Inspections, Compliance, Enforcement, and Criminal Investigations

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1 Page 1 of 6 Home Inspections, Compliance, Enforcement, and Criminal Investigations Enforcement Actions Warning Letters Inspections, Compliance, Enforcement, and Criminal Investigations A Nelson & Co., Ltd. 7/26/12 Department of Health and Human Services Public Health Service Food and Drug Administration Silver Spring MD Warning Letter VIA UPS MAIL WL: July 26, 2012 Mr. Najib Fayad Chief Operations Officer A Nelson & Co., Ltd 5-9 Endeavour Way Wimbledon, London SW19 8UH United Kingdom Dear Mr. Fayad: During our November 14 to 17, 2011, inspection of your pharmaceutical manufacturing facility, A Nelson & Co., Ltd., located at 5-9 Endeavour Way, Wimbledon, London, United Kingdom, investigators from the Food and Drug Administration (FDA) identified significant 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 products 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. These drugs are also misbranded under Sections 503 and 301 of the Act. We have reviewed your firm s response of December 07, 2011, and note that it lacks sufficient corrective actions. The following are examples of violations that our investigators observed during the inspection: CGMP VIOLATIONS 1. Your firm does not have adequate written procedures for production and process controls designed to assure that the drug products you manufacture have the identity, strength, quality, and purity they purport or are represented to possess [21 C.F.R (a)]. Three examples of violations of (a) are as follows:

2 Page 2 of 6 a. During the inspection, the investigator observed glass fragments present during the manufacture of Kali Phos 30 c Clikpak, Batch # Specifically, glass fragments were observed in the Clikpak Assembly (b)(4) enclosed area where open glass vials are inserted into the outer plastic Clikpak sheaths and move uncovered on the conveyance mechanism. Your firm failed to implement adequate measures to prevent glass contamination and had no documentation to demonstrate that appropriate line clearance and cleaning is conducted following occurrences of glass breakage, which has been a recurring problem. Your response indicates that a planned process deviation was put in place until a failure mode effect analysis risk assessment could be completed, which was to occur by March The objective of this risk assessment was to determine the required engineering upgrades to help keep glass out of the drug product. Your response also mentioned that no complaints were received for glass found in the product. Your response is found unacceptable as quality can not be added to a product that has been already manufactured and released for distribution. We are concerned that you may have released product for distribution without fully investigating the root cause of the presence of glass fragments, implementing a corrective and preventive action plan, and evaluating impact on all products manufactured using this line. Please note that the lack of current customer complaints alone is neither a verification of a robust quality system nor that you have appropriate process controls in place to conclude that glass fragments may not be present in your products. In your response to this letter, you should provide a risk assessment for all products in the U.S. market that are within expiry. Please also include supporting data that any engineering upgrades you have undertaken to improve the processing line are effective in preventing glass particles from entering your products. b. The investigator also observed for Batch #36659 that one out of every six bottles did not receive the dose of active homeopathic drug solution due to the wobbling and vibration of the bottle assembly during filling of the active ingredient. The active ingredient was instead seen dripping down the outside of the vial assembly. Your firm lacked controls to ensure that the active ingredient is delivered to every bottle. Your response indicates that the line speed was unusually high, and you state that you have corrected the problem to prevent recurrence. However, your response is inadequate because it does not provide a risk assessment for the U.S.-distributed products previously manufactured on the faulty line. Please provide a risk assessment for all products within expiry, distributed to the U.S., manufactured on the line at high speed. Additionally, provide evidence that the line has been successfully validated to ensure each bottle contains the appropriate dose of active homeopathic drug solution. c. The dosing process has not been validated appropriately. Specifically, your surrogate validation study, Medication of un-medicated pillules with (b)(4), visually demonstrates the variability of the amount of (b)(4) for the pillules in one vial. Your firm lacks control of the variation for the amount of the active ingredient in the pillules. The validation study demonstrated that pillules at the top of the bottle contain more active ingredient than pillules at the bottom. There are no controls in place to ensure that the dosing procedure is homogenous and reproducible. Please provide evidence that the dosing process is uniform, as well as a risk assessment for all Clikpak products, distributed to the U.S., dosed with an inconsistent or excessive amount of active ingredient, regarding their safety for consumers.

