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近日，WHO在其技術報告TRS1060中發布了新的《藥用輔料GMP》-2025，現將中英文翻譯分享給大家：
Annex 3
附錄 3
WHO good manufacturing practices for excipients used in pharmaceutical products
世衛組織藥用輔料良好生產規范
Republication of WHO good manufacturing practices for excipients used in pharmaceutical products, WHO Technical Report Series No. 1052, Annex 2, with two appendices.
重新發布WHO關于藥用輔料良好生產實踐的規定,出自WHO技術報告系列第1052號文件附錄2,附有兩個附錄。
Background
背景
The WHO guideline Good manufacturing practices: supplementary guidelines for the manufacture of pharmaceutical excipients was published in the WHO Technical Report Series No. 885, Annex 5, 1999.
WHO指南《良好生產規范:藥用輔料制造的補充指南》于1999年發布在WHO技術報告系列第885號,附錄5中。
As excipients are sometimes used in large quantities in pharmaceutical dosage forms, and may contain impurities, they can affect the quality of a finished pharmaceutical product.
由于制劑中輔料有時用量較大,且可能含有雜質,這可能會影響藥物成品的質量。
The manufacturer of the finished pharmaceutical product is normally dependent on the excipient manufacturer to supply excipients meeting the required specification. An appropriately established and implemented quality management system evaluating and controlling risks in the production and quality control of such excipients is therefore required.
通常,藥物成品的制造商依賴輔料制造商提供符合要求規格的輔料。因此,需要建立并實施適當的質量管理體系,以評估和控制輔料生產及質量控制過程中的風險。
Excipient manufacturers should be required to apply the appropriate principles of good manufacturing practices (GMPs) in producing pharmaceutical excipients. Reports of pharmaceutical products that contain contaminated excipients, or excipients with impurities leading to the death of patients, have further highlighted the importance of reviewing the original guideline. Furthermore, the concept of ongoing improvement, the lifecycle approach, better quality management systems, risk management, and management review should be described in such a guideline, alongside the necessary good storage, good trade and good distribution practices, to ensure quality throughout the supply chain, as applicable.
輔料制造商應遵循適當的良好生產規范(GMP)原則來生產藥用輔料。含有污染輔料或因輔料雜質導致患者死亡的藥品報告進一步突顯了重新審視原始指南的重要性。此外,持續改進的概念、生命周期方法、先進質量管理體系、風險管理以及管理評審應在此類指南中描述,同時還應包括適當的良好儲存、良好貿易和良好分銷實踐,以確保整個供應鏈的質量。
The manufacturer of excipients used in pharmaceutical products should be able to identify risks associated with the production (including stages of manufacturing, route of synthesis) and quality control of its products. This includes the premises, equipment, utilities, storage and distribution. The manufacturer of such excipients should assess those risks and identify appropriate measures to mitigate such risks. The effectiveness of the measures should be evaluated to ensure that they are appropriate.
藥用輔料制造商應能夠識別與輔料生產(包括制造階段、合成路線)及其質量控制相關的風險。這包括生產場所、設備、公用設施、儲存和分銷。輔料制造商應評估這些風險并確定適當的措施來減輕這些風險。措施的有效性應得到評估,以確保其適當性。
This document provides information on GMP that should be implemented to assist manufacturers to produce and control excipients used in pharmaceutical products that will meet their intended specifications, in a consistent manner. Risk assessment may be useful in determining which excipient should be manufactured in accordance with this guideline.
本文件提供了應實施的GMP信息,以幫助制造商以一致的方式生產和控制藥用輔料,使其符合預期的規格。風險評估可能有助于確定哪些輔料應根據本指南生產。
1. Introduction and scope
1. 引言與適用范圍
1.1 The purpose of this document is to provide guidance for the production, control, storage and distribution of excipients used in pharmaceutical products, focusing on good manufacturing practices (GMP) under an appropriate system for managing quality. It is also intended to help ensure that such excipients meet the requirements for quality and purity that they purport or are represented to possess.
本文件旨在為藥用輔料的生產、控制、存儲和分發提供指導,重點關注在適當的質量管理系統下實施良好生產規范(GMP)。同時,本文件也旨在確保這些輔料符合其聲稱或代表的質量和純度要求。
1.2 The document does not cover aspects of protection of the environment, or safety aspects for the personnel engaged in the manufacture and control of excipients.
本文件不涵蓋環境保護方面的內容,也不包括參與輔料制造和控制的人員的安全方面內容。
1.3 Excipients are often used in large quantities in industrial chemistry, as well as in the food and cosmetic industry. Specifications for excipients used in these applications may vary. It may not always be appropriate for use in pharmaceutical products. It is the responsibility of the finished product manufacturer and of the applicant to ensure that the finished product is manufactured using excipients of a suitable grade conforming to its intended use.
輔料在工業化學、食品和化妝品行業中常被大量使用。這些應用中的輔料規格可能有所不同,不一定適用于藥品生產。最終產品制造商和申請者有責任確保最終產品使用符合預期用途的適當等級的輔料。
1.4 Excipients should be of appropriate quality, as they could affect the safety, quality and efficacy of finished pharmaceutical products.
輔料應具備適當的品質,因為它們可能會影響藥物成品的安全性、質量和有效性。
1.5 The manufacturer of the finished pharmaceutical product is highly dependent on the excipient manufacturer to provide materials that are homogeneous in chemical and physical characteristics, and of the desired quality.
藥物成品制造商高度依賴輔料制造商提供化學和物理特性均一且符合預期用途的輔料。
1.6 In general, excipients are used as purchased, with no further refining or purification. Consequently, impurities present in the excipient will be carried over to the finished pharmaceutical product.
通常情況下,輔料按購買狀態使用,無需進一步提純或精煉。因此,輔料中的雜質會轉移到藥物成品中。
1.7 To achieve the objective of ensuring that excipients used in pharmaceutical products are of appropriate quality, an appropriate level of GMP should be established, implemented and maintained during their production, packaging, repackaging, labelling, quality control, release, storage, distribution and other related activities. Additional measures should be taken when manufacturing excipients for which scientific literature, information in the public domain or historical data indicate the presence of higher risk due to potential formation of toxic impurities during manufacturing or contamination during storage and distribution.
為了確保藥品中使用的輔料具有適當的品質,應在輔料的生產、包裝、重新包裝、標簽、質量控制、放行、存儲、分發及其他相關活動中建立、實施并維持適當水平的GMP。當制造輔料時,如果科學文獻、公共領域的信息或歷史數據表明存在較高風險,可能會在制造過程中形成有毒雜質或在存儲和分發過程中發生污染,應采取額外措施。
1.8 Manufacturers of excipients for pharmaceutical use should have a specific analytical testing procedure to ensure suitability for its intended use. Pharmacopoeial and regulatory requirements should be considered by the manufacturers as a reference for these analytical tests. Information in the public domain should also be considered. Risk management principles should be implemented in order to identify and mitigate risks.
藥用輔料制造商應具備特定的分析測試程序,以確保其適用于預期用途。藥典和監管要求應作為這些分析測試的參考。公共領域中的相關信息也應予以考慮。應實施風險管理原則,以識別和減輕風險。
1.9 A thorough knowledge and understanding of the processes and associated risks are required. This includes all unit operations and processing steps, including key steps in the process, critical parameters (such as time, temperature or pressure), the use of recovered solvent or mother liquor, environmental conditions, equipment used, protection from contamination and monitoring points.
需具備對工藝及其相關風險的全面理解和掌握。這包括所有單元操作和加工步驟,包括工藝中的關鍵步驟、關鍵參數(如時間、溫度或壓力)、回收溶劑或母液的使用、環境條件、所用設備、防止污染的措施以及監控點。
2. Glossary
2. 術語表
2.1 The definitions given below apply to the terms used in this document. They have been aligned to the extent possible with the terminology in related WHO guidelines and good practices included in the WHO Quality Assurance of Medicines Terminology Database – List of Terms and related guidelines.? But may have different meanings in other contexts.
下述定義適用于本文件中使用的術語,并在可能的情況下與WHO相關指南和良好實踐中的術語保持一致,這些術語和實踐包括在WHO藥品質量保證術語數據庫——術語列表及相關指南中,但其在其他上下文中可能具有不同的含義。
acceptance criteria
Numerical limits, ranges or other suitable measures for acceptance of test results.
接受標準-用于接受測試結果的數值限制、范圍或其他適當度量標準。
adulterated
Pertaining to an intermediate or product (in part or in whole) that is contaminated, unsafe, not shown to be safe, filthy, or produced under unsanitary conditions, or found to have been produced, controlled, stored or distributed not in compliance with good manufacturing practices (such as described in this guideline); or contains any substance that may reduce its quality or purity or render it injurious to health.
