1. Introduction 序

One of the biggest issues facing the pharmaceutical industry and patients today is quality, integrity and security of the pharmaceutical supply chain, preventing contamination (adulteration) and eliminating counterfeits. Quality Systems, Supplier Quality Management and Supply Chain Integrity have come into focus in the recent past. A suitable Supplier Qualification Program has hence to be implemented by each user of purchased APIs (or intermediates). A major element of such a supplier qualification program is the Quality Agreement between the manufacturer of the API/intermediate and the buyer or user of the API/intermediate. It increases transparency and traceability by improving the supply relationship between all parties involved in the manufacturing and distribution of APIs and intermediates.

当今制药行业和患者面临的最大问题之一，是药品供应链的质量、完整性和安全性，即防止污染（掺假）和杜绝假冒伪劣产品。近年来，质量体系、供应商质量管理和供应链完整性已成为关注焦点。因此，每一个采购原料药（或中间体）的用户都必须实施合适的供应商资质认证计划。这一供应商资质认证计划的一个主要组成部分，是原料药/ 中间体制造商与原料药/ 中间体买方或用户之间的质量协议。它通过改善参与原料药和中间体制造及分销的各方之间的供应关系，提高了透明度和可追溯性。

Many companies, both users or buyers and manufacturers of APIs and intermediates, have developed their own Quality Agreement templates, often been designed to cover multiple types of products (APIs, intermediates, pharmaceutical excipients, and even packaging components), or to be used for both the purchase of (generic) APIs and contract manufacturing of (exclusive) substances (final APIs or intermediates). The high degree of diversity of agreements to be maintained increases complexity on both sides, resulting in extensive discussions between companies, and significant time and resources spent during all the review loops. It is a real challenge for all organisations to keep control over all the individual agreements and commitments made between the various parties (as regards, e.g., timelines, document provisions, notifications vs. prior approvals), which can be minimised by the use of standardised templates.

许多公司，无论是原料药及中间体的用户、买方，还是制造商，都制定了自己的质量协议模板。这些模板通常旨在涵盖多种类型的产品（原料药、中间体、药用辅料，甚至包装组件），或者既用于（仿制药）原料药的采购，也用于（独家）物质（最终原料药或中间体）的合同制造。需要维护的协议种类繁多，这增加了双方的工作复杂性，导致公司之间要进行大量讨论，在所有审核环节中耗费大量时间和资源。对所有组织来说，管控各方之间的各项协议和承诺（例如，在时间期限、文件条款、通知与事先批准等方面）是一项真正的挑战，而使用标准化模板可以将这种挑战降到最低。

Since APIC is committed to improving the relationship between API/intermediate users or buyers and API/intermediate manufacturers, APIC has developed this Quality Agreement Guideline plus the corresponding template. The APIC Task Force consisted of members from both specialised API/intermediate manufacturers and companies primarily making finished drug products. Hence APIC believes that the result represents best industry practice considering the needs and requirements of both parties that enter into such a Quality Agreement.

由于APIC 致力于改善原料药/中间体用户或买方与原料药/中间体制造商之间的关系，因此APIC 制定了本质量协议指南及相应的模板。APIC 特别工作组的成员既来自专业的原料药/中间体制造商，也来自主要生产成品药的公司。因此，APIC 认为，该成果体现了最佳行业实践，兼顾了签订此类质量协议双方的需求和要求。

1.1 What is a Quality Agreement? 质量协议是什么？

A Quality Agreement under the scope of this guideline is a legally binding agreement that is mutually negotiated and concluded between (the Quality Departments of) API/intermediate manufacturers and their customers. It is intended to define, in a formalised manner, responsibilities relative to quality tasks to assure the manufacture and supply of safe materials (APIs or intermediates) acceptable for pharmaceutical use. A Quality Agreement is based on the quality procedures in place at both the API/intermediate manufacturer and its customer. The Quality Agreement also includes commitments between the parties regarding (a) the provision of information, documents, or samples, and (b) communication and notification rules including contacts. It creates mutual understanding of the quality & regulatory requirements relevant for material supply and both the API/intermediate manufacturer’s and customer’s respective obligations related to quality. By clearly delineating responsibilities, costly product quality issues resulting from miscommunication can be reduced or eliminated.

本指南范围内的质量协议是原料药/ 中间体制造商（的质量部门）与其客户之间经相互协商达成的具有法律约束力的协议。其目的是以正式的方式明确与质量任务相关的责任，确保生产和供应可用于制药的安全物料（原料药或中间体）。质量协议基于原料药/ 中间体制造商及其客户现有的质量程序制定。质量协议还包括双方在以下方面的承诺：（a）提供信息、文件或样品；（b）沟通和通知规则，包括联系人信息。它使双方对物料供应相关的质量和监管要求，以及原料药/ 中间体制造商和客户各自的质量相关义务达成共识。通过明确划分责任，可以减少或消除因沟通不畅导致的高昂产品质量问题。

A Quality Agreement is a major element of an API/intermediate user’s supplier qualification program but, of course, it is not a substitute for the supplier qualification processes, including audits as necessary, and for understanding the supplier processes and capabilities.

质量协议是原料药/中间体用户供应商资质认证计划的重要组成部分，但它当然不能替代供应商资质认证过程，这其中包括必要的审计，以及对供应商流程和能力的了解。

A Quality Agreement should not contain any commercial or liability related terms, which should exclusively be dealt with in a Supply Agreement. This very common view is also shared by the US FDA, as clearly stated in its guidance on Quality Agreements (see chapter 4 of this document).

