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QA：Quality Assurance，質(zhì)量保證

一、中國(guó)GMP對(duì)QA的要求：

第二節(jié)質(zhì)量保證

第八條質(zhì)量保證是質(zhì)量管理體系的一部分。企業(yè)必須建立質(zhì)量保證系統(tǒng)，同時(shí)建立完整的文件體系，以保證系統(tǒng)有效運(yùn)行。

第九條質(zhì)量保證系統(tǒng)應(yīng)當(dāng)確保：

(一) 藥品的設(shè)計(jì)與研發(fā)體現(xiàn)本規(guī)范的要求；

(二) 生產(chǎn)管理和質(zhì)量控制活動(dòng)符合本規(guī)范的要求；

(三)管理職責(zé)明確；

(四)采購(gòu)和使用的原輔料和包裝材料正確無(wú)誤；

(五)中間產(chǎn)品得到有效控制；

(六)確認(rèn)、驗(yàn)證的實(shí)施；

(七)嚴(yán)格按照規(guī)程進(jìn)行生產(chǎn)、檢查、檢驗(yàn)和復(fù)核；

(八)每批產(chǎn)品經(jīng)質(zhì)量受權(quán)人批準(zhǔn)后方可放行；

(九)在貯存、發(fā)運(yùn)和隨后的各種操作過(guò)程中有保證藥品質(zhì)量的適當(dāng)措施；

(十)按照自檢操作規(guī)程，定期檢查評(píng)估質(zhì)量保證系統(tǒng)的有效性和適用性。

第十條藥品生產(chǎn)質(zhì)量管理的基本要求：

(一)制定生產(chǎn)工藝，系統(tǒng)地回顧并證明其可持續(xù)穩(wěn)定地生產(chǎn)出符合要求的產(chǎn)品；

(二)生產(chǎn)工藝及其重大變更均經(jīng)過(guò)驗(yàn)證；

(三)配備所需的資源，至少包括：

1.具有適當(dāng)?shù)馁Y質(zhì)并經(jīng)培訓(xùn)合格的人員；

2.足夠的廠(chǎng)房和空間；

3.適用的設(shè)備和維修保障；

4.正確的原輔料、包裝材料和標(biāo)簽；

5.經(jīng)批準(zhǔn)的工藝規(guī)程和操作規(guī)程；

6.適當(dāng)?shù)馁A運(yùn)條件。

(四)應(yīng)當(dāng)使用準(zhǔn)確、易懂的語(yǔ)言制定操作規(guī)程；

(五)操作人員經(jīng)過(guò)培訓(xùn)，能夠按照操作規(guī)程正確操作；

(六)生產(chǎn)全過(guò)程應(yīng)當(dāng)有記錄，偏差均經(jīng)過(guò)調(diào)查并記錄；

(七)批記錄和發(fā)運(yùn)記錄應(yīng)當(dāng)能夠追溯批產(chǎn)品的完整歷史，并妥善保存、便于查閱；

(八)降低藥品發(fā)運(yùn)過(guò)程中的質(zhì)量風(fēng)險(xiǎn)；

(九)建立藥品召回系統(tǒng)，確保能夠召回任何一批已發(fā)運(yùn)銷(xiāo)售的產(chǎn)品；

(十)調(diào)查導(dǎo)致藥品投訴和質(zhì)量缺陷的原因，并采取措施，防止類(lèi)似質(zhì)量缺陷再次發(fā)生。

二、ICH Q7中對(duì)質(zhì)量管理的描述。

QUALITY MANAGEMENT 質(zhì)量管理
2.1 Principles 原則
2.10 Quality should be the responsibility of all persons involved in manufacturing.

質(zhì)量應(yīng)該是所有參與生產(chǎn)的人員的職責(zé)。
2.11 Each manufacturer should establish, document, and implement an effective system for managing quality that involves the active participation of management and appropriate manufacturing personnel.

