- Delivery Method:
- VIA Electronic Mail
- Issuing Office:
- Division of Pharmaceutical Quality Operations II
Case #: 666442
Dear Ms. Riesgo and Ms Menendez:
The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Dextrum Laboratories Inc., FEI 3003092372, at 6993 NW 82nd Avenue, Suites 20-23, and 25, Miami, Florida, from July 10 to 18, 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 August 7, 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 failed to conduct at least one test to verify the identity of each component of a drug product (21 CFR 211.84(d)(1)).
Your firm is a contract manufacturer of over-the-counter (OTC) drug products, including oral cough and cold drug products marketed for both adults and children. You failed to perform adequate identity testing of each component lot used in the manufacture of your OTC drug products, including (b)(4) and dextromethorphan active pharmaceutical ingredients.
Furthermore, your firm failed to adequately test each shipment of each lot of incoming components at high-risk of diethylene glycol (DEG) or ethylene glycol (EG) contamination. This includes, but is not limited to, testing of glycerin you use in manufacturing drug products to determine its appropriate identity. Identity testing for this and certain other high-risk drug components1 include a limit test in the United States Pharmacopeia (USP) to ensure that the component meets the relevant safety limits for levels of DEG or EG. Because you did not perform identity testing on each shipment of each lot using the USP identification test that detects these hazardous impurities, you failed to assure the acceptability of these components for use in manufacture 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 high-risk for DEG or EG contamination at https://www.fda.gov/media/167974/download.
In your response, you state that incoming raw materials are accompanied by a certificate of analysis (COA) that is compared to the USP monograph specifications and verified with “some testing.” You also state that raw material samples will be sent on a “periodic schedule (to be determined)” to a third-party laboratory for testing against the COA.
Your response is inadequate as it lacks a commitment to perform at least one identity test for each drug product component. Additionally, you did not indicate that you would perform any retrospective review to ensure materials previously used were suitable for their intended use, such as testing of components (or reserve samples of finished OTC drug products if a reserve sample of a component lot is unavailable) to ensure distributed drug products conform with all appropriate specifications for purity, strength, and quality, including the relevant safety limits for levels of DEG or EG.
In response to this letter, provide:
- A commitment to provide DEG and EG test results, no later than 30 calendar days from the date of this letter, from testing retains for all lots of high-risk 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 the presence of DEG and EG.
- A full risk assessment for your drug products that are within expiry which 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 (CAPA) 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. 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 revalidation. In addition, include a commitment to always conduct at least one specific identity test for each incoming component lot. 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 USP monograph.
- The chemical quality control specifications you use to test 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.
2. Your firm failed to conduct microbiological testing before use of each lot of a component with potential for objectionable microbiological contamination in light of its intended use. (21 CFR 211.84(d)(6)).
Your firm produces (b)(4) water that is used as a component in the production of many of your OTC drug products. Your firm failed to adequately monitor the microbiological quality of the water you use to manufacture your aqueous-based OTC drug products. Specifically, you only test your (b)(4) water for microbiological attributes and total organic carbon (TOC) on a (b)(4) basis. Water for pharmaceutical must be suitable for its intended use and routinely tested to ensure ongoing conformance with appropriate chemical and microbiological attributes.
In response to this letter, provide:
- A commitment to perform retrospective testing of aqueous-based finished drug product retains, within expiry, to ensure they meet all microbiological quality attributes.
- A summary of your program for qualifying and overseeing contract facilities that test the (b)(4) water you produce.
- A commitment to perform increased microbiological testing of your (b)(4) water system until a qualification of the system is complete and an appropriate monitoring procedure is established.
- A commitment to develop a procedure governing your program for ongoing control, maintenance, and monitoring that ensures the system consistently produces water that meets (b)(4) Water, USP monograph specifications and appropriate microbial limits.
In addition, your acceptance criteria for total plate count when performing microbiological testing of your (b)(4) water system is stringently “[n]o detectable levels ((b)(4) cfu/mL)”. Testing performed by your third-party laboratory indicates that you are meeting that specification for all (b)(4) of your points-of-use in your water system, even though you identified dead legs in points-of-use (b)(4) and (b)(4) in January 2023. Provide:
o Your quality agreement with the third-party laboratory that performs microbiological testing of your (b)(4) water.
o Your procedure for collecting, storing, and transporting (b)(4) water samples to your third-party laboratory, including chain-of-custody requirements.
- Identify if any additives/processes are introduced to the (b)(4) water samples prior to transporting to your third-party laboratory.
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)).
Your firm failed to adequately validate your production and process controls. As such, you do not have assurance that you are capable of consistently manufacturing OTC drug products with defined quality attributes. For example, your firm contract manufactures an OTC drug product, (b)(4), but failed to adequately validate your production and process controls specifically for this product. Your production and process validation protocol, “Process Qualification (PQ) Protocol – Mixing / Formulation
Process” categorizes all drug products you manufactured into three groups, based on therapeutic indication and route of administration. In each of the three groups, you conducted process validation activities for the “(b)(4)” drug. You have not provided an adequate scientific justification that the process validation studies conducted for “(b)(4)” drug in each group is adequate and fully representative of the production and process controls for the other approximately (b)(4) drug products you manufacture.
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 include intensive monitoring and testing throughout each significant process stage to characterize intra-batch variation and evaluates batches to 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.
In your response, you state that your firm will review actively manufactured drug products and determine which products need validation (including (b)(4)), all new drug products introduced will be validated, and validations for existing drug products will be performed as orders are received.
Your response is inadequate as it does not address or otherwise include a risk assessment for any marketed drug products manufactured and distributed with a lack of adequate process validation. Additionally, you did not put any interim controls in place pending the completion of adequate process validations.
In response to this letter, provide:
- A commitment to engage a qualified third-party to perform an independent review and oversight of all validation activities at your firm.
- A commitment, and proposal, to perform increased finished product testing until all product process validations are complete.
- 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 (PPQ), and ongoing monitoring of both intra-batch and inter-batch variation to ensure a continuing state of control.
- A timeline for performing appropriate PPQ for each of your marketed drug products.
- 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.
- An assessment of each drug product process 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.
- Timelines for completed PPQ for marketed drug products for which a state of control has not been adequately established.
Repeat Violations Observations at Facility
In previous inspections FDA cited similar CGMP observations. You proposed specific remediation for these observations in your responses. Repeated failures demonstrate that executive management oversight and control over the manufacture of drugs is inadequate.
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/regulatoryinformation/search-fda-guidance-documents/quality-systems-approach-pharmaceutical-current-good-manufacturing-practice-regulations.
CGMP Consultant Recommended
Based upon the nature of the violations we identified at your firm, you should engage a consultant qualified as set forth in 21 CFR 211.34 to evaluate your operations and to assist your firm in meeting CGMP requirements. The qualified consultant should also perform a comprehensive six-system audit2 of your entire operation for CGMP compliance and evaluate 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 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 # 666442.
Please electronically submit your reply, on company letterhead, to Dayna I. Martínez, 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 Dayna I. Martinez via phone at (787) 399-9905 or email at firstname.lastname@example.org.
Acting Program Division Director
Office of Pharmaceutical Quality Operations,
1 Components with higher risk of DEG or EG contamination compared to other drug components.
2 i.e., Quality System, Facilities & Equipment System, Materials System, Production System, Packaging & Labeling System, and Laboratory Control System per FDA’s guidance document Quality Systems Approach to Pharmaceutical CGMP Regulations.