【GMP缺陷】g011 201406 FDA警告信(天津某药厂)
Warning Letter
CERTIFIED MAIL WL: 320-14-09
RETURN RECEIPT REQUESTED
June 10, 2014
Mr.Li Zhengen
General Manager
Tianjin Zhongan Pharmaceutical Co.Ltd.
No.188 Fukang Road
Xiqing District
Tianjin 300384
China
Dear Mr.Li Zhengen:
During our September 23-27, 2013 inspection of your pharmaceutical manufacturing facility, Tianjin Zhongan Pharmaceutical Co.Ltd., located at No.188 Fukang Road, Xiqing District, Tianjin, China, an investigator from the U.S.Food and Drug Administration (FDA) identified significant deviations of current good manufacturing practice (CGMP) for the manufacture of active pharmaceutical ingredients (APIs).These deviations cause your APIs to be adulterated within the meaning of Section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (the Act), 21 U.S.C.351(a)(2)(B), in that the methods used in, or the facilities or controls used for, their manufacture, proceing, packing, or holding do not conform to, or are not operated or administered in conformity with, CGMP.
We have conducted a detailed review of your firm’s response and note that it lacks sufficient corrective actions.
Our investigator observed specific deviations during the inspection, including, but not limited to, the following:
检查中所发现的缺陷包括，但不仅限于以下
1.Failure to adequately complete and follow written procedures for cleaning equipment and its release for use in API manufacture, and to maintain adequate records of major equipment usage.
未能完全遵守书面的设备清洁程序，将其放行用于原料药生产，主要设备使用记录不充分。
Your firm failed to ensure that employees adequately cleaned (b)(4) after use.Your (b)(4) equipment cleaning standard operating procedures (SOP-HE 063-02 - instruction 4.2.2.1, SOP-HE 064-02 – instruction 4.3.4.3, and SOP-HE 055-02 – instruction 4.2.1.1), require that employees visually inspect equipment after the cleaning proce.Our inspection found (b)(4) in the manufacturing workshop for (b)(4) with various levels of contamination and foreign objects inside, including what looked like the remains of a pen in one of the (b)(4).Your employees had labeled this equipment as clean.These (b)(4) are used for the manufacture of multiple APIs.
你公司未能保证员工对使用后的设备进行充分的清洁。XX设备清洁SOP中，要求员工在清洁完成后目视检查。我们检查中发现YY产品生产车间XX设备有不同程度的污染，设备里面发现异物，一台XX设备中的异物貌似一支笔，而你们的员工已将该设备标识为已清洁。这些XX设备用于多个原料药生产。
In addition, your firm’s production system did not maintain equipment logs or other documents that adequately record manufacturing operations performed on individual pieces of equipment.
另外，你公司的生产系统没有保持各设备的使用日志或其它文件，以充分记录各设备生产操作。
We note that your production operation supervisors and Quality Unit (QU) failed to detect and correct these deficient cleaning practices.
我们注意到你们的生产操作主管和质量部门未能察觉和纠正这些有缺陷的清洁操作。
Your response is inadequate because it does not addre the extent of these deficient practices throughout your facility, or the impact on the quality of your active ingredients.Additionally, you do not commit to maintain equipment logs or other documents that record all of the manufacturing operations performed on individual pieces of equipment.
你们的回复不够充分，因为回复中并没有说明这些缺陷操作在整个工厂普遍程度，以及对你们的活性成份质量的影响。另外，你们没有承诺保持设备日志，或其它文件记录各设备上所进行的生产操作。
In response to this letter, you should prepare and implement a corrective action plan sufficient to addre and prevent the recurrence of these deficiencies.The corrective action plan should detail the systemic improvements to be made, including, but not limited to, improved management oversight of cleaning operations, commitment to maintain individual equipment records (e.g., equipment logs), and training all relevant personnel in cleaning procedures.You should also demonstrate the sufficiency and effectivene of this corrective action plan.
在回复本警告信时，你们应该制订并实施一份纠正措施计划，对这些缺陷进行说明并防止其再次发生。该纠正措施计划应详细说明要进行的系统性提高，包括但不仅限于，提高管理层对清洁操作的监督，承诺维持各设备的记录（例如设备日志），对所有相关人员进行清洁程序培训。你还应该证明这些纠正措施计划的充分性和有效性。
2.Failure to conduct adequate change control to evaluate all changes that could affect the production and control of intermediates or APIs.