每個(gè)生產(chǎn)企業(yè)應(yīng)該建立、文件化并執(zhí)行一個(gè)有管理層和適當(dāng)?shù)纳a(chǎn)人員參與的有效的管理質(zhì)量的體系。
2.12 The system for managing quality should encompass the organisational structure, procedures, processes and resources, as well as activities necessary to ensure confidence that the API will meet its intended specifications for quality and purity. All quality related activities should be defined and  documented.

管理質(zhì)量的體系應(yīng)該包含組織架構(gòu)、程序、流程和資源，以及確保原料藥有信心符合預(yù)期的質(zhì)量和純度標(biāo)準(zhǔn)的必要的活動(dòng)。所有質(zhì)量相關(guān)的活動(dòng)都應(yīng)該規(guī)定并使其文件化。
2.13 There should be a quality unit(s) that is independent of production and that fulfills both quality assurance (QA) and quality control (QC) responsibilities. This can be in the form of separate QA and QC units or a single individual or group, depending upon the size and structure of the orgnization.

應(yīng)該有一個(gè)獨(dú)立于生產(chǎn)并且要履行質(zhì)量保證（QA）和質(zhì)量控制(QC）職責(zé)的質(zhì)量單元（或質(zhì)量部門(mén)）。根據(jù)組織的大小和架構(gòu)，這個(gè)質(zhì)量單元可以由單獨(dú)的QA和QC單元或一個(gè)人或團(tuán)隊(duì)組成。
2.14 The persons authorised to release intermediates and APIs should be specified.

應(yīng)當(dāng)指定被授權(quán)放行中間體和原料藥的人員。
2.15 All quality related activities should be recorded at the time they are performed.

所有質(zhì)量相關(guān)的活動(dòng)都應(yīng)該在其執(zhí)行的時(shí)候就記錄。
2.16 Any deviation from established procedures should be documented and explained.  Critical deviations should be investigated, and the investigation and its conclusions should be documented.

任何與已經(jīng)建立的程序的偏離都應(yīng)該記錄（或登記在案并解釋。

2.17 No materials should be released or used before the satisfactory completion of evaluation by the quality unit(s) unless there are appropriate systems in place to allow for such use (e.g. release under quarantine as described in Section 10.20 or the use of raw materials or intermediates pending completion of evaluation).

在質(zhì)量單元（部門(mén)）圓滿(mǎn)完成評(píng)價(jià)前物料不應(yīng)該放行或使用，除非在合適的位置有合適的系統(tǒng)允許這樣的使用(比如在第10.20章節(jié)中描述的待驗(yàn)狀態(tài)下的放行或等待完成評(píng)價(jià)時(shí)的原料或中間體的使用）。
2.18 Procedures should exist for notifying responsible management in a timely manner of regulatory inspections, serious GMP deficiencies, product defects and related actions (e.g., quality related complaints, recalls, regulatory actions, etc.).

應(yīng)該存在以一種及時(shí)的方式通知負(fù)責(zé)的管理層相關(guān)監(jiān)管檢查、嚴(yán)重的GMP缺陷、產(chǎn)品缺陷和相關(guān)措施的程序（比如質(zhì)量相關(guān)的投訴、召回、監(jiān)管行動(dòng)等）。
2.2 Responsibilities of the Quality Unit(s)

質(zhì)量單元的職責(zé)
2.20 The quality unit(s) should be involved in all quality-related matters.

質(zhì)量單元應(yīng)該參與所有質(zhì)量相關(guān)的事項(xiàng)。
2.21 The quality unit(s) should review and approve all appropriate quality-related documents.

