清洁验证检查FDA指南(中英文对照)
PDATR-29清洁验证中英对照（第一章—简介）
1. Introduction介绍1.1 Background背景In recent years, cleaning has achieved a position of increasing importance in the pharmaceutical industry. The current good manufacturing practices (CGMP) regulations recognize that cleaning is a critical issue to ensure product quality. Virtually every aspect of manufacturing involves cleaning, from the initial stages of bulk production to the final dosage form.近年来清洁作业逐渐在制药界占有重要的地位。
现行的GMP法规也指出清洁作业是保证产品质量的关键性工作。
自大宗原料的生产以迄最终剂型的制造作业，几乎每一个制造工序均含有清洁作业。
The CGMPs in the United States, Europe and other parts of the world have provided the pharmaceutical industry with general guidance for cleaning requirements. For example, in the U.S., section 211.67 of part 21 of the Code of Federal Regulations (CFR) states that "Equipment and utensils shall be cleaned, maintained, and sanitized at appropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements." Section 211.182 of part 21 of the CFR identifies that cleaning procedures must be documented appropriately, and that a cleaning and use log should be established. In addition to CGMPs, various inspectional guideline documents published by the FDA contain expectations regarding cleaning in the pharmaceutical industry. Cleaning is also addressed in the PIC recommendations on cleaning validation and in the SFSTP Commission report "Validation desprocédés de nettoyage."美国、欧洲及全球其他地区均有制药界清洁作业的通则性指南。
FDA清洁验证检查指南(中英文对照)
FDA清洁验证检查指南（中英文对照）清洗过程验证检查指南GUIDE TOINSPECTIONS VALIDATION OF CLEANINGPROCESSES请注意：本指南是检查官和其他FDA人员的参考材料。
本指南不受FDA约束，并没有赋予任何人任何权利、特权、收益或豁免权。
I．介绍I. INTRODUCTION自从机构文件，包括原料药化学制剂检查指南和生物制剂检查指南，大体上提到该清洗问题以来，就出现了关于清洗过程验证的大量讨论。
这些机构文件清晰的建立了要验证的清洗过程需要达到的要求。
本指南是为了通过讨论实际操作是可接受的(或不可接受的)，来建立检查要求的一致性和统一性。
同时，对清洗验证需要了解的是，像其他过程验证一样，可能有不止一种方法来对过程进行验证。
最后，任何验证过程的测试就是指科学数据是否显示出系统与要求相符和产生的结果是否符合预先定义的参数指标。
本指南只适用于化学残留物的设备清洗。
II．背景对于FDA来说，要求设备在使用前进行清洗并不新奇。
1963GMP 法规(部分133.4)中指出“设备***应该按照清洁和有序的方式进行维护***。
”在1978 CGMP法规中也包含了非常相似的有关设备清洗的章节(211.67)。
当然，清洁设备的主要理由是防止药品被污染或掺假。
在历史上，FDA检查官寻找由于对设备不当的清洗和维护和/或不良的灰尘控制系统而带来的总体不卫生情况。
而且，从历史上来说，FDA对非青霉素药品中的青霉素污染或药品中的活性激素或荷尔蒙交叉污染更加关注。
有很多药品在过去十年中被撤回就是因为实际的或潜在的青霉素的交叉污染。
导致FDA对由于不满足要求的过程导致交叉污染的可能性的进一步关注的案例是，1988年对成品药消胆胺树脂USP的撤回。
用于生产成品的原料药被生产农用杀虫剂中产生的中间体和降解物污染。
本案例中的交叉污染被认为是由于回收溶剂的重新使用。
回收溶剂由于缺乏对溶剂桶的重新使用的控制而被污染。
设备清洗清洁验证1
（3）残留溶剂限度标准：
n 可用于清洗的化学溶剂（三级溶剂）在 下批生产中允许的溶剂残留小于初始溶 剂浓度的0.5%
设备清洗清洁验证1
3、微生物检测：
n 清洁设备的微生物限度标准应该等同于 所生产的产品的微生物限度。
n 清洗周期验证。
设备清洗清洁验证1
清洁验证取样方法：
n 擦拭取样（表面直接取样法） 棉签取样
设备清洗清洁验证1
FDA清洗验证的要求通则：
n 建立书面标准操作程序（SOP） n 必须建立书面的清洁方法验证通则。 n 清洗方法验证通则要规定执行验证的负
责人、批准验证工作的负责人、验证标 准（合格标准）、再验证时间 n 制订专一特定的书面验证计划 n 记录严正结果 n 最终的验证报告
设备清洗清洁验证1
设备清洗清洁验证1
清洁验证：
n 清洁验证Cleaning validation n 可证明用于直接与产品接触的设备表面
的清洁的程序具有再现ቤተ መጻሕፍቲ ባይዱ与有效性的书 面证据。
设备清洗清洁验证1
清洁验证的基本要求：
n 评估工艺过程确定应去除残留的类型。 n 选择合适的清洁剂 n 检查生产设备组成确定清洁方法，取样
n 最终冲洗水取样 漂洗液样品
设备清洗清洁验证1
棉签取样
n 优势：
1. 属于物理取样 2. 适用于多种表面取样 3. 价格经济 4. 可以在任何的表面取样 5. 允许取样多种药物残渣 6. 可以在干燥或潮湿的表面取样 7. 溶剂可以很好帮助残渣分散在稀释液内
设备清洗清洁验证1
棉签取样
n 劣势：
1. 依赖取样技术
设备清洗清洁验证1
3rew
演讲完毕，谢谢听讲!
FDA清洁验证指南(中英文对照)
Validation of Cleaning Processes清洁工艺验证GUIDE TO INSPECTIONS VALIDATION OF CLEANING PROCESSES清洁工艺验证检查指南Mike Ma Sort outXiao GangNote: This document is reference material for investigators and other FDA personnel. The document does not bind FDA, and does no confer any rights, privileges, benefits, or immunities for or on any person(s).注意：本指南是审计官和其他FDA人员的参考资料。