摻假-指中間產品或最終產品(部分或全部)受到污染、不安全、未被證明安全、骯臟、或在不衛生的條件下生產,或被發現未按照良好生產規范(如本指南所述)進行生產、控制、存儲或分發;或含有任何可能降低其質量或純度或對其健康有害的物質。
auditing
An independent and objective activity designed to add value to and improve an organization's operations by helping it to accomplish its objectives, using a systematic, disciplined approach to evaluate and improve the effectiveness of risk management, control and governance processes.
審計-一種獨立且客觀的活動,旨在通過幫助組織實現其目標來增加其運營的價值并改進其運營,采用系統且紀律嚴明的方法評估和改進風險管理、控制和治理過程的有效性。
batch（or lot)
A specific quantity of material produced in a single process or series of processes so that it is expected to be homogeneous within specified limits. In the case of continuous production, a batch corresponds to a defined fraction of the production. The batch size can be defined either by a fixed quantity or by the amount produced in a fixed time interval.
批(或批次)-特定數量的物料在一個單一過程或一系列過程中生產,預期在指定的限值內保持均勻性。在連續生產的情況下,批次可能對應于生產的一部分。批大小可以通過固定數量或固定時間間隔內生產的數量來定義。
batch number (or lot number). A unique combination of numbers, letters or symbols that identifies a batch (or lot) and from which the production and distribution history can be determined.
批號(或批號)-一組唯一的數字、字母或符號,用于標識一批(或一批次),并從中可以確定該批的生產和分發歷史。
calibration. The demonstration that a particular instrument or device produces results within specified limits by comparison with those produced by a reference or traceable standard over an appropriate range of measurements.
校準-通過與參考標準或可追溯標準在適當量程內進行比較,證明特定儀器或設備產生結果在規定限值內的過程。
change control. A formal system by which qualified representatives of appropriate disciplines review proposed actual changes that might affect a validated status. The intent is to determine the need for action that would ensure that the system is maintained in a validated state.
變更管制-一種正式系統,由相關學科的合格代表審查可能影響驗證狀態的提議或實際變更。其目的是確定是否需要采取行動以確保系統保持在驗證狀態。
computer system. A group of hardware components and associated software, designed and assembled to perform a specific function or group of functions.
計算機系統-一組硬件組件及其相關軟件,設計和組裝以執行特定功能或一組功能。
computerized system. A process or operation integrated with a computer system.
計算機化系統-與計算機系統集成的過程或操作。
contamination. The undesired introduction of impurities of a chemical or microbiological nature or of foreign matter into or onto a raw material, intermediate, or excipient during production, sampling, packaging or repackaging, storage, or transport.
污染-在生產、取樣、包裝或重新包裝、儲存或運輸過程中,非預期地將化學或微生物雜質或外來物質引入或附著于原料、中間體或賦形劑中的過程。
critical. Describes a process step, process condition, test requirement or other relevant parameter or item that must be controlled within predetermined criteria to ensure that the excipient meets its specification.
關鍵-描述必須在預設標準內控制的過程步驟、過程條件、測試要求或其他相關參數或項目,以確保賦形劑符合其規格。
cross-contamination. Contamination of a material or product with another material or product.
交叉污染-一種物料或產品被另一種物料或產品污染的過程。
deviation. Departure from an approved instruction or established standard.
偏差：偏離已批準的指令或既定標準。
excipient for pharmaceutical use. Substance, other than the active ingredient, that has been appropriately evaluated for safety and is included in a drug delivery system: (a) aid in the processing of the drug delivery system during its manufacture; (b) protect, support or enhance stability, bioavailability or patient acceptability; (c) assist in product identification; and (d) enhance any other attribute of the overall safety and effectiveness of the drug during storage or use.
用于制藥的賦形劑-除活性成分外的物質,已適當評估其安全性并包含在藥物遞送系統中,以(a)在藥物遞送系統的制造過程中輔助處理;(b)保護、支持或提高穩定性、生物利用度或患者接受度;(c)幫助產品識別;以及(d)提高藥物在儲存或使用過程中的整體安全性和有效性。
expiry date (or expiration date). The date placed on the container or labels of an excipient designating the time during which the excipient is expected to remain within established shelf-life specifications if stored under defined conditions and after which it should not be used.
有效期(或失效期)-在容器或賦形劑標簽上標注的日期,表明在特定儲存條件下賦形劑預期保持在規定貨架壽命標準內的期限,之后不應使用。
finished pharmaceutical product. WHO: A product that has undergone all stages of production, including packaging in its final container and labelling. A finished pharmaceutical product may contain one or more active pharmaceutical ingredients.
藥品成品-WHO:經過所有生產階段的產品,包括最終容器的包裝和標簽。成品藥品可能包含一種或多種活性藥物成分。
impurity. An undesired component in an excipient.
雜質-輔料中的非期望組分。
impurity profile. A description of the impurities present in an excipient.
雜質譜-描述輔料中雜質的特征。
in - process control (or process control). Checks performed during production in order to monitor, and, if appropriate, to adjust the process or to ensure that the intermediate or product conforms to its specifications.
過程控制(或工藝控制)-生產過程中進行的檢查,以監控過程,并在適當的情況下調整過程,或確保中間體或最終產品符合其規格。
intermediate. A material produced during steps of the processing of an excipient for pharmaceutical use. Pharmaceutical use that undergoes further molecular change or purification before it becomes an excipient for pharmaceutical use. Intermediates may or may not be isolated.
中間體-在輔料用于制藥過程中產生的材料,經過進一步的分子變化或純化后成為可用于制藥的輔料。中間體可能或可能不進行分離。
lot. See “batch”.
批-見 “批次” 。
lot number. See “batch number”.
批號-見 “批次號” 。
manufacture. All operations of receipt of materials, production, packaging, repackaging, labelling, relabelling, quality control, release, storage and distribution of an excipient and related controls.
生產-指輔料及其相關控制的接收、生產、包裝、重新包裝、標簽、重新標簽、質量控制、放行、儲存和分發的所有操作。
material. A general term used to denote raw materials (starting materials, reagents, solvents), process aids, intermediates, active pharmaceutical ingredients, and packaging and labelling materials.
物料-用于表示原料(起始材料、試劑、溶劑)、工藝輔助材料、中間體、活性藥物成分以及包裝和標簽材料的通用術語。
mother liquor. A concentrated solution from which the product is obtained by evaporation, freezing or crystallization. (Or: The residual liquid that remains after the crystallization or isolation processes. A mother liquor may contain unreacted materials, intermediates, levels of the excipient for pharmaceutical use, or impurities. It may be used for further processing).
母液-通過蒸發、冷凍或結晶從其中獲得產品的濃溶液。(或:結晶或分離過程后剩余的液體。母液可能包含未反應的材料、中間體、可用于制藥的輔料的水平或雜質。它可以用于進一步的加工)。
packaging material. Any material intended to protect an intermediate or excipient for pharmaceutical use during storage and transport.
包裝材料-任何用于在儲存和運輸過程中保護中間體或藥用輔料的材料。
procedure. A documented description of the operations to be performed, the precautions to be taken and measures to be applied, directly or indirectly related to the manufacture of an intermediate or excipient for pharmaceutical use.
程序-對要執行的操作、應采取的預防措施以及直接或間接與中間體或藥用輔料的生產相關的措施進行書面描述。
process aids. Materials, excluding solvents, used as an aid in the manufacture of an intermediate or excipient for pharmaceutical use that do not themselves participate in a chemical or biological reaction (for example, filter aid or activated carbon).
輔助工藝材料-除溶劑外,用于制藥過程中中間體或輔料制造的輔助材料,本身不參與化學或生物反應(例如,過濾輔助材料或活性碳)。
production. All operations involved in the preparation of an excipient for pharmaceutical use, from receipt of materials through processing and packaging of the excipient for pharmaceutical use.
生產-涉及藥用輔料制備的所有操作,從原材料接收開始,經過輔料的加工和包裝。
qualification. Action of proving and documenting that equipment or ancillary systems are properly installed, work correctly and actually lead to the expected results. Qualification is part of validation, but the individual qualification steps alone do not constitute process validation.
確認-證明和記錄設備或輔助系統已正確安裝、運行正常并確實能產生預期結果的過程。確認是驗證的一部分,但單獨的確認步驟并不構成過程驗證。
quality assurance (QA). The sum total of the organized arrangements made with the object of ensuring that all excipients for pharmaceutical use are of the quality required for their intended use and that quality systems are maintained.
質量保證(QA)-為確保所有用于制藥的輔料符合預期用途的質量要求,并維持質量體系所采取的組織化安排的總和。
quality control (QC). Checking or testing that specifications are met.
質量控制(QC)-檢查或測試以確保符合規定要求。
quality unit. An organizational unit independent of production that fulfils both QA and 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 organization.
質量單位-一個獨立于生產部門的組織單元,負責履行QA和QC職責。這可以是獨立的QA和QC部門,也可以是一個單獨的個人或團隊,取決于組織的規模和結構。
quarantine. The status of materials isolated physically or by other effective means pending a decision on their subsequent approval or rejection.