質(zhì)量單元應(yīng)該審核和批準(zhǔn)所有質(zhì)量相關(guān)的文件。
2.22 The main responsibilities of the independent quality unit(s) should not be delegated. These responsibilities should be described in writing and should include but not necessarily be limited to:

獨(dú)立的質(zhì)量單元的主要職責(zé)不應(yīng)該被委托（給他人）。這些職責(zé)應(yīng)該書(shū)面描述并應(yīng)該包括但不必限于以下內(nèi)容：
1. Releasing or rejecting all APIs. Releasing or rejecting intermediates for use outside the control of the manufacturing company;

放行或拒收所有原料藥。放行或拒收在生產(chǎn)企業(yè)控制范圍之外使用的中間體；
2. Establishing a system to release or reject raw materials, intermediates, 
packaging and labelling materials;

建立一個(gè)放行或拒收原料、中間體、包材和標(biāo)簽的系統(tǒng)；

3. Reviewing completed batch production and laboratory control records of critical process steps before release of the API for distribution;

放行銷(xiāo)售的原料藥前審核關(guān)鍵工藝步驟的已完成的批生產(chǎn)記錄和實(shí)驗(yàn)控制記錄；
4. Making sure that critical deviations are investigated and resolved;

確保關(guān)鍵偏差得到調(diào)查和解決；
5. Approving all specifications and master production instructions;

批準(zhǔn)所有標(biāo)準(zhǔn)和生產(chǎn)工藝規(guī)程；
6. Approving all procedures impacting the quality of intermediates or APIs;

批準(zhǔn)所有影響中間體或原料藥質(zhì)量的規(guī)程；
7. Making sure that internal audits (self-inspections) are performed;

確保進(jìn)行內(nèi)部審計(jì)（自檢）；
8. Approving intermediate and API contract manufacturers;

批準(zhǔn)中間體和原料藥的合同生產(chǎn)商；
9. Approving changes that potentially impact intermediate or API quality;

批準(zhǔn)潛在影響中間體或原料藥質(zhì)量的變更；
10. Reviewing and approving validation protocols and reports;

審核和批準(zhǔn)驗(yàn)證方案和報(bào)告；
11. Making sure that quality related complaints are investigated and resolved;

確保質(zhì)量相關(guān)的投訴得到調(diào)查和解決；
12. Making sure that effective systems are used for maintaining and calibrating critical equipment;

確保有有效的系統(tǒng)用于維護(hù)和校驗(yàn)關(guān)鍵設(shè)備；
13. Making sure that materials are appropriately tested and the results are reported;

確保物料都得到適宜的檢測(cè)并報(bào)告其結(jié)果；
14. Making sure that there is stability data to support retest or expiry dates and storage conditions on APIs and/or intermediates where appropriate; 

確保在適當(dāng)?shù)那闆r下，有穩(wěn)定性數(shù)據(jù)支持中間體或原料藥的復(fù)驗(yàn)期或有效期和儲(chǔ)存條件。
15. Performing product quality reviews (as defined in Section 2.5).

進(jìn)行產(chǎn)品質(zhì)量回顧（在2.5章節(jié)中定義）

 

三、WHO GMP中的描述

Quality management in the drug industry 醫(yī)藥行業(yè)的質(zhì)量管理

In the drug industry at large, quality management is usually defined as the aspect of management function that determines and implements the “quality policy”,i.e. the overall intention and direction of an organization regarding quality, as formally expressed and authorized by top management. The basic elements of quality management are:

在大的醫(yī)藥行業(yè)中，質(zhì)量管理常常被定義為管理職能中規(guī)定并執(zhí)行“質(zhì)量政策”的那方面職能。比如組織質(zhì)量相關(guān)的總體意圖和方向，由最高管理層正式表達(dá)和授權(quán)。質(zhì)量管理的基本要素有\(zhòng)：

— an appropriate infrastructure or “quality system”, encompassing the organizational structure, procedures, processes and resources;

一個(gè)適當(dāng)?shù)幕A(chǔ)架構(gòu)或“質(zhì)量體系”，包含組織架構(gòu)、程序、流程和資源；
— systematic actions necessary to ensure adequate confidence that a product (or service) will satisfy given requirements for quality. The totality of these actions is termed “quality assurance”.

