- Delivery Method:
- Via Email
Recipient NameMr. Adelfo Enriquez Rios
Recipient TitlePresident and CEO
- Zermat International S.A. de C.V.
Calle Lazaro Cardenas No. 47
Unidad Habitacional San Jeronimo, Tepetlacalco
Tlalnepantla De Baz
54090 Tlalnepantla, Méx.
- Issuing Office:
- Center for Drug Evaluation and Research | CDER
Warning Letter 320-23-12
April 6, 2023
Dear Mr. Rios:
The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Zermat Internacional S.A. de C.V., FEI 3003659249, at Calle Lazaro Cardenas No. 47, Unidad Habitacional San Jeronimo, Tepetlacalco, Tlalnepantla De Baz, from October 10 to October 14, 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 November 2, 2022, 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 investigators observed specific violations including, but not limited to, the following.
1. Your firm failed to thoroughly investigate any unexplained discrepancy or failure of a batch or any of its components to meet any of its specifications, whether or not the batch has already been distributed (21 CFR 211.192).
Your firm did not adequately investigate out-of-specification (OOS) results. Specifically, you released and distributed batches of over-the-counter (OTC) (b)(4) drug product lots# (b)(4) and (b)(4) with OOS results for viscosity without an investigation. Our review also noted that lot# (b)(4) was OOS for specific gravity and no further investigation occurred.
In your response, you acknowledge that you do not have a procedure to handle OOS results. You state that the specification of the drug product was incorrect, and the results were compared against the wrong acceptance criteria. However, the certificates of analysis of these lots included a note stating that the product was approved with high viscosity. You also acknowledge a low specific gravity result for lot# (b)(4).
Your response is inadequate. You do not provide a retrospective review to ensure that you have fully identified and thoroughly investigated all OOS results and discrepancies. In addition, you do not provide your OOS procedure or an implementation date. You also do not include supporting evidence and a scientific rationale for the modified specification included in your response.
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 (OOS) Test Results for Pharmaceutical Production at https://www.fda.gov/media/158416/download.
In response to this letter, provide the following:
- 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 retrospective, independent review of all invalidated OOS (including in-process and release/stability testing) results for US products for the last three years from the initial date of inspection and a report summarizing the findings of the analysis, including the following for each OOS:
o Determine whether the scientific justification and evidence relating to the invalidated OOS result conclusively or inconclusively demonstrates causative laboratory error.
o For investigations that conclusively establish laboratory root cause, provide rationale and ensure that all other laboratory methods vulnerable to the same or similar root cause are identified for remediation.
o For all OOS results found by the retrospective review to have an inconclusive or no root cause identified in the laboratory, include a thorough review of production (e.g., batch manufacturing records, adequacy of the manufacturing steps, suitability of equipment/facilities, variability of raw materials, process capability, deviation history, complaint history, batch failure history). Provide a summary of potential manufacturing root causes for each investigation, and any manufacturing operation improvements.
- A comprehensive review and remediation plan for your OOS result investigation systems. The CAPA should include but not be limited to addressing the following:
o Quality unit oversight of laboratory investigations
o Identification of adverse laboratory control trends
o Resolution of causes of laboratory variation
o Initiation of thorough investigations of potential manufacturing causes whenever a laboratory cause cannot be conclusively identified
o Adequately scoping of each investigation and its CAPA
o Revised OOS investigation procedures with these and other remediations
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)).
You did not have stability data that adequately demonstrates your drug products met established chemical and microbial specifications throughout their assigned shelf life.
For example, your stability procedure requires an organoleptic assessment (odor, color, appearance) of your OTC drug products only at four-weeks. Although, your procedure references long-term stability at ambient temperature, your firm did not provide evidence of long-term stability. In addition, the temperature storage condition is not monitored throughout the study and there are no protocols for humidity.
In your response, you state that you will test existing lots of drug product to confirm the expiration date. You commit to identifying a third party for the storage of stability samples. Additionally, you claim to have created a testing program to assess the stability characteristics of drug products.
Your response is inadequate. You have not provided your stability protocols, any updates regarding the new testing results, and interim actions with specified implementation dates.
In response to this letter, provide the following:
- 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.
