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9月8日，FDA公布一封针对美国本土企业的警告信。主要的违规项包括缺乏稳定性研究数据、未能有效执行清洁验证，以及未能独立履行质量控制部门的职责。其中，针对如何执行清洁验证，如确定最差情况，该警告信提出了多项建议。
以下是该警告信的主要内容：
August 25, 2020
Dear Mr. Palm:
2020年8月25日
亲爱的Palm先生：
The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Calvin Scott and Company Inc., FEI 1619076, at 209 Eubank Blvd NE, Albuquerque, New Mexico, from March 9 to 12, 2020.
2020年3月9日至12日，美国FDA检查了您的药品生产工厂Calvin Scott and Company Inc.，FEI 1619076，地址为新墨西哥州阿尔伯克基市209 Eubank Blvd NE。
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 210 and 211).
该警告信总结了严重违反制剂CGMP规定的情况。请参阅21CFR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).
由于您用于生产、加工、包装或储存的方法、设施或控制措施不符合CGMP，因此根据FD＆C法案501(a)(2)(B)条及21 U.S.C.351(a)(2)(B) 条的规定，您的药品被认为是掺假。
We reviewed your April 1, 2020, response in detail and acknowledge receipt of your subsequent correspondence.
我们已审核了您的2020年4月1日的详细回复，并确认收到您的后续信件。
During our inspection, our investigator observed specific violations including, but not limited to, the following.
在我们的检查过程中，调查员发现了具体的违规行为，包括但不限于以下行为。
稳定性研究
1. Your firm failed to assure that the drug product bore an expiration date that was supported by appropriate stability testing (21 CFR 211.137(a)).
1.您的公司未能确保该药品的有效期有适当的稳定性测试支持(21 CFR 211.137(a))。
You repackaged some drug products into container-closure systems that were not equivalent to the manufacturer’s container-closure system. Specifically, for the drug product hydrochlorothiazide tablets, USP, 25 mg you repackaged this product from (b)(4) into heat-sealed pouches with one transparent side.
您将某些药品进行了分包装，所用的容器密封系统与原生产商的容器密封系统不同。具体来说，对于氢氯噻嗪片 USP 25mg，您将该产品从XX包分包装到带有透明面的热封袋中。
Your firm does not have stability data to support the expiration dates you assigned to this repackaged drug product. The manufacturer’s container requires that the drug product be dispensed “in tight, light-resistant container as defined in the USP.”
您的公司没有稳定性数据，来支持您分配给该分包装药品的有效期。生产商标识要求将药品“分装在USP定义的密闭、耐光的容器中”。
In your response, you stated that you have discontinued using heat-sealed pouches that are clear on one side and will test your replacement container-closure systems to demonstrate that they meet manufacturer recommendations for light protection.
在您的答复中，您表示已停止使用一侧透明的热封袋，并将测试更换的容器密闭系统，以证明它们满足生产商关于遮光的建议。
We further acknowledge your decision to recall all drug products that you repackaged into heat-sealed pouches with one transparent side instead of a light-resistant container closure system.
我们进一步确认，知晓您决定召回所有含透明面包装的热封袋药品（非耐光容器封闭系统）。
Your response is inadequate because your container-closure system assessment did not address other vulnerabilities of the drug products beyond light sensitivity. This includes but is not limited to moisture vapor transmission, oxygen transmission, and compatibility of the container-closure system with the drug product. In addition, you did not provide a stability protocol and data to evaluate if the expiration dates assigned to your repackaged drug products are appropriate.
您的回答是不充分的，因为您对容器密闭系统评估，不能解决光敏性以外的其它药品问题。这包括但不限于湿气透过率、氧气透过率以及容器密闭系统与药品的相容性。此外，您没有提供稳定性草案和数据，来评估分配给分包装药品的有效期是否合适。
In response to this letter, provide:
针对此信，请提供：
• A comprehensive assessment of your stability program and CAPA plan to ensure that the expiration dates assigned to your repackaged products are scientifically justified. This plan should also include an assessment of the stability of products currently on the U.S. market within expiry. Your remediation program should include, but not be limited to:
•稳定性计划的全面评估和CAPA计划，以确保分配给分包装产品的有效期在科学上是合理的。该计划还应包括：对效期内的美国市场上产品进行稳定性评估。您的补救计划应包括但不限于：
o Stability indicating methods and protocol for repackaged products
o Stability studies for products in their repackaged container-closure system
o An ongoing program in which representative batches of products are added to the program to determine if shelf-life claims remain valid
o Detailed definition of the specific attributes to be tested at each station (timepoint)
o分包装产品的稳定性指示方法和草案
o分包装的容器密闭系统中产品的稳定性研究
o正在进行的计划，其中将代表性批次的产品添加到其中，确定有效期声明是否有效
o每个点(时间点)要测试的特定属性的详细定义
• All procedures that describe these and other elements of your remediated stability program.
•针对稳定性补救计划的这些以及其它元素，其所有相关的描述性程序。
清洁验证
2. Your firm failed to establish and follow adequate written procedures for cleaning and maintenance of equipment (21 CFR 211.67(b)).
