US FDA Data integrity findings

Your firm failed to ensure that laboratory records included complete data derived from all tests necessary to ensure compliance with established specifications and standards (21 CFR 211.194(a)). Your firm is a contract testing laboratory that conducts testing of various application and nonapplication drug products for the US market. Your laboratory records lacked complete and original data demonstrating that you performed the required testing. You did not accurately complete laboratory records contemporaneously at the time you performed the laboratory activities. Our investigator observed (b)(4) microbial test samples that lacked complete documentation on raw data test sheets (e.g., the test sheets had blank spaces where entries should have been recorded). While your summary reports included final plate counts, your raw data test sheets for some of the samples covered in these reports lacked complete documentation of plate counts. In your response, you stated these samples were not from drug products intended for the U.S. market. However, your firm maintains one quality system and has one set of procedures for testing U.S. and non-U.S. drug products. Thus, the quality unit (QU) failure is applicable to all drug products you test. Additionally in your response, you identify the documentation deficiencies to be “consistent with an institutional procedural and cultural gap rather than individual misconduct or a coordinated effort to conceal or falsify results.” This indicates that these violative practices are used for all drugs you test, including those for the U.S. market. We acknowledge that your response indicated you will increase the QU presence during testing until procedural improvements, training effectiveness verification, and compliance monitoring demonstrate sustained adherence. Your response is inadequate because it does not include an assessment of your paper-based documentation system to identify and correct vulnerabilities in your current controls. Additionally, you did not provide evidence that you performed a retrospective review to identify any additional instances of incomplete or non-contemporaneous documentation. Microbial testing, an essential quality control step, is integral in preventing distribution of unsafe products. Integrity of data is fundamentally compromised when there is a failure to record or maintain complete and accurate records of test results or conditions associated with drug testing. Furthermore, the lack of reliable data compromises the QU’s ability to exercise its function of ensuring compliance with applicable standards. 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. 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 comprehensive assessment of documentation systems used throughout your laboratory operations to determine where documentation practices are insufficient. Include a detailed corrective action and preventive action (CAPA) plan that comprehensively remediates your firm’s documentation practices to ensure you retain attributable, legible, complete, original, accurate, contemporaneous (ALCOA) records throughout your operation. A comprehensive CAPA, overseen by a qualified consultant, for handling microbiological sampling media to ensure robust and reliable data. Establish a system that ensures uninterrupted custody and full reconciliation of all microbiological samples, including but not limited to: o unique labeling of each sample o signatures of all staff who handle the sample o complete tracking of sample integrity and custody o date and time of each activity (e.g., sample collection, delivery, incubation, removal from incubator) o digital time-stamped photos of all plates o signatures of personnel performing reading of microbial counts o provisions for verifications and routine quality assurance oversight.

Your firm failed to establish an adequate quality unit, and the responsibilities and procedures applicable to the quality control unit are not in writing and fully followed (21 CFR 211.22(a) and (d)). Your quality unit (QU) failed to establish and exercise its authority to adequately oversee the manufacture, packing, holding, review, and release of your (b)(4) over-the-counter (OTC) drug products, such as (b)(4) . Your firm’s inadequate quality oversight resulted in significant deficiencies in documentation practices, batch record review, investigations, and quality system controls to ensure compliance with CGMP requirements. For example, your QU failed to ensure: Investigation of any unexplained discrepancy or failure of a batch or any of its components to meet any specifications (21 CFR 211.192). Establishment of suitable quality oversight procedures (e.g., raw material handling, review of production records, and recalls) (21 CFR 211.22(a)). Batch production and control records that include documentation of the accomplishment of each significant step in the manufacture, processing, packing, or holding of the batch, for each batch of drug product (21 CFR 211.188(b)). Establishment of written procedures describing the handling of all written and oral complaints regarding a drug product (21 CFR 211.198(a)). In your response, you commit to procedural changes related to batch records, such as discontinuing the use of correction fluid (white-out) and improved temperature monitoring practices. However, your response is inadequate because it does not adequately acknowledge or address the QU’s failure to exercise its responsibility and authority to ensure the accuracy, integrity, review, and approval of CGMP records. Specifically, your response fails to address significant data integrity lapses documented at your facility which include backdating of quality release labels, entry of temperature data when the thermometer was inoperable, and lack of batch records to document manufacturing activities for drug products. Your firm’s quality systems are inadequate. For help implementing quality systems and risk management approaches to meet the requirements of CGMP regulations 21 CFR parts 210 and 211, see FDA’s guidance documents: Quality Systems Approach to Pharmaceutical CGMP Regulations at https://www.fda.gov/media/71023/download Q9(R1) Quality Risk Management at https://www.fda.gov/media/167721/download ICH Q10 Pharmaceutical Quality System at https://www.fda.gov/media/71553/download In response to this letter provide: A comprehensive assessment of documentation systems used throughout your manufacturing and laboratory operations to determine where documentation practices are insufficient. Include a detailed corrective action and preventive action (CAPA) plan that comprehensively remediates your firm’s documentation practices to ensure you retain attributable, legible, complete, original, accurate, and contemporaneous records throughout your operation. 