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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.
當(dāng)今制藥行業(yè)和患者面臨的最大問(wèn)題之一，是藥品供應(yīng)鏈的質(zhì)量、完整性和安全性，即防止污染（摻假）和杜絕假冒偽劣產(chǎn)品。近年來(lái)，質(zhì)量體系、供應(yīng)商質(zhì)量管理和供應(yīng)鏈完整性已成為關(guān)注焦點(diǎn)。因此，每一個(gè)采購(gòu)原料藥（或中間體）的用戶都必須實(shí)施合適的供應(yīng)商資質(zhì)認(rèn)證計(jì)劃。這一供應(yīng)商資質(zhì)認(rèn)證計(jì)劃的一個(gè)主要組成部分，是原料藥/ 中間體制造商與原料藥/ 中間體買(mǎi)方或用戶之間的質(zhì)量協(xié)議。它通過(guò)改善參與原料藥和中間體制造及分銷(xiāo)的各方之間的供應(yīng)關(guān)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.
許多公司，無(wú)論是原料藥及中間體的用戶、買(mǎi)方，還是制造商，都制定了自己的質(zhì)量協(xié)議模板。這些模板通常旨在涵蓋多種類(lèi)型的產(chǎn)品（原料藥、中間體、藥用輔料，甚至包裝組件），或者既用于（仿制藥）原料藥的采購(gòu)，也用于（獨(dú)家）物質(zhì)（最終原料藥或中間體）的合同制造。需要維護(hù)的協(xié)議種類(lèi)繁多，這增加了雙方的工作復(fù)雜性，導(dǎo)致公司之間要進(jìn)行大量討論，在所有審核環(huán)節(jié)中耗費(fèi)大量時(shí)間和資源。對(duì)所有組織來(lái)說(shuō)，管控各方之間的各項(xiàng)協(xié)議和承諾（例如，在時(shí)間期限、文件條款、通知與事先批準(zhǔn)等方面）是一項(xiàng)真正的挑戰(zhàn)，而使用標(biāo)準(zhǔn)化模板可以將這種挑戰(zhàn)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 致力于改善原料藥/中間體用戶或買(mǎi)方與原料藥/中間體制造商之間的關(guān)系，因此APIC 制定了本質(zhì)量協(xié)議指南及相應(yīng)的模板。APIC 特別工作組的成員既來(lái)自專(zhuān)業(yè)的原料藥/中間體制造商，也來(lái)自主要生產(chǎn)成品藥的公司。因此，APIC 認(rèn)為，該成果體現(xiàn)了最佳行業(yè)實(shí)踐，兼顧了簽訂此類(lèi)質(zhì)量協(xié)議雙方的需求和要求。
1.1 What is a Quality Agreement? 質(zhì)量協(xié)議是什么？
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.
本指南范圍內(nèi)的質(zhì)量協(xié)議是原料藥/ 中間體制造商（的質(zhì)量部門(mén)）與其客戶之間經(jīng)相互協(xié)商達(dá)成的具有法律約束力的協(xié)議。其目的是以正式的方式明確與質(zhì)量任務(wù)相關(guān)的責(zé)任，確保生產(chǎn)和供應(yīng)可用于制藥的安全物料（原料藥或中間體）。質(zhì)量協(xié)議基于原料藥/ 中間體制造商及其客戶現(xiàn)有的質(zhì)量程序制定。質(zhì)量協(xié)議還包括雙方在以下方面的承諾：（a）提供信息、文件或樣品；（b）溝通和通知規(guī)則，包括聯(lián)系人信息。它使雙方對(duì)物料供應(yīng)相關(guān)的質(zhì)量和監(jiān)管要求，以及原料藥/ 中間體制造商和客戶各自的質(zhì)量相關(guān)義務(wù)達(dá)成共識(shí)。通過(guò)明確劃分責(zé)任，可以減少或消除因溝通不暢導(dǎo)致的高昂產(chǎn)品質(zhì)量問(wèn)題。
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.
質(zhì)量協(xié)議是原料藥/中間體用戶供應(yīng)商資質(zhì)認(rèn)證計(jì)劃的重要組成部分，但它當(dāng)然不能替代供應(yīng)商資質(zhì)認(rèn)證過(guò)程，這其中包括必要的審計(jì)，以及對(duì)供應(yīng)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).