质量协议不应包含任何商业或责任相关条款，这些条款应专门在供应协议中处理。美国食品药品监督管理局（FDA）也认同这一普遍观点，在其质量协议指南中明确指出了这一点（见本文档第4 章）。

1.2 Relation to Supply Agreements 与供应协议的关系

Supply Agreements (also known as Commercial Agreements) document the legal and business relationship between API/intermediate manufacturers and their customers. Quality Agreements usually complement the Supply Agreements (if present). If and to the extent a Quality Agreement has been agreed upon, it is basically recommended to avoid quality provisions in Supply Agreements, whenever and to the extent possible, and rather to include a simple reference to the specific, complementary Quality Agreement. Items not directly related to Quality and regulatory compliance (e.g., Safety, Health & Environment items) should rather be included in the Supply Agreement. Nonetheless, one may frequently find combined agreements, often called “Technical Agreements”, mixing Quality/GMP/Regulatory items with detailed product-specific (“technical”) contents and other topics. It is recommended to implement separate agreements because these are easier to maintain.

供应协议（也称为商业协议）记录了原料药/中间体制造商与其客户之间的法律和业务关系。质量协议通常是对供应协议（如果有的话）的补充。如果并且在一定程度上已达成质量协议，基本上建议尽可能避免在供应协议中包含质量条款，而是简单提及具体的补充质量协议。与质量和法规符合性没有直接关系的条款（例如，安全、健康与环境条款）应包含在供应协议中。尽管如此，人们经常会看到合并协议，通常称为“技术协议”，其中将质量/药品生产质量管理规范（GMP/法规条款与详细的特定产品（“技术”）内容及其他主题混在一起。建议采用单独的协议，因为这样更易于维护。

Quality and Legal review of Supply Agreements should assure quality provisions are aligned/included in the corresponding Quality Agreements. Since Supply and Quality Agreement are often not generated at the same time or reviewed by the same people it is a must to define which document governs in case of conflict (see section III.3 of the Quality Agreement structure given in chapter 5).

对供应协议进行质量和法律审查时，应确保质量条款与相应的质量协议保持一致并纳入其中。由于供应协议和质量协议往往不是同时制定，也不是由同一批人审核，因此必须明确在出现冲突时以哪份文件为准（见第5 章质量协议结构的第三节第3 条）。

 

2. Purpose and Scope 目的和范围

2.1 Purpose

This document intends to provide expert guidance to the API/intermediate industry and its customers for the implementation and maintenance of appropriate Quality Agreements.

本文件旨在为原料药/中间体行业及其客户提供专业指导，以帮助他们签订和维护恰当的质量协议。

It is obvious that consistent standards for such agreements will provide the following benefits to the industry: 显然，此类协议的统一标准将为行业带来以下益处：

·Lower workload (by reduced drafting time)降低工作量（通过缩短起草时间）

·Faster implementation (by reduced review times)加快实施速度（通过缩短审核时间）

·Less complexity (by reduced diversity)降低复杂性（通过减少多样性）

Following this document will provide the current “state of the art” for Quality Agreements in the pharmaceutical (API/intermediate) supply chain.

遵循本文件将为制药（原料药/中间体）供应链中的质量协议提供当前的 “最佳实践”。

The APIC Quality Agreement Guideline and the corresponding template are designed to be a flexible model for preparing Quality Agreements wherever such an agreement is desired. It defines the appropriate items that should be addressed in a Quality Agreement. The template is designed to be global in scope and contents, thus being suitable for the use in all regions.

APIC 质量协议指南及相应模板旨在作为一个灵活的模型，用于在有需要的情况下起草质量协议。它明确了质量协议中应涉及的适当条款。该模板在范围和内容上具有通用性，因此适用于所有地区。

2.2 Scope

The guideline and template cover agreements between the API/intermediate manufacturer and its customers (whether users or distributors). The document does not cover the purchase of chemical/non-GMP raw materials by the API/intermediate manufacturer: the template is not really suitable for this purpose, but some parts of the template may be used to compile an agreement in that case. Furthermore, the template may not always be suitable for Atypical APIs. In such cases, the template may be adjusted, or alternative templates may be used, as appropriate (e.g., IPEC template; see reference 1). 

本指南和模板涵盖原料药/ 中间体制造商与其客户（无论是用户还是经销商）之间的协议。本文件不涵盖原料药/ 中间体制造商对化学/ 非药品生产质量管理规范（GMP）原材料的采购情况：该模板并不真正适用于此目的，但在这种情况下，模板的某些部分可用于编制相关协议。此外，该模板可能并不总是适用于非典型原料药。在这种情况下，可根据适当情况对模板进行调整，或者使用其他替代模板（例如，国际药用辅料协会（IPEC）模板）。

If the API is sold to a distributor by the original manufacturer and further sold by the distributor to one or multiple end-customers (MAHs), the following should be considered:

如果原料药由原制造商出售给经销商，然后经销商再将其进一步出售给一个或多个终端客户（上市许可持有人），则应考虑以下几点：

Best option from a legal and regulatory perspective, and recommended by APIC, is the closure of a 3-way agreement by API manufacturer and distributor with each end-customer. Prerequisite is that the API manufacturer knows all end-customers supplied through the distributor. The APIC Quality Agreement template may also be used for such 3-way agreements by adding a third column in the compliance section. Disadvantage of this option, from the API manufacturer’s view, is the potentially high number and complexity of Quality Agreements to be maintained. 