確保一個(gè)產(chǎn)品（或服務(wù)）有足夠信心會(huì)滿(mǎn)足質(zhì)量要求的不要的系統(tǒng)化的行動(dòng)。全部這些行動(dòng)被稱(chēng)之為“質(zhì)量保證”。
Within an organization, quality assurance serves as a management tool. In contractual situations, quality assurance also serves to generate confidence in the supplier. The concepts of quality assurance, GMP and quality control are interrelated aspects of quality management. They are described here in order to emphasize their relationship and their fundamental importance to the production and control of pharmaceutical products.

在一個(gè)組織內(nèi)，質(zhì)量保證是一種管理工具。在委托情況下，質(zhì)量保證也用于產(chǎn)生對(duì)供應(yīng)商的信心。質(zhì)量保證、GMP和質(zhì)量控制的概念是質(zhì)量管理的相關(guān)要素。它們?cè)谶@里描述是為了強(qiáng)調(diào)它們的關(guān)系和它們對(duì)于藥品生產(chǎn)和控制的根本的重要性。
1. Quality assurance 質(zhì)量保證
1.1 Principle. 原則

“Quality assurance” is a wide-ranging concept covering all matters that individually or collectively influence the quality of a product. It is the totality of the arrangements made with the object of ensuring that pharmaceutical products are of the quality required for their intended use. Quality assurance therefore incorporates GMP and other factors, including those outside the scope of this guide such as product design and development.

“質(zhì)量保證”是一個(gè)涵蓋所有個(gè)體或集體影響產(chǎn)品質(zhì)量的因素很寬泛的概念。它是做出的確保藥品質(zhì)量符合其預(yù)定用途的目標(biāo)的所有安排的總和。所以質(zhì)量保證整合了GMP和其他因素，包括那些不在本指南范圍比如產(chǎn)品設(shè)計(jì)和開(kāi)發(fā)內(nèi)的那些因素。
1.2 The system of quality assurance appropriate to the manufacture of pharmaceutical products should ensure that:

適用于藥品生產(chǎn)的質(zhì)量保證體系應(yīng)該確保：
(a) pharmaceutical products are designed and developed in a way that takes account of the requirements of GMP and other associated codes such as those of good laboratory practice (GLP) 1 and good clinical practice (GCP);

藥品在一定程度上考慮GMP和其他相關(guān)法規(guī)比如GLP和GCP的要求進(jìn)行設(shè)計(jì)和開(kāi)發(fā)；
(b) production and control operations are clearly specified in a written form and GMP requirements are adopted;

用書(shū)面的形式明確規(guī)定生產(chǎn)和控制操作并采用GMP要求；
(c) managerial responsibilities are clearly specified in job descriptions;

在崗位描述中明確規(guī)定管理職責(zé)；
(d) arrangements are made for the manufacture, supply and use of the correct starting and packaging materials;

為正確的起始物料和包裝材料的生產(chǎn)、供應(yīng)和使用做出一些安排；
(e) all necessary controls on starting materials, intermediate products, and bulk products and other in-process controls, calibrations, and validations are carried out;

實(shí)施所有對(duì)起始物料、中間產(chǎn)品和最終產(chǎn)品的必要的控制和其他中間過(guò)程控制、校驗(yàn)和驗(yàn)證；
(f) the finished product is correctly processed and checked, according to the defined procedures;

按照規(guī)定的程序正確地加工和檢查最終產(chǎn)品；
(g) pharmaceutical products are not sold or supplied before the authorized persons (see also sections 9.11 and 9.12) have certified that each production batch has been produced and controlled in accordance with the requirements of the marketing authorization and any other regulations relevant to the production, control and release of pharmaceutical products;