質(zhì)量協(xié)議不應(yīng)包含任何商業(yè)或責(zé)任相關(guān)條款，這些條款應(yīng)專(zhuān)門(mén)在供應(yīng)協(xié)議中處理。美國(guó)食品藥品監(jiān)督管理局（FDA）也認(rèn)同這一普遍觀點(diǎn)，在其質(zhì)量協(xié)議指南中明確指出了這一點(diǎn)（見(jiàn)本文檔第4 章）。
1.2 Relation to Supply Agreements 與供應(yīng)協(xié)議的關(guān)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.
供應(yīng)協(xié)議（也稱(chēng)為商業(yè)協(xié)議）記錄了原料藥/中間體制造商與其客戶之間的法律和業(yè)務(wù)關(guān)系。質(zhì)量協(xié)議通常是對(duì)供應(yīng)協(xié)議（如果有的話）的補(bǔ)充。如果并且在一定程度上已達(dá)成質(zhì)量協(xié)議，基本上建議盡可能避免在供應(yīng)協(xié)議中包含質(zhì)量條款，而是簡(jiǎn)單提及具體的補(bǔ)充質(zhì)量協(xié)議。與質(zhì)量和法規(guī)符合性沒(méi)有直接關(guān)系的條款（例如，安全、健康與環(huán)境條款）應(yīng)包含在供應(yīng)協(xié)議中。盡管如此，人們經(jīng)常會(huì)看到合并協(xié)議，通常稱(chēng)為“技術(shù)協(xié)議”，其中將質(zhì)量/藥品生產(chǎn)質(zhì)量管理規(guī)范（GMP/法規(guī)條款與詳細(xì)的特定產(chǎn)品（“技術(shù)”）內(nèi)容及其他主題混在一起。建議采用單獨(dú)的協(xié)議，因?yàn)檫@樣更易于維護(hù)。
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).
對(duì)供應(yīng)協(xié)議進(jìn)行質(zhì)量和法律審查時(shí)，應(yīng)確保質(zhì)量條款與相應(yīng)的質(zhì)量協(xié)議保持一致并納入其中。由于供應(yīng)協(xié)議和質(zhì)量協(xié)議往往不是同時(shí)制定，也不是由同一批人審核，因此必須明確在出現(xiàn)沖突時(shí)以哪份文件為準(zhǔn)（見(jiàn)第5 章質(zhì)量協(xié)議結(jié)構(gòu)的第三節(jié)第3 條）。
2. Purpose and Scope 目的和范圍
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.
本文件旨在為原料藥/中間體行業(yè)及其客戶提供專(zhuān)業(yè)指導(dǎo)，以幫助他們簽訂和維護(hù)恰當(dāng)?shù)馁|(zhì)量協(xié)議。
It is obvious that consistent standards for such agreements will provide the following benefits to the industry: 顯然，此類(lèi)協(xié)議的統(tǒng)一標(biāo)準(zhǔn)將為行業(yè)帶來(lái)以下益處：
·Lower workload (by reduced drafting time)降低工作量（通過(guò)縮短起草時(shí)間）
·Faster implementation (by reduced review times)加快實(shí)施速度（通過(guò)縮短審核時(shí)間）
·Less complexity (by reduced diversity)降低復(fù)雜性（通過(guò)減少多樣性）
Following this document will provide the current “state of the art” for Quality Agreements in the pharmaceutical (API/intermediate) supply chain.
遵循本文件將為制藥（原料藥/中間體）供應(yīng)鏈中的質(zhì)量協(xié)議提供當(dāng)前的 “最佳實(shí)踐”。
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 質(zhì)量協(xié)議指南及相應(yīng)模板旨在作為一個(gè)靈活的模型，用于在有需要的情況下起草質(zhì)量協(xié)議。它明確了質(zhì)量協(xié)議中應(yīng)涉及的適當(dāng)條款。該模板在范圍和內(nèi)容上具有通用性，因此適用于所有地區(qū)。
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).
本指南和模板涵蓋原料藥/ 中間體制造商與其客戶（無(wú)論是用戶還是經(jīng)銷(xiāo)商）之間的協(xié)議。本文件不涵蓋原料藥/ 中間體制造商對(duì)化學(xué)/ 非藥品生產(chǎn)質(zhì)量管理規(guī)范（GMP）原材料的采購(gòu)情況：該模板并不真正適用于此目的，但在這種情況下，模板的某些部分可用于編制相關(guān)協(xié)議。此外，該模板可能并不總是適用于非典型原料藥。在這種情況下，可根據(jù)適當(dāng)情況對(duì)模板進(jìn)行調(diào)整，或者使用其他替代模板（例如，國(guó)際藥用輔料協(xié)會(huì)（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:
如果原料藥由原制造商出售給經(jīng)銷(xiāo)商，然后經(jīng)銷(xiāo)商再將其進(jìn)一步出售給一個(gè)或多個(gè)終端客戶（上市許可持有人），則應(yīng)考慮以下幾點(diǎn)：
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.
從法律和監(jiān)管的角度來(lái)看，最佳選擇，同時(shí)也是APIC 所推薦的，是原料藥制造商、經(jīng)銷(xiāo)商與每一位終端客戶簽訂三方協(xié)議。前提是原料藥制造商知曉通過(guò)經(jīng)銷(xiāo)商供貨的所有終端客戶。通過(guò)在合規(guī)性部分添加第三列，APIC 質(zhì)量協(xié)議模板也可用于此類(lèi)三方協(xié)議。從原料藥制造商的角度來(lái)看，這一選擇的缺點(diǎn)是需要維護(hù)的質(zhì)量協(xié)議數(shù)量可能較多，并且復(fù)雜程度較高。
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).
