WARNING LETTER
Diora Kimya Sanayi ve Ticaret Limited Sirketi
MARCS-CMS 688271 —
October 17, 2024
Delivery Method:
VIA UPS
Reference #:
320-25-05
Product:
Drugs
Recipient:
Recipient Name
Ms. Elif M. Diri
Recipient Title
CEO and Owner
Diora Kimya Sanayi ve Ticaret Limited Sirketi
Baspinar Osb 2 Bolge, Street No: 26
Mahallesi, 83226 Nolu Caddesi
27500
Sehitkamil
/
Gaziantep
Turkey
Issuing Office:
Center for Drug Evaluation and Research (CDER)
United States
Warning Letter
320-25-05
October 17, 2024
Dear Ms. Diri:
The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Diora Kimya Sanayi ve Ticaret Limited Sirketi, FEI 3013927966, at Baspinar Osb 2 Bolge, Street No: 26, Mahallesi, 83226 Nolu Caddesi, Sehitkamil, Gaziantep, from May 27 to 31, 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 product is 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).
Personal CARE Antibacterial Soap (NDC 72133-049) is not duly listed with FDA as required by section 510(j) of the FD&C Act. Failure to provide any listing information required by section 510(j) is prohibited under section 301(p) of the FD&C Act, 21 U.S.C. 331(p), and will render a drug misbranded under section 502(o) of the FD&C Act, 21 U.S.C. 352(o). Introduction or delivery for introduction of such product into interstate commerce is prohibited under section 301(a) of the FD&C Act, 21 U.S.C. 331(a). These violations are described in more detail below.
We reviewed your July 5, 2024 response to our Form FDA 483 in detail and acknowledge receipt of your subsequent correspondence.
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 an over-the-counter (OTC) topical drug product,
(b)(4)
. You failed to perform adequate identity testing of each component lot used in the manufacture of your drug product. You also relied on your suppliers’ certificate of analysis (COA) without establishing the reliability of your component suppliers’ test analyses at appropriate intervals.
We also note that you make your drug product with ingredients such as glycerin that are susceptible to Diethylene Glycol (DEG) and Ethylene Glycol (EG) substitution. See FDA’s guidance document
Testing of Glycerin, Propylene Glycol, Maltitol Solution, Hydrogenated Starch Hydrolysate, Sorbitol Solution, and Other High-Risk Drug Components for Diethylene Glycol and Ethylene Glycol
to help you meet the CGMP requirements when manufacturing drugs containing ingredients at high-risk for DEG or EG contamination at https://www.fda.gov/media/167974/download.
In your response, you state that you will suspend the use of components that have not undergone identity testing. Additionally, you state that you will conduct a review of the current inventory and perform identity testing.
Your response is inadequate. You did not provide adequate details of your supplier qualification program, including how you will ensure appropriate incoming testing will be performed for each component, i.e., complete testing against the COAs or appropriate justification to perform reduced testing of selected quality attributes (other than identification) based on supplier reliability. Additionally, you did not consider testing retain samples or otherwise conduct an analysis of previously used drug product components to ensure all quality attributes were met.
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.
2. 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 failed to perform appropriate testing on your drug product prior to release for distribution. You stated to our investigator that assay testing was not performed on approximately
(b)(4)
batches of your including
(b)(4)
distributed to the U.S. market between 2022 and 2024. Additionally, your firm transcribed component test results for
(b)(4)
and glycerin from your supplier’s COA directly to your finished product COA without confirmation of the results.
In your response, you state that you will develop and validate
(b)(4)
assay methods. You also state that you will revise your standard operating procedures and retrain your employees. Additionally, you state that you will remove
(b)(4)
and glycerin from your COA.
Your response is inadequate. You failed to demonstrate how removing
(b)(4)
and glycerin from your COA is appropriate for your drug product. You also did not consider a risk assessment or retrospective review of products that have been released without appropriate testing.
Testing is essential to ensure that the drug products you manufacture conform to all predetermined quality attributes appropriate for their intended use. Because you lacked adequate testing of each batch of your drug products, you do not know whether they conform to all appropriate finished product specifications and are suitable for release to consumers.
3. 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 failed to adequately validate your production and process controls used in the manufacture of your drug product. You have not completed process validation and cleaning validation studies for your non-dedicated equipment. Additionally, you lacked documentation that the equipment used to manufacture your drug product was qualified and suitable for its intended use.
