- Delivery Method:
- UPS Next Day
Recipient NameDr. Ali N. Syed
- Avlon Industries, Inc.
1999 N. 15th Avenue
Melrose Park, IL 60160
- Issuing Office:
- Division of Pharmaceutical Quality Operations III
July 18, 2023
Dear Dr. Syed:
The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Avlon Industries, Inc., FEI 3007090726, at 1999 N. 15th Avenue, Melrose Park, from January 17 to 24, 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 February 13, 2023 response and acknowledge receipt of your subsequent correspondence. 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 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(d)(1) and 211.84(d)(2)).
Your firm failed to test your incoming components for identity prior to manufacturing your over-the-counter (OTC) drug products (e.g., active ingredients, glycerin, and water as a component). Additionally, you relied on certificates of analysis (COAs) from unqualified suppliers for specifications such as purity, strength, and quality. By not adequately analyzing your components for identity, purity, strength, and quality, you failed to ensure your incoming components meet appropriate specifications.
Identity testing for each shipment of each lot of components used in drug product manufacturing is required, and you may only rely on COA for other component attributes by validating the suppliers’ test results at appropriate intervals.
Glycerin and propylene glycol are ingredients used in some of your drug products, including Keracare® Dry & Itchy Scalp Anti-Dandruff Moisturizing Conditioner and As I Am Dry & Itchy Scalp Care Dandruff Conditioner, and are examples of components with higher risk of DEG or EG contamination compared to other drug components. The identity testing of glycerin and other high-risk components such as propylene glycol may include a limit test per the United States Pharmacopeia (USP) to ensure that the component meets the relevant safety limits for the levels of diethylene glycol (DEG) or ethylene glycol (EG). Because you did not perform the identity testing on each container on each shipment of each high-risk drug component lot using the USP identification test that detects these hazardous impurities, you failed to assure the acceptability of the high-risk components used in the manufacture of your drug products.
The use of glycerin or propylene glycol 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.
In response to this letter, provide:
- Results of tests for DEG and EG in retain samples of all glycerin lots or any other high-risk components (such as propylene glycol) used to manufacture your drug products.
- A full risk assessment for 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 ingredient(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 action and preventive action (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 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.
- The chemical and microbiological quality control specifications you use to test and release each incoming lot of components for use in manufacturing.
- A summary of results obtained from testing all components to evaluate the reliability of the COA from each component manufacturer. Include your standard operating procedure (SOP) that describes this COA validation program.
2. 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, and to follow all of your written production and process control procedures. (21 CFR 211.100(a) and 211.100(b)).
Lack of Process Validation
You failed to provide data to demonstrate that you adequately validate your manufacturing processes used to manufacture your OTC drug products and demonstrate that your processes are reproducible and controlled to consistently yield drugs of uniform character and 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 for industry, 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.
Lack of Cleaning Validation
You failed to provide evidence that you performed cleaning validation for the equipment (e.g., mixing tanks, hoses, filling lines, and packaging lines) used to manufacture your OTC drug products. This is a repeat observation from the 2017 FDA inspection. Additionally, you lacked cleaning and usage logs for production tanks (i.e., kettles), or any holding tanks used in manufacturing your bulk drug products.
You manufacture drug products using the same equipment that you use to manufacture nonpharmaceutical products such as cosmetics. Chemical and microbiological residues on equipment from previous manufacturing activities can adversely impact the purity, quality, and safety of drug products also manufactured on that equipment.
Inadequate Water System
Your firm uses water as a component to manufacture your OTC drug products. You failed to provide documentation that you performed a qualification of your (b)(4) Water system. You also failed to show that your water system is monitored adequately to ensure it consistently produces water that meets appropriate microbial limits. Routine monitoring of microbial counts and identity of contamination in the system is integral to ensuring oversight of ongoing state of control and suitability of water for use in manufacturing operations. These are repeat observations from the 2017 FDA inspection.
(b)(4) water 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 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 process performance qualification for each of your marketed drug products.
- Include your 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.
- Appropriate improvements to your cleaning validation program, with special emphasis on incorporating conditions identified as worst case in your drug manufacturing operation. This should include, but not be limited to, identification and evaluation of all worst-case:
o Drugs with higher toxicities
o Drugs with higher drug potencies
o Drugs of lower solubility in their cleaning solvents
o Drugs with characteristics that make them difficult to clean
o Swabbing locations for areas that are most difficult to clean
o Maximum hold times before cleaning
- A summary of updated SOPs that ensure an appropriate program is in place for verification and validation of cleaning procedures for products, processes, and equipment.
- A comprehensive remediation plan for the design, control, and maintenance of the water system, including a (b)(4) water system validation report. Also include the summary of any improvements made to system design and to the program for ongoing control and maintenance.
- A procedure for your water system monitoring that specifies routine microbial testing of water to ensure its acceptability for use in each batch of drug products produced by your firm.
- The current action/alert limits for total counts and objectionable organisms used for your (b)(4) Water system. Ensure that the total count limits for your (b)(4) water are appropriately stringent in view of the intended use of each of the products produced by your firm.
- A procedure governing your program for ongoing control, maintenance, and monitoring that ensures the remediated system consistently produces water that meets (b)(4) Water, USP monograph specifications and appropriate microbial limits.
3. 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. FDA investigators observed multiple documents related to CGMP activities that had not been completed, such as:
- CGMP-related policies
- Standard operating procedures (SOPs)
- Validation plans
- Stability program
- Corrective actions and preventive actions (CAPA)
- Annual product review (APR)
- CGMP training
An adequate QU overseeing all manufacturing operations is necessary to consistently ensure drug quality. See FDA’s guidance document Quality Systems Approach to Pharmaceutical CGMP Regulations for help in 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 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 complete assessment of documentation systems used throughout your manufacturing 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, and contemporaneous records throughout your operation.
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 audit1 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.
Please address your reply via email to: ORAPHARM3_RESPONSES@fda.hhs.gov
Attention: Russell K. Riley
U.S. Food and Drug Administration
Division of Pharmaceutical Quality Operations III
Your written notification should refer to the Warning Letter Case Number above (#652903). If you have questions regarding the contents of the letter, please contact Mr. Riley at (630) 277-1908.
CDR Jeffrey D. Meng
Program Division Director
Division of Pharmaceutical Quality Operations III
1 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.