Inspections, Compliance, Enforcement, and Criminal Investigations
ANIP Acquisition Company 8/21/09
Department of Health and Human Services
|Public Health Service
Food and Drug Administration
|New Orleans District
404 BNA Drive
Suite 500 Building 200
Nashville, TN 37217
August 21, 2009
WARNING LETTER NO. 2009-NOL-17
Delivery Signature Requested
Arthur S. Przybyl
Chief Executive Officer
ANIP Acquisition Company
7131 Ambassador Road, Suite 150
Woodlawn, Maryland 21244
Re: ANIP Acquisition Company
3600 25th Avenue
Gulfport, Mississippi 39501
Dear Mr. Przybyl:
During an inspection of your drug manufacturing facility, located at 3600 25th Avenue, Gulfport, Mississippi on February 10 - 13, and 19,2009, investigators from the U.S. Food and Drug Administration (FDA) found serious violations of the Federal Food, Drug, and Cosmetic Act (the Act) including violations from FDA's current good manufacturing practice (CGMP) regulations, Title 21, Code of Federal Regulations, Parts 210 and 211 (21 CFR 210 & 211). These CGMP violations were listed on an Inspectional Observations, Form FDA 483, issued to Preston D. Wright, Director of Quality, at the close of the inspection. These CGMP violations cause your firm's human drug products to be adulterated within the meaning of Section 501 (a)(2)(B) of the Act [21 United States Code (USC) 351(a)(2)(B)], because the methods used in, or the facilities or controls used for, the manufacture, processing, and holding of drugs do not conform with CGMP regulations to assure such drugs meet the requirements of the Act as to safety, and have the identity and strength, and meet the quality and purity characteristics, which they purport or are represented to possess.
In addition, this inspection revealed your firm is marketing unapproved drugs in violation of Sections 301(a) and (d) of the Act [21 USC 331(a) and (d)] and 505(a) of the Act [21 USC 355(a)]. Furthermore, the drugs are misbranded in violation of Section 502(t)(1) [21 USC 352(f)(1)].
I. CGMP Violations
The CGMP deviations documented during the inspection include, but are not limited to, the following:
1. The procedures applicable to the quality control unit are not fully followed, as required by 21 CFR 211.22(d). For example, although the firm's procedures state the Quality Control Unit (QCU) is responsible for establishing adequate analytical methods, the QCU approved testing methods and/or procedures are not appropriate for the acceptance of raw materials or the release for distribution of finished drug products including, but not limited to dissolution, solubility and viscosity testing for all tannate products.
The finished drug product, (b)(4) tablets (Phenylephrine Tannate 25 mg and Chlorpheniramine Tannate 9 mg), lot number HRT002, manufactured on January 25-28, 2009, lacks an appropriate dissolution profile specification. The dissolution method tests some of the components, but is not capable of detecting the active tannate ingredients in the finished product. The dissolution specifications are not adequate for use.
The finished drug product, (b)(4) Tannate Suspension (Brompheniramine Maleate 6 mg, Phenylephrine HCL 10 mg and Carbetapentane Citrate 25 mg per 5 mL), lot number FPC009, manufactured on June 20,2008, lacks an adequate dissolution and viscosity specification. There is no documentation to show the dissolution characteristics of the finished drug product are adequate, because dissolution testing was excluded from manufacturing process validation, release, and stability studies. In addition, documentation did not record whether variability was observed during testing.
We acknowledge your response dated April 16,2009, in which Robert J. Jamnick, Executive Director of Global Quality, committed to review the dissolution, solubility, and viscosity methods of all your tannate products, and "if feasible" develop the necessary studies to establish adequate methods. Please note it is a CGMP requirement to establish methods which are adequate for their intended use.
2. Laboratory controls do not include determination of conformance to appropriate written specifications for the acceptance of each lot within each shipment of components used in the manufacture, processing, packing, or holding of drug products, as required by 21 CFR 211.160(b)(1). Specifically, review of raw material testing records for Phenylephrine Tannate, lot number (b)(4) and Chlorpheniramine Tannate, lot number (b)(4), revealed your firm fails to identify each peak (or absorption band) of spectra obtained using USP <197K> FT-IR identity test for functional groups characteristic of phenylephrine-based and chlorpheniramine-based compounds.
Review of the USP <197K> FT-IR identity test spectra obtained for the active pharmaceutical ingredients (API) listed above revealed all of the spectra generated for each API had comparable peaks in all areas of the mid-IR spectrum. The established USP <197K> FT-IR identity test method lacks the capability to detect physio-chemical changes of incoming API raw materials or distinguish one of the above referenced APIs from another. Therefore, your firm's identity test method is inadequate for the identification and quantitation of tannate APIs (e.g., Chlorpheniramine Tannate and Phenylephrine Tannate). In addition, your firm fails to document whether your identity testing procedures can detect extraneous materials in lots of incoming APIs, as required by 21 CFR 211.160(b).
