- Delivery Method:
- VIA Electronic Mail
Recipient NameCharlene A. Paz
Recipient TitleCo-Owner and Quality Unit Manager
- Lex Inc.
7155 NW 77th Terrace
Medley, FL 33166
- Issuing Office:
- Division of Pharmaceutical Quality Operations II
Case #: 656056
Dear Ms. Paz:
The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Lex Inc., FEI 1031041, at 7155 NW 77th Terrace, Medley, Florida, from February 13 to February 28, 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, 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 March 22, 2023, response to our Form FDA 483 in detail and acknowledge receipt of your subsequent correspondence.
During our inspection, our investigators observed specific violations including, but not limited to, the following.
1. 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’s quality system was inadequate. Your quality unit (QU) did not provide adequate oversight for the manufacture of your over the counter (OTC) drug products. For example, your QU failed to ensure:
- Adequate oversight, including but not limited to authority and responsibility for:
o Written procedures for QU roles and responsibilities
o Approval or rejection of all components and drug products
o Review of production and control records to assure completeness and no errors that need investigation
o Approval or rejection of all procedures or specifications impacting the identity, strength, quality, and purity of drug products.
- Each lot of components, drug product containers, and closures was withheld from use until the lot was sampled, tested, or examined, as appropriate, and released for use.
In your response, you state that you intend to establish and implement new procedures to comply with CGMP. However, you do not provide detailed corrective actions and preventive actions (CAPA), updated procedures for change management, annual product reviews, well-defined QU roles, and timeframes for implementation. You also do not indicate how your QU will provide oversight of your operations to ensure all requirements are met and that errors are identified prior to the release of batches.
An adequate QU overseeing all elements of CGMP is necessary to consistently ensure drug product quality. Your firm’s quality systems are inadequate. See FDA’s guidance document Quality Systems Approach to Pharmaceutical CGMP Regulations at: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/quality- systems-approach-pharmaceutical-current-good-manufacturing-practice-regulations for help in implementing quality systems and risk management approaches to meet the requirements of CGMP regulations 21 CFR parts 210 and 211.
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:
- A determination of whether procedures used by your firm are robust and appropriate.
- Provisions for QU oversight throughout your operations to evaluate adherence to appropriate practices.
- A complete and final review of each batch and its related information before the QU disposition decision.
- Oversight and approval of investigations and discharging of all other QU duties to ensure identity, strength, quality, and purity of all products.
2. Your firm failed to withhold from use each lot of components, drug product containers, and closures until the lot had been sampled, tested, or examined, as appropriate, and released for use by the quality control unit. 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(a), 211.84(d)(1), and 211.84(d)(2)).
You failed to adequately test incoming components used to manufacture finished drug products. For example,
- You lacked sufficiently specific identity tests for potential diethylene glycol (DEG) and ethylene glycol (EG) contamination of glycerin and propylene glycol ingredients used in the manufacturing of drug products. Some of your firm’s products formulated with glycerin or propylene glycol are intended for oral use in pediatric populations.
In your response, you commit to revise the raw material specifications for glycerin and propylene glycol to include appropriate identity testing prior to release for manufacturing drug products.
Your response is inadequate. You do not include appropriate identity testing on glycerin and propylene glycol lots currently in your inventory. Additionally, you fail to provide sufficient evidence demonstrating adequate identity testing on all containers of all lots of glycerin and propylene glycol prior to their use in the manufacture of drug products. You lack appropriate testing of representative samples of each lot of high-risk components. Without appropriate testing of components, you cannot ensure the quality and safety 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 High-Risk Drug Components for Diethylene Glycol and Ethylene Glycol to help you meet the CGMP requirements when manufacturing drugs containing ingredients at risk for DEG or EG contamination, at https://www.fda.gov/media/167974/download.
- Your incoming component tests, including those for your pediatric OTC cough and cold products, did not include identity testing on each component lot prior to their use. Several API lots were released into production without performing adequate acceptance testing, including identity. For example, an API, (b)(4), was used to manufacture (b)(4) without qualifying your supplier and performing identification testing.
In your response, you commit to outsource the testing of all incoming components to a local laboratory as well as updating procedures for acceptance of incoming components. You also plan to revise your procedures to include all required testing for raw materials and to test retain samples of previously released lots of components.
Your response is inadequate. You fail to address the full scope and impact of the CGMP deficiencies as well as the associated risks to drug product quality, including addressing the risks posed to batches already in distribution. Without appropriate testing of components and ingredients, you cannot ensure the quality and safety of your drug products.
- You did not adequately establish the reliability of your raw material suppliers, including your API suppliers. For example, you acknowledged that you have not qualified your suppliers and you did not follow your written procedure, LAB 06 Version #3.
