Proandre SL MARCS-CMS 567234 —
Recipient NameMr. Manuel Suarez Marin
Recipient TitleGeneral Manager
- Proandre SL
Calle Condestable De Portugal 43-45
- Issuing Office:
- Center for Drug Evaluation and Research
Via UPS Warning Letter 320-19-12
Return Receipt Requested
February 13, 2019
Mr. Manuel Suarez Marin
Calle Condestable De Portugal 43-45
Dear Mr. Suarez Marin:
The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Proandre SL at Calle Condestable De Portugal 43-45, Granollers, Barcelona, from June 11 to 14, 2018.
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).
In addition, as formulated and labeled, the OTC drug products Proandre Antibacterial Soap Liquid and Proandre Hand Sanitizer Liquid are misbranded under sections 502(c) and (x) of the FD&C Act, 21 U.S.C. 352(c) and (x). Introduction of such products into interstate commerce is prohibited under section 301(a) of the FD&C Act, 21 U.S.C. 331(a).
We reviewed your September 10, 2018, response in detail.
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 over-the-counter (OTC) drug products including Proandre Antibacterial Soap Liquid, (b)(4), and (b)(4) without testing for identity and strength. Our investigator documented that you only test your finished drug products for specific gravity, pH, refraction value, and microbiological tests.
In your response, you indicated you will request that your contract laboratory perform identity and strength tests on drug products manufactured in the future. Your response is inadequate because you provided no timeline for this action and did not include a plan to test retain samples of drug products within expiry that have been distributed to the U.S. market.
In response to this letter, provide:
- Your updated Standard Operating Procedure (SOP) for finished drug product release testing that includes tests for identity and strength as well as product specifications and test methods. Provide your timeline for implementing these corrective actions.
- Your plan to perform complete testing of retain samples for all distributed drug products that remain within expiry in the market.
2. Your firm failed to follow an adequate written testing program designed to assess the stability characteristics of drug products (21 CFR 211.166(a)).
You did not follow the testing time points of your stability program, which included stability testing at three months, six months, one year, and two years. Specifically, for one lot of your (b)(4), you performed three-month stability testing on the same day the lot was packaged and you performed six-month stability testing nine months after the initial stability testing.
In your response, you provided your revised “Product Stability Report” procedure. However, this procedure did not include identity and strength testing of the active ingredients at each time point. In addition, you did not indicate any changes made to your stability program to ensure that drug products are tested during the remaining stability intervals described in your protocol.
In response to this letter, provide:
- A full summary of stability data results for all batches within expiry. Include the time points, methods used for microbiological and chemical testing, written stability protocols that were followed, and any updated test data used to determine if the potency of your products is maintained throughout their shelf life.
- A comprehensive assessment and corrective action and preventative action (CAPA) plan to ensure the adequacy of your stability program. Your CAPA plan should include, but not be limited to, a remediated SOP describing your stability program, stability-indicating methods, stability studies to support each drug product in its container-closure system before distribution is permitted, an ongoing program in which representative batches of each product are added each year to the program to determine if the shelf life claim remains valid, and specific attributes to be tested at each time point.
3. Your firm failed to prepare batch production and control records with complete information relating to the production and control of each batch of drug product produced (21 CFR 211.188).
Your batch production and control records do not include complete information.
Our inspector reviewed several batch records and found use of white-out correction liquid, unintelligible data, and/or missing information such as density test results and the date of approval of the batch. Several entries were over written and crossed out with no signature, date, or explanation.
In addition, laboratory test results (e.g., viscosity, density, appearance, and odor) lacked initials or signature of a second person showing that the original records have been reviewed for accuracy, completeness, and compliance with established standards.
In your response, you provided a document titled “Manufacturing Guide” where you added entries for dates, signatures, and second person verification in some key production steps. This guide included a batch record for (b)(4) that lacks verification signatures at significant steps.
Data Integrity Remediation
Your quality system does not adequately ensure the accuracy and integrity of data to support the safety, effectiveness, and quality of the drugs you manufacture. See FDA’s guidance document Data Integrity and Compliance With Drug CGMP for guidance on establishing and following CGMP compliant data integrity practices at https://www.fda.gov/downloads/drugs/guidances/ucm495891.pdf. We strongly recommend that you retain a qualified consultant to assist in your remediation. In response to this letter, provide the following.