未能对所有可能影响中间体或原料药生产和控制的变更进行充分的变更控制，评估其影响。
a.Your firm failed to identify, document, evaluate, and approve several changes in production.Specifically, the equipment referenced in the flow chart in Drug Master File (DMF) (b)(4) for the manufacture of (b)(4) API differed from the equipment actually used.The DMF (b)(4) flow chart contains a step for (b)(4) that follows the (b)(4) step.Firm officials stated that your firm no longer conducted the (b)(4) during the manufacture of this API.You did not evaluate whether this change was appropriate based on its impact on product quality, or validate the effectivene of change implementation.In addition, you failed to conduct a change control investigation or document the significant changes in your manufacturing proce as required by your change control SOP SMP-QA 009-08.
你公司未能对生产中的几个变更进行识别、记录、评估和批准。尤其是，在DMF流程图中所指明用于生产XX原料药的设备，与实际生产所用设备不相符合。XX原料药的DMF中流程图有一步YY是在ZZ之后的，公司正式声明说你们在该原料药生产中已不再有YY那一步了。你们没有基于对产品质量影响情况评估该变更是否适当，或验证变更实施的有效性。另外，你们没有根据你公司变更控制SOP的要求进行变更控制调查，或在生产工艺中记录重大变更。
b.Your firm failed to conduct a change control investigation or document the significant changes in(b)(4) systems as required by your change control procedure SMP-QA 009-08.In the (b)(4) system used for the manufacture of (b)(4) APIs, you connected an (b)(4) device via (b)(4) hose to a port on the(b)(4) system piping ((b)(4)) at the entrance to holding tank #V20129.Furthermore, in the (b)(4) system used for the manufacturing of (b)(4) USP, you relocated the (b)(4) tank; you extensively altered the piping system throughout the facility; and you added an (b)(4) unit.Also, the drawings for both systems were not current.
你公司未能根据变更控制程序对XX系统中的重大变更进行变更控制调查或记录。在XX原料药生产所用的YY系统中，你们将设备ZZ通过软管连接至YY系统上的端口，接至贮罐#V20129的进料口。并且，在USP生产所用的YY系统中，你将MM贮罐重新定位，你们大面积地替换了整个工厂的管理系统，增加了一个NN单元。两个系统的图都与现状不符。
In your response, you state that you revised and implemented procedure SMP-QA-009-08 “SMP for Changes Control” on June 20, 2012.Although you had previously trained your employees in this procedure, the examples described above show that they failed to comply with it.Your response does not contain significant detail on how you will ensure compliance with procedure SMP-QA-009-08.In addition, the revised procedure indicates that it does not apply retroactively to existing equipment for which critical changes have been made without adequate change control.
在你们的回复中，你声称你们于2012年6月20日修订并实施了变更控制SMP。尽管你预先培训了你们的员工，上述例子说明你们并没法按程序操作。你们的回复未包括如何保证符合SMP程序的详细信息。另外，修订后的程序显示该程序并不适用于对已有设备进行追溯，但这些设备被作了关键性变更且并没有进行充分地控制。
In response to this letter, you should conduct a retrospective aement of all changes you have made to equipment and procedures used in the manufacture of all (b)(4) and (b)(4) APIs.Provide the report of this aement and the impact of these changes on product quality.Also, describe how your firm will correct the deficient change management system and ensure full implementation and compliance in the future.
对本警告信的回复中，你们应对你们用于XX原料药生产的设备变更进行回顾性评估，提交评估报告，说明这些变更对产品质量的影响。还要描述你公司如何纠正有缺陷的变更管理体系，保证将来全面实施并符合要求。
3.Failure to adequately review and investigate product deviations.
未能对产品偏差进行充分审核和调查
During our inspection, the investigator observed that the (b)(4) manufacturing workshop (b)(4), used for (b)(4)steps, contained significant particulate material, (b)(4) fluid, and a plastic tube (apparently from a pen) in the bottom of the various (b)(4).These (b)(4) were labeled as clean.The samples collected of the residues were insufficient to allow for an adequate investigation.You did not initiate an investigation prior to the investigator’s observation.Your investigation consisted of a high performance liquid chromatography (HPLC) aay test for(b)(4), the last API manufactured in that (b)(4), even though the sample was a complex mixture of (b)(4)phases.You conducted no further testing, and disposed of the sample after the HPLC analysis.