In your response, you commit to perform supplier qualification.
Your response is inadequate because you do not provide a detailed plan to evaluate supplier reliability. Your procedure does not specify the need to comprehensively assess component attributes and it did not establish appropriate intervals for requalification.
We acknowledge that, after the inspection and a discussion with FDA on May 12, 2023, you sent for analysis retains of bulk glycerin, propylene glycol, (b)(4), (b)(4) and (b)(4) that you had used to manufacture drug products that are in distribution and within expiry. Based on the provided results, you concluded there was no DEG/EG contamination in the samples of retains tested.
From the discussion with FDA, you also stated you would test appropriate representative samples of incoming high-risk component lots for potential DEG/EG contamination prior to manufacturing drug products.
In response to this letter, provide:
- A full risk assessment for drug products that are within expiry which may 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 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.
- A description of how you will test each component lot for conformity with all appropriate specifications for identity, strength, quality, and purity. Include a list of test specifications and test methods for each component. If you intend to accept any results from your supplier’s Certificate of Analysis (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 revalidation. In addition, include a commitment to conduct at least one specific identity test for each incoming component lot, as required. 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 United States Pharmacopeia (USP) monograph for identity.
- A risk assessment of components qualified and released for use in manufacturing without appropriate testing for purity, strength, and quality.
- The chemical quality control specifications you use to test and determine suitability of each incoming lot of high-risk drug components to determine acceptability for use in manufacturing.
- 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.
- A summary of results obtained from testing all components to evaluate the reliability of the COA from each component manufacturer.
- A summary of your program for qualifying and overseeing contract facilities that test components and the drug products you manufacture.
3. 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)).
Your firm lacked an adequate process validation program and sufficient validation studies for your drug product manufacturing processes. For example, your process validation program was not inclusive for all products you manufacture. During the inspection, you acknowledged your process performance qualification (PPQ) studies were incomplete.
In your response you state a lack of a validation plan is the root cause of the problems and you commit to complete process validation activities. You also note that you will provide a procedure and timelines for completion of validation studies.
Your response does not commit to ensuring prospective PPQ studies are completed prior to distribution of products, nor do you include a risk assessment for any marketed drug products.
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. PPQ 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.
Without adequate process validation studies, incorporating all manufacturing inputs and parameters that can affect product quality, your firm lacks basic assurance that you can reproducibly deliver products that meet specifications.
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 your response to this letter, provide:
- A timeline for performing appropriate PPQ for each of your marketed drug products, including how you will ensure proper validation prior to distribution of drugs.
- 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.
- A risk assessment for the distributed drug product produced using inadequately validated process.
4. Your firm failed to routinely calibrate, inspect, or check according to a written program designed to assure proper performance of automatic, mechanical, electronic equipment, or other types of equipment, including computers, used in the manufacture, processing, packing, and holding of a drug product. Your firm also 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 (a) and (b)).
- You could not provide documentation that your OTC drug product manufacturing equipment was suitable for its intended use and that it was qualified. You acknowledged that you did not qualify your OTC drug production equipment.
In your response, you commit to providing an equipment qualification plan. You also state you have qualification protocols that have not been completed.
Your response is inadequate. Your response does not include your equipment qualification plan, equipment qualification protocols, a timeline for completion, and a risk assessment for the drug products you produced using unqualified equipment.
- Laboratory equipment used to generate analytical data for finished drug product release lacked restricted access and sufficient controls. For example, some laboratory staff had administrator rights allowing uncontrolled access to delete or modify high performance liquid chromatography (HPLC) files. You had no mechanism to facilitate traceability of individuals who deleted or modified data generated by computerized systems. Furthermore, your firm did not adequately maintain backups of data generated by your laboratory equipment.
In your response, you acknowledge your lack of knowledge regarding the use of the HPLC software.
Your response is inadequate. Your response does not provide adequate details of required improvements and expertise (e.g., management oversight, competencies) to assure data integrity. Your response also does not include provisions for retrospective review and CAPA for the accuracy and integrity of data to support the safety, effectiveness, and quality of the drugs you manufacture. Additionally, your response does not address data retention.
- You did not routinely calibrate your production scales used for weighing drug product components, including API, to reflect actual operating ranges. For example, your (b)(4) calibration check only documented one weight.
In your response, you acknowledge that you failed to adequately calibrate your production scales.
Your response is inadequate. Your response does not include sufficient details on how you will calibrate scales and you do not provide procedures for calibration or a plan to assess previously manufactured drug product batches that may have been impacted by inconsistencies with specified production weights. You also do not provide a plan to assess other equipment that may not have been calibrated appropriately.
Without complete and accurate records, you cannot ensure your firm makes appropriate batch release, stability, and other decisions that are fundamental to ongoing assurance of drug product quality.
