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  5. Gulsah Uretim Kozmetik Sanayi Anonim Sirketi - 611591 - 05/13/2021
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Gulsah Uretim Kozmetik Sanayi Anonim Sirketi MARCS-CMS 611591 —

Delivery Method:

Recipient Name
Mr. Ali Kaya
Recipient Title
Vice General Manager
Gulsah Uretim Kozmetik Sanayi Anonim Sirketi

No: 6 Omerli Mahallesi Arnavutkoy

Issuing Office:
Center for Drug Evaluation and Research | CDER

United States

Warning Letter 320-21-46

May 13, 2021

Dear Mr. Kaya:

Your facility is registered with the United States Food and Drug Administration (FDA) as a manufacturer of over-the-counter (OTC) drug products. FDA has reviewed the records you submitted in response to our April 23, 2020, request for records and other information pursuant to section 704(a)(4) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) for your facility, Gulsah Uretim Kozmetik Sanayi Anonim Sirketi; FEI 3010734749, at No: 6 Omerli Mahallesi Arnavutkoy, Istanbul.

This warning letter summarizes significant violations of current good manufacturing practice (CGMP) regulations for finished pharmaceuticals. See Title 21 Code of Federal Regulations (CFR) parts 210 and 211 (21 CFR parts 210 and 211).

Because your methods, facilities or controls for manufacturing, processing, packing, or holding do not appear to conform to CGMP, your drug products are adulterated within the meaning of section 501(a)(2)(B) of the FD&C Act (21 U.S.C. 351(a)(2)(B)).

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)).

Your firm listed OTC drug products with the FDA, including (b)(4), such as (b)(4), containing (b)(4)% (b)(4). Your response to our request for records and other information under section 704(a)(4), indicates that you did not conduct adequate finished drug product testing on drug products shipped to the United States.

During the teleconference (t-con) held on July 16, 2020, to obtain clarification on your written response, and a follow-up t-con held on January 19, 2021, you confirmed that you do not conduct testing for identity and strength of the active ingredient (b)(4), prior to release for each batch of drug product distributed to the U.S market. You also stated in your response that this testing is not required because the formulation is stable.

Without adequate testing, there is no scientific evidence to support that your drug product batches conform to the label claim prior to release.

Following our 704(a)(4) request, we noted that you shipped several lots of (b)(4) to the United States.

In response to this letter, provide the following for all drug products imported to the United States prior to and after our 704(a)(4) request:

• A list of chemical and microbial specifications, including test methods, used to analyze each lot of your drug products before a lot disposition decision.
• An action plan and timelines for conducting full chemical and microbiological testing of reserve samples to determine the quality of all batches of drug product distributed to the United States that are within expiry as of the date of this letter.
• A summary of all results obtained from testing reserve samples from each batch. If such testing reveals substandard quality drug products, take rapid corrective actions, such as notifying customers and product recalls.
• A comprehensive, independent assessment of your laboratory practices, procedures, methods, equipment, documentation, and analyst competencies. Based on this review, provide a detailed plan to remediate and evaluate the effectiveness of your laboratory system.

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 validate and establish the reliability of your component supplier’s test analyses at appropriate intervals (21 CFR 211.84(d)(1) and (2)).

Based on the records and information you provided, you have not demonstrated that you are testing incoming lots of the active pharmaceutical ingredient (API) used to manufacture your OTC drug products to determine their identity. In addition, your firm released an API for use in drug manufacturing based on a component supplier’s analysis report, although you had not established the reliability of the analysis through appropriate validation.

For example, in response to our initial 704(a)(4) requests for information on identity testing for each lot of component, you did not provide evidence of such testing. In the subsequent t-con held on January 19, 2021, you stated that you do not perform identity testing for each lot of incoming (b)(4) but rely only on vendor Certificates of Analysis (CoA). In the same t-con we requested documents containing the testing performed to qualify the (b)(4) supplier. In response to this request, you provided documents on February 1, 2021, which included Control Forms, Analytical Method, and a third-party Analysis Report for (b)(4). The documents provided are not enough evidence to demonstrate vendor qualification and establish the reliability of your (b)(4) API supplier.

You can rely on vendor CoA for quality attributes, provided you conduct at least one test to verify the identity of each component lot before use in the drug product manufacturing. Additionally, you should have established reliability of supplier’s analyses through adequate initial validation and subsequent verification of supplier’s test results at appropriate intervals.

