September 18, 2012
D'Lana M. Halbert, CEO/Owner
Dr. David S. Halbert, President/Owner
4150 E. Overland Trail
Abilene, Texas 79601
Dear Mrs. and Dr. Halbert:
During our December 20 through 22, 2011 inspection of your pharmaceutical manufacturing facility, Clavel Corporation, located at 4150 E. Overland Trail, Abilene, Texas, an investigator from the Food and Drug Administration (FDA) identified violations of Current Good Manufacturing Practice (CGMP) regulations for Finished Pharmaceuticals, Title 21, Code of Federal Regulations, Parts 210 and 211. These violations cause your drug product(s) to be adulterated within the meaning of section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (the Act) [21 U.S.C. § 351(a)(2)(B)] in that the methods used in, or the facilities or controls used for, their manufacture, processing, packing, or holding do not conform to, or are not operated or administered in conformity with, CGMP.
We have reviewed your firm's responses of January 11, and February 6, 2012, and note that both responses lack sufficient corrective actions.
Specific violations observed during the inspection include, but are not limited, to the following:
1. Your firm has failed to establish a quality control unit with the responsibility and authority to approve or reject all components, drug, product container and closures, in-process materials, packaging material, labeling, and drug products [21 C.F.R. § 211.22(a)].
For example, the production manager at your firm also serves as the firm's only Quality Control employee and can change components of a drug product without approval or any evaluation of the effect it would have on the finished products. In addition, your firm has not established written procedures describing the responsibilities of your firm's QCU or designating the personnel with QCU authority.
The revised procedures submitted with your responses are inadequate because QC responsibilities are delegated to non QC personnel. For example, the revised manufacturing procedures state that batch records are to be approved by the "production manager or designee." The new procedure for examining active pharmaceutical ingredients states that members of the quality assurance or manufacturing staffs can release quarantined APIs. Please revise all SOPs in accordance with the regulations. (If your firm has only one person designated as the QC staff, an appropriately trained individual may be designated as an alternate).
In addition, these procedures were not approved by your firm's QCU.
2. Your firm failed to withhold from use each lot of components until the lot has been sampled, tested, or examined, as appropriate and released for use by the quality control unit [21 C.F.R. § 211.84(a)].
For example, your firm has not established specifications and does not test for the quality of the purchased deionized water used in the manufacture of your drug products. Your firm relies upon a certificate of analysis (COA) from the vendor without performing vendor qualification.
In your responses you did not commit to testing the water to ensure this component is of acceptable quality. The vendor certification provided with the response is a description of the deionization process but does not include information regarding critical quality attributes of the water such as microbial content, total organic carbon, and conductivity.
3. Your firm has not established adequate written procedures describing in sufficient detail the receipt, identification, storage, handling, sampling, testing and approval or rejection of drug product components [ 21 C.F.R. § 211.80(a)].
For example, your firm has not established adequate testing procedures for incoming drug product components. Your firm does not test incoming drug components with exception of one identity test for menthol which has not been validated. In addition, your firm does not have an identified area to store components and containers and closures under quarantine until they are tested or examined prior to release.
We acknowledge the statements in your responses that you have established a new quarantine procedure for drug components using hold and release stickers. However, the new procedures provided with the response do not address the use of these stickers, do not address review of COAs for incoming components, and do not clearly indicate that QCU has responsibility for release of drug components from quarantine. In addition, the new procedures do not require or describe any tests for the acceptance of incoming product components except for the unvalidated (b)(4) test for menthol and the (b)(4) test for emu oil.
4. Your firm has failed to establish a written testing program designed to assess the stability characteristics of drug products in order to determine appropriate storage conditions and expiration dates [21 C.F.R. § 211.166(a)].
For example, you firm failed to establish a written test program to assess the stability characteristics for your firm's drug products, including but not limited to:
- Blue Stop Max for Pain, 8 and 16 oz, Batch #(b)(4) manufactured on 12/16/11
- PSI Cream for Psoriasis, 4 oz tubes, Batch #(b)(4) manufactured on 10/12/11
- Albert's Bug Revenge Sting and Bite Relief, 1 oz tubes, Batch #(b)(4) manufactured on 07/19/11
- Blue Stop-E Pain Reliever for Animal Use, 16 oz, Batch #(b)(4) manufactured on 9/15/11.
You could not provide documentation to support the (b)(4) year expiration date currently placed on your drug products.