- Provide an update of the stability testing results along with test methods used and acceptance criteria.
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)).
You failed to adequately validate your manufacturing processes for (b)(4) produced in the (b)(4) filling line. You are responsible for assuring your manufacturing processes will consistently result in drug products meeting predefined quality attributes.
In your response, you include process qualification protocols for your OTC drug products.
Your response is inadequate. You have not demonstrated that your manufacturing process is designed, controlled and reproducible to yield a product of uniform character and quality. Failure to perform adequate process validation can result in product quality attribute failure. In addition, your response does not include timeframes and interim actions.
Your firm lacks an ongoing program for monitoring process control to ensure stable manufacturing operations and consistent drug quality. 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/files/drugs/published/Process-Validation--General-Principles-and-Practices.pdf.
In response to this letter, provide the following:
- 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 appropriate process performance qualification (PPQ) for each of your marketed drug products.
- Include your updated process performance protocol(s), 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.
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 an adequate written procedure for annual product review and an adequate written procedure for complaint handling. In addition, discrepancies related to OOS values were noted during the inspection but not identified by your quality unit at the time of release.
In your response, you state that a written procedure has been established for annual product review. You also commit to updating the complaint procedure to include your QU’s involvement, root cause analysis, and corrective actions and preventive actions.
Your response is inadequate. You do not provide evidence of the procedures and timeframes of implementation. You also do not indicate how your QU will provide oversight of your operations to ensure that errors are identified prior to the release of batches.
Significant findings in this letter demonstrate that your firm does not operate an effective quality system in accordance with CGMP. In addition to the lack of effective production operations oversight to ensure reliable facilities and equipment, we found your quality unit is not enabled to exercise proper authority and/or has insufficiently implemented its responsibilities. You should immediately and comprehensively assess your company’s global manufacturing operations to ensure that systems, processes, and the products manufactured conform to FDA requirements.
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 response to this letter provide the following:
- 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
Our review also found you manufacture OTC drug products with the active ingredient (b)(4) without determining the levels of “arsenic” and a “limit of (b)(4)”, as required by the United States Pharmacopeia (USP).
In response to this letter, provide a copy of the certificate of analysis for all (b)(4) lots received by your firm during the last 3 years and your firm’s procedure for testing incoming raw materials.
FDA cited similar CGMP violations at your site in a previous inspection that covered another type of OTC drug product. At that time, your firm discontinued the distribution and manufacturing of that drug product. However, the current inspection found repeated violations related to process validation and stability. These repeated failures demonstrate that management oversight and control over the manufacture of drug products are inadequate.
CGMP Consultant Recommended
Because you failed to correct repeat violations, we strongly recommend engaging a consultant qualified as set forth in 21 CFR 211.34 to assist your firm in meeting CGMP requirements. 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.
Your quality system does not adequately ensure the accuracy and integrity of data to support the safety, effectiveness, and quality of the drugs you manufacture. See FDA’s guidance document Data Integrity and Compliance With Drug CGMP for guidance on establishing and following CGMP compliant data integrity practices at https://www.fda.gov/media/119267/download.
We strongly recommend that you retain a qualified consultant to assist in your remediation. In response to this letter, provide:
A. A comprehensive investigation into the extent of the inaccuracies in data records and reporting including results of the data review for drugs distributed to the United States. Include a detailed description of the scope and root causes of your data integrity lapses.
B. A current risk assessment of the potential effects of the observed failures on the quality of your drugs. Your assessment should include analyses of the risks to patients caused by the release of drugs affected by a lapse of data integrity and analyses of the risks posed by ongoing operations.
C. A management strategy for your firm that includes the details of your global corrective action and preventive action plan. The detailed corrective action plan should describe how you intend to ensure the reliability and completeness of all data generated by your firm including microbiological and analytical data, manufacturing records, and all data submitted to FDA.
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.
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 refusing admission of articles manufactured at Zermat International S.A. de C.V. calle Lazaro Cardenas No. 47 Unidad Habitacional San Jeronimo, Tepetlacalco, Tlalnepantla De Baz, Tlalnepantla 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 3003659249 and ATTN: Rebecca Parrilla.
Office of Manufacturing Quality
Office of Compliance
Center for Drug Evaluation and Research