11.10.2017
Frequent GMP Violations in pharmaceutical Companies (1): Testing and Release for Distribution制药企业常见GMP违规（1）：销售检测和放行 The testing of a medicinal product before its release for distribution is one of the most important manufacturing steps and a core function of quality control.There is no inspector, neither with the FDA nor with one of the European supervisory agencies who won't take a close look at the quality control department responsible for this final test. In fact, an inspector will want tomake sure that the staff members of this department perform their tasks inexact compliance with GMP regulations. It is therefore surprising that serious GMPviolations occurring in this sensitive area, which directly affects the safetyof end users, are amongst the most common described in FDA warning letters. Most cases are not just about singular misconduct of laboratory personnel or an unassessed deviation in an analysis result, butfundamental GMP deficiencies. An analysis of the warning letters of the past 24 months emphasises this fundamental flaw in the quality management system, because of which finished medicinal products are released into the market without their compliance with final specifications being tested. In many cases, this does not only concern content determinations, but also absent testsfor microbiological contamination.
药品在放行销售之前的测试是一个重要的生产步骤，也是质量部门的核心功能。但凡是检查员，不管是FDA的还是EU监管机构的，都会仔细看看质量部门对这个最终测试的职责。实际上，检查人员会想要确定此部门的人员的确是按照GMP法规的要求在执行其任务。因此，如果说在这个敏感地带还有严重的GMP违规情况发生，着实让人惊讶，这会直接影响最终用户的安全性，并且这一点也是FDA警告信中最常述及的问题。大多数案例并不仅仅是化验室人员奇葩的误操作，或者是对分析结果偏差没有进行评估，而是根本性的GMP缺陷。对过去24个月的警告信的分析强调了质量管理体系中这些根本性的瑕疵，由于此类缺陷，检查结果没有显示其符合最终质量标准，药品就被放行销售了。在许多案例中，这可不仅仅是含量检测，还有一些是没做微生物污染测试。
The legal basis regulating the final testing and product release can be found in 21CRF 211.165, subsection (a)-(f). The corresponding description of defects in warning letters mostly sounds like this:
在21CFR211.165子部(a)-(f)中可以找到关于最终检测和产品放行的法律规定。在警告信中相关的描述大多听起来是这样的：
"Your firm does not have, for each batch of drug product, appropriate laboratory determination of satisfactory conformance to final specifications for the drug product, including the identity and strength of each active ingredient and freedom from objectionable microorganisms, prior to release …"
“你公司未对每批药品在放行前进行适当的化验检测以确定其符合药品的最终质量标准，包括每种活性成分的鉴别和数量，以及没有致病菌……”
Or或者是
"Your firm failed to establish and document the accuracy, sensitivity, specificity,and reproducibility of its test methods …"
“你公司未能建立和记录其分析方法的准确度、灵敏度、专属性和重复性……”
The following compilation of findings from several warning letters issued between October 2016 and September 2017 (fiscal year 2017) contains details about the type of GMP violation. It is representative for a period of 24 months (fiscal years 2016/2017).
以下是2016年10月至2017年9月期间（2017财年）签发的几封警告信中缺陷的汇总，其中包括了关于该类GMP违规的详细内容。它是过去24个月的代表（2017/2017财年）。
| | |
Baoying County Fukang Medical Appliance Co., Ltd.;
Baoying County, China | | Neither content determinations nor microbiological testing have been performed before release. Records of further chemical analyses do not exist. |
| | 放行前未检测含量，也未检查微生物。没有其它化学分析记录。 |
Pharmco Laboratories, Inc.; Titusville, USA | Products for topical application | The method of content determination for benzoyl peroxide and salicylic acid has not been validated, nor was the equivalency of these methods with the procedures described in the USP proven. |
| | 过氧化苯甲酰和水杨酸含量检测方法没有验证，也没有与USP方法进行等同性证明。 |
Zhejiang Bangli Medical Products Co., Ltd.; Yongkang City, China | | No testing for identity, purity and strength of the active components. |
| | |
Howard Phillips, LLC; Millerton, USA | Sterile products for topical application | There was generally no final testing performed before the release, neither identity and content determination nor tests for sterility and microbiological integrity. |
| | 放行前通常都不做最终检测，不做鉴别和含量检测，也不做无菌和微生物完整性检测。 |
Yusef Manufacturing Laboratories, LLC; Clearfield, USA | Products for topical application | No testing for identity and strength of active ingredients or microbiological quality. A post-analysis by the FDA showed that the active substance level was too low. |
| | 活性成分没做鉴别和剂量检测，没做微生物测试。FDA的分析显示活性物质水平太低。 |
ChemRite CoPac, Inc.; Lannon, USA | | No tests for compliance with microbiological specifications. Results for analysis of the objectionable organism P. aeruginosa was declared with 1 CFU/ml in the batch protocol, even though there were no tests performed by the company or the contract manufacturers. |
| | 没做微生物测试。批记录显示致病菌绿脓杆菌结果，但公司和合同生产商都没有做过这个检测。 |
Sage Products, Inc.; Cary, USA | | The procedure used for testing the bioburden is unsuitable. An attempt to validate the method failed. Products were released regardless. A post-analysis of several batches in accordance with USP methods after various customer complaints showed a high bioburden. |
| | 用于生物负载的检测方法不适用。方法验证失败，但仍放行了产品。几起客户投诉之后使用USP方法检测了几批，显示生物负载很高。 |
Foshan Flying Medical Products Co., Ltd.; Foshan City, China | Finished medicinal products | No testing for identity or strength stated on the label; testing for absence of objectionable microorganisms was never performed. |
| | 没有检测标签上声明的鉴别和剂量。从来没做过致病菌检测。 |
Asmentioned before, this type of fundamental violations of GMP rules has not onlyappeared in the most recent warning letters. In fact, their number has been ona high level for at least two years.
正如前面提到的，此类根本性的GMP违规情况不仅仅出现在最近的警告信上，实际上，在过去2年其数量一直居高不下。
Ananalysis of further GMP violations frequently found in warning letters willfollow shortly.
本刊将于近期推出对更多常见GMP违规情况的分析。
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发表于 2017-10-13 17:07:05
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