首页 > 资讯 > 因批准前检查缺陷导致的完全回应函将会更多？

出自识林

2016-06-05 Lachman CONSULTANTS

过去两个月中，FDA对两个潜在的重磅炸弹药物的申请发布完全回应函（CRL）。收到CRL几乎是申请人在焦急的等待申请命运时等来的最糟糕的FDA沟通信件。自2008年完全回应函最终规定发布以来，如果FDA在审评结束后认为NDA或ANDA以其目前的形式未做好获批准备，FDA会向申请人发送CRL。大多数发出的CRL是出于对安全性和有效性的担忧或化学、生产和控制或生物等效性缺陷。然而，值得注意的是，最近发出的两封CRL是由于来自批准前检查（PAI）的生产观察项。将来是否会有更多CRL基于药品质量办公室新的整合审评程序来自于检查和生产缺陷？FDA是否真正通过整合跨产品审评学科的审评和检查实现质量只有一个声音？

PAI通常是在药品批准过程中最后完成的审评之一，意味着，如果发现缺陷可能影响患者对产品的可获得性。PAI的三个主要目标是：准备用于商业生产的场地状态，与申请中的承诺相符和数据可靠性；即，申请中递交数据的真实性、可靠性和准确性

随着供应链全球化和更家依赖合同制造商，无论新药产品在哪里制造，申请持有人不应该忽略支持药品制造的各种各样质量体系。PAI成功的关键是真正了解这样一个关键检查的目的，随后有条不紊的制定计划。

下面是关于PAI的快速回顾。通常被审查以证明企业已为商业制造做好准备的关键要素包括但不限于以下内容：

• 与新药制剂有关的整体现场GMP符合性
• 充足的设施、设备、关键公用设施 – 设施本身状况如何？是否有很好的维护？
• 申报批批记录（包括原始数据）
• 产品研发报告
• 工艺研发过程中的变更控制、偏差处理
• 取样计划 – 是否具有统计意义和代表性？
• 质量体系 – 偏差、实验室调查、产品处理、投诉和不良反应事件管理
• 稳定性程序
• 供应商资质程序；质量协议
• 交叉污染控制
• 培训
• 分析方法

与申请中的承诺相符要求配方、生产记录和分析方法与申请中CMC部分填写的内容一致。这意味着FDA将审评在申请中递交的设备、程序和支持性记录，核实这类设备的存在并用于申请中所列批次。此外，FDA将核实生产工艺与用于在申请中递交的生物等效性或临床批次的生产工艺相同，验证申请中递交的方法用于其预定用途，以及稳定性批次根据申请文件适当地贮存。

数据可靠性问题在过去几年中已经有许多报道，并且在常规GMP检查中被发现。数据可靠性问题也可能发生在PAI期间。FDA将审评原始数据（打印件和电子数据）以核实数据的准确性和真实性，并在申请递交的数据（生产和实验室数据）和检查期间审查的数据之间寻找无法解释的不一致。此外，将评估企业对色谱和/或独立系统以及生产计算机化系统的电子原始数据管理的控制，以保证数据不能被改变、删除或操控。其它可能导致数据可靠性的有问题的做法包括非同步记录、丢弃数据、无原始数据、文件倒填日期和重新运行样品以获得更好（或合格）的结果。

除了安排PAI的后勤工作，为检查员准备好现成的文件和加强内部管理，企业应预备好与检查员沟通交流的现场工作人员。企业是否对参与检查的人员分配好角色和职责？更重要的是，他们是否已经接受过如何回答检查员问题的培训？

最后，一直处于准备好接受检查的状态是管理责任！不要让你的PAI破坏可能的批准。时刻处于完全状态、做好心理准备，机灵点儿。

Lachman CONSULTANTS - Arlene Ocampo
编译：识林-椒
识林^®www.shilinx.com版权所有，未经许可不得转载。如需使用请联系admin@shilinx.com

