质量管理 自检/审计


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Verde Cosmetic Labs LLC
MARCS-CMS 622534 — MARCH 30, 2022
March 30, 2022
Dear Mr. Stern:
The U.S. Food and Drug Administration inspected your drug manufacturing facility, Verde Cosmetic Labs LLC, FEI 3014015976, at 19845 Nordhoff Street, Northridge, California 91324, from September 27 to October 15, 2021.
美国食品和药物管理局于2021年9月27日至10月15日检查了企业位于加利福尼亚州91324北岭市Nordhoff街19845号的药品生产工厂Verde cosmetics Labs LLC, FEI 3014015976。
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).
本警告信总结了成品药严重违反现行良好生产规范(CGMP)规定的情况。参见《联邦法规法典》第21篇,第210和211部分(21 CFR第210和211部分)。
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).
由于生产、加工、包装或贮存方法、设施或控制不符合CGMP,企业的药品根据《联邦食品、药品和化妆品法案》(FD&C法案)第501(a)(2)(B)条21 U.S.C. 351(a)(2)(B)属于掺假药品。
We reviewed your November 2, 2021, response to our Form FDA 483 in detail and acknowledge receipt of your subsequent correspondence.
FDA详细审查了企业于2021年11月2日对FDA 483表格的回复,并确认收到了企业后续的信函。
During our inspection, our investigator 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).

1. 质量管理部门没有履行其职责确保所生产的药品CGMP合规并且符合鉴别、规格、质量和纯度的既定标准(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)).
在每批药品放行前进行微生物检验并进行审查(21 CFR 211.165(b))。Adequate investigations of out-of-specification (OOS) results and written procedures to conduct thorough investigations (21 CFR 211.192).
充分调查OOS结果和进行彻底调查的书面程序(21 CFR 211.192)。
Appropriate documentation and assessment of changes (21 CFR 211.100(a)).
适当的变更记录和评估(21 CFR 211.100(a))。
Establishment of an adequate, ongoing stability program (21 CFR 211.166(a)).
制定充分的、持续的稳定性计划(21 CFR 211.166(a))。
Performance of appropriate annual product reviews (21 CFR 211.180(e)).
执行适当的年度产品审查(21 CFR 211.180(e))。
In your response, you stated, “Verde rarely releases 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:
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 list of chemical and microbial test methods and specifications used to analyze each lot of your drug product before making a lot disposition decision, and the associated written procedures


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

o 监督和批准调查以及所有其他QU职责的履行,以确保所有产品的鉴别,规格,质量和纯度

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:
o Stability-indicating methods


o Stability studies for each drug product in its marketed container-closure system before distribution is permitted


o 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


o Detailed definition of the specific attributes to be tested at each station (time point)


o 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)).

2.未能建立生产和工艺控制的书面规程,以确保药品具有其声称或表明拥有的鉴别、规格、质量和纯度[ 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 qualification 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 suitability of equipment for its intended use, 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 qualification 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 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)).

3.未能建立并遵守适当的设备清洁和维护的书面规程。 (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 nondrug products manufactured at your facility. Your firm utilizes (b)(4) filling lines during 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 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 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 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 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 具有高毒性的药物

o drugs with higher drug potencies

o 具有高药效的药物

o drugs of lower solubility in their cleaning solvents

o 清洁溶剂中溶解度低的药物;

o drugs with characteristics that make them difficult to clean

o 具有难以清洁特性的药物;

o swabbing locations for areas that are most difficult to clean

o 最难清洁区域的擦拭位置。

o maximum hold times before cleaning

o 清洁前的最长放置时间

In addition, describe the steps that must be taken in your change management system before 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)).

4. 在实施时未能遵守和记录实验室控制,未能记录和解释与实验室操作规程的偏差。

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.
此外,FDA审查了检查人员收集的PW系统测试结果,发现与企业程序中指定的限度相比,大量水样OOS测试结果。例如,企业的电导率规格是(b)(4)。然而,FDA的审查发现多个OOS结果高达2.30 μS/cm。此外,企业的总有机碳规格是(b)(4) ppm。然而,FDA的审查发现多个OOS结果高达5.12 ppm。这些OOS结果未进行调查。
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 into 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.
Quality Systems


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.
贵公司的质量体系不充分。参见FDA指导文件《药品CGMP法规质量体系方法》,帮助实施质量体系和风险管理方法,以满足CGMP法规21 CFR 210和211部分的要求,网址:https://www.fda.gov/media/71023/download。
Process Validation


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.
CGMP Consultant Recommended


Based upon the nature of the violations we identified at your firm, 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.
基于FDA发现的违规行为的性质,我们强烈建议聘请一位符合21 CFR 211.34中规定的合格顾问来帮助贵公司满足CGMP要求。使用顾问并不能减轻贵公司遵守CGMP的义务。贵公司的执行管理层仍有责任解决所有缺陷,以确保持续的CGMP符合性。


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 the FDA to withhold issuance of Export Certificates. The 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 identify your response with unique identifier CMS 622534. Electronic responses may be submitted to ORAPHARM4_Responses@fda.hhs.gov with ATTN: CDR Steven E. Porter, Jr. or send your written responses to:
CDR Steven E. Porter, Jr.
Director, Division of Pharmaceutical Quality Operations IV
U.S. Food and Drug Administration
1907 Fairchild Road
Irvine, CA 92612
If you have questions regarding this letter, please contact LCDR Rumany Penn, Compliance Officer, at (949) 608-4409, or by email at Rumany.Penn@fda.hhs.gov.
CDR Steven E. Porter, Jr.
Director, Division of Pharmaceutical Quality Operations IV
发布于 2022-08-18 10:48:32 © 著作权归作者所有