在检查中，检查人员发现用于YY生产步骤的XX生产车间有一个重要的微粉物料，MM流体，在该物料的底部有一个塑料的管子（显然是一支笔的部件），而这些NN被标示为清洁。所收集的残留物样品不足以进行充分的调查。你们未在检查官发现之前启动调查。你们的调查包括对XX的HPLC含量检测，在XX中生产最后一个原料药的检测，而未考虑样品是XX多相混合物。你们没有进行深入测试，在HPLC分析后即将样品处理了。
In your response, you state that you revised procedure SMP-QA-007-03 “SMP of Deviation” to addre these iues.Your response in insufficient because it does not describe or addre the extent of these problems, or their impact on the quality of your APIs.
在你们的回复中，你们声称你们修订了偏差程序SMP来处理上述问题。你们的回复是不充分的，因为在回复中没有描述或说明这些问题的程度，或其对你们原料药质量的影响。
In response to this letter, you should provide an aement of your deviations system.Provide a corrective action plan to ensure adequate investigations are conducted for all deviations.This includes, but is not limited to, hiring qualified personnel to perform investigations, improving the training program, maintaining a sufficient number of staff, conducting timely remediation, and improving deviation investigation procedures.
在对本警告信的回复中，你们应提交对你们的偏差系统的评估。提交一份纠正措施计划，以保证对所有偏差进行充分的调查。其中应包括，但不仅限于，聘请一名具备资质的人员实施调查，提升培训程序，维持足够的员工数量，进行及时的修正，提升偏差调查程序。
We also note that you did not adequately control your Certificates of Analysis (COAs).Your employees in the Foreign Trade Office generated and iued COAs for your products, and your Quality Unit did not control, or retain records of all such COAs.For example, the (b)(4) USP API, batch #(b)(4), was imported into the U.S.with a different COA than the one you retained on record for that batch.You should investigate this significant recordkeeping deficiency, and ensure control of all of the COAs you iue for your products.It is your responsibility to ensure that all of your documents are properly controlled and maintained in compliance with CGMPs.
我们还注意到你们没有对COA进行充分的控制。你们的外贸办公室的员工制作并签发产品COA，你们质量部门未进行控制，或对所有这些COA进行留存。例如，XXUSP版本原料药，批号YY，出口至美国，所出具的COA与你们保存在该批记录里的并不一致。你们应对记录保存方面该重大缺陷进行调查，保证你们签的发所有产品COA受控。你们有责任保证所有的文件均受到适当控制，并保持符合CGMP要求。
Your firm’s inadequate qualification of critical production equipment is also a concern.Specifically, you did not maintain current technical drawings of any (b)(4), or the (b)(4) production equipment used in manufacturing of(b)(4), and (b)(4) APIs.In addition, the qualification documents for these (b)(4) did not include important installation verification parameters such as material of construction, the volume capacity, (b)(4), configuration/location of (b)(4), or material of (b)(4).You should ensure that the contact surfaces of your production equipment are not reactive, additive, or absorptive so as to prevent impact on the quality of your products beyond appropriate limits.
你公司对关键生产设备的确认不够充分也是受到关注的问题。尤其是，你们不能维护所有XX或用于ZZ原料生产的YY设备图纸与实际一致。另外，这些XX的确认文件未包括对重要安装参数的确认，如结构材质、容积、XX、参数/定位或XX材质。你们应保证你们生产设备与产品接触表面不会与产品反应、不会吸附或溶出，以防止对你们产品产生超出适当限度的影响。
Executive management has the responsibility to ensure the quality, safety, and integrity of the products manufactured at your facility.A fundamental part of this responsibility is ensuring timely investigation and resolution of iues to prevent the distribution of defective products.FDA strongly recommends that your executive management immediately undertake a comprehensive evaluation of global manufacturing operations to ensure compliance with CGMP regulations.As part of these efforts, it is imperative that you build a robust quality system, and aure proper management oversight of operations and quality.Your inability to detect and prevent the above deficient practices, as well as other deficiencies found during the inspection, indicate that your current quality system is ineffective at achieving overall compliance with CGMP.
