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质量管理 自检/审计

FDA警告信22/03/30--QU资质、工艺验证、清洁验证以及纯化水系统不符合cGMP要求(中英)

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QU资质、工艺验证、清洁验证以及纯化水系统不符合cGMP要求,FDA发出警告信。
WARNING LETTER
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.
在我们的检查过程中,我们的调查人员发现了具体的违规行为,包括但不限于以下几点。
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:
贵公司生产非处方(OTC)外用药物产品,如防晒霜、止痛药和痤疮治疗。企业的质量部门(QU)没有对OTC药品的生产进行充分的监督。例如,企业的QU未能确保以下内容:
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.
回复中,企业表示,“Verde很少放行没有微生物结果的产品。在引用的例子中,QC在收到最终报告之前通过电话向微生物实验室获得口头结果。在收到所有检测结果的记录(包括分析证书)之前放行药品是不可接受的,并可能导致不符合一项或多项质量属性的药品被分发给消费者。企业还表示,“以前的质量部门员工不称职,未能履行职责”,他们已经不在公司了。另外,企业表示会招聘更多有质量的员工。企业的回复是不充分的,因为未能评估上述缺陷是如何影响药品质量的。也未能确定企业将如何确保额外的质量人员将充分弥补这些质量缺陷。
An adequate QU overseeing all CGMP operations is necessary to ensure consistent drug quality.
为确保药品质量的一致性,必须有一个监督所有CGMP操作的适当的质量部门。
In response to this letter, provide the following:

针对本函,请提供:

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:
一份全面的评估和整改计划,以确保企业的QU得到有效运作的权限和资源。评估还应包括但不限于:
o A determination of whether procedures used by your firm are robust and appropriate

o确定贵公司所用的规程是否稳健和适用

o Provisions for QU oversight throughout your operations, to evaluate adherence to appropriate practices

o规定QU在整个操作过程进行监督以评估对适用规范的遵守情况

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在做出批次处置决定之前,用于分析每批药品的化学和微生物检测方法和规范清单,以及相关的书面程序

o A complete and final review of each batch and its related information before the QU disposition decision

o在QU处置决定之前对每批次及其相关信息的完整和最终审核

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.
对企业的整体系统进行全面、独立的评估,用于调查偏差、差异、投诉、OOS结果和故障。提供一份详细的行动计划来纠正这个系统。行动计划应包括但不限于:调查能力、范围确定、根本原因评估、纠正措施和预防措施(CAPA)有效性、QU监督和书面程序的显著改进。说明贵公司将如何确保所有阶段的调查都得到适当执行。
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.
对变更管理系统进行全面、独立的评估。该评估应包括但不限于企业规程,以确保变更得到QU证明、审查并批准。企业的变更管理规程还应包括确定变更有效性的规定。
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:
一份综合独立的评估和CAPA计划,以确保企业的稳定性计划的充分性。企业的整改计划应包括但不限于:
o Stability-indicating methods

o具有稳定指示性的方法

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

o允许分销前容器密封系统中每种药品的稳定性研究

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持续计划,每年增加每个产品的代表性批次以确定货架期声明是否仍然有效

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

o每个点(时间点)要检测的具体属性的详细定义

o All procedures that describe these and other elements of your remediated stability program

描述整改稳定性计划的以上要素和其他要素的所有规程

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.
企业的药品缺乏足够的工艺验证。例如,企业向我们的调查人员证实,没有书面的和批准的用于企业的止痛药产品工艺验证的方案。虽然企业提供了包含三种防晒药品的“配方和灌装工艺验证”文件,但该文件缺乏审核和批准签名。此外,企业对灌装线设备缺乏适当的确认。
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.
回复中,企业声称将对止痛药产品进行回顾性验证,并修改验证程序。企业还表示,将审核“配制和灌装工艺验证”文件和其他验证文件,以确保它们得到了适当的审核和记录。
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.
企业的答复不充分。没有对在未经验证状态下生产的分销药品进行充分的风险评估。此外,页没有提供足够的更正细节以确保在放行前进行前瞻性验证研究。也没有描述企业将如何确保此后对每种药品保持一致的控制状态。此外,企业没有讨论如何对现有员工进行再培训和招聘新员工来确保企业设备的合格程序得到遵守。
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.
工艺验证是评估一个工艺在整个生命周期中设计的可靠性和控制状态。生产工艺的每一个重要阶段都必须进行适当的设计,并且必须确保原材料、中间体和成品药品的质量。工艺确认研究确定是否建立了初始控制状态。成功的工艺验证研究在商业销售前是必要的。此后,对工艺性能和产品质量的持续警惕监督是必要的,以确保在整个产品生命周期中保持稳定的生产操作。
In response to this letter, provide the following:

针对本函,请提供:

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.
对每个药品工艺进行评估,以确保有一个数据驱动的科学合理的分析来识别和控制所有可变性来源,这样企业的生产工艺将始终符合适当的规格和生产标准。这包括但不限于评估设备的预期用途的适用性、监控和测试系统的可检测性的充分性(包括企业和合同检测实验室使用的分析方法)、原材料的质量以及每个生产工艺步骤和控制的可靠性。
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.
验证计划以及相关规程的详细总结,以确保整个产品生命周期的受控状态。描述企业的工艺性能确认计划,以及对批内和批间差异的持续监控,以确保持续的受控状态。
A timeline for performing process performance qualification for each of your marketed drug products.
每一种上市药品的工艺性能确认时间表。
Your process performance protocols and written procedures for qualification of equipment and facilities.
工艺性能确认计划和设备、设施确认的书面规程。
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.
一份详细的程序,用于设计、验证、维护、控制和监控企业的每个生产工艺,包括警惕地监控批内和批间差异,以确保持续的受控状态。此外,还要包括设备和设施的确认计划。
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.
企业的CAPA计划对设施和设备实施日常的、警惕的运营管理监督。除其他事项外,该计划应确保及时发现设备/设施性能问题,有效执行维修,遵守适当的预防性维修时间表,及时对设备/设施进行技术升级,并改进持续管理审查的系统。
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:
没有证明企业的清洁程序足以防止工厂生产的OTC药品和非药品之间的交叉污染。贵公司在药品生产过程中使用了xx灌装线,该灌装线生产多种药品和化妆品。我们的调查人员观察到这些灌装管道和相关设备的清洁和维护不足。具体地说:
Inadequate Cleaning Validation

清洁验证不充分

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.
企业xx管式灌装机、xx线的清洁验证方案中声明它是贵公司“生产部门使用的所有灌装机的代表”。然而,xx灌装线不使用相同的设备,并且未能提供证据或科学理由证明xx管灌装线、xx线的清洗代表企业其他灌装线。
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).
此外,该清洁验证方案包含了xx防晒药物产品,说明“由于配方的性质和产品中活性物质的数量(即xx),它们被认为是最差的情况。”但是,企业未能提供科学的理由来说明为什么这些产品被认为是“最差情况”,以及它们如何代表贵公司生产的所有药品。我们注意到,贵公司生产的其他OTC防晒药品中活性成分xx的比例较高,以及其他具有不同活性成分的外用药品(例如,痤疮膏、镇痛膏和乳液)。
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.
回复中,贵公司承诺完成其他灌装线的清洁验证,评估其他药品是否为“最差情况”,如果需要,进行额外的验证研究。此外,企业表示将审核xx线上的产品,包括风险评估,并将记录选择xx作为代表性的理由。企业的回复是不充分的,因为没有提供足够的纠正细节,并且没有讨论在完成这些纠正之前,设备是否仍将用于药品的生产。
Inadequate Documentation and Verification of Equipment Cleaning

设备清洁的文件和验证不充分

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).”
未能按照企业的程序要求,在使用前适当记录和验证灌装线设备的清洁情况。例如,在xx批记录中,生产人员和质量代表签字确认前一批xx批xx批已清除,相关灌装设备已清洗并准备使用。但是,在设备维护日志表上没有记录xx批xx灌装线设备的使用和清洁情况。相反,日志中记录了之前的使用和清洁是“xx批次:xx批次”。
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.
回复中,贵公司承诺调查FDA检查员注意到的批次的缺失信息,并进行再培训。企业的回复是不充分的,因为没有提供关于扩大调查以确保所有生产的药品都被记录的信息,以及企业如何确保所有相关设备都被适当清洁的信息。另外,企业没有讨论为什么贵公司在批记录中签字确认这些活动是完整的,尽管企业的设备日志表上缺少相关信息。
Lack of Purified Water (PW) System Sanitization

缺乏纯化水(PW)系统消毒

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.
根据贵公司的PW系统消毒程序,企业的PW系统将消毒xx。然而,不能提供证据证明企业的水系统在FDA检查时间内已消毒。
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.
回复中,企业声称质量部将继续在xx基础上对PW系统进行消毒,并将导致质量部未能正确记录消毒记录的偏差。企业的回复是不充分的,因为没有提供证据证明PW系统在那段时间内进行了适当的消毒,企业也没有讨论缺乏消毒对药品生产和生产设备清洁中使用的PW的质量有什么影响。
In response to this letter, provide the following:

针对本函,请提供:

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.
对清洁效果进行全面、独立的回顾性评估,以评估交叉污染危害的范围。包括识别残留物,其他可能被不当清洗的生产设备,以及评估是否交叉污染的产品可能已放行。评估应识别清洁程序和实践的任何不足之处,并包括用于生产多个产品的每一个生产设备。
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.
一份CAPA计划,基于企业清洁程序的回顾性评估,包括对清洁过程和做法的适当整改措施,以及完成时间。提供设备清洗生命周期管理过程中漏洞的详细汇总。描述企业的清洁计划的改进,包括清洁效率的提高;改进所有产品和设备清洁执行的持续验证;以及所有其他需要的整改措施。
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:
对企业的清洁验证程序进行适当改进,特别强调纳入药品生产操作中确定为最坏情况的条件。这应包括但不限于查明和评价所有最坏的情况:
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.
此外,描述在引入新生产设备或新产品之前,在企业的变更管理系统中必须采取的步骤。
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.
更新的标准操作程序(sop)的总结,以确保产品、工艺和设备的清洗程序有适当的验证和确认计划。
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.
贵公司使用PW作为生产药品的成分。没有遵循水系统程序,包括在xx基础上对水系统进行适当的取样,并定期记录压力表的监测情况。
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.
回复中,企业承诺对PW系统进行xx抽样和xx检查。承诺将检查记录到适当的日志表上,并对为何没有执行检查启动一个偏差。还提供了对这些遗漏PW样本影响的风险评估。企业的结论是“关于水检验,也没有出现OOS事件。”企业的回复是不充分的,因为没有充分说明PW系统采样的缺乏如何影响产品的质量,特别是考虑到水系统消毒的缺乏和我们审查中注意到的大量OOS水样结果。
(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.
鉴于在生产操作中广泛使用PW以及生产的产品指示,监控是不够的。此外,贵公司未能按照程序中描述的这些最小时间表进行。如果没有常规的水质监测,就无法保证PW符合适合药品生产的最低微生物和化学标准。
In response to this letter, provide the following:

针对本函,请提供:

A comprehensive, independent assessment of your water system design, control, and maintenance.
对水系统设计、控制和维护进行全面、独立的评估。
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.
PW系统验证报告。还包括对系统设计、持续控制和维护程序的任何改进的总结。
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.
水系统监测程序,规定了水的常规微生物检测,以确保其可用于公司生产的每批药品。
The current action/alert limits for total counts and objectionable organisms used for your purified water system.
贵公司的纯化水系统目前所使用的总数量和不良生物的行动/警报限。
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.
一份详细的风险评估,说明观察到的水系统故障对目前在美国销售的所有药品批次质量的潜在影响。指定企业为响应风险评估将采取的行动,例如客户通知和产品召回。
Quality Systems

重量体系

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

工艺验证

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.
请参阅FDA指南文件工艺验证:FDA认为工艺验证的适当元素的一般原则和方法的一般原则和做法,网址是https://www.fda.gov/media/71021/download。
CGMP Consultant Recommended

CGMP顾问推荐

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。
Conclusion

结论

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.
在这封信中引用的违规行为并不是企业设施中存在的所有违规行为的清单。企业有责任调查和确定任何违规行为的原因,并防止其再次发生或其他违规行为的发生。
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.
请及时纠正违规行为。未能及时并充分地解决该问题可能会导致无需另行通知的监管或法律行动,包括但不限于扣押和禁令。未解决的违规行为也可能妨碍其他联邦机构授予合同。
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.
未能解决违规问题还可能导致FDA拒绝签发出口证书。FDA可能会拒绝批准贵公司作为药品生产商的新申请或补充申请,直到任何违规行为被完全解决,并且我们确认企业符合CGMP。我们可能会重新检查,以核实企业是否完成了针对任何违规行为的纠正措施。
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.
这封信告知我们的发现,并为企业提供解决上述缺陷的机会。收到此信后,请在15个工作日内书面回复本办公室。说明你已经采取了什么措施来解决任何违规,并防止其再次发生。在回复这封信时,企业可以提供额外的信息供我们考虑,我们将继续评估企业的活动和做法。如果企业不能在15个工作日内完成纠正措施,说明延迟的原因和完成计划。
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.
Sincerely,
/S/
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