FDA警告信：常州颐成化工&奥地利Schrofner Cosmetics GmbH
翻译：julia 来源：Julia法规翻译
ViaUPS
Warning Letter 320-18-23
Return Receipt Requested
January 2, 2018
Ms. Yan Chen
General Manager
Yicheng Chemical Corporation
Fuchen Garden, Suite 1-402,Xinbei District
Changzhou, Jiangsu, 213001
China
Dear Ms. Chen:
The U.S. Food and DrugAdministration (FDA) inspected your drug manufacturing facility, YichengChemical Corporation at Fuchen Garden, Suite 1-402, Xinbei District, Changzhou,Jiangsu, from July 17 to 21, 2017.
美国FDA于2017年4月6-14日检查了你们位于江苏常州新北区府琛花园1-402的常州颐成化工有限公司生产场所。
This warning letter summarizessignificant deviations from current good manufacturing practice (CGMP) foractive pharmaceutical ingredients (API).
本警告信总结了API生产严重违反CGMP的行为。参见21CFR第210和211部分。
Because your methods,facilities, or controls for manufacturing, processing, packing, or holding donot conform to CGMP, your API are adulterated within the meaning of section501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), 21U.S.C. 351(a)(2)(B).
由于你们的API生产、加工、包装或保存的方法、场所或控制不符合CGMP要求，你们的API根据FDCA的501(a)(2)(B)以及21 U.S.C. 351(a)(2)(B)被认为是掺假药品。
We reviewed your August 4,2017, response in detail. It lacks sufficient corrective actions.
我们已详细审核了你公司2017年8月4日的回复。它缺乏足够的纠正措施。
During our inspection, ourinvestigator observed specific deviations including, but not limited to, thefollowing.
检查期间，我们的调查人员发现的具体问题包括但不仅限于以下：
1. Failureto package (b)(4) drugs (including (b)(4) and (b)(4)) and other drugs underappropriate conditions to avoid potential cross-contamination. 未能在适当条件下包装XX药品（包括XX和YY）和其它药品以避免潜在交叉污染
Your firm failed to useseparate facilities to manufacture (b)(4) and (b)(4) API. Yourmanagement stated that you weighed and repackaged (b)(4) (for example, (b)(4)USP and (b)(4) EP) and (b)(4) API, in the same room usingnon-dedicated equipment.
你公司未能使用单独的场所来生产XX和YY原料药。你们的管理人员声称你们在同一房间使用非专用设备称重和重新包装了XX（例如XX USP和XX EP）和XX原料药。
In your response, you statedthat you would continue to use non-dedicated facilities, and will designate atime to handle, repack, and relabel (b)(4) in an area which would becleaned before and after such operations.
在你们的回复中，你们声称你们不会再使用非专用设备，会指定在同一区域内处置、重新包装和重新标签XX的时间，该区域在每次操作前后都会进行清洁。
Your response was inadequate.Cleaning cannot substitute for proper segregation. Cross-contamination withyour (b)(4) can initiate life-threatening allergic reactions or otherdrug-induced (b)(4) reactions. Your current practices demonstrate anunacceptably high risk of (b)(4) API cross-contamination into other APIrepackaged at your facility. You should conduct all (b)(4) manufacturingactivities in dedicated, segregated facilities with separate air handlingsystems and production equipment.
你们的回复是不充分的。清洁不能替代恰当的隔离。与你们的XX的交叉污染可能会发生致命的过敏反应，和其它药源性XX反应。你们当前的做法显示出XX原料药对其它在你们工厂重新包装的原料药具有无法接受的交叉污染高风险。你们应在具有单独空气处理系统和生产设备的专用、隔离的工厂进行所有XX的生产活动。
No safe level of (b)(4) contaminationhas been determined. Susceptible patients exposed to extremely low levels of(b)(4)and other (b)(4) may suffer severe allergic responses. Such low levelsare difficult to detect with current analytical methods.
XX的污染安全水平并未确定。易感患者暴露于极低水平的XX和其它都可能导致严重的过敏反应。在当前分析方法下此低水平是难以检出的。
We recommend that youretrospectively assess whether any (b)(4) API packaged by your firm werecontaminated with (b)(4). However, be mindful that any test intended todetect (b)(4) contamination provides only limited confidence, because ofmethod limitations and sample size. This low detectability, the severe risk topatients, and the limitations of production controls to precludecross-contamination underscore the importance of meeting the minimum standardof manufacture in completely separate facilities.