2.您的公司未建立并遵循适当的书面程序，来清洁和维护设备(21 CFR 211.67(b))。
You repackaged various drug products that shared product contact surfaces on non-dedicated repackaging lines. You lacked cleaning validation studies to demonstrate that your cleaning procedures for this non-dedicated equipment are adequate to prevent cross-contamination between the drug products repackaged at your facility.
您分包装各种药品时，在非专用分包装线上存在的共享产品接触面。您缺乏清洁验证研究，就您对这种非专用设备的清洁程序，无法证明其足以防止在工厂分包装药品之间发生交叉污染。
In your response, You acknowledged that you have not performed cleaning validation and that you have ceased distribution of repackaged drug products until products have been tested for identity, strength, quality, and purity. You stated that you initiated a cross-contamination testing study in which you will repack drug products identified as depositing the most residue onto the repackaging line. Samples from these repackaged drug products will then be sent to a third-party testing laboratory for carryover cross-contamination analyses.
在答复中，您承认您尚未执行清洁验证，且在对产品完成鉴别、强度、质量和纯度测试之前，您已停止分发这些分包装的药品。您表示，您已经启动了一项交叉污染测试研究，在该研究中，您将分包装的产品确定为在线上有最多残留的药品。分包装药品的样品将被送到第三方检测实验室进，行残留交叉污染分析。
Your response is inadequate because you did not perform an appropriate study to demonstrate that your cleaning program is effective.
您的回答不充分，因为您没有进行适当的研究，来证明您的清洁程序有效。
In response to this letter, provide:
针对此信，请提供：
• A comprehensive assessment and Corrective and Preventive Action (CAPA) plan 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.
•您清洁程序的全面评估以及纠正和预防措施(CAPA)计划，其中包括对您的清洁工艺和实践的适当补救措施、以及完成时间表。针对管理设备清洁的生命周期的流程，提供漏洞的详细摘要。描述您的清洁程序的改进，包括增强清洁效果；就对所有产品和设备正确执行清洁，提供持续确认的改进；以及所有其它需要的补救措施。
• 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:
•对清洁验证程序进行了适当的改进，特别着重于纳入在药品生产过程中确定为最差情况的条件。最差情况的识别和评估，应包括但不限于：
o products with higher toxicities
o products with higher potencies
o products of lower solubility in your cleaning solvents
o products 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
o具有较高毒性的
o产品具有较高活性的
o产品在清洁溶剂中溶解度较低的产品
o具有使其难以清洁的特性的产品
o 清洁最困难区域的擦拭位置
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.
另外，描述在引入新的生产设备或新产品之前，变更管理系统必须采取的步骤。
• A summary of updated SOPs that ensure an appropriate program is in place to verify and validate cleaning procedures for products, processes, and equipment.
•更新的SOP的摘要，以确保制定适当的程序，来验证和确认产品、工艺和设备的清洁程序。
• A comprehensive, independent written evaluation of packaging and labeling operations, with emphasis on failure modes, capability, and design sufficiency. Provide an analysis including but not limited to the following factors:
•对包装和贴标操作进行全面、独立的书面评估，重点是失效模式、功能和设计充分性。提供分析，包括但不限于以下因素：
o All human interactions with equipment before, during, and after (e.g., clearance) operations to identify all points with potential for human error
o Equipment design and suitability for intended use
o Capability of all process steps
o Retrospective review of batches (i.e., defect types and frequencies; deviations; complaints; related investigations)
o Analysis of equipment maintenance and repair history
o Sufficiency of all detection systems and related analytics
o Facility layout and personnel/material flow
o A comprehensive final inspection of packaging integrity and labeling accuracy, and full recording of the number and type of defects
o在操作之前、期间和之后(例如，清场)进行的人与设备的所有交互作用，以识别所有可能造成人为错误的点
o设备设计和预期用途的适用性
o所有工艺步骤
o批生产的回顾性审查(即缺陷类型和频率；偏差；投诉；相关调查)
o设备维护和维修历史分析
o 所有检测系统的充分性和相关分析
o设备布局和人/物流
o包装完整性和标签准确性的全面检查，并完整记录缺陷的数量和类型
质量部门
3. Your firm failed to establish a quality control unit with the responsibility and authority to approve or reject all components, drug product containers, closures, in-process materials, packaging materials, labeling, and drug products (21 CFR 211.22(a)).
3.您的公司未能建立具有责任和授权的质量控制部门，以批准或拒绝所有组件、药品容器、密封件、在制品、包装材料，标签和药品 (21 CFR 211.22(a)) 。
You failed to establish a quality unit (QU) to carry out quality control unit responsibilities, including but not limited to final review and approval functions for drug products you distributed. Multiple personnel in your manufacturing operation had the authority to perform quality control unit responsibilities, including release of drug products for distribution. However, there is no assurance that you have appropriate separation of approval or rejection authority for final drug product release from personnel performing repackaging operations. Final drug product release should be performed by a QU, which should be independent of production.