隔離-材料在物理隔離或其他有效手段下隔離的狀態,待決定其后續批準或拒絕。
raw material. A general term used to denote starting materials, reagents and solvents intended for use in the production of intermediates or excipients for pharmaceutical use.
原料-用于生產中間體或用于制藥的輔料的起始材料、試劑和溶劑的通用術語。
reprocessing. Introducing an intermediate or excipient for pharmaceutical use, including one that does not conform to standards or specifications, back into the process and repeating a crystallization step or other appropriate chemical or physical manipulation steps (for example, distillation, filtration, chromatography or milling) that are part of the established manufacturing process. Continuation of a process step after an in - process control test has shown that the step is incomplete is considered to be part of the normal process and not to be reprocessing.
重新加工-將中間體或用于制藥的輔料(包括不符合標準或規格的)重新引入生產過程,并重復結晶步驟或其他適當的化學或物理操作步驟(例如,蒸餾、過濾、色譜法或粉碎),這些步驟是已建立的制造過程的一部分。在過程控制測試表明某步驟不完整后繼續該過程步驟被視為正常過程,而不是重新加工。
reworking. Subjecting an intermediate or excipient for pharmaceutical use that does not conform to standards or specifications to one or more processing steps that are different from the established manufacturing process to obtain an intermediate or excipient of acceptable quality for pharmaceutical use (for example, recrystallizing with a different solvent).
返工-對不符合標準或規格的中間體或用于制藥的輔料進行一個或多個不同于已建立制造過程的加工步驟,以獲得可用于制藥的合格中間體或輔料(例如,使用不同溶劑重結晶)。
shelf-life. The period of time during which an excipient, if stored correctly, is expected to comply with the specification, normally as determined by stability studies. The shelf-life is used to establish the retest or expiry date.
保質期-指如果儲存條件正確,輔料在一定期間內預期符合規定要求的時間,通常通過穩定性研究確定。保質期用于確定復檢或失效日期。
signed (signature). The record of the individual who performed a particular action or review. This record can be in the form of initials, full handwritten signature, personal seal or an authenticated and secure electronic signature.
簽署(簽名)-執行特定行動或審查的個人的記錄。此記錄可以是首字母縮寫、全名的手寫簽名、個人印章或經過認證的安全電子簽名的形式。
solvent. An inorganic or organic liquid used as a vehicle for the preparation of solutions or suspensions in the manufacture of an intermediate or excipient for pharmaceutical use.
溶劑-用于制藥中間體或輔料制備溶液或混懸液的有機或無機液體。
specification. A list of tests, references to analytical procedures and appropriate acceptance criteria that are numerical limits, ranges or other criteria for the test described. It establishes the set of criteria to which a material should conform to be considered acceptable for its intended use. “Conformance to specification”means that the material, when tested according to the listed analytical procedures, will meet the listed acceptance criteria.
規格-列出的測試、分析程序的參考以及適當的接受標準,這些標準是數值限制、范圍或其他測試標準。它確立了一組標準,材料應符合這些標準才能被認為適合其預期用途。“符合規格”-意味著材料在根據列出的分析程序進行測試時將滿足列出的接受標準。
validation. A documented programme that provides a high degree of assurance that a specific process, method or system will consistently produce a result meeting a predetermined acceptance criteria.
驗證-一種文件化的計劃,提供高度保證,確保特定過程、方法或系統能夠一致地產生符合預定接受標準的結果。
validation protocol. A written plan stating how validation will be conducted and defining acceptance criteria. For example, the protocol for a manufacturing process identifies processing equipment, critical process parameters and operating ranges, product characteristics, sampling, test data to be collected, number of validation runs and acceptable test results.
驗證計劃-書面計劃,說明驗證將如何進行并定義接受標準。例如,制造過程的驗證方案確定了加工設備、關鍵工藝參數和操作范圍、產品特性、取樣、需要收集的測試數據、驗證運行次數以及可接受的測試結果。
verification. The application of methods, procedures, tests and other evaluations, in addition to monitoring, to determine compliance with established requirements and specifications.
確認(verification)-除了監控外,應用方法、程序、測試和其他評估,以確定是否符合已建立的要求和規定。
3. Quality management
3. 質量管理
3.1 Manufacturers involved in the production, control, storage and distribution of excipients for pharmaceutical use should establish, document, implement and maintain a comprehensively designed and clearly defined quality management system.
生產、控制、儲存和分發藥用輔料的制造商應建立、記錄、實施并維持一個全面設計且定義清晰的質量管理體系。
3.2 Senior management should assume responsibility for the quality management system, as well as the quality of the excipients for pharmaceutical use manufactured, controlled, released, stored and distributed.
高級管理層應承擔質量管理體系以及所生產、控制、放行、儲存和分發的藥用輔料質量的責任。
3.3 The quality management system should encompass the quality policy, organizational structure, procedures, processes and resources. All parts of the quality management system should be adequately resourced and maintained.
質量管理體系應涵蓋質量政策、組織結構、程序、過程和資源。質量管理體系的所有部分都應得到充分資源的支持并得到維護。
3.4 The quality management system should cover all activities necessary to ensure that excipients for pharmaceutical use will meet their intended specifications, including quality and purity.
質量管理體系應涵蓋所有必要的活動,以確保用于制藥的輔料符合其預定規格,包括質量和純度。
3.5 The quality management system should incorporate the principles of good practices, which should be applied to the life cycle stages of excipients for pharmaceutical use. This includes steps such as the receipt of raw materials, production, packaging, testing, release, storage and distribution.
質量管理體系應融入良好實踐的原則,這些原則應應用于用于制藥的輔料生命周期的各個階段。這包括原材料的接收、生產、包裝、檢驗、放行、儲存和分發等步驟。
3.6 All quality-related activities and procedures should be defined and documented manually or electronically.
所有與質量相關的工作活動和程序都應被定義并以手工或電子方式記錄。
3.7 All quality-related activities should be recorded at the time they are performed.
所有與質量相關的工作活動都應在執行時進行記錄。
3.8 The quality management system should ensure that:
質量管理體系應確保以下幾點:
sufficient resources are available (for example, equipment, personnel, materials);
充足的資源可用(例如,設備、人員、材料);
excipients for pharmaceutical use are produced, controlled, stored and distributed in accordance with the recommendations in this document and other associated guidelines, such as good quality control laboratory practices and good storage and distribution practices, where appropriate;
用于制藥的輔料的生產、控制、儲存和分發應按照本文件和其他相關指南(如良好質量控制實驗室實踐和良好儲存與分發實踐)中的推薦進行;
managerial roles, responsibilities and authorities are clearly specified in job descriptions;
管理角色、職責和權限在職位描述中應明確指定;
operations and other activities are clearly described in a written form, such as standard operating procedures and work instructions;
操作和其他活動應在書面形式(如標準操作程序和工作指導書)中清晰描述;
appropriate arrangements are made for the manufacture, supply and use of the correct containers and labels;
為制造、供應和使用正確的容器和標簽作出適當安排;
all necessary controls are in place;
所有必要的控制措施均已到位;
calibrations, verification or validations are carried out where necessary;
必要時進行校準、驗證或驗證;
the excipient for pharmaceutical use is correctly processed and checked according to the defined procedures and specifications;
用于制藥的輔料根據定義的程序和規格正確處理和檢查;
deviations, suspected product defects, out-of-specification test results and any other nonconformances or incidents are reported,investigated and recorded. An appropriate level of root cause analysis is applied during such investigations and the most likely root causes are identified;
偏差、疑似產品缺陷、超出規格的測試結果以及任何其他不符合或事件均被報告進行了調查和記錄。在這些調查過程中,適當進行了根本原因分析,并確定了最可能的根本原因。
proposed changes are evaluated and approved prior to implementation. After implementation of a change that could impact the quality or the product, an evaluation should be undertaken to confirm that the quality objectives were achieved and that there was no unintended adverse impact on product quality;
在實施變更之前,提議的變更應經過評估并獲得批準。在實施可能影響產品質量或產品的變更之后,應進行評估以確認是否達到了質量目標,并且沒有對產品質量產生意外的負面影響;
appropriate corrective actions and preventive actions, as well as checks on the effectiveness of those actions (where appropriate), are identified and taken;
應識別并采取適當的糾正措施和預防措施,并在適當的情況下檢查這些措施的有效性;
where required, processes are in place to ensure the management of any outsourced activities that may impact product quality, purity and integrity;
如有需要,應有流程確保對外包活動的管理,這些活動可能影響產品的質量、純度和完整性;
a batch of an excipient for pharmaceutical use is not released and supplied before it has been released by the quality unit with the assurance that the batch has been produced and controlled in accordance with product specifications, and with the recommendations in this document and any other regulations relevant to the production, control and release of these products;
在質量部門確認該批次按照產品規格和本文件及任何其他相關法規的要求生產并控制之前,制藥用輔料的批次不得被釋放和供應;
there is a system for handling complaints, returns and recalls;
應有處理投訴、退貨和召回的系統;
there is a system for self-inspect;
應有自我檢查的系統;
there is a system for product quality review.
