- Delivery Method:
- Certified Mail
Recipient NameMs. Edith Scheiner
- Homeocare Laboratories, Inc.
7 Odell Plaza Suite 142-146
Yonkers, NY 10701
- Issuing Office:
- Division of Pharmaceutical Quality Operations I
June 22, 2020
Dear Ms. Edith Scheiner:
The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Homeocare Laboratories, Inc., FEI 3008420443, at 7 Odell Plaza Suite 142-146, Yonkers, NY, from December 2 to 13, 2019.
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).
Your firm manufactures the over-the-counter (OTC) drug product “BIOIDENTICAL USP PROGESTERONE CREAM.” “BIOIDENDICAL USP PROGESTERONE CREAM” is an unapproved new drug in violation of section 505(a) of the FD&C Act, 21 U.S.C. 355(a). In addition, FDA reviewed your website at https://homeocare.com in March and May, 2020 and has determined that your “Acute Asthma Relief,” “Anxiety Relief,” “Cholestop,” “Fibromyalgia Relief,” “HBP Relief,” “IBS Relief,” “Insomnia Relief,” “Memo-Rx,” “Stress Relief,” and “Vigofem Plus For Women” products are unapproved new drugs. Introducing or delivering these unapproved new drug products for introduction into interstate commerce violates sections 505(a) and 301(d) of the FD&C Act, 21 U.S.C. 355(a), 331(d). These violations are described in more detail below.
Many of your products, including your “Acute Asthma Relief,” “Cholestop,” “Fibromyalgia Relief,” “HBP Relief,” “Memo-Rx,” and “Vigofem Plus For Women,” are especially concerning from a public health perspective because they claim to cure, mitigate, treat, or prevent serious and/or life-threatening conditions such as asthma, hypercholesterolemia, and hypertension, and may cause consumers to forgo, delay, or discontinue medical treatments that have been found safe and effective for such conditions through the FDA review process. In addition, as described below, your firm has significant violations of CGMP regulations. Your firm’s poor manufacturing practices are particularly concerning because the labeling for several of your products state that they contain potentially toxic ingredients, such as “Aconitum Napellus,” “Arsenicum album,” and “Belladona,” thereby presenting additional risk of serious harm to patients. In addition, your poor manufacturing practices are also concerning because some of your products are marketed for use in children, who may be at greater risk for adverse reactions associated with certain drug products due to differences in their ability to absorb, metabolize, distribute, or excrete such drug products or their metabolites.
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)).
You manufacture OTC drugs including a drug containing the potent hormone progesterone. You lacked adequate testing for each batch of your finished drug products before release. For example, you released finished drugs without testing them for identity, strength, content uniformity, or impurities. Without this testing, you lack assurance of the quality of the drug products that you released.
In your response, you said that you no longer manufacture OTC drugs and that you would evaluate drug product stability for those drugs you have released by monitoring “odor, appearance, and micros.” However, your response is inadequate because your proposed stability evaluation cannot adequately assess the stability characteristics of your finished drug products (e.g., assay, impurity). In addition, you failed to evaluate the impact of your lack of controls on the quality and safety of your drugs released to the U.S. market.
In response to this letter, provide the following:
• A list of chemical and microbial specifications, including test methods, used to analyze each lot of your drug products before a lot 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.
• 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 comprehensive, independent assessment and corrective and preventive action 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.
2. Your firm failed to test samples of each component for identity and conformity with all appropriate written specifications for purity, strength, and quality. Your firm also failed to validate and establish the reliability of your component supplier’s test analyses at appropriate intervals (21 CFR 211.84(d)(1) & (2)).
You failed to adequately control your incoming components used to manufacture both OTC and homeopathic drug products. For example, you received components from unqualified suppliers and used them in production without conducting adequate testing to determine their identity, purity, strength, and quality. Instead, you relied solely on suppliers’ certificates of analysis (COA) without establishing reliability of your supplier’s analysis through appropriate validation. There is a lack of assurance that your components meet all appropriate specifications.
In your response, you said that you would do a physical audit of one of your suppliers and that components were tested for identity by a third-party analytical laboratory. However, your response is inadequate because you failed to provide supporting documentation for the testing of each component to verify its identity and documentation for the qualification of all your suppliers. If you intend to rely on your suppliers’ COA in lieu of full testing, you must still conduct at least an identity test on each component. You must also periodically validate the supplier's test results. In addition, you also said in your response that all vendor surveys were sent, completed, and found to be acceptable. However, during the inspection, your firm communicated that vendors declined to complete the survey and that you were using components in production from unapproved vendors.