从法律和监管的角度来看，最佳选择，同时也是APIC 所推荐的，是原料药制造商、经销商与每一位终端客户签订三方协议。前提是原料药制造商知晓通过经销商供货的所有终端客户。通过在合规性部分添加第三列，APIC 质量协议模板也可用于此类三方协议。从原料药制造商的角度来看，这一选择的缺点是需要维护的质量协议数量可能较多，并且复杂程度较高。

Alternative, but less favourable option would be closure of a Quality Agreement between API manufacturer and distributor, and closure of further individual agreements between the distributor and each end-customer. All information and documentation related to the API (e.g., regulatory statements, change notifications) would be provided to end-customers solely by the distributor, who should have the full oversight. The end-customer would contact the distributor in all quality or regulatory matters, but not the API manufacturer directly. This approach is not permitted in some markets (e.g., in Japan where the MAH needs to have a Quality Agreement with the API manufacturer, not with the distributor).

另一种选择，但不太理想的做法是，原料药制造商与经销商签订质量协议，并且经销商与各个终端客户分别签订协议。所有与原料药相关的信息和文件（例如，监管声明、变更通知）都仅由经销商提供给终端客户，经销商应对此进行全面监督。终端客户在所有质量或监管事务方面应联系经销商，而不是直接联系原料药制造商。在某些市场，这种做法是不被允许的（例如，在日本，上市许可持有人需要与原料药制造商签订质量协议，而不是与经销商签订）。

From a practical point of view, the first option would allow audits at the API manufacturer by the end-customer (MAH). The second option would basically only permit audits by the distributor (and certainly 3rd party auditors as well); if agreed by all parties, joint audits by distributor and end-customer(s) might be considered.

从实际角度来看，第一种选择允许终端客户（上市许可持有人）对原料药制造商进行审计。第二种选择基本上只允许经销商（当然也包括第三方审计机构）进行审计；如果各方达成一致，也可以考虑由经销商和终端客户进行联合审计。

Closure of Quality Agreements directly between API manufacturer and end-customer(s) would also be possible in theory. However, as there is no business relationship between these two parties, this option is not recommended in practice.

从理论上来说，原料药制造商与终端客户之间直接签订质量协议也是可行的。然而，由于这两方之间不存在业务关系，所以在实际操作中不建议采用这种方式。

The template is suitable for both “generic APIs” and “exclusive substances”, including when they are supplied for use in clinical trials.

该模板适用于“非专利原料药” 和 “专有物质”，包括这些物质被供应用于临床试验的情况。

The term “generic API” is used for all APIs that in principle can be obtained from multiple sources, or are manufactured and supplied to multiple customers, as opposed to APIs that are sold only by the originator company or its exclusive licensees. Such generic APIs are off-patent; they are usually described in pharmacopoeial monographs, and supplied based on standard specifications. “Exclusive substances” are APIs or intermediates exclusively made for one customer who typically owns intellectual property rights on the process. This activity is also referred to as “Contract Manufacturing” or “Custom Synthesis”. It can be managed under a toll manufacturing supply agreement where main raw material(s) is furnished by Customer to Supplier.

“非专利原料药” 这一术语适用于原则上可从多个渠道获取的所有原料药，或者是指那些生产出来供应给多个客户的原料药，与之相对的是仅由原始研发公司或其独家被许可方销售的原料药。此类非专利原料药已不受专利保护；它们通常在药典专论中有记载，并根据标准规格进行供应。“专有物质” 是专门为某个客户生产的原料药或中间体，该客户通常对生产工艺拥有知识产权。这种活动也被称为 “合同生产” 或 “定制合成”。它可以根据委托生产供应协议进行管理，在这种协议下，主要原材料由客户提供给供应商。

“Supplier” is used broadly in this guideline and the corresponding template for a company that provides the “Product”, i.e., an API or API intermediate, to its “Customer”. The terms “Contract Acceptor” (instead of “Supplier”) and “Contract Giver” (instead of “Customer”) are considered synonymous in practice, and may hence be used alternatively, if preferred by the parties; they are quite common in the custom synthesis area. 

在本指南及相应模板中，“供应商” 被广泛用于指代向其 “客户” 提供 “产品”（即原料药或原料药中间体）的公司。在实际应用中，“合同承接方”（而非 “供应商”）和 “合同委托方”（而非 “客户”）这两个术语被认为是同义的，因此如果双方愿意，可交替使用；它们在定制合成领域相当常见。

Two separate templates were previously developed by APIC to cover generic APIs and exclusive substances. However, it was acknowledged that a vast majority of the requirements are similar for both categories and that these requirements are ultimately built to ensure the safety and efficacy of a finished drug, irrespective of those categories. Preference was then given to one standard template where some additional requirements usually applicable to exclusive substances are indicated as options. 

