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資訊詳情

案例分析 | 印度某藥企收到FDA警告信!

分類:
行業新聞
作者:
發布時間:
2020/03/02 14:46
近日,FDA發布了對印度GPT GPT Pharmaceuticals Pvt. Ltd的警告信,具體問題如下:
1、QU未能確保:
對殘留溶劑OOS檢測結果進行充分調查;
對含量和雜質檢測方法進行驗證;
具備充分的記錄和報告文件規范,包括文件控制。
2、OOS后復測,獲得合格結果,認為原始檢測的OOS結果不具有代表性,在沒有充分科學論證前提下就忽略了初始的OOS結果。
3、生產設備的產品接觸的表面有肉眼可見鐵銹、凹痕和刮痕。
4、分析人員使用安捷倫服務賬號登錄,具有所有管理權限,可以中斷HPLC運行,卻無法追蹤至具體人員。
5、未以適當的時間間隔清潔、維護和(藥品屬性需要時)消毒和/或滅菌設備和工器具,以防止發生故障或污染從而改變藥品的安全性、鑒別、含量、質量或純度使其超出官方或其它既定要求。
6、未對計算機或相關系統執行適當的控制。
7、HPLC測試刪除、中斷和單針運行。
問題分析:
1、未能確保對含量和雜質檢測方法進行驗證。
導致藥品不合格的因素有很多,例如自身雜質超標、含量比例不合格、生產過程受到污染等。
企業應該確保潔凈室潔凈度符合要求,潔凈檢測儀器的選擇也尤為重要。一般來說,潔凈室等級要求較高的企業,建議使用吉林潔凈度在線監測系統,實時監測潔凈室環境。
2、生產設備的產品接觸的表面有肉眼可見鐵銹、凹痕和刮痕。
(1)生銹的原因可能是環境濕度超過了臨界濕度,金屬銹蝕的速度加快;
(2)凹痕和刮痕可能是搬移產品時候產生的,并且掉落的金屬微粒,可能會對潔凈室造成污染。
3、未以適當的時間間隔清潔、維護和(藥品屬性需要時)消毒和/或滅菌設備和工器具。
潔凈室是需要定期進行檢測各項指標是否合格,檢測儀器也需要進行自檢,例如吉林塵埃粒子計數器和吉林浮游菌采樣器在使用前都有規定的自檢時間。
警告信原文及翻譯
Warning Letter 320-20-13
December 17, 2019
Dear Mr. Adityan:
The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, GPT Pharmaceuticals Pvt. Ltd., FEI 3008311641, at Plot No. 6/3, Road No. 11, Nacharam, Hyderabad, from June 24 to28, 2019.
美國FDA于XXXX年XX月XX日至XX月XX日檢查了你們位于XX的XXXX生產場所。
This warning letter summarizes significant violations of current good manufacturing practice (CGMP) regulations for finished pharmaceuticals. See Title 21 Code of Federal Regulations (CFR), parts210 and 211 (21 CFR parts 210 and 211).
本警告信總結了制劑生產嚴重違反CGMP的行為。參見21CFR第210與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).
由于你們的制劑生產、加工、包裝或保存的方法、場所或控制不符合CGMP要求,你們的藥品根據FDCA的501(a)(2)(B)以及21 U.S.C. 351(a)(2)(B)被認為是摻假藥品。
We reviewed your July 17, 2019, response to our Form FDA 483 in detail and acknowledge receipt of your subsequent correspondence.
我們已詳細審核了你公司XXXX年XX月XX日的回復,并此告知已收到后續通信。
During our inspection, our investigators observed specific violations including, but not limited to, the following.
檢查期間,我們的調查人員發現的具體問題包括但不僅限于以下:
1.  Your firm’s quality control unit failed to exercise its responsibility to ensure drug products manufactured are incompliance with CGMP, and meet established specifications for identity, strength, quality, and purity (21 CFR 211.22). 
貴公司的質量控制部門未能履行其職責,確保藥品生產符合CGMP要求,以及符合既定的鑒別、含量、質量和純度標準(21 CFR 211.22)。
During the inspection, our investigators observed that your quality unit (QU) did not provide adequate oversight for the manufacturing of bulk (b)(4). For example, your QU failed to ensure thefollowing:
在檢查期間,我們的檢查員發現你們質量部門(QU)沒有對散裝XX的生產進行充分的監控。例如你們QU未能確保:
Out-of-specification (OOS) test results for residual solvents were adequately investigated.
對殘留溶劑OOS檢測結果進行充分調查。
Test methods for assay and impurities were validated.
對含量和雜質檢測方法進行驗證。
Adequate record and report documentation practices, including document control, were in place.