另一種選擇，但不太理想的做法是，原料藥制造商與經(jīng)銷(xiāo)商簽訂質(zhì)量協(xié)議，并且經(jīng)銷(xiāo)商與各個(gè)終端客戶分別簽訂協(xié)議。所有與原料藥相關(guān)的信息和文件（例如，監(jiān)管聲明、變更通知）都僅由經(jīng)銷(xiāo)商提供給終端客戶，經(jīng)銷(xiāo)商應(yīng)對(duì)此進(jìn)行全面監(jiān)督。終端客戶在所有質(zhì)量或監(jiān)管事務(wù)方面應(yīng)聯(lián)系經(jīng)銷(xiāo)商，而不是直接聯(lián)系原料藥制造商。在某些市場(chǎng)，這種做法是不被允許的（例如，在日本，上市許可持有人需要與原料藥制造商簽訂質(zhì)量協(xié)議，而不是與經(jīng)銷(xiāo)商簽訂）。
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.
從實(shí)際角度來(lái)看，第一種選擇允許終端客戶（上市許可持有人）對(duì)原料藥制造商進(jìn)行審計(jì)。第二種選擇基本上只允許經(jīng)銷(xiāo)商（當(dāng)然也包括第三方審計(jì)機(jī)構(gòu)）進(jìn)行審計(jì)；如果各方達(dá)成一致，也可以考慮由經(jīng)銷(xiāo)商和終端客戶進(jìn)行聯(lián)合審計(jì)。
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.
從理論上來(lái)說(shuō)，原料藥制造商與終端客戶之間直接簽訂質(zhì)量協(xié)議也是可行的。然而，由于這兩方之間不存在業(yè)務(wù)關(guān)系，所以在實(shí)際操作中不建議采用這種方式。
The template is suitable for both “generic APIs” and “exclusive substances”, including when they are supplied for use in clinical trials.
該模板適用于“非專(zhuān)利原料藥” 和 “專(zhuān)有物質(zhì)”，包括這些物質(zhì)被供應(yīng)用于臨床試驗(yàn)的情況。
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.
“非專(zhuān)利原料藥” 這一術(shù)語(yǔ)適用于原則上可從多個(gè)渠道獲取的所有原料藥，或者是指那些生產(chǎn)出來(lái)供應(yīng)給多個(gè)客戶的原料藥，與之相對(duì)的是僅由原始研發(fā)公司或其獨(dú)家被許可方銷(xiāo)售的原料藥。此類(lèi)非專(zhuān)利原料藥已不受專(zhuān)利保護(hù)；它們通常在藥典專(zhuān)論中有記載，并根據(jù)標(biāo)準(zhǔn)規(guī)格進(jìn)行供應(yīng)。“專(zhuān)有物質(zhì)” 是專(zhuān)門(mén)為某個(gè)客戶生產(chǎn)的原料藥或中間體，該客戶通常對(duì)生產(chǎn)工藝擁有知識(shí)產(chǎn)權(quán)。這種活動(dòng)也被稱(chēng)為 “合同生產(chǎn)” 或 “定制合成”。它可以根據(jù)委托生產(chǎn)供應(yīng)協(xié)議進(jìn)行管理，在這種協(xié)議下，主要原材料由客戶提供給供應(yīng)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.
在本指南及相應(yīng)模板中，“供應(yīng)商” 被廣泛用于指代向其 “客戶” 提供 “產(chǎn)品”（即原料藥或原料藥中間體）的公司。在實(shí)際應(yīng)用中，“合同承接方”（而非 “供應(yīng)商”）和 “合同委托方”（而非 “客戶”）這兩個(gè)術(shù)語(yǔ)被認(rèn)為是同義的，因此如果雙方愿意，可交替使用；它們?cè)诙ㄖ坪铣深I(lǐng)域相當(dāng)常見(jiàn)。
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制定了兩份不同的模板，分別用于非專(zhuān)利原料藥和專(zhuān)有物質(zhì)。然而，人們認(rèn)識(shí)到，這兩類(lèi)物質(zhì)的絕大多數(shù)要求是相似的，并且這些要求歸根結(jié)底是為了確保成品藥的安全性和有效性，而不論其屬于哪一類(lèi)物質(zhì)。因此，更傾向于采用一份標(biāo)準(zhǔn)模板，其中一些通常適用于專(zhuān)有物質(zhì)的額外要求被列為可選項(xiàng)。
Besides the IPEC Quality Agreements guideline/template mentioned above, the following documents may be useful in establishing Quality Agreements:
除了上述國(guó)際藥用輔料協(xié)會(huì)（IPEC）的質(zhì)量協(xié)議指南/ 模板之外，以下文件在制定質(zhì)量協(xié)議時(shí)可能會(huì)有所幫助：
·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 最佳實(shí)踐質(zhì)量協(xié)議指南》（參考文獻(xiàn) 2）是一份全面的指導(dǎo)文件，旨在幫助客戶和供應(yīng)商高效管理質(zhì)量協(xié)議的啟動(dòng)、談判、實(shí)施以及持續(xù)維護(hù)工作。該文件涵蓋了藥品生產(chǎn)商所采購(gòu)的各類(lèi)與質(zhì)量相關(guān)的供應(yīng)品和服務(wù)（原料藥、輔料、包裝材料、合同實(shí)驗(yàn)室服務(wù)等），并且包含了用于各種目的的示例表述。不過(guò)，該文件并未提供額外的質(zhì)量協(xié)議模板，而是引用了現(xiàn)有的模板，例如歐洲原料藥協(xié)會(huì)（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.
