人用藥所用輔料的GMP水平確定用正式風(fēng)險(xiǎn)評(píng)價(jià)指引

1、人用藥所用輔料的GMP水平確定用正式風(fēng)險(xiǎn)評(píng)估指南Guideli nesof 19 March 2015on the formalised risk assessme nt for ascerta ining the appropriate goodmanu facturi ng practice for excipie nts of medici nal products for huma nuse(Text with EEA releva nee)(2015/C 95/02)In troduct ion概述These guideli nes are based on the fifth pa

2、ragraph of Article 47 of Directive 2001/83/EC (1).這些指南是基于指令 2001/83/EC(1)第47條款第5段落的。Accordi ng to the seco nd paragraph of Article 46(f) of Directive 2001/83/EC, the manu facturi ng authorisatio n holder is required to en sure that the excipie nts are suitable|for use in medici nal products by ascer

3、ta ining what the appropriate good manu facturi ng|practice (GMP) is. The appropriate GMP for excipie nts of medici nal products for huma n|use shall be ascerta ined on the basis of a formalised risk assessme nt in accorda nee with these guideli nes. The risk assessme nt shall take into acco unt req

4、uireme nts un der other appropriate quality systems as well as the source and intended use of the excipients and previous in sta nces of quality defects. The manu facturi ng authorisati on holder shall en sure that the appropriate GMP ascerta ined is applied. The manu facturi ng authorisati on holde

5、r shall docume nt the measures take n.根據(jù)指令2001/83/EC(1)第46(f)條款第2段，生產(chǎn)許可持有人應(yīng)保證輔料適用于其在藥品 中的用途，確認(rèn)怎樣的GMP是適當(dāng)?shù)?。人藥用輔料適當(dāng)?shù)腉MP應(yīng)根據(jù)這些指南，基于正式的風(fēng)險(xiǎn)評(píng)估進(jìn)行確定。風(fēng)險(xiǎn)評(píng)估應(yīng)考慮在其它適當(dāng)質(zhì)量體系下的要求，以及輔料來源和輔料用途，和之前的質(zhì)量缺陷情況。生產(chǎn)許可持有人應(yīng)保證所確定的適當(dāng)?shù)腉MP是適用的。生產(chǎn)許可持有人應(yīng)記錄所采取的措施。The excipie nt risk assessme nt/risk man ageme nt procedure should be in cor

6、porated in the pharmaceutical quality system of the manu facturi ng authorisati on holder.輔料風(fēng)險(xiǎn)評(píng)估/風(fēng)險(xiǎn)管理程序應(yīng)結(jié)合在生產(chǎn)許可持有人的藥品質(zhì)量體系中。Manu facturi ng authorisatio n holders should have the risk assessme nt/man ageme nt docume ntati on for appropriate GMP for excipie nts available on site for review by GMP in s

7、pectors. Con siderati on should be give n to shari ng releva nt in formati on from the risk assessme nt with the excipie nt manu facturer to facilitate con ti nu ous improveme nt.生產(chǎn)許可持有人應(yīng)有針對(duì)輔料所用的適當(dāng)?shù)腉MP要求的風(fēng)險(xiǎn)評(píng)估/管理文件記錄，并能提供能GMP審核人員審核。應(yīng)考慮與輔料生產(chǎn)商共享風(fēng)險(xiǎn)評(píng)估所產(chǎn)生的相關(guān)信息，以促進(jìn)持 續(xù)改進(jìn)。A risk assessment as set out in thes

8、e guidelines should be carried out for excipients for authorised medici nal products for huma n use by 21 March 2016.自2016年3月21日起，人用上市藥品用的輔料應(yīng)實(shí)施這些指南中要求的風(fēng)險(xiǎn)評(píng)估。CHAPTER 1 SCOPE第1章范圍These guideli nes apply to the risk assessme nt for ascerta ining the appropriate GMP for excipie nts for medici nal product