此前，APIC制定了两份不同的模板，分别用于非专利原料药和专有物质。然而，人们认识到，这两类物质的绝大多数要求是相似的，并且这些要求归根结底是为了确保成品药的安全性和有效性，而不论其属于哪一类物质。因此，更倾向于采用一份标准模板，其中一些通常适用于专有物质的额外要求被列为可选项。

Besides the IPEC Quality Agreements guideline/template mentioned above, the following documents may be useful in establishing Quality Agreements:

除了上述国际药用辅料协会（IPEC）的质量协议指南/ 模板之外，以下文件在制定质量协议时可能会有所帮助：

·The “Rx-360 Best Practices Quality Agreement Guide” (reference 2) constitutes a comprehensive guidance document that is intended to assist both customers and suppliers in efficiently managing the initiation, negotiation, implementation, and ongoing maintenance of Quality Agreements. The document covers all kinds of quality-relevant supplies and services purchased by drug product manufacturers (APIs, excipients, packaging materials, contract labs, etc.), and it includes example language for various purposes. It does, however, not provide additional Quality Agreement templates but refers to existing ones, e.g., the APIC template.

·《Rx-360 最佳实践质量协议指南》（参考文献 2）是一份全面的指导文件，旨在帮助客户和供应商高效管理质量协议的启动、谈判、实施以及持续维护工作。该文件涵盖了药品生产商所采购的各类与质量相关的供应品和服务（原料药、辅料、包装材料、合同实验室服务等），并且包含了用于各种目的的示例表述。不过，该文件并未提供额外的质量协议模板，而是引用了现有的模板，例如欧洲原料药协会（APIC）的模板。

·The “SOCMA Quality Agreement Template” (reference 3) does not – from a content perspective – too much differ from the APIC template. In special cases, it has proven to be a suitable alternative, especially for US customers.

·从内容角度来看，《美国特种化学品制造协会（SOCMA）质量协议模板》（参考文献 3）与欧洲原料药协会（APIC）的模板没有太大差异。在特殊情况下，已证实该模板是一个合适的替代选择，尤其适用于美国客户。

 

3. Legal Requirements 法规要求

Quality Agreements have become a common tool in our business and are intensively demanded by the authorities to be implemented. They have increasingly been referred to or described in international guidelines. Today, authorities basically do not consider the establishment of Quality Agreements as the sole responsibility of the drug product manufacturer anymore, but there are expectations at many national authorities also towards the API manufacturer to have Quality Agreements in place with its customers (MAHs).

质量协议已成为我们业务中的一种常用工具，并且受到监管部门的强烈要求予以实施。国际准则中也越来越多地提及或描述质量协议。如今，监管部门基本上不再认为制定质量协议仅是药品生产商的唯一责任，许多国家的监管部门也期望原料药制造商与其客户（上市许可持有人）签订质量协议。

Written contracts/agreements defining the responsibilities and communication processes for quality-related activities of the involved parties are mandatory for “contract manufacture” (see EU GMP Guide Part I, chapter 7 [see reference 4], and ICH Q7 Guideline, chapter 16 [see reference 5]) or “outsourced activities” (see ICH Q10 Guideline, chapter 2.7 [see reference 6]), respectively. In principle, it is the responsibility of the contract giver to request the closure of such a contract/agreement with its contract acceptor(s).

对于“合同生产”（见欧盟药品生产质量管理规范指南第一部分，第7 章[参考文献4]，以及国际人用药品注册技术协调会（ICH）Q7 指南，第16 章[参考文献5]）或 “外包活动”（见ICH Q10 指南，第2.7 章[参考文献6]），必须签订书面合同/ 协议，明确相关方在质量相关活动中的职责和沟通流程。原则上，合同委托方有责任要求与合同承接方签订此类合同/ 协议。

The situation is similar for “purchased (starting) materials” (see EU GMP Guide Part I, chapter 5.28 [see reference 4] or ICH Q10, chapter 2.7), in other words the purchase of “generic” APIs.

对于“采购的（起始）物料”（见欧盟药品生产质量管理规范指南第一部分，第5.28 章[见参考文献4] 或国际人用药品注册技术协调会（ICH）Q10 指南，第2.7 章），情况类似，也就是说，对于 “非专利” 原料药的采购也是如此。

In line with the above, some countries are requesting such agreements. For instance, the French “Code de la Santé Publique” (article R5124-47) [see reference 7] requires a written contract on the respective GMP obligations between the manufacturers of medicines and their raw material manufacturers.

与上述情况一致，一些国家要求签订此类协议。例如，法国《公共卫生法典》（第R5124-47 条）[见参考文献7] 要求药品制造商与其原材料制造商之间就各自的药品生产质量管理规范（GMP）义务签订书面合同。

In the United States, Quality Agreements are simply assumed but not necessarily a (legal) requirement. The Food and Drug Administration (FDA) has issued guidance for industry on Quality Agreements in the pharmaceutical industry (“Contract Manufacturing Arrangements for Drugs - Quality Agreements“, see reference 8). This guideline covers “manufacturing activities of the parties involved in contract drug manufacturing subject to CGMP”, and it makes reference to ICH Q7, chapter 16.11.

在美国，质量协议虽然被普遍认可，但不一定是（法律层面的）要求。美国食品药品监督管理局（FDA）已发布了关于制药行业质量协议的行业指南（《药品合同生产安排 —— 质量协议》，见参考文献8）。该指南涵盖了 “受现行药品生产质量管理规范（CGMP）约束的药品合同生产中各相关方的生产活动”，并且引用了国际人用药品注册技术协调会（ICH）Q7 指南的第16.11 章。

Specifically, this guidance addresses the relationship between “owners” and “contract facilities”. For purposes of its guidance for industry, the FDA defines owners as “manufacturers of APIs, drug substances, in-process materials, finished drug products, including biological products, and combination products” and contract facilities as “parties that perform one or more manufacturing operations on behalf of an owner or owners”.