您未能建立质量部门(QU)，来履行质量控制部门的职责，包括但不限于对所分发药品的最终审核和批准功能。生产运营中的多个人员授权执行质量控制单元的职责，包括放行药品，以进行分销。但是，这不能保证您将最终药品的批准或拒绝的授权，是与执行分包装操作的人员适当分开的。最终药物的放行应由QU进行，该QU应该与生产无关。
In your response, you noted that you lack a QU, and have engaged a consultant to assist you with implementing your plans for remediation. You added that you have temporarily retained an experienced individual to carry out responsibilities as Quality Assurance Director, until this position is permanently filled. You also stated you are in the process of hiring a Quality Control (QC) Technician to carry out QC related functions.
在答复中，您指出您缺乏QU，并聘请了一名顾问来协助您实施补救计划。您还补充说，在此职位被永久填补之前，您已经临时聘请了经验丰富的人员来担任QA总监的职责。您还表示，您正在聘请QC技术员，来执行与QC相关的功能。
Your response is inadequate because you failed to assure that your QU functions independently, and with appropriate responsibility and authority. You must provide your QU with the appropriate responsibility, authority, and enough resources to carry out its responsibilities and consistently ensure drug quality.
您的答复不充分，因为您无法确保QU能够独立运行，并有适当的责任和权力。您必须向QU提供适当的责任、权限和足够的资源，以履行其职责，并始终如一地确保药品质量。
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
请参阅FDA指导文件《药品CGMP法规的质量体系方法》，以帮助实施质量体系和风险管理方法，满足CGMP法规21 CFR第210和211部分的要求，网址为https://www.fda.gov/media/71023/download
In response to this letter, provide:
针对此信，请提供：
• A comprehensive independent 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:
•全面的独立评估和补救计划，以确保您的QU拥有有效运作的权限和资源。评估还应包括但不限于：
o A description of how you will ensure that your QU functions independently of other units
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 discharge of all other QU duties to ensure identity, strength, quality, and purity of all products
o说明如何确保您的QU独立于其它部门职能
o确定公司所使用的程序是否健全和适当
o整个运营过程中，对QU监督规定的评估，已确定对良好实践的遵守情况
o在QU决定处置之前，对每批产品及其相关信息进行完整和最终审查
o进行监督和批准，调查并履行所有其他QU职责，以确保所有产品的鉴别、强度、质量和纯度；
• A retrospective evaluation of your products that remain on the U.S. market. Address any product quality risks or issues that occurred due to deficient practices or deviations. Include a full CAPA plan and provide notifications to customers as needed (and recalls, as appropriate).
•对仍保在美国市场上的产品进行回顾性评估。解决由于操作不当或偏差引起的任何产品质量风险或问题。包括完整的CAPA计划，并根据需要向客户提供通知(适当时召回)。
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.
根据我们在您公司中发现的违规行为的性质，我们强烈建议雇用一名符合21 CFR 211.34规定的合格顾问，以帮助您的公司满足CGMP要求。
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.
您聘用顾问并不能免除公司遵守CGMP的义务。您公司的执行管理层仍然负责解决所有缺陷和系统性缺陷，以确保持续符合CGMP。
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 these violations and for preventing their recurrence or the occurrence of other violations.
本信函中引用的违规行为并非旨在列出与您的产品相关的所有违规行为。您有责任调查和确定这些违规的原因，并防止其再次发生或发生其它违规情况。
If you are considering an action that is likely to lead to a disruption in the supply of drugs produced at your facility, FDA requests that you contact CDER’s Drug Shortages Staff immediately, at drugshortages@fda.hhs.gov, so that FDA can work with you on the most effective way to bring your operations into compliance with the law. Contacting the Drug Shortages Staff also allows you to meet any obligations you may have to report discontinuances or interruptions in your drug manufacture under 21 U.S.C. 356C(b). This also allows FDA to consider, as soon as possible, what actions, if any, may be needed to avoid shortages and protect the health of patients who depend on your products.
如果您考虑采取的行动可能会导致您药物的供应中断，则FDA要求您立即联系CDER的药物短缺人员(drugshortages@fda.hhs.gov)，以便FDA可以与您以最有效的方式沟通，使您的运营符合法律规定。根据21 USC 356C(b)，与药品短缺人员联系，还可以使您履行报告药品供应中断的义务。这也使FDA可以尽快考虑可能需要采取什么措施，以避免短缺，并保护依赖您产品的患者的健康。
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.
及时纠正此信中引用的违规行为。不及时纠正这些违法行为，可能会导致采取法律行动(恕不另行通知)，包括但不限于：扣押和强制令。此警告信中未解决的违反行为也可能阻止其它联邦机构给予合同。
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.
FDA还可能拒绝批准出口证书申请，对于新药申请或补充申请，也不会批准将您的工厂列为供应商或生产商，直到上述违法行为得到纠正。我们可能会重新检查，以确认您已完成纠正措施。
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.
文章来源：PharmLink
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