WARNING LETTER
Soliteint Kozmetikai KFT
MARCS-CMS 685146 —
October 10, 2024
Delivery Method:
VIA Electronic Mail
Reference #:
320-25-03
Product:
Drugs
Recipient:
Recipient Name
Dr. Hossam Mostafa
Recipient Title
Managing Director
Soliteint Kozmetikai KFT
Fot, Pest
Moricz Zsigmond UT 37
2151
Hungary
Issuing Office:
Center for Drug Evaluation and Research (CDER)
United States
October 10, 2024
Warning Letter
320-25-03
Dear Dr. Mostafa:
The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Soliteint Kozmetikai KFT, FEI 3007001714, at Moricz Zsigmond UT 37, Fot, from April 15 to 19, 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 May 10, 2024 response to our Form FDA 483 in detail. Your response is inadequate because you failed to provide supportive documentation or adequate evidence of corrective actions taken 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 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, and conduct for each batch of drug product, appropriate laboratory testing, as necessary, required to be free of objectionable microorganisms (21 CFR 211.165(a) and 211.165(b)).
Your firm failed to adequately test the over-the-counter (OTC) external analgesic drug products you manufacture under contract (i.e.,
(b)(4)
,
(b)(4)
, and Asutra Relieve your pain) for identity, and strength of each active ingredient prior to release and distribution.
Without adequate testing, you do not have scientific evidence that your drug product batches conform to appropriate specifications prior to release.
In response to this letter, provide:
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.
A list of chemical and microbial specifications, including test methods, used to analyze each batch of your drug products before a batch disposition decision.
o 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.
o A summary of all results obtained from testing reserve samples from each batch of your drug products that remain within expiry. If such testing reveals substandard quality drug products, take rapid corrective actions, such as notifying customers and product recalls.
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 211.84(d)(2)).
Inadequate API Testing
Your firm failed to ensure that incoming lots of active pharmaceutical ingredients (API) were suitable for use in manufacturing. For example, your firm used menthol and
(b)(4)
to manufacture OTC external analgesic drug products based on a component supplier’s certificate of analysis (COA). However, you did not perform identity testing nor did your firm establish the reliability of the supplier’s analysis through appropriate validation. Although you stated that you routinely assessed your suppliers, the most recent inspection documented the last assessment was performed in March 2001.
Inadequate Component Water
Testing
Due to problems with your water treatment system, your firm used
(b)(4)
water as a component in your drug products. You failed to provide data supporting the frequency of testing of your water system for total organic carbon. Pharmaceutical water must be suitable for its intended use, and routinely and adequately tested to ensure ongoing conformance with appropriate chemical and microbiological attributes.
Additionally, your water systems require monitoring to ensure the absence of biofilm forming microbes, e.g.,
Burkholderia cepacia
complex (BCC), in non-sterile, water-based topical drug products. For more information regarding the significance of BCC contamination in drug products, see FDA’s July 7, 2021 advisory for drug manufacturers.
1
Products Containing Glycerin
Glycerin, along with other high-risk components, require identification testing per the USP to ensure that it meets safety limits for diethylene glycol (DEG) or ethylene glycol (EG). 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 glycerin used in the manufacture of your drug products.
The use of ingredients contaminated with DEG or EG has resulted in various lethal poisoning incidents in humans worldwide. See FDA’s guidance document
Testing of Glycerin, Propylene Glycol, Maltitol Solution, Hydrogenated Starch Hydrolysate, Sorbitol Solution, and Other HighRisk 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 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 COAs 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. In the case of glycerin, propylene glycol, and certain additional high-risk components we note that this includes the performance of parts A, B, and C of the USP monograph.
A summary of results obtained from testing all components to evaluate the reliability of the COA from each component manufacturer. Include your SOP 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 comprehensive, independent assessment of your water system design, control, and maintenance.
A thorough remediation plan to install and operate a suitable water system. Include a robust ongoing control, maintenance, and monitoring program to ensure the remediated system design consistently produces water adhering to
(b)(4)
Water, USP monograph specifications and appropriate microbial limits.
Regarding the latter, ensure that your total microbial count limit for water is appropriate in view of the intended use of the products produced by your firm.
A detailed risk assessment addressing the potential effects of the observed water system failures on the quality of all drug product lots currently in U.S. distribution or within expiry. Specify actions that you will take in response to the risk assessment, such as customer notifications and product recalls.
A commitment to provide DEG and EG 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 batches for the presence of DEG and EG.
A full risk assessment for drug products that are within expiry which contain any ingredient at risk for DEG or EG contamination (including, but not limited to, glycerin). Take prompt and appropriate actions to determine the safety of all lots of the component(s) and any related drug product that could contain DEG or EG, 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.
3. 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 failed to conduct process validations for the OTC drug products you manufacture intended for the U.S. market.
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 includes intensive monitoring and testing throughout each significant process stage to characterize intra-batch variation and evaluates batches to 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 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 PPQ for each of your marketed drug products.
Your 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.
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 firm lacked adequate procedures for an effective Quality Management System, including procedures describing the roles and responsibilities and controls for your quality unit over your OTC drug product manufacturing operations. You could not provide procedures for your CAPA, quality status labeling of components and OTC drug products, and control of master batch records.
Additionally, your firm does not perform adequate stability testing to support the expiration date of
(b)(4)
assigned to the OTC external analgesic drug products.
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 response to this letter, 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.
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.
Responsibilities as a Contractor
Drugs must be manufactured in conformance with CGMP. FDA is aware that many drug manufacturers use independent contractors such as production facilities, testing laboratories, packagers, and labelers. FDA regards contractors as extensions of the manufacturer.
You are responsible for the quality of drugs you produce as a contract facility regardless of agreements in place with product owners. You are required to ensure that drugs are made in accordance with section 501(a)(2)(B) of the FD&C Act for safety, identity, strength, quality, and purity. See FDA’s guidance document
Contract Manufacturing Arrangements for Drugs: Quality Agreements
at https://www.fda.gov/media/86193/download.
Drug Production Ceased
We acknowledge your commitment to cease production of all OTC drugs at this facility for the U.S. market.
If you plan to resume any manufacturing operations regulated under the FD&C Act, notify this office before resuming your drug manufacturing operations. You are responsible for resolving all deficiencies and systemic flaws to ensure your firm is capable of ongoing CGMP compliance. In your notification to the Agency, provide a summary of your remediations to demonstrate that you have appropriately completed all CAPA.
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 4, 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 Soliteint Kozmetikai KFT, Moricz Zsigmond UT 37, Fot, 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 3007001714 and ATTN: Carrie Hughes.
Sincerely,
/S/
Francis Godwin
Director
Office of Manufacturing Quality
Office of Compliance
Center for Drug Evaluation and Research
CC:
Mr. Tamas Kalman, CEO, Wanadis KFT
kalman.tamas@wanadiscosmetics.com
___________________
1
https://www.fda.gov/drugs/drug-safety-and-availability/fda-advises-drug-manufacturers-burkholderiacepacia-complex-poses-contamination-risk-non-sterile
Content current as of:
10/22/2024
Regulated Product(s)
Drugs