·從內(nèi)容角度來(lái)看，《美國(guó)特種化學(xué)品制造協(xié)會(huì)（SOCMA）質(zhì)量協(xié)議模板》（參考文獻(xiàn) 3）與歐洲原料藥協(xié)會(huì)（APIC）的模板沒(méi)有太大差異。在特殊情況下，已證實(shí)該模板是一個(gè)合適的替代選擇，尤其適用于美國(guó)客戶。
3. Legal Requirements 法規(guī)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).
質(zhì)量協(xié)議已成為我們業(yè)務(wù)中的一種常用工具，并且受到監(jiān)管部門(mén)的強(qiáng)烈要求予以實(shí)施。國(guó)際準(zhǔn)則中也越來(lái)越多地提及或描述質(zhì)量協(xié)議。如今，監(jiān)管部門(mén)基本上不再認(rèn)為制定質(zhì)量協(xié)議僅是藥品生產(chǎn)商的唯一責(zé)任，許多國(guó)家的監(jiān)管部門(mén)也期望原料藥制造商與其客戶（上市許可持有人）簽訂質(zhì)量協(xié)議。
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).
對(duì)于“合同生產(chǎn)”（見(jiàn)歐盟藥品生產(chǎn)質(zhì)量管理規(guī)范指南第一部分，第7 章[參考文獻(xiàn)4]，以及國(guó)際人用藥品注冊(cè)技術(shù)協(xié)調(diào)會(huì)（ICH）Q7 指南，第16 章[參考文獻(xiàn)5]）或 “外包活動(dòng)”（見(jiàn)ICH Q10 指南，第2.7 章[參考文獻(xiàn)6]），必須簽訂書(shū)面合同/ 協(xié)議，明確相關(guān)方在質(zhì)量相關(guān)活動(dòng)中的職責(zé)和溝通流程。原則上，合同委托方有責(zé)任要求與合同承接方簽訂此類(lèi)合同/ 協(xié)議。
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.
對(duì)于“采購(gòu)的（起始）物料”（見(jiàn)歐盟藥品生產(chǎn)質(zhì)量管理規(guī)范指南第一部分，第5.28 章[見(jiàn)參考文獻(xiàn)4] 或國(guó)際人用藥品注冊(cè)技術(shù)協(xié)調(diào)會(huì)（ICH）Q10 指南，第2.7 章），情況類(lèi)似，也就是說(shuō)，對(duì)于 “非專(zhuān)利” 原料藥的采購(gòu)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.
與上述情況一致，一些國(guó)家要求簽訂此類(lèi)協(xié)議。例如，法國(guó)《公共衛(wèi)生法典》（第R5124-47 條）[見(jiàn)參考文獻(xiàn)7] 要求藥品制造商與其原材料制造商之間就各自的藥品生產(chǎn)質(zhì)量管理規(guī)范（GMP）義務(wù)簽訂書(shū)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.
在美國(guó)，質(zhì)量協(xié)議雖然被普遍認(rèn)可，但不一定是（法律層面的）要求。美國(guó)食品藥品監(jiān)督管理局（FDA）已發(fā)布了關(guān)于制藥行業(yè)質(zhì)量協(xié)議的行業(yè)指南（《藥品合同生產(chǎn)安排 —— 質(zhì)量協(xié)議》，見(jiàn)參考文獻(xiàn)8）。該指南涵蓋了 “受現(xiàn)行藥品生產(chǎn)質(zhì)量管理規(guī)范（CGMP）約束的藥品合同生產(chǎn)中各相關(guān)方的生產(chǎn)活動(dòng)”，并且引用了國(guó)際人用藥品注冊(cè)技術(shù)協(xié)調(diào)會(huì)（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”.
