Inspections, Compliance, Enforcement, and Criminal Investigations
Virbac Inc. 10-Dec-08
Department of Health and Human Services
Public Health Service
Kansas City District
Telephone: (913) 752-2100
December 10, 2008
RETURN RECEIPT REQUESTED
Ref. KAN 2009-03
President & Chief Executive Officer
3200 Meacham Blvd.
Fort Worth, Texas 76137
Dear Mr. Martinez:
During an inspection of your firm located at 13001 St. Charles Rock Road, Bridgeton, Missouri, on July 21 through July 29, 2008, investigators from the United States Food and Drug Administration (FDA) documented numerous violations of current Good Manufacturing Practice(cGMP) regulations, Title 21 Code of Federal Regulations, Parts 210 and 211 (21 CFR Parts 210 and 211). The documented violations cause drug products manufactured at your facility 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, and storage are not in conformity with CGMP requirements to assure that safety, identity, strength, quality, and purity characteristics are met. This letter addresses the results of that inspection and also your August 26, 2008, response to the Inspectional Observations form (Form FDA 483) that was given to your firm at the conclusion of the inspection.
In addition, in an unrelated review of your promotional material for Iverhart Max® (ivermectin/pyrantel pamoate/praziquantel) Chewable Tablets, NADA 141-257 and Iverhart Plus® (ivermectin/pyrantel pamoate) Flavored Chewables, ANADA 200-302, the Center for Veterinary Medicine, Division of Surveillance (DOS) reviewed your tri-fold brochure entitled "Once a month. . .for life" and website (http://www.virbacvet.com/iverhart). The brochure, which addresses both of these Iverhart® products, was submitted as promotional material in your 18 month Semi-Annual Drug Experience Report (DER) submission for Iverhart Max® and also appears to be available through a link on your website. The website was submitted as promotional material in a Special DER for both Iverhart Max® (ivermectin/pyrantel pamoate/praziquantel) Chewable Tablets and Iverhart Plus® (ivermectin/pyrantel pamoate) Flavored Chewables. The brochure and website contain representations or suggestions, not approved or permitted for use in labeling, that Iverhart Max® (ivemectin/pyrantel pamoate/praziquantel) Chewable Tablets and Iverhart Plus® (ivermectin/pyrantel parnoate) Flavored Chewables are more effective than has been demonstrated by substantial evidence or substantial clinical experience. Cf. 21 CFR 202.1(e)(6)(i). Therefore, these products are misbranded. 21 U.S.C. §§ 352(a) and 352(n).
Failures to Meet Current Good Manufacturing Practice Requirements:
Section 501(a)(2)(B) of the Act, 21 U.S.C. § 351 (a)(2)(B), provides that a drug shall be deemed to be adulterated "if the methods used in . . . . its manufacture, processing, packing, or holding do not conform to . . . current good manufacturing practice to assure that such drug meets the requirements of this Act as to the safety and has the identity and strength, and meets the quality and purity characteristics, which it purports or is represented to possess." The Agency has set out regulations containing current good manufacturing practices for finished pharmaceuticals in 21 C.F.R. Parts 210 and 211. Specifically, your violations of these good manufacturing practice regulations include, but are not limited to, the following:
1. Failure to have a quality control unit that has the authority to review records relating to production and storage of drug products to assure that no errors have occurred or, if errors have occurred, that they have been fully investigated, as required by 21 CFR 211.22(a). For example, Quality Assurance was not made aware of temperature excursions in the refrigerated storage areas or temperature and relative humidity excursions in the stability chambers containing drug products. Thus, investigation into such storage control failures was not performed, as required by 21 CFR 211.22(a).
We received your response to the Form FDA-483, dated August 26, 2008, and reviewed it as it relates to the specific observations noted on the Form FDA-483. This response is similar in nature to that received after your July 2007 inspection. Due to the number of repeat violations, we find that your response does not provide adequate assurance to our office that you have identified the underlying causes for your failures or implemented, full control over your Quality System. In your response to this Warning Letter, we ask that you describe the changes being made to your quality system that will prevent such serious quality system violations from recurring.