FDA不受本指南的约束，也没有授予任何人任何权利、特权、收益或豁免权。
1 of 14ContentI. INTRODUCTION 简介 (3)II. BACKGROUND 背景 (3)III. GENERAL REQUIREMENTS 常规要求 (5)IV. EVALUATION OF CLEANING VALIDATION清洁验证的评估 (6)V. ESTABLISHMENT OF LIMITS 确定限度 (11)VI. OTHER ISSUES 其他问题 (12)VII. REFERENCES 参考资料 (13)2 of 14Validation of cleaning procedures has generated considerable discussion since agency documents, including the Inspection Guide for Bulk Pharmaceutical Chemicals and the Biotechnology Inspection Guide, have briefly addressed this issue. These Agency documents clearly establish the expectation that cleaning procedures (processes) be validated.自从机构文件，包括化学原料药制剂检查指南和生物技术制剂检查指南简明的提及清洁验证规程以来，就对清洁规程验证产生了大量的讨论。
PDATR-29清洁验证中英对照(序&目录)
3. Cleaning Validation 清洁验证
3.1 The Cleaning Validation Program 清洁验证程序
3.2 Product Grouping 产品分类
3.3 Manufacturing Equipment Grouping 生产设备分类
3.4 Cleaning Method Groupings 清洁方法分类
4.4 Other Contaminants to be Removed 其他应清除的微生物
4.5 Cleaning Agent and Surface Interactions 清洁剂与表面直接的相互作用
5. Cleaning of Equipment 设备的清洗
5.1 Types of Cleaning Proed 半自动 Automated 全自动
Preface
序
This document provides guidance relative to the validation of cleaning for a broad range of processing systems and product types within the pharmaceutical industry. This effort commenced in 1991 in conjunction with individuals representing the biotechnology community. Early on it was agreed to separate the development of cleaning validation guidance into "biotechnology" and "pharmaceutical" segments. The committees worked in parallel for a number of years and shared early drafts to ensure that what would be produced by each committee would be compatible. The biotech effort culminated in PDA's 1995 publication of "Cleaning and Cleaning Validation: A Biotechnology Perspective". The "pharmaceutical" committee continued the development of its document after the publication of the biotech effort, and completed its stand alone guidance in the fall of 1997. 本文件旨在作为制药设备清洁验证的指南，以配合制药工业中范围宽广的生产系统及产 品类型。本小组自1991年起致力于本文件的撰写，当时开始与生物技术工作人员共同工 作。工作初期，大家认同把清洁验证的研究按“生物科技”和“制药”区分处理；在数 年间两组人员平行进行相关的开发工作，并相互共享初期所拟定的草案，以保证两方面 意见相同的事项。PDA于1995年将“生物技术”方面的研究所得出版为"Cleaning and Cleaning Validation: A Biotechnology Perspective"。制药方面的研究小组随后继续研究， 于1997年秋季完成起研究工作。
FDA清洁验证审计指南
Validation of Cleaning Processes(7/93)SHARETWEETLINKEDINPIN ITMORE SHARING OPTIONSLINKEDINPIN ITEMAILPRINTGUIDE TO INSPECTIONS VALIDATION OF CLEANINGPROCESSESNote: This document is reference material for investigators and other FDApersonnel. The document does not bind FDA, and does no confer any rights, privileges, benefits, or immunities for or on any person(s).I. INTRODUCTIONValidation of cleaning procedures has generated considerable discussionsince agency documents, including the Inspection Guide for BulkPharmaceutical Chemicals and the Biotechnology Inspection Guide, havebriefly addressed this issue. These Agency documents clearly establish the expectation that cleaning procedures (processes) be validated.This guide is designed to establish inspection consistency and uniformity by discussing practices