EMA对GMP无菌生产附录的修订来到十字路口
首页 > 资讯 > EMA对GMP无菌生产附录的修订来到十字路口 出自识林
EMA对GMP无菌生产附录的修订来到十字路口
2015-04-01 2015年2月5日, EMA, PIC/S发布了欧盟GMP指南附录1(无菌药品的生产)的修订概念文件草案,征求意见截止到2015年3月31日。预计将在10月份发布附录1草案,届时仍有6个月的时间来发表意见。附录1之前的修订分别在1996、2003、2007年,今年的修订将更为彻底。本次修订意在反映最近技术上的进步,要求按照ICH Q9风险管理、Q10质量管理系统来进行厂房、设备、无菌生产工艺的设计和实施,同时也解决历史文档中不准确和模糊的地方。 PDA就此专门设立了工作组征求意见。PDA主席 Hal Baseman 在3月16日的PDA年会上表示,更多情况下,PDA会基于科学立场考虑问题,而不仅是归纳行业现行做法,或者简单遵从监管者要求。他举例如下:“过去,生产商致力于在HEPA表面的空气流速达到90立方英尺/分钟。这一气流速度标准,是发明HEPA过滤器的海军工程师在二战时期制定的。现在不应停留在过去的技术水平,流速不应该是个固定数字,应该根据洁净间操作、动态气流、烟雾试验、悬浮粒子等级和进行的操作,得出最佳气流速度。 到目前,PDA已经有70项议题,其中38个涉及文档的第一部分。 1. 气流速度测量 2. 轧盖机的A级环境 3. 层流 vs. 单向流 4. ≥0.5μm 和 ≥5μm总颗粒的监测 5. 环境监测样品的培养温度 6. 使用前、后灭菌过滤器的完整性测试(PUPSIT) 7.使用两个灭菌过滤器进行产品无菌过滤 8. 注射用水生产方法的要求 最后Gori 建议大家不要贸然采用PDA的建议。企业为了欧盟上市产品,仍然需要符合欧盟要求,除非碰到的调查员用常识判断并且接受了大家的解释。 编译:识林-榕,识林-蕤 Resource Version For Reference Comments on the Annex 1 revision's concept paper are due March 31. Also, there will be another six months to comment after EMA and PIC/S issue a draft guideline in October. EMA and PIC/S previously revised the Annex 1 guideline in 1996, 2003 and 2007, but none of those revisions were as thorough as the one they' reconducting now.Why this revision? The guideline needs to reflect recent advances in technology as well as the International Conference on Harmonization's Q9 risk management and Q10 quality systems guidelines. There also are some historical inaccuracies and ambiguities in the document that the authorities intend to address. Hopkins, an inspector with the United Kingdom's Medicines Healthcare products Regulatory Agency, added some reasons of his own. The industry is losing its technical skill level. Much work has shifted to emerging economies where manufacturers still are “learning by deficiencies.” Also, there are new and emerging technologies, and areas still not covered by the guideline, such as media fills, small batches, active pharmaceutical ingredient campaigns, closed systems and blow fill seal technologies. PDA established an expert group that began meeting in July and on March 13 issued Part 1 of a new two-part points-to-consider document. “Rather than just present what people are doing in the industry or what our position might be in regard to what regulators are asking for, what we decided to do was focus on real science,” PDA Chair Hal Baseman told reporters March 16 at the PDA annual meeting in Las Vegas. “What is the state of the art there?” Baseman asked. “Well, the state of the art is not a number. The state of the art is to go in and look at your clean room operation, take a combination of dynamic air profile, smoke studies if you will, particulate levels, what's going on there, and devise from that what is the optimal velocity. … Today, the state of the art is to take a true risk-based design approach to it.” Gabriele Gori, GSK Vaccines, who with Baseman co-chairs PDA's points-to-consider task force, on March 18 described key positions PDA is taking in Part 1 of its points-to-consider document and requested input on possible additional topics for Part 2. Gori also updated the PDA meeting on the work of another task force, co-chaired by Jette Christensen, Novo Nordisk, and Bob Darius, GSK, that is comparing three sterile manufacturing GMP guidelines –the 2004 FDA guidance,a 2011 World Health Organization technical report annex and the current 2008 version of the EU GMP Annex 1. PDA plans to publish that workgroup's detailed comparison in May with the idea of encouraging regulators to identify key differences between the documents and perhaps further align their expectations PDA has so far developed 70 points consider, 38 of which it addressed in Part 1 of the document. Gori described some of the key positions in his remarks.
Unlike other GMP guides, Annex 1 gives a value for airflow velocity at the working position rather than at the HEPA filter face. PDA accepts the value, 0.45 meters per second, plus or minus 20%, but wants it measured 15 to 30 centimeters from the filter face. The association would add that the airflow should be unidirectional and sufficient to protect exposed product as well as packaging components and surfaces that contact the product.
There is no need for Annex 1 to continue requiring Grade A air over capping stations outside the aseptic core, or, as PIC/S clarified in 2010, near the HEPA filters that supply air to the capping stations, PDA says.
PDA says Annex 1 should require unidirectional rather than laminar airflow in Grade A critical zones because laminar airflow is unnecessary and virtually impossible.
Over the years, industry has chafed at the Annex 1 requirement to apply limits to air particles in Grade A environments and at-rest Grade B environments that are five microns or more in size.
PDA recommends that manufacturers be expected to choose temperature regimens for environmental sample incubation that are appropriate for the microorganisms of concern, and suggests that the use of non-selective microbial growth media such as casein soya bean digest agar and a single temperature within a 20 to 35 degree C range, plus or minus 2.5 degrees, should suffice.
PDA recommends case-by-case comprehensive risk assessments on whether to perform pre-use, post-sterilization integrity testing of sterilizing grade filters. The assessment should be done by line and by product, PDA says.
PDA says the authorities should not require redundant sterilizing filters in series, but that use of filters in parallel can be appropriate. Regardless, sterilizing filters should be placed to minimize the number of downstream aseptic connections.
PDA recommends allowing the use of any validated method such as reverse osmosis for achieving sufficient quality for water for injection. Gori cautioned the audience against adopting the PDA recommendations prematurely. “You still need to comply with the European requirements for the European markets, unless you have some investigator who's using common sense and accepts our interpretation.” 适用岗位:
工作建议:
适用范围: 文件要点:
以上仅为部分要点,请阅读原文,深入理解监管要求。 解读法规指南:FDA无菌药品生产指南 适用岗位:
工作建议:
适用范围: 要点总结:
结论: 法规指南解读:ICH Q10 Pharmaceutical Quality System 适用岗位(必读):
工作建议:
文件适用范围: 要点总结:
以上仅为部分要点,请阅读原文,深入理解监管要求。 岗位必读建议:
文件适用范围: 文件要点总结:
以上仅为部分要点,请阅读原文,深入理解监管要求。 适用岗位及工作建议:
文件适用范围: 文件要点总结: 以上仅为部分要点,请阅读原文,深入理解监管要求。 |