3 Page 3 of 6 2. Your firm does not have laboratory records that include complete data derived from all tests necessary to assure compliance with established specifications and standards [21 C.F.R (a)]. For example, in some cases, the analytical testing documentation for raw materials did not include sample solution preparations, sample weight, the method number used, the initials of the analyst who performed the test, and the date of the analysis. Your response indicates that the laboratory will stop using notebooks and replace them with analytical test forms and that a project team will prioritize the new analytical forms and plan for full implementation by the end of Your response is inadequate because it does not include an interim plan to ensure adequate documentation in the notebooks prior to the implementation of the new forms. Please provide evidence that laboratory analyses will be documented adequately prior to the implementation of the new analytical forms. Your response should also include a list of the specific SOPs and laboratory records that you plan to revise to ensure all records of test data are complete. 3. Your firm has failed to calibrate instruments and recording devices at suitable intervals in accordance with an established written program containing specific directions, schedules, limits for accuracy and precision, and provisions for remedial action in the event accuracy and/or precision limits are not met [21 C.F.R (b)(4)]. Two examples of violations of (b)(4) are as follows: a. Your firm does not have an established written program to calibrate/qualify the Perkin Elmer Clarus gas chromatograph (GC) at suitable intervals. b. Your firm did not calibrate and qualify the Jasco high performance liquid chromatography (HPLC) instrumentation adequately, in that there is no periodic qualification or evaluation of the pump, oven, injector, or detector. The Use and Calibration of HPLC procedure does not include criteria to define adequate calibration of the instrument. Your response indicates that a use, maintenance, and qualification procedure for the GC will be separated from the procedure for the Determination of (b)(4) and (b)(4) by Gas Chromatography by March Additionally, your response indicates that the HPLC procedure will be revised to include operational performance and acceptance criteria by March Please provide an analysis of your analytical data used to release raw materials for production of products in U.S. distribution and provide evidence that you are in compliance with 21 C.F.R We remind you that you are responsible for ensuring that your firm s drug manufacturing operations comply with applicable requirements, including CGMP regulations. FDA expects A Nelson & Co., Ltd. to undertake a comprehensive and global assessment of your manufacturing operations to ensure that your processes, and ultimately, the drug products you manufacture, conform to FDA requirements. MISBRANDING VIOLATIONS FDA reviewed your firm s labeling information for products including, but not limited to: Arnica and Arnileve. Based on our review of the labeling for these products at and these products are misbranded

4 Page 4 of 6 under Sections 503 and 301 of the Federal Food, Drug, and Cosmetic Act (the Act) (21 U.S.C. 353 and 331). Misbranding [ 503(b)(4) and 301(a)] According to the labeling on your website, the above listed products are intended to cure, mitigate, treat, or prevent diseases, or to affect the structure or function of the body. Your product labeling documents the intended uses of your products including, but not limited to the following: Arnica: Homeopathy, such as the homeopathic remedy Rhus tox and Arnica, has been traditionally used to help relieve the symptoms of rheumatoid and osteoarthritis. Arnileve: Apply Arnileve Arnica Cream liberally to the affected area in order to reduce inflammation and hasten recovery time. Based on the above labeling and claims, these products are drugs under section 201(g)(1)(B) of the Act (21 U.S.C. 321(g)(1)(B)), because they are intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man, and under section 201(g)(1)(C) of the Act (21 U.S.C. 321(g)(1)(C)), because they are intended to affect the structure or any function of the body. Section 503(b)(1) of the Act (21 U.S.C. 353(b)(1)) identifies criteria for determining the prescription status of a product. The products listed above are prescription drugs within the meaning of section 503(b)(1) of the Act because they are intended to treat diseases that require diagnosis and treatment by a physician or are intended to provide treatment for symptoms usually caused by an underlying disease process that requires diagnosis and treatment by a physician. Because they may be dispensed only by prescription of a licensed practitioner, these products are misbranded under Section 503(b)(4) of the Act (21 U.S.C. 353(b)(4)) in that their labels fail to bear the symbol, "Rx only."1 Your marketing of these misbranded products violates Sections 301(a) and (k) of the Act (21 U.S.C. 331(a) and (k)). We recognize that these products are labeled as homeopathic drugs with active ingredients measured in homeopathic strengths. The definition of "drug" in section 201(g)(1) of the Act (21 U.S.C. 321(g)(1)) includes articles recognized in the official Homeopathic Pharmacopeia of the United States (HPUS), or any supplement to it. Homeopathic drugs are subject to the same regulatory requirements as other drugs; nothing in the Act exempts homeopathic drugs from any of the requirements related to adulteration, labeling, misbranding, or approval. We acknowledge that many homeopathic drugs are manufactured and distributed without FDA approval under enforcement policies set out in the Agency s Compliance Policy Guide entitled, Conditions Under Which Homeopathic Drugs May be Marketed (CPG ) (the CPG). As its title suggests, the CPG identifies specific conditions under which homeopathic drugs may ordinarily be marketed; thus, in order to fall under the enforcement policies set forth in the CPG, a homeopathic product must meet the conditions set forth in the CPG. One of those conditions is compliance with Section 503(b) of the Act. Under the CPG, only homeopathic products intended solely for self-limiting disease conditions amenable to self-diagnosis (of symptoms) and treatment may be marketed OTC. Homeopathic products offered for conditions not amenable to OTC use must be marketed as prescription products.2 The violations cited in this letter are not intended to be an all-inclusive statement of violations that exist at your facility. You are responsible for investigating and determining the causes of the violations identified above and for preventing their recurrence and the occurrence of other violations. If you wish to continue to ship your products to the United States, it is the responsibility of your firm to ensure compliance with all U.S. standards for CGMP and all applicable U.S. laws and regulations. Until all corrections have been completed and FDA has confirmed corrections of the violations

