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Legal context for publishing the detailed guidelines: Article 47 of Directive 2001/83/EC on the Community code relating to medicinal products for human use and Regulation 2019/6 on the Community code relating to veterinary medicinal products. This document provides technical guidance on the principles and guidelines of good manufacturing practice (GMP) for medicinal products as laid down in Commission Directive (EU) 2017/1572 for medicinal products for human use, Directive 91/412/EEC for veterinary use, and Commission Delegated Regulation (EU) 2017/1569 for investigational medicinal products for human use and arrangements for inspections supplementing Regulation (EU) No 536/2014 on clinical trials. This Annex is intended to assist national authorities in the application of the EU legislation. Only the Court of Justice of the European Union is competent to authoritatively interpret Union law. 解读：说明了三种无菌产品适用于本附录，人用药、兽用药和IMP。对于无菌的IMP，无菌保证是确保临床试验安全性的一个重要因素，应当是需要fully满足本附录要求的。 Reasons for changes: The GMP/GDP Inspectors Working Group and the PIC/S Committee jointly recommend that the current version of annex 1, on the manufacture of sterile medicinal products, is revised to reflect changes in regulatory and manufacturing environments. The new guideline should clarify how manufacturers can take advantage of new possibilities deriving from the application of an enhanced process understanding by using innovative tools as described in the ICH Q9 and Q10 guidelines. The revision of Annex 1 should also take into account related changes in other GMP chapters and annexes as well as in other regulatory documents. The revised guideline will seek to remove ambiguity and inconsistencies and will take account of advances in technologies. 解读：修订的目的是符合行业的变化，确实从上一版的附录一正式实施至今也超过十年了，国内参照此附录起草的附录一，也用了超过十年了。说得很好，拒绝对新技术的模棱两可和不一致，但是是不是对新技术的描述和理解，也过于超前了呢？ Document map Section Number General overview 1. Scope Includes additional areas (other than sterile products) where the general principles of the annex can be applied. 2. Principle General principles as applied to the manufacture of sterile products. 3. Pharmaceutical Quality System (PQS) Highlights the specific requirements of the PQS when applied to sterile products. 4. Premises General guidance regarding the specific needs for premises design and also guidance on the qualification of premises including the use of Barrier Technology. 5. Equipment General guidance on the design and operation of equipment. 6. Utilities Guidance regarding the special requirements of utilities such as water, gas and vacuum. 7. Personnel Guidance on the requirements for specific training, knowledge and skills. Also gives guidance regarding the qualification of personnel. 8. Production and specific technologies Guidance on the approaches to be taken regarding aseptic and terminal sterilization processes. Guidance on the approaches to sterilization of products, equipment and packaging components. Also guidance on different technologies such as lyophilization and Form-Fill-Seal where specific requirements apply. 9. Environmental and process monitoring This section differs from guidance given in section 4 in that the guidance here applies to ongoing routine monitoring regarding the design of systems and setting of action limits alert levels and reviewing trend data. The section also gives guidance on the requirements of Aseptic Process Simulations (APS). 10. Quality control (QC) Guidance on some of the specific Quality Control requirements relating to sterile products. 11. Glossary Explanation of specific terminology. 解读：很有意义的章节，看过后就知道这个文件是不是完整了。2008年的版本，上来就是 Principles，没有任何的概括性介绍，不像样子。同时，在map中也说明了这个文件的很多重要的知识点，至少我是看出了PQS、APS、新技术和设备等几个知识点，必然是它所关注的。 1 Scope The manufacture of sterile products covers a wide range of sterile product types (active substance, excipient, primary packaging material and finished dosage form), packed sizes (single unit to multiple units), processes (from highly automated systems to manual processes) and technologies (e.g. biotechnology, classical small molecule manufacturing systems and closed systems). This Annex provides general guidance that should be used in the design and control of facilities, equipment, systems and procedures used for the manufacture of all sterile products applying the principles of Quality Risk Management (QRM), to ensure that microbial, particulate and endotoxin/pyrogen contamination is prevented in the final product. 解读：首先，对于老工艺和新工艺，认为都是可以生产无菌产品的，例如manual processes，这种方式国内已经很少见了，甚至IMPs的制备，都很少有人还用手动的工艺了。我理解，这里的手动工艺应该指的并不是手动的灌装工艺，而是可验证的低风险无菌生产工艺（例如冻干工艺中的进出箱，2016年在京津冀某家国内大型中药制药企业看到的中药注射液的冻干产品，还是人工进出箱，但是semi-stoppering却属于较低风险的状态）或是最终灭菌产品的部分工艺。其次，这个章节中说了一个很关键的内容，就是无菌产品的污染风险的三个分类，这是与产品其它性质无关的污染，只要是无菌产品就会有这些污染的风险：微生物、颗粒和热原/内毒素。这三个风险贯穿于本附录的始终。 QRM applies to this document in its entirety and will not, normally, be referred to in specific paragraphs. Where specific limits or frequencies or ranges are specified, these should be considered as a minimum requirement. They are stated due to historical regulatory experience of issues that have been identified and have impacted the safety of patients. 解读：本附录中直接规定限度、频次或范围的地方，都代表最低的要求。这些地方之所以做规定，是因为基于过去的合规历史和对患者的风险，这些地方都是容易出问题的。但这种直接规定，确实和QRM的原则有违背，所以在这里特别说明一下。 The intent of the Annex is to provide guidance for the manufacture of sterile products. However, some of the principles and guidance, such as contamination control strategy, design of premises, cleanroom classification, qualification, validation, monitoring and personnel gowning, may be used to support the manufacture of other products that are not intended to be sterile such as certain liquids, creams, ointments and low bioburden biological intermediates, but where the control and reduction of microbial, particulate and endotoxin/pyrogen contamination is considered important. Where a manufacturer elects to apply guidance herein to non-sterile products, the manufacturer should clearly document which principles have been applied and acknowledge that compliance with those principles should be demonstrated. 解读：没啥可说的，非无菌产品要是谁按照Annex 1来进行控制，那得是附加值多高的产品？ |
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