具備充分的記錄和報告文件規范,包括文件控制。
You receive active pharmaceutical ingredients (API) from suppliers and process them into (b)(4). Your QU failed to adequately investigate OOS results for the residual solvent, (b)(4), for API batches (b)(4). You retested the API, obtained passing results, and released these API batches for use in production. You disregarded the initial OOS results without adequate scientific justification.
你們從供應商處接收了API,并將其進行加工至XX。你們的QU未能充分調查API批號XX的殘留溶劑的OOS結果。你們復測了該API,獲得了合格結果,然后將這些API批次放行用于生產。你們在沒有充分科學論證前提下就忽略了初始的OOS結果。
(b)(4) is a (b)(4) solvent and known (b)(4). Solvents in (b)(4) should not be employed in the manufacture of drug substances, excipients, and drug products because of their unacceptable toxicity. However, if the use of (b)(4) solvents, such as (b)(4), is unavoidable in order to produce a drug, then the levels should be restricted. For more information on residual solvents, see FDA’s guidance documentQ3C-Tablesand List at https://www.fda.gov/media/71737/download.
XX為XX類溶劑,已知XX。XX中的XX不應用于原料藥、輔料和制劑的生產,因為其具有不可接受的毒性。如果使用XX溶劑如XX是某藥品生產所不可避免的,則其水平應受到限制。殘留溶劑更多信息參見FDA指南文件Q3C—表格與清單。
Your response stated that you retested each of the batches of (b)(4) API for (b)(4) content and all retest results were within specification. Your response also concluded the original failures for residual (b)(4) were not representative and did not compromise product quality. However, your response failed to provide justification to disregard the initial OOS results or a plan for how your QU will ensure OOS results are adequately investigated. You also did not provide adequate corrective action to ensure appropriate documentation of testing performed as part of your OOS investigations.
你們的回復聲稱你們復測了XX API的所有批次中XX含量,所有復測結果均在標準范圍內。你們的回復還得出結論說原始檢測的殘留XX結果不具有代表性,對產品質量沒有影響。但是,你們的回復未提交忽略初始OOS結果的論證,亦未提交你們QU要如何確保OOS結果會受到充分調查的計劃。你們亦未提交充分的糾正措施,以確保適當記錄所執行的檢測,作為你們OOS調查的一部分。
For more information about handling failing,out-of-specification, out-of-trend, or other unexpected results and documentation of your investigations, see FDA’s guidance document Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production athttps://www.fda.gov/media/71001/download.
處理失敗、OOS、OOT或其它非預期結果和你們調查文件的更多信息,參見FDA指南文件“藥品OOS結果調查”。
In response to this letter, provide 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 notbe limited to:
在回復本函時,請提交一份全面評估和補救計劃,以確保你們QU被授予權限和提供資源可有效履責。該評估亦應包括但不限于:
Residual solvents test of retains samples of API you received, as well as (b)(4) you distributed. If such testing reveals substandard quality drugs, take rapid corrective actions, such as notifying customers and product recalls.
對你們已收到的API和你們已銷售的XX的留樣的殘留溶劑檢測。如果檢測發現藥品質量不合格,應即刻采取措施,如通知客戶和召回產品。
A list of all residual solvents used in your facility or at your suppliers, and your risk-based plans to strictly limit (or discontinue) any (b)(4) solvents in raw materials you receive and drugs you produce. Include specifications for all residual solvents used in API you receive.