9、s for huma n use. Accord ing to Article 1(3b) of Directive 2001/83/EC, an excipie nt is any con stitue nt of a medici nal product other tha n the active substa nee and the packagi ng material.這些指南適用于風(fēng)險(xiǎn)評(píng)估，來評(píng)價(jià)應(yīng)用適當(dāng)?shù)腉MP于人用藥所用輔料管理。根據(jù)指令2001/83/EC的第1(3b)條款，一種輔料是藥品中除活性物質(zhì)和包裝材料外任意的組成部分。These guideli nes do no

10、t cover substa nces added to stabilise active substa nces that cannot exist on their own.這些指南不涵蓋添加入藥品中用于那些不能單獨(dú)存在，而需要在活性物質(zhì)中添加穩(wěn)定劑來使活性物質(zhì)穩(wěn)定的成份。CHAPTER 2 DETERMINATION OF APPROPRIATE GMP BASED ON TYPE AND USEOF EXCIPIENT第2章基于輔料類型和用途的適當(dāng)?shù)腉MP決策In EudraLex Volume 4, Guideli nes for Good Manu facturi ng Pract

11、ice, Medici nal Products for Human and Veterinary Use, Part III: GMP related documents, ICH guideline Q9 on Quality Risk Man ageme nt (ICH Q9), prin ciples and examples of tools for quality risk|man ageme nt that can be applied to differe nt aspects of pharmaceutical quality, in clud ing excipie nts

12、, can be found. |在歐盟藥品法卷4，人用和獸用藥品 GMP指南，第3部分，GMP相關(guān)文件，ICH指南Q9 質(zhì)量風(fēng)險(xiǎn)管理中，可以找到能應(yīng)用于藥品質(zhì)量，包括輔料，不同方面的質(zhì)量風(fēng)險(xiǎn)管理的原則 和工具實(shí)例。These quality risk management principles should be used to assess the risks presented to the quality, safety and fun cti on of each excipie nt and to classify the excipie nt in questi on, e.g.

13、 as low risk, medium risk or high risk. Quality risk management tools such as those listed in EudraLex Volume 4, Part III, ICH Q9 (e.g. hazard analysis and critical control points HACCP) should be used for this purpose.這些質(zhì)量風(fēng)險(xiǎn)管理原則應(yīng)用于評(píng)估每種輔料所呈現(xiàn)的質(zhì)量、安全和功能方面的風(fēng)險(xiǎn)For each excipie nt from each manu facturer u

14、sed, the manu facturi ng authorisati on holder should ide ntify the risks prese nted to the quality, safety and function of each excipie nt|from its source be that ani mal, min eral, vegetable, syn thetic, etc. through to its in corporati on in the fini shed pharmaceutical dose form. Areas for con s

15、iderati on should in clude, but are not limited to:來自于每個(gè)生產(chǎn)商的每種輔料，生產(chǎn)許可持有人應(yīng)從其來源-動(dòng)物、礦物、植物、合成等-識(shí)別每種輔料的質(zhì)量、安全和功能風(fēng)險(xiǎn)，通過其結(jié)合于制劑成品的方式。要考慮的內(nèi)容應(yīng)包括但不僅限于：tran smissible spon giform en cephalopathy;TSE風(fēng)險(xiǎn)potential for viral contamination;病毒污染的可能性pote ntial for microbiological or en dotox in/pyroge n con tam in ati on

16、;微生物或內(nèi)毒素/熱原污染可能性potential, in general, for any impurity originating from the raw materials, e.g.aflatox ins or pesticides, or gen erated as part of the process and carried over, e.g. residual solve nts and catalysts;原料中產(chǎn)生的任何雜質(zhì)存在的可能性，例如，黃曲霉素或殺蟲劑，或作為工藝一部分產(chǎn)生和帶入的雜質(zhì)，例如，殘留溶劑和催化劑sterility assuranee for exc

17、ipients claimed to be sterile;聲明無菌的輔料的無菌保證pote ntial for any impurities carried over from other processes, in abse nee of dedicated equipme nt an d/or facilities;非專用設(shè)備和/或設(shè)施中其它工藝帶入任何雜質(zhì)的可能性environmen tal con trol and storage/tra nsportatio n con diti ons in clud ing cold cha in management, if appropri

