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  5. Neva Global Grup Sanayi Ic Ve Dis Ticaret Anonim Sirketi - 699000 - 03/12/2025
  1. Warning Letters

WARNING LETTER

Neva Global Grup Sanayi Ic Ve Dis Ticaret Anonim Sirketi MARCS-CMS 699000 —

Delivery Method:
VIA Electronic Mail
Reference #:
320-25-54
Product:
Drugs
Recipient:
Recipient Name
Mr. Ahmet Koyuncu
Recipient Title
CEO and Chairman of the Board of Directors
Neva Global Grup Sanayi Ic Ve Dis Ticaret Anonim Sirketi

14/1 Akcaburgaz Mahallesi, 137. Sokak
34522 Esenyurt/İstanbul
Turkey

Issuing Office:
Center for Drug Evaluation and Research (CDER)

United States

Warning Letter 320-25-54

March 12, 2025

Dear Mr. Koyuncu:

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Neva Global Grup Sanayi Ic Ve Dis Ticaret Anonim Sirketi, FEI 3018589922, at 14/1 Akcaburgaz Mahallesi, 137. Sokak, Esenyurt, Istanbul, from September 16 to 20, 2024.

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 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 October 4, 2024 response to our Form FDA 483 in detail.

CGMP Violations

During our inspection, our investigator observed specific violations including, but not limited to, the following.

1. 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 211.84(d)(2)).

Your firm manufactures over-the-counter (OTC) drug products such as (b)(4). You failed to perform adequate identity testing of each component lot used in the manufacture of your OTC drug products, including for (b)(4) and active ingredients (b)(4) and (b)(4). You also relied on your suppliers’ certificate of analysis (COA) without establishing the reliability of your component suppliers’ test analyses at appropriate intervals.

(b)(4)

You failed to adequately test your incoming (b)(4), used as an active pharmaceutical ingredient, for (b)(4). The use of (b)(4) contaminated with (b)(4) has resulted in various lethal poisoning incidents in humans worldwide. (b)(4).

(b)(4)

You failed to adequately test each shipment of each lot of (b)(4) for identity, a component at high-risk of (b)(4) contamination. Identity testing for (b)(4) and certain other high-risk drug components1 includes a limit test in the United States Pharmacopeia (USP) to ensure the component meets the relevant safety limits for levels of (b)(4). Because you did not perform identity testing on each shipment of each lot using the USP identification test that detects these hazardous impurities, you failed to assure the acceptability of this component for use in the manufacture of your drug products.

The use of ingredients contaminated with (b)(4) has resulted in various lethal poisoning incidents in humans worldwide. (b)(4) contamination at (b)(4).

In your response, you state that you will acquire a high-performance liquid chromatograph (HPLC) to perform analysis of incoming materials to verify compliance with FDA’s testing requirements. Your response is inadequate. You did not provide a detailed plan for how components will be tested, including test methods and review of compendial requirements. You also did not adequately detail how you will verify the reliability of your suppliers’ COA, nor how you will perform qualification of your suppliers. Further, you did not consider a retrospective assessment, such as identity testing of reserve samples, or assessment by other methods, of the components used in your OTC drug products that were distributed in the United States within expiry.

Without adequate testing, you do not have scientific evidence that the components conform to appropriate specifications before use in the manufacture of your drug products. Historically, we note that the Agency has detected (b)(4) in (b)(4) originating in Turkey.

