GUIDE TO INSPE CTIONS OF STE RILE DRUG
SUB STANCE MANUFA CTURERS
FDA无菌原料药检查指南
Note:This documen t is referenc e material fo r investigato rs and otherFDA personnel. The documen t does not bi nd FDA, and d oes no confer any rights,privileges, b enefits, or i mmunities for or on any pe rson(s).七冲门
注：本文件是FDA现场检查官和其他FDA人员的参考资料。本文件并不束缚FDA，也不赋予任何人任何权利、特权、利益或豁免权。
One of the more dif ficult proces s to inspec t and one whi ch has pren ted considera ble problemsover the year s is that ofthe manufactu re of sterile bulk drug su bstances. Wit hin the pastveral years, there havebeen a number of batches o f sterile bul k drug substa nces from dif ferent manufa cturers which exhibited mi crobiological contaminatio n. One manufa cturer had ap proximately 100 batches co ntaminated in a 6 month ti me period. An other had app roximately 25batches cont aminated in a similar peri od. Other man ufacturers ha ve had recall s due to thelack of
assur ance of steri lity. Althoug h the Inspect ion Guide for Bulk Drug Su bstances prov ides some dir ection for th e inspectionof the steril e bulk drug s ubstance, itdoes not prov ide the detai led direction needed.
多年来现场检查最难的、也是出现问题最多的领域就是无菌原料药的生产。在过去几年中，有数批来自不同制造商的无菌原料药出现了微生物污染。一个制造商在6个月中有100批产品有污染。另一个在相同的时间内出现了25批污染。其它一些生产商由于缺少无菌保证而召回了产品。虽然大宗原料药的现场检查指南在对无菌原料药的检查上提供了一些指导，但它未能提供所需要的详细指导。
I.INTRODUCTI ON简介
In the m anufacture of the sterilebulk powders, it is import ant to recogn ize that ther e is no furth er processing of the finis hed sterile b ulk powder to remove conta minants or im purities such as particula tes, endotoxi ns and degrad ants.
熵变和焓变
在大宗无菌粉的制造中，认识到下面一点很重要，即最终无菌粉生产出来之后，再也没有别的处理来去除微粒、内毒素和降解物。
A s with otherinspections,any rejectedbatches, alon g with the va rious reasons for rejectio n, should
beidentified ea rly in the in spection to p rovide direct ion for the i nvestigator.For example,lists of batc hes rejectedand/or retest ed over a per iod of time s hould be obta ined from the manufacturer to provide d irection forcoverage to b e given to sp ecific proces s or system s. Becau so me of the act ual sterile b ulk
operation s may not been, and bec au of the c omplexity ofthe process,it is particu larly importa nt to reviewreports and s ummaries, suc h as validati on studies, r eject lists,Environmental Monitoring S ummary Report s, QA Investi gation Logs,etc. The sy stems and oth ers are discu sd in the B asic Inspecti on Guide. Thi s is particul arly importan t for the for eign sterilebulk drug sub stance manufa cturer wheretime is limit ed. In the pr eparation for a sterile bu lk drug subst ance inspecti on, a flow ch art with themajor process ing steps sho uld be obtain ed. Generally, the manufac ture of a ste rile bulk sub stance usuall y includes th e following s teps:
健康的饮食
牛羊成群与其它检查一样，在检查的早期，应向检查官提供拒绝使用的批（不合格批）及拒绝的各种理由，以使检查官把握方向。例如，应从制造商处获得一段时间内拒绝的批（不合格批）清单，为检查具体的工艺或系统提供方向。由于某些实际无菌操作可能看不见，同时加上工艺的复杂性，审阅一些报告和总结，如验证研究、拒绝（不合格批）清单、环境监控总结报告、质量保证调查记录等就变得非常重要。这些系统和相关部分在基本现场检查指南中有论述。这对海外无菌原料药制造商尤其重要，因为
受时间所限。在准备无菌原料药现场检查时，应获得包含主要工艺步骤的流程图。通常，无菌原料药的生产包含如下步骤：
1. C onversion ofthe non-steri le drug subst ance to the s terile form b y dissolvingin a solvent, sterilizatio n of the solu tion by filtr ation and col lection in asterilized re actor (crysta llizer).
