Delta Kozmetik Sanayi Ve Ticaret-Selim Yesil

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Delta Kozmetik Sanayi Ve Ticaret-Selim Yesil, FEI 3010166780, at Bolgesi Aydinli Sb Mahallesi, 6 12 Istanbul Endustri Veticaret Serbest, Sokak Tuzla, Istanbul, from September 12 to September 16, 2022.

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 7, 2022 response to our Form FDA 483 in detail and acknowledge receipt of your subsequent correspondence. Your response is inadequate because it did not provide sufficient detail or evidence of corrective actions to bring your operations into compliance with CGMP.

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

1. Your firm failed to test samples of each component for identity and conformity with all appropriate written specifications for purity, strength, and quality. 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)).

You failed to adequately test your incoming components for identity before using the components to manufacture your over-the-counter (OTC) drug products. You also failed to adequately qualify your suppliers, as you have not validated the test results of your suppliers’ analyses and instead relied on your suppliers’ responses to your vendor questionnaire.

Additionally, you relied on certificates of analyses (COAs) from these unqualified suppliers for specifications such as purity, strength, and quality. By not analyzing your components for identity, purity, strength, and quality, you failed to ensure that your incoming components meet appropriate specifications.

In response to this letter, provide:

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.

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)).

Your firm has not established that your processes used to manufacture your drug products are appropriately validated. You failed to conduct process validation studies for numerous drug products you manufactured and distributed to the United States, and the process validation studies that you performed were inadequate because they lacked appropriate testing (e.g., assay testing of active ingredients) on the finished drug products. Further, you also lacked appropriate qualification of equipment used to manufacture your drug products.

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 you maintain a stable manufacturing operation throughout the product lifecycle.

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/media/71021/download.

In response to this letter, provide:

A remediation plan that better assures ongoing management oversight throughout the manufacturing lifecycle of all drug products. Provide a more data-driven and scientifically sound program that identifies sources of process variability, and assures that manufacturing operations meet appropriate parameters and quality standards. This includes, but is not limited to, evaluating suitability of equipment for its intended use, ensuring quality of input materials, determining the capability and reliability of each manufacturing process step and its controls, and vigilant ongoing monitoring of process performance and product quality.

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, and ongoing monitoring of both intra-batch and inter-batch variation to ensure a continuing state of control.

A timeline for performing process performance qualification (PPQ) for each of your marketed drug products.

Include your process performance protocols, and written procedures for qualification of equipment and facilities.

Provide 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 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 failed to demonstrate that you established and followed an adequate stability program to determine appropriate storage conditions and expiration dates of drug products manufactured at your facility. For example, your stability program lacked appropriate testing of your drug products, including testing of active ingredients, impurities, and other degradation products.

Without appropriate stability studies, you lack scientific evidence to support whether your drug products meet established specifications and retain their quality attributes through their expiry.

In response to this letter, provide:

A comprehensive, independent assessment and corrective action and preventive action (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.

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 assist your firm in meeting CGMP requirements and in response to this Warning Letter. The qualified consultant should also perform a comprehensive audit of your entire operation for CGMP compliance and evaluate the completion and efficacy of your CAPA 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 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 your firm on Import Alert 66-40 on January 11, 2023. In addition, FDA previously placed your firm on Import Alert 66-78 on May 17, 2021, due to violative sampling results of your (b)(4) drug product.

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 Delta Kozmetik Sanayi Ve Ticaret-Selim Yesil, Bolgesi Aydinli Sb Mahallesi, 6 12 Istanbul Endustri Veticaret Serbest, Sokak Tuzla, 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 3010166780 and ATTN: Bryce Hammer.