- Delivery Method:
- VIA UPS
Recipient NameMs. Britt N. Schendekehl
- Dental-Kosmetik GmbH & Co. KG
- Issuing Office:
- Center for Drug Evaluation and Research | CDER
10903 New Hampshire Avenue
Silver Spring, MD 20993
January 16, 2020
Warning Letter 320-20-19
Dear Ms. Schendekehl:
The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Dental-Kosmetik GmbH & Co., FEI 3001623034, at Katharinenstr. 4, Dresden from July 15 to 19, 2019.
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 August 2, 2019, response to our Form FDA 483 in detail. 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 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, and your firm's quality control unit did not review and approve those procedures, including any changes (21 CFR 211.100(a)).
You failed to adequately validate the processes used to manufacture your drug products.
Inadequate Control of Manufacturing Processes
You have not performed process performance qualification studies, nor do you have an ongoing program for monitoring process control to ensure stable manufacturing operations and consistent drug quality for products shipped to the U.S. market. Your firm's process validation consisted of testing the first production batch followed by a joint decision between your Research and Development (R&D) and Quality Assurance departments on whether or not to release the batch.
In addition, your firm had to significantly deviate from your batch manufacturing instructions in order to achieve passing results. For example, an out-of-specification (OOS) result for a bulk batch of (b)(4) required (b)(4) to obtain passing results for viscosity and density. Your procedure "Nonconformity Management" is inadequate as it does not require an investigation and identification of root causes when products do not meet quality requirements, and allows for repeat testing and adjustments until you obtain passing results.
In your response, you stated, in part:
- "Due to the variability the production process cannot be validated in general, instead all relevant parameters are controlled by measurements."
- " .. . small deviations are considered acceptable, as they do not influence the general usability of the product."
Your response is inadequate because you failed to commit to perform appropriate process validation for each of your products and to fully remediate your systems for investigations.
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
For more information about handling failing, out-of-specification, out-of-trend, or other unexpected results and documentation of your investigations, see FDA's guidance document Investigating Out-of-Specification (00S) Test Results for Pharmaceutical Production at https://www.fda.gov/media/71001/download
In response to this letter, provide:
- An assessment of drug product processes to ensure that there is a data-driven and scientifically sound program that identifies and controls all sources of variability, such that your production processes will consistently meet appropriate specifications and manufacturing standards. This includes, but is not limited to, evaluating suitability of equipment for its intended use, sufficiency of detectability in your monitoring and testing systems, quality of input materials, and reliability of each manufacturing process step and control.
- 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. Also include your program for qualification of your equipment and facility.
Include your process performance protocol(s), and written procedures for qualification of equipment and facilities.
- A timeline for performing process performance qualification for your drug products marketed to the U.S.
- A comprehensive, independent assessment of your overall system for investigating deviations, discrepancies, complaints, OOS results, and failures. Provide a detailed action plan to remediate this system. Your action plan should include, but not be limited to, significant improvements in investigation competencies, scope determination, root cause evaluation, corrective and preventive action (CAPA) effectiveness, quality assurance unit oversight, and written procedures. Address how your firm will ensure all phases of investigations are appropriately conducted.
Inadequate Control of (b)(4) System
You use (b)(4) as a component in your drug product and to clean production equipment. You have not established that your (b)(4) system is adequately designed, controlled, maintained, and monitored to ensure it consistently produces (b)(4) that meets (b)(4) USP monograph specifications and appropriate microbial limits. Your (b)(4) system has not been validated to produce (b)(4) USP. You also lacked appropriate testing of (b)(4) from your system. For example, you also acknowledged that you do not perform conductivity testing on (b)(4) generated from your system.
Pharmaceutical (b)(4) must be suitable for its intended use and routinely tested to ensure ongoing conformance with appropriate chemical and microbiological attributes.
In your response, you acknowledged that you do not currently have the means to produce (b)(4), and committed to check for possible alternatives. Your response is inadequate because you failed to describe how you will ensure that (b)(4) will be used in the manufacture of your drug products.
In response to this letter, provide:
- All microbial monitoring test results from your (b)(4) system for the past three years including sampling and sanitization dates.
- Interim measures that will be implemented to ensure (b)(4) with the appropriate quality attributes is used in the production of your drug products.
- A thorough remediation plan to install and operate a suitable (b)(4) system. Include a robust ongoing control, maintenance, and monitoring program to ensure the new system consistently produces (b)(4)adhering to (b)(4), USP monograph specifications and appropriate microbial limits.
- A validation report for the (b)(4) system obtained after an appropriately designed system has been installed. Include the system validation protocol and complete test results.
- Revised procedures governing the updated (b)(4) system, including provisions that require collection of (b)(4) samples from your (b)(4) system for microbiological counts and microbial identification testing.