A. A comprehensive investigation into the extent of the inaccuracies in data records and reporting including results of the data review for drugs distributed to the United States. Include a detailed description of the scope and root causes of your data integrity lapses.
B. A current risk assessment of the potential effects of the observed failures on the quality of your drugs. Your assessment should include analysesof the risks to patients caused by the release of drugs affected by a lapse of data integrity and analyses of the risks posed by ongoing operations.
C. A management strategy for your firm that includes the details of your global CAPA plan. The detailed CAPA should describe how you intend to ensure the reliability and completeness of all data generated by your firm including microbiological and analytical data, manufacturing records, and all data submitted to FDA.
D. A quality unit procedure with clearly-defined responsibilities and procedures including approval and rejection authorities, second person verification, and yearly CGMP training that covers good documentation practices and ALCOA (accurate, legible, contemporaneously recorded, original, attributable) principles.
Your firm’s quality systems are inadequate. See FDA’s guidance document Quality Systems Approach to Pharmaceutical CGMP Regulations for help implementing quality systems and risk management approaches to meet the requirements of CGMP regulations 21 CFR, parts 210 and 211 at https://www.fda.gov/downloads/Drugs/Guidances/UCM070337.pdf.
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.
Proandre Antibacterial Soap Liquid and Proandre Hand Sanitizer Liquid are drugs as defined by section 201(g)(1)(B) of the FD&C Act, 21 U.S.C. 321(g)(1)(B) because they are intended for the diagnosis, cure, mitigation, treatment, or prevention of disease, and/or under section 201(g)(1)(C) of the FD&C Act, 21 U.S.C. 321(g)(1)(C) because they are intended to affect the structure or any function of the body. Specifically, these products are intended as OTC consumer antiseptics.
Examples of claims observed on your products’ labels for Proandre Antibacterial Soap Liquid and Proandre Hand Sanitizer Liquid that establish the intended uses of the products as defined in 21 CFR 201.128 include, but may not be limited to, the following:
The labeling for such drugs, like all OTC drugs, must comply with all of the requirements of section 502 of the FD&C Act and all pertinent regulations found in 21 CFR. However, your products do not meet these requirements for the reasons described below.
Proandre Antibacterial Soap Liquid and Proandre Hand Sanitizer Liquid contain labeling information both in English and Spanish. Dual language labeling with English and another language is permissible when labeled in accordance to 21 CFR 201.15 and not otherwise false or misleading. Please note, 21 CFR 201.15 states that “all words, statements, and other information required by or under authority of the act to appear on the label or labeling shall appear thereon in the English language” . . . and “if the label contains any representation in a foreign language, all words, statements, and other information required by or under authority of the act to appear on the label shall appear thereon in the foreign language.” The labeling for Proandre Antibacterial Soap Liquid and Proandre Hand Sanitizer Liquid is misbranded under section 502(c) of the FD&C Act, 21 U.S.C. 352(c), because they are not labeled in accordance to 21 CFR 201.15. Specifically, the labels do not include a Drug Facts panel in the Spanish language.
Proandre Antibacterial Soap Liquid and Proandre Hand Sanitizer Liquid are misbranded under section 502(x) of the FD&C Act, 21 U.S.C. 352(x) because the products’ labels fail to disclose a domestic address or domestic telephone number through which the responsible person may receive a report of a serious adverse event with such drug. Please note that section 201(k) of the FD&C Act defines the term label as “...a display of written, printed, or graphic matter upon the immediate container of any article; and a requirement made by or under the authority of the FD&C Act that any word, statement, or other information appear on the label shall not be considered to be complied with unless such…also appears on the outside container….” Therefore, the domestic address or domestic telephone number must appear on the immediate container label and on the outside container label if one exists.
The introduction or delivery for introduction of a misbranded drug into interstate commerce is prohibited under section 301(a) of the FD&C Act, 21 U.S.C. 331(a). Therefore, the marketing of Proandre Antibacterial Soap Liquid and Proandre Hand Sanitizer Liquid violates this provision of the FD&C Act.
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 November 16, 2018.
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 Proandre SL at Calle Condestable De Portugal 43-45, Granollers, Barcelona, 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:
U.S. Food and Drug Administration
White Oak Building 51, Room 4226
10903 New Hampshire Avenue
Silver Spring, MD 20993
Please identify your response with FEI 3006763819.
Office of Manufacturing Quality
Office of Compliance
Center for Drug Evaluation and Research