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/regulatory-information/search-fda-guidance-documents/data- integrity-and-compliance-drug-cgmp-questions-and-answers.
In response to this letter, provide:
- 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.
- A comprehensive, independent assessment and corrective action and preventive action (CAPA) plan for computer system security and integrity. Include a report identifying design and control vulnerabilities and appropriate remediations for each of your laboratory and manufacturing computer systems. This should include, but not be limited to:
o A list of all hardware and equipment (standalone and network) in your laboratory.
o Identification of vulnerabilities in hardware and software, encompassing both networked and non-networked systems (e.g., programmable logic controller (PLC)).
o A list of all software configurations (both equipment software and laboratory information management system (LIMS)) and versions, details of all user privileges, and oversight responsibilities for each of your laboratory systems. Regarding user privileges, specify user roles and associated user privileges (including the specific permissions allowed for anyone who has administrative rights) for all staff who have access to the laboratory computer systems, their organizational affiliation, and title. Also describe how you will ensure laboratory staff are not given administrative rights, or other permissions that compromise data retention or reliability.
o System security provisions including, but not limited to, whether unique usernames and passwords are always used, and their confidentiality safeguarded.
o Detailed procedures for robust use and review of audit trail data, and current status of audit trail implementation for each of your systems.
o Interim control measures and procedural changes for the control, review, and full retention of laboratory data.
o Technological improvements to increase the integration of data generated through electronic systems from standalone equipment (e.g., balances, pH meters, water content testing) into the LIMS network.
o A detailed summary of your procedural updates and associated training, including, but not limited to, system security control to prevent unauthorized access, appropriate user role assignments, secondary review of all analyses, and other system controls.
o Your remediated program for ensuring strict ongoing control over electronic and paper-based data to ensure all additions, deletions, or modifications of information in your records are authorized, and all data is retained. Provide your full CAPA plan and any improvements made to date.
o Provisions for oversight from quality assurance (QA) managers, executives, and internal auditors with appropriate IT expertise (e.g., understanding of infrastructure, configuration, network requirements, strict segregation of administrative rights).
o An independent, thorough retrospective assessment into the impact of laboratory system design, control, and staff practices on your data accuracy, completeness, and retention for the last three years.
- Your CAPA plan and updated SOPs to implement routine, vigilant operations management oversight of facilities and equipment This plan should ensure, among other things, prompt detection of equipment/facilities performance issues, adherence to appropriate preventive maintenance schedules, and improved systems for ongoing management review.
- Your remediated calibration program, including but not limited to scale calibrations (e.g., daily calibration checks with certified weights; ensuring routine checks represent actual operational ranges).
Ineffective Quality System
Significant findings in this letter demonstrate that your firm does not operate an effective quality system in accord 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. See FDA’s guidance document Quality Systems Approach to Pharmaceutical CGMP Regulations at: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/quality- systems-approach-pharmaceutical-current-good-manufacturing-practice-regulations for help implementing quality systems and risk management approaches to meet the requirements of CGMP regulations 21 CFR, parts 210 and 211.
Quality Unit Authority
Your inspectional history indicates that your quality unit is not able to fully exercise its authority and/or responsibilities. Your firm must provide the quality unit with the appropriate authority and sufficient resources to carry out its responsibilities and consistently ensure drug quality.
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.
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/regulatory-information/search-fda-guidance-documents/contract-manufacturing-arrangements- drugs-quality-agreements-guidance-industry.
Repeat Violations at Facility
In a previous warning letter (FLA-05-13) and previous inspections, dated June 28 to July 8, 2004; August 15 to August 24, 2005; June 15 to June 23, 2009; January 25 to
March 1, 2011; and September 10 to September 16, 2016, FDA cited similar CGMP violations. You proposed specific remediation for these violations in your response. Repeated failures demonstrate that executive management oversight and control over the manufacture of drugs is inadequate.
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. Failure to promptly and adequately address this matter may result in regulatory or legal action without further notice including, without limitation, seizure and injunction. Unresolved violations may also prevent other Federal agencies from awarding contracts.
Failure to address violations may also cause FDA to withhold issuance of Export Certificates. 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 address any violations.
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.
Your written notification should refer to case #656056.
Please electronically submit your reply, on company letterhead, to Rebecca Asente, Compliance Officer, at ORAPHARM2_RESPONSES@fda.hhs.gov, and copy Ronda Loyd-Jones, Director, Compliance Branch at email@example.com.
If you have questions regarding the contents of this letter, you may contact Rebecca Asente via (504) 846-6104 or Rebecca.firstname.lastname@example.org.
Monica R. Maxwell
Program Division Director
Office of Pharmaceutical Quality Operations, Division II