18、ate;環(huán)境控制和存貯運(yùn)輸條件，適當(dāng)時(shí)包括冷鏈管理supply cha in complexity;供應(yīng)鏈復(fù)雜程度stability of excipie nt;輔料穩(wěn)定性packagi ng in tegrity evide nee.包裝完整性證據(jù)Additi on ally, with respect to the use and fun cti on of each excipie nt, the manu facturi ng authorisation holder should consider:另外，關(guān)于每種輔料的使用和功能，生產(chǎn)許可持有人應(yīng)考慮：the pharmaceutic

19、al form and use of the medici nal product containing the excipie nt;|含有輔料的藥品劑型和藥品的用途the function of the excipie nt in the formulati on, e.g. lubrica nt in a tablet product or preservative material in a liquid formulati on, etc.;輔料在制劑中的功能，例如，片劑產(chǎn)品中的潤滑劑或液體制劑中的防腐劑等the proport ion of the excipie nt in th

20、e medici nal product compositi on;輔料在藥品成分中的所占比例daily patie nt in take of the excipie nt;患者日攝入輔料量any known quality defects/fraudule nt adulterati ons, both globally and at a local compa ny level related to the excipie nt;全球范圍或當(dāng)?shù)毓痉秶c輔料有關(guān)的所有已知的質(zhì)量缺陷/造假情況whether the excipie nt is a composite;輔料是否是一種組分kn

21、own or potential impact on the critical quality attributes of the medicinal product;對(duì)藥品關(guān)鍵質(zhì)量屬性的已知或潛在的影響other factors as ide ntified or known to be releva nt to assuri ng patie nt safety.識(shí)別的或已知的與保證患者安全相關(guān)的其它因素Having established and docume nted the risk profile of the excipie nt, the manu facturi ng|aut

22、horisati on holder should establish and docume nt the eleme nts of EudraLex Volume 4 that he believes are n eeded to be in place in order to control and maintain the quality of|the excipie nt, e.g. Annex 1 or/a nd Annex 2; Part II: Basic Requireme nts for ActiveSubsta nces used as Starting Materials

23、.在建立和記錄輔料的風(fēng)險(xiǎn)概況之后，生產(chǎn)許可持有人應(yīng)建立和記錄歐盟藥品法第4卷的要素，這些要素應(yīng)是公司認(rèn)為其為控制和維護(hù)輔料質(zhì)量所必須的，例如附錄1和/或附錄2，第2部分用作起始物料的活性物質(zhì)的基本要求。These eleme nts will vary depe nding on the source, the supply cha in and the subseque ntuse of the excipie nt, but as a minimum the follow ing high level GMP eleme nts should becon sidered by the ma

24、nu facturi ng authorisati on holder:這些要素會(huì)根據(jù)輔料的來源、供應(yīng)鏈和隨后的使用而不同，但生產(chǎn)許可持有人最少應(yīng)考慮以 下水平的GMP要素：establishme nt and impleme ntati on of an effective pharmaceutical quality system;建立和實(shí)施有效的藥品質(zhì)量體系sufficie nt compete nt and appropriately qualified pers onn el;具備充足的具備適當(dāng)資質(zhì)的人員defi ned job descripti ons for man ageri

25、al and supervisory staff resp on sible formanu facturi ng and quality activities;對(duì)生產(chǎn)和質(zhì)量活動(dòng)定義管理人員和主管員工的崗位職責(zé)training programmes for all staff involved in manufacturing and quality activities;所有涉及生產(chǎn)和質(zhì)量活動(dòng)的員工的培訓(xùn)程序training programmes related to health, hygiene and clothing as identified asn ecessary to the

26、 inten ded operati ons;健康、衛(wèi)生和更衣有關(guān)的培訓(xùn)程序，必要時(shí)應(yīng)識(shí)別適用于其既定操作provisi on and maintenance of premises and equipme nt appropriate to theinten ded operati ons;設(shè)施和設(shè)備的結(jié)構(gòu)和維護(hù)適合于其既定操作docume ntati on system(s) coveri ng all processes and specificati ons for the variousmanufacturing and quality operations;文件記錄體系覆蓋所有不同

