丹麦生产商收到FDA的所谓无标题信函

GMP News
21/09/2016

Danish Manufacturer receives a so-called Untitled Letter from the FDA due to Deviations from GMP

丹麦生产商收到FDA的所谓无标题信函

A Danish pharmaceutical manufacturer of antiallergic products has received a so-called "Untitled Letter" from the FDA after an inspection at his production site in March 2016. The letter was issued because of deviations from diverse GMP rules. Unlike a Warning Letter, an Untitled Letter is issued by the FDA when there is no immediate danger for patients' health if the deviations observed are not corrected immediately. The FDA therefore uses such letters for less serious GMP deviations. By contrast with a Warning Letter, an Untitled Letter contains no statement warning the manufacturer that failure to promptly correct a violation may result in an enforcement action.

一个丹麦的抗过敏药品生产商在2016年3月FDA检查过后收到FDA签发的所谓“无标题信函”。签发信函是因为该公司有多项GMP偏差。与警告信不同，当发现的偏差不立即改正不会对患者健康造成直接危害时，FDA就会签发无标题函。FDA将此类信函用于不那么严重的GMP违规行为。与警告信相反，无标题信息并不包括不能及时纠正就会采取强制措施的警示性声明。

A Form 483 preceded the present Untitled Letter. This form contained all the inspection observations which - for the FDA - haven't been sufficiently reacted to. But also repeated deviations which had already been identified during an inspection in 2014 in the USA have been admonished.

在无标题信函之前有一份483表，表中包括了FDA检查中发现的所有缺陷，这些缺陷目前还没有充分纠正。有些缺陷在2014年FDA检查中已经发现了，属于重复缺陷，已被FDA训诫。

In detail, the violations are: 具体来说违规情况有：

Deviations in aseptic manufacturing due to inappropriate measures to prevent microbiological contamination

由于防止微生物污染措施不当引起的无菌生产偏差

• The WFI system has not been properly tested for TOC and endotoxins at the points of use.
• WFI系统使用点没有适当测试TOC和内毒素
• There is no procedure in place to specify how to handle exceedings of microbiological limits.
• 没有程序说明如何处理微生物超限
• Environmental isolates are not used for growth promotion studies of media used in media fill simulations
• 用于培养机灌装模拟的培养基促生产试验未使用环境隔离器
• No CAPA measures taken after 80 exceedings of microbiological limits (within 2 years).
• 在2年中有80起微生物超限，但没有采取CAPA措施
  

Insufficient calibration and inspection/maintenance of automatic, mechanical or electronic equipment

自动化、机械或电子设备校正、检查/维护不充分

• Missing re-qualification of a lyophilizer (since 2000)
• 冻干机没有进行再确认（自2000年以来）
• Abortion of a batch due to the leaking of the lyophilizer
• 冻干机泄漏，导致一批生产中断
• No maintenance measures taken after malfunctions of the filling machine (e.g. overfilling, empty vials, missing stoppers)
• 在灌装机发生故障后没有采取维护措施（例如，溢出、空瓶、无塞）
  

Failure in the stability programme 稳定性试验失败

• There is no procedure in place to describe when and where samples have to be selected for stability testing of the product.
• 没有程序说明什么时间在哪儿选择样品进行产品稳定性测试
• Since 2014, around 125 stability samples of the drug product and the drug substance haven't been tested at the required time points.
• 自2014年以来，约有125个制剂和原料药稳定性试验样品都没有按照要求的时间点进行检测
  

Furthermore, the FDA states that the response of the manufacturer to the Form 483 was insufficient. The FDA criticises that the responses to too many deviations was only that the procedures will be updated and training will be improved. For the FDA, there is a need for further discussion.

还有，FDA说生产商对483表的回复不充分。FDA批评说对许多偏差的回复都仅是要更新程序，加强培训。FDA需要进一步讨论。

Please also see the detailed FDA Untitled Letter to the Danish manufacturer of antiallergic products.

