退货程序、工艺验证、分析方法、稳定性研究及QU职责等不符合cGMP要求，FDA发出警告信。
WARNING LETTER
Health Plus Inc.
MARCS-CMS 616877 — DECEMBER 29, 2021
December 29, 2021
Dear Ms. Mediratta:
The U.S. Food and Drug Administration inspected your drug manufacturing facility, Health Plus Inc., FEI 2027164, at 13837 Magnolia Avenue, Chino, California, from June 23 to July 1, 2021.
美国食品和药物管理局于2021年6月23日至7月1日检查了企业位于加州Chino Magnolia Avenue 13837的药品生产设施Health Plus Inc, FEI 2027164。
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 product is 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 July 20, 2021 response to our Form FDA 483 in detail and acknowledge receipt of your subsequent correspondence.
由于你们生产、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。2021年7月20日FDA详细审查了企业对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FDA检查过程中，我们的调查员观察到具体的违规行为，包括但不限于以下行为。
1. Your firm failed to ensure that returned drugs meet appropriate standards of safety, identity, strength, quality and purity prior to redistributing (21 CFR 211.204).
1. 贵公司未能确保退货在重新销售前符合适当的安全性、鉴别、规格、质量和纯度标准(21 CFR 211.204)。
Your firm’s handling of returned drug product before its redistribution is inadequate. For example, during the inspection, you were not able to provide documentation of adequate inspection and investigation of the returned product confirming the label conditions under which the returned drug product was held, stored, or shipped before its return and before redistributing. Furthermore, you failed to perform adequate testing to ensure the safety, identity, strength, quality, and purity of the returned product. Organoleptic examination alone is not sufficient to ensure that a product maintains its safety, identity, strength, purity, and quality after it has been in a situation where it may have been exposed to improper storage conditions.
贵公司对退货药品再分配前的处理不充分。例如，在检查期间，企业未能提供对退货产品进行充分检查和调查的文件，以确认退货产品在退货前和重新分销前存储或运输的标签条件。此外，企业未能进行足够的检测以确保退回产品的安全性、鉴别、规格、质量和纯度。在产品可能暴露在不适当的存储条件下后，单独的目视检查不足以确保产品保持其安全性、鉴别性、规格、纯度和质量。
Before redistribution, you combined returned capsules from various lots into new batches with new lot numbers. These new lots did not have uniform character and quality, including capsules that would expire in less than three years. However, you then assigned these comingled batches new lot numbers and granted them an additional three-year shelf life. The new expiration dates are not supported by stability data and, in some instances, exceeded the expiration date of the returned product by up to 18 months. Your batch production records did not indicate you performed testing on these comingled batches before their redistribution.
在重新销售之前，企业将从不同批次退回的胶囊组合成具有新批号的新批次。这些新批次没有统一的特性和质量，包括胶囊将在3年内过期。然而，企业随后给这些合并批次分配了新的批号，并赋予它们额外的3年货架期。新的有效期没有稳定数据支持，在某些情况下，超过退货产品的有效期长达18个月。企业的批生产记录没有表明企业在重新销售前对这些混合批次进行了检验。
Your practices of conducting organoleptic examination on the returned product that was subjected to unknown conditions before return, making comingled batches by combining returned drug product with various lot numbers and expiration dates, and assigning a new product shelf life disregarding the expiration dates of the returned product are unacceptable.
企业在退货前对条件未知的退货产品进行目视检查，将不同批号和过期日期的退货药品组合成混合批次，以及不考虑退货产品的过期日期而指定新产品的保质期的做法是不可接受的。
In response to this letter, provide the following:
针对本函，请提供：
• A comprehensive, independent assessment and remediation plan to ensure the adequacy of your returned drug product handling and processing for redistribution. Provide a detailed action plan and associated procedures that should include, but not be limited to, the following:
•一份全面、独立的评估和整改计划，以确保退回的药品处理和再分配加工的充分性。提供详细的行动计划和相关程序，应包括但不限于以下内容:
o Documentation of the conditions under which returned drug products have been held, stored, or shipped before, during and after return, reason for the return, quantity returned, date of disposition, and ultimate disposition, including procedures for destruction if doubt exists as to drug quality.
o退货药品在退货前、退货期间和退货后被保存、储存或运输条件的文件，退货原因、退货数量、处理日期和最终处理，包括对药品质量有疑问时的销毁程序。
o A procedure for ensuring the conditions under which returned drug products were held, stored, or shipped did not adversely affect the safety, identity, strength, quality or purity of the drug products.
o确保已退回药品的保持、储存或运输条件不会对药品的安全性、鉴别、规格、质量或纯度产生不利影响的程序。
• Provide your action plan to address any product quality risks associated with the redistributed batches in the United States, including potential customer notifications and recalls.