2. Failure to follow standard operating procedures that assure drug products have the identity, strength, quality, and purity they purport or are represented to possess, as required by 21 C.F.R. 211.100(b). For example, the inspection documented the failure to follow the Warehouse Standard Operating Procedure #0211-034, which states, [(b)(4)]
3. Failure to follow written production and process procedures for sampling and testing to assure batch uniformity and integrity of drug products, as required by 21 CFR 21l.110. Specifically, the firm did not comply with the Receiving Warehouse Standard Operating Procedure #0211-034. This SOP states, [(b)(4)] The SOP further requires that personnel fill out a supplemental form and Quality Assurance must review and sign the form. When temperature excursions occurred, as noted on the Equipment Log Receiving Controlled Storage Unit on July 7, 14, and 17, 2008, there were no entries on the Refrigerated Chamber Temperature Log notifying Quality Assurance of the excursions and no record of any supplemental form being filled out by personnel and reviewed by Quality Assurance.
4. Failure to employ laboratory controls that establish scientifically sound and appropriate test procedures designed to assure that drug products conform to appropriate standards of identity, strength, quality, and purity, as required by 21 CFR 211.160(b). Specifically:
The High Performance Liquid Chromatography (HPLC) method for analysis of Praziquantel in Worm X Plus does not describe the interpretation of impurity peaks located at different time intervals.
The HPLC method for analysis of Ivermectin in Iverhart III Tablets does not clearly specify the number of samples to prepare, when to run a placebo, or how to prepare the placebo. This method also includes inconsistent comparisons of placebo peaks (i.e., retention time vs. relative retention time).
We reviewed your August 26, 2008 response to the FDA-483. Please provide completed corrective actions in your response to the Warning Letter. We also request that you address how you plan on preventing these significant laboratory method control issues from recurring.
5. Failure to calibrate HPLC Instruments for the wavelength accuracy on the detector or the heating and cooling capabilities of the thermostat controlled column, as required by 21 CFR 211.160(b)(4). These instruments are used for assay analysis of finished drug products.
We reviewed your August 26, 2008 response to the FDA-483. Please provide completed corrective actions in your response to the Warning Letter. We also request that you address how you plan on preventing these significant laboratory calibration control issues from recurring.
6. Failure to investigate all batches of the same drug product that may have been associated with a specific failure or discrepancy an make a written record of the investigation, as required by 21 C.F.R. 211.192. Specifically:
The firm confirmed the stability out of specification results for [(b)(4)] Horse & Colt Wormer, but did not document an assessment of the product's release/stability specifications for other product lots of [(b)(4)] Horse & Colt Wormer which had been manufactured and/or released
Unsubstantiated Effectiveness Claims:
Iverhart Max® (ivermectin/pyrantel pamoate/praziquantel) Chewable Tablets is an oral tablet formulation containing ivermectin, pyrantel pamoate, and praziquantel. Iverhart Max® is approved for use in dogs to prevent canine heartworm disease by eliminating the tissue stage of heartworm larvae (Dirofilaria immitis) for a month (30 days) after infection and for the treatment and control of roundworms (Toxocara canis, Toxascaris leonina), hookworms (Ancylosioma caninum, Uncinaria stenocephala, Ancylostoma braziliense) and tapeworms (Dipylidium caninum, Taenia pisiformis).
Iverhart Plus® (ivermectin/pyrantel pamoate) Flavored Chewables is an oral tablet formulation containing ivermectin and pyrantel pamoate. Iverhart Plus®is approved for use in dogs to prevent canine heartworm disease by eliminating the tissue stage of heartworm larvae (Dirofilaria immitis) for a month (30 days) after infection and for the treatment and control of ascarids (Toxocara canis, Toxascaris leonine), and hookworms (Ancylostoma caninum, Uncinaria stenocephala, and Ancylostoma braziliense).
The tri-fold brochure and the website give general information about heartworm disease and intestinal parasites and then state, "Iverhart Max treats and controls these intestinal parasites in your dog, thereby reducing the potential risk to your family that comes in daily contact with the dog." (emphasis in original). This statement implies the drug is effective for reducing the risk of parasitic zoonosis in humans when the drug is not approved for this use. Additionally, the website for Iverhart® products states, "Some of the parasites that infect dogs can also infect people. Some of the parasites that infect dogs are zoonotic -they can be transmitted between animals and humans. Using simple preventive measures, you can maintain your pet's health and safeguard your family. The best way to prevent heartworm disease and treat and control intestinal parasites is to give your dog IVERHART MAX® or IVERHART PLUS® - the heartworm preventatives that also act against potential zoonotic parasites."