應有產品質量管理的系統。
3.9 The quality unit should be independent of production. The responsibilities of the unit should be clearly defined and documented.
質量部門應獨立于生產部門。該部門的職責應明確界定并形成文件。
3.10 The person or persons authorized to release excipients for pharmaceutical use should have appropriate qualifications, and be specified.
負責批準用于制藥的輔料的人員或人員應具備適當的資質,并明確指定。
3.1 Quality risk management
3.1 質量風險管理
3.11 There should be a system for managing risks (1). The system for quality risk management should be comprehensive and should cover a systematic process for the assessment, control, communication and review of risks in the production, testing, packaging, storage and distribution of excipients for pharmaceutical use. Controls identified should be appropriate, ensure that risks are eliminated or mitigated, and ultimately protect the patient from receiving a pharmaceutical product containing the wrong, contaminated or unsuitable excipients for pharmaceutical use.
應建立風險管理體系(1)。質量風險管理的體系應當全面,應涵蓋評估、控制、溝通和審查生產、檢測、包裝、儲存和分發制藥用輔料過程中風險的系統性過程。識別出的控制措施應當適當,確保風險被消除或減輕,并最終保護患者免于接受含有錯誤、污染或不適合使用的輔料的藥品。
3.12 In order to perform an adequate excipient risk assessment, it would be useful to provide some high-level guidance using an appropriate risk profile or ranking using a question - based risk ranking and filtering system. For example:
為了進行充分的輔料風險評估,使用適當的風險評估或分級系統提供一些高層次的指導是有益的,例如基于問題的風險評估和篩選系統。例如:
functionality of excipient in formulation輔料在配方中的功能
route of administration給藥途徑
potential for contamination污染可能性
excipient complexity輔料復雜性
prior knowledge or experience with excipient對輔料的先前知識或經驗
packaging size包裝規格
3.13 Similarly, a risk score should be calculated for the supply chain (for example, complexity of supply chain, prior knowledge of supply chain, excipient manufacturer performance history, packaging suitability, quality management system standard and certification).
同樣,供應鏈的風險評分也應進行計算(例如,供應鏈的復雜性、供應鏈的先前知識、輔料制造商的歷史表現、包裝的適用性、質量管理體系的標準和認證)。
3.14 Note: see WHO guidelines on quality risk management (1).
注意:參見世界衛生組織關于質量風險管理的指南(1)。
3.2 Management review
3.2 管理評審
3.15 There should be a system for regular management review. All elements of the quality management system should be included.
應建立定期管理評審的體系,質量管理體系的所有要素均應納入評審范圍。
3.16 Management should ensure that the quality management system achieves its intended objectives and measures managing and performance in areas such as:
管理層應確保質量管理體系實現其預期目標,并在諸如以下方面衡量管理績效:
self - inspections, inspections, quality audits and supplier's audits
自檢、檢查、質量審核和供應商審核
complaints, returns and recalls投訴、退貨和召回
changes and deviations變更和偏差
rejected batches拒收批次
quality control, out - of - specification results and out - of - trend results質量控制、超出規格結果和超出趨勢結果
maintenance維護
qualification and validation
資質認定和驗證
corrective and preventive actions糾正和預防措施
risk management風險管理
3.17 Key performance indicators should be identified and monitored with the view of continual improvement.
應識別并監控關鍵績效指標,以實現持續改進。
3.18 Records of meetings, discussions and actions should be maintained.
應保持會議、討論和行動記錄。
4. Complaints
4.投訴
4.1 There should be a written procedure describing the recording and investigation of complaints.
應有書面程序詳細說明投訴的記錄和調查過程。
4.2 All decisions made and measures taken as a result of a complaint should be recorded.
投訴處理過程中作出的所有決定和采取的措施均應予以記錄。
4.3 Complaint records should include at least the following:
投訴記錄應至少包括以下內容：
date of receiving the complaint;
投訴接收日期;
name, address and other relevant details of complainant;
投訴人姓名、地址及其他相關詳細信息;
details of the complaint, including name of the excipient and batch number;
投訴詳情,包括輔料名稱和批號;
details of the investigation and action taken;
調查和采取措施的詳細信息;
copy of the response provided;
提供給投訴人的回復副本;
final decision based on the outcome of the investigation.
根據調查結果作出的最終決定。
4.4 Where necessary, the appropriate corrective action and follow - up action should be taken after the investigation and evaluation of a complaint.如有必要,應在投訴調查和評估后采取適當的糾正措施和后續措施。
4.5 Where necessary, a recall of the batch or batches should be considered.
如有必要，應考慮召回相關批次產品。
4.6 Records of complaints should be retained in order to evaluate trends.
應保留投訴記錄以評估趨勢。
5. Recalls
5.召回
5.1 There should be a written, authorized procedure describing the managing of a prompt and effective recall of an excipient for pharmaceutical use. Where the recall is as a result of a contaminated or adulterated excipient, or any other reason where the excipient could cause harm to a patient, the manufacturer should report this to the relevant authority without delay.
應有書面且授權的程序,詳細說明藥品用輔料的召回管理,確保召回及時且有效。若召回是由于污染或摻假的輔料,或任何其他可能導致患者受到傷害的原因,則制造商應在不延遲的情況下向相關主管部門報告。
5.2 The recall procedure should indicate the responsibilities of personnel involved in the recall, how the recall should be initiated, who should be informed about the recall and how the recalled material should be handled.
召回程序應明確參與召回人員的職責,召回應如何啟動,應通知哪些人員,以及如何處理召回的物料。
5.3 The recall of an excipient for pharmaceutical use should be documented. Records should be kept.
藥品用輔料的召回應有記錄。應保存相關記錄。
6. Returns
6.回收
6.1 There should be a written procedure describing the handling of returned excipients for pharmaceutical use.
應有書面程序描述用于制藥的回收輔料的處理方法。
6.2 Returned investigational products should be clearly identified and stored in a dedicated area in a controlled manner.
回收的實驗用產品應明確標識,并以受控方式存放在專用區域。
6.3 Inventory records of returned products should be kept.
回收產品的庫存記錄應予以保留。
Destruction
銷毀
6.4 The disposition of the returned product should be approved by the quality unit. The conditions under which the excipient for pharmaceutical use had been stored and shipped should be considered when deciding on the fate of the returned product. If the condition of the container itself casts doubt on the safety, quality or purity of the excipient, the product should be destroyed, unless scientific justification can be provided that proves that the product meets the appropriate predefined quality standards.
返回產品的處理應由質量部門批準。在決定返回產品的命運時,應考慮用于制藥的輔料在儲存和運輸過程中所處的條件。如果容器本身的狀況對輔料的安全性、質量和純度產生懷疑,除非能夠提供科學依據證明產品符合相應的預定義質量標準,否則應予以銷毀。
6.5 A certificate of destruction should be available containing the necessary detail to enable traceability of the product, batch and related information.
應提供銷毀證明,其中包含必要的細節以實現產品的可追溯性,包括批次和其他相關信息。
6.6 Where returned excipient containers are reused, all previous labelling should be removed. The containers should be appropriately cleaned and there should be no risk of contamination from one material to another.
當回收使用返回的輔料容器時,應移除所有之前的標簽。容器應進行適當的清洗,并且不應存在一種材料對另一種材料造成污染的風險。
7. Self - inspection, quality audits, and supplier’s audits and approvals
7.自檢、質量審核和供應商審核與批準
7.1 There should be written standard operating procedures and programmes for periodic self - inspections, quality audits and supplier audits.
應有書面的標準操作程序和計劃,用于定期進行自檢、質量審核和供應商審核。
7.2 Self - inspections should be performed routinely in accordance with a self - inspection programme.
自檢應按照自檢計劃定期進行。
7.3 The team responsible for self - inspection should consist of personnel with the appropriate knowledge and experience. Team members may be from inside or outside the manufacturer, but members of the team should be free from bias.
負責自檢的團隊應由具備適當知識和經驗的人員組成。團隊成員可以來自制造商內部或外部,但團隊成員應無偏見。
7.4 Areas to be covered in self - inspections may include:
自檢應涵蓋的領域可能包括:
premises
場所
personnel
人員
equipment
設備
maintenance and calibration
維護與校準
storage conditions of materials and finished products
原材料和成品的儲存條件
production and in - process controls
生產和過程控制
quality control
質量控制
documentation, data generation and data integrity
文檔、數據生成與數據完整性
change control and deviations management
變更控制與偏差管理
complaints and recalls
投訴與召回
qualification and validation
資質確認與驗證
cleaning procedures.
清潔程序
7.5 The client's end use should be considered during inspection of excipient manufacturers. It is particularly important to know whether the excipient will be used in the preparation of a sterile dosage form. The excipient manufacturer is responsible for ensuring that excipients are pyrogen free if the manufacturer makes such a representation in specifications, labels or a drug master file.