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 assessment of your overall system for investigating deviations, discrepancies, complaints, out-of-specification (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, CAPA effectiveness, quality unit oversight, and written procedures. Address how your firm will ensure all phases of investigations are appropriately conducted.

Your firm failed to clean, maintain, and, as appropriate for the nature of the drug, sanitize and/or sterilize equipment and utensils at appropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements (21 CFR 211.67(a)). Your firm failed to adequately clean and maintain non-dedicated drug manufacturing equipment used to fill OTC drug products. For example, our investigator observed stagnant (b)(4) product residue inside the tubing on the filling line with residue accumulating in crevices and on surfaces that come into direct contact with the drug product. In your response, you state that you developed a comprehensive cleaning procedure and implemented a cleaning validation program. However, your response is inadequate because you fail to address the impact of your inadequate cleaning practices on drug products that remain in distribution. In addition, your response does not address how you will document cleaning in your batch record. It is your responsibility to ensure that you use only appropriately designed and maintained equipment in the manufacture of your drug products. In response to this letter, provide: A comprehensive, independent retrospective assessment of your cleaning effectiveness to evaluate the scope of cross-contamination hazards. Include the identity of residues, other manufacturing equipment that may have been improperly cleaned, and an assessment whether cross-contaminated products may have been released for distribution. The assessment should identify any inadequacies of cleaning procedures and practices and encompass each piece of manufacturing equipment used to manufacture more than one product. A CAPA plan, based on the retrospective assessment of your cleaning program, that includes appropriate remediations to your cleaning processes and practices and timelines for completion. Include the following as part of the assessment and CAPA plan: o a detailed summary of vulnerabilities in your process for lifecycle management of equipment cleaning. o a list of improvements with an explanation how each will enhance cleaning effectiveness. o improved ongoing verification of proper cleaning execution for all products and equipment. o any other needed remediations. Your CAPA plan to implement routine, vigilant operations management oversight of facilities and equipment. This plan should incorporate oversight from a qualified independent consultant and ensure, among other things, prompt detection of equipment/facilities performance issues, effective execution of repairs, adherence to appropriate preventive maintenance schedules, timely technological upgrades to the equipment/facility infrastructure, and improved systems for ongoing management review. Inadequate Microbiological Testing of Finished Drug Product Additionally, we observed deficient microbiological testing specifications and test methods for your finished non-sterile OTC (b)(4) drug products. We noted that you limited microbiological testing to aerobic plate counts only and used a method intended for non-pharmaceutical use. Test methods must be validated to show that they are suitable for their intended use and are equivalent to or better than applicable USP compendial methods. The reproducibility of your test methods is essential to determine if your drug products meet established specifications. Data Integrity Remediation Your quality system does not adequately ensure the 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: Questions and Answers (https://www.fda.gov/regulatory-information/search-fda-guidance-documents/data-integrity-and-compliance-drug-cgmp-questions-and-answers) 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 comprehensive investigation into the extent of the inaccuracies and inconsistencies in data, records, and reporting including results of the data review for drugs distributed in the United States. Include a detailed description of the scope and root causes of all data integrity deviations. A retrospective risk assessment of the potential effects of each observed deviation on the quality of your drugs. Your assessment should include analyses of the risks to patients caused by the release of drugs affected by each occurrence of a data integrity event. The assessment should also determine risks posed by current operational conditions, and any needed interim measures. A management strategy for your firm that includes the details of your global corrective action and preventive action plan to implement attributable, legible, complete, original, accurate, and contemporaneous records throughout your operation. The detailed corrective action plan should describe how you intend to ensure the reliability and completeness of all data, including microbiological and analytical data, manufacturing records, and all data submitted to FDA.

