Inspections, Compliance, Enforcement, and Criminal Investigations

Kanebo Cosmetics Inc. 4/1/13


Department of Health and Human Services logoDepartment of Health and Human Services

Public Health Service
Food and Drug Administration
 Silver Spring, MD  20993 


Warning Letter
WL: 320-13-14 
CERTIFIED MAIL                                                                        
April 1, 2013

Mr. Keiji Kawamura
Plant Manager
Kanebo Cosmetics Inc.
Odawara Plant
5-3-28, Kotobuki-Cho, Odawara-Shi
Kanagawa, 250-0002, Japan
Dear Mr. Kawamura:
During our September 3, 2012 through September 6, 2012 inspection of your pharmaceutical manufacturing facility, Kanebo Cosmetics Inc., located at 5-3-28, Kotobuki-Cho, Odawara-Shi, Kanagawa, Japan, investigator(s) from the U.S. 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 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 acknowledge receipt of your firm’s correspondence dated October 16, 2012.
Our investigator observed specific violations during the inspection, including, but not limited to, the following:
1.    Your firm does not 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)).
For example, your firm did not determine the purity and strength of the active ingredient(s) in any batch of your (b)(4) over-the-counter (OTC) drug products manufacturedprior to June 2012. These products are currently in the U.S. market.  In response to this letter, provide scientifically sound and appropriate written test procedures, sampling plans, and specifications for your (b)(4) drug products, including documentation of validation for all non-compendial analytical methods. Provide test results of all your drug product batches within expiry that have been distributed to the U.S. to demonstrate conformance to final specifications, and to support your product label claims as to the amount of active ingredient(s). Describe and provide supportive documentation for any corrective action and/or market action you will take for product batches that are non-conforming or lack appropriate product release testing.  In addition, explain how you will assure adequate finished product testing for all future drug product batches prior to release.
2.    Your firm does not have a written testing program designed to assess the stability characteristics of drug products in order to determine appropriate storage conditions and expiration dates (21 CFR 211. 166(a)).
For example, your accelerated stability studies do not include assays to assess the purity and strength of the active ingredients.  Moreover, your firm has not conducted long term stability studies for (b)(4) OTC drug products distributed to the U.S. market.     
In response to this letter, describe your action plan for the product batches within expiry that have been distributed to the U.S. market without stability data. Provide documentation to support the expiration dates you assigned to your drug products currently in U.S. distribution. Also, explain how you will assure that each of your drug products is routinely tested according to a stability program that your quality unit approves and that addresses each of the requirements described in 21 CFR 211.166. In addition, include assurance that your analytical methods are stability-indicating and validated (or verified, if methods are compendial).
3.    Your firm failed to test samples of each component for conformity with all appropriate written specifications for purity, strength, and quality (21 CFR 211.84(d)(2)).
For example, your firm did not perform testing for purity, strength, and quality of incoming lots of (b)(4), and (b)(4) active pharmaceutical ingredients (APIs) used in the manufacture of your (b)(4) drug products.  Instead, you relied solely on certificates of analysis (COAs) provided by the suppliers without establishing the reliability of the supplier's analyses through appropriate validation of the supplier's test results at appropriate intervals.  
In your response to this letter, provide procedures that mandate conducting at least one specific identity test for each incoming lot of API component.  Please also provide similar procedures for any tests that you have not demonstrated to be reliable from your suppliers’ COAs. Describe your sampling procedure, including specifying what constitutes a representative sample for each attribute to be tested for each incoming lot of API.  Test and provide results for the reserve samples, within expiration period, of all lots of APIs that were used in the manufacture of finished drug products distributed to the U.S. market. Additionally, include your API supplier qualification procedures and the outcomes of your qualification studies.
4.    Your firm failed to establish adequate written procedures for production and process controls designed to assure that the drug products you manufacture have the identity, strength, quality, and/or purity they purport or are represented to possess (21 CFR 211.100(a)).
For example, the manufacturing processes for your (b)(4) OTC drug products intended for the U.S. market are not validated.
In response to this letter, provide validation protocols with scientifically justified acceptance criteria and results of the validation studies. If you have not completed your process validation, please provide a schedule with milestones for its completion.  Describe in-process controls your firm will institute to ensure that your processes are performing as intended.
The items listed above, as well as other deficiencies our investigator(s) found, lead us to question the effectiveness of your current quality system to achieve overall compliance with CGMP at your facility. It is apparent that you have not implemented a robust quality system at your firm. Examples of other CGMP deficiencies observed during the inspection are the failure to qualify manufacturing equipment, failure to conduct cleaning validation, failure to validate all non-compendial analytical methods, and failure to qualify the purified water system.  Moreover, your firm does not have effective procedures in place to handle and investigate deviations, non-conformances, and out-of-specification (OOS) results.  To ensure that your drug products meet the quality and purity characteristics that they purport, or are represented to possess, please reference the CGMP regulations at 21 CFR Parts 210 and 211 located at the link, and the FDA guidance entitled Process Validation: General Principles and Practices located at the link
Due to serious CGMP issues at your firm, we recommend you engage a third party consultant with appropriate CGMP expertise to assess your firm’s facility, procedures, processes, and systems to ensure that the drugs you manufacture have appropriate identity, strength, quality, and purity.
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 the violations identified above and for preventing their recurrence and the occurrence of other violations. 
Until all corrections have been completed and FDA has confirmed corrections of the violations 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, your failure to correct these violations may result in FDA continuing to refuse admission of articles manufactured at Kanebo Cosmetics Inc., Odawara, Kanagawa, Japan, 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 CGMP 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 and prevent the recurrence of violations, and provide copies of supporting documentation. If you cannot complete corrective actions within fifteen working days, state the reason for the delay and the date by which you will have completed the corrections. Additionally, if you no longer manufacture or distribute the drug product(s) at issue, provide the date(s) and reason(s) you ceased production.
Please send your reply to the following address:
An T. Vu, Ph.D.
Compliance Officer
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
10903 New Hampshire Avenue
Silver Spring, MD 20993
Michael Smedley
Acting Director
Office of Manufacturing and Product Quality
Office of Compliance

Page Last Updated: 04/16/2013
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