我们建议你们回顾评估是否你们公司所包装的全部XX原料药均受到XX的污染。由于受到方法限制和样品量限制，要考虑所有检出XX污染的测试企图只能提供有限的可信度。低的可检出度、对患者的严重风险，以及排队交叉污染的生产控制局限性使得在完全隔离工厂中符合最低标准的重要性更为突出。
For additional information,please refer to our guidance for industry, (b)(4)
更多信息参见我们的行业指南。
If you continue to repackage (b)(4)products, indicate how you will assure that drugs manufactured at yourfacility will be free from (b)(4) contamination. In your responseto this letter include your plans for decontaminating, renovating, andrequalifying your facility. Include decontamination agent(s), youranalytical methodology for environmental testing, your acceptance criteria, andthe studies you used to support your decontamination plan.
如果你们还要继续重新包装XX产品，请说明你们要如何确保在你们工厂所生产的药品不会受到XX的污染。在你们对此函的回复中，请包括你们清除污染、重新改造和重新确认你们工厂的计划。包括除污染剂、你们的环境测试分析方法学、你们的可接受标准和你们用以支持你们除污染计划的研究。
If you continue to repackageany (b)(4) products, submit your comprehensive plan for completesegregation of these products from (b)(4). Furthermore, include yourproposed action plan to address the hazards posed by any drugs with potential (b)(4)contamination.
如果你们要继续重新包装任何XX产品，请提交你们将这些产品与XX完全隔离的全面计划，包括你们提议的处理受到XX潜在污染所有药品而具有的危害的行动计划。
2. Failureof your quality unit to review batch production records prior to distributionof an API batch. 你们质量部门未能在API批准放行之前审核批生产记录
Your firm failed to haverepackaging batch records. Furthermore, your quality unit lacked writtenprocedures for API repackaging batch review, approval, and release prior todistribution.
你们公司没有重新包装批记录。另外，你们质量部门缺乏在销售之前对API重新包装批审核、批准和放行的书面程序。
In response to this letter,provide your repackaging batch review and release procedure which ensures thatAPI repackaged at your facility are in compliance with CGMP.
在回复此函时，请提交你们的批重新包装审核和放行程序，确保你工厂重新包装的API符合CGMP。
3. Failureto maintain complete traceability of API in commercial distribution. 未能维护商业销售中API的完整可追溯性
Your firm lacked documentationor procedures to ensure that each batch can be traced from your API suppliers,through your repackaging operations, and into commercial distribution.
你公司缺乏文件记录或程序来确保每批均可从你的API供应商追溯到你们的重新包装操作，直到商业化销售。
In response to this letter,provide your procedure to ensure the integrity, traceability, and transparencyof your API supply chain.
在回复此函时，请提交你们的程序以确保你们API供应链的完整性、可追溯性和透明度。
CGMP consultant recommended CGMP顾问建议
Based upon the nature of thedeviations we identified at your firm, we strongly recommend engaging aconsultant qualified to evaluate your operations and to assist your firm inmeeting CGMP requirements. Your use of a consultant does not relieve yourfirm’s obligation to comply with CGMP. Your management remains responsible forfully resolving all deficiencies and ensuring ongoing CGMP compliance.
依据违规情况，我们强烈建议你们使用一位符合21CFR211.34要求的顾问来协助你们公司符合CGMP要求。你们使用顾问并不解除你们公司符合CGMP的义务。你们公司的高级管理层仍负有义务全面解决所有缺陷，确保持续CGMP符合性。
Additional API CGMP guidance
FDA considers the expectationsoutlined in ICH Q7 in determining whether API are manufactured in conformancewith CGMP. See FDA’s guidance document, Q7 Good Manufacturing PracticeGuidance for Active Pharmaceutical Ingredients, for guidance regarding CGMPfor the manufacture of API, athttps://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM073497.pdf.
FDA在确定API生产是否符合CGMP要求时参照的是ICH Q7中所列要求。更多指南信息参见上述网址。
Conclusion结论
Deviations cited in thisletter are not intended as an all-inclusive list. You are responsible forinvestigating these deviations, for determining the causes, for preventingtheir recurrence, and for preventing other deviations.
此函中所引用的违规并不是全部。你们有责任对这些偏差进行调查，确定原因，防止其再次发生，防止其它偏差的发生。
FDA placed your firm on ImportAlert 66-40 on August 11, 2017.
FDA已于2017年8月1日将你公司置于进口禁令66-40清单中。
Until you correct all deviationscompletely and we confirm your compliance with CGMP, FDA may withhold approvalof any new applications or supplements listing your firm as a drugmanufacturer.