具體而言，本指南闡述了“所有者” 與 “合同生產(chǎn)機(jī)構(gòu)” 之間的關(guān)系。就其對(duì)行業(yè)的指導(dǎo)意義而言，美國(guó)食品藥品監(jiān)督管理局將 “所有者” 定義為 “原料藥、藥用物料、中間體、藥品（包括生物制品）以及組合產(chǎn)品的制造商”，并將 “合同生產(chǎn)機(jī)構(gòu)” 定義為 “代表一個(gè)或多個(gè)所有者開(kāi)展一項(xiàng)或多項(xiàng)生產(chǎn)操作的相關(guān)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”.
雖然美國(guó)食品藥品監(jiān)督管理局（FDA）的指導(dǎo)文件側(cè)重于合同生產(chǎn)，但對(duì)于所采購(gòu)原料藥的協(xié)議要求，卻沒(méi)有這樣的指導(dǎo)準(zhǔn)則。在其指南中，F(xiàn)DA 僅鼓勵(lì) “僅從事與藥品分銷(xiāo)相關(guān)生產(chǎn)活動(dòng)的實(shí)體在適當(dāng)情況下遵循本指導(dǎo)文件中的建議” 。
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，美國(guó)食品藥品監(jiān)督管理局指出：“質(zhì)量協(xié)議不應(yīng)涵蓋諸如保密、定價(jià)或成本問(wèn)題、交付條款，或責(zé)任與損害賠償限制等一般性商業(yè)條款和條件。” 該機(jī)構(gòu)建議 “質(zhì)量協(xié)議應(yīng)與諸如主服務(wù)協(xié)議或供應(yīng)協(xié)議等商業(yè)合同分開(kāi)，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《藥品、類(lèi)藥品、化妝品及再生醫(yī)療產(chǎn)品質(zhì)量保證標(biāo)準(zhǔn)部令》（見(jiàn)參考文獻(xiàn)9）以及《藥品和類(lèi)藥品生產(chǎn)管理及質(zhì)量管理標(biāo)準(zhǔn)部令》（見(jiàn)參考文獻(xiàn)10）規(guī)定，藥品上市許可持有人應(yīng)與其生產(chǎn)商（藥品上市許可申請(qǐng)文件中提及的生產(chǎn)商）簽訂合同，“以確保生產(chǎn)商正確且高效地開(kāi)展生產(chǎn)管理和質(zhì)量管理工作”。通常情況下，對(duì)于這些良好質(zhì)量規(guī)范（GQP）協(xié)議，會(huì)使用一個(gè)與歐洲原料藥協(xié)會(huì)（APIC）模板有顯著差異的特定模板。
4. Format and Structure of a Quality Agreement
質(zhì)量協(xié)議的格式與結(jié)構(gòu)
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.
本歐洲原料藥協(xié)會(huì)（APIC）指南的附錄構(gòu)成了一份可供直接使用的質(zhì)量協(xié)議（關(guān)于此類(lèi)協(xié)議的典型架構(gòu)，見(jiàn)5.2）。引言和總則部分闡述了該協(xié)議的適用范圍以及條款和條件。“質(zhì)量責(zé)任” 部分（在某些情況下也稱(chēng)為 “責(zé)任劃分”）包含了質(zhì)量協(xié)議中通常應(yīng)有的主要質(zhì)量和監(jiān)管要點(diǎn)以及相應(yīng)責(zé)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，該模板并未提及藥品質(zhì)量體系的每一項(xiàng)內(nèi)容，因?yàn)槟切┮殉浞趾w在適用的質(zhì)量/ 藥品生產(chǎn)質(zhì)量管理規(guī)范標(biāo)準(zhǔn)（如模板第1 部分所述）中的質(zhì)量要求無(wú)需在協(xié)議中重復(fù)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.
質(zhì)量責(zé)任可根據(jù)情況分配給一方或雙方。為了方便快捷地進(jìn)行概述，該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.
該模板的格式具有靈活性，它提供了大多數(shù)質(zhì)量協(xié)議所需的所有單項(xiàng)要素。
There are different possibilities how both parties may benefit from the use of a standardised template:雙方可以通過(guò)使用標(biāo)準(zhǔn)化模板，以多種不同的方式從中獲益：
·The template may completely replace an own agreement該模板可以完全替代一份自行擬定的協(xié)議
·The template may be used as a basis for a (slightly) modified, customized draft agreement該模板可用作（稍作）修改后的定制化協(xié)議草案的基礎(chǔ)。
·Certain sections of the template may be used when drafting an own agreement在起草一份屬于自己的協(xié)議時(shí)，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.如果雙方都將模板中的措辭視為良好的行業(yè)慣例，那么這些措辭可用于解決糾紛。
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，該模板構(gòu)成了就質(zhì)量協(xié)議展開(kāi)任何進(jìn)一步談判的理想共同出發(fā)點(diǎn)（見(jiàn)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.在必要時(shí)或應(yīng)任何一方要求，可在標(biāo)準(zhǔn)文本中添加特定國(guó)家或特定產(chǎn)品的相關(guān)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.