Input to and output from the electronic records and data are not checked for accuracy.

Failure to ensure that all specifications, sampling plans, test procedures are scientifically sound and appropriate to ensure that your API conform to established standards of quality and purity. Your firm manufactures the API, clomiphene citrate USP for U.S. distribution, intended for pharmacy compounding. Data Integrity Concerns Your firm failed to establish adequate controls over analytical testing data. Multiple instances of unreported sample injections for related…

significant violations were observed including, but not limited to, the following: 1. Your firm’s quality control unit failed to exercise its responsibility to ensure drug products are manufactured in compliance with CGMP, and meet established specifications for identity, strength, quality, and purity. Your firm also 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 211.22 and 21 CFR 211.192). Your firm manufactures multiple OTC (b)(4) drug products labeled and formulated to contain active ingredients such as (b)(4) . These drug products are also labeled and formulated to contain the inactive ingredient talc. Both talc and asbestos are naturally occurring minerals that may be found in close proximity in the earth. Asbestos is a potential contaminant in talc and is a known human carcinogen when inhaled. 1,2 Additionally, published scientific literature dating back to the 1960s has suggested a possible association between the use of (b)(4) containing talc in the (b)(4) area and the incidence of (b)(4) , potentially linked to asbestos contamination of the talc. 3 The (b)(4) you produce can be used on areas of the body which may be an exposure risk (e.g., inhalation or (b)(4) area). Your drug products are considered higher-risk drugs as they pertain to patient safety regarding asbestos contamination of talc due to the risk of inadvertent inhalation or potential use in the (b)(4) area. Your quality unit (QU) did not effectively exercise its authority to ensure test procedures and specifications for talc are scientifically sound and appropriate (see 21 CFR 211.160(b)). Furthermore, you did not demonstrate that your firm’s QU has adequate oversight of your contract testing facility. In particular, your QU did not adequately review or approve methods used by your contract laboratory. For example, your QU failed to assure that contract facilities are testing according to your procedures which require you to follow current United States Pharmacopeia (USP) specifications and that results are supported by sufficient information to provide an accurate determination of compliance for identification of talc and absence of asbestos. The infrared (IR) instrument report does not specify the wavenumbers of peak maxima as required in USP for the identification testing conducted. The current USP monograph test for absence of asbestos includes the evaluation of the presence of tremolite chlorite and serpentines through scale expansions of spectra at the required wavenumbers of (b)(4) cm- 1 , and in the range of (b)(4) cm- 1 to (b)(4) cm- 1 . Your instrument report for the spectroscopy was (b)(4) cm- 1 to (b)(4) cm- 1 and did not include any scale expansions. Your spectra does not evaluate for the presence of serpentines in the range of (b)(4) cm- 1 and (b)(4) cm- 1 . Additionally, in the identification testing records provided, the IR spectral data shows wavenumber values identical to three decimal places across two independently collected talc samples, which is statistically unlikely and raises concerns regarding the authenticity of the reported results. Furthermore, our review indicates that your QU failed to investigate data discrepancies associated with identification testing for talc. IR data for talc lot (b)(4) identified no maximas, on a scale of approximately (b)(4) cm⁻¹ to (b)(4) cm⁻¹ scan. The USP identification by IR Absorption has a specification of maxima at (b)(4) cm⁻¹, (b)(4) cm⁻¹, and (b)(4) cm⁻¹. From the scale of the scan, the second peak maxima does not appear to be at a wavenumber greater than (b)(4) cm- 1 . Data for your most recent talc lot (b)(4) lacks data showing any maxima. The maximas, or lack thereof, in the data you submitted is not consistent with the USP specification for talc. Your quality system has not adequately ensured 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: Questions and Answers for guidance on establishing and following CGMP compliant data integrity practices at https://www.fda.gov/media/119267/download. Your QU is responsible for fully exercising its authority and responsibilities, including responsibility for approving or rejecting all procedures or specifications impacting the identity, strength, quality, and purity of the drug product. 