You also failed to qualify your
(b)(4)
system, which supplies
(b)(4)
as a component used in your drug product. Pharmaceutical
(b)(4)
must meet the
(b)(4)
USP monograph, be suitable for its intended use, and routinely tested to ensure ongoing conformance with appropriate chemical and microbiological attributes.
In your response, you state that you will develop and implement process controls and complete process and cleaning validation. You also state that you will create new procedures and implement training for your employees.
Your response is inadequate. You failed to provide supportive documentation or timelines for your drug process validation or your equipment qualification program, and your interim production plans are unclear. You also did not provide a protocol driven cleaning validation procedure. Further, you did not consider a retrospective impact assessment of these deficiencies on the quality of your products currently in 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.
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 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. 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.
Establishment Registration and Drug Listing Violations
Under section 510 of the FD&C Act, 21 U.S.C. 360, and 21 CFR Part 207 of FDA regulations, firms that manufacture, prepare, propagate, compound, or process drugs in the United States or that are offered for import into the United States must be registered with the FDA. Every person who is required to register must, at the time of initial registration, list all drugs manufactured, prepared, propagated, compounded, or processed for commercial distribution under section 510(j)(1) of the FD&C Act, 21 U.S.C. 360(j)(1). In addition, in accordance with section 510(j)(2) of the FD&C Act, 21 U.S.C. section 360(j)(2), and 21 CFR 207.57(b), registrants are required to submit updated drug listing information to FDA twice each year, in June and December, notifying FDA if this information has changed. Under 21 CFR 207.57(b)(2) registrants may satisfy the listing update requirement with respect to unchanged listing information by making a single no change certification during the October 1st through December 31st annual registration period. If the drug listing data is not updated or certified, the outdated listing data will get inactivated at the next scheduled FDA inactivation period, see 84 FR 40417.1
1
Personal CARE Antibacterial Soap (NDC 72133-049) was not certified as required and was inactivated as of January 31st, 2024.
Therefore, your product Personal CARE Antibacterial Soap (NDC 72133-049) is not included in a list required by section 510(j) of the FD&C Act while in commercial distribution, rendering this drug to be misbranded under section 502(o) of the FD&C Act, 21 U.S.C. 352(o). 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). In addition, failure to provide listing information in accordance with 510(j) of the FD&C Act is prohibited under section 301(p) of the FD&C Act, 21 U.S.C. 331(p).
It remains your responsibility to ensure that Personal CARE Antibacterial Soap (NDC 72133049) and all products manufactured at your establishments comply with all registration and listing requirements under section 510 of the FD&C Act, 21 U.S.C. 360, and 21 CFR Part 207 of FDA regulations. Registration and listing information and instructions on how to properly register an establishment or submit drug listings can be found at Electronic Drug Registration and Listing Instructions | FDA.
Cosmetics Manufactured for Distribution in the United States
Some of the products you manufacture appear to be cosmetics, as defined in section 201(i) of the FD&C Act (21 U.S.C. 321(i). A cosmetic is deemed adulterated under section 601(c) of the FD&C Act (21 U.S.C. 361(c)) if it has been prepared, packed, or held under insanitary conditions whereby it may have become contaminated with filth or whereby it may have been rendered injurious to health. Some conditions that cause the drug products you manufacture to be adulterated may also cause any cosmetics you manufacture to be adulterated. We note that 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. Further, your facility may be subject to requirements under the Modernization of Cosmetic Regulations Act of 2022 (MoCRA). Information on MoCRA requirements may be found at https://www.fda.gov/cosmetics/cosmetics-laws-regulations/modernization-cosmetics-regulationact-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 your firm on Import Alert 66-40 on October 16, 2024.
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 Baspinar Osb 2 Bolge, Street No: 26, Mahallesi, 83226 Nolu Caddesi, Sehitkamil, Gaziantep, 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 3003067499 and ATTN: Daniel W. Brisker.
Identify your response with FEI 3013927966.
Sincerely,
/S/
Francis Godwin
Director
Office of Manufacturing Quality
Office of Compliance
Center for Drug Evaluation and Research
__________________
1
https://www.regulations.gov/document/FDA-2019-N-2374-0001
Content current as of:
10/22/2024
Regulated Product(s)
Drugs