1.通过在溶媒中溶解，将非无菌原料药转换为无菌原料药。溶液通过过滤除菌后收集在一个无菌反应罐中（即结晶罐）。
2. Aptic p recipitationor crystalliz ation of thesterile drugsubstance inthe sterile r eactor.
2. 在无菌反应罐中进行无菌沉淀或结晶。
3. Aptic isolation of the sterilesubstance bycentrifugatio n or filtrati on.
3. 通过离心或过滤实现无菌分离。
4. A ptic drying, milling and blending ofthe sterile s ubstance.
4.无菌干燥、磨粉和混合。
淮阴侯
5. Aptic samp ling and pack aging the dru g substance.
5.无菌抽样和包装。
Th e operation s should be p erformed in c lod systems, with minima l operator ha ndling. Any a ptic operat ions performe d by an opera tor(s) otherthan in a clo d system sh ould be ident ified and car efully review ed.
冷盘菜谱大全
这些操作应在密闭系统进行，尽可能少的人工参与。如果操作员在密闭系统之外进行无菌操作，应当标示出来并仔细审查。
可怕的反义词II. CO MPONENTS组成部分
In addition t o the impurit y concerns fo r the manufac ture of bulkdrug substanc es, there isa concern wit h endotoxinsin the manufa cture of thesterile bulkdrug substanc es. The valid ation report,which demons trates the re moval, if pre nt, of endo toxins to acc eptable level s, should bereviewed. Som e manufacture rs have comme nted that sin ce an organic solvent is t ypically ud for the conv ersion of the non-sterilebulk drug sub stance to the sterile bulk drug substan ce, that endo toxins will b e reduced atthis stage. A s with any op eration, this may or may n ot be correct. Fo
r example, in an inspe ction of a ma nufacturer wh o conducted e xtensive stud ies of the co nversion (cry stallization)of the non-s terile substa nce to the st erile drug su bstance, they found no cha nge from theinitial endot oxin level. O rganic solven ts were udin this conve rsion. Thus,it is importa nt to reviewand asss th is aspect ofthe validatio n report.
除了担心无菌原料药的杂质之外，内毒素是无菌原料药生产中的另一担心。应当审阅去除内毒素的验证报告。一些制造商认为，由于使用了有机溶媒来把非无菌原料药转换为无菌原料药，内毒素在此阶段已经减少。如其它操作一样，这可能正确，也可能不正确。例如，在对进行了大量非无菌原料药转变为无菌原料药试验的制造商进行现场检查时，他们发现内毒素的含量没有变化。转换中使用了有机溶媒。因此，审阅和评估此方面的验证报告很重要。
In the vali dation of thi s conversion(non-sterileto sterile) f rom an endoto xin perspecti ve, challenge studies canbe carried ou t on a labora tory or pilot scale to det ermine the ef ficiency of t he step. Once it is establ ished that th e process wil l result in a cceptable end otoxin levels, some monito ring of the p roduction bat ches would be appropriate. As with anyvalidation pr ocess, the pu rpo and eff iciency of ea ch step shoul d be evaluate d. For exampl e, if the con version (crys tallization)from the non-sterile to th e sterile sub stance is toreduce endoto xins by one l og, then data should suppo rt this step.
从内毒素角度来看该转变的验证(非无菌到无菌)，挑战性试验应放在实验室或中试规模来确定该步骤的有效性。一旦确定该工艺可以带来可接受的内毒素含量，只需对生产批做一些监控。如任何验证过程一样，每一步的目的和有效性均需评估。例如，如果非无菌到无菌的转变（结晶）减少了1个log值的内毒素，那么，应有数据支持该步骤。
S ince endotoxi ns may not be uniformly di stributed, it is also impo rtant to moni tor the biobu rden of the n on-sterile su bstance(s) be ing sterilize d. For exampl e, gram negat ive contamina ts in a non-s terile bulk d rug substance prior to ste rilization ar e of concern,particularly if the steri lization (fil tration) andcrystallizati on steps do n ot reduce the endotoxins t o acceptablelevels. There fore, microbi ological, aswell as endot oxin data onthe criticalcomponents an d operational steps should be reviewed.
由于内毒素可能不是均匀分布，因此，监控灭菌中的非无菌原料药的生物负荷也很重要。例如，应关注灭菌前非无菌原料药中的某些革兰氏阴性菌污染，特别是如果灭菌（过滤）和结晶过程不能减少内毒素含量。因此，应当审阅关键设备部分和操作环节的微生物和内毒素数据。
III. F ACILITY设施
Fac ility designfor the apt ic processing of sterile b ulk drug subs tances should have the sam e de
sign feat ures as an SV P aptic pro cessing facil ity. The wo uld include t emperature, h umidity and p ressure contr ol. Becau s terile bulk a ptic facili ties are usua lly larger, p roblems withpressure diff erentials and sanitization have been en countered. Fo r example, amanufacturerwas found tohave the gown ing area unde r greater pre ssure than th e adjacent as eptic areas.The need to r emove solvent vapors may a lso impact on area pressur ization.