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: 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, including an evaluation of your contract facility qualification program, to evaluate adherence to appropriate practices. o Gap analysis for your approved specifications, test methods and laboratory practices for drug components (active and inactive) and those conducted at your contract facility. If notable differences are observed, provide an impact analysis and corrective actions, which may include retrospective testing. 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 lapses. A comprehensive review and remediation plan for your Out-of-specification (OOS) result investigation systems. The corrective action and preventive action (CAPA) should include but not be limited to addressing the following: o QU 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 approved and released for use one or more lots of components, drug product containers, or closures that did not meet the appropriate written specifications of identity, strength, quality, and purity and related tests under 21 CFR 211.84(d) (21 CFR 211.84(e)). Your firm released talc component lot (b)(4) that did not meet the specification for identity. IR spectral data submitted for talc USP had the wavenumbers of “ (b)(4) ” and “ (b)(4) ”, and the USP specification is maxima at (b)(4) cm– 1 , (b)(4) cm– 1 , and (b)(4) cm– 1 . There was no third wavenumber identification in your records for the sample. The standard used also had only two maximas identified, of “ (b)(4) ” and “ (b)(4) ”. Additional records submitted for talc testing of other lots, do not show any maximas on the spectral instrumentation record. As a manufacturer, you have a responsibility to sample, test, and examine, as appropriate, drug components before use in production to ensure acceptable specifications for identity, strength, quality, and purity are met. Because you have not performed appropriate testing that detects asbestos in your talc components, among other things, you failed to assure the acceptability of these drug components for use in manufacture of your drug products. In response to this letter, provide: Identity, assay and impurity test results from testing retains for all lots of talc containing drug components used in the manufacture of your drug products. Alternatively, if a retain of a component lot is unavailable, perform retain sample testing of all implicated finished drug product batches for asbestos. Provide this information within 30 calendar days of the date of this letter. A description of how you will test each component lot for conformity with all appropriate written specifications for identity, strength, quality, and purity. If you intend to accept any results from your supplier’s Certificates of Analysis (COA) instead of testing each component lot for strength, quality, and purity, specify how you will 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. A retrospective, independent review of all results for components used for U.S. products for the last three years and a report summarizing the findings of the analysis. Reformulation to No Longer Use Talc in High-Risk Dosage Forms In response to our request for records you indicated that you are in the process of reformulating to remove talc as an ingredient and replace with a suitable alternative. In response to this letter provide an update on your reformulation efforts to move to an alternative not associated with risk of talc. Quality Specifications Regarding Talc Talc is a USP article, whose specification can be found in the current USP talc monograph. As mentioned above, the specific test for asbestos is included in the talc monograph. Be advised that drugs including components, such as talc, that are recognized in the USP are generally required to meet the current applicable USP monograph under section 501(b) of the FD&C Act. FDA reviewed your specifications for talc components and they are incomplete when compared to the current USP specification. We note that the USP has recently revised its monograph for talc which includes updated technical requirements for asbestos testing in talc and is currently scheduled to be official in (b)(4) . Use of Contract Manufacturers 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 your drugs regardless of agreements in place with your contract facilities. You are required to ensure that drugs are made in accordance with section 501(a)(2)(B) of the FD&C Act to ensure 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.