更多信息，参见官网。

无标题信函介绍

来自FDA官网：http://www.fda.gov/AboutFDA/Transparency/TransparencyInitiative/ucm284105.htm

If a person or firm violates the Federal Food, Drug and Cosmetic Act (FD&C Act), FDA may give them an opportunity to take voluntary and prompt action to correct the violation before FDA initiates an enforcement action.  FDA will issue either a Warning Letter or an Untitled Letter, depending upon the nature of the violation.

如果自然人或公司违反了FDCA，FDA可能会在启动强制措施之前给他们一个机会自己采取及时措施改正违规行为。这时FDA就会签发一封警告信或无标题信函，具体发何种信函则取决于违规行为的性质。

FDA uses Warning Letters for violations that may lead to enforcement action if they are not promptly and adequately corrected.  FDA uses Untitled Letters for violations that are not as significant as those that trigger warning letters.  Unlike a Warning Letter, an Untitled Letter does not include a statement warning that failure to promptly correct a violation may result in an enforcement action.

对于那些如果不能及时充分地纠正可能会导致强制措施的违规情况，FDA会签发警告信。而如果违规情况并没有触发警告信那样严重，则FDA会签发无标题信函。与警告信不同，无标题信息并不包括不能及时纠正就会采取强制措施的警示性声明。

See: FDA Warning Letters

Previously, only some Centers posted Untitled Letters on FDA’s website.  As a result of the Agency’s Transparency Initiative, the Centers are working to disclose more Untitled Letters on FDA’s website.  The Agency believes that posting additional Untitled Letters may increase public accountability of firms, which may deter future violations and increase compliance with the law.  However, due to limited resources, the Agency is not able to post all Untitled Letters at this time.

之前，只有一些中心会在FDA官网上贴出无标题信函。随着政府部门透明度倡议的提出，各中心现在会在FDA官网上公开更多无标题信函。当局信息贴出这些信函可以增加这些公司的社会责任感，阻止进一步的违规行为，提升法规符合性。但是，由于资源有限，当局目前尚无法贴出所有的无标题信函。

Interested parties may access the available Untitled Letters and similar correspondence below.

有兴趣的各方可以从网站获得一些无标题信函和类似的通信资料。

来源：GMP News

21/09/2016

Danish Manufacturer receives a so-called Untitled Letter from the FDA due to Deviations from GMP

丹麦生产商收到FDA的所谓无标题信函

A Danish pharmaceutical manufacturer of antiallergic products has received a so-called "Untitled Letter" from the FDA after an inspection at his production site in March 2016. The letter was issued because of deviations from diverse GMP rules. Unlike a Warning Letter, an Untitled Letter is issued by the FDA when there is no immediate danger for patients' health if the deviations observed are not corrected immediately. The FDA therefore uses such letters for less serious GMP deviations. By contrast with a Warning Letter, an Untitled Letter contains no statement warning the manufacturer that failure to promptly correct a violation may result in an enforcement action.

一个丹麦的抗过敏药品生产商在2016年3月FDA检查过后收到FDA签发的所谓“无标题信函”。签发信函是因为该公司有多项GMP偏差。与警告信不同，当发现的偏差不立即改正不会对患者健康造成直接危害时，FDA就会签发无标题函。FDA将此类信函用于不那么严重的GMP违规行为。与警告信相反，无标题信息并不包括不能及时纠正就会采取强制措施的警示性声明。

A Form 483 preceded the present Untitled Letter. This form contained all the inspection observations which - for the FDA - haven't been sufficiently reacted to. But also repeated deviations which had already been identified during an inspection in 2014 in the USA have been admonished.

在无标题信函之前有一份483表，表中包括了FDA检查中发现的所有缺陷，这些缺陷目前还没有充分纠正。有些缺陷在2014年FDA检查中已经发现了，属于重复缺陷，已被FDA训诫。

In detail, the violations are: 具体来说违规情况有：

Deviations in aseptic manufacturing due to inappropriate measures to prevent microbiological contamination