无菌原料药的无菌加工设施的设计应与SVP无菌设施具有相同的设计特征。这包括温度、湿度和压力控制。由于原料药无菌设施通常较大，常常遇到压差和消毒问题。例如，在现场检查中发现，一个生产商更衣区域的压力比临近无菌区的压力更大。有时需要排除溶媒蒸汽也可能影响着洁净区域的压差。Unnecessaryequipment and/or equipment that cannotbe adequately sanitized, s uch as wooden skids and fo rklift trucks, should be i dentified. In quire about t he movement o f large quant ities of ster ile drug subs tance and the location ofpass-throughareas between the sterilecore and non-sterile areas. Obrve the areas, rev iew environme ntal monitori ng results an d sanitizatio n procedures.
非必要设备和/或无法充分消毒的设备，如木质托盘和叉车，应当予以鉴定。询问大量无菌原料药的转运和位于无菌核心区和非无菌区之间传递区域的位置。观察这些区域，审阅环境监控结果和消毒程序。
The CGMP Reg ulations proh ibit the uof asbestos f ilters in the final filtra tion of solut ions. At pres ent, it would be difficult for a manufa cturer to jus tify the uof asbestos f ilters for fi ltration of a ir or solutio ns. Inquire a bout the uof asbestos f ilters.
cGMP法规禁止在溶液的最终过滤时使用石棉过滤器。目前，制造商很难找出使用石棉过滤器来过滤空气或溶液的理由。询问厂家石棉过滤器的使用。
Fa cilities ud for the char ge or additio n of non-ster ile component s, such as th e non-sterile drug substan ce, should be similar to t ho ud for the compound ing of parent eral solution s prior to st erilization.The concern i s soluble ext raneous conta minants, incl uding endotox ins, that may be carried t hrough the pr ocess. Obrv e this area a nd review the environmenta l controls an d specificati ons to determ ine the viabl e and non-via ble particula te levels all owed in thisarea.
用于非无菌组分，如非无菌原料药的投料或加料的设施，应当与灭菌前注射液的配料设施相同。需要关注的是可溶解的外来污染物，包括内毒素，它们可能贯穿于生产过程。观察这个区域，审阅环境控制和标准，以确定可允许的活性和非活性微粒水平。
IV. PROCESSI NG加工
Sterilepowders are u sually produc ed by dissolv ing the non-s terile substa nce or reacta nts in an org anic solventand then filt ering the sol ution through a sterilizin g filter. Aft er filtration, the sterile bulk materia l is parate d from the so lvent by crys tallization o r precipitati on. Other met hods includedissolution i n an aqueoussolution, fil tration steri lization andparation by crystallizat ion/filtratio n. Aqueous so lutions can a lso be steril e filtered an d spray dried or lyophiliz ed.
无菌粉的生产通常在有机溶媒中溶解非无菌物质或反应物并通过除菌过滤器过滤。过滤后，无菌大宗物料通过结晶或沉淀被分离出来。其它方法包括在水溶液中溶解，过滤除菌和通过过滤或结晶离析。水溶液也可以经无菌过滤、喷雾干燥或冻干。
In t he handling o f aqueous sol utions, prior to solvent e vaporation (e ither by spra y drying or l yophilization), check theadequacy of t he system and controls tominimize endo toxin contami nation. In so me instances,piping syste ms for aqueou s solutions h ave been show n to be the s ource of endo toxin contami nation in ste rile powders.There should be a print a vailable of t he piping sys tem. Trace th e actual pipi ng, compare i t with the pr int and assur e that thereare no "deadlegs" in thesystem.
在水溶液的处理中，在溶液挥发前（喷雾烘干或冻干），检查系统的充足性和对减少内毒素污染的控
制。在某些情况下，输送水溶液的管线被发现是无菌粉中内毒素污染的来源。应当有管路系统的打印图纸。跟踪实际管路，与图纸相对照，保证系统中没有“死角”。
Thevalidation da ta for the fi ltration (ste rilization) p rocess should also be revi ewed. Determi ne the firm's criteria for lection of the filter a nd the freque ncy of changi ng filters. D etermine if t he firm knows the bioburde n and examine their proced ures for inte grity testing filters.
过滤（结晶）过程的验证数据应当审阅。确定公司选择过滤器的标准以及更换频率。确定公司是否知道生物负荷并检查他们过滤器完整性检测的程序。
微波炉的尺寸
F ilters mightnot be change d after eachbatch is ster ilized. Deter mine if there is data to j ustify the in tegrity of th e filters for the time per iods utilized and that "gr ow through" h as not occurr ed.
