Warning Letter to Yunnan Hande Bio-Tech[1]. Co. Ltd (中英对照).doc

Warning Letter to Yunnan Hande Bio-Tech. Co. Ltd.Dear Ms. Lei:During our May 17-21, 2010 inspection of your active pharmaceutical ingredient (API) manufacturing facility, Yunnan Hande Bio-Tech Co., Ltd., located at Jinding Tech-Zone, No. 3 Platform, Kunming, China, investigator(s) from the Food and Drug Administration (FDA) identified significant deviations from Current Good Manufacturing Practice (CGMP) for the manufacture of APIs. These deviations cause your API(s) 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, processing, packing, or holding do not conform to, or are not operated or administered in conformity with CGMP. We have reviewed your firms response of June 2, 2010, and note that it lacks sufficient corrective actions.Specific deviations observed during the inspection include, but are not limited, to the following:1. Failure to thoroughly investigate complaints for APIs batches that do not meet the United States Pharmacopeia (USP) compendial requirements that may have been associated with the specific failure or discrepancy. In addition, your investigation was not extended to other batches that may also be affected.During the review of a customer complaint for lot (b)(4), related to an out-of-specification in the optical rotation test, our inspection team noticed that the optical rotation test was conducted in a room with no temperature control during the sample analysis. Your firm does not monitor the temperature of the sample inside the polarimeter chamber as required by the USP chapter . Your procedure DM No. 21-3, “Optical Rotation of (b)(4),” requires that a temperature correction factor be used when the reading is above or below 20; however you failed to apply the correction factor to any of the lots tested. Your quality unit confirmed this discrepancy during our inspection. You indicated that your firm monitors the sample temperature when conducting the optical rotation test by annotating the air condition thermostat reading of the room. However, our investigators found that the temperature of the Quality Control (QC) laboratory, where the optical rotation is conducted, is not controlled because there is no air conditioner in the room. Please clarify this discrepancy in your response to this letter.Because your optical rotation testing was not conducted under the required environmental conditions, the test results generated may be inaccurate. In your response, you indicate that the temperature in the sampler (and in the room) will be maintained at 20 0.5. However, USP requires that the temperature of the sample be maintained at 25C 0.5 during the analysis. We recommend that you revise your procedures accordingly.Although the above test is not conducted in accordance to the USP requirements, we are concerned that your Certificate of Analysis (COA) for (b)(4) API indicates that: “we hereby certify that the (b)(4) Drug Substance manufactured by Yunnan Hande Bio-Tech Co Ltd is meeting the quality specification of US Pharmacopeia.” This is a repeat observation from our 2004 inspection where investigators found USP was not followed.In your response, please provide evidence that all lots of (b)(4) API manufactured and within expiration comply with the USP compendial requirements. Also, indicate whether you intend to issue new COAs to your customer(s) and what actions you intend to implement in those cases where the USP specification is not met. Your firm needs to implement adequate corrective and preventive actions to ensure that the QC personnel are qualified to conduct all analyses in your laboratory, and that those supervising laboratory operations are qualified to ensure scientifically rigorous operations.2. Failure to have adequate procedures for the reprocessing of API batches and stability data to ensure that the API batches are not adversely affected by the formation of by products and overreactive materials.Your SOP 5018-9, “Leftover Products