•提供企业的行动计划，以解决在美国分销的批次相关的任何产品质量风险，包括潜在的客户通知和召回。
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, and your firm’s quality control unit did not review and approve those procedures, including any changes (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，贵公司的质量部门未审查和批准这些规程，包括任何变更。[ 21 CFR 211.100(a) ]
Your firm did not adequately validate the process used to manufacture your over-the-counter drug product Super Colon Cleanse Stimulant Laxative. Your firm changed the formulation of your Super Colon Cleanse Stimulant Laxative in December 2017, including the removal of multiple components. You did not issue a process validation protocol and associated analytical testing report until November and December 2018, respectively, a year after your reformulation. Additionally, the only data supporting your November 2018 validation protocol, dated October 21, 2014, was from a test of the previous formulation and does not reflect the current drug product formulation. Since the December 2017 formulation change, your firm has manufactured and released at least (b)(4) batches of the drug product which you distributed to the U.S. market with inadequate process validation data.
贵公司没有充分验证用于生产非处方药产品超级结肠清洁刺激泻药的工艺。贵公司在2017年12月更改了超级结肠清洁刺激泻药的配方，包括去除多种成分。企业在重新配制一年后的2018年11月和12月才分别发布工艺验证方案和相关分析测试报告。此外，支持企业2018年11月验证方案的唯一数据(日期为2014年10月21日)来自对之前配方的检测，不反映当前药品配方。自2017年12月剂型变更以来，贵公司在工艺验证数据不充分的情况下生产并放行了至少xx批次的药品，这些药品已销售到美国市场。
In your response, you stated that you would create a new standard operating procedure (SOP) for process validation and would document and review the results of the process validation study. Additionally, you indicated that you would commence manufacturing the first process validation batch in August 2021.
在企业的回复中，企业声称将为工艺验证创建一个新的标准操作程序(SOP)，并将记录和审核工艺验证研究的结果。另外，企业表示将于2021年8月开始生产第一批工艺验证批次。
Your response is inadequate because failure to conduct process validation studies can result in product quality attribute failures. You also failed to address your justification for continuing to manufacture the drug product when you have not adequately demonstrated that your manufacturing processes are reproducible and controlled to yield a drug product of uniform character and quality.
企业的回复是不充分的，因为不进行工艺验证研究可能导致产品质量属性失败。企业也未能提出继续生产该药品的理由，因为企业没有充分证明生产工艺是可复制的，并对其进行控制，以生产出具有统一特性和质量的药品。
In response to this letter, provide the following:
针对本函，请提供：
• 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.
•一份对确保产品整个生命周期内受控状态的验证计划以及相关规程的详细总结。请描述工艺性能确认计划，以及对批内和批间变异的持续监控，以确保持续受控状态。。
• A timeline for performing appropriate process performance qualification for your marketed drug product.
•对上市药品进行适当工艺性能确认的时间表。
• 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.
• 请提供一份关于设计、验证、维护、控制和监控每种生产工艺的详细计划，包括对批内和批间变异的警戒性监控以确保持续受控状态。还请包括设备和设施的确认计划。
• 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, and 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.
• 一份针对每种药品工艺的评价，确保具备数据驱动且科学合理的计划，识别和控制所有变异源，使生产工艺将始终如一符合适当的技术参数和生产标准。应包括但不限于，评估设备是否适预期用途、监测和检验系统是否具备足够的可检出能力、确保投料质量以及每个生产工艺步骤和控制的可靠性。
• 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 quality unit (QU). Your change management program should also include provisions for determining change effectiveness.
•对企业的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，企业的程序，以确保变更是合理的，经质量部门(QU)评审和批准。企业的变更管理程序还应该包括确定变更有效性的规定。
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 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.
工艺验证评估一个工艺在整个生命周期中设计和控制状态的可靠性。生产工艺的每个重要阶段都必须进行适当的设计，并确保原材料、中间体和成品药的质量。工艺确认研究确定是否建立了初始受控状态。
Successful process qualification studies are necessary before commercial distribution. Thereafter, ongoing vigilant oversight of process performance and product quality is necessary to ensure you maintain a stable manufacturing operation throughout the product lifecycle.