In your responses you stated you "reexamined" samples from previously produced lots of the four products identified during the inspection as drugs. However, you failed to describe the sampling and test procedures used, documentation of the test results, or to include documentation to demonstrate that the tests used are stability indicating.
In addition, your responses are inadequate because you failed to assess all of your firm's products. Your responses only commit to perform stability studies to "new OTC products as they are introduced."
5. Your firm has not established adequate written procedures for the cleaning and maintenance of equipment used in the manufacture, processing, packing or holding of drug products [21 C.F.R. § 211.67(b)].
Your firm does not use dedicated equipment to manufacture cosmetics and drugs and you have not validated your cleaning procedures to show effective removal of residues of products or cleaning compounds.
In your responses you stated that you have added a sanitization step to the deaning procedure and that the new cleaning procedure has been validated by laboratory testing. However, you did not include any test results. The responses reference a new laboratory procedure "LB-001, Monitoring of Manufacturing Environments" but this was not provided. In addition, although the new log sheets appear to include more complete cleaning information your firm still has not established logs for individual pieces of equipment.
Unapproved Over-the-Counter (OTC) Drugs
Your firm manufactures numerous products that are positioned as cosmetics. However, as presently formulated, labeled, and promoted, many of these products are unapproved drugs in violation of Section 505(a) of the Federal Food, Drug. and Cosmetic Act (the Act) [21 U.S.C. § 355].
Based on the labeling of products that we have reviewed, multiple products are drugs as defined by Section 201(g)(1) of the Act [21 U.S.C. § 321(g)(1)] because they are intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or function of the body of man. The following is an example of one of your violative products.
"PediSof-D Diabetic Foot Cream"
The package labeling for "PediSof-D Diabetic Foot Cream" states that it is "'[d]esigned to help prevent deterioration of the skin that is often caused by poor circulation in diabetics" and to ''[u]se daily to maintain overall foot health ...." In addition, the package label includes a consumer testimonial that the product "eases my foot pain ...." Furthermore, based on the package labeling PediSof-D Diabetic Foot Cream is specifically intended for diabetic patients. For example, the product name itself identifies the product as a "Diabetic Foot Cream" and the package labeling states that the product is the "Doctor's Choice for maintaining healthy feet in diabetics" and "For Diabetics." Based on these labeled claims, PediSof-D Diabetic Foot Cream is a drug as defined by Section 201(g)(1) of the Act [211 U.S.C. § 321(g)(1)] because the product is intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or function of the body of man.
As a drug, "PediSof-D Diabetic Foot Cream," which is being marketed over-the counter (OTC), requires an approved application in order to be legally marketed. Specifically, as formulated and labeled, PediSof-D is not covered under any OTC monograph that sets forth conditions for general recognition of safety and effectiveness, nor are we aware of products intended specifically for diabetic foot health otherwise being considered under FDA's OTC Drug Review.
Furthermore, we are not aware of evidence to show that "PediSof-D Diabetic Foot Cream," as formulated and labeled, is generally recognized as safe and effective. Therefore, "PediSof-D Diabetic Foot Cream" is a new drug within the meaning of Section 201(p) of the Act [21 U.S.C. § 321(p)]. In addition, we are not aware of "PediSof-D Diabetic Foot Cream" being the subject of an approved application. As a new drug without an approved application the current marketing of "PediSof-D Diabetic Foot Cream" violates Section 505(a) of the Act [21 U.S.C. § 355(a)].
Under Section 301(d) of the Act [21 U.S.C. § 331(d)], a new drug may not be introduced or delivered for introduction into interstate commerce unless an FDA approved application is in effect for it. "PediSof-D Diabetic Foot Cream" does not have an approved application, and its introduction into interstate commerce violates this provision of the Act.
Please note that the cited issues and violations in this example are not intended to be an all-inclusive statement of violations that exist with your products. In addition to "PediSof-D Diabetic Foot Cream," a limited review of many of your products, including but not limited to "Blue-Stop Max," "Albert's Bug Revenge," and "PSI Cream for Psoriasis," finds that the products are marketed with drug intended uses even though they are positioned as cosmetics and therefore are considered drugs. In order to be legally marketed as over-the-counter drugs, these products as formulated and labeled must either be generally recognized as safe and effective (including by conforming to a final monograph), be otherwise eligible for inclusion in the OTC Drug Review (including by conforming to the proposed requirements under a tentative final monograph), or have an FDA approved application. In addition, the products as OTC drugs must be meet all the requirement of such, and the labels must be formatted in accordance with the "Drug Facts" labeling requirements as described in 21 CFR § 201.66 and must meet all other general OTC drug labeling requirements.
