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近日，WHO在其技術(shù)報告TRS1060中發(fā)布了新的《藥用輔料GMP》-2025，現(xiàn)將中英文翻譯分享給大家：
Appendix 1
附錄 1
Risk management in the production and control of excipients used in pharmaceutical products
制藥產(chǎn)品中輔料的生產(chǎn)與控制中的風(fēng)險管理
Introduction
引言
1.1 The WHO good manufacturing practices for excipients used in pharmaceutical products requires the application of risk management principles in the production, control and distribution of these excipients.
WHO關(guān)于制藥產(chǎn)品中輔料的良好生產(chǎn)規(guī)范要求在輔料的生產(chǎn)、控制和分發(fā)過程中應(yīng)用風(fēng)險管理原則。
1.2 It is essential that manufacturers of these excipients assess the risks and identify hazards associated with the production and control and, when applicable, packaging, storage, repackaging and distribution of these excipients. This will enable manufacturers, packers and distributors to identify and to establish, implement and maintain controls as part of the quality system, to ensure the quality, safety and purity of excipients and their suitability for their intended use.
制造這些輔料的生產(chǎn)商必須評估生產(chǎn)過程中的風(fēng)險和控制過程及相關(guān)風(fēng)險(如適用,包括包裝、儲存、重新包裝和分發(fā)),以確保生產(chǎn)商、包裝商和分銷商能夠識別并建立、實施和維持質(zhì)量管理體系中的控制措施,從而確保輔料的質(zhì)量、安全性和純度及其適合預(yù)期用途。
1.3 It may further assist manufacturers to identify, for example:
這還有助于生產(chǎn)商識別,例如:
whether separate, dedicated facilities are required for certain excipients;
是否需要為某些輔料專門設(shè)置獨立的設(shè)施;
whether premises, equipment, instruments and utilities are suitable for their intended use in production and control of excipients;
是否需要確保廠房、設(shè)備、儀器和公用設(shè)施適合生產(chǎn)及控制輔料的預(yù)期用途；
what level and scope of qualification and validation is required;
需要進(jìn)行何種程度的確認(rèn)和驗證;
whether there are any possible sources of contamination, including impurities;
是否存在任何可能的污染源,包括雜質(zhì);
what scope of documentation is required for the management of production and control of excipients;
需要何種范圍的文件管理來管理和控制輔料的生產(chǎn)及控制；
whether subcontractors such as warehouses and transporters are suitable for distribution with no physical contamination.
是否需要合適的外包商(如倉庫和運輸商)進(jìn)行分發(fā),以確保無物理污染。
1.4 The extent and application of risk assessment may go beyond the above-mentioned examples to ensure continuous improvement in the facility.
風(fēng)險評估的范圍和應(yīng)用可能超出上述示例,以確保設(shè)施的持續(xù)改進(jìn)。
2.Scope
2.范圍
2.1 This document provides guidance to manufacturers, packers and distributors of excipients used in pharmaceutical products, to identify risks and harms that may have a negative impact on the production, control, quality and purity of the excipient. It provides details in relation to the identification of potential contamination or cross - contamination risk of the excipients used in pharmaceutical products.
本文件為制藥輔料制造商、包裝商和分銷商提供了指導(dǎo),旨在識別可能對輔料的生產(chǎn)、控制、質(zhì)量和純度產(chǎn)生負(fù)面影響的風(fēng)險和危害。文件詳細(xì)介紹了制藥產(chǎn)品中使用的輔料潛在污染或交叉污染風(fēng)險的識別方法。
2.2 This document also provides useful information to manufacturers, packers and distributors on what to look for in their excipient suppliers.
本文件還為制造商、包裝商和分銷商提供了有關(guān)其輔料供應(yīng)商應(yīng)關(guān)注內(nèi)容的實用信息。
3.Risk identification and risk assessment
3.風(fēng)險識別與評估
3.1 There should be a document, such as a standard operating procedure, that describes the policy, approach and process of risk identification and risk assessment.
應(yīng)有一份文件,如標(biāo)準(zhǔn)操作程序,描述風(fēng)險識別和風(fēng)險評估的政策、方法和流程。
3.2 The risk assessment should be performed in accordance with the principles described in guidelines such as the WHO guidelines on quality risk management (1) and ICH Q9 (2).