在檢查輔料制造商時,應考慮輔料的最終用途。特別是要了解輔料是否將用于制備無菌制劑。如果制造商在規范、標簽或藥品主文件中作出此類聲明,輔料制造商有責任確保輔料無熱原。
7.6 Self - inspection should also ensure that appropriate measures are in place to prevent contamination of materials during storage and production.
自檢還應確保采取適當措施,防止儲存和生產過程中材料受到污染。
7.7 The outcome of the self - inspection should be documented, including corrective actions and preventive actions.
自檢的結果應予以記錄,包括糾正措施和預防措施。
8. Personnel
8.人員
8.1 There should be an adequate number of personnel with appropriate qualifications, training or experience to perform their respective activities.
應有足夠數量的具備相應資格、培訓或經驗的人員,以履行各自的職責。
8.2 Responsibilities should be specified in written job descriptions.
職責應在書面崗位描述中明確規定。
8.3 Training should be regularly conducted and should include, for example, GMP and the particular operations of the employee. Assessment of understanding of training topics should be done and documented.
應定期開展培訓,培訓內容應包括,例如,GMP 及員工的具體操作。應對培訓主題的理解進行評估,并記錄在案。
8.4 Records of training should be maintained.
應保存培訓記錄。
9. Sanitation and hygiene
9.消毒和衛生
9.1 Excipients for pharmaceutical use should be protected from contamination. A documented risk assessment should identify controls to be implemented to ensure appropriate sanitation and hygiene actions are taken.
藥用輔料應防止受到污染。應進行文件化的風險評估,以識別所需實施的控制措施,確保采取適當的衛生與清潔行動。
9.2 Written procedures should be followed for cleaning and sanitization, as appropriate, of manufacturing areas, equipment and utilities.
應遵循書面程序對制造區域、設備和公用設施進行清潔和消毒(如需)。
9.3 Personnel should practise good hygiene and health habits.
人員應養成良好的衛生和健康習慣。
9.4 Personnel should wear clean clothing suitable for their activities. The wearing of appropriate protective clothing should apply to all persons entering production areas where products or materials are handled. Additional personal protective equipment should be worn when necessary.
人員應穿著適合其活動的干凈衣物。所有進入處理藥品或材料的生產區域的人員均應穿戴適當的防護服。必要時,應穿戴額外的個人防護裝備。
9.5 Personnel should avoid direct contact with starting materials and excipients for pharmaceutical use.
人員應避免直接接觸用于制藥的起始物料和輔料。
9.6 Smoking, eating, drinking, chewing and the storage of food should not be allowed in production and quality control areas.
生產區和質量控制區不允許吸煙、進食、飲水、嚼口香糖以及儲存食物。
9.7 Personnel with an infectious disease or who have open lesions on the exposed surface of the body should not engage in activities that could result in compromising the quality of excipients for pharmaceutical use.
患有傳染性疾病或身體暴露部位有開放性傷口的人員不應參與可能影響藥用輔料質量的活動。
9.8 Jewellery and electronic devices such as mobile phones should only be used in authorized areas.
僅在指定區域允許佩戴首飾和電子設備,如手機等。
10. Documentation
10.文件
10.1 Documents such as standard operating procedures, specifications and others related to the production and control of excipients for pharmaceutical use should be prepared, reviewed, updated, approved and distributed according to written procedures.
用于藥用輔料生產和控制的標準操作程序、規范及其他相關文檔應根據書面程序準備、審核、更新、批準并分發。
10.2 The issuance, revision, withdrawal and retention of documents should be appropriately controlled in accordance with good documentation practices.
文檔的發行、修訂、撤回和保存應根據良好的文件管理實踐適當控制。
10.3 Documents should be retained for a defined period of time. The retention time of the documents should be justified to ensure availability of information in case of need. This time should be longer than the product retest or expiry date.
文檔應保存一段時間。文檔的保存期限應經過合理論證,以確保在需要時能夠獲取相關信息。該期限應長于產品的復檢或有效期。
10.4 Where documents require the entry of data, these entries should be clear, legible and indelible. Entries should be in compliance with good documentation practices and data integrity requirements.
當文檔需要錄入數據時,這些數據應清晰、可讀且不可擦除。錄入的數據應符合良好的文件管理實踐和數據完整性要求。
10.5 Records should be made or completed when any action is taken and in such a way that all significant activities are traceable to the person making the entry, including signatures and dates. Corrections made to incorrect entries should be dated and signed, with a description of the reason for the change, as appropriate.
應在采取任何行動時記錄或完成記錄,并確保所有重要活動均可追溯到錄入人員,包括簽名和日期。對錯誤錄入的修正應注明日期并簽名,并在適當情況下說明更改原因。
10.6 Electronic documents and records should meet the requirements for good documentation practices, and good practices for computerized systems.
電子文件和記錄應符合良好記錄實踐的要求,并符合計算機化系統的良好實踐要求。
10.1 Standard operating procedures and records
10.1標準操作程序與記錄
10.7 Standard operating procedures and associated records should be available for at least the following:
標準操作程序及相關記錄應至少包括以下內容:
equipment設備
analytical apparatus and instruments
分析儀器和設備
out-of-specification results
不合格結果
maintenance and calibration
維護與校準
cleaning and sanitization
清潔與消毒
personnel matters, such as training, clothing and hygiene
人員事務,如培訓、著裝和衛生
qualification and validation
資質認定與驗證
self-inspection and audits
自查與審核
complaints
投訴
recalls召回
returns
退貨
10.8 The standard operating procedures for sampling should specify the person or section authorized to take samples and the sampling instructions.
用于取樣的標準操作程序應明確規定有權取樣的人員或部門以及取樣指示。
10.9 The standard operating procedures describing the details of the batch (lot) numbering system should ensure that each batch of excipient for pharmaceutical use is identified with a specific batch number.
描述批次(批號)編號系統的詳細標準操作程序應確保每批用于制藥的輔料都有特定的批號標識。
10.10 Records of analytical analysis should be maintained.
分析記錄應予以保存。
10.11 Written release and rejection procedures should be available.
書面的放行與拒收程序應可供查閱。
10.12 Records should be maintained of the distribution of each batch of excipient for pharmaceutical use.
應保存每批用于制藥的輔料分發的記錄。
10.13 Records should be kept for major and critical equipment, as appropriate, of any qualifications, calibrations, maintenance, cleaning or repair operations, including the dates and the identities of the people who carried out these operations.
根據需要,應保存重大和關鍵設備的相關記錄,包括任何資質認定、校準、維護、清潔或修理操作的日期及執行這些操作的人員身份。
10.2 Specifications
10.2規格
10.14 Specifications should be established and maintained for starting materials, packaging materials, excipients for pharmaceutical use, and other related materials where necessary.
應建立并維護起始物料、包裝材料、藥品用輔料及其他相關物料的規格,必要時應進行此項工作。
10.15 Quality attributes, acceptance limits and test procedures should be defined. Relevant pharmacopoeial monographs, when available, should be considered for use or to be used as a basis for the development of internal manufacturer's specifications.
質量屬性、接受限值和檢驗程序應予以定義。當藥典中有相關條目時,應考慮使用這些條目,或將其作為制定內部制造商規范的基礎。
10.16 A positive identification test uniquely applicable to the excipients should be established through analytical technology, such as infrared spectrophotometry and chromatography.
應通過分析技術,如紅外光譜法和色譜法,建立一種獨特適用于輔料的陽性鑒別試驗。
10.17 Appropriate limits for impurities should be specified. These limits should be based upon appropriate toxicological data, or limits described in national compendial requirements. Manufacturing processes should be adequately controlled so that the impurities do not exceed such established specifications.
應明確規定雜質的適當限值。這些限值應基于適當的毒理學數據,或參照國家藥典要求中的限值。制造過程應得到充分控制,以確保雜質不超出已建立的規格。
10.18 Where excipients are extracted from or purified by the use of organic solvents, specifications should include tests and limits for residues of solvents and other reactants.
如果輔料是從有機溶劑中提取或通過有機溶劑進行純化,則規范中應包括溶劑及其他反應物殘留物的檢驗和限值。
10.19 Container specifications should be established for all excipients to ensure consistency in protecting the product during storage and transport, to maintain the stability of the product, and to protect against contamination and infestation.
應為所有輔料建立容器規范,以確保在儲存和運輸過程中產品的一致性保護,維持產品的穩定性,并防止污染和蟲害。
10.3 Batch documentation
10.3批次文檔
10.20 Procedures such as a master batch manufacturing document with instructions for each excipient for pharmaceutical use should be prepared and authorized (dated and signed).
應準備并授權(注明日期并簽字)用于制藥用途的主批次制造文檔,其中應包含每種輔料的操作指令。
10.21 A master batch manufacturing document should include the following:
主批次制造文檔應包括以下內容
the name of the excipient for pharmaceutical use being manufactured;正在制造的制藥用途輔料的名稱
a complete list of materials (formula) and quantities;完整的物料清單(配方)及其數量
the production location;生產地點
equipment to be used;所需使用的設備
detailed production instructions, in - process controls and flow chart, if needed;詳細的生產指令、過程控制和流程圖(如需)
where appropriate, precautions to be followed;如有必要,應注明應遵循的注意事項
labelling and packaging materials and instructions.