We have not received documentation showing your firm is testing for the specific identification of tannate APIs. Identity testing must be able to clearly discriminate between compounds which are closely related in their molecular structure.
3. The laboratory controls do not include the establishment of scientifically sound and appropriate specifications and test procedures designed to assure drug products conform to appropriate standards of identity, strength, quality, and purity, as required by 21 CFR 211.160(b). Specifically, ANIP has not established specifications or testing procedures to determine the acceptable amount of free tannic acid and galloquinate in the finished drug products. Tannic acid and galloquinate are key ingredients in the manufacturing process and affect the performance of the drug product.
4. The written stability program for drug products does not include reliable, meaningful and specific test methods which include dissolution testing and the establishment of controlled-release drug product dissolution specifications for any of the marketed tannate drug products to ensure finished drug product performance at expiry, as required by 21 CFR 211.166(a)(3).
5. Each batch of tannate drug product is not tested to determine conformance to the specifications for the rate of release for each active ingredient, as required by 21 CFR 211.1679c). Specifically, there are no established dissolution specifications for (b)(4) Suspension (Brompheniramine Maleate 6 mg, Phenylephrine HCI 10 mg, and Carbetapentane Citrate 25 mg per 5 mL).
We acknowledge the commitment in your response dated February 18,2009, to remove from the market products containing the ingredients Dextromethorphan Tannate and Brompheniramine Tannate. We note you also manufacture other products which contain tannates. Please provide documentation regarding any actions taken by your firm regarding the removal of the products, listed below, from the market.
II. Unapproved and Misbranded Prescription Drugs
Based on the information collected during the inspection, you manufacture the following prescription drugs, including but not limited to:
• Aldex CT chewable tablets (Diphenhydramine HC112.5 mg, Phenylephrine HCI 5 mg)
• (b)(4) tannate for oral suspension (Pyrilamine Maleate 16 mg, Phenylephrine HCl 5 mg)
• (b)(4) tannate for oral suspension (Pyrilamine Maleate 16 mg, Phenylephrine HCI 5 mg, Dextromethorphan HBr 15 mg)
• (b)(4) suspension (Dextromethorphan HBr 15 mg, Pseudoephedrine HCl 30 mg, Guaifenesin 175 mg)
• (b)(4) tannate suspension (Carbetapentane Citrate 20 mg, Pseudoephedrine HCl 30 mg)
• (b)(4) tannate suspension (Carbetapentane Citrate 7.5 mg, Guaifenesin 200mg)
• (b)(4) tannate suspension (Carbetapentane Citrate 7.5 mg, Pseudoephedrine HCI 30 mg)
• Brompheniramine Phenylephrine Tannate Suspension (Phenylephrine Tannate 20 mg, Brompheniramine Tannate 12 mg)
• (b)(4) chewable tablets (Phenylephrine HCl 10 mg, Pyrilamine Maleate 16 mg)
• (b)(4) chewable tablets (Phenylephrine HCl 10 mg, Pyrilamine Maleate 16 mg, Dextromethorphan HBr 15 mg)
• Duratuss AC 12 tannate suspension (Dextromethorphan HBr 15 mg, Diphenhydramine HCI 12.5 mg, Phenylephrine HCI 15 mg)
• Duratuss DM 12 tannate suspension (Dextromethorphan Hydrobromide 15 mg, Guaifenesin 225 mg)
• Guaifenesin and Phenylephrine Hydrochloride syrup (each 5 ml contains: Guaifenesin 200 mg, Phenylephrine Hydrochloride 5 mg)
• (b)(4) tablets (Phenylephrine Tannate 25 mg, Chlorpheniramine Tannate 9 mg)
• Respi-TANN tannate suspension and (b)(4) (each 5 ml contains: Carbetapentane Citrate 20 mg, Pseudoephedrine HCI 30 mg)
• (b)(4) (Carbetapentane Citrate 20 mg, Pseudoephedrine HC130 mg)
• Respi-TANN PD tannate suspension and (b)(4) (each 5 ml contains: Carbetapentane Citrate 7.5 mg, Pseudoephedrine HC130 mg)
• (b)(4) tannate suspension grape flavor (each 5 ml contains: Carbetapentane Citrate 7.5 mg, Guaifenesin 200 mg)
• TanaCof XR Antihistamine (each 5ml contains: Brompheniramine Tannate 8 mg)
• TanaHist-D Pediatric Suspension Drops (Chlorpheniramine Tannate 2 mg Phenylephrine Tannate 6 mg)
• TanaHist-PD Pediatric Suspension Drops (each ml contains: Chlorpheniramine Tannate 2 mg)
• (b)(4) tannate suspension (Guaifenesin 200 mg, Phenylephrine HCI 20 mg, Dextromethorphan HBr 40 mg)
• (b)(4) tannate suspension Extended Release Dosing Grape Flavor (Guaifenesin 200 mg, Phenylephrine HCI 20 mg, Dextromethorphan HBr 40 mg)
• (b)(4) (Guaifenesin 150 mg, Carbetapentane Citrate 7.5 mg)
• (b)(4) Grape Flavor (Guaifenesin 150 mg, Carbetapentane Citrate 7.5 mg)
• (b)(4) tannate suspension (Brompheniramine Maleate 6 mg, Phenylephrine HCI 10 mg)
• (b)(4)Chewable Tablets (Brompheniramine Maleate 6 mg, Phenylephrine HCI 15 mg)
• (b)(4) tannate suspension (Brompheniramine Maleate 6 mg, Phenylephrine HCI 10 mg, Carbetapetane Citrate 25 mg)
• (b)(4) Cherry Bubblegum flavored tannate suspension (each 5 ml contains: Pseudoephedrine HCI 15 mg, Pyrilamine Maleate 15 mg)