風(fēng)險評估應(yīng)遵循如世界衛(wèi)生組織(WHO)質(zhì)量風(fēng)險管理指南(1)和國際 Conference on Harmonization(ICH)Q9(2)中所述的原則進(jìn)行。
3.3 A suitable, appropriate risk assessment tool should be used by a multidisciplinary team performing the risk assessment. Failure mode and effects analysis (FMEA) and hazard analysis and critical control point (HACCP) are examples of such frequently used tools.
在進(jìn)行風(fēng)險評估時,應(yīng)由多學(xué)科團(tuán)隊使用合適的、適當(dāng)?shù)脑u估工具。失效模式與效應(yīng)分析(FMEA)和危害分析與關(guān)鍵控制點(HACCP)是常用的此類工具。
3.4 Although a quantitative or qualitative analysis can be done, quantitative assessments are recommended.
盡管可以進(jìn)行定量或定性分析,但推薦進(jìn)行定量評估。
3.5 The risk assessment should be thorough, comprehensive and appropriately documented. It should cover a variety of aspects, including raw materials, packaging materials, processing steps, solvents, equipment, utilities, environment, storage, distribution, intended use of the excipient, and the dosage form of the finished pharmaceutical product in which it may be used.
風(fēng)險評估應(yīng)全面、徹底,并適當(dāng)記錄。它應(yīng)涵蓋多個方面,包括原材料、包裝材料、加工步驟、溶劑、設(shè)備、公用工程、環(huán)境、儲存、分發(fā)、輔料的預(yù)期用途,以及可能使用該輔料的最終藥物制劑。
3.6 A list of the potential risks (such as biological, chemical and physical) that may be introduced or increased in each area listed in paragraph 3.5 above should be identified and assessed.
應(yīng)識別并評估在第3.5段中列出的每個區(qū)域可能引入或增加的潛在風(fēng)險(如生物、化學(xué)和物理方面)。
3.7 In performing the risk assessment, the following basic questions (listed as examples) should be addressed:
在進(jìn)行風(fēng)險評估時,應(yīng)回答以下基本問題(作為示例列出):
What might go wrong? (The use of “Why” may be useful.)
可能會發(fā)生什幺問題?(使用“為什幺”可能有助于分析。)
The materials, equipment, utilities or excipient (finished product) may be contaminated. The contaminants may be hazardous or may be sensitizing - and may be carried over into another product causing possible contamination. This may in turn result in an adulterated product, or may be harmful to patients consuming a pharmaceutical product that is contaminated with a material containing traces of such a substance.
原材料、設(shè)備、公用工程或輔料(最終產(chǎn)品)可能被污染。污染物可能是有害的,也可能是致敏性的,并可能轉(zhuǎn)移到另一產(chǎn)品中造成污染。這可能會導(dǎo)致被篡改的產(chǎn)品,或者對使用含有此類物質(zhì)痕跡的材料的藥物產(chǎn)品進(jìn)行服用的患者造成危害。
What is the nature of possible risks?
可能風(fēng)險的本質(zhì)是什幺?
The contaminants or material may be hazardous or poisonous and contaminate other materials, for example excipients, active pharmaceutical ingredients (APIs) or pharmaceutical products.
污染物或材料可能具有危害性或毒性,并可能污染其他材料,例如輔料、活性藥物成分(API或藥品。
What is the probability of contamination?
污染的可能性有多大?
Consider the chemical structure, manufacturing process, storage and distribution. Is it possible that materials can be substituted, mixed or otherwise contaminated? Can impurities form and be present? The probability should be evaluated with appropriate tools.
考慮化學(xué)結(jié)構(gòu)、生產(chǎn)工藝、存儲和分發(fā)等因素。材料是否有可能被替代、混合或其他方式污染?是否可能形成雜質(zhì)并存在?應(yīng)使用適當(dāng)工具評估其可能性。
Is it possible to detect them?
是否能夠檢測到它們?
Contaminants, impurities and residues in materials may be present on equipment surfaces, in the environment, in solvents and in water. Carrier material may be difficult to remove. In addition, it may be difficult to analyse and quantify their presence unless appropriate, analytical procedures that are adequately sensitive are used.
材料中的污染物、雜質(zhì)和殘留物可能存在于設(shè)備表面、環(huán)境中、溶劑中或水中。載體材料可能難以去除。此外,除非使用足夠靈敏的分析程序,否則可能難以分析和量化它們的存在。
What are the consequences (the severity)?
后果(嚴(yán)重性)是什幺?
