首页 > 资讯 > 实时放行检验时代的到来？

出自识林

2015-11-18 Lachman CONSULTANTS

通常制药生产包括在生产过程的最终阶段对产品取样的实验室检验以保证作为产品放行的一部分的产品质量。然而，传统放行检验不再是用于确保产品放行前质量的唯一可接受方法。2015年9月15日，欧盟委员会发布修订版指南草案《EU GMP附录17：实时放行检验》。该草案文件用于提供关于实时放行检验（RTRT）的最新指导。该指南草案目前正在征求来自行业和公众的意见，截止日期为2015年12月11日。

什么是实时放行检验？指南草案中描述的关于该方法实施的要求是什么？

如指南草案定义，RTRT是“在线监测和控制的组合”，贯穿整个生产过程，被认为可以为批次放行提供足够的质量保证而不需要对生产工艺所生产产品（原料药、制剂和具体生物制品）执行终材料检验。

RTRT不是一个新概念。2001年7月，欧盟委员会发布原始的欧盟GMP附录17 “参数放行”。但，第一版仅关注最终灭菌产品日常放行的参数放行。拟议修订文件反映了在过程分析技术、QbD和质量风险管理原则方面的进步。在原始EU指南之后，FDA发布了指南文件，指出整个生产过程中工艺控制的适当组合与有效的监测和确认能够提供比仅对最终物料的传统检验更强的产品质量保障：（1）2004年9月“PAT-创新药物开发、生产和质量保证的框架工作行业指南”；（2）2006年6月“Q9 – 质量风险管理行业指南”；和（3）2009年8月“Q8（R2）药物研发 – 第二部分药物研发附录行业指南”。

实施RTRT策略的主要标准要求是： 1. 相关在线物料属性和过程参数的实时测量和控制应被证明能够准确预测对应成品属性。
2. 相关已评估的物料属性和过程控制的有效组合应建立在物料、产品和工艺知识的科学证据之上。
3. 组合过程测量（过程参数和物料属性）和在生产过程中产生/收集的任何其它检验数据应为RTRT和批次处理决定提供稳健的基础。

随着最近关于连续工艺技术在制药行业使用的讨论升级，RTRT的时代可能已经真正到来。然而，应该记住的是，在评估过程中和实施RTRT策略之前应考虑与相关监管机构交流，因为像其它新技术一样，你永远不知道FDA或其它监管机构将重点关注什么问题？

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

Real Time Release Testing – Has its Time Come?
By James Davidson | November 17, 2015

Generally, pharmaceutical manufacturing involves laboratory testing on product sampled at the end of the manufacturing process to assure the product quality as part of the product release. However, traditional release testing is not the only acceptable approach used to assure the quality product prior to release. On September 15, 2015, the European Commission published a revised draft Guidance, “Annex 17: Real Time Release Testing.” This draft document is intended to provide updated guidance on Real Time Release Testing (RTRT). This draft guidance is currently available for comments and input from the industry and public until December 11, 2015.

So, what is Real Time Release Testing and what requirements does the draft Guidance describe regarding the implementation of this approach?

As defined by the draft Guidance, RTRT is “a combination of in-process monitoring and controls” throughout the entire manufacturing process that are deemed to provide sufficient quality assurance for batch release without the need to perform analysis of the final materials that are the product of the manufacturing process (drug substance, drug product, and specified biologics).

RTRT is not a new concept. In July 2001, the European Commission published the original Annex 17 to the EU Guide to Good Manufacturing Practice, “Parametric Release.” However, this first version only focused on the application of Parametric Release for the routine release of terminally sterilized products. The proposed revised document reflects the advances in the application of process analytical technology, QbD, and quality risk management principles. Since the original EU guidance, the following FDA Guidance documents have been published, indicating that an appropriate combination of process controls together with effective monitoring and verification throughout the manufacturing process can provide greater assurance of product quality than just a traditional testing of the final materials: (1) Guidance for Industry “PAT – A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance,” September 2004; (2) Guidance for Industry “Q9 – Quality Risk Management,” June 2006; and (3) Guidance for Industry “Q8 (R2) Pharmaceutical Development – Part II Pharmaceutical Development Annex,” August 2009.

The main criteria required for implementing an RTRT strategy are:

1. Real time measurement and control of relevant in-process material attributes and process parameters should be demonstrated to be accurate predictors of the corresponding finished product attributes.

2. The valid combination of relevant assessed material attributes and process controls as the surrogates of finished product attributes should be established with scientific evidence founded on material, product, and process knowledge.

3. The combined process measurements (process parameters and material attributes) and any other test data generated/gathered during the manufacturing process should provide a robust foundation for RTRT and the batch disposition decision.

With the recent increased level of discussions regarding the use of continuous processing technology in the pharmaceutical industry, RTRT’s time likely has really arrived. However, it should be kept in mind that interaction with the relevant regulatory agency during the assessment process and prior to the implementation of an RTRT strategy should be considered because, like anything else new, you never know where the FDA or other regulatory authority will land on the issue.