• (b)(4) Grape Flavored tannate suspension (each 5 ml contains: Dextromethorphan HBr 15 mg, Pseudoephedrine HCI 15 mg, Pyrilamine Maleate 15 mg)
The above products are drugs within the meaning of Section 201(g) of the Act, [21 USC 321(g)] because, as demonstrated by their labeling, they are intended for use in the diagnosis, cure, mitigation, treatment, or prevention of diseases. Further, they are "new drugs" within the meaning of Section 201(P) of the Act [21 USC 321(p)] because they are not generally recognized as safe and effective for their labeled uses. Under Sections 301(d) and 505(a) of the Act [21 USC 331(d) and 355(a)], a new drug may not be introduced into or delivered for introduction into interstate commerce unless an application approved by FDA under either Section 505(b) or G) of the Act [21 USC 355(b) or 0)] is in effect for the drug. Based on our information, there are no FDA-approved applications on file for these drug products.
Additionally, because the above prescription drug products are intended for conditions which are not amenable to self-diagnosis and treatment by individuals who are not medical practitioners, adequate directions cannot be written so a layman can use these products safely for their intended uses.
Consequently, their labeling fails to bear adequate directions for use, as required under Section 502(f)(1) of the Act [21 USC 352(f)(1)], and because the products lack required approved applications, they are not exempt from this requirement under 21 CFR 201.115. The introduction or delivery for introduction into interstate commerce of these products without approved new drug applications violates Section 30l(a) and (d) of the Act [21 USC 331(a) and (d)].
Please be advised your April 16,2009, response to the FDA 483, regarding unapproved drugs is not adequate or acceptable. The response identified the following drug production as being discontinued: TanaHist D, TanaHist PD, (b)(4) Suspension and Tablets, Brompheniramine Tablets, (b)(4) Suspension, Tablets, (b)(4) Suspension, TanaCof XR Suspension, (b)(4) Tablets, (b)(4) Suspension, (b)(4) Tablets, Respi-TANN PD Suspension, and (b)(4) Suspension. Partial discontinuation of your marketed unapproved drugs is not sufficient. You must discontinue manufacturing and distributing all of your drug products which require FDA approval. If you are no longer marketing these products, you must update the Drug Listing files in accordance with 21 CFR 207.30(a)(2).
The violations cited in this letter are not intended to be an all-inclusive statement of violations which exist at your facility. You are responsible for investigating and determining the causes of the violations identified above and for preventing their recurrence or the occurrence of other violations. It is your responsibility to assure your firm complies with all requirements of federal law and FDA regulations.
You should take prompt action to correct the violations cited in this letter. Failure to promptly correct these violations may result in legal action without further notice, including, without limitation, seizure and injunction. Other federal agencies may take this warning letter into account when considering the award of contracts. Additionally, FDA may withhold approval of requests for export certificates, or approval of pending new drug applications listing your facility as a manufacturer until the above violations are corrected. A re-inspection may be necessary.
As stated above, you must cease manufacturing and distributing all your unapproved new drug products. Within fifteen (15) working days of receipt of this letter, please notify this office in writing of the specific steps you have taken to correct violations. Include an explanation of each step being taken to prevent the recurrence of violations, as well as copies of related documentation reflecting corrections. If you cannot complete corrective action within fifteen (15) working days, state the reason for the delay and the time within which you will complete the correction. If you no longer manufacture or market the tannate products, your response should so indicate, including the date on which, you ceased production. You can find guidance and information for the regulated industry regarding regulations for drug products through links at FDA's website at http://www.fda.gov/oc/industry/. Also respond within five working days, regarding the actions you have taken to remove any products from the market.
Your reply should be directed to the U.S. Food and Drug Administration, Attention: Cynthia R. Gibson, Compliance Officer, at the above address. If you have questions regarding any issue in this letter, please contact Ms. Gibson at (251) 344-8208, extension 105.
New Orleans District
Enclosure: Form FDA 483
cc: James Marken
Vice President of Operations
ANIP Acquisition Company
3600 25th Avenue
Gulfport, Mississippi 39501