In your response, provide:

  • 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 revalidation. In addition, include a commitment to always conduct at least one specific identity test for each incoming component lot. In the case of (b)(4) and certain additional high-risk components we note that this includes the performance of parts A, B, and C of the USP monograph.
  • A commitment to provide (b)(4) test results, no later than 30 calendar days from the date of this letter, from testing retains for all lots of high-risk drug components used in the manufacture of drug products. Alternatively, if a retain of a component lot is unavailable, perform retain sample testing of all implicated finished drug product lots for the presence of (b)(4).
  • A full risk assessment for drug products that are within expiry which contain any ingredient at risk for (b)(4) contamination (including, but not limited to, (b)(4)). Take prompt and appropriate actions to determine the safety of all lots of the component(s) and any related drug product that could contain (b)(4), including customer notifications and product recalls for any contaminated lots. Identify additional appropriate corrective actions and preventive actions (CAPA) that secure supply chains in the future, including, but not limited to, ensuring that all incoming raw material lots are from fully qualified manufacturers and free from unsafe impurities. Detail these actions in your response to this letter.
  • The chemical and microbiology quality control specifications you use to test each incoming lot of each incoming lot of components, including, high-risk drug components to determine acceptability for use in manufacturing.
  • 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.
  • 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.

2. Your firm failed to establish adequate 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 failed to adequately validate your production and process controls used in the manufacture of your OTC drug products. You also lacked adequate documentation that the equipment used to manufacture and test your drug product was qualified and suitable for its intended use.

In your response, you state that you will establish critical process parameters and a written procedure and protocol to perform process validation of OTC drugs.

Your response is inadequate. You did not provide supportive documentation for your drug process validation, and your equipment qualification program and interim production plans are unclear. You also did not consider a retrospective impact assessment of these deficiencies on the quality of your products currently in U.S. distribution.

Process validation evaluates the soundness of design and state of control of a process throughout its lifecycle. Each significant stage of a manufacturing process must be designed appropriately and assure the quality of raw material inputs, in-process materials, and finished drugs. Process qualification studies determine whether an initial state of control has been established. Successful process qualification studies are necessary before commercial distribution. Thereafter, ongoing vigilant oversight of process performance and product quality is necessary to ensure that you maintain a stable manufacturing operation throughout the product lifecycle.

Without adequate process validation, incorporating all manufacturing inputs and parameters that can affect product quality, your firm lacks basic assurance that you can reproducibly deliver products that meet specifications. See FDA's guidance for industry, Process Validation: General Principles and Practices for general principles and approaches that the FDA considers appropriate elements of process validation at https://www.fda.gov/media/71021/download.

In response to this letter, provide:

  • A detailed summary of your validation program for ensuring a state of control throughout the product lifecycle, along with associated procedures.
  • Describe your program for process performance qualification (PPQ), and ongoing monitoring of both intra-batch and inter-batch variation to ensure a continuing state of control.
  • A timeline for performing appropriate PPQ for each of your marketed drug products.
  • Process performance protocol(s), and written procedures for qualification of equipment and facilities.
  • A detailed program for designing, validating, maintaining, controlling and monitoring each of your manufacturing processes that includes vigilant monitoring of intra-batch and inter-batch variation to ensure an ongoing state of control. Also, include your program for qualification of your equipment and facility.

3. Your firm failed to establish an adequate written testing program designed to assess the stability characteristics of drug products. (21 CFR 211.166(a)).

Your firm did not establish an adequate ongoing stability testing program to demonstrate that your OTC drug products met established specifications for identity, strength, quality, and purity for the duration of their labeled (b)(4) shelf lives.

In your response, you state that you will create a stability protocol outlining the stability, testing, objectives, methodologies, and responsibilities. You also state that you will train your employees accordingly.

Your response is inadequate. You did not provide data to demonstrate that the chemical and microbiological properties of your drug products will remain within specification throughout their expiry period. You also failed to provide interim measures to address whether your drug products that remain on the market are supported by adequate stability data.

Without appropriate stability studies, you do not have scientific evidence to support whether your drug products meet established specifications and retain their quality attributes through their
labeled expiry.

In your response, provide:

  • A comprehensive, independent assessment and CAPA 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.

4. Your firm’s quality control unit failed to exercise its responsibility to ensure drug products manufactured are in compliance with CGMP, and meet established specifications for identity, strength, quality, and purity (21 CFR 211.22).