that have been found acceptable (or unacceptable).Simultaneously, one must recognize that for cleaning validation, as withvalidation of other processes, there may be more than one way to validate a process. In the end, the test of any validation process is whether scientificdata shows that the system consistently does as expected and produces a result that consistently meets predetermined specifications.This guide is intended to cover equipment cleaning for chemical residuesonly.II. BACKGROUNDFor FDA to require that equipment be clean prior to use is nothing new, the 1963 GMP Regulations (Part 133.4) stated as follows "Equipment *** shallbe maintained in a clean and orderly manner ***." A very similar section on equipment cleaning (211.67) was included in the 1978 CGMP regulations. Of course, the main rationale for requiring clean equipment is to preventcontamination or adulteration of drug products. Historically, FDAinvestigators have looked for gross insanitation due to inadequate cleaning and maintenance of equipme nt an d/or poor dust con trol systems. Also,historically speak ing, FDA was more concerned about the con tam in ati onof nonpenicillin drug products with penicillins or the cross-contamination ofdrug products with pote nt steroids or horm on es. A nu mber of productshave bee n recalled over the past decade due to actual or pote ntial peni cilli n cross-c on tam in ati on.One eve nt which in creased FDA aware ness of the pote ntial for cross con tam in ati on due to in adequate procedures was the 1988 recall of afinished drug product, Cholestyramine Resin USP. The bulk pharmaceutical chemical used to produce the product had become con tam in ated with low levels of in termediates and degrada nts from the producti on of agricultural pesticides. The cross-c on tam in ati on in that case is believed to have bee n due to the reuse of recovered solve nts. The recovered solve nts had bee n con tam in ated because of a lack of con trol over the reuse of solve ntdrums. Drums that had bee n used to store recovered solve nts from apesticide producti on process were later used to store recovered solve ntsused for the res in manu facturi ng process. The firm did not have adequate con trols over these solve nt drums, did not do adequate testi ng ofdrummed solve nts, and did not have validated clea ning procedures for the drums.Some shipme nts of this pesticide con tam in ated bulk pharmaceutical were supplied to a second facility at a different location for finishing. This resulted in the contamination of the bags used in that facility's fluid bed dryers withpesticide contamination. This in turn led to cross contamination of lotsproduced at that site, a site where no pesticides were no rmally produced.FDA instituted an import alert in 1992 on a foreign bulk pharmaceuticalmanu facturer which manu factured pote nt steroid products as well as non-steroidal products using com mon equipme nt. This firm was a multi-usebulk pharmaceutical facility. FDA con sidered the pote ntial for cross-contamination to be significant and to pose a serious health risk to thepublic. The firm had only recently started a cleaning validation program atthe time of the