一份你們工廠或你們供應商所用所有殘留溶劑的清單,以及你們基于風險的嚴格限制(或中斷)你們接收的原料和你們生產的藥品中的所有XX溶劑的計劃。包括在你們接收的API中所有殘留溶劑的標準。
A retrospective, independent review of all invalidated OOS (including in-process and release/stability testing) results for U.S. drugs, irrespective of whether the batch was ultimately distributed in the U.S. and a report summarizing the findings of the     analysis, including the following for each OOS:
一份對所有宣布無效美國藥品(無論該批次是否最終銷售至美國)OOS的獨立回顧審核(包括中控和放行/穩定性測試)結果,以及一份分析所發現問題的總結報告,包括每個OOS的以下內容:
Determine whether the scientific justification and evidence relating to the invalidated OOS result conclusively or inconclusively demonstrates causative laboratory error
確定宣布無效的OOS結果相關的科學論證和證據是否能得出結論,顯示有實驗室錯誤導致這些結果
For investigations that conclusively establish laboratory root cause, provide rationale and ensure that all other laboratory methods vulnerable to the same or similar root cause are identified for remediation
如果調查中發現有可得出結論的實驗室根本原因,請提交理由,并確保所有受相同或類似根本原因影響的其它實驗室方法被識別出來進行補救
For all OOS results found by the retrospective review to have an inconclusive or no root cause identified in the laboratory, include a thorough review of production: batch manufacturing records, adequacy of the manufacturing steps, suitability of equipment/facilities, variability of raw materials, process capability,  deviation history, complaint history, batch failure history. Summarize  potential manufacturing root causes for each investigation, and any manufacturing operation improvements 
如果回顧性審核中發現有OOS結果不能得出結論,或未發現實驗室根本原因,則包括一份對生產批次生產記錄、生產步驟充分性、設備/設施適用性、原料波動性、工藝能力、偏差歷史、投訴歷史、批失敗歷史的徹底審核??偨Y每個調查所發現的可能生產根本原因,以及所有生產操作改進措施。
A comprehensive review and remediation plan for your OOS result investigation systems. The corrective action and preventive action (CAPA) plan should include but not be limited to the following:
一份對你們OOS結果調查系統的全面審核和補救計劃。CAPA計劃應包括但不僅限于:
Quality unit oversight of laboratory investigations
質量部門對實驗室調查的監管
Identification of adverse laboratory control trends
識別不良實驗室控制趨勢
Resolution of causes of laboratory variation
實驗室變動原因的解決方案
Initiation of thorough investigations of potential manufacturing causes whenever a laboratory cause cannot be conclusively identified
在未識別出可歸因的實驗室原因時,對可能的生產原因啟動徹底調查
Adequately scoping of each investigation and its CAPA
充分劃定每個調查及其CAPA的范圍
Revised OOS investigation procedures with these and other remediations 
修訂后的OOS調查程序,包括這些和其它補救措施
Provisions for QU oversight throughout your operations to evaluate adherence to appropriate practices.
QU批準所有操作以評估是否遵守適當規范的條款
Oversight and approval of investigations and discharging of all other QU duties to ensure identity, strength, quality, and purity of all drugs you manufacture.
監管和批準調查,履行所有其它QU職責,以確保你們生產的所有藥品的鑒別、含量、質量和純度
2.  Your firm failed to clean, maintain, and, as appropriate for the nature of the drug, sanitize and/or sterilize equipmentand utensils at appropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements (21 CFR211.67(a)). 
你公司未以適當的時間間隔清潔、維護和(藥品屬性需要時)消毒和/或滅菌設備和工器具,以防止發生故障或污染從而改變藥品的安全性、鑒別、含量、質量或純度使其超出官方或其它既定要求(21 CFR 211.67(a))。
Our investigator observed that your dedicated equipment such as the (b)(4) and (b)(4) used to manufacture (b)(4) had visible rust, dents, and scratches on product contact surfaces.
我們的調查員發現你們用于生產XX的專用設備如XX和XX與產品接觸的表面有肉眼可見鐵銹、凹痕和刮痕。
Your response stated that you did not verify the cleanliness of all surfaces because the manufacturing area and entire equipment train is dedicated. You also stated that your Quality Unit would verify equipment cleaning. However, your response did not provide a plan for ensuring routine maintenance of your facility, including equipment maintenance, repairs, and replacement.
你們的回復聲稱你們并未核查所有表面的清潔情況,因為生產區域和整個設備鏈是專用的。你們還聲稱你們QU會核查設備的清潔情況。但是你們的回復并未提交一份確保對你們設施進行定期維保的計劃,包括設備維護、維修和更換。
In response to this letter, provide:
在回復本函時請提交:
Your CAPA plan to implement routine, vigilant operations management oversight of facilities and equipment. This plan should ensure, among other things, prompt detection of equipment/facilities performance issues, effective execution of repairs, adherence to appropriate preventive maintenance schedules, timely technological upgrades to the equipment/facility infrastructure, and improved systems for ongoing management review.
你們執行日常、預警操作管理對設施和設備進行監管的CAPA計劃。該計劃應能確保(除其它事情外)快速發現設備/設施性能問題、有效執行維修、遵守適當的預防性維保計劃、及時更新設備/設施基礎設施,以及改進系統進行持續管理審核。
A CAPA plan, based on the retrospective assessment, 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.
一份基于回顧評估制訂的CAPA計劃,其中包括對你們清潔程序和規范的適當補救,以及完成時間表。提交一份關于你們的設備清潔生命周期管理流程中的弱點的詳細總結。說明你們清潔程序的改進,包括改進清潔效果、改進后的所有產品和設備執行適當清潔的持續確認,以及所有需要的補救措施。
3.  Your firm failed to exercise appropriate controls over computer or related systems to assure that only authorized personnel institute changes in master production and control records, or other records (21 CFR 211.68(b)). 