In response to this letter, provide the following:
• 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.
• The chemical and microbiological quality control specifications you use to test and release each incoming lot of component for use in manufacturing.
• 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.
• A summary of results obtained from testing all components to evaluate the reliability of the COA from each component manufacturer. Include your SOP that describes this COA validation program.
• A summary of your program for qualifying and overseeing contract facilities that test the drug products you manufacture.
3. Your firm failed to clean, maintain, and, as appropriate for the nature of the drug, sanitize and/or sterilize equipment and utensils at appropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements (21 CFR 211.67(a)).
Documents collected during inspection indicate that you produced a potent drug (progesterone hormone) and other drugs, including the homeopathic drug product Arnica Cream, using shared equipment. You failed to validate your cleaning procedures to ensure that your other drugs were not cross-contaminated with the potent compound, progesterone.
In your response, you said that you stopped manufacturing OTC drugs and created a new cleaning validation. While you committed to ceasing OTC drug manufacturing, you continued to manufacture other drugs, such as homeopathic drugs. Your response is also inadequate because there is a lack of assurance that drugs you released are not contaminated with undeclared progesterone. In addition, the cleaning validation you developed only evaluates the ability to remove a detergent and did not ensure that drugs you manufactured on shared equipment were not cross-contaminated with other drugs.
In response to this letter, provide the following:
• A comprehensive, independent retrospective assessment of your cleaning effectiveness to evaluate the scope of cross-contamination hazards. Include the identity of residues, other manufacturing equipment that may have been improperly cleaned, and an assessment whether cross-contaminated products may have been released for distribution. The assessment should identify any inadequacies of cleaning procedures and practices and encompass each piece of manufacturing equipment used to manufacture more than one product. The assessment should also include testing of retain samples of all drugs manufactured using shared equipment for progesterone contamination and 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.
• 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.
4. 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 do not have adequate controls in place to ensure your OTC drugs are consistently produced to meet their attributes, such as strength and purity. For example, you did not validate your processes before releasing drugs you manufactured. You subsequently released drug products without adequately validating your manufacturing process.
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 ensure the quality of raw material inputs, in-process materials, and finished drugs. Failure to conduct these studies can result in lack of understanding of process variables, which increases the risk of product quality attribute failures. 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 document 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.
In your response you confirmed that process validation was not conducted and that you are no longer manufacturing OTC drugs. However, your response is inadequate because you failed to evaluate the impact to drug quality and safety because of your lack of control over your manufacturing process.
In response to letter, provide the following:
• A risk assessment for all distributed drug products you manufactured using an inadequate production process.
• 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, and ongoing monitoring of both intra-batch and inter-batch variation to ensure a continuing state of control.
• A timeline for performing appropriate process performance qualification (PPQ) for each of your marketed drug products.
• Include your process performance protocol(s), and written procedures for qualification of equipment and facilities.
• 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.
• An assessment of each drug product process to ensure that there is a data-driven and scientifically sound program that identifies and controls all sources of variability so that your production processes will consistently meet appropriate specifications and manufacturing standards.
• This includes, but is not limited to, evaluating suitability of equipment for its intended use, sufficiency of detectability in your monitoring and testing systems, quality of input materials, and reliability of each manufacturing process step and control.
CGMP Consultant Recommended
Based upon the nature of the violations we identified at your firm, we strongly recommend engaging 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.
Unapproved New Drug Violations
On September 7, 2017, you received a warning letter notifying you, in part, that you marketed and distributed misbranded drugs within the meaning of section 503(b)(4) of the FD&C Act, 21 U.S.C. 353(b)(4). Although you modified or removed the claims cited in the 2017 warning letter, based on our review of the current claims on your website in March and May 2020, you continue to market and distribute homeopathic drug products that violate the FD&C Act, including unapproved new drugs, as described below.
