FDA 483 Warning Letter Dated MARCH 30, 2022
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).
During our inspection, our investigator observed specific violations including, but not limited to, the following.
USFDA 483 Warning Letter
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 manufactures over-the-counter (OTC) topical drug products such as sunscreens, pain relief, and acne treatments. Your Quality Unit (QU) did not provide adequate oversight for the manufacture of your OTC drug products. For example, your QU failed to ensure the following:
- Microbiological testing was performed and reviewed prior to release for each batch of drug product (21 CFR 211.165(b)).
- Adequate investigations of out-of-specification (OOS) results and written procedures to conduct thorough investigations (21 CFR 211.192).
- Appropriate documentation and assessment of changes (21 CFR 211.100(a)).
- Establishment of an adequate, ongoing stability program (21 CFR 211.166(a)).
- Performance of appropriate annual product reviews (21 CFR 211.180(e)).
In your response, you stated, “We rarely release products without microbiological results. In the instances cited, verbal results were obtained by QC [Quality Control] via phone call to the microbiological laboratory” before receiving the final report. Releasing drug products before receiving records (including certificates of analysis) of all testing results is unacceptable and poses the risk that drug products that fail to meet one or more quality attributes will be distributed to consumers.
You also stated that your “previous quality department staff were not competent and failed to execute their duties,” and that they are no longer with your company. Additionally, you stated that you will recruit additional quality staff. Your response is inadequate because you failed to assess how the deficiencies noted above may have affected drug quality. You also failed to identify how you will ensure that additional quality staff will remediate these quality deficiencies adequately.
An adequate QU overseeing all CGMP operations is necessary to ensure consistent drug quality.
In response to this letter, provide the following:
- 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 list of chemical and microbial test methods and specifications used to analyze each lot of your drug product before making a lot of disposition decisions, and the associated written procedures.
- 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.
- A comprehensive, independent assessment of your overall system for investigating deviations, discrepancies, complaints, 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, QU oversight, and written procedures. Address how your firm will ensure all phases of investigations are appropriately conducted.
- A comprehensive, independent assessment of your change management system. This assessment should include, but not be limited to, your procedure(s) to ensure changes are justified, reviewed, and approved by your QU. Your change management program should also include provisions for determining change effectiveness.
- A comprehensive, independent assessment and CAPA plan to ensure the adequacy of your stability program.
Your remediated program should include, but not be limited to:
- Stability-indicating methods.
- Stability studies for each drug product in its marketed container-closure system before distribution is permitted.
- An ongoing program in which representative batches of each product are added each year to the program to determine if the shelf-life claim remains valid.
- Detailed definition of the specific attributes to be tested at each station (time point).
- All procedures that describe these and other elements of your remediated stability 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 (21 CFR 211.100(a)).
Your firm lacked adequate process validation for your drug products.
For example, you confirmed to our investigator that you did not have a written and approved protocol for process validation for your pain-relief drug products. While you provided the “Compounding and Filling Process Validation” document that incorporated three sunscreen drug products, the document lacked review and approval signatures. In addition, you lacked appropriate qualifications for your filling line equipment.
In your response, you stated that you will perform a retrospective validation of your pain-relief drug products and revise your validation procedures. You also stated that you will review the “Compounding and Filling Process Validation” document and other validation documents to ensure that they have been appropriately reviewed and documented appropriately.
Your response is inadequate. You have not provided an adequate risk assessment of distributed drug products manufactured in an unvalidated state. In addition, you have not provided adequate details of your corrections to ensure that prospective validation studies are performed before distribution. You also have not described how you will ensure that you maintain a consistent state of control thereafter for each of your drug products. Further, you did not discuss how retraining of current staff and recruitment of new staff will ensure that your procedures for qualifying your equipment will be followed.
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 must 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 that you maintain a stable manufacturing operation throughout the product lifecycle.
In response to this letter, provide the following:
- 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 the suitability of equipment for its intended use, the sufficiency of detectability in your monitoring and testing systems (including analytical methods used by you and contract testing labs), quality of input materials, and reliability of each manufacturing process step and control.
- 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 timeline for performing process performance qualifications for each of your marketed drug products.
- Your process performance protocols 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.
- Your CAPA plan is 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, 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.
3. Your firm failed to establish and follow adequate written procedures for cleaning and maintenance of equipment (21 CFR 211.67(b)).
You have not demonstrated that your cleaning procedures are adequate to prevent cross-contamination between the OTC drug products and non-drug products manufactured at your facility. Your firm utilizes (b)(4) filling lines during the manufacturing of your drug products, which are shared among multiple drug products and cosmetics. Our investigator observed inadequate cleaning and maintenance of these filling lines and associated equipment. Specifically:
Inadequate Cleaning Validation
The cleaning validation protocol for your (b)(4) Tube Filler, line (b)(4) stated that it was “representative of all filling machines used in the production department” at your firm. However, filling lines (b)(4) do not use identical equipment, and you failed to provide evidence or scientific justification for how the cleaning of (b)(4) Tube Filler, line (b)(4) is representative of your other filling lines.
