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IsCost Pressure becoming the Main Reason for GMP Non-Compliance and Drug Shortages? 成本压力是否正在成为GMP不符合和药品短缺的主要原因？ It has been a hot inspection summer. FDA Warning Lettersand EU Non-Compliance Reports seem to increase at the moment. It is worryingthat the GMP non-compliance issues apparently get more serious than in thepast. But what is the reason? 刚刚渡过了一个炎热的检查夏季，FDA警告信和EU不符合报告貌似增加不少。令人担忧的是GMP不符合问题显然比过去严重了很多。这是什么原因呢？ Many deviations found refer to data integrity. Here twodifferent areas are covered. First: inadequate computer systems andmaintenance. For example, electronic records that were not archived correctly anddata that was deleted - either by mistake or due to inadequate systems. Thesecond area is the more worrying part. Staff in production and QC have verylittle or no knowledge of what is expected. They are simply not trained in GMP.Going through these many findings on Data Integrity one can loose faith. Thisis not a new topic. It is simply a lack of knowledge in Good DocumentationPractice. Principles like no data should be deleted or modified without anexplanation and visually retaining the original data. In addition everyactivity needs to be documented in a timely manner etc. This is no "rocketscience"! In the past we saw Warning Letters which went into the detailsof validation procedures or analytical activities. But now the non complianceis so basic that every person who received an initial GMP training should knowabout how to avoid it. 发现的许多偏差是关于数据完整性的。这里包括2个不同的领域。一个是计算机系统及其维护不够充分。例如，电子记录存档不正确，数据被删除---被误删，或者是由于系统不够好。第二个领域则是让为更为担心的。生产和QC的员工对于要求知之甚少。他们接受了简单的GMP培训。看看这许多数据完整性缺陷，人们可能会失去信心。现在这已经不是新的话题了。它仅仅是因为缺乏优良文件规范而已。类似 数据不应被删除或修改而没有解释，也看不到原始数据的保存这样的原则性问题。另外，每个活动都需要及时记录等。并没有什么高级科技！过去，我们看到警告信讲到验证过程或分析活动的详细情况，而现在，不符合性问题是如此低级，每个接受了入门GMP培训的人都应该知道如何避免这种错误。 In parallel to the above described "trend of non-GMPcompliance" we see another trend. That is the trend to put more and morepressure on the cost of manufacturing. Every country has to deal withincreasing costs for their health care system. This has resulted in increasingpressure for medicinal products (lower prices). To save costs alsomanufacturing has come under pressure. First, APIs moved to low cost countries,especially to Asia. Then generic manufacturing of medicinal products also movedfor the same reason. The remaining sites in Europe and the US also came underpressure to reduce costs. In the past a medicinal product was manufactured inmany countries by different manufacturing sites. Today, for cost optimizationthe number of sites has been reduced. Sometimes only one or two sites exist,and an API is possibly only available from a single source in Asia. Ifinspectors find GMP problems at the remaining site(s), it will immediately leadto drug shortages because there is not enough capacity left at other sites tostep in. This has become the main reason for drug shortages in the US and EU. 除了上述“GMP不符合趋势”外，同时我们还看到另一个趋势。那就是生产成本压力日益增大的趋势。每个国家必须面对其健康医疗系统成本增加问题。这已经导致了药品压力增加（价格更低）。为了节省成本 ，生产也倍感压力。首先，原料药转移到低成本 国家，尤其转至亚洲。然后仿制药品也因为相同原因被转移。在欧洲和美国剩下的工厂也要承受降低成本的压力。在过去，药品在许多国家由不同的生产场所生产，而今天，为了成本 优化，工厂数据已经减少。有时只有一个或两个药厂存在，一个原料药可能只有一个亚洲来源。如果检查人员在剩下的场所发现GMP问题，将立即会导致药品短缺，因为另一个场所没有足够的产能来跟进空出的市场。在美国和欧盟，这已经成为药品短缺的主要原因。 In Spain inspectors just recently detected a site whichwas expected to manufacture according to EU GMP. However, they were unable to,simply because they didn't have enough staff. The inspectors of the Alcor plantin the city of Guadalajara found "that the company does not havesuitable facilities, personnel and materials resources to ensure proper compliancewith GMP. A total number of 29 deficiencies were identified. Eight of them wereclassified as major." 在西班牙，检查员刚刚发现一个工厂本来应该按EU GMP生产，但是他们不符合，简单地说，因为他们没有足够的员工。