QA：Quality Assurance，質量保證

一、中國GMP對QA的要求：

第二節(jié)質量保證

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

第九條質量保證系統(tǒng)應當確保：

(一) 藥品的設計與研發(fā)體現本規(guī)范的要求；

(二) 生產管理和質量控制活動符合本規(guī)范的要求；

(三)管理職責明確；

(四)采購和使用的原輔料和包裝材料正確無誤；

(五)中間產品得到有效控制；

(六)確認、驗證的實施；

(七)嚴格按照規(guī)程進行生產、檢查、檢驗和復核；

(八)每批產品經質量受權人批準后方可放行；

(九)在貯存、發(fā)運和隨后的各種操作過程中有保證藥品質量的適當措施；

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

第十條藥品生產質量管理的基本要求：

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

(二)生產工藝及其重大變更均經過驗證；

(三)配備所需的資源，至少包括：

1.具有適當的資質并經培訓合格的人員；

2.足夠的廠房和空間；

3.適用的設備和維修保障；

4.正確的原輔料、包裝材料和標簽；

5.經批準的工藝規(guī)程和操作規(guī)程；

6.適當的貯運條件。

(四)應當使用準確、易懂的語言制定操作規(guī)程；

(五)操作人員經過培訓，能夠按照操作規(guī)程正確操作；

(六)生產全過程應當有記錄，偏差均經過調查并記錄；

(七)批記錄和發(fā)運記錄應當能夠追溯批產品的完整歷史，并妥善保存、便于查閱；

(八)降低藥品發(fā)運過程中的質量風險；

(九)建立藥品召回系統(tǒng)，確保能夠召回任何一批已發(fā)運銷售的產品；

(十)調查導致藥品投訴和質量缺陷的原因，并采取措施，防止類似質量缺陷再次發(fā)生。

二、ICH Q7中對質量管理的描述。

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

質量應該是所有參與生產的人員的職責。
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.

每個生產企業(yè)應該建立、文件化并執(zhí)行一個有管理層和適當的生產人員參與的有效的管理質量的體系。
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.

管理質量的體系應該包含組織架構、程序、流程和資源，以及確保原料藥有信心符合預期的質量和純度標準的必要的活動。所有質量相關的活動都應該規(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.

應該有一個獨立于生產并且要履行質量保證（QA）和質量控制(QC）職責的質量單元（或質量部門）。根據組織的大小和架構，這個質量單元可以由單獨的QA和QC單元或一個人或團隊組成。
2.14 The persons authorised to release intermediates and APIs should be specified.

應當指定被授權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.

所有質量相關的活動都應該在其執(zhí)行的時候就記錄。
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.

任何與已經建立的程序的偏離都應該記錄（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).

在質量單元（部門）圓滿完成評價前物料不應該放行或使用，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)中描述的待驗狀態(tài)下的放行或等待完成評價時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.).

應該存在以一種及時的方式通知負責的管理層相關監(jiān)管檢查、嚴重的GMP缺陷、產品缺陷和相關措施的程序（比如質量相關的投訴、召回、監(jiān)管行動等）。
2.2 Responsibilities of the Quality Unit(s)

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

質量單元應該參與所有質量相關的事項。
2.21 The quality unit(s) should review and approve all appropriate quality-related documents.

質量單元應該審核和批準所有質量相關的文件。
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:

獨立的質量單元的主要職責不應該被委托（給他人）。這些職責應該書面描述并應該包括但不必限于以下內容：
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;

建立一個放行或拒收原料、中間體、包材和標簽的系統(tǒng)；

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

放行銷售的原料藥前審核關鍵工藝步驟的已完成的批生產記錄和實驗控制記錄；
4. Making sure that critical deviations are investigated and resolved;

確保關鍵偏差得到調查和解決；
5. Approving all specifications and master production instructions;

批準所有標準和生產工藝規(guī)程；
6. Approving all procedures impacting the quality of intermediates or APIs;

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

確保進行內部審計（自檢）；
8. Approving intermediate and API contract manufacturers;

批準中間體和原料藥的合同生產商；
9. Approving changes that potentially impact intermediate or API quality;

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

審核和批準驗證方案和報告；
11. Making sure that quality related complaints are investigated and resolved;

確保質量相關的投訴得到調查和解決；
12. Making sure that effective systems are used for maintaining and calibrating critical equipment;

確保有有效的系統(tǒng)用于維護和校驗關鍵設備；
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并報告其結果；
14. Making sure that there is stability data to support retest or expiry dates and storage conditions on APIs and/or intermediates where appropriate; 

確保在適當的情況下，有穩(wěn)定性數據支持中間體或原料藥的復驗期或有效期和儲存條件。
15. Performing product quality reviews (as defined in Section 2.5).