Unapproved Veterinary Drug
In addition, your firm also manufactures Blue Stop-E, a topical pain relief product for use in treating swollen muscles and joints in working and show animals. We have determined this product violates sections 512(a) and 501(a)(5) of the Act [21 U.S.C. §§ 360b(a) and § 351(a)(5)].
Product labeling, identifies Blue Stop-E Pain Reliever with EMU oil and MSM (rnethylsulfonylmethane). In addition, Blue Stop-E lists the following additional ingredients: Aloe Vera Gel, Soybean Oil, MSM, Menthol, EMU Oil, Mineral Oil, Glycerin, Kokum Butter, Witch Hazel, Coconut Oil, Tocopheryl Acetate (Vitamin E), Carbomer 940, Glucosamine, Propylene Glycol, Triethanolamine, DMDM, Tetra Sodium EDTA, Hydantoin, Diazolidinyl Urea, Natural Herbs and Other Botanicals, FC&C Blue.
The product labeling for Blue Stop-E identifies its intended uses as follows: "Pain Reliever" and "Directions For Use: Apply Liberally to Painful Swollen Muscles and Joints 2-3 times daily...(For Animal Use Only)" Based on these uses, Blue Stop-E is a drug within the meaning of section 201(g)(1) of the Act [21 U.S.C. § 321(g)(1)] because it is intended for use in the cure, mitigation, treatment, or prevention of disease in animals or to affect the structure or function of the body of animals. Further, Blue Stop-E appears to be a "new animal drug" under section 201(v) of the Act [21 U.S.C. § 321(v)], because it is not generally recognized among experts qualified by scientific training and experience to evaluate the safety and effectiveness of animal drugs, as safe and effective for use under the conditions prescribed, recommended, or suggested in the labeling. It is not the subject of an approved new animal drug application, conditionally approved new animal drug application, or index listing under sections 512, 571, and 572 of the FD&C Act [21 U.S.C. §§ 360b, 360ccc, and 360ccc-1]. To be legally marketed, a new animal drug must have an approved new animal drug application, conditionally approved new animal drug application, or index listing under sections 512, 571, and 572 of the Act [21 U.S.C. §§ 360b, 360ccc, and 360ccc-1]. Therefore, the product is unsafe within the meaning of section 512(a) of the FD&C Act [21 U.S.C. § 360b(a)] and is adulterated under section 501(a)(5) of the FD&C Act [21 U.S.C. § 351(a)(5)]. Introduction of an adulterated drug into interstate commerce is prohibited under section 301(a) of the FD&C Act [21 U.S.C. § 331(a)].
To ensure that all drugs marketed in the U.S., prescription and over-the-counter, have been shown to be safe and effective, FDA published a Compliance Policy Guide (CPG) Section 440.100, Marketed Unapproved Drugs at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatorylnformation/Guidances/UCM070290.pdf. FDA expects manufacturers of products requiring approval to submit applications to the agency showing that their products are safe and effective. The CPG describes the very strict criteria under which the Act permits drugs to be marketed without approval. The CPG also outlines the Agency's enforcement policies aimed at efficiently and rationally bringing all drugs requiring approved applications into the approval process.
We remind you that you are responsible for ensuring that you firm's drug manufacturing operations comply with applicable requirements, including the CGMP regulations. We recommend that you engage a third party consultant having appropriate CGMP expertise to assess your firm's facilities procedures, processes, and systems to ensure that your drug products have their appropriate identity, strength, quality and purity. We also recommend that you hire a qualified consultant to provide CGMP guidance and training that focuses on the responsibilities and procedures applicable to the quality unit.
The violations cited in this letter are not intended to be an all-inclusive statement of violations that exist at your facility. You are respons'ible for investigating and determining the causes of the violations identified above and for preventing their recurrence and the occurrence of other violations. It is your responsibility to assure compliance with all requirements of federal law and FDA regulations.
Please respond within 30 days of receipt of this letter. Please notify this office in writing of the specific steps that you have taken to correct violations. Include an explanation of each step taken to prevent the recurrence of violations and copies of supporting documentation.
Your reply should be sent to the following address: Elvia Cervantes, Compliance Officer, U.S. Food and Drug Administration, Dallas District Office, 4040 North Central Expressway, Suite 300, Dallas, Texas 75204. If you have any questions about the content of this letter, please contact Ms. Elvia Cervantes at (214) 253-5236.
Reynaldo R. Rodriguez, Jr.
Dallas District Director