具体而言，本指南阐述了“所有者” 与 “合同生产机构” 之间的关系。就其对行业的指导意义而言，美国食品药品监督管理局将 “所有者” 定义为 “原料药、药用物料、中间体、药品（包括生物制品）以及组合产品的制造商”，并将 “合同生产机构” 定义为 “代表一个或多个所有者开展一项或多项生产操作的相关方”。

While the FDA guidance document is focused on contract manufacturing, there is no such guideline for requirements of agreements for purchased APIs. In its guide the FDA only encourages “entities that engage in manufacturing related solely to drug distribution to follow the recommendations in this guidance document, as appropriate”.

虽然美国食品药品监督管理局（FDA）的指导文件侧重于合同生产，但对于所采购原料药的协议要求，却没有这样的指导准则。在其指南中，FDA 仅鼓励 “仅从事与药品分销相关生产活动的实体在适当情况下遵循本指导文件中的建议” 。

Furthermore, the FDA states that “Quality Agreements should not cover general business terms and conditions such as confidentiality, pricing or cost issues, delivery terms, or limits on liability or damages”. The agency recommends that “Quality Agreements be separate documents, or at least severable, from commercial contracts such as master services agreements or supply agreements”.

此外，美国食品药品监督管理局指出：“质量协议不应涵盖诸如保密、定价或成本问题、交付条款，或责任与损害赔偿限制等一般性商业条款和条件。” 该机构建议 “质量协议应与诸如主服务协议或供应协议等商业合同分开，或者至少是可分割的。”

The Japanese “Ministerial Ordinance on Standards for Quality Assurance for Drugs, Quasi-drugs, Cosmetics and Regenerative medical products” [see reference 9] and the “Ministerial Ordinance on Standards for Manufacturing Control and Quality Control of Drugs and Quasi-Drugs” [see reference 10] require that the Marketing Authorisation Holders of drugs should conclude a contract with their manufacturers (mentioned in the MA dossier) “to ensure that the manufacturing control and quality control are conducted properly and efficiently by the manufacturers”. Typically, for these GQP (Good Quality Practice) Agreements a specific template is used that significantly differs from the APIC template.

日本的《药品、类药品、化妆品及再生医疗产品质量保证标准部令》（见参考文献9）以及《药品和类药品生产管理及质量管理标准部令》（见参考文献10）规定，药品上市许可持有人应与其生产商（药品上市许可申请文件中提及的生产商）签订合同，“以确保生产商正确且高效地开展生产管理和质量管理工作”。通常情况下，对于这些良好质量规范（GQP）协议，会使用一个与欧洲原料药协会（APIC）模板有显著差异的特定模板。

 

4. Format and Structure of a Quality Agreement
质量协议的格式与结构

4.1 General Aspects 概述

The appendix to this APIC guideline constitutes a ready-to-use Quality Agreement (see typical structure of such an agreement in 5.2). The introduction and general provisions sections address the scope and terms and conditions of the agreement. The “Quality Responsibilities” section – in some cases also called “division (or: delimitation) of responsibilities” – includes the main quality and regulatory points and corresponding responsibilities that should typically be found in a Quality Agreement.

本欧洲原料药协会（APIC）指南的附录构成了一份可供直接使用的质量协议（关于此类协议的典型架构，见5.2）。引言和总则部分阐述了该协议的适用范围以及条款和条件。“质量责任” 部分（在某些情况下也称为 “责任划分”）包含了质量协议中通常应有的主要质量和监管要点以及相应责任。

The template does, however, not mention every item of the pharmaceutical quality system since quality requirements that are sufficiently covered by reference to the applicable quality/GMP standard (as stated in section 1 of the template) do not need to be reiterated in the agreement.

然而，该模板并未提及药品质量体系的每一项内容，因为那些已充分涵盖在适用的质量/ 药品生产质量管理规范标准（如模板第1 部分所述）中的质量要求无需在协议中重复提及。

The quality responsibilities may be assigned to one or both parties, as appropriate. In order to allow a convenient and quick overview a tabular format has been chosen for that section.

质量责任可根据情况分配给一方或双方。为了方便快捷地进行概述，该部分采用了表格形式。

The format of the template is intended to be flexible with the template offering all the single elements needed for most Quality Agreements.

该模板的格式具有灵活性，它提供了大多数质量协议所需的所有单项要素。

There are different possibilities how both parties may benefit from the use of a standardised template:双方可以通过使用标准化模板，以多种不同的方式从中获益：

·The template may completely replace an own agreement该模板可以完全替代一份自行拟定的协议

·The template may be used as a basis for a (slightly) modified, customized draft agreement该模板可用作（稍作）修改后的定制化协议草案的基础。

·Certain sections of the template may be used when drafting an own agreement在起草一份属于自己的协议时，可以使用模板中的某些部分。

·The template’s wording may be used to resolve dispute if mutually understood as good industry practice.如果双方都将模板中的措辞视为良好的行业惯例，那么这些措辞可用于解决纠纷。

Hence the template constitutes the ideal common starting point for any further negotiations on a Quality Agreement (see chapter 6 of this guideline).因此，该模板构成了就质量协议展开任何进一步谈判的理想共同出发点（见本指南的第6 章）。

Where necessary or requested by either party, country-specific or product-specific requirements may be added to the standard text.在必要时或应任何一方要求，可在标准文本中添加特定国家或特定产品的相关要求。

The template is available in English only as the English language is the most used language in global business and communication, hence constitutes the best common basis between parties of different native tongues.