成功的工艺确认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，以确保企业在整个产品生命周期中保持稳定的生产操作。
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/regulatory-information/search-fda-guidance-documents/process-validation-general-principles-and-practices.
请参阅FDA指南文件《工艺验证:一般原则和实践》，了解FDA认为工艺验证的适当元素的一般原则和方法，网址为：https://www.fda.gov/regulatory-information/search-fda-guidance-documents/process-validation-general-principles-and-practices。
3. Your firm failed to establish and document the accuracy, sensitivity, specificity, and reproducibility of its test methods (21 CFR 211.165(e)).
3.未能建立并记录检验方法的精确度、灵敏度、专属性、重现性。(21 CFR 211.165(e))
You did not adequately validate the method for assay used for your Super Colon Cleanse laxative drug product release specification. Specifically, per your specifications, the (b)(4) Spectrophotometer method for assay is to be conducted at the wavelength of (b)(4) as indicated in your finished drug product specifications. However, according to the data in the validation report you used the wavelength of (b)(4). In addition, the method validation report did not include system suitability, nor did it demonstrate that your modified method is fit for purpose.
企业没有充分验证超级结肠清洁泻药制剂放行说明书中使用的检验方法。具体来说，根据企业的规程，用于测定的xx分光光度计法应在企业成品规格中所示的xx波长下进行。然而，根据验证报告中的数据，企业使用了xx的波长。此外，方法验证报告未包括系统适用性，也未证明修改的方法是适用的。
In your response, you stated that the method validation for assay was conducted at the correct wavelength. Your response is inadequate as follows.
在企业的回复中，企业声称在正确的波长下进行了检测方法的验证。企业的回复是不充分的，如下
• It lacked supporting documentation to support your claim that the method validation for assay was conducted at the correct wavelength.
• 缺乏支持性文件来支持企业声称的检测方法验证是在正确的波长进行的。
• It did not provide a risk assessment for the drug product released using the assay method that was not adequately validated nor a justification for continuation of the drug product currently on the market.
•未提供使用未充分验证的分析方法放行的药品的风险评估，也未提供当前市场上药品继续使用的理由。
In response to this letter, provide the following:
针对本函，请提供：
• A comprehensive, independent assessment of your laboratory practices, procedures, methods, equipment, documentation, and analyst competencies. Based on this review, provide a detailed plan to remediate and evaluate the effectiveness of your laboratory system.
一份对企业的实验室做法、程序、方法、设备、文件和分析员能力进行全面、独立的评估。在此回顾的基础上，提供一份详细的计划来整改和评估企业实验室系统的有效性。
• A comprehensive, independent assessment of all test methods to ensure that they are adequately validated and suitable for their intended purposes.
•对所有检验方法进行全面、独立的评估，以确保它们得到充分验证并适合其预期用途。
• A retrospective assessment of reserve samples for all finished drug products that are currently on the market, using an adequately validated test method, to ensure that your drug products conform to the drug product specification.
•使用充分验证的检验方法对目前上市的所有药品的留样进行回顾性评估，以确保企业的药品符合标准。
• A review of the completeness, consistency, accuracy of data from your use of uncontrolled documents (e.g., legal pads) to document the data.
•对企业使用非受控文件(例如，信纸)记录数据的完整性、一致性和准确性进行审查。
• A review of applicable compendial methods for your product.
•审查适用于企业产品的药典方法。
Refer to FDA’s guidance documents Q2(R1) Validation of Analytical Procedures and Analytical Procedures and Methods Validation for Drugs and Biologics for general principles and approaches for method validation at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/q2r1-validation-analytical-procedures-text-and-methodology-guidance-industry and https://www.fda.gov/regulatory-information/search-fda-guidance-documents/analytical-procedures-and-methods-validation-drugs-and-biologics, respectively.
方法验证的一般原则和方法参见FDA指南文件Q2(R1)《药物和生物制剂分析方法验证》https://www.fda.gov/regulatory-information/search-fda-guidance-documents/q2r1-validation-analytical-procedures-text-and-methodology-guidance-industry和分别为https://www.fda.gov/regulatory-information/search-fda-guidance-documents/analytical-procedures-and-methods-validation-drugs-and-biologics。
4. Your firm failed to follow a written testing program designed to assess the stability characteristics of drug products and to use results of stability testing to determine appropriate storage conditions and expiration dates (21 CFR 211.166(a)).