Processing Procedure,” allows for the manufacture of (b)(4) API batches using reserved or retained samples, batch tails ends, and expired (b)(4) API. The reserved samples are (b)(4) under a new lot number. You fail to demonstrate that the quality of the new batch is not affected throughout the shelf life of the API. We are also concerned that you allow the reuse of retain and expired samples maintained for (b)(4) years (or up to (b)(4) years for lot distributed) without determining if the quality of the API has been adversely affected due to the formation of degradants or impurities. You also fail to have an evaluation of the individual batches prior to being (b)(4) into a new batch.In response to this letter, provide a retrospective evaluation of the lots that have been manufactured using the above practice. Include evidence that your decision to manufacture (b)(4) using expired and retain samples, (b)(4) tails ends batches is preceded by a careful evaluation to ensure that the quality of the API is not adversely affected due to the potential formation of byproduct and over-reacted material. Note your firm should ensure that the manual process used to produce these batches is validated and adequately described in the approved DMF.3. Failure to have an adequate performance qualification (calibration) program for the QC laboratory instruments.Your HPLC calibration lacks a carry over test (sample injection residual test), sample energy (intensity of light source), and lamp use hours determination. You fail to challenge the analytical balances for minimum weight, measurement for uncertainty, and drift value. In addition, you do not calibrate the Karl Fisher syringe used during (b)(4) API water content analysis.Your firm also fails to maintain raw data associated with the re-qualification and calibration of your laboratory instruments. During the inspection the investigators were informed that the annual requalification and calibration of your laboratory equipment (e.g., HPLC, GC, polarimeter, and analytical balance) is performed by the (b)(4). However, you were unable to provide raw data or documentation regarding the qualification and calibration of your instruments and data to demonstrate that your quality unit reviewed and approved the work performed by your contractor.During our inspection, our investigators learned that the calibration program does not include parameters to challenge the precision and accuracy of the laboratory instruments. Your firm acknowledged that your firm lacks a written procedure describing the qualification and calibration of the laboratory equipment.We are concerned that the inspection of 2004 reported similar deficiencies related to the qualification of your laboratory equipment. In your response, please provide information to show that the above deficiencies have not adversely affected the accuracy of the analytical results used to release your APIs.4. Failure to have adequate analytical procedures designed to assure that your APIs conform to appropriate specification. For example, a. The FTIR assay does not include a (b)(4) USP standard during the performance of the identification analysis nor are the critical analytical parameters documented.Your firm does not concurrently analyze the FTIR samples with a (b)(4) reference standard. Instead, you analyze the sample against a spectrum stored in the memory of the FTIR. During our inspection, you were unable to provide data to show when and how you prepared and qualified the FTIR spectrum standard.Additionally, the investigators found that the FTIR parameter (e.g. number of samples scanned, resolution, and bean slitter) are not documented in your laboratory record. Moreover, the expiration date of (b)(4) reagent lot (b)(4), used during the sample preparation is unknown. Also SOP DM No. 02-04 does not include instructions to (b)(4) the (b)(4) reagent under a (b)(4), which is an activity conducted by the QC technicians.b. The suitability of your testing method