進行產品質量回顧（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，質量管理常常被定義為管理職能中規(guī)定并執(zhí)行“質量政策”的那方面職能。比如組織質量相關的總體意圖和方向，由最高管理層正式表達和授權。質量管理的基本要素有\(zhòng)：

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

一個適當的基礎架構或“質量體系”，包含組織架構、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”.

確保一個產品（或服務）有足夠信心會滿足質量要求的不要的系統(tǒng)化的行動。全部這些行動被稱之為“質量保證”。
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.

在一個組織內，質量保證是一種管理工具。在委托情況下，質量保證也用于產生對供應商的信心。質量保證、GMP和質量控制的概念是質量管理的相關要素。它們在這里描述是為了強調它們的關系和它們對于藥品生產和控制的根本的重要性。
1. Quality assurance 質量保證
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.

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

適用于藥品生產的質量保證體系應該確保：
(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和其他相關法規(guī)比如GLP和GCP的要求進行設計和開發(fā)；
(b) production and control operations are clearly specified in a written form and GMP requirements are adopted;

用書面的形式明確規(guī)定生產和控制操作并采用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；
(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、供應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;

實施所有對起始物料、中間產品和最終產品的必要的控制和其他中間過程控制、校驗和驗證；
(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;

在被授權的人員確認每批產品已經按照上市許可和其他與藥品的生產、控制和放行相關的法規(guī)生產和控制前藥品不能銷售或供應；
(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企業(yè)儲存、銷售和后續(xù)處理的滿意的安排以確保質量在它們整個貨架期都得到保持；
(i) there is a procedure for self-inspection and/or quality audit that regularly appraises the effectiveness and applicability of the quality assurance system;

有一個定期評價質量保證體系的質量和適用性的自檢和/或質量審計程序；
(j) deviations are reported, investigated and recorded;

偏差被報告、調查和記錄；

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

有批準可能對產品質量有影響的變更；
(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.

應該執(zhí)行對藥品質量的定期評價，目標是確認工藝的一致性并確保其持續(xù)改進。
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.

生產企業(yè)必須承擔藥品質量的職責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有因為安全性、質量和功效不足對患者產生風險。達到這個質量目標是高層管理者的職責需要公司內不同部門和所有層級的員工、公司的供應商和經銷商的參與和承諾。為了可靠地達到質量目標必須有一個全面設計和正確實施的質量保證結合GMP和質量控制的體系。這個體系應該完全文件化并監(jiān)控其有效性。質量保證體系的所有部分都要配備足夠的有資質的人員并且應該合適和足夠的廠房、設備和設施。

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是質量保證的一部分，確保產品可以被持續(xù)地生產和控制以符合適用其預期用途和滿足上市許可的質量標準。GMP的主要目標是減少藥品生產的固有風險。這些風險基本有兩個類型：交叉污染（特別是非預期的污染）和混亂（混淆）例如由貼在容器上的錯誤標簽引起的。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;

所有生產工藝都要明確規(guī)定、根據經驗系統(tǒng)審核并證明其能夠有能力持續(xù)一致地生產要求符合它們標準的質量的藥品；
(b) qualification and validation are performed;

進行確認和驗證；

(c) all necessary resources are provided, including:

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

合適的有資質并經過培訓的人員；
(ii) adequate premises and space;

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

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

合適的物料、容器和標簽；

(v) approved procedures and instructions;

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

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

足夠的人員、實驗室和設備用于中間過程控制；
(d) instructions and procedures are written in clear and unambiguous language, specifically applicable to the facilities provided;

用清晰并沒有歧義的語言編寫的說明書和程序
(e) operators are trained to carry out procedures correctly;

培訓操作人員正確地執(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;

在生產中做記錄（手工和/或通過記錄儀）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在事實上被執(zhí)行，產品的數量和質量跟期望的一樣；任何重大偏差都被完整記錄并調查；
(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和銷售的可以幫助追蹤到一批產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;

正確地儲存和分發(fā)產品減少對其質量的風險；
(i) a system is available to recall any batch of product from sale or supply;

可用的從銷售或供應端召回任意批產品的系統(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.

對已銷售產品的投訴進行檢查、調查質量缺陷的原因并采取適當措施避免缺陷產品再次出現。