4.未能建立并遵循书面检验程序来评估药品稳定性特征，并使用此类稳定性检测的结果来确定适当的储存条件和有效期[ 21 CFR 211.166(a) ]。
Your firm’s stability program is inadequate. Specifically, you only placed (b)(4) of your Super Colon Cleanse Stimulant Laxative drug product on stability and failed to perform any stability testing since at least September 2017. Furthermore, you did not have any stability data for drug product manufactured using the new formulation. Therefore, you lack sufficient stability data to substantiate the (b)(4) expiration of this drug product.
贵公司的稳定计划不充分。具体来说，企业只对超级结肠清洁刺激性泻药产品的xx进行了稳定性测试，并且至少自2017年9月以来没有进行任何稳定性测试。此外，企业没有使用新配方生产的药品的任何稳定性数据。因此，企业缺乏足够的稳定性数据来证明该药品的xx有效期。
In your response, you stated that the delay in conducting a stability study was because of restrained resources for the QU. You stated that you will initiate long-term stability testing for ongoing (b)(4) stability testing and accelerated stability testing for the determination of the expiration dating period of the drug product.
在企业的回复中，企业称延迟进行稳定性研究是因为QU的资源有限。企业称将为正在进行的xx稳定性试验和加速稳定性试验启动长期稳定性试验，以确定药品的有效期。
Your response is inadequate because your firm has been aware of the inadequacy of your stability program since the 2013 inspection. Subsequent inspections in 2015, 2018, and 2021, all had identical or similar observations in your stability program. Your response lacked information on what you did between 2013 and the current inspection to remediate your stability program.
企业的回复是不充分的，因为贵公司已经意识到2013年检查以来企业的稳定性计划不充分。在2015年、2018年和2021年的后续检查中，企业的稳定性项目都有相同或类似的观察结果。企业的回复中缺乏关于企业在2013年至目前检查期间为整改企业的稳定计划所做的工作。
In response to this letter, provide the following:
针对本函，请提供：
• A comprehensive assessment and corrective action and preventive action (CAPA) plan to ensure the adequacy of your stability program. Your CAPA plan should include, but not be limited to:
•一份全面的评估以及纠正措施和预防措施(CAPA)计划，以确保企业的稳定性计划的充分性。企业的CAPA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 (timepoint)
o 每个点（时间点）要检测的具体属性的详细定义
• 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
Refer to FDA’s guidance document Q1A(R2) Stability Testing of New Drug Substances and Products for general principles and approaches for stability testing at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/q1ar2-stability-testing-new-drug-substances-and-products.
关于稳定性测试的一般原则和方法，请参阅FDA指南文件Q1A(R2)《新原料药和产品的稳定性测试》：https://www.fda.gov/regulatory-information/search-fda-guidance-documents/q1ar2-stability-testing-new-drug-substances-and-products。
5. Your firm’s quality control unit failed to approve or reject all procedures or specifications impacting on the identity, strength, quality, and purity of the drug product (21 CFR 211.22(c)).
5. 企业的质量管理部门未能批准或拒绝对药品的鉴别、规格、质量及纯度有影响的所有操作规程或质量标准。(21 CFR 211.22(c))
You failed to establish, review, and approve all procedures, including those which may impact the safety, identity, strength, quality, and purity of your drug product. Specifically, your QU failed to implement SOPs that are critical to ensure the quality of the drug product, such as the SOPs for operating the equipment used to manufacture the drug product.
企业未能建立、审核和批准所有规程，包括那些可能影响药品的安全性、鉴别、规格、质量和纯度的规程。具体来说，企业的QU未能实施对确保药品质量至关重要的sop，例如用于操作药品生产设备的sop。
In your response, you stated that you will create and revise corresponding SOPs. Your response is inadequate because you failed to provide supporting documentation (e.g., draft SOPs, training). Additionally, you provided similar responses to repeat or similar observations in the 2012, 2013, and 2018 inspections. Therefore, we have no assurance that your corrective actions will be implemented.
在企业的回复中，企业表示将创建和修改相应的标准操作规程。企业的回复是不充分的，因为没有提供支持文件(例如，标准操作规程草案，培训)。此外，企业在2012年、2013年和2018年的检查中对重复或类似的观察结果提供了类似的反应。因此，我们无法保证企业的纠正措施得到实施。
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得到有效运作的授权和资源。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确定贵公司使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规定在整个运营过程中进行QU监督，以评估对适当做法的遵守情况
o A complete and final review of each batch and its related information before the QU disposition decision
o在作出QU处置决定之前，对每批及其相关信息进行全面和最终审查
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履行所有其他QU职责，以确保所有产品的鉴别，规格，质量和纯度
• A complete assessment of documentation systems used throughout your manufacturing and laboratory operations to determine where documentation practices are insufficient. Include a detailed CAPA plan that comprehensively remediates your firm’s documentation practices to ensure you retain attributable, legible, complete, original, accurate, contemporaneous records throughout your operation.