標簽和包裝材料及其操作指令
10.22 A record should be available for the excipient for pharmaceutical use produced. It should contain detailed information relating to the production and control thereof.
應為用于制藥用途的輔料生產保留記錄,該記錄應包含與生產及控制相關的詳細信息。
10.23 The manufacturing record should provide traceable information, including the following:
制造記錄應提供可追溯的信息,包括以下內容:
the batch number批號
dates and, when appropriate, times日期和必要時的時間
identification number of equipment used使用設備的識別編號-
actual results from testing測試的實際結果
information regarding any sampling performed
任何取樣的相關信息
signatures of operators and supervisors
操作員和監督者的簽名
records of packaging, packaging materials and labels
包裝、包裝材料和標簽的記錄
records of any deviations that occurred任何偏差的記錄
results of release testing.
放行測試的結果
10.24 The manufacturer should demonstrate that:
制造商應證明以下事項:
the batch is homogeneous and compliant with its specification;批次是均勻且符合其規格的;
a capable process is used to ensure batch-to-batch consistency;使用了能力足夠的工藝以確保批次間的穩定性;
a batch has not been commingled with material from other batches for the purpose of either hiding or diluting an adulterated substance;批次未與其他批次的材料混合以掩蓋或稀釋摻假物質;
samples have been taken, where required, in accordance with a sampling plan that ensures a representative sample is taken;根據確保取樣代表性的取樣計劃進行了必要的取樣;
the batch has been analysed using scientifically established tests and procedures;批次使用了科學驗證的測試和程序進行了分析;
the shelf-life of the excipient for pharmaceutical use is supported by scientific justification, including data and literature citations, taking account of the stability of the excipient in its packaging.
藥用輔料的貨架期得到了科學依據的支持,包括數據和文獻引用,考慮到輔料在包裝中的穩定性。
10.25 Where computerized systems are used in the production of a batch, the electronic data and records should comply with the guidelines on good practices for computerized systems. The system should be suitable for the intended use.
在使用計算機系統進行批次生產時,電子數據和記錄應遵守計算機化系統良好實踐指南。系統應適合預期用途。
10.26 When computerized systems are in use, aspects such as access and privileges, data integrity, audit trail, and back-up systems should be considered during risk assessment, with appropriate controls identified and implemented.
在使用計算機系統時,應考慮訪問和權限、數據完整性、審計追蹤和備份系統等方面的因素,在風險評估過程中識別并實施適當的控制措施。
10.4 Labels
10.4標簽
10.27 Excipients for pharmaceutical use should be labelled. Labels should be clear, unambiguous and in compliance with national or regional legislation, as appropriate. Procedures for handling incorrect labellingshould be established, covering the investigation, evaluation and treatment of nonconforming products.
藥用輔料應進行標注。標簽應清晰、無歧義,并符合國家或地區相關法律法規的要求。應建立處理不正確標注的程序,涵蓋對不合格產品的調查、評估和處理。
10.28 Information on labels should include as a minimum the following:
標簽信息至少應包括以下內容:
the name of the excipient and grade;輔料的名稱及其規格;
the batch number assigned by the manufacturer;制造商指定的批號;
the expiry or retest date, if applicable;有效期或復驗日期(如適用);
any special storage conditions or handling precautions that may be necessary;任何必要的特殊儲存條件或處理注意事項;
warnings and any other appropriate precautions;警告及其他適當的注意事項;
the name and address of the manufacturer.
制造商的名稱和地址。
10.29 For further information, see WHO Guideline on data integrity and WHO Good manufacturing practices: guidelines on validation. Appendix 5: Validation of computerized systems (2, 3).
如需進一步信息,請參見WHO關于數據完整性的指南以及世界衛生組織良好生產規范:驗證指南。附錄5:計算機化系統的驗證(2, 3)。
11. Premises
11.廠房
11.1 The premises where excipients for pharmaceutical use are manufactured should provide sufficient space for the production, quality control testing and storage operations.
制備藥用輔料的廠房應提供足夠的空間以滿足生產、質量控制檢測和儲存操作的需求。
11.2 The premises should be located, constructed, cleaned and maintained to suit the operations to be carried out.
廠房應根據即將開展的操作進行選址、建設、清潔和維護。
11.3 The layout and design of the premises should aim to minimize the risk of errors, mix-ups, contamination and cross-contamination. In addition, it should allow effective cleaning and maintenance without any adverse effect on the quality of the products.
廠房的布局和設計應旨在最大限度地減少錯誤、混料、污染和交叉污染的風險。此外,還應便于有效清潔和維護,而不對產品質量產生不利影響。
11.4 Only authorized persons should have access to relevant areas.
只有經授權人員才可進入相關區域。
11.5 Adequate lighting should be provided.
應提供充足的照明。
11.6 The decision to use a separate or dedicated facility for the manufacturing of high-risk excipients used in pharmaceutical manufacturing should be based on the outcome of a holistic risk assessment performed by the excipient manufacturer. The risk assessment should take into account the requirement of health-based exposure limits, as described in the literature (4, 5).
在制藥過程中使用獨立或專用設施來制造高風險輔料的決定,應基于輔料制造商進行全面風險評估的結果。風險評估應考慮基于健康暴露限值的要求,如文獻所述(4, 5)。
11.7 Note: The method used to achieve this separation will depend on the nature, extent and risk of the overall operation.
注：實現這種隔離的方法將取決于整體操作的性質、程度和風險。
12. Equipment and utilities
12.設備與公用設施
12.1 Equipment and utilities should be selected, located, designed, constructed and maintained to suit the operations to be carried out.
設備與公用設施應根據擬進行的操作進行選擇、定位、設計、建設和維護。
12.2 The installation and use of equipment and utilities should aim to minimize the risk of errors and contamination, cross - contamination, build - up of dust or dirt and, in general, any adverse effect on the quality of products.
設備與公用設施的安裝和使用應旨在最大限度地減少錯誤、污染、交叉污染、灰塵或污垢的積累以及對產品質量的任何其他不利影響。
12.3 Written procedures should be established and followed for repairs, maintenance and cleaning. These operations should not have any adverse effect on the quality of the excipient for pharmaceutical use. Records of these activities should be maintained.
應建立書面程序并遵循維修、維護和清潔操作。這些操作不應對用于制藥的輔料質量產生任何不利影響。應記錄這些活動。
12.4 Equipment and instruments identified as being part of the quality management system should be appropriately controlled. These include those used in production and quality control. The control programme should include standardization, verification, and calibration of reagents, instruments, apparatus, gauges, and recording devices at defined, suitable intervals. Written procedures should contain specific instructions, schedules, acceptance limits and handling of the excursions. Records should be maintained.
應對質量管理體系中識別為組成部分的設備和儀器進行適當控制。這些包括用于生產和質量控制的設備。控制計劃應包括在規定的時間間隔內對試劑、儀器、裝置、量具和記錄設備進行標準化、驗證和校準。書面程序應包含具體指示、時間表、接受限度和異常處理方法。應記錄這些記錄。
12.5 Reagents, lubricants, instruments, apparatus, gauges and recording devices that can affect the quality of the product should not be used.
可能影響產品質量的試劑、潤滑劑、儀器、裝置、量具和記錄設備不應使用
12.6 Computerized systems that may impact the quality of the excipient for pharmaceutical use should be appropriately validated. Quality data should comply with the requirements for data integrity, including data management, audit trails, access and privileges for users.
可能影響用于制藥的輔料質量的計算機化系統應適合其預期用途。這些系統應適當驗證。質量數據應符合數據完整性的要求,包括數據管理、審計追蹤、用戶權限和訪問。
12.7 An appropriate level of validation should be performed for computerized systems.
應對計算機化系統進行適當水平的驗證。
12.8 Equipment, utilities and computer systems should be commissioned and qualified, as appropriate.
設備、公用設施和計算機系統應在適當的情況下進行安裝和確認。
12.9 Utilities such as heating, ventilation and air - conditioning (HVAC), water, nitrogen and compressed air systems should be appropriate for their intended use, should not have any negative impact on either operations or the quality of the excipient for pharmaceutical use, and should not be a source of contamination.
如加熱、通風和空調(HVAC)、水、氮氣和壓縮空氣系統等公用設施應適合其預期用途,不應對其操作或用于制藥的輔料質量產生任何負面影響,也不應成為污染源。
12.10 Where HVAC systems are used, air should be filtered to an appropriate level. The design should ensure that the risk of contamination or cross -contamination is minimized and that specified environmental conditions, where required, are achieved and maintained, at the required grade or class, temperature and relative humidity.
在使用 HVAC 系統的情況下,空氣應過濾至適當水平。設計應確保將污染或交叉污染的風險最小化,并在必要時實現和維持指定的環境條件,包括所需的級別或類別、溫度和相對濕度。
12.11 Water purification systems, where used, should be suitably designed, installed, maintained and operated. Water should be sampled and tested, and should meet its relevant specification.