Also, this cleaning validation protocol incorporated (b)(4) sunscreen drug products, stating they “are considered to be the worst case scenario due to the nature of the formula and the amount of active material (i.e., (b)(4)) in the product.” However, you failed to provide scientific justification for why these products are considered “worst case” and how they are representative of all drug products manufactured at your firm. We note that your firm manufactures other OTC sunscreen drug products with higher percentages of the active ingredient (b)(4), and other topical drug products with different active ingredients (for example, acne creams and pain-relief balms and lotions).
In your response, your firm committed to completing cleaning validation for your other filling lines and assessing if other drug products are “worst case” and, if required, performing additional validation studies. In addition, you stated that you would review products made on lines (b)(4), including a risk assessment, and that you will document your justification for selecting the (b)(4) as being representative. Your response is inadequate because you did not provide adequate details about your corrections, and you did not discuss whether the equipment will still be used in the manufacturing of drug products before the completion of these corrections.
Inadequate Documentation and Verification of Equipment Cleaning
You failed to appropriately document and verify the cleaning of your filling line equipment before use, as required by your procedure.
For example, on your batch record for (b)(4), Batch (b)(4), your production staff and a quality representative confirmed by signature that the previous batch of (b)(4), Batch (b)(4), was cleared and the associated filling equipment was cleaned and ready for use. However, there is no entry on your equipment maintenance log sheet that documents the use and cleaning of your filling line equipment for (b)(4), Batch (b)(4). Instead, the log sheet notes the previous use and cleaning was for “(b)(4), Batch: (b)(4).”
In your response, your firm committed to investigating the missing entries for the batches noted by our investigator and to performing retraining. Your response is inadequate because you have not provided details about expanding your investigation into ensuring that all drug products manufactured were documented, and how you are assured that all associated equipment was appropriately cleaned. In addition, you do not discuss why your firm had signed off these activities in your batch records as being complete, despite the missing entries on your log sheets.
Lack of Purified Water (PW) System Sanitization
According to your firm’s PW system sanitization procedure, your PW system will be sanitized (b)(4). However, you could not provide evidence to show that your water system had been sanitized within (b)(4) of the time of the FDA inspection.
In your response, you stated that your quality department will continue to sanitize your PW system on a (b)(4) basis and will open a deviation into the quality department’s failure to log sanitizations properly. Your response was inadequate because you did not provide evidence that the PW system was sanitized appropriately during that time period, nor did you discuss what impact a lack of sanitization has on the quality of PW used in both the manufacturing of your drug products and the cleaning of manufacturing equipment.
In response to this letter, provide the following:
- 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 of 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. Provide a detailed summary of vulnerabilities in your process for lifecycle management of equipment cleaning. Describe improvements to your cleaning program, including enhancements to cleaning effectiveness; improved ongoing verification of proper cleaning execution for all products and equipment; and all other needed remediations.
- Appropriate improvements to your cleaning validation program, with special emphasis on incorporating conditions identified as worst cases in your drug manufacturing operation. This should include but not be limited to, the identification and evaluation of all worst cases:
- Drugs with higher toxicities.
- Drugs with higher drug potencies.
- Drugs of lower solubility in their cleaning solvents.
- Drugs with characteristics that make them difficult to clean.
- Swabbing locations for areas that are most difficult to clean.
- Maximum hold times before cleaning.
In addition, describe the steps that must be taken in your change management system before the introduction of new manufacturing equipment or a new product.
A summary of updated standard operating procedures (SOPs) that ensure an appropriate program is in place for verification and validation of cleaning procedures for products, processes, and equipment.
4. Your firm failed to document at the time of performance required laboratory control mechanisms and to record and justify any deviations from required laboratory control mechanisms (21 CFR 211.160(a)).
Your firm uses PW as a component to manufacture your drug products. You failed to follow your water system procedure, including performing appropriate sampling of your water system on a (b)(4) basis and routinely documenting the monitoring of pressure gauges.
In addition, our review of the PW system testing results collected by our investigator found numerous water sampling OOS test results when compared to the limits specified in your procedure.
For example, your conductivity specification is (b)(4). However, our review found multiple OOS results up to 2.30 μS/cm. Further, your total organic carbon specification is (b)(4) ppm. However, our review found multiple OOS results up to 5.12 ppm. These OOS results were not investigated.
In your response, you committed to performing the (b)(4) sampling and the (b)(4) checks of your PW system. You committed to logging the checks onto the appropriate log sheets and to opening a deviation into why this was not being performed. You also provided a risk assessment of the impact of these missed PW samples. You concluded that “as for the water testing, there were also no OOS events.” Your response is inadequate because you did not adequately address how the lack of PW system sampling impacted the quality of your products, especially given the lack of water system sanitization and the numerous OOS water sample results noted during our review.
(b)(4) monitoring is insufficient given your extensive use of PW in manufacturing operations and the indications of the products you produce. In addition, your firm failed to adhere to these minimal schedules as described in your procedures. Without routine water monitoring, you lack the assurance that your PW meets the minimum microbiological and chemical standards suitable for the manufacture of your drug products.
In response to this letter, provide the following:
- A comprehensive, independent assessment of your water system design, control, and maintenance.
- A PW 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 purified water system.
- 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. Specify actions that you will take in response to the risk assessment, such as customer notifications and product recalls.
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.
See FDA’s guidance document Process Validation: General Principles and Practices for general principles and approaches that the FDA considers appropriate elements of process validation, at https://www.fda.gov/media/71021/download.
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.