- An effective program for ongoing control, maintenance, and monitoring that ensures the remediated system that you install consistently produces (b)(4) that meets (b)(4), USP, monograph specifications and appropriate microbial limits (including both total count and objectionable microbes). Regarding the latter, ensure that your total microbial count limit for (b)(4) 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 (b)(4) system failures on the quality of all drug product lots currently in U.S. distribution. Specify actions that you will take in response to the risk assessment, such as customer notifications and product recalls.
2. 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)).
Your firm does not have an adequate stability testing program to demonstrate that the chemical and microbiological characteristics of your over-the-counter drug products remain acceptable throughout their labeled expiry period.
A. You did not have long-term stability test data to support the three-year expiration date assigned to your (b)(4) products. Your product expiration dates were based on only three months of accelerated stability testing. Your accelerated stability testing data is also inadequate, because you tested the samples only at the (b)(4), and not at appropriate intervals. In addition, you released for distribution your commercial size pack of (b)(4) into U.S. markets before completing the three-month accelerated stability study.
B. Your stability program did not include an adequate number of batches of each drug product. For example, your stability program included only a research and development batch, and the (b)(4) commercial batch. No additional batches were placed on stability throughout the lifecycle of your products.
In addition, retain samples of (b)(4) batch numbers (b)(4) tested approximately (b)(4) after manufacture showed significant reduction in the amount of (b)(4). You lacked other data to support the expiration date.
In your response, you stated that you could not delay the delivery process due to (b)(4) of additional shipping time required for the U.S. market, therefore you have to perform stability tests parallel to the shipping process. Your response is unacceptable as you released the product for distribution without data to support the labeled three-year expiry period.
You also stated that the stability program for U.S. products will be revised to include (b)(4) stability tests and additional measurements. However, you did not provide a CAPA plan with timelines to remediate this issue.
In regard to your accelerated stability data, you determined the formulation was "sufficiently stable" because you found the (b)(4) concentration stable for (b)(4)," even though you identified a reduction in the (b)(4)." You added that you will reformulate the product due to this issue.
Your response is inadequate because you did not provide an adequate explanation with data to address the observed reduction in the concentration of "(b)(4)" and its impact on the labeled three-year expiry period.
In response to this letter, provide your investigation into degradation of (b)(4) concentration and an assessment of the impact of this degradation on distributed drug product. Also provide:
• A comprehensive, independent, assessment and CAP A 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 shelf-life claims remain 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.
3. 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 (2)).
You lacked adequate testing of the incoming (b)(4) active pharmaceutical ingredient (API) to determine identity, purity, and other appropriate quality attributes. In addition, your firm had not established the reliability of your suppliers' analyses through appropriate validation.
You may not rely upon the supplier's Certificates of Analyses (COA) to verify the identity of your (b)(4) API.
In your response, you stated that all your raw materials are sourced from trusted long-standing suppliers. Your response is unacceptable because you failed to demonstrate that your (b)(4) API supplier is qualified. In addition, you did not commit to conduct at least (b)(4) specific identity test for each incoming lot of (b)(4) API.
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 the use of unsuitable components, containers, and closures.
- 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 (b)(4) specific identity test for (b)(4) 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 SOP that describes this COA validation program.
- A description of how you test incoming glycerin raw material lots for the presence of diethylene glycol and ethylene glycol, prior to releasing lots for use in drug product manufacturing.
Products Containing Glycerin
You manufacture drugs that contain glycerin. The use of glycerin contaminated with diethylene glycol has resulted in various lethal poisoning incidents in humans worldwide. See FDA's guidance document Testing of Glycerin for Diethylene Glycol to help you meet the COMP requirements when manufacturing drugs containing glycerin at: https://www.fda.gov/media/71029/download
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
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 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. 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 that exist at your facility. You are responsible for investigating and determining the causes of these violations and for preventing their recurrence or the occurrence of other violations.
FDA placed your firm on Import Alert 66-40 on January 10, 2020.
Until you correct all violations completely and we confirm your compliance with CGMP, FDA may withhold approval of any new drug applications or supplements listing your firm as a drug manufacturer.
Failure to correct these violations may also result in the FDA continuing to refuse admission of articles manufactured at Dental-Kosmetik GmbH & Co., Dresden, 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 may be subject to refusal of 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).
After you receive this letter, respond to this office in writing within 15 working days. Specify what you have done since our inspection to correct your violations and to prevent their recurrence. 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-OMO-Communications@fda.hhs.gov or mail your reply to:
Ganesh N Joshi
Consumer Safety Officer
U.S. Food and Drug Administration
White Oak Building 51, Room 4237
10903 New Hampshire A venue
Silver Spring, MD 20993
Please identify your response with FEI 3001623034.
Office of Manufacturing Quality
Office of Compliance
Center for Drug Evaluation and Research
Dr. Helmut Roschinger
Dental-Kosmetik GmbH & Co.