在贵公司未能完成所有偏差纠正并且由我们确认你们符合CGMP之前，FDA可能会搁置所有将你公司列为药品生产的新申报和增补申报的批准。
Failure to correct thesedeviations may also result in FDA continuing to refuse admission of articlesmanufactured at Yicheng Chemical Corporation at Fuchen Garden, Suite 1-402,Xinbei District Changzhou, Jiangsu into the United States under section801(a)(3) of the FD&C Act, 21 U.S.C. 381(a)(3). Under the same authority,articles may be subject to refusal of admission, in that the methods andcontrols used in their manufacture do not appear to conform to CGMP within themeaning of section 501(a)(2)(B) of the FD&C Act, 21 U.S.C. 351(a)(2)(B).
未能纠正这些偏差可能还会导致FDA依据FDCA第801(a)(3)条和21 U.S.C. 381(a)(3)拒绝接受在上述地址生产的产品进入美国。
After you receive this letter,respond to this office in writing within 15 working days. Specify what you havedone since our inspection to correct your deviations and to prevent theirrecurrence. If you cannot complete corrective actions within 15 working days,state your reasons for delay and your schedule for completion.
在收到此函后，请在15个工作日内回复至本办公室。在回复中说明自从检查后，你们做了哪些工作来纠正你们的偏差，防止其再次发生。如果不能在15个工作日内完成纠正措施，说明延迟的原因以及完成计划。
Send your electronic reply to CDER-OC-OMQ-Communications@fda.hhs.govor mail your reply to:
Joseph Lambert,Pharm.D.
Compliance Officer
U.S. Food and Drug Administration
White Oak Building 51, Room4359
10903 New Hampshire Avenue
Silver Spring, MD 20993
USA
Please identify your responsewith FEI 3004102971.
Sincerely,
/S/
Francis Goodwin
Acting Director
Office of ManufacturingQuality
Office of Compliance
Center for Drug Evaluation andResearch
FDA警告信：奥地利Schrofner Cosmetics GmbH
ViaUPS
Warning Letter 320-18-22
December 20, 2017
Mr. Stefan Schrofner
CEO
Schrofner Cosmetics Gmbh
Robiningstrabe 26a
Salzburg, 5020
Austria
Dear Mr. Schrofner:
The U.S. Food and DrugAdministration (FDA) inspected your drug manufacturing facility, Schrofner Cosmetics GmbH, at Robiningstrabe 26a, Salzburg, from July 17–19, 2017.
美国FDA于2017年4月6-14日检查了你们位于奥地利萨尔斯堡的Schrofner Cosmetics GmbH生产场所。
This warning letter summarizessignificant violations of current good manufacturing practice (CGMP)regulations for finished pharmaceuticals. See 21 CFR, parts 210 and 211.
本警告信总结了制剂生产严重违反CGMP的行为。参见21CFR第210和211部分。
Because your methods,facilities, or controls for manufacturing, processing, packing, or holding donot conform to CGMP, your drug products are adulterated within the meaning ofsection 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (FD&CAct), 21 U.S.C. 351(a)(2)(B).
由于你们的制剂生产、加工、包装或保存的方法、场所或控制不符合CGMP要求，你们的制剂根据FDCA的501(a)(2)(B)以及21 U.S.C. 351(a)(2)(B)被认为是掺假药品。
We reviewed your responsereceived on August, 8, 2017, in detail. Your response did not provide adequatecorrective actions for any of the observations made during the inspection.
我们已详细审核了你公司2017年8月8日的回复。你们的回复中并未提交针对检查期间所发现缺陷的充分纠正措施。
During our inspection, ourinvestigators observed specific violations including, but not limited to, thefollowing.
检查期间，我们的调查人员发现的具体问题包括但不仅限于以下：
1. Your firmfailed to establish an adequate quality control unit and procedures applicableto the quality control unit with the responsibility and authority to approve orreject all components, drug product containers, closures, in-process materials,packaging materials, labeling, and drug products (21 CFR 211.22(a) and (d)). 你公司未能建立足够的质量控制部门和适用于质量部门的程序，赋予其职责和权力批准或拒绝所有组分、药品容器、密闭器、中间体、包材、标签和药品(21 CFR211.22(a) and (d))。
Your firm lacked an adequatequality control unit.
你们公司缺乏足够的质量控制部门。
You also failed to establishwritten procedures for numerous functions of the quality unit. For example,there were no procedures or documentation for the following manufacturingoperations.
你们没有为许多的质量部门职责建立书面程序。例如，以下生产操作均没有程序或文件记录：
Process validation 工艺验证
Cleaning validation 清洁验证
Annual product quality review 年度产品质量回顾
Packaging and labeling operations 包装和标签操作
Line clearance 清场
Calibration and use of measurement devices校正和使用测量装置
Sampling 取样
Change control 变更控制
Deviations偏差
Out-of-Specification investigations OOS调查
2. Your firmfailed to establish and follow adequate written procedures for the preparationof master production and control records designed to assure uniformity frombatch to batch (21 CFR 211.186(a)). 你们公司未建立和遵守足够的书面程序制订主生产和分析记录，用以确保批与批之间的一致性(21 CFR211.186(a)).