对企业整个生产和实验室操作过程中使用的文件系统进行全面评估，以确定文件规范的不足之处。包括一份详细的CAPA计划，全面纠正贵公司的文件记录，以确保企业在整个操作过程中保留可归因的、易读的、完整的、原始的、准确的、同步的记录。
• Your action plan to address any product quality or patient safety risks for your drug product in U.S. distribution, including potential customer notifications and recall.
•解决企业在美国销售的任何产品质量或患者安全风险的行动计划，包括潜在的客户通知和召回。
Refer to FDA’s guidance document: Quality Systems Approach to Pharmaceutical CGMP Regulations for general principles and approaches at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/quality-systems-approach-pharmaceutical-current-good-manufacturing-practice-regulations.
参考FDA的指导文件:药品CGMP法规的质量体系方法的一般原则和方法https://www.fda.gov/regulatory-information/search-fda-guidance-documents/quality-systems-approach-pharmaceutical-current-good-manufacturing-practice-regulations。
Quality Unit Authority
质量部门的职权
Your inspectional history and significant findings in this letter indicate that your QU is not fully exercising its authority and/or responsibilities. Your firm must provide the QU with the appropriate authority and sufficient resources to carry out its responsibilities and consistently ensure drug quality.
企业的检查历史和本函中的重大发现表明企业的QU没有充分行使其权力和/或责任。贵公司必须向QU提供适当的权限和足够的资源，以履行其职责并持续确保药品质量。
Repeat Observations at Facility
设施重复观察结果
In a previous inspection conducted in 2018, FDA cited similar CGMP observations. You proposed specific remediation for these observations in your response. Repeated failures demonstrate that executive management oversight and control over the manufacture of drugs is inadequate.
在2018年进行的一次检查中，FDA引用了类似的CGMP观察结果。企业在回复中提出了针对这些观察结果的具体整改措施。屡次失败表明，行政管理层对药品生产的监督和控制不足。
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. We also recommend that the qualified consultant perform a comprehensive audit of your entire operation for CGMP compliance, and that the consultant evaluates the completion and efficacy of your CAPA before you pursue resolution of your firm’s compliance status with FDA.
基于我们在贵公司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。我们还建议有资质的顾问对企业的整个操作进行CGMP符合性的全面审计，在解决贵公司对FDA的合规状况之前，顾问评估企业CAPA的完成情况和有效性。
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.
使用顾问并不减轻贵公司遵守CGMP的义务。贵公司的执行管理层仍然负责解决所有缺陷，以确保持续遵守CGMP。
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.
本函中引用的违规行为并非贵公司设施中存在的所有违规行为。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发生其他违规行为。
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.
及时纠正任何违规行为。未能及时和充分解决此问题可能导致无需进一步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阻止其他联邦机构授予合同。
Failure to address violations may also cause FDA to withhold issuance of Export Certificates. 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.
未能解决违规问题也可能导致FDA拒绝签发出口证书。FDA可能会拒绝批准将贵公司列为药品制造商的新申请或补充申请，直到所有违规行为得到完全解决，并且我们确认企业符合CGMP。我们可能会重新检查，以验证企业已完成纠正措施，以解决任何违规行为。
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.
本函通知企业我们的调查结果，并为企业提供解决上述缺陷的机会。收到本函后，请在15个工作日内以书面形式回复本办公室。指定企业为解决任何违规行为并防止其再次发生所做的工作。在我们继续评估企业的活动和做法时，企业可以回复本函，提供更多信息供我们考虑。如果企业无法在15个工作日内完成纠正措施，请说明延迟的原因和完成时间表。
Send your electronic reply to ORAPHARM4_Responses@FDA.HHS.GOV or mail your reply to:
CDR Steven E. Porter, Jr.
Director, Division of Pharmaceutical Quality Operations IV
U.S. Food & Drug Administration
19701 Fairchild Road
Irvine, California 92612-2506
Please identify your response with unique identifier 616877.
If you have any further questions, please contact Nayan Patel, Compliance Officer, by email at Nayan.Patel1@fda.hhs.gov or by phone at (303) 236-3010.
Sincerely,
/S/
Steven E. Porter, Jr.
Program Division Director
Division of Pharmaceutical Quality Operations IV