These representations or suggestions have not been approved or permitted for use in the labeling of Iverhart® products. In addition, CVM is not aware of substantial evidence or substantial clinical experience to support the effectiveness of Iverhart® products for the prevention of zoonotic disease in humans. The tri-fold brochure and the Iverhart products website thus contain representations or suggestions, not approved or permitted for use in the labeling, that Iverhart® products are more effective than has been demonstrated by substantial evidence or substantial clinical experience. Statements that the use of Iverhart Max® and Iverhart Plus® in dogs prevent zoonotic disease in humans are particularly troublesome because early diagnosis and treatment in humans may be delayed.
The Iverhart Max® brochure and Iverhart® products website overstate the effectiveness of Iverhart Max® and Iverhart Plus® in violation of 21 CFR 202.1(e)(6)(1). Accordingly, these drugs are misbranded. 21 U.S.C. §§ 352(a) and 352(n).
This letter is not intended to be an all-inclusive list of violations at your facility. It is your responsibility to ensure compliance with applicable laws and regulations administered by FDA. The specific violations noted in this letter and in the Form FDA 483 issued at the closeout of the inspection may be symptomatic of serious problems in your firm's quality assurance and laboratory systems. You should investigate and determine the causes of the violations, and take prompt actions to correct the violations and to bring your products into compliance. In addition, it is your responsibility to ensure that your advertisements and promotional materials for Iverhart Max@ and Iverhart Plus®, as well as for your other products, comply with the requirements of the Act and its implementing regulations.
You should take prompt actions to correct the violations addressed in this letter. Failure to promptly correct these violations may result in regulatory action being initiated by the Food and Drug Administration without further notice. These actions include, but are not limited to, seizure and/or injunction. Also, federal agencies are advised of the issuance of all Warning Letters so that they may take this information into account when considering the award of contracts.
Please notify this office within fifteen (15) working days of receiving this letter of the steps you have taken to bring your firm into compliance with the law. Your response should include a description of the status of corrective actions taken to address the violations as well as detailed plans on how you will prevent the violations from recurring. Specifically, you should describe the changes made or being made to your quality system that will prevent such serious quality system violations from recurring, and address how you plan on preventing the significant laboratory method control and calibration issues from recurring. If your planned corrections will occur over time, please include a timetable for implementation of those corrections. If corrective action cannot be completed within 15 working days, state the reason for the delay and the time within which the corrections will be completed.
We have received your updated responses dated 10/8/2008 and 11/21/2008 to the Form FDA 483 you received in July 2008. These responses are currently under review. If you believe these updated responses address the issues cited in this Warning Letter, please advise us so in your response to this Warning Letter. If we need more information related to your 10/8/2008 and 11/21/2008 responses to the FDA 483, we will address the need for more information in a separate letter.
In addition, we request that you immediately cease the dissemination of violative promotional material for Iverhart Max® and Iverhart Plus® such as those described above. Specifically, you should cease the dissemination of the tri-fold brochure and the violative statements on the website for Iverhart Max® and Iverhart Max® and any other materials that may contain similar information. Future advertisements and promotional materials should accurately address the claims for the prevention and treatment of the appropriate intestinal parasites described in the currently approved labeling, without overstating the effectiveness. Because the violations described above are serious, we request that your submission include a comprehensive plan of action to disseminate a truthful, non-misleading, and complete corrective message about the issues discussed in this letter to the audience(s) that received the violative advertisements.
Your reply to this Warning Letter should be sent to Amy Devine, Compliance Officer, Food & Drug Administration, Kansas City District, Southwest Region, 11630 West 801th Street, Lenexa, Kansas 66214-3340. If you have any questions about the content of this letter, please contact Ms. Devine at 913-752-2719.
John W. Thorsky
Kansas City District
cc: James M. Deimeke
Director of Quality Assurance
13001 St. Charles Rock Rd.
Bridgeton, MO 63044