該模板僅提供英文版本，因?yàn)橛⒄Z(yǔ)是全球商業(yè)和交流中使用最廣泛的語(yǔ)言，因此它構(gòu)成了不同母語(yǔ)方之間的最佳共同基礎(chǔ)。
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.
質(zhì)量協(xié)議中提及的時(shí)間期限可以采用描述性的方式給出（最常見(jiàn)的表述有：立即、迅速、毫不遲延、及時(shí)、在合理期限內(nèi)），也可以采用精確的數(shù)字來(lái)表示。這些描述性術(shù)語(yǔ)的廣泛認(rèn)可的定義可以在本文檔的術(shù)語(yǔ)表中找到。同時(shí)，應(yīng)考慮所涉地區(qū)之間的時(shí)差問(wèn)題。
4.2 Standard Structure 標(biāo)準(zhǔn)結(jié)構(gòu)
The following sections should normally be included in a Quality Agreements:
·以下部分通常應(yīng)包含在質(zhì)量協(xié)議中：
I.Introduction/Purpose/Scope引言/ 目的/ 范圍
I.1Parties to the agreement協(xié)議各方
I.2Products covered by the agreement協(xié)議所涵蓋的產(chǎn)品
I.3Site(s) involved涉及的場(chǎng)所
I.4Definitions and abbreviations (optional)定義和縮寫(xiě)（可選）
II.General Provisions一般條款
II.1Effective date生效日期
II.2Term of agreement協(xié)議期限
II.3Assignment轉(zhuǎn)讓
II.4Related agreements相關(guān)協(xié)議
II.5Amendments修正案
II.6Confidentiality (optional)保密（可選）
II.7Resolution of quality disputes (optional)質(zhì)量爭(zhēng)議的解決（可選）
II.8Choice of law (optional)法律適用（可選）
II.9Survival clause (optional)存續(xù)條款（可選）
III.Quality Responsibilities質(zhì)量責(zé)任
IV.Signatories簽署人
V.Contacts聯(lián)系人
VI.List of Appendices附錄清單
VII.History / Change Log歷史記錄/ 變更日志
4.3 How to create your “working template”?如何創(chuàng)建你的“工作模板”？
Simply take the APIC template (Appendix) and只需采取（APIC）模板（附錄）并
·Remove all explanatory “notes”, unless deemed helpful for clarification purposes,除去所有解釋性的“注釋”，除非這些注釋對(duì)澄清內(nèi)容有幫助。
·Keep or remove the articles “for exclusive PRODUCT”, as applicable in your specific case,根據(jù)你具體情況的適用性，保留或刪除“針對(duì)專(zhuān)屬產(chǎn)品” 的條款。
·Keep or remove the “optional” text and/or select the appropriate “alternative” text, as needed.根據(jù)需要，保留或刪除“可選” 文本，以及 / 或者選擇合適的 “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.
如需了解更多詳細(xì)信息，還可查看模板目錄之后的“第一至第三部分使用說(shuō)明”；順便說(shuō)一下，這些說(shuō)明也應(yīng)刪除。
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模板之前進(jìn)行這一操作。此后，你個(gè)人的核心模板就可以隨時(shí)使用了，只需填寫(xiě)可變信息即可（例如，客戶地址、你方站點(diǎn)地址、相關(guān)產(chǎn)品、聯(lián)系數(shù)據(jù)）。最后，你可以添加任何所需的附錄（例如，產(chǎn)品規(guī)格、經(jīng)批準(zhǔn)的分包商），并將其指定為附錄A、附錄B 等。
5. Negotiation and Maintenance談判與維護(hù)
5.1 Negotiation, Review and Approvals談判、審核與批準(zhǔn)
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.
在開(kāi)始談判之前，雙方的期望應(yīng)當(dāng)予以明確，例如協(xié)議的范圍（涵蓋的產(chǎn)品、服務(wù)、地點(diǎn)），是使用標(biāo)準(zhǔn)模板還是使用單獨(dú)擬定的文件。此外，建議雙方從一開(kāi)始就共同商定審核的時(shí)間安排。
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.
一般來(lái)說(shuō)，如果使用標(biāo)準(zhǔn)化模板（理想情況下由法務(wù)預(yù)先審核），談判會(huì)變得更加輕松和快捷。對(duì)于許多供應(yīng)商或客戶而言，“時(shí)間因素” 也極具說(shuō)服力，促使他們接受使用標(biāo)準(zhǔn)模板（“如果我們能就ABC 模板達(dá)成一致，我們或許能在兩周內(nèi)準(zhǔn)備好簽署協(xié)議”）。第五章第一節(jié)中已經(jīng)給出了關(guān)于如何使用標(biāo)準(zhǔn)模板的不同選擇方案。
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.