Some impurities may cause harm and could even be carcinogenic and teratogenic.
某些雜質(zhì)可能導(dǎo)致危害,甚至能致癌和致畸。
4.Individual excipient risk assessment
4.單獨的輔料風(fēng)險評估
4.1 Risk assessment should be done for every excipient produced. A checklist may be prepared and used to identify and assess risks and harms.
應(yīng)對每種生產(chǎn)的輔料進(jìn)行風(fēng)險評估?？梢詼?zhǔn)備并使用檢查表來識別和評估風(fēng)險及危害。
4.2 In assessing the risk, consideration should be given to the raw materials used, solvents used (fresh and recovered), premises (separated, segregated or in common), equipment (dedicated, disposable or not), water, environment and any other possible impacting factor.
在評估風(fēng)險時,應(yīng)考慮所使用的原料、溶劑(新鮮和回收的)、設(shè)施(分離、隔離或共用)、設(shè)備(專用、一次性或非一次性)、水、環(huán)境以及其他可能的影響因素。
4.3 Consideration should be given to the possible toxicity of the excipient (for example, when contaminated or can contaminate), the risk of the excipient being contaminated, adulterated or cross - contaminated, cleanability of equipment, presence of impurities, and degradation, where applicable.
應(yīng)考慮輔料的潛在毒性(例如,當(dāng)受污染或能污染時)、輔料受污染、摻假或交叉污染的風(fēng)險、設(shè)備的清潔性、雜質(zhì)的存在、以及適用時的降解問題。
4.4 The risk of contaminated solvents being used in the synthesis should be assessed.
應(yīng)評估在合成過程中使用受污染溶劑的風(fēng)險。
4.5 The risk of formation of impurities should be assessed.
應(yīng)評估雜質(zhì)形成的風(fēng)險。
5.Collective excipient production assessment
5.集體制劑輔料生產(chǎn)評估
5.1 In addition to individual excipient risk assessment as described above, where several excipients are produced or packed in the same facility, the risk of contamination should be identified and assessed. In particular, where a risk has been identified in one or more excipients handled in the same facility or common equipment chains, the risk of cross - contamination should be assessed.
除上述對單個輔料進(jìn)行的風(fēng)險評估外,如果多個輔料在同一設(shè)施中生產(chǎn)或包裝,應(yīng)對這些輔料的生產(chǎn)風(fēng)險進(jìn)行綜合評估。污染應(yīng)當(dāng)被識別和評估。特別是在同一設(shè)施處理的一種或多種輔料中已識別出風(fēng)險,或在共用設(shè)備鏈中存在風(fēng)險時,應(yīng)當(dāng)評估交叉污染的風(fēng)險。
6.Nitrosamine contamination
6.硝酸胺污染
6.1 Although very few excipients can form nitrosamine impurities, the risk of nitrosamine formation or contamination should be identified and assessed. For example, nitrite in potable water used in production and present in the environment, packaging materials or ink should be considered (3, 4).
盡管很少有輔料能夠形成氮胺雜質(zhì),但仍應(yīng)識別和評估氮胺形成或污染的風(fēng)險。例如,生產(chǎn)過程中使用的飲用水中的亞硝酸鹽以及環(huán)境、包裝材料或油墨中的亞硝胺應(yīng)予以考慮(3, 4)。
7.Example
7.示例
7.1 The example below follows a similar approach to FMEA.
以下示例遵循類似FMEA的方法。
7.2 Risk statement: Are the premises appropriately designed, located and maintained for the manufacture of excipients used in pharmaceutical products?
風(fēng)險聲明:生產(chǎn)場所是否設(shè)計、定位和維護(hù)得當(dāng),以適于制造用于制藥產(chǎn)品的輔料?
7.3 Risk statement: Are pieces of equipment appropriately designed, located and maintained for the manufacture of excipients used in pharmaceutical products?
風(fēng)險聲明:用于制藥產(chǎn)品的輔料制造的設(shè)備是否設(shè)計、布置和維護(hù)得當(dāng)?
7.4 Risk statement: Are the materials used in the production of the excipient of appropriate quality and purity, or is there a risk of formation of impurities and undesired contaminants that may be present in pharmaceutical products?
風(fēng)險聲明:生產(chǎn)輔料所用的材料是否具有適當(dāng)?shù)钠焚|(zhì)和純度,是否存在形成雜質(zhì)和非預(yù)期污染物的風(fēng)險,這些雜質(zhì)和污染物可能存在于藥品中?