27、生產(chǎn)和質(zhì)量操作的加工和質(zhì)量標(biāo)準(zhǔn)«systems for cod ing and ide ntify ing start ing materials, in termediates and excipie ntsto allow full traceability; |起始物料、中間體和輔料的編碼和識(shí)別系統(tǒng)可以進(jìn)行全程追蹤 qualificati on program of suppliers;供應(yīng)商確認(rèn)程序 system for quality con trol of the excipie nt and a resp on sible pers on in depe ndent f

28、rom product ion to release the batches;有系統(tǒng)對(duì)輔料進(jìn)行質(zhì)量控制，有一個(gè)責(zé)任人獨(dú)立于生產(chǎn)以外來放行批次«rete nti on of records for incoming materials and excipie nts and rete nti on ofsamples of excipie nts for the periods required by EudraLex Volume 4, Part II;進(jìn)廠物料和輔料記錄應(yīng)保存，輔料留樣時(shí)間應(yīng)符合歐洲藥品法第4卷第二部分要求«systems to en sure that

29、any activity con tracted out is subject to a writte n con tract;系統(tǒng)保證所有外包活動(dòng)都有書面合同«maintenance of an effective system whereby compla ints are reviewed andexcipie nts may be recalled;有效系統(tǒng)的維護(hù)，客訴進(jìn)行審核，輔料可能被召回«cha nge man ageme nt and deviati on man ageme nt system;變更管理和偏差管理系統(tǒng)* self- in spect ion

30、 program;自檢程序* environmen tal control and storage con diti ons.|環(huán)境控制和存貯條件CHAPTER 3 DETERMINATION OF EXCIPIENT MANUFACTURER S RISK PROFILE第3章 確定輔料生產(chǎn)的風(fēng)險(xiǎn)概況After determ in ati on of the appropriate GMP, a gap an alysis of the required GMP aga instthe activities and capabilities of the excipie nt manu fa

31、cturer should be performed.在確定了適當(dāng)?shù)?GMP后，應(yīng)針對(duì)輔料生產(chǎn)商的活動(dòng)和能力進(jìn)行所要求的GMP的差距分析。Data/evide nee to support the gap an alysis should be obta ined through audit or fromin formati on received from the excipie nt manu facturer.用以支持差距分析的數(shù)據(jù)/證據(jù)應(yīng)通過審計(jì)獲得，或從輔料生產(chǎn)商處收到的信息獲得。Certificati on of quality systems an d/or GMP held

32、by the excipie nt manu facturer and thesta ndards aga inst which these have bee n gra nted should be con sidered as such certificatio n may fulfil the requireme nts.質(zhì)量體系的證書和/或輔料生產(chǎn)商持有的GMP證書，和頒發(fā)證書所依據(jù)的標(biāo)準(zhǔn)應(yīng)進(jìn)行考慮,因?yàn)樵撜J(rèn)證可能滿足這些要求。Any gaps identified between the required GMP and the activities and capabilities

33、 of theexcipie nt manu facturer should be docume nted. Furthermore, the manu facturi ngauthorisation holder should perform a further risk assessment to determine the risk profile,e.g. low risk, medium risk or high risk, for that excipie nt manu facturer. EudraLex Volume 4,Part III, ICH Q9 should be

34、used for that purpose. Quality risk man ageme nt tools such as|those listed there HACCP etc. should be used for this.所識(shí)別出的GMP要求和輔料生產(chǎn)商的活動(dòng)與能力之間的差距應(yīng)進(jìn)行記錄。另外，生產(chǎn)許可持有人應(yīng)實(shí)施進(jìn)一步風(fēng)險(xiǎn)評(píng)估，以決定該輔料生產(chǎn)商的風(fēng)險(xiǎn)概況，例如，低風(fēng)險(xiǎn)、中等風(fēng)險(xiǎn)或高風(fēng)險(xiǎn)。歐盟藥品法第 4卷，第3部分，ICHQ9應(yīng)用于此目的。質(zhì)量風(fēng)險(xiǎn)管理工具，例 如列于其中的那些-HACCP等-應(yīng)用于此。The manu facturi ng authorisati on holder should have a series of strategies ranging from accepta nee through con trol to un acceptable for the differe nt risk profiles and based on these a control strategy, e.g. audit, document retrieval and testing, should be established.生產(chǎn)許可持有人應(yīng)制訂有一系