Due to continuing CGMP iues at your firm, we recommend you engage a third party consultant with appropriate CGMP expertise to ae your firm’s facility, procedures, procees, and systems to ensure that the APIs you manufacture have the appropriate identity, strength, quality, and purity.
鉴于你公司CGMP问题长期存在，我们推荐你们聘用一位具有适当CGMP专业知识的第三方顾问，可以接触你公司的设施、程序、工艺和系统，保证你们生产的原料药具有适当的均一性、含量、质量和纯度。
Please note that a guidance document entitled “Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients” (ICH CGMP guidance), prepared under the auspices of the International Conference on Harmonization (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use, describes current good manufacturing practice (CGMP) for the manufacture of APIs.The guidance is intended to help ensure that all APIs meet the standards for quality and purity they purport or are represented to poe.FDA considers the expectations outlined in ICH Q7, as well as alternatives intended to accomplish the same goals and provide an equivalent level of quality aurance, in determining whether a firm’s APIs have been manufactured, proceed, packed, and held according to current good manufacturing practice under section 501(a)(2)(B) [21 USC 351(a)(2)(B)] of the Act.To obtain the ICH CGMP guidance document for your reference, please refer to the following page of FDA’s website: http://www.fda.gov/cder/guidance/4286fnl.htm.
Furthermore, we remind you that you are required to submit any addition, deletion, or other change to the information in your Drug Master File (DMF) to the FDA under 21 CFR 314.420.Additionally, you are required to notify each person authorized to reference the information in your DMF of the pertinent changes.
The deviations cited in this letter are not intended to be an all-inclusive list of deviations that exist at your facility.You are responsible for investigating and determining the causes of the deviations identified above and for preventing their recurrence and the occurrence of other deviations.
If, as a result of receiving this warning letter or for other reasons, you are considering a decision that could reduce the number of finished drug products or active pharmaceutical ingredients produced by your manufacturing facility, FDA requests that you contact CDER\'s Drug Shortages Program immediately, as you begin your internal discuions, at drugshortages@fda.hhs.gov so that we can work with you on the most effective way to bring your operations into compliance with the law.Contacting the Drug Shortages Program also allows you to meet any obligations you may have to report discontinuances in the manufacture of your drug under 21 U.S.C.356C(a)(1), and allows FDA to consider, as soon as poible, what actions, if any, may be needed to avoid shortages and protect the health of patients who depend on your products.
Until all corrections have been completed and FDA has confirmed corrections of the deviations and your firm’s compliance with CGMP, FDA may withhold approval of any new applications or supplements listing your firm as an API manufacturer.In addition, your failure to correct these deviations may result in FDA refusing admiion of articles manufactured at Tianjin Zhongan Pharmaceutical Company Limited located at 188 Fukang Road, Xiqing District, Tianjin, China into the United States under Section 801(a)(3) of the Act, 21 U.S.C.381(a)(3).The articles may be subject to refusal of admiion pursuant to Section 801(a)(3) of the Act, 21 U.S.C.381(a)(3), in that the methods and controls used in their manufacture do not appear to conform to CGMP within the meaning of Section 501(a)(2)(B) of the Act, 21 U.S.C.351(a)(2)(B).
Within fifteen working days of receipt of this letter, please notify this office in writing of the specific steps that you have taken to correct and prevent the recurrence of deviations, and provide copies of supporting documentation.If you cannot complete corrective actions within fifteen working days, state the reason for the delay and the date by which you will have completed the corrections.Additionally, if you no longer manufacture or distribute the APIs at iue, provide the dates and reasons you ceased production.Please identify your response with FEI # 3003671775.
Please send your reply to:
Joseph Duran
Compliance Officer
FDA/CDER/OC/OMPQ/DIDQ
10903 New Hampshire Ave
White Oak Building 51, Room 4237
Silver Spring, MD 20993
Sincerely, /S/
Thomas Cosgrove, J.D.Acting Director
Office of Manufacturing and Product Quality
Office of Compliance
Center for Drug Evaluation and Research
Warning Letter to Yunnan Hande BioTech[1]. Co. Ltd (中英对照)（整理）
