Inspections, Compliance, Enforcement, and Criminal Investigations

Casmara Cosmetics, S.A. 2/12/18

 

  

Black HHS-Blue FDA Logo

 

 

 
10903 New Hampshire Avenue
Silver Spring, MD 20993 

 

Via UPS                                                                                 Warning Letter 320-18-32
Return Receipt Requested
 
February 12, 2018
           
 
Mr. Jose Sequi Gonzalez
President
Casmara Cosmetics, S.A.
Calle Ciudad de Lira, No. 29 y 31
Paterna (Valencia) 46988
Spain
 
Dear Mr. Sequi Gonzalez:
 
The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Casmara Cosmetics, S. A., at Calle Ciudad de Lira, No. 29 y 31, Paterna (Valencia), from May 29 to 31, 2017.
 
This warning letter summarizes significant violations of current good manufacturing practice (CGMP) regulations for finished pharmaceuticals. See 21 CFR, parts 210 and 211.
 
Because your methods, facilities, or controls for manufacturing, processing, packing, or holding do not conform to CGMP, your drug products are adulterated within the meaning of section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), 21 U.S.C. 351(a)(2)(B).
 
We reviewed your June 8, 2017, response in detail and acknowledge receipt of your subsequent correspondence.
 
During our inspection, our investigator observed specific violations including, but not limited to, the following.
 
1.    Your firm failed to 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)).
 
You released your over-the-counter (OTC) drug products, such as (b)(4) lotion and (b)(4), without testing these products for the identity and strength of each active ingredient. Testing your active ingredients is essential to ensuring the drug products you manufacture meet established specifications for the chemical and microbial attributes they purport to possess.
  
2.    Your firm failed to conduct at least one test to verify the identity of each component of a drug product. Your firm also failed to establish the reliability of component supplier analysis on which you rely in lieu of certain tests through appropriate validation of the supplier's test results at appropriate intervals (21 CFR 211.84(d)(l) and (2)).
 
You failed to test incoming active pharmaceutical ingredients and other components used to manufacture OTC drug products to determine their identity, purity, strength, and other appropriate quality attributes. Instead, your firm relied solely on certificates of analysis from unqualified suppliers.
 
In addition, you manufacture some of your products using (b)(4), but did not perform an identity test for incoming shipments of this component. You failed to determine whether (b)(4) or (b)(4) was within appropriate limits according to the USP standards for (b)(4). (b)(4) contamination in pharmaceuticals has caused lethal poisoning incidents in humans worldwide.
 
See FDA's guidance document, Testing of (b)(4) for (b)(4), to help you meet the CGMP requirements when manufacturing drugs containing (b)(4), at (b)(4).
 
3.    Your firm failed to follow an adequate written testing program designed to assess the stability characteristics of drug products and to use results of such stability testing to determine appropriate storage conditions and expiration dates (21 CFR 211.166(a)).
 
Your stability program is inadequate. While you have some data that supports a (b)(4) expiry, this data is insufficient because you failed to include testing for active ingredients. You also failed to demonstrate that the chemical and physical properties of your OTC drug products will remain acceptable throughout the (b)(4) expiry you claim for your products.
 
4.    Your firm failed to establish written procedures for production and process control designed to assure that the drug products you manufacture have the identity, strength, quality, and purity they purport or are represented to possess (21 CFR 211.100(a)).
 
You have not validated the processes used to manufacture your OTC drug products. You did not perform process qualification studies, and lacked an ongoing program for monitoring process control to ensure stable manufacturing operations and consistent drug quality.
 
See FDA’s guidance document, Process Validation: General Principles and Practices, for general principles and approaches that FDA considers appropriate elements of process validation, at https://www.fda.gov/downloads/drugs/guidances/ucm070336.pdf.
 
In addition, your batch production records lacked sufficient instructions to ensure reproducibility of your manufacturing processes. Your procedures do not include defined process parameters, such as (b)(4) times, (b)(4) speeds, (b)(4), and bulk hold times. You must have adequate records to document the steps in your manufacturing processes and demonstrate that they remain in control.
 
Inadequate Response
 
Your responses to the FDA inspection did not provide sufficient details or evidence that your firm will remediate your operations to ensure compliance with CGMP.
 