In response to this letter, provide the following for all drug products imported to the United States prior to and after our 704(a)(4) request:

• A comprehensive independent review of your material system to determine whether all suppliers of components, containers, and closures, are each qualified and the materials are assigned appropriate expiration or retest dates. The review should also determine whether incoming material controls are adequate to prevent use of unsuitable components, containers, and closures.
• The chemical and microbiological quality control specifications you use to test and release each incoming lot of component for use in manufacturing.
• A description of how you will test each component lot for conformity with all appropriate specifications for identity, strength, quality, and purity. If you intend to accept any results from your supplier's CoA instead of testing each component lot for strength, quality, and purity, specify how you will robustly establish the reliability of your supplier's results through initial validation as well as periodic re-validation. In addition, include a commitment to always conduct at least one specific identity test for each incoming component lot.
• A summary of results obtained from testing all components to evaluate the reliability of the CoA from each component manufacturer. Include your standard operating procedure that describes this CoA validation program.
• A summary of your program for qualifying and overseeing contract facilities that test the drug products you manufacture.
• A remediated program that ensures appropriate selection of suppliers who produce raw materials for your firm, suitability of each material grade sourced from the supplier for its intended use, ongoing scrutiny of their supply chain, and appropriate incoming lot controls.

3. Your firm failed to establish and follow an adequate written testing program designed to assess the stability characteristics of drug products and to use results of stability testing to determine appropriate storage conditions and expiration dates (21 CFR 211.166(a)).

You did not provide adequate stability data to demonstrate that the chemical properties of your drug products remain acceptable throughout the labeled expiry period.

For example, the accelerated stability data for (b)(4), submitted in response to our 704(a)(4) request did not include testing for the active ingredient, (b)(4). Thus, the data did not demonstrate that the drug’s active ingredient is stable throughout its shelf life. Further, the data provided did not include testing for degradation products. In the t-con held on January 19, 2021, you stated that you do not perform analytical testing for (b)(4) during stability studies.

Without appropriate stability data, you cannot ensure your drug products meet established specifications and all pre-determined quality criteria throughout the drug product’s assigned shelf-life.

In response to this letter, provide the following for all drug products imported to the United States prior to and after our 704(a)(4) request:

• A comprehensive, independent assessment and corrective and preventive action plan to ensure the adequacy of your stability program. Your remediated program should include, but not be limited to:
    o Stability indicating methods
    o Stability studies for each drug product in its marketed container-closure system before distribution is permitted
    o 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
    o Detailed definition of the specific attributes to be tested at each station (timepoint)

• All procedures that describe these and other elements of your remediated stability program.

Quality Systems

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/media/71023/download.

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. We also recommend that the qualified consultant perform a comprehensive audit of your entire operation for CGMP compliance and that the consultant evaluates the completion and efficacy of your corrective actions and preventive actions before you pursue resolution of your firm’s compliance status with FDA.

Your use of a consultant does not relieve your firm’s obligation to comply with CGMP. Your firm’s executive management remains responsible for resolving all deficiencies and systemic flaws to ensure ongoing CGMP compliance.


The violations cited in this letter are not intended to be an all-inclusive list of violations associated with your drug products. You are responsible for investigating and determining the causes of these violations and for preventing their recurrence or the occurrence of other violations.

Note that FDA placed all drug products manufactured by your firm on Import Alert 66-40 on March 29, 2021, as the methods used in and the controls used for the manufacture, processing, packing, or holding of these drug products does not appear to conform to current good manufacturing practice within the meaning of section 501(a)(2)(B) of the FD&C Act. Drugs and drug products that appear to be adulterated or misbranded may be detained or refused admission without physical examination pursuant to section 801(a)(3) of the FD&C Act, 21 U.S.C. 381(a)(3).

All drugs and drug products manufactured by your firm may remain listed on this import alert until there is evidence establishing that the conditions that gave rise to the appearance of these violations have been resolved, and the FDA has confidence that future entries will be in compliance with the FD&C Act. This may include an inspection prior to the FDA considering the appearance of adulteration to be addressed.

Correct any violations promptly. FDA may withhold approval of any new drug applications or supplements listing your firm as a drug manufacturer until any violations are completely addressed and we confirm your compliance with CGMP. We may re-inspect to verify that you have completed corrective actions to any violations.

This letter notifies you of our findings and provides you with an opportunity to address the above deficiencies. After you receive this letter, respond to this office in writing within 15 working days. Specify what you have done to correct your violations and to prevent their recurrence. In response to this letter you may provide additional information for our consideration as we continue to assess your activities and practices. 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. Identify your response with FEI 3010734749 and ATTN: Ganesh Joshi.


Francis Godwin
Office of Manufacturing Quality
Office of Compliance
Center for Drug Evaluation and Research

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