不過(guò)，對(duì)模板進(jìn)行修改時(shí)應(yīng)謹(jǐn)慎操作，并且只有在必要時(shí)才進(jìn)行修改，以避免漫長(zhǎng)的談判過(guò)程。建議（通用的）活性藥物成分（API）制造商在客戶要求簽訂質(zhì)量協(xié)議時(shí)，基于亞太地區(qū)（APIC）模板準(zhǔn)備一份質(zhì)量協(xié)議，以此開(kāi)啟與客戶的談判流程。在合同制造領(lǐng)域（即針對(duì)專(zhuān)屬產(chǎn)品的情況），流程通常會(huì)是另外一種模式。
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.
不過(guò)，對(duì)模板進(jìn)行修改時(shí)應(yīng)謹(jǐn)慎操作，并且只有在必要時(shí)才進(jìn)行修改，以避免漫長(zhǎng)的談判過(guò)程。建議（通用的）活性藥物成分（API）制造商在客戶要求簽訂質(zhì)量協(xié)議時(shí)，基于亞太地區(qū)（APIC）模板準(zhǔn)備一份質(zhì)量協(xié)議，以此開(kāi)啟與客戶的談判流程。在合同制造領(lǐng)域（即針對(duì)專(zhuān)屬產(chǎn)品的情況），流程通常會(huì)是另外一種模式。
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.
質(zhì)量協(xié)議的談判和審核應(yīng)始終是相關(guān)各方不同部門(mén)共同協(xié)作的工作：質(zhì)量代表負(fù)責(zé)對(duì)質(zhì)量條款進(jìn)行談判和審核，法律代表負(fù)責(zé)對(duì)法律條款進(jìn)行談判和審核。其他部門(mén)（如采購(gòu)部門(mén)、市場(chǎng)部門(mén)等）也可在適當(dāng)?shù)臅r(shí)候參與其中。建議在談判階段，由單一的職能部門(mén)（最好是質(zhì)量部門(mén)）作為整個(gè)公司的代表發(fā)聲。
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.
活性藥物成分（API）/ 中間體制造商和客戶方的質(zhì)量代表必須確保能夠滿足質(zhì)量條款，也就是說(shuō)，協(xié)議中的各項(xiàng)義務(wù)要與各自場(chǎng)所建立的質(zhì)量體系相一致[注意：如果協(xié)議影響到雙方的多個(gè)場(chǎng)所或附屬機(jī)構(gòu)，這一點(diǎn)非常重要]，并且雙方都必須了解協(xié)議條款對(duì)患者安全和產(chǎn)品質(zhì)量的影響。
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.
為了能夠?qū)φ勁须A段修改的措辭或新增的要求進(jìn)行審查，并確保透明度和可追溯性，應(yīng)使用“修訂跟蹤模式”，也就是采用顯示修訂痕跡的版本，而不是無(wú)修訂痕跡的版本。只有在所有各方都對(duì)協(xié)議草案感到滿意之后，才應(yīng)在簽字前直接創(chuàng)建一份無(wú)修訂痕跡的“凈潔” 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.
質(zhì)量協(xié)議中的語(yǔ)言表達(dá)清晰至關(guān)重要。質(zhì)量協(xié)議不容許存在模棱兩可之處。一般建議質(zhì)量協(xié)議的措辭保持“簡(jiǎn)潔” 或“非法律化”（至少除“一般條款” 外的所有部分），因?yàn)橘|(zhì)量協(xié)議主要是為質(zhì)量相關(guān)人員編寫(xiě)的，這些人員必須理解并遵守協(xié)議條款。
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.
建議對(duì)協(xié)議最終草案進(jìn)行法務(wù)審查，無(wú)論質(zhì)量協(xié)議是一份獨(dú)立文件，還是與供應(yīng)協(xié)議同時(shí)進(jìn)行談判。如果質(zhì)量協(xié)議沒(méi)有經(jīng)過(guò)法務(wù)部門(mén)的合格審查，公司可能會(huì)面臨潛在的法律責(zé)任。不過(guò)，除非存在潛在的法律責(zé)任，否則解釋藥品生產(chǎn)質(zhì)量管理規(guī)范（GMP）和修改措辭并非法務(wù)代表的工作。法務(wù)代表的工作是從為公司提供一定程度保護(hù)的角度來(lái)審視該文件。
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:
以下措辭建議旨在避免就質(zhì)量協(xié)議中的要求和承諾產(chǎn)生未來(lái)的爭(zhēng)議以及意外的責(zé)任，并且這些建議已在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.在質(zhì)量協(xié)議中，請(qǐng)勿使用諸如“供應(yīng)商保證”“供應(yīng)商聲明并保證” 之類(lèi)的表述或類(lèi)似表述。尤其是“保證” 一詞，會(huì)引發(fā)采購(gòu)方的額外權(quán)利、無(wú)過(guò)錯(cuò)責(zé)任，還會(huì)導(dǎo)致訴訟時(shí)效延長(zhǎng)。
·Instead use “neutral” expressions like “SUPPLIER shall“, “SUPPLIER undertakes”, or “SUPPLIER shall make reasonable endeavours” (but not “best” endeavours).相反，應(yīng)使用“中立” 的表述，例如“供應(yīng)商應(yīng)”“供應(yīng)商承諾” 或“供應(yīng)商應(yīng)盡合理努力”（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).