Examples of statements on the websites https://www.womenshealthnetwork.com and https://homeocare.com that provide evidence of the intended uses of your products include, but are not limited to, the following:
From https://www.womenshealthnetwork.com, where consumers can purchase “BIOIDENTICAL USP PROGESTERONE CREAM”:
• “Advanced Progesterone formula is naturally-balancing . . . With our new USP Progesterone Cream, you’ll get the balancing support women need – especially in the years before menopause – in a formula that’s bioidentical, fully adaptogenic . . . It’s bioidentical, which means it’s precisely the same progesterone as your own body produces. Unlike the synthetic progestins used in pharmaceutical products, bioidentical progesterone can be utilized by your body as a building block for other hormones, helping it make what it needs, when it needs it . . . it’s safe for your long-term use – from perimenopause through post-menopause – for symptom relief”
From https://homeocare.com, on the product webpage for “Acute Asthma Relief”:
• “Asthma is defined as an inflammation of the airways that results in the temporary narrowing of the airways that transport air from the nose and mouth to the lungs. Homeocares [sic] specialized Acute Asthma Relief helps relieve all of the symptoms associated with Asthma. . . Acute Asthma Relief a great alternative to traditional over the counter remedies.”
• The product name, “Acute Asthma Relief.”
From https://homeocare.com, on the product webpage for “Anxiety Relief”:
• “Anxiety disorders are the most common psychiatric illnesses affecting children and adults . . . HomeoCares [sic] ANXIETY relief formula helps relieve . . . panic attack.”
• The product name, “Anxiety Relief.”
From https://homeocare.com, on the product webpage for “Cholestop”:
• “[I]f there is too much cholesterol in the bloodstream, the excess may be deposited on the wall of the arteries causing narrowing and blockages that may lead to an increased risk of cardiovascular diseases”
• The product name, “Cholestop.”
• “What to do? . . . CHOLESTOP TM is a natural homeopathic formula composed of ingredients traditionally known to stimulate and regulate hepatic functions.”
• “CHOLESTEROL LOWERING FORMULA”
• “Uses: Helps reduce cholesterol levels.”
• “CHOLESTEP TM is composed of:
. . .
o Carduus Marianus (St. Mary’s thistle) . . . indicated in arteriosclerosis.
. . .
o Cholesterinum (Cholesterine) . . . hypercholesterolemia.
o Chrysanthellum Americanum (Chrysantellum) has a beneficial effect on triglycerides and cholesterol.”
From https://homeocare.com, on the product webpage for “Fibromyalgia Relief”:
• “Fibromyalgia is a syndrome defined as chronic musculoskeletal pain accompanied by a variety of other symptoms such as intense fatigue, headaches, flu-like symptoms, sleep disturbances, morning stiffness, bowel irritation, numbness and tingling in extremities and more. . . . HomeoCare Fibromyalgia Relief taken regularly will bring more freedom from pain while increasing your comfort level.”
• The product name, “Fibromyalgia Relief.”
From https://homeocare.com, on the product webpage for “HBP Relief”:
• “Hypertension, if left untreated, can lead to serious cardiovascular conditions such as heart attacks and strokes.”
Homeocare Laboratories, Inc., Yonkers FEI 3008420443 page 9
• The product name, “HBP Relief.”
• “HBP Relief was created to help promote healthy circulation.”
• “Uses: Temporarily relieves symptoms associated with hypertension.”
From https://homeocare.com, on the product webpage for “IBS Relief”:
• “HomeoCare IBS Relief gently helps relieve bloating, cramps, diarrhea, and constipation symptoms.”
• “IRRITABLE BOWEL SYNDROME RELIEF”
• The product name, “IBS Relief.”
• “Uses: For the temporary relief of diarrhea; constipation; abdominal cramps and bloating associated with irritable bowel syndrome.”
From https://homeocare.com, on the product webpage for “Insomnia Relief”:
• “HomeoCare INSOMNIA Relief will help you regain your natural sleep cycle without knocking you out. . . . [I]nsufficient sleep is associated with a number of chronic diseases and conditions such as diabetes, cardiovascular disease . . . and depression . . . Not getting enough sleep is associated with the onset of these diseases and also may complicate their management and outcome.”
From https://homeocare.com, on the product webpage for “Memo-Rx”:
• “Memory loss can be caused by many different factors ranging from the following: *Alcoholism *Alzheimer’s Disease *Brain Tumor *Cerebrovascular disease . . . *Dementia”
From https://homeocare.com, on the product webpage for “Stress Relief”:
• “Stress that continues without relief can lead to . . . a negative stress reaction . . . leading to physical symptoms such as . . . elevated blood pressure . . . depression . . . stress can also bring on or worsen certain symptoms or diseases. Stress is linked to six of the leading causes of death: heart disease, cancer, lung ailments, accidents, cirrhosis of the liver, and suicide.”
