Grupo Quimico SRL

The U.S. Food and Drug Administration (FDA) inspected your contract testing laboratory, Grupo Quimico SRL, FEI 3012281081, at Irlanda 2033, Montevideo, from November 20 to 22, 2023.

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, the drugs you tested 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 December 8, 2023 response to our Form FDA 483 in detail. Your response is inadequate because you failed to provide supportive documentation for evaluation 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.

Your laboratory records did not include all testing data to support the drug product analysis performed.

Out-of-Specification (OOS) Results Not Reviewed

Your quality unit (QU) only reviews printed analytical results. During the inspection, our investigator found unprocessed and unreported high-performance liquid chromatography (HPLC) sample injections for several batches of (b)(4) drug product, which is marketed in the United States. When your firm subsequently processed the drug product sample injections after their discovery by the investigator, the injections were determined to be OOS for ingredient (b)(4) assay. The printed data for these batches, reviewed by your QU, failed to include these OOS results or indicate that additional sample analysis had been conducted. The final analytical results reported to your client were passing and did not include the OOS data.

Manual Sample Integration Not Indicated

Your firm performed manual integration of sample assay peaks. The printed data reviewed by your QU did not indicate that manual integration was performed. Manual integration should be reviewed by your QU to ensure it is performed adequately.

All data must be complete, accurate, and retained to enable appropriate assessments and decisions by the QU and customers. The lack of control over the integrity of your data raises questions about the authenticity and reliability of your analytical data and the quality of your drug products.

2. Your firm failed to establish laboratory controls that include scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure that components, drug product containers, closures, in-process materials, labeling, and drug products conform to appropriate standards of identity, strength, quality, and purity (21 CFR 211.160(b)).

Your firm did not have adequate procedures governing the collection, review, and integration of data generated through electronic systems. For example, your procedures did not require evaluation of electronic data which included reprocessed sample integration, aborted runs, single injection data, and electronic audit trails (when available). Accordingly, your QU failed to review this data. Further, manual integration is performed without a governing procedure.

Additionally, analysts routinely perform (b)(4) system suitability injections of samples which does not comply with existing analytical method standard operating procedures (SOPs). Further, HPLC test method TE3-020-01 for (b)(4) drug product does not define system suitability acceptance criteria for repeatability, peak tailing, and resolution.

Laboratories must establish and implement procedures to ensure the robustness and consistency of testing and data review.

3. Your firm failed to exercise appropriate controls over computer or related systems to assure that only authorized personnel institute changes in master production and control records, or other records (21 CFR 211.68(b)).

Your firm did not have appropriate controls over your analytical equipment and software to prevent deletion of data and record all modifications to data. Specifically, electronic data generated by your HPLC software recording the testing of drug products, could be deleted by your analysts. Additionally, your HPLC systems “HPLC 03” and “HPLC 04” did not have audit trails enabled.

Your customers rely on the integrity of your laboratory data to make decisions regarding drug quality. It is important to maintain strict control over electronic data to ensure that all laboratory data is retained and that any additions or modifications of information in your electronic records are authorized and appropriately documented.

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/files/drugs/published/Data-Integrity-and-Compliance-With-Current-Good-Manufacturing-Practice-Guidance-for-Industry.pdf.

We strongly recommend that you retain an independent third-party qualified consultant to assist in your remediation. In response to this letter, provide:

A comprehensive investigation into the extent of the inaccuracies in data records and reporting. Your investigation should include:

o A detailed investigation protocol and methodology; a summary of all laboratories, manufacturing operations, and systems to be covered by the assessment; and a justification for any part of your operation that you propose to exclude. o Interviews of current and former employees to identify the nature, scope, and root cause of data inaccuracies. We recommend that these interviews be conducted by a qualified third party. o An assessment of the extent of DI deficiencies at your facility. Identify omissions, alterations, deletions, record destruction, non-contemporaneous record completion, and other deficiencies. Describe all parts of your facility’s operations in which you discovered DI lapses. o A comprehensive retrospective evaluation of the nature of the testing DI deficiencies. We recommend that a qualified third party with specific expertise in the area where potential breaches were identified should evaluate all DI lapses.

A current risk assessment of the potential effects of the observed failures on the quality of drugs tested by you. Your assessment should include analyses of the risks to patients caused by the release of drugs affected by a lapse of DI and analyses of the risks posed by ongoing operations.

A management strategy for your firm that includes the details of your global corrective action and preventive action (CAPA) plan. Your strategy should include:

o A detailed corrective action plan that describes how you intend to ensure the reliability and completeness of all the data you generate including analytical data, manufacturing records, and all data submitted to FDA. o A comprehensive description of the root causes of your DI lapses including evidence that the scope and depth of the current action plan is commensurate with the findings of the investigation and risk assessment. Indicate whether individuals responsible for DI lapses remain able to influence CGMP-related or drug application data at your firm. o Interim measures describing the actions you have taken or will take to protect patients and to ensure the quality of your drugs, such as notifying your customers, recalling product, conducting additional testing, adding lots to your stability programs to assure stability, drug application actions, and enhanced complaint monitoring. o Long-term measures describing any remediation efforts and enhancements to procedures, processes, methods, controls, systems, management oversight, and human resources (e.g., training, staffing improvements) designed to ensure the integrity of your company’s data. o A commitment to have a qualified consultant conduct extensive annual audits, for at least two years, to assist in evaluating CAPA effectiveness after you have executed your DI remediation protocol. o Inform FDA if you will be assigning DI oversight responsibility to an individual who is fully empowered to receive anonymous complaints from employees reporting DI concerns and with the authority to ensure any potential breach is promptly investigated (by independent quality assurance function, along with expertise from outside entities whenever needed). o A status report for any of the above activities already underway or completed.

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 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.

Also describe how top management supports quality assurance and reliable operations, including, but not limited to, timely provision of resources to proactively address emerging manufacturing/quality issues and to assure a continuing state of control.

A complete assessment of documentation systems used throughout your manufacturing and laboratory operations to determine where documentation practices are insufficient. Include a detailed CAPA plan that comprehensively remediates your firm’s documentation practices to ensure you retain attributable, legible, complete, original, accurate, contemporaneous records throughout your operation.

Based upon the nature of the violations we identified at your firm, we strongly recommend engaging a consultant (i.e., an independent third party) 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.

FDA considers contractors as extensions of the manufacturer’s own facility. Your failure to comply with CGMP may affect the quality, safety, and efficacy of the drugs you test for your clients. It is essential that you understand your responsibility to operate in full compliance with CGMP when performing analytical work for your customers. As part of this responsibility, it is essential that you provide prompt, complete, and transparent analytical information to your customers (e.g., manufacturers) to enable them to handle their quality responsibilities related to batch evaluation and contractor oversight.

For additional information refer to FDA’s Guidance for Industry Contract Manufacturing Arrangements for Drugs: Quality Agreements (https://www.fda.gov/media/86193/download).

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 contract testing laboratory 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 address any violations.

Failure to address any violations may also result in the FDA refusing admission of articles manufactured by your clients and test at Grupo Quimico SRL, Irlanda 2033, Montevideo, 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 3012281081 and ATTN: Christina Capacci-Daniel.