如果使用水凈化系統,應確保其設計、安裝、維護和運行符合要求。水質應進行采樣和檢測,并符合相關規范。
12.12 Compressed air and nitrogen generation systems should be designed and controlled in accordance with the outcomes of risk assessment.
壓縮空氣和氮氣生成系統的設計與控制應根據風險評估的結果進行。
12.13 Measuring and control devices requiring calibration should be calibrated at defined intervals.
需要校準的測量和控制設備應按規定的間隔進行校準。
13. Materials
13.材料
13.1 Materials, including raw materials and packaging materials, should be sourced from approved suppliers.
材料,包括原料和包裝材料,應從已批準的供應商處采購。
13.2 A procedure for supplier approval and supplier monitoring should be followed. Records should be maintained.
應遵循供應商審批和供應商監控的程序。應保存相關記錄。
13.3 Written procedures should be followed for the receiving, sampling, storage, testing and release of materials for use.
應遵循書面程序進行材料的接收、取樣、儲存、測試和放行,以供使用。
13.4 Materials should meet their agreed specifications. Materials that may have a negative impact on the quality of the excipient for pharmaceutical use should not be used.
材料應符合其約定的技術規格。可能對藥用輔料質量產生負面影響的材料不應使用。
13.5 Materials should be stored in accordance with their status and labelling.
材料應根據其狀態和標簽要求進行儲存。
13.6 Specific tests, based on risk assessment of the material and pharmacopoeial requirements, should be done where applicable. Impurities should be identified and appropriately controlled.
根據材料的風險評估和藥典要求,在適用的情況下,應進行特定的測試。雜質應被識別并適當控制。
13.7 A procedure for handling nonconforming products should be established covering the investigation, evaluation and treatment of nonconforming products. The disposition of nonconforming materials, intermediates and finished products should be approved by the quality unit and recorded.
應建立處理不合格品的程序,涵蓋不合格品的調查、評估和處理。不合格材料、中間體和成品的處置需由質量部門批準并記錄。
13.8 Recovered materials, such as solvents, should only be used if scientifically justifiable, and if they meet their relevant specification. The process of recovery should follow written procedures, and records should be maintained.
回收材料,如溶劑,僅在科學上合理且符合其相關技術規格的情況下方可使用。回收過程應遵循書面程序,并應保存相關記錄。
13.9 Materials used in batches of excipients for pharmaceutical use should be traceable.
藥用輔料批次使用的材料應可追溯。
13.10 Materials from waste should be appropriately treated and discarded in a manner that will not have any negative effect on the environment.
廢棄物中的材料應適當處理并以不會對環境產生負面影響的方式丟棄。
13.11 A procedure for waste management should be followed. Records of waste treatment and disposal should be maintained.
應遵循廢棄物管理程序。應記錄廢棄物處理和處置情況。
14. Production
14.生產
14.1 Raw materials for manufacturing of excipients for pharmaceutical use should be weighed or measured in appropriate areas, under appropriate conditions, using suitable devices.
制藥用賦形劑的原材料應在適當區域、在適當條件下,使用合適的設備進行稱重或測量。
14.2 The material to be used in production should be kept in suitable containers bearing labels with required details, such as the name of the material and a traceable control number.
生產中使用的物料應存放在適當的容器中,并附有標簽,標簽上應包含物料名稱和可追溯的控制編號等必要信息。
14.3 Equipment in production areas should be labelled, for example, with an asset or other unique identification number and, if applicable, calibration status.
生產區內的設備應進行標識,例如,使用資產編號或其他唯一的標識編號,如適用,還應標明校準狀態。
14.4 Where appropriate, materials should not be kept for periods longer than the validated hold time.
如有必要,物料不應存放超過驗證的保存期。
14.5 The extent, stringency and type of testing (for example, in - process), as well as acceptance criteria, should be defined. All tests and results should be fully documented as part of the batch record.
測試的范圍、嚴格程度和類型(例如,在線檢測),以及接受標準應明確規定。所有測試和結果應詳細記錄在批記錄中。
14.6 The sampling process should not increase the risk of contamination of the material. Samples should be handled with care and their integrity maintained.
取樣過程不應增加物料被污染的風險。取樣時應小心處理,確保樣本的完整性。
14.7 Manufacturers should have written procedures and related documents for the production and control of excipients for pharmaceutical use.
制藥用賦性劑的生產和控制應有書面程序及相關文件。
14.8 Batches should be produced following written procedures or instructions.
批次應按照書面程序或指示進行生產。
14.9 The manufacturing process should be described in detail, and risks associated with the production and control of the excipient for pharmaceutical use should be appropriately controlled. This includes requirements specified in the recognized pharmacopoeia, transmissible spongiform encephalopathy (TSE) or bovine spongiform encephalopathy (BSE), and impurities.
制藥用賦形劑的制造過程應詳細描述,并應適當控制與生產及控制賦形劑相關的風險。這包括被認可藥典中規定的各項要求,可傳播海綿狀腦病(TSE)或牛海綿狀腦病(BSE),以及雜質。
14.10 Batches should be produced using suitable equipment in an appropriate environment, and should be protected from possible contamination and cross-contamination.
生產批次應使用合適的設備在適當的環境中生產,并應防止可能的污染和交叉污染。
14.11 In - process sampling and testing should be done in accordance with written instructions. Records should be maintained.
中間體的取樣和檢測應按照書面指令進行。應保存記錄。
14.12 Checks and maintenance operations should not affect the quality of the excipient for pharmaceutical use.
檢查和維護操作不應影響制藥用輔料的質量。
14.13 Changes and deviations in production should be managed through the relevant procedures.
生產中的變更和偏差應通過相關程序進行管理。
14.14 Blending operations should be controlled to ensure homogeneity of the final batch. A blended batch should be assigned a unique batch number, and batches used in the blend should be traceable.
混合操作應受控以確保最終批次的均勻性。混合批次應分配唯一的批次編號,并且用于混合的批次應可追溯。
14.15 A sampling procedure should be followed to ensure that a sample collected from the blend is representative of the batch.
應遵循取樣程序，以確保從混合物中采集的樣品代表整個批次。
14.16 Each batch of product to be mixed should be produced in accordance with the batch manufacturing document, be tested separately, and meet the corresponding specifications. The mixed batch should be tested and should be in compliance with its specified.
每個待混合的產品批次應按照批次生產文件生產,單獨檢測,并符合相應的規格。混合批次應進行檢測并符合其規格。
14.17 Blending or mixing of batches should be controlled and validated. Procedures and records should be maintained. Blending of batches to salvage out-of-specification batches or adulterated material is not an acceptable practice.
混合或混合批次的操作應受控并進行驗證。應保存操作和記錄程序。將批次混合以挽救不合格批次或摻假材料的做法是不可接受的。
14.18 Manufacturers should regularly review the capability of the process and ensure batch-to-batch consistency of the excipient for pharmaceutical use, meeting its specification.
藥用輔料的生產過程應定期進行能力評估,并確保批次間的一致性,符合其規格。
14.19 Written procedures should be followed for the receipt, identification, quarantine, sampling, examination or testing, and release/rejection, and handling of packaging and labelling materials. Records should be kept.
應遵循書面程序接收、識別、隔離、取樣、檢驗或測試、放行/拒收以及處理包裝和標簽材料。應保存記錄。
14.20 Packaging materials such as containers should provide adequate protection against deterioration or contamination of the excipient for pharmaceutical use. They should be clean and dry, and should not be reactive, additive or absorptive.
包裝材料如容器應提供足夠的保護,防止制藥用輔料的退化或污染。它們應清潔干燥,且不應具有反應性、添加劑性或吸濕性。
14.21 Printed packaging materials such as labels should be in the prescribed format.
印刷包裝材料如標簽應符合規定格式。
14.22 Access to printed packaging material storage areas should be controlled.
打印包裝材料存儲區的訪問應受到控制。
14.23 Stock should be reconciled at periodic intervals, including received, issued, and returned quantities. Discrepancies found should be investigated.
庫存應在定期間隔進行核對,包括收貨、發放和退貨的數量。發現的差異應進行調查。
14.24 Batch coded labels not used for the specified batch, and obsolete and outdated labels, should be destroyed. Reconciliation should be done. Records should be maintained.
對于未用于指定批次的批次編碼標簽,以及過時和過期的標簽,應予以銷毀,并進行核對和記錄。
14.25 Written procedures should be followed for packaging operations. Controls should be in place to prevent any mix - ups during packaging. These should include line opening and line closing checks, segregation between packaging lines, and verification of materials on the packaging line prior to the start of packaging.
應遵循書面操作程序進行包裝操作。應實施控制措施,防止包裝過程中出現混淆,這些措施應包括生產線開啟和關閉檢查、包裝生產線之間的隔離,以及在開始包裝前對包裝線上的材料進行驗證。
14.1Rework
14.1返工
14.26 Reworking should only be undertaken when the outcome of a risk assessment indicates that this is acceptable and approved by the quality unit.