for your residual solvent determination has not been demonstrated and verified. Additionally, your acceptance criteria are different to the established by the USP.Your system suitability test requires that (b)(4) injections of standard be performed and that a Relative Standard Deviation (RSD) of (b)(4)% be met in order for the test to be acceptable. This acceptance criterion is contrary to the USP requirement chapter . During our inspection, you were unable to provide validation data to support your current RSD criteria. Your response is inadequate in that you failed to provide scientific rationale to justify the change in your analytical method for system suitability requirements. In response to this letter, please provide a valid % RSD and the analytical data to support it.The deviations detailed in this letter are not intended to be an all-inclusive statement 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 you wish to continue to ship APIs to the United States, it is the responsibility of your firm to ensure compliance with all U.S. standards for CGMP and all applicable U.S. laws and regulations.Until all corrections have been completed and FDA has confirmed corrections of the deviations and your firms compliance with CGMP, FDA may withhold approval of any new applications or supplements listing your firm as an API manufacturer. In addition, failure to correct these deviations may result in FDA refusing admission of articles manufactured at Yunnan Hande Bio-Tech Co., Ltd., Kunming, Peoples Republic of China, 650033 into the United States. The articles are subject to refusal of admission 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 Current Good Manufacturing Practice 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 deviations. Include an explanation of each step being taken to prevent the recurrence of deviations and copies of supporting documentation. If you cannot complete corrective action within fifteen working days, state the reason for the delay and the date by which you will have completed the correction. Additionally, your response should state if you no longer manufacture or distribute (b)(4) API, and provide the date(s) and reason(s) you ceased production. Please identify your response with FEI # 2002808537.在我们2010年，5月17-21对你们API生产设施的检查中，（Yunnan Hande Bio-Tech Co., Ltd. located at Jinding Tech-Zone, No. 3 Platform, Kunming, China），FDA检查员发现了API生产中与cGMP严重偏离的现象。在FDA 21 U.S.C. 351(a)(2)(B)中501(a)(2)(B)部分定义中，你们生产、加工、包装中使用方法、生产设备或控制方法与cGMP不符的这些偏差导致你们的API掺杂不纯。我们评阅了你们公司2010年6月2日的回复，注意到其缺少足够的整改措施。在审查中观察到偏差包括，但是不仅仅为以下几条：1未能彻底调查与USP要求不符合的API批次，另外，你们的调查没有拓展到其他有可能受影响的批次。在批次(b)(4)用户投诉的审查中，相关的一个不合格的旋光度测试中，我们的审查小组注意到旋光度测试的样品分析在一个没有温度控制的房间中进行。你们公司不监控旋光仪中样品温度，而在USP中要求监控样品温度。你们的操作法DM No. 21-3，在温度低于20条件下读数时，“(b)(4)的旋光度”要求使用温度校正因子，但是你们在任何批次的检测中均没有使用校正因子。你们质量部门在我们的审查中确认了这一点。你们指出在进行旋光度测试中，通过标注空调温度计读数来进行了样品温度的监测，但是我们的审查员发现进行旋光度测试的QC实验室的温度没有受到控制，因为在房间里面没有安装空调。请在回复信中对其进行解释。因为你们的旋光度测试没有在要求的环境条件下进行，得到的测试结果有可能不准确。在你们的回复中，你们指出在取样器以及房间中的温度可以保持20 0.5，但是USP中要求在分析过程中样品温度应该保持在25 0.5。我们建议你们相应的修订你们操作法。尽管上述的测试没有根据USP的要求进行，但在你们的API(b)(4)COA指出“我们在此保证由Yunnan Hande Bio-Tech Co Ltd生产的原料(b)(4)符合了USP的质量规范”。在2004年的审查中也出现了这种情况，当时审查员发现你们不符合USP的要求。在你们的回复中，请提供所有所生产的和在有效期内的API(b)(4)批次符合USP要求的证据。同样的，指出你们是否有意向为你们的用户提供新的COAs以及你们将采取何种措施来应对不符合USP规范的情况。你们公司需要实施合适的校正和预防性措施来保证QC员具有足够的资格再实验室中进行所有的分析测试，并且那些监控实验室的措施能够保证科学的严格操作。2没有合理的措施保证API批次的重加工和稳定性数据，保证API批次不受副产物和过度活性物质的干扰。你们的SOP 5018-9“剩余产品加工法”，允许API(b)(4)批次的生产使用保留的样品、批尾料和过期的(b)(4)API。保留的样品为新批号下的(b)(4)。你们没有很好的证明新批次的质量在保质期内不受影响。我们还注意到，在XXX年至XXX年期间销售的产品中,你们将过期的样品及留样样品重新进行了回收利用而没有确定API的质量是否受到产生的降解产物或杂质的影响。你们同样没有对单独的批次在成为(b)(4)进入到新批次之前进行评价。在对于这封信的回复中，请提供一个回顾性的已生产批次的评价。包括你们决定使用过期的及留样样品生产(b)(4)的证据，以及(b)(4)尾料批次使用前经过仔细的评价以保证API的质量不受到潜在副产物和过度反应的物料的不良影响的证据。标注你们公司应该保证人工操作生产的批次是有效的，并且在批准DMF中进行了正确的描述。3QC实验室仪器没有进行正确的性能资格认证（校准）程序。你们的HPLC校准缺少了CARRY OVER的测试（样品进样残留测试），样品能量（灯光强度），和灯使用小时数的确定。你们没有对分析天平的最小称量量、不确定度和漂移值进行确定和测试。另外，你们没有校准在(b)(4)API的水分测定中使用的卡氏注射器。你们公司同样没有保留(b)(4)使用的实验室仪器（如HPLC、GC、旋光仪和分析天平）重新鉴定和校准的相关原始资料。你们不能够提供关于仪器