In response to this letter, provide the following:
  • The test methods and specifications you use to analyze each batch of drug product prior to release, including both chemical and microbial quality attributes. Include a summary of all test results obtained from full testing of all batches of OTC drug products intended for the U.S. market still within expiry.
  • Timelines for testing all in-date drug products intended for the U.S., for identity and strength of active ingredients and all other appropriate quality attributes, including total count and objectionable microorganisms. If you find that you released any batch for which release test results were found to be out-of-specification, indicate the corrective actions you will take, such as customer notifications and product recalls.
  • Batch release specifications for all incoming components. Describe the tests you will conduct for each batch of incoming components.
  • A summary of test results obtained from full testing of each of your incoming components to validate suppliers’ certificates of analysis. Include your procedures to ensure that you test for the identity of each incoming lot of components.
  • Your procedures to ensure that you test all lots of (b)(4). Provide a current risk assessment of all OTC drug products that contain (b)(4) intended for the U.S. market still within expiry. Provide the results of the testing of retain samples of these lots for (b)(4) and (b)(4).
  • A current risk assessment of the OTC drug products intended for the U.S. market still within expiry that are not supported by adequate stability testing.
  • Timelines for process performance qualification for each of your drug products. For any drugs distributed to the U.S. before validation activities are completed, provide an interim plan to ensure the quality of drug products that you continue to manufacture and distribute. Provide a detailed summary of your approach for routinely monitoring intra-batch and inter-batch variation. 
CGMP Consultant Recommended
 
Based upon the nature of the violations we identified at your firm, we strongly recommend engaging a consultant, qualified as set forth in 21 CFR 211.34, to assist your firm in meeting CGMP requirements. Your use of a consultant does not relieve your firm’s obligation to comply with CGMP. Your firm’s executive management remains responsible for fully resolving all deficiencies and ensuring ongoing CGMP compliance.
 
Labeling Concerns
 
We collected 33 labels during the May 2017 inspection, including labels for (b)(4), and (b)(4) OTC drug products. As a manufacturer and/or distributer of OTC drug products, it is your responsibility to comply with all requirements of Federal law and FDA regulations, to ensure that your products are safe and effective, and to ensure that your products do not violate the provisions of the FD&C Act.
 
Products that are marketed and indicated for use as (b)(4) are subject to the Final Rule for (b)(4) Drug Products for Over-the-Counter Human Use (b)(4). If the intent is to market them as OTC drug products within the scope of FDA’s OTC Drug Review, they must meet the conditions set forth in (b)(4). Otherwise, FDA-approved applications must be in effect.
 
Conclusion
 
Violations cited in this letter are not intended as an all-inclusive list. You are responsible for investigating these violations, for determining the causes, for preventing their recurrence, and for preventing other violations.
 
FDA placed your firm on Import Alert 66-40 on October 12, 2017.
 
Until you correct all violations completely and we confirm your compliance with CGMP, FDA may withhold approval of any new applications or supplements listing your firm as a drug manufacturer.
 
Failure to correct these violations may also result in FDA continuing to refuse admission of articles manufactured at Casmara Cosmetics, S. A., at Calle Ciudad de Lira, No. 29 y 31, Paterna (Valencia), into the United States under section 801(a)(3) of the FD&C Act, 21 U.S.C. 381(a)(3). Under the same authority, articles may be subject to refusal of admission, 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 FD&C Act, 21 U.S.C. 351(a)(2)(B).
 
After you receive this letter, respond to this office in writing within 15 working days. Specify what you have done since our inspection to correct your violations and to prevent their recurrence. If you cannot complete corrective actions within 15 working days, state your reasons for delay and your schedule for completion.
 
Send your electronic reply to CDER-OC-OMQ-Communications@fda.hhs.gov or mail your reply to:
           
Metitia Gramby Sanders, Consumer Safety Officer
U.S. Food and Drug Administration
White Oak Building 51, Room 4359
10903 New Hampshire Avenue
Silver Spring, MD 20993
USA   
  
Please identify your response with FEI 3004619185.
 
 
Sincerely,
/S/ 
Francis Godwin
Acting Director
Office of Manufacturing Quality
Office of Compliance
Center for Drug Evaluation and Research

Page Last Updated: 02/20/2018
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