该模板仅提供英文版本，因为英语是全球商业和交流中使用最广泛的语言，因此它构成了不同母语方之间的最佳共同基础。

Timelines mentioned in a Quality Agreement may be given in a descriptive way (most common terms: immediately, promptly, without undue delay, in a timely manner, within a reasonable period of time) or by a precise figure. Widely accepted definitions of the descriptive terms can be found in the glossary of this document. Time differences between the regions involved should be considered.

质量协议中提及的时间期限可以采用描述性的方式给出（最常见的表述有：立即、迅速、毫不迟延、及时、在合理期限内），也可以采用精确的数字来表示。这些描述性术语的广泛认可的定义可以在本文档的术语表中找到。同时，应考虑所涉地区之间的时差问题。

4.2 Standard Structure 标准结构

The following sections should normally be included in a Quality Agreements:

·以下部分通常应包含在质量协议中：

I.Introduction/Purpose/Scope引言/ 目的/ 范围

I.1Parties to the agreement协议各方

I.2Products covered by the agreement协议所涵盖的产品

I.3Site(s) involved涉及的场所

I.4Definitions and abbreviations (optional)定义和缩写（可选）

II.General Provisions一般条款

II.1Effective date生效日期

II.2Term of agreement协议期限

II.3Assignment转让

II.4Related agreements相关协议

II.5Amendments修正案

II.6Confidentiality (optional)保密（可选）

II.7Resolution of quality disputes (optional)质量争议的解决（可选）

II.8Choice of law (optional)法律适用（可选）

II.9Survival clause (optional)存续条款（可选）

III.Quality Responsibilities质量责任

IV.Signatories签署人

V.Contacts联系人

VI.List of Appendices附录清单

VII.History / Change Log历史记录/ 变更日志

4.3 How to create your “working template”?如何创建你的“工作模板”？

Simply take the APIC template (Appendix) and只需采取（APIC）模板（附录）并

·Remove all explanatory “notes”, unless deemed helpful for clarification purposes,除去所有解释性的“注释”，除非这些注释对澄清内容有帮助。

·Keep or remove the articles “for exclusive PRODUCT”, as applicable in your specific case,根据你具体情况的适用性，保留或删除“针对专属产品” 的条款。

·Keep or remove the “optional” text and/or select the appropriate “alternative” text, as needed.根据需要，保留或删除“可选” 文本，以及 / 或者选择合适的 “替代” 文本

For further details, also see the “Use instructions for sections I to III” after the table of contents in the template; these instructions should be removed as well, by the way.

如需了解更多详细信息，还可查看模板目录之后的“第一至第三部分使用说明”；顺便说一下，这些说明也应删除。

You have to do this exercise only once, prior to the first use of the APIC template. Thereafter, your individual core template is ready for instant use and has to be filled with the variable information only (e.g., CUSTOMER address, your sites(s) address(es), PRODUCT concerned, contact data). Finally, you may add any required appendices (e.g., PRODUCT specifications, approved sub-contractors), assigned as e.g., Appendix A, Appendix B etc. 

你只需在首次使用APIC模板之前进行这一操作。此后，你个人的核心模板就可以随时使用了，只需填写可变信息即可（例如，客户地址、你方站点地址、相关产品、联系数据）。最后，你可以添加任何所需的附录（例如，产品规格、经批准的分包商），并将其指定为附录A、附录B 等。

 

5. Negotiation and Maintenance谈判与维护

5.1 Negotiation, Review and Approvals谈判、审核与批准

Prior to starting negotiations, the expectations of both parties should be clarified, e.g., scope of the agreement (products, services, sites to be covered), use of a standard template vs. use of an individual document. Furthermore, it is recommended to mutually agree upon a timeline for review at the very beginning.

在开始谈判之前，双方的期望应当予以明确，例如协议的范围（涵盖的产品、服务、地点），是使用标准模板还是使用单独拟定的文件。此外，建议双方从一开始就共同商定审核的时间安排。

Basically, negotiation will become significantly easier and faster if standardized templates – ideally pre-reviewed by Legal – are used. The “time argument” will also be most convincing for a number of suppliers or customers to accept the use of a standard template (“if we can agree upon the ABC template, we may be ready for signature within two weeks”). Different options how to use a standard template have been given in chapter 5.1 already.

一般来说，如果使用标准化模板（理想情况下由法务预先审核），谈判会变得更加轻松和快捷。对于许多供应商或客户而言，“时间因素” 也极具说服力，促使他们接受使用标准模板（“如果我们能就ABC 模板达成一致，我们或许能在两周内准备好签署协议”）。第五章第一节中已经给出了关于如何使用标准模板的不同选择方案。

Modifying the template should, however, be done with care and only as necessary to avoid lengthy negotiations. It is suggested that the (generic) API manufacturer prepares a Quality Agreement based on the APIC template to begin the negotiation process with its customer when a Quality Agreement is requested. In Contract Manufacturing (i.e., for exclusive PRODUCT) the process will typically run the other way round.

不过，对模板进行修改时应谨慎操作，并且只有在必要时才进行修改，以避免漫长的谈判过程。建议（通用的）活性药物成分（API）制造商在客户要求签订质量协议时，基于亚太地区（APIC）模板准备一份质量协议，以此开启与客户的谈判流程。在合同制造领域（即针对专属产品的情况），流程通常会是另外一种模式。

Individuals negotiating should have full knowledge of the rationale behind the text. It is best practice to provide justification for any changes to major terms, to explain why a certain paragraph is written as it is, or to have a reasoned justification ready for any non-negotiable elements to explain why the clause cannot be changed. If major changes are made to the standard template, especially the general provisions, Legal experts may need to be consulted. It would significantly facilitate the discussion if any such alterations are clearly indicated by the drafting party to the other party (e.g., by coloured text) as this will help to achieve speedier closure of agreements.