5 Page 5 of 6 and your firm s compliance with CGMP, FDA may withhold approval of any new applications or supplements listing your firm as a drug product manufacturer. In addition, failure to correct these violations may result in FDA refusing admission of articles manufactured at A Nelson & Co., Ltd., located at 5-9 Endeavour Way, Wimbledon, London, United Kingdom, into the United States. The articles are subject to refusal of admission pursuant to section 801(a)(3) of the Act [21 U.S.C. 381(a)(3)], in that, the methods and controls used in their manufacture do not appear to conform to Current Good Manufacturing Practice within the meaning of section 501(a) (2)(B) of the Act [21 U.S.C. 351(a)(2)(B)]. Within fifteen working 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 being taken to prevent the recurrence of violations and copies of supporting documentation. If you cannot complete corrective action within fifteen working days, state the reason for the delay and the date by which you will have completed the correction. Additionally, your response should state if you no longer manufacture or distribute the drug products manufactured at this facility, and provide the dates and reasons you ceased production. Please identify your response with FEI # If you have questions or concerns regarding this letter, contact Allison A. Aldridge, Ph.D., Compliance Officer, at the below address and telephone number. U.S. Food and Drug Administration Center for Drug Evaluation and Research Office of Manufacturing and Product Quality Division of International Drug Quality White Oak, Building 51, Room New Hampshire Ave Silver Spring, MD Tel: (301) Fax: (301) Sincerely, /Steven Lynn/ Steven Lynn Director Office of Manufacturing and Product Quality Office of Compliance Center for Drug Evaluation and Research 1 The Agency s guidance, Conditions Under Which Homeopathic Drugs May be Marketed (CPG ), states that, in accordance with 503(b)(1) of the Act, homeopathic drug products offered for conditions that require diagnosis or treatment by a licensed practitioner must bear the prescription legend, "Caution: Federal law prohibits dispensing without prescription. This guidance was issued by the agency in In 1997, Congress enacted the Food and Drug Administration Modernization Act (FDAMA); section 126 of FDAMA amended 503(b)(4) of the Act to require that the label of a prescription drug must bear the symbol Rx only. 2 We note that the CPG also states that, if the HPUS specifies a distinction between nonprescription (OTC) and prescription status of a product based on strength (e.g., 30X), and that distinction is more restrictive than section 503(b) of the Act, the more stringent criteria (i.e., the HPUS criteria) will apply. It follows from this that, if the HPUS specifies a distinction between OTC and prescription status based on strength, and that distinction is less restrictive than section 503(b) of the Act, the section 503(b) criteria will apply regardless of the HPUS distinction. Page Last Updated: 08/07/2012

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