 201(p)(1) of the FD&C Act and that all such products are deemed to be new drugs and require an approved new drug application under section 505 of the FD&C Act to be lawfully marketed. 21 CFR 310.530.
Furthermore, as an OTC combination psoriasis/skin protectant drug products, your “50,000 IU Vitamin D3+K2 CREAM” must conform to the conditions of use set forth in the Over-the-Counter Monograph M032: Drug Products for the Control of Dandruff, Seborrheic Dermatitis, and Psoriasis for Over-the-Counter Human Use (henceforth “M032”), encompassed under the final administrative order OTC000021 and the Over-the-Counter Monograph M016: Skin Protectant Drug Products for Over-the-Counter Human Use (henceforth “M016”) encompassed under the final administrative order OTC000005. However, your “50,000 IU Vitamin D3+K2 CREAM” does not conform to conditions specified in either M032 or M016 because its labeling has intended uses such as, “PSORIASIS & ECZEMA RELIEF” and “help heal wounds” that go beyond the general intended uses described in M032 and M016. Neither final order allows for such a combination of a psoriasis and a skin protectant. There is no basis under the FD&C Act under which these products would be legally marketed without an approved application.
2
We recognize that the “Semaglutide Homeopathic Formula” labeling describes the products as being “homeopathic.”
First, we note that under section 201(g)(1) of the FD&C Act, 21 U.S.C. 321(g)(1), the term “drug” includes articles recognized in the official Homeopathic Pharmacopeia of the United States (HPUS), or any supplement to it. Homeopathic drug products are subject to the same statutory requirements as other drugs; nothing in the FD&C Act exempts homeopathic drugs from any of the requirements related to adulteration, misbranding, or FDA approval.
In addition, FDA issued a guidance in December 2022 that describes how the Agency intends to prioritize enforcement and regulatory actions for homeopathic drug products marketed in the United States without the required FDA approval. (See Homeopathic Drug Products: Guidance for FDA Staff and Industry, available at https://www.fda.gov/media/163755/download). For purposes of this guidance, FDA defines a “homeopathic drug product” as “a drug product that is labeled as ‘homeopathic,’ and is labeled as containing only active ingredients and dilutions (e.g., 10X, 20X) listed for those active ingredients in the Homeopathic Pharmacopeia of the United States (HPUS).” Your product includes semaglutide, which is not listed in the HPUS; thus, this product falls outside the scope of products addressed in this guidance.
3
Components with higher risk of DEG or EG contamination compared to other drug components.
Content current as of:
08/27/2024
Regulated Product(s)
Drugs