不过，对模板进行修改时应谨慎操作，并且只有在必要时才进行修改，以避免漫长的谈判过程。建议（通用的）活性药物成分（API）制造商在客户要求签订质量协议时，基于亚太地区（APIC）模板准备一份质量协议，以此开启与客户的谈判流程。在合同制造领域（即针对专属产品的情况），流程通常会是另外一种模式。

The negotiation and review of a Quality Agreement should always be a collaborative effort of different departments of the parties involved: Quality representatives negotiate and review the quality sections, and Legal representatives negotiate and review the legal provisions. Other departments (e.g., Purchasing, Marketing) may be involved, as appropriate. It is recommended that in the negotiation phase a sole functional unit, preferably the Quality Unit, acts as the voice of the entire company.

质量协议的谈判和审核应始终是相关各方不同部门共同协作的工作：质量代表负责对质量条款进行谈判和审核，法律代表负责对法律条款进行谈判和审核。其他部门（如采购部门、市场部门等）也可在适当的时候参与其中。建议在谈判阶段，由单一的职能部门（最好是质量部门）作为整个公司的代表发声。

The Quality representatives at API/intermediate manufacturer and customer must assure that the quality provisions can be met, i.e., that the obligations of the agreement are consistent with the quality systems established at the respective sites [Note: this is very important in case multiple sites or affiliates at either party are affected by the agreement], and both parties must understand the impact of the agreement provisions on patient safety and product quality.

活性药物成分（API）/ 中间体制造商和客户方的质量代表必须确保能够满足质量条款，也就是说，协议中的各项义务要与各自场所建立的质量体系相一致[注意：如果协议影响到双方的多个场所或附属机构，这一点非常重要]，并且双方都必须了解协议条款对患者安全和产品质量的影响。

In order to allow review of any modified wording or any requirements added during the negotiation phase and to ensure transparency and traceability the “track changes mode”, i.e., redline rather than clean versions should be used. A “cleaned” version would be created only directly before signature, after all parties are satisfied with the draft agreement.

为了能够对谈判阶段修改的措辞或新增的要求进行审查，并确保透明度和可追溯性，应使用“修订跟踪模式”，也就是采用显示修订痕迹的版本，而不是无修订痕迹的版本。只有在所有各方都对协议草案感到满意之后，才应在签字前直接创建一份无修订痕迹的“净洁” 版本。

Clarity of language in the Quality Agreement is essential. Quality Agreements have no room for ambiguity. It is generally recommended that the wording of Quality Agreements is kept “simple” or “non-legal” (at least all sections except the “general provisions”) since it is primarily written for Quality people, and these people have to understand and follow the provisions.

质量协议中的语言表达清晰至关重要。质量协议不容许存在模棱两可之处。一般建议质量协议的措辞保持“简洁” 或“非法律化”（至少除“一般条款” 外的所有部分），因为质量协议主要是为质量相关人员编写的，这些人员必须理解并遵守协议条款。

A Legal review of the final draft agreement is recommended, irrespective if the Quality Agreement is a stand-alone document or if the Supply Agreement is negotiated at the same time. Not having the Quality Agreement undergo a qualified review by Legal department may expose the company to potential liability. It is, however, not the Legal representatives’ task to interpret GMPs and change the language unless potential liability exists. It is their job to look at the document from the point of view of someone who is providing a level of protection to the company.

建议对协议最终草案进行法务审查，无论质量协议是一份独立文件，还是与供应协议同时进行谈判。如果质量协议没有经过法务部门的合格审查，公司可能会面临潜在的法律责任。不过，除非存在潜在的法律责任，否则解释药品生产质量管理规范（GMP）和修改措辞并非法务代表的工作。法务代表的工作是从为公司提供一定程度保护的角度来审视该文件。

The following wording recommendations aim to avoid future dispute and unexpected liability with respect to requirements and commitments in Quality Agreements, and they have been considered in the APIC template:

以下措辞建议旨在避免就质量协议中的要求和承诺产生未来的争议以及意外的责任，并且这些建议已在APIC模板中得到了考量：

·Do not use expressions such as “SUPPLIER guarantees”, “SUPPLIER represents and warrants”, or similar in Quality Agreements. “Guarantee”, in particular, triggers extended rights of the purchaser, liability without any fault, and leads to extended statute of limitations.在质量协议中，请勿使用诸如“供应商保证”“供应商声明并保证” 之类的表述或类似表述。尤其是“保证” 一词，会引发采购方的额外权利、无过错责任，还会导致诉讼时效延长。

·Instead use “neutral” expressions like “SUPPLIER shall“, “SUPPLIER undertakes”, or “SUPPLIER shall make reasonable endeavours” (but not “best” endeavours).相反，应使用“中立” 的表述，例如“供应商应”“供应商承诺” 或“供应商应尽合理努力”（但不要用“最大” 努力）。

When a supply agreement exists or is being generated at the same time as the Quality Agreement, the reviewers should assure that any quality provisions captured in the supply agreement are also reflected and/or not contradicted in the Quality Agreement. Preferably, no quality provisions should be captured in a Supply Agreement (see also chapters 2 and 4).