你公司未對計算機或相關系統執行適當的控制,以確保只有經過授權的人員方可對主生產和檢驗記錄或其它記錄進行修改(21 CFR 211.68(b))。
Our investigator observed your laboratory equipment lacked appropriate controls. For example, from January 1, 2018, to June 25, 2019, audit trails from (b)(4) Agilent 1260 Infinity Series II high-performance liquid chromatography (HPLC) instruments showed a pattern of aborted runs and single run entries for testing (b)(4). Single run entries included analyses of multiple peaks or split peaks without documented investigations or adequate scientific justifications. Your employees used the Agilent Service Account login, with full administrative privileges, to abort HPLC testing runs without being attributable to a specific individual.
我們調查人員發現你們的實驗室設備缺乏適當控制。例如,2018年1月1日至2019年6月25日,安捷倫1260 Infinity 系列II HPLC審計追蹤顯示有運行中斷和XX檢測單針運行記錄。單針運行記錄包括多峰或裂峰分析,但沒有調查記錄或足夠的科學論證。你們的員工使用了安捷倫服務賬號登錄,具有所有管理權限,可以中斷HPLC運行,卻無法追蹤至具體人員。
Your response identified the number of deleted, aborted, and single runs during your HPLC testing. However, your response did not provide adequate investigations or evidence of corrective actions put in place to prevent these data integrity issues from recurring.
你們的回復說找出了你們HPLC測試中刪除、中斷和單針運行的數量。但是你們的回復并未提交足夠的調查或制訂的糾正措施證據,以防止這些數據完整性問題重復發生。
Data Integrity Remediation
數據完整性補救措施
Your quality system does notadequately ensure the accuracy and integrity of data to support the safety, effectiveness, and quality of the drugs you manufacture. See FDA’s guidance documentData Integrity and Compliance With Drug CGMP for guidance on establishing and following CGMP compliant data integrity practices at https://www.fda.gov/media/119267/download.
你們的質量體系不能充分確保數據的準確性和完整性,無法支持你們生產的藥品的安全性、有效性和質量。參見FDA指南文件“數據完整性和藥品GMP合格”指導建立和遵守CGMP合格數據完整性規范。
We acknowledge that you are using a consultant to audit your operation and assist in meeting FDA requirements.
我們知悉你們正聘用顧問對你們的操作進行審計并協助你們符合FDA要求。
In response to this letter,provide the following:
在回復此函時請提交以下信息:
A. A comprehensive investigation into the extent of the inaccuracies in data records and     reporting. Your investigation should include: 
一份對數據記錄和報告不準確性程度的全面調查。你們的調查應包括
A detailed investigation protocol and methodology; a summary of all laboratories, manufacturing operations, and systems to be covered by the assessment; and a justification for any part of your operation that you propose to exclude.
詳細的調查方案和方法學,所有實驗室、生產操作和評估所覆蓋的系統的總結,如有除外部分請論證
Interviews of current and former employees to identify the nature, scope, and root cause of data inaccuracies. We recommend that these interviews be conducted by a qualified third party.
對現有和已離職員工進行面談,找出數據不準確的程度、范圍和根本原因。我們建議這些面談由有資質的第三方進行。
An assessment of the extent of data integrity deficiencies at your facility. Identify omissions, alterations, deletions, record destruction, non-contemporaneous record completion, and other deficiencies. Describe all parts of your facility’s operations in which you discovered data integrity lapses.
你們工廠數據完整性缺陷的程度的評估。識別出省略、修改、刪除、記錄銷毀、不同步記錄填寫和其它缺陷。說明你們已發現的數據完整性問題所涉及的工廠操作。
A comprehensive retrospective evaluation of the nature of the testing and manufacturing data integrity deficiencies. We recommend that a qualified third party with specific expertise in the area where potential breaches were identified should evaluate all data integrity lapses.
一份對檢測和生產數據完整性缺陷情況的全面回顧性評估。我們建議由具備在已發現可能有問題的領域的專業能力的有資質的第三方對所有數據完整性問題進行評估。
B. A current risk assessment of the potential effects of the observed failures on the quality of your drugs. Your assessment should include analyses of the risks to patients caused by the release of drugs affected by a lapse of data integrity and analyses of the risks posed by ongoing operations. 你們藥品質量中所發現的不合格情況的潛在影響的當前風險評估。你們的評估應包括由于受到數據完整性問題影響的藥品放行導致的患者風險的分析,以及持續運營所具有的風險。
C. A management strategy for your firm that includes the details of your global corrective action and preventive action plan. Your strategy should include: 
你們公司的管理策略,包括你們全球CAPA計劃詳細情況。你們的策略應包括:
A detailed corrective action plan that describes how you intend to ensure the reliability and completeness of all the data you generate including analytical data, manufacturing records, and all data submitted to FDA.
