- Delivery Method:
- VIA UNITED PARCEL SERVICE
Recipient NameMr. Frederick J. Horowitz
Recipient TitleChief Executive Officer/President
- A.P. Deauville, LLC
594 Jersey Ave, Unit C
New Brunswick, NJ 08901
- Issuing Office:
- Division of Pharmaceutical Quality Operations I
CMS # 586306
November 8, 2019
Dear Mr. Horowitz:
The U.S. Food and Drug Administration (FDA) conducted an inspection at A.P. Deauville, LLC, FEI 3004007943, at 594 Jersey Avenue, Unit C, New Brunswick, NJ from April 9 to May 2, 2019.
This warning letter summarizes significant violations of current good manufacturing practice (CGMP) regulations for finished pharmaceuticals. See 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 May 20, 2019 response to our Form FDA 483 in detail 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 investigator observed specific violations including, but not limited to, the following.
1. Your firm 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 211.192).
Inadequate Investigation of Water System Failures
Your firm failed to investigate multiple failures of your water system to meet chemical and microbial limits. On July 23, 2018, your contract laboratory reported out-of-limit (OOL) test results for microbial total plate count for your water system. The total plate count from the water sample was 870 CFU/mL, exceeding your limit of (b)(4) CFU/mL. You failed to investigate the OOL test result. Despite the failure, you used water from this system as a component to manufacture multiple batches of your over-the-counter (OTC) topical drug product, Soft Whisper Dandruff Shampoo. In addition, you failed to investigate multiple failures of your water system, including total organic carbon (TOC) results and conductivity results.
In response to this letter, provide a detailed risk assessment addressing the potential effects of the observed water system failures on the quality of all drug product lots currently in U.S. distribution and within expiry. Specify actions that you will take in response to the risk assessment, such as customer notifications and product recalls.
Inadequate Investigation of Product Complaints
You received multiple complaints regarding possible allergic reactions to your OTC topical drug products. Some complaints described rashes and blistering; one described an abscess requiring medical attention. You failed to adequately investigate and resolve these customer complaints. Additionally, you failed to establish a procedure to handle complaints for your OTC drug product, Soft Whisper Dandruff Shampoo.
In response to this letter, provide:
• A retrospective review of drug product complaint batches for product within expiry.
• 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, corrective action and preventive action (CAPA) effectiveness, quality unit oversight, and written procedures. Address how your firm will ensure all phases of investigations are appropriately conducted.
2. Failure to establish an adequate quality unit and the responsibilities and procedures applicable to the quality control unit are not in writing and fully followed. (211.22(a)&(d))
Your quality unit (QU) failed to identify and investigate deviations from manufacturing instructions of batches released for distribution.
For example, the instructions for Soft Whisper Dandruff Shampoo batch 082821F612 included a processing temperature with a minimum of (b)(4)°F, but the recorded process temperature was (b)(4)°F. Soft Whisper Dandruff Shampoo batch 012921A521 included instructions to mix at (b)(4) RPM but the recorded mixing speed was (b)(4) RPM.
Additionally, you failed to implement adequate written procedures for the following:
• Responsibilities of the QU;
• Change controls; and
• Investigations (e.g., OOS, deviations, and complaints).
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.
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 (21 CFR 211.100(a))
Your firm lacks an ongoing program for monitoring process control to ensure stable manufacturing operations. You have not demonstrated that your manufacturing process is capable of consistently producing drugs of uniform character and quality.
Inadequate Control of Manufacturing Processes
Your firm did not validate the process used to manufacture your drug product, Soft Whisper Dandruff Shampoo. Additionally, your firm failed to qualify the equipment used to manufacture your drug products.
In response to this letter, 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 process performance qualification for marketed drug products.
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.
Inadequate Control of Water System
You did not ensure adequate control over your (b)(4) water system. Your water system was frequently “turned-off” and you lacked routine monitoring data necessary to demonstrate that the system had established and maintained a state of control. Specifically, you could not provide chemical and microbiological test results to evaluate whether your firm can consistently produce water that meets the (b)(4) specifications and appropriate microbial limits. You use water from this system as a component in your drug products and to clean production equipment.
In response to this letter, provide:
• A comprehensive assessment of your water system design, control, and maintenance.
• A thorough remediation plan to install and operate a suitable water system. Include a robust ongoing control, maintenance, and monitoring program to ensure the remediated system design consistently produces water adhering to (b)(4) specifications and appropriate microbial limits. Ensure that your total microbial count limit for water is appropriate in view of the intended use of the products produced by your firm.
• 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, and ongoing monitoring of both intra-batch and inter-batch variation to ensure a continuing state of control.
• 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.
4. 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)).
You have not conducted cleaning validation studies in support of your drug products. You also have not established cleaning procedures for the equipment used to manufacture your Soft Whisper Dandruff Shampoo.
In addition, during the inspection we noted apparent product residue, product transfer line leaks, and a general lack of maintenance and cleaning of your manufacturing equipment and facility.
In response to this letter, provide:
• 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
In addition, describe the steps that must be taken in your change management system before introducing new manufacturing equipment or a new product.
• 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.
• Photographic evidence of your equipment and facility repairs.
Repeat observations at facility
In the two previous inspections, FDA cited similar CGMP observations. You proposed specific remediation for these observations in your responses.
These repeated failures demonstrate that your facility’s oversight and control over the manufacture of drugs is inadequate.
Quality System Guidance
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.
CGMP Consultant Recommended
Based upon the nature of the violations we identified at your firm and 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.
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 these violations and for preventing their recurrence or the occurrence of other violations.
Correct the violations cited in this letter promptly. Failure to promptly correct these violations may result in legal action without further notice including, without limitation, seizure and injunction. Unresolved violations in this warning letter may also prevent other Federal agencies from awarding contracts.
FDA may also withhold approval of requests for export certificates and approval of pending new drug applications or supplements listing your facility as a supplier or manufacturer until the above violations are corrected. We may re-inspect to verify that you have completed your corrective actions.
After you receive this letter, respond to this office in writing within 15 working days. Specify what you have done since our inspection to correct your violations and to prevent their recurrence. If you cannot complete corrective actions within 15 working days, state your reasons for delay and your schedule for completion.
Send your electronic response to firstname.lastname@example.org. Please identify your response with FEI #3004007943 and refer to Warning Letter CMS# 586306.
If you have questions, please contact Compliance Officer Liatte Closs at Liatte.Closs@fda.hhs.gov or Compliance Officer Nancy Scheraga at Nancy.Scheraga@fda.hhs.gov.
Program Division Director/District Director
Office of Pharmaceutical Quality Operations
Division I/New Jersey District