Your quality unit (QU) did not provide adequate oversight for the manufacture of your OTC drug products. For example, your QU failed to ensure the following:

  • Adequate written records for major equipment cleaning and maintenance (21 CFR 211.182).
  • Adequate written procedures for laboratory controls that include scientifically sound and appropriate specifications for finished drug products (21 CFR 211.160(b)).
  • Performance of periodic (i.e., at least annual) product reviews (21 CFR 211.180(e)).

Your QU and management stated multiple times during the inspection to our investigator that you were unaware that OTC products are considered drugs based on U.S. regulations, despite the labeling of your products as drugs.

An adequate QU overseeing all manufacturing operations is necessary to consistently ensure drug quality. 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.

In your response, provide:

  • A comprehensive assessment and remediation plan to ensure your QU is given the authority and resources to effectively function. The assessment should also include, but not be limited to:
    o A determination of whether procedures used by your firm are robust and appropriate.
    o Provisions for QU oversight throughout your operations to evaluate adherence to appropriate practices.
    o A complete and final review of each batch and its related information before the QU disposition decision.
    o Oversight and approval of investigations and discharging of all other QU duties to ensure identity, strength, quality, and purity of all products.

CGMP Consultant Recommended

Based upon the nature of the violations we identified at your firm, you should engage a consultant qualified as set forth in 21 CFR 211.34 to evaluate your operations and to assist your firm in meeting CGMP requirements if your firm intends to resume manufacturing drugs for the U.S. market. The qualified consultant should also perform a comprehensive six-system audit of your entire operation for CGMP compliance and evaluate the completion and efficacy of your CAPAs 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.

Drug Import Information

Based on information collected during the inspection and FDA import records, there appear to be discrepancies in the electronic import entry submissions for your drug products, specifically regarding the declaration of the correct manufacturer. Prior to distributing products intended for the United States, you should ensure that the firms shipping or importing your drug products, and the entry filers transmitting the electronic data to U.S. Customs and Border Protection and FDA, are declaring your firm as the manufacturer, as well as using your registration number and product listing number(s). If other firms are shipping your products they may be declared as the shipper; however, your firm needs to be declared as the manufacturer. See 21 CFR 1.74(a)(1).

Cosmetics Manufactured for Distribution in the United States

In addition, we note that some of the products you manufacture may be regulated as cosmetics, as defined in section 201(i) of the FD&C Act (21 U.S.C. 321(i)). Any cosmetics you manufacture must comply with applicable statutory and regulatory requirements, including the FD&C Act. Under section 301(a) of the FD&C Act (21 U.S.C. 331(a)), it is a prohibited act to introduce or deliver for introduction into interstate commerce a cosmetic that is adulterated or misbranded.

Further, your facility may be subject to requirements of the Modernization of Cosmetics Regulation Act of 2022 (MoCRA). Information on MoCRA requirements may be found at https://www.fda.gov/cosmetics/cosmetics-laws-regulations/modernization-cosmetics-regulation-act-2022-mocra.

Conclusion

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 any violations and for preventing their recurrence or the occurrence of other violations.

FDA placed products offered for import into the United States from your firm on Import Alert 66-40 on February 12, 2025.

Correct any violations promptly. FDA may withhold approval of new 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.

Failure to address any violations may also result in the FDA continuing to refuse admission of articles manufactured at Neva Global Grup Sanayi Ic Ve Dis Ticaret Anonim Sirketi, at 14/1 Akcaburgaz Mahallesi, 137. Sokak, Esenyurt, Istanbul, into the United States under section 801(a)(3) of the FD&C Act, 21 U.S.C. 381(a)(3). Articles under this authority that appear to be adulterated may be detained or refused 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).

This letter notifies you of our findings and provides you 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 address any 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 3018589922 and ATTN: Daniel W. Brisker.

Sincerely,
/S/

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

Cc:
Registered U.S. Agent:
Mehmet Akif Tutuncu
KYNC Design, LLC
mehmet@kyncdesign.com

_____________________

1 Components with higher risk of (b)(4) contamination compared to other drug components.

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