當(dāng)存在供應(yīng)協(xié)議，或者供應(yīng)協(xié)議與質(zhì)量協(xié)議同時(shí)制定時(shí)，審核人員應(yīng)確保供應(yīng)協(xié)議中包含的任何質(zhì)量條款也在質(zhì)量協(xié)議中有所體現(xiàn)，并且不會(huì)相互矛盾。最好是供應(yīng)協(xié)議中不包含任何質(zhì)量條款（另見(jiàn)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.
由于所有質(zhì)量協(xié)議都需要具有法律約束力的簽名，因此各方有責(zé)任確保質(zhì)量協(xié)議中的簽名能夠體現(xiàn)代表各方的具有法律約束力的簽字。根據(jù)每家公司的簽署規(guī)則，可能需要兩個(gè)甚至更多的簽名。至少應(yīng)有一個(gè)簽名來(lái)自經(jīng)授權(quán)的質(zhì)量部門(mén)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.
一旦雙方完成了對(duì)協(xié)議內(nèi)容的討論，他們應(yīng)當(dāng)就簽字 / 審批流程達(dá)成一致（例如，由誰(shuí)先簽字？），以及最終獲批合同的形式（例如，使用手寫(xiě)簽名還是電子簽名，采用紙質(zhì)副本還是PDF 文件，每一方所需的硬拷貝份數(shù)，是所有簽名都在同一頁(yè)上，還是將有一個(gè)或多個(gè)簽名的頁(yè)面匯編在一起）。從法律角度來(lái)看，所有這些選擇基本上都是可以接受的，所以最終的決定將取決于雙方公司的內(nèi)部規(guī)定或偏好。有些公司習(xí)慣在質(zhì)量協(xié)議的每一頁(yè)上都簽姓名首字母，但從法律角度來(lái)說(shuō)，這并非必要。
5.2 Maintaining Agreements協(xié)議的維護(hù)
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.
任何質(zhì)量協(xié)議都應(yīng)可供承擔(dān)協(xié)議中規(guī)定義務(wù)的所有人員或單位隨時(shí)查閱。建議建立一個(gè)系統(tǒng)，用以跟蹤源自各類(lèi)質(zhì)量協(xié)議的承諾。
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.
所有質(zhì)量協(xié)議一經(jīng)批準(zhǔn)，雙方在整個(gè)有效期內(nèi)都必須使其保持為最新版本。對(duì)于修訂 / 附錄流程，應(yīng)使其便于進(jìn)行簡(jiǎn)單的更新，也就是說(shuō)，在進(jìn)行更新時(shí)無(wú)需將整個(gè)文件重新經(jīng)過(guò)審核和批準(zhǔn)步驟，例如在進(jìn)行聯(lián)系方式或規(guī)格更新時(shí)。任何修訂/ 附錄都應(yīng)與原始協(xié)議一并留存。
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.
由于組織架構(gòu)、職責(zé)、協(xié)議范圍、監(jiān)管環(huán)境或其他方面可能會(huì)隨著時(shí)間發(fā)生變化，雙方應(yīng)定期對(duì)現(xiàn)有的質(zhì)量協(xié)議進(jìn)行審查?；旧?，對(duì)于已確立的質(zhì)量協(xié)議，有不同的方式來(lái)確定審查頻率：定期審查（例如，在編制年度產(chǎn)品質(zhì)量回顧（PQR）時(shí)，或每?jī)傻饺赀M(jìn)行一次回顧），或者基于風(fēng)險(xiǎn)確定審查頻率。將這兩種方式結(jié)合起來(lái)可能是最佳解決方案，例如，在沒(méi)有關(guān)鍵質(zhì)量事件或重大風(fēng)險(xiǎn)的情況下，設(shè)定三年的審查周期。
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 術(shù)語(yǔ)
8. Appendix 附錄
·APIC Quality Agreement Template for APIs (27 pages)APIC質(zhì)量協(xié)議模板（27 頁(yè)）
9. History / Change Log 歷史記錄/ 變更日志
|
Version 版本 |
Published in 出版時(shí)間 |
Description of change(s), incl. reason, where appropriate 變更描述，包括（如適用）變更原因 |
|
1 |
2009 |
New document (guideline plus two templates for each generic and exclusive substances) 新文件（指南以及針對(duì)通用物質(zhì)和專(zhuān)屬物質(zhì)各有兩份模板） |
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