在被授權(quán)的人員確認(rèn)每批產(chǎn)品已經(jīng)按照上市許可和其他與藥品的生產(chǎn)、控制和放行相關(guān)的法規(guī)生產(chǎn)和控制前藥品不能銷(xiāo)售或供應(yīng)；
(h) satisfactory arrangements exist to ensure, as far as possible, that the pharmaceutical products are stored by the manufacturer, distributed, and subsequently handled so that quality is maintained throughout their shelf-life;

存在盡可能確保藥品由生產(chǎn)企業(yè)儲(chǔ)存、銷(xiāo)售和后續(xù)處理的滿(mǎn)意的安排以確保質(zhì)量在它們整個(gè)貨架期都得到保持；
(i) there is a procedure for self-inspection and/or quality audit that regularly appraises the effectiveness and applicability of the quality assurance system;

有一個(gè)定期評(píng)價(jià)質(zhì)量保證體系的質(zhì)量和適用性的自檢和/或質(zhì)量審計(jì)程序；
(j) deviations are reported, investigated and recorded;

偏差被報(bào)告、調(diào)查和記錄；

(k) there is a system for approving changes that may have an impact on product quality;

有批準(zhǔn)可能對(duì)產(chǎn)品質(zhì)量有影響的變更；
(l) regular evaluations of the quality of pharmaceutical products should be conducted with the objective of verifying the consistency of the process and ensuring its continuous improvement.

應(yīng)該執(zhí)行對(duì)藥品質(zhì)量的定期評(píng)價(jià)，目標(biāo)是確認(rèn)工藝的一致性并確保其持續(xù)改進(jìn)。
1.3 The manufacturer must assume responsibility for the quality of the pharmaceutical products to ensure that they are fit for their intended use, comply with the requirements of the marketing authorization and do not place patients at risk due to inadequate safety, quality or efficacy. The attainment of this quality objective is the responsibility of senior management and requires the participation and commitment of staff in many different departments and at all levels within the company, the company’s suppliers, and the distributors. To achieve the quality objective reliably there must be a comprehensively designed and correctly implemented system of quality assurance incorporating GMP and quality control. It should be fully documented and its effectiveness monitored. All parts of the quality assurance system should be adequately staffed with competent personnel, and should have suitable and sufficient premises, equipment, and facilities.

生產(chǎn)企業(yè)必須承擔(dān)藥品質(zhì)量的職責(zé)以確保它們適用于其既定的用途，符合上市許可的要求并且沒(méi)有因?yàn)榘踩?、質(zhì)量和功效不足對(duì)患者產(chǎn)生風(fēng)險(xiǎn)。達(dá)到這個(gè)質(zhì)量目標(biāo)是高層管理者的職責(zé)需要公司內(nèi)不同部門(mén)和所有層級(jí)的員工、公司的供應(yīng)商和經(jīng)銷(xiāo)商的參與和承諾。為了可靠地達(dá)到質(zhì)量目標(biāo)必須有一個(gè)全面設(shè)計(jì)和正確實(shí)施的質(zhì)量保證結(jié)合GMP和質(zhì)量控制的體系。這個(gè)體系應(yīng)該完全文件化并監(jiān)控其有效性。質(zhì)量保證體系的所有部分都要配備足夠的有資質(zhì)的人員并且應(yīng)該合適和足夠的廠(chǎng)房、設(shè)備和設(shè)施。

2. Good manufacturing practices for pharmaceutical products (GMP) 

藥品的GMP
2.1 Good manufacturing practice is that part of quality assurance which ensures that products are consistently produced and controlled to the quality standards appropriate to their intended use and as required by the marketing authorization. GMP are aimed primarily at diminishing the risks inherent in any pharmaceutical production. Such risks are essentially of two types: cross contamination (in particular of unexpected contaminants) and mix-ups (confusion) caused by, for example, false labels being put on containers. Under GMP:

GMP是質(zhì)量保證的一部分，確保產(chǎn)品可以被持續(xù)地生產(chǎn)和控制以符合適用其預(yù)期用途和滿(mǎn)足上市許可的質(zhì)量標(biāo)準(zhǔn)。GMP的主要目標(biāo)是減少藥品生產(chǎn)的固有風(fēng)險(xiǎn)。這些風(fēng)險(xiǎn)基本有兩個(gè)類(lèi)型：交叉污染（特別是非預(yù)期的污染）和混亂（混淆）例如由貼在容器上的錯(cuò)誤標(biāo)簽引起的。在GMP下：
(a) all manufacturing processes are clearly defined, systematically reviewed in
the light of experience, and shown to be capable of consistently manufacturing pharmaceutical products of the required quality that comply with their specifications;

所有生產(chǎn)工藝都要明確規(guī)定、根據(jù)經(jīng)驗(yàn)系統(tǒng)審核并證明其能夠有能力持續(xù)一致地生產(chǎn)要求符合它們標(biāo)準(zhǔn)的質(zhì)量的藥品；
(b) qualification and validation are performed;

進(jìn)行確認(rèn)和驗(yàn)證；

(c) all necessary resources are provided, including:

提供所有必須的資源，包括：
(i) appropriately qualified and trained personnel;

合適的有資質(zhì)并經(jīng)過(guò)培訓(xùn)的人員；
(ii) adequate premises and space;

足夠的廠(chǎng)房和空間；
(iii) suitable equipment and services;

合適的設(shè)備和服務(wù)；
(iv) appropriate materials, containers and labels;

合適的物料、容器和標(biāo)簽；

(v) approved procedures and instructions;

批準(zhǔn)的程序和工藝規(guī)程；
(vi) suitable storage and transport;

合適的儲(chǔ)存和運(yùn)輸；
(vii) adequate personnel, laboratories and equipment for in-process controls;

足夠的人員、實(shí)驗(yàn)室和設(shè)備用于中間過(guò)程控制；
(d) instructions and procedures are written in clear and unambiguous language, specifically applicable to the facilities provided;

用清晰并沒(méi)有歧義的語(yǔ)言編寫(xiě)的說(shuō)明書(shū)和程序
(e) operators are trained to carry out procedures correctly;

培訓(xùn)操作人員正確地執(zhí)行程序；
(f) records are made (manually and/or by recording instruments) during manufacture to show that all the steps required by the defined procedures and instructions have in fact been taken and that the quantity and quality of the product are as expected; any significant deviations are fully recorded and investigated;

在生產(chǎn)中做記錄（手工和/或通過(guò)記錄儀）以顯示所有由規(guī)定的程序和規(guī)程要求的所有步驟都已經(jīng)在事實(shí)上被執(zhí)行，產(chǎn)品的數(shù)量和質(zhì)量跟期望的一樣；任何重大偏差都被完整記錄并調(diào)查；
(g) records covering manufacture and distribution, which enable the complete history of a batch to be traced, are retained in a comprehensible and  accessible form;

以可理解和可以獲取的形式保存涵蓋生產(chǎn)和銷(xiāo)售的可以幫助追蹤到一批產(chǎn)品的完整的歷史的記錄；
(h) the proper storage and distribution of the products minimizes any risk to their quality;

正確地儲(chǔ)存和分發(fā)產(chǎn)品減少對(duì)其質(zhì)量的風(fēng)險(xiǎn)；
(i) a system is available to recall any batch of product from sale or supply;

可用的從銷(xiāo)售或供應(yīng)端召回任意批產(chǎn)品的系統(tǒng)；
(j) complaints about marketed products are examined, the causes of quality defects investigated, and appropriate measures taken in respect of the defective products to prevent recurrence.

對(duì)已銷(xiāo)售產(chǎn)品的投訴進(jìn)行檢查、調(diào)查質(zhì)量缺陷的原因并采取適當(dāng)措施避免缺陷產(chǎn)品再次出現(xiàn)。