检查员在印度ALCOR工厂发现“公司没有适当的设施、人员和物料来源，无法保证符合GMP。总共发现29个缺陷，其中8个为主要缺陷。” And the company was not able to solve the issues detectedduring the inspection. In the Inspection Report it was stated: "thecompany proposed a corrective action plan on 8 and 29 July 2016. After itsevaluation, on 2 August 2016 the inspectorate concludes there are manyoutstanding issues and that Alcor S.L. does not comply with EU GMPrequirements. In general the proposed corrective actions were insufficient,diffuse and do not provide a description about the extent of the measures, soto ensure the correction of the major deficiencies. In particular, thoserelated to the lack of personnel remain unsolved, and the accumulation of tasksand responsibilities in some personnel is a risk to quality. It does not ensurethe proper conduct of the activities required for EU GMP compliance." 公司没能解决在检查中发现的这些问题。在检查报告中说到：“公司在2016年7月8日和29日分别给出了一份整改计划。在对计划进行评估后，检查组于2016年8月2日得出结论认为有许多突出的问题，ALCO公司不符合EU GMP要求。总体来说其所提出的整改措施是不充分的、混乱的，没有提供所采取措施的涉及深度的描述，无法确保纠正主要缺陷。尤其是与人手短缺相关的问题仍未解决，任务积压以及多职责集于一些人员身上对于质量构成风险。无法确保实施EU GMP符合所需的活动。” A very similar issue can be identified in multipleWarning Letters issued by the FDA this year. Many of them contain DataIntegrity matters. In addition to a lack of adequate IT systems and ITprocedures (e.g. on how to archive data electronically) many issues relate tobasic Good Documentation Practice principles. Companies did not invest in staffand in the initial and ongoing training of staff. A number of Warning Letterstherefore included a kind of standard "Data Integrity Remediation"requirement - and comprised among others: 今年FDA签发的多封警告信中也发现了非常类似的问题。很多警告信中都有数据完整性问题。除了缺乏足够的IT系统和IT程序外（例如，如何采用电子方式归档数据），许多问题是与GDP原则相关的。公司没有为员工投资，没有花钱为其员工进行初始培训和持续培训。因些大量警告信中包括了一种标准的“数据完整性弥补”要求---其中有一些内容如下： "Long-term measures describing any remediationefforts 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." “描述所有用以保证你们公司数据完整性的，弥补和增强公司程序、流程、方法、控制、系统、管理层监管和人力资源（例如培训、人员改善）的长期措施”。 If we bring the two trends together, we can see evidencethat pressure to reduce production costs will inevitably lead to activities toreduce facilities and staff. The remaining staff might not be able to performall tasks and receives less GMP training to save costs. A good inspector cansee this trend very easily. Taking a look at the training records and the openissues in the corrective action plan is often enough to discover the problem. 如果我们把两个趋势放在一起，我们可以看到有证据证明降低生产成本的压力会不可避免地导致消减工厂和员工的行为。剩下的员工可能无法完成所有任务，并且接受的GMP培训会减少以此消减成本。一个优秀的检查员可以很容易地看到此趋势。看看培训记录，看看整改计划中尚未完成的问题，通常就足以发现问题了。 What could be the way out of this? One scenario might beto assess the GMP problems with regard to their root cause. A company with agood compliance history that has a GMP compliance issue should be treateddifferently to a company that violates basic GMP problems - like lack of GoodDocumentation Practice. If a company falsifies data, deletes records byintention (not by mistake), this company should face more serious consequencesthan a company with a good compliance history and with a good quality culture.Quality Metrics like those proposed by the FDA could become a tool to make thedifference visible. There is no easy solution. But we need to work on this tosafeguard patient safety. 那么出路在哪里呢？有一个方法是根据其根本原因来评估GMP问题。一个具有良好的符合性历史而有GMP符合性问题的公司，与另一个违背基本GMP原则---像缺乏优良文件规范---的公司应区别对待。如果一个公司伪造数据、有意删除记录（不是无意），则相比于具有良好符合性历史具备良好质量文化的公司，该公司应面临更为严重的后果。与FDA所提议的其它工具一样，质量量度可以成为显示差异的一个工作。这里可没有简便的解决方案，但我们必须为此奋斗以保护患者安全。
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发表于 2016-9-29 12:30:00
置顶卡
变色卡
发表于 2016-9-29 12:46:38
——这个检查官真NB，的确人是最基本要素，连人员都不够，肯定是不可能做好GMP的，虽然企业有多努力和理由，反正我是不相信。在中国，大厂招人好招一点，人员基本能满足，而小厂就可怜很多，老板也巴不得一个部门就一两个人（其中部门领导还是亲戚啥的关系）。人是资源中最重要的资源，人的技能、知识、意识、沟通、培训、能力等综合因素是其他任何资源都无法取代的。