詳細的CA計劃,描述你們準備如何確保你們生成的所有數據的可靠性和完整性,包括分析數據、生產記錄和所有提交給FDA的數據。
A comprehensive description of the root causes of your data integrity lapses, including evidence that the scope and depth of the current action plan is commensurate with the findings of the investigation and risk assessment. Indicate whether individuals responsible for data integrity lapses remain able to influence CGMP-related or drug application data at your firm.
一份對你們數據完整性問題根本原因的全面描述,包括當前行動計劃的范圍和深度與調查和風險評估發現相稱的證據。說明負責數據完整性的人員是否還有能力影響你公司與CGMP有關或藥品申報數據。
Interim measures describing the actions you have taken or will take to protect patients and to ensure the quality of your drugs, such as notifying your customers, recalling product, conducting additional testing, adding lots to your stability programs to assure stability, drug application actions, and enhanced complaint monitoring.
臨時措施,描述你們已采取或將采取用來保護患者和確保你們藥品質量的措施,如通知你們的客戶、召回產品、執行額外檢測、增加批次至穩定性計劃以確保穩定性、藥品申報措施和加強投訴監測。
Long-term measures describing any remediation efforts and enhancements to procedures, processes, methods, controls, systems, management oversight, and human resources (e.g., training, staffing improvements) designed to ensure the integrity of your company’s data.
長期措施,其中描述所有對用以確保你們公司數據完整性的程序、流程、方法、控制、系統、管理監管和人力資源(例如培訓、員工提高)的彌補和提升。
A status report for any of the above activities already underway or completed.
上述活動已開展或已經完成的狀態報告。
Concerns with Drug Suppliers
對藥品供應商的擔憂
You previously sourced (b)(4) API from (b)(4) who refused FDA inspection and was placed on Import Alert (b)(4) on (b)(4). Accordingly, FDA placed your firm on Import Alert 99-32 until you no longersourced drugs from (b)(4) and you committed to revise your API supplier qualification program.
你們之前從XX處采購XX API,該公司拒絕了FDA的現場檢查要求,已于XX日被放置于進口禁令中。相應地,FDA已將你公司放置于進口禁令99-32中,直到你們不再從XX處采購藥品,你們已承諾會修訂你們的API供應商確認程序。
Conclusion 
結論
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.
此函中所引用的違規并不是全部。你們有責任對這些偏差進行調查,確定原因,防止其再次發生,防止你們設施內其它偏差的發生。
If you are considering an action that is likely tolead 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.
如果你們在考慮要采取的措施可能會導致你們工廠所生產的藥品供應中斷,FDA要求你立即聯系CDER藥品短缺負責人員,這樣FDA可以與你們一起采用最為高效的方式引導你們的操作符合法規要求。聯系藥品短缺負責人員還能讓你滿足依據21 U.S.C. 356C(b)你可能必須報告你們藥品中止或中斷的義務,讓FDA盡快考慮是否需要采取何種措施來避免短缺,保護依賴于你們藥品的患者健康。
FDA placed your firm on Import Alert 66-40 on December 16, 2019.
FDA已于2018年8月1日將你公司置于進口禁令66-40中。
Until you correct all violations completely and weconfirm your compliance with CGMP, FDA may withhold approval of any new drug applications or supplements listing your firm as a drug manufacturer.
在貴公司未能完成所有偏差糾正并且由我們確認你們符合CGMP之前,FDA可能會擱置所有將你公司列為藥品生產的新申報和增補申報的批準。
Failure to correct these violations may also result in the FDA continuing to refuse admission of articles manufactured at GPT Pharmaceuticals Pvt. Ltd., FEI 3008311641, at Plot No. 6/3, Road No. 11, Nacharam, Hyderabad into the United States under section 801(a)(3) of the FD&C Act, 21 U.S.C. 381(a)(3). Articles under this authority may be subject to refusal of admission, 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 FD&C Act, 21 U.S.C. 351(a)(2)(B).
未能糾正這些偏差可能還會導致FDA依據FDCA第801(a)(3)條和21 U.S.C. 381(a)(3)拒絕接受在上述地址生產的產品進入美國。
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.
在收到此函后,請在15個工作日內回復至本辦公室。在回復中說明自從檢查后,你們做了哪些工作來糾正你們的偏差,防止其再次發生。如果不能在15個工作日內完成糾正措施,說明延遲的原因以及完成計劃。
 

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