由于防止微生物污染措施不当引起的无菌生产偏差

• The WFI system has not been properly tested for TOC and endotoxins at the points of use.
• WFI系统使用点没有适当测试TOC和内毒素
• There is no procedure in place to specify how to handle exceedings of microbiological limits.
• 没有程序说明如何处理微生物超限
• Environmental isolates are not used for growth promotion studies of media used in media fill simulations
• 用于培养机灌装模拟的培养基促生产试验未使用环境隔离器
• No CAPA measures taken after 80 exceedings of microbiological limits (within 2 years).
• 在2年中有80起微生物超限，但没有采取CAPA措施
  

Insufficient calibration and inspection/maintenance of automatic, mechanical or electronic equipment

自动化、机械或电子设备校正、检查/维护不充分

• Missing re-qualification of a lyophilizer (since 2000)
• 冻干机没有进行再确认（自2000年以来）
• Abortion of a batch due to the leaking of the lyophilizer
• 冻干机泄漏，导致一批生产中断
• No maintenance measures taken after malfunctions of the filling machine (e.g. overfilling, empty vials, missing stoppers)
• 在灌装机发生故障后没有采取维护措施（例如，溢出、空瓶、无塞）
  

Failure in the stability programme 稳定性试验失败

• There is no procedure in place to describe when and where samples have to be selected for stability testing of the product.
• 没有程序说明什么时间在哪儿选择样品进行产品稳定性测试
• Since 2014, around 125 stability samples of the drug product and the drug substance haven't been tested at the required time points.
• 自2014年以来，约有125个制剂和原料药稳定性试验样品都没有按照要求的时间点进行检测
  

Furthermore, the FDA states that the response of the manufacturer to the Form 483 was insufficient. The FDA criticises that the responses to too many deviations was only that the procedures will be updated and training will be improved. For the FDA, there is a need for further discussion.

还有，FDA说生产商对483表的回复不充分。FDA批评说对许多偏差的回复都仅是要更新程序，加强培训。FDA需要进一步讨论。

Please also see the detailed FDA Untitled Letter to the Danish manufacturer of antiallergic products.

更多信息，参见官网。

无标题信函介绍

来自FDA官网：http://www.fda.gov/AboutFDA/Transparency/TransparencyInitiative/ucm284105.htm

If a person or firm violates the Federal Food, Drug and Cosmetic Act (FD&C Act), FDA may give them an opportunity to take voluntary and prompt action to correct the violation before FDA initiates an enforcement action.  FDA will issue either a Warning Letter or an Untitled Letter, depending upon the nature of the violation.

如果自然人或公司违反了FDCA，FDA可能会在启动强制措施之前给他们一个机会自己采取及时措施改正违规行为。这时FDA就会签发一封警告信或无标题信函，具体发何种信函则取决于违规行为的性质。

FDA uses Warning Letters for violations that may lead to enforcement action if they are not promptly and adequately corrected.  FDA uses Untitled Letters for violations that are not as significant as those that trigger warning letters.  Unlike a Warning Letter, an Untitled Letter does not include a statement warning that failure to promptly correct a violation may result in an enforcement action.

对于那些如果不能及时充分地纠正可能会导致强制措施的违规情况，FDA会签发警告信。而如果违规情况并没有触发警告信那样严重，则FDA会签发无标题信函。与警告信不同，无标题信息并不包括不能及时纠正就会采取强制措施的警示性声明。

See: FDA Warning Letters

Previously, only some Centers posted Untitled Letters on FDA’s website.  As a result of the Agency’s Transparency Initiative, the Centers are working to disclose more Untitled Letters on FDA’s website.  The Agency believes that posting additional Untitled Letters may increase public accountability of firms, which may deter future violations and increase compliance with the law.  However, due to limited resources, the Agency is not able to post all Untitled Letters at this time.

之前，只有一些中心会在FDA官网上贴出无标题信函。随着政府部门透明度倡议的提出，各中心现在会在FDA官网上公开更多无标题信函。当局信息贴出这些信函可以增加这些公司的社会责任感，阻止进一步的违规行为，提升法规符合性。但是，由于资源有限，当局目前尚无法贴出所有的无标题信函。

Interested parties may access the available Untitled Letters and similar correspondence below.

有兴趣的各方可以从网站获得一些无标题信函和类似的通信资料。

来源：

Julia