Your firm did not prepare anymaster production records or batch production records for your drug product, (b)(4).Without master batch records, you cannot assure the uniformity of your drugproducts from batch to batch.
你们公司未为你们的药品XX制订任何的主生产记录和批生记录。没有主批记录，你们不能确保你们药品的批间均一性。
3. Your firmfailed to have, for each batch of drug product, appropriate laboratorydetermination of satisfactory conformance to final specifications for the drugproduct, including the identity and strength of each active ingredient, priorto release (21 CFR 211.165(a)).你们公司未对每批药品进行适当的化验室测试，确保其在放行之前符合药品的最终标准，包括每种活性成分的鉴别和剂量(21CFR 211.165(a))。
Your firm released yourfinished drug product, (b)(4), without testing for the identity andstrength of the active ingredient, (b)(4). Without this testing youcannot determine if your drug products conformed to specifications.
你们公司放行了你们的制剂产品XX，而没有检测其活性成份XX的鉴别和剂量。没有这些测试，你们无法确定你们的药品是否符合标准要求。
4. Your firmfailed to test samples of each component for conformity with all appropriatewritten specifications for identity, purity, strength, and quality (21 CFR211.84(d)(1) & (2)).你们公司未能实施至少一项检测来核查药品的每种成分的鉴别。你们公司也没有对每种成分进行检查，确认其符合所有适当的书面纯度、含量和质量标准(21CFR 211.84(d)(1) & (2))。
Your firm failed to testincoming active pharmaceutical ingredients and other components you use inmanufacturing(b)(4) to ensure that each component met specifications.You relied on your suppliers’ certificates of analysis for the identity of eachincoming component without performing one specific identity test.
你们公司未能测试进厂原料药以及其它你们用于XX生产的组份，以确保每种成分均符合标准。你们依赖于你们的供应商COA中进厂组份的鉴别，而未实施特定的鉴别测量。
Conclusion结论
Violations cited in thisletter are not intended as an all-inclusive list. You are responsible forinvestigating these violations, for determining the causes, for preventingtheir recurrence, and for preventing other violations.
此函中所引用的违规并不是全部。你们有责任对这些偏差进行调查，确定原因，防止其再次发生，防止其它偏差的发生。
FDA placed your firm on ImportAlert 66-40 on October 20, 2017.
FDA已于2017年10月20日将你公司置于进口禁令66-40清单中。
Until you correct allviolations completely and we confirm your compliance with CGMP, FDA maywithhold approval of any new applications or supplements listing your firm as adrug manufacturer.
在贵公司未能完成所有偏差纠正并且由我们确认你们符合CGMP之前，FDA可能会搁置所有将你公司列为药品生产的新申报和增补申报的批准。
Failure to correct theseviolations may also result in FDA continuing to refuse admission of articlesmanufactured at Schrofner Cosmetics Gmbh, Robiningstrabe 26a, Salzburg, intothe United States under section 801(a)(3) of the FD&C Act, 21 U.S.C.381(a)(3). Under the same authority, articles may be subject to refusal ofadmission, in that the methods and controls used in their manufacture do notappear to conform to CGMP within the meaning of section 501(a)(2)(B) of theFD&C Act, 21 U.S.C. 351(a)(2)(B).
未能纠正这些偏差可能还会导致FDA依据FDCA第801(a)(3)条和21 U.S.C. 381(a)(3)拒绝接受在上述地址生产的产品进入美国。
After you receive this letter,respond to this office in writing within 15 working days. Specify what you havedone since our inspection to correct your violations and to prevent theirrecurrence. If you cannot complete corrective actions within 15 working days,state your reasons for delay and your schedule for completion.
在收到此函后，请在15个工作日内回复至本办公室。在回复中说明自从检查后，你们做了哪些工作来纠正你们的偏差，防止其再次发生。如果不能在15个工作日内完成纠正措施，说明延迟的原因以及完成计划。
Send your electronic reply to CDER-OC-OMQ-Communications@fda.hhs.govor mail your reply to:
Chelsea Sealey
Compliance Officer
U.S. Food and DrugAdministration
White Oak Building 51, Room4359
10903 New Hampshire Avenue
Silver Spring, MD 20993
USA
Please identify your responsewith FEI 3010632712.
Sincerely,
/S/
Francis Godwin
Acting Director
Office of ManufacturingQuality
Office of Compliance
Center for Drug Evaluation andResearch