From https://homeocare.com, on the product webpage for “Vigofem Plus For Women”:
• “Uses: Relieves . . . depression.”
• “VigoFem Plus . . . can counteract the effects of . . . post-partum depression.”
The above labeling claims for the products “BIOIDENDICAL USP PROGESTERONE CREAM,” “Acute Asthma Relief,” “Anxiety Relief,” “Cholestop,” “Fibromyalgia Relief,” “HBP Relief,” “IBS Relief,” “Insomnia Relief,” “Memo-Rx,” “Stress Relief,” and “Vigofem Plus For Women,” demonstrate that they are drugs as defined by section 201(g)(1)(B) and/or 201(g)(1)(C) of the FD&C Act, 21 U.S.C. 321(g)(1)(B), 321(g)(1)(C), because they are intended to cure, mitigate, treat, or prevent disease and/or intended to affect the structure or function of the body.
“BIOIDENTICAL USP PROGESTERONE CREAM” is intended for use as a hormone drug product for topical use. According to 21 CFR 310.530, any OTC drug product labeled as containing hormones, such as progesterone, and marketed for topical use as a hormone cream cannot be considered generally recognized as safe and effective for its intended use and requires an FDA approved application to be lawfully marketed in the United States. Therefore, “BIOIDENTICAL USP PROGESTERONE CREAM” is a new drug within the meaning of section 201(p) of the FD&C Act, 21 U.S.C. 321(p). As a new drug, “BIOIDENTICAL USP PROGESTERONE CREAM” may not be legally marketed in the United States absent approval of an application filed in accordance with section 505(a) of the FD&C Act, 21 U.S.C. 355(a). “BIOIDENTICAL USP PROGESTERONE CREAM” is not the subject of an FDA-approved application, and therefore, the current marketing of this product violates section 505(a) of the FD&C Act, 21 U.S.C. 355(a). Introduction or delivery for introduction of such product into interstate commerce is prohibited under section 301(d) of the FD&C Act, 21 U.S.C. 331(d).
Your “Acute Asthma Relief,” “Anxiety Relief,” “Cholestop,” “Fibromyalgia Relief,” “HBP Relief,” “IBS Relief,” “Insomnia Relief,” “Memo-Rx,” “Stress Relief,” and “Vigofem Plus For Women,” products are “new drugs” as defined by 201(p) of the FD&C Act, 21 U.S.C. 321(p), because they are not generally recognized as safe and effective for use under the conditions prescribed, recommended, or suggested in their labeling. Under section 505(a) of the FD&C Act, 21 U.S.C. 355(a), new drugs may not be introduced or delivered for introduction into interstate commerce without an approved application from FDA in effect. No approved application pursuant to section 505 of the FD&C Act, 21 U.S.C. 355, is in effect for these products. 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).
We recognize that “Acute Asthma Relief,” “Anxiety Relief,” “Cholestop,” “Fibromyalgia Relief,” “HBP Relief,” “IBS Relief,” “Insomnia Relief,” “Memo-Rx,” “Stress Relief,” and “Vigofem Plus For Women” are marketed as homeopathic drugs. 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 approval.
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 these violations and for preventing their recurrence or the occurrence of other violations.
Correct the violations cited in this letter promptly. Failure to promptly correct these violations may result in legal action without further notice including, without limitation, seizure and injunction. Unresolved violations in this warning letter may also prevent other Federal agencies from awarding contracts.
FDA may also withhold approval of requests for export certificates and approval of pending new drug applications or supplements listing your facility as a supplier or manufacturer until the above violations are corrected. We may re-inspect to verify that you have completed your corrective actions.
After you receive this letter, respond to this office in writing within 15 working days. Specify what you have done since our inspection to correct your violations and to prevent their recurrence. 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 ORAPHARM1_RESPONSES@fda.hhs.gov and CDER-OC-OMQ-Communications@fda.hhs.gov. If you have any questions, please contact Yvette Johnson, Compliance Officer at Yvette.Johnson@fda.hhs.gov. Please identify your response with FEI 3008420443.
Program Division Director/District Director
OPQO Division I/New Jersey District