当存在供应协议，或者供应协议与质量协议同时制定时，审核人员应确保供应协议中包含的任何质量条款也在质量协议中有所体现，并且不会相互矛盾。最好是供应协议中不包含任何质量条款（另见第二章和第四章）。

Since all Quality Agreements require legally binding signatures, it is the responsibility of each party to assure the signatures in the Quality Agreement reflect the legally binding signatures representing each party. Depending on the signing rules in each company two or even more signatures might be required. At least one signature should come from an authorised Quality Unit representative.

由于所有质量协议都需要具有法律约束力的签名，因此各方有责任确保质量协议中的签名能够体现代表各方的具有法律约束力的签字。根据每家公司的签署规则，可能需要两个甚至更多的签名。至少应有一个签名来自经授权的质量部门代表。

Once the parties have finished their discussion on the content, they should agree upon the signature/approval process (e.g., who signs first?) and the form of the final approved contract (e.g., use of wet ink vs. electronic signatures, paper copies vs. pdf files, number of –where required– hardcopies for each party, all signatures on one page vs. compilation of pages with one or more signatures). All these options are basically acceptable from a Legal view, so the parties’ company-internal rules or preferences will determine the outcome. Some companies are used to initial each page of the Quality Agreement, which is, however, not required from a Legal perspective.

一旦双方完成了对协议内容的讨论，他们应当就签字 / 审批流程达成一致（例如，由谁先签字？），以及最终获批合同的形式（例如，使用手写签名还是电子签名，采用纸质副本还是PDF 文件，每一方所需的硬拷贝份数，是所有签名都在同一页上，还是将有一个或多个签名的页面汇编在一起）。从法律角度来看，所有这些选择基本上都是可以接受的，所以最终的决定将取决于双方公司的内部规定或偏好。有些公司习惯在质量协议的每一页上都签姓名首字母，但从法律角度来说，这并非必要。

5.2 Maintaining Agreements协议的维护

Any Quality Agreement should be readily available to all persons or units with obligations stipulated in the agreement. It is recommended to have a system in place for tracking commitments originating from the various Quality Agreements.

任何质量协议都应可供承担协议中规定义务的所有人员或单位随时查阅。建议建立一个系统，用以跟踪源自各类质量协议的承诺。

Once approved all Quality Agreements must be kept current by both parties during the entire effective period. An amendment/addendum process should allow for simple updating, i.e. updating without requiring the entire document to go back through review and approval steps, e.g., for contact or specification updates. Any amendment/addendum should be maintained with the original agreement.

所有质量协议一经批准，双方在整个有效期内都必须使其保持为最新版本。对于修订 / 附录流程，应使其便于进行简单的更新，也就是说，在进行更新时无需将整个文件重新经过审核和批准步骤，例如在进行联系方式或规格更新时。任何修订/ 附录都应与原始协议一并留存。

Since organisations, responsibilities, scope of the agreement, regulatory environment or other aspects may change over the time, both parties should review the existing Quality Agreement in regular intervals. Basically, there are different options to define the review frequency for an established Quality Agreement: periodic review (e.g., during the compilation of the annual PQRs or every 2 or 3 years) or a frequency based on risk. A combination of both options might be the best solution, e.g., a 3-years review period in the absence of critical quality incidents or significant risks.

由于组织架构、职责、协议范围、监管环境或其他方面可能会随着时间发生变化，双方应定期对现有的质量协议进行审查。基本上，对于已确立的质量协议，有不同的方式来确定审查频率：定期审查（例如，在编制年度产品质量回顾（PQR）时，或每两到三年进行一次回顾），或者基于风险确定审查频率。将这两种方式结合起来可能是最佳解决方案，例如，在没有关键质量事件或重大风险的情况下，设定三年的审查周期。

 

6. References

1.The IPEC Quality Agreement Guide and Template 2017

2.Rx-360 Best Practices Quality Agreement Guide, version 3, 2022

3.SOCMA Quality Agreement Template, April 2010

4.EU GMP Guide Part I, Basic Requirements for Medicinal Products

5.ICH Q7 Guideline “Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients”, November 2000 

6.ICH Q10 Guideline “Pharmaceutical Quality System”, June 2008

7.Code de la Santé Publique Française, article R5124-47, January 2017

8.FDA Guidance for Industry: Contract Manufacturing Arrangements for Drugs - Quality Agreements -, November 2016

9.MHLW Ministerial Ordinance No. 136, September 2004

10.Ministerial Ordinance on Standards for Manufacturing Control and Quality Control of Drugs and Quasi-Drugs” (MHLW Ordinance No.179, 2004/revised July 2014)

11.EC “Guidelines of 19 March 2015 on principles of Good Distribution Practice of active substances for medicinal products for human use” (2015/C 95/01)

12.Annex 5 WHO good distribution practices, WHO Technical Report Series, No. 957, 2010 

 

7. Glossarys 术语

 

8. Appendix 附录

·APIC Quality Agreement Template for APIs (27 pages)APIC质量协议模板（27 页）

 

9. History / Change Log 历史记录/ 变更日志

Version 版本	Published in 出版时间	Description of change(s), incl. reason, where appropriate 变更描述，包括（如适用）变更原因
1	2009	New document (guideline plus two templates for each generic and exclusive substances) 新文件（指南以及针对通用物质和专属物质各有两份模板）