7.5 Risk statement: Are the utilities appropriately designed, located, maintained and controlled to prevent contamination of material, and prevent the risk of the formation of impurities and contaminants?
風(fēng)險聲明:設(shè)施是否設(shè)計、布局、維護(hù)和控制得當(dāng),以防止材料污染,并防止雜質(zhì)和污染物的形成風(fēng)險?
7.6 Risk statement: Are the personnel appropriately trained and qualified to ensure that their actions and conduct do not present a risk of contamination of materials?
風(fēng)險聲明:相關(guān)工作人員是否得到了適當(dāng)?shù)呐嘤?xùn)和資質(zhì)認(rèn)證,以確保其行為和行為規(guī)范不會對材料造成污染的風(fēng)險?
7.7 Risk statement: Is the production process appropriately developed and controlled to ensure that interaction between materials, or any step in production and purification, will not result in contamination of the excipient, resulting in a material of unacceptable quality and purity?
風(fēng)險聲明:生產(chǎn)工藝是否已適當(dāng)開發(fā)和控制,以確保材料之間的相互作用或生產(chǎn)工藝和純化過程中的任何步驟不會導(dǎo)致輔料受到污染,從而產(chǎn)生不符合質(zhì)量與純度要求的物料?
7.8 Risk statement: Is the repackaging process appropriately controlled to prevent any risk of contamination, mix - up or substitution of materials that may result in a material of unacceptable quality and purity?
風(fēng)險聲明:重新包裝過程是否得到了適當(dāng)控制,以防止任何可能造成材料質(zhì)量或純度不符合要求的風(fēng)險,包括污染、混淆或替換材料?
7.9 Risk statement: Is the storage process appropriately controlled, in accordance with storage requirements, to prevent any risk of uncontrolled degradation, increase in level of impurity, contamination, mix - up or substitution of materials that may result in a material of unacceptable quality and purity?
風(fēng)險聲明:存儲過程是否得到了適當(dāng)控制,以符合存儲要求,從而防止任何由于未經(jīng)控制的降解、雜質(zhì)水平增加、污染、物料混用或替代而導(dǎo)致的不合格物料和不純物質(zhì)的風(fēng)險?
7.10 Risk statement: Is the distribution process appropriately controlled, in accordance with good practices, to prevent any risk of uncontrolled degradation, increase in level of impurity, contamination, mix - up or substitution of materials that may result in a material of unacceptable quality and purity?
風(fēng)險聲明:分發(fā)過程是否按照良好實踐適當(dāng)控制,以防止任何由于未經(jīng)控制的降解、雜質(zhì)水平增加、污染、物料混用或替代而導(dǎo)致的不符合質(zhì)量與純度要求的物料的風(fēng)險?
8.Risk control
8.風(fēng)險控制
8.1 Once risks and harms have been identified and assessed, controls should be identified to mitigate the risks and harms.
一旦識別并評估了風(fēng)險和危害,應(yīng)確定相應(yīng)的控制措施以減輕這些風(fēng)險和危害。
8.2 Controls should be proven to be effective.
控制措施應(yīng)被證明是有效的。
9.Risk communication
9.風(fēng)險溝通
9.1 Risks and controls should be appropriately communicated to the relevant personnel or interested parties.
風(fēng)險和控制措施應(yīng)適當(dāng)?shù)叵蛳嚓P(guān)人員或利益相關(guān)方進(jìn)行溝通。
10.Risk review
10.風(fēng)險審查
10.1 Risk assessment and risk controls should be reviewed when changes are considered, for example, introduction of new excipients or products to the facility, changes in manufacturing process, changes in equipment, or change in suppliers of materials and solvents.
當(dāng)考慮進(jìn)行變更時,例如引入新的輔料或產(chǎn)品、生產(chǎn)工藝變更、設(shè)備變更或原材料和溶劑供應(yīng)商變更,應(yīng)審查風(fēng)險評估和風(fēng)險控制措施。
10.2 Risk review may be done periodically, and when a change has been made (as listed in section 10.1 above), to ensure that the mitigating tools are still effective and the risk has not changed or increased.
風(fēng)險審查應(yīng)定期進(jìn)行,并在上述第3節(jié)所列的變更發(fā)生時進(jìn)行,以確保減輕工具仍然有效,且風(fēng)險沒有發(fā)生變化或增加。
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