僅在風險評估結果表明這是可接受的并通過質量部門批準的情況下,才能進行返工。
14.27 Batches that have been reworked should be subjected to appropriate quality control testing and stability testing, if required. A reworked batch should be released by the quality unit when it has been determined, by applying the relevant analytical testing procedures, that the specification has been met.
經返工的批次應接受適當的質量控制測試和穩定性測試(如需)。返工的批次應由質量部門在通過相關分析測試程序確定符合規定后批準放行。
14.28 Records should be maintained.
應進行記錄。
14.2 Reprocessing
14.2 重新加工
14.29 Reprocessing should only be undertaken if this activity and process have been evaluated internally and found to be acceptable.
只有在對該活動和過程進行內部評估并確認其可接受后方可進行。
14.30 Records should be maintained.
應當建立并維護記錄。
15.Qualification and validation
15. 確認與驗證
15.1 The scope and extent of qualification and validation should be determined based on risk management principles.
確認與驗證的范圍和程度應基于風險管理原則來確定。
15.2 Manufacturers should be able to provide documented evidence to show that premises, equipment, utilities, procedures and processes are appropriate and are consistently rendering the specified outcome.
制造商應能夠提供文件證明,表明設施、設備、公用設施、程序和過程是合適的,并且能夠持續地產生預期的結果。
15.3 Authorized procedures, protocols and records should be maintained for qualification and validation performed.
應維護批準的程序、方案和記錄,以記錄所進行的驗證和確認工作。
15.4 The extent of qualification and validation may be further justified when considering the data from development and scale - up, process capability studies, and product quality reviews.
驗證和確認的程度可進一步通過考慮開發和放大生產、工藝能力研究以及產品質量評審的數據進行論證。
16.Quality control
16.質量控制
16.1 The layout of the quality control section should be appropriate.
質量控制部分的布局應適當。
16.2 Personnel should be suitably qualified and trained.
人員應具備適當的資質并經過培訓。
16.3 Materials, including raw materials, packaging materials (as applicable) and excipients for pharmaceutical use, should be tested for compliance with their current specifications by following authorized procedures, as described in pharmacopoeias, if available, or by validated in - house procedures.
原輔料(包括原料、包裝材料和藥品使用的輔料),應按照現行標準要求,通過授權程序進行測試,如藥典中有相關標準,則應遵循藥典規定;否則,應使用經過驗證的內部程序進行測試。
16.4 Laboratory equipment and instruments should be appropriate for their intended use. These should be suitably designed, installed, labelled, used, maintained, qualified and calibrated (where so determined), according to written procedures. Records should be kept.
實驗室設備和儀器應適合其預期用途。這些設備應設計合理、安裝正確、標識清晰、使用正確、維護得當,并根據書面程序進行合格驗證和校準(如需)。應保留相關記錄。
16.5 Equipment and instruments that are out of order or out of calibration should be clearly identified to indicate that they are not to be used.
出現故障或未校準的設備和儀器應明顯標識,以表明不得使用。
16.6 Authorized procedures should be used for activities including sampling, operation of equipment and instruments, and analysis.
應使用授權程序進行包括取樣、設備和儀器操作以及分析在內的各項活動。
16.7 Analytical test procedures should be developed and validated to control potential and actual impurities that have been identified following a risk assessment and used routinely to ensure that each batch meets the specification.
分析測試程序應根據風險評估識別的潛在和實際雜質進行開發和驗證,并定期使用,以確保每批產品符合標準。
16.8 To facilitate traceability of each analysis, a record of analysis should be maintained. This includes a certificate of analysis.
為了便于追溯每項分析,應記錄分析過程。這包括分析證書。
16.9 Records of analysis should normally include at least the following:
分析記錄通常應包括以下內容:
name of the excipient for pharmaceutical use;藥用輔料的名稱;
batch number;批號;
test results and reference to any specifications (limits) and test procedures;
測試結果及任何標準(限值)和測試程序的參考;
date and reference number of testing;測試日期及編號;
date and initials of the persons who performed the testing and the person who verified the testing and the calculations, where appropriate;測試人員及驗證測試和計算人員的姓名及簽名日期;
a clear statement of release or rejection (or other status decision) and the date and signature of the designated responsible person.
明確的放行或拒收(或其他狀態決定)聲明及指定負責人的日期和簽名。
16.10 Test results should be incorporated into a certificate of analysis.
測試結果應納入分析證書中。
16.11 Out-of-specification results should be thoroughly investigated and documented as per defined procedures. Appropriate actions should be taken.
出現超出規格的結果應進行徹底調查并記錄,按照定義的程序進行。應采取適當的措施。
16.12 Reference and retention samples should be kept in a secure, suitable location under appropriate conditions. An appropriate quantity should be kept to allow investigation and testing, when these are required.
參考樣品和保留樣品應存放在安全且適合的地點,并在適當條件下保存。應保留足夠的樣品數量,以便在需要時進行調查和測試。
16.13 Where stability testing is indicated, a procedure and programme should be followed. The procedure and programme should include:
如需進行穩定性測試,應遵循相應的程序和計劃。程序和計劃應包括:
a written schedule that is reviewed at least annually;
書面的時間表,至少每年審查一次;
reference to the number of batches and frequency of a batch to be placed on stability;
關于進行穩定性測試的批次數量和批次頻率的說明；
type of containers to be used;使用的容器類型;
conditions of storage, including stress conditions (such as elevated temperature, light, humidity or freezing), where appropriate;存儲條件,包括可能的應力條件(如高溫、光照、濕度或冷凍）；
use of stability - indicating test procedures, as applicable.如適用,使用指示穩定性的測試方法。
16.14 The results from stability testing should be reviewed and trended. An expiry or retest date should be allocated based on scientific data.
應對穩定性測試結果進行審核和趨勢分析。應根據科學數據確定有效期或復驗期。
16.15 Storage conditions should be specified on the label if these are identified (for example, protection from light, temperature).
如果確定了存儲條件(例如,防光、防溫),應在標簽上標明存儲條件。
17.Life cycle and continuous improvement principles
17.生命周期和持續改進原則
17.1 Manufacturers of excipients for pharmaceutical use should implement the life cycle approach and continuous improvement philosophy. These principles should be applied, in the relevant areas of the premises, to equipment, instruments, utilities, products and processes.
藥用輔料制造商應采用生命周期方法和持續改進理念。這些原則應在相關場地區域內應用于設備、儀器、公用設施、產品和工藝過程。
17.2 Manufacturers should implement measures to continuously improve the quality management system, manufacturing and testing procedures, andthe quality of their products. These measures may include the review of root causes of nonconformances, quality complaint investigations and outcomes, and results from self - inspections, audits and other trends.
制造商應采取措施持續改進質量管理體系、制造和檢測程序以及產品質量。這些措施可能包括對不符合項根本原因的審查、質量投訴調查及其結果、自我檢查、審核及其他趨勢的結果。
18.1Storage and distribution
18.1儲存與分發
18.1 Storage areas should be appropriately designed, constructed and maintained. They should be kept clean and dry. There should be sufficient space and suitable ventilation.
儲存區域應適當設計、建造和維護。應保持清潔和干燥,并有足夠的空間和適當的通風。
18.2 Storage areas should normally be under cover with sufficient space. Where excipients for pharmaceutical use are stored outside buildings, risk assessment should be done to determine the necessary controls to protect the products from contamination and deterioration.
儲存區域通常應有遮蓋,并有足夠的空間。如果藥品輔料存放在建筑物外,應進行風險評估,以確定必要的控制措施,以防止產品受到污染和變質。
18.3 Excipients for pharmaceutical use should be stored in suitable containers, under appropriate storage conditions. Where special storage conditions are required, these should be provided, controlled, monitored and recorded.
藥品輔料應存放在合適的容器中,并在適當的儲存條件下存放。如果需要特殊的儲存條件,應提供并控制這些條件,進行監控并記錄。
18.4 There should be a written programme for pest control in storage and other relevant areas.
應有書面的害蟲控制計劃,適用于儲存和其他相關區域。
18.2 Distribution
18.2 分發
18.5 Excipients for pharmaceutical use should be distributed through traceable routes. Product, batch, container identity and integrity should be maintained at all times. All labels should remain legible.
藥品輔料應通過可追溯的路線進行分發。產品、批次、容器的身份和完整性應在所有時間保持。所有標簽應保持清晰可讀。
18.6 Excipients for pharmaceutical use should be transported in accordance with the conditions stated on the labels.
藥品輔料應按照標簽上規定的條件進行運輸。
18.7 Distribution records should be sufficiently detailed to allow traceability in case of a recall.
分發記錄應詳細到足以在召回時進行追溯。
18.8 Note: for further information, see WHO Good trade and distribution practices for pharmaceutical starting materials (6).
注:更多信息,請參見世界衛生組織關于藥品起始材料的優良貿易和分銷實踐(6)。
來源：Internet
