近日,FDA官网挂出了对中国核苷和核苷酸类药物生产上市公司新乡拓新生化/新乡制药的警告信,警告信涉及的制药厂有两家:

• 新乡制药,地址:北干道建设西路30号,日期:2015年9月14、16日

• 新乡拓新生化,地址:牧野路和德源路交叉路口,日期:2015年9月15、17、18日

  
  

相关缺陷如下:

1.    未能适当地维护用于API生产的设备,使用开放式设备未能减少污染风险。(产品接触表面和反应器产品堆积,以及油漆脱落,预防性维护无记录或记录不详细)

2.  未能适当的维护、修理,和保持用于生产API的洁净厂房以防止使用开放式设备的污染。(厂房有缝隙、孔洞,洁净室和产品中转发现飞虫,并怀疑飞虫由这些缝隙和孔洞飞入)

FDA在警告信中回复他们修补部分厂房并更换一些设备的计划是不充分的。并评论:“你们的厂房和设备在如此荒废的状态,已经无药可救了。”FDA建议:“小范围的修补并不能充分纠正问题并预防再次发生”并要求“彻底改造两个厂房,并提交完成改造的图像证据”。

以下是这封警告信的内容:

Via UPS  Warning Letter 320-16-28

美国FDA检查了河南新乡市的如下生产基地

?Xinxiang Pharmaceutical Co., Ltd., at No. 30 Jianshe West Road, Beigandao, on September 14 and 16, 2015 (FEI 3002773156).

?新乡制药,地址:北干道建设西路30号,日期:2015年9月14、16日(FEI 3002773156).

?Xinxiang Tuoxin Biochemical Co., Ltd., at Muye and Deyuan Road cross street, on September 15, 17, and 18, 2015 (FEI 3008259785). 

?新乡拓新生化,地址:牧野路和德源路交叉路口,日期:2015年9月15、17、18日

 本警告信汇总了对活性药物成分(API)CGMP的重大偏差。

 由于你们的方法、设施,或生产、加工、包装或保存的控制不符合CGMP,你们的API根据21 U.S.C.联邦食品、药品、化妆品法(FD&C Act)501(a)(2)(B)章节被认定为掺假。

 我们详细审阅了你们于2015年10月6日的回复,也收到了之后的回复。

During our inspections at both facilities, our investigator observed specific deviations including, but not limited to, the following.在我们检查两个基地期间,我们的检查员观察到具体的偏差包括但不限于如下:

 1.    Failure to properly maintain equipment used in the manufacture of API and minimize the risk of contamination where open equipment is used.

 未能适当地维护用于API生产的设备,使用开放式设备未能减少污染风险。

 我们的检查员观察到非专用药物生产设备处于失修状态。例如,你们的 (b)(4) 的产品接触表面和反应器存在严重 (b)(4) ,产品堆积,以及油漆脱落。

The documented state of disrepair demonstrates that you have not implemented an adequate preventive maintenance program. Although you have preventive maintenance schedules, our investigator found that for those preventative maintenance activities you state were conducted, you do not have records documenting their performance, and those records you did have lacked sufficient detail.记录的荒废状态证明你们没有实施充分的预防性维护程序。尽管你们有预防性维护时间计划,我们的检查员发现你们说已经执行了的这些预防性维护活动,你们没有记录记载它们的执行,并且你们有做的那些记录缺乏足够的细节。

 2.    Failure to properly maintain, repair, and keep clean buildings used in the manufacture of API in a manner that prevents contamination where open equipment is used.

 未能适当的维护、修理,和保持用于生产API的洁净厂房以防止使用开放式设备的污染。

 你们使用开放式设备生产API。我们的检查员发现开放式(b)(4)正上方的天花板有油漆脱落,其可能已经掉入你们的开放式设备中并污染了你们的API。我们的检查员还发现窗户和门周围的缝隙,以及开放式(b)(4)正上方的天花板处的孔洞。洁净室和产品中转(b)(4)发现有飞虫,可能是由这些缝隙和孔洞飞入的。

In your response, you stated that you would repair parts of your facility and replace some of your equipment. You did not provide details regarding your planned repairs and replacements, such as purchase orders and photographs of the renovations and replacements. As indicated above, at the time of our inspection, your facilities and equipment were in such a state of disrepair as to be unsalvageable; small or minor repairs will not adequately correct the problems and prevent their recurrence. In response to this letter, provide your written plans to renovate both facilities entirely, and submit photographic evidence of the completed renovations. 在你们的回复中,你们说你们会修补你们的部分厂房并更换你们的一些设备。你们没有提供关于你们所计划的修补和设备更换的细节。如上所属,在我们检查的时候,你们的厂房和设备在如此荒废的状态,已经无药可救了。小范围的修补并不能充分纠正问题并预防再次发生。回复这封警告信时,提供你们的书面计划来彻底改造两个厂房,并提交完成改造的图像证据。
CGMP consultant recommendedCGMP顾问建议

Based upon the nature of the deviations we identified at your firm, we strongly recommend engaging a third-party consultant qualified to evaluate your operations to assist your firm in meeting CGMP requirements. Your use of a consultant does not relieve your firm’s obligation to comply with CGMP. Your firm’s executive management remains responsible for fully resolving all deficiencies and ensuring ongoing CGMP compliance. 

Conclusion结论Deviations cited in this letter are not intended as an all-inclusive list. You are responsible for investigating these deviations, for determining the causes, for preventing their recurrence, and for preventing other deviations in all your facilities. FDA placed both facilities on Import Alert 66-40 on April 6, 2016. Until you completely correct all deviations and we confirm your compliance with CGMP, FDA may withhold approval of any new applications or supplements listing either of your facilities as a drug manufacturer. Failure to correct these deviations may also result in FDA continuing to refuse admission of articles manufactured in Xinxiang City, Henan, at Xinxiang Pharmaceutical Co., Ltd., No. 30 Jianshe West Road, Beigandao, and Xinxiang Tuoxin Biochemical Co., Ltd., at Muye and Deyuan Road cross street, into the 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 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). After you receive this letter, you have 15 working days to respond to this office in writing. Specify what you have done since our inspection to correct your deviations 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.