Complete Response Letters Due to Failed PAIs – More to Come?
By Arlene Ocampo | June 2, 2016 原文地址

Over the course of the past two months, FDA issued a complete response letter (CRL) relative to the applications for two potential blockbuster drugs. Receiving a CRL is almost the worst FDA correspondence for an applicant as it anxiously awaits the fate of its application. Since the rule was made final in 2008 (Federal Register /Vol. 73, No. 133 /Thursday, July 10, 2008 /Rules and Regulations, Application for Approval to Market a New Drug: Complete Response Letter; Amendments to Unapproved Applications pdf), FDA has sent an applicant a CRL if FDA, upon the completion of its review, does not deem the NDA or ANDA is ready for approval in its present form. CRLs have mostly been issued based on safety and efficacy concerns or chemistry and manufacturing control (CMC) or bioequivalence deficiencies. However, it is noteworthy that the two recently issued CRLs were issued due to manufacturing observations from the pre-approval inspection (PAI). Will there be more CRLs to come inspectional and manufacturing deficiencies based on the new integrated review process within the Office of Pharmaceutical Quality? Will FDA truly speak with one quality voice by integrating review and inspection across product review disciplines?

The PAI is usually one of the last reviews completed during the drug approval process, which, if found deficient, may affect the availability of the product to the patient. Three main goals of a PAI are: site’s state of readiness for commercial manufacturing, conformance with the commitments in the application and data integrity; i.e. authenticity, reliability and accuracy of data submitted in the application.

With the globalization of the supply chain and more dependence on contract manufacturers, the application holder should not lose sight of the myriad of quality systems in support of the manufacture of drug product regardless where the new drug product is made. The key to a successful PAI is truly understanding the purpose of such a critical inspection and subsequently methodically plan for it.

The following is a quick refresher on PAIs.

Key items that are typically reviewed to demonstrate a firm is ready for commercial manufacturing include but are not limited to the following:

• Overall site GMP compliance as it relates to the new drug dosage form
• Adequacy of facility, equipment, critical utilities – how does the facility present itself? Is it well maintained?
• Batch records for submission batches (including raw data)
• Product development report
• Change control, deviations initiated during process development
• Sampling plans – are they statistical and representative?
• Quality systems – management of deviations, laboratory investigations, product disposition, complaints, adverse events
• Stability program
• Supplier qualification program; Quality Agreements
• Cross contamination controls
• Training
• Analytical methods

Conformance with the commitments in the application require that the formulation, manufacturing records and analytical methods are in accordance with what was filed in the CMC section of the application. This means that FDA will review equipment, procedures and supporting records submitted in the application and verify that such equipment exist and was used for the batches listed in the application. Additionally, FDA will verify that the manufacturing process is the same that was used for the bioequivalence or clinical batches submitted in the application, the method filed in the application is validated for its intended use, and that stability batches are stored appropriately per the application.

Data integrity (or lack thereof) has been given a lot of press in the last couple of years and has been uncovered during routine GMP inspections. It could also happen during a PAI. FDA will review raw data (hard copy and electronic) to verify accuracy and authenticity of data and look for unexplained discrepancies between data (manufacturing and laboratory) submitted in the application versus data reviewed during the inspection. Furthermore, firm’s controls for management of electronic raw data that reside in chromatographic and/or stand-alone systems as well as manufacturing computerized systems will be evaluated to assure data cannot be altered, deleted or manipulated. Other questionable practices that can lead to data integrity include non-contemporaneous recording, discarding data, no raw data, document back dating and re-running samples to obtain better (or passing) results.

In addition to setting the logistics for a PAI, having documents readily available for the investigator(s) and beefing up housekeeping, the firm should have site personnel ready for interacting with the investigator(s). Has the firm assigned roles and responsibilities for those participating during the inspection and more importantly, have they been trained to respond to the investigator’s questions?

Lastly, it is a management responsibility to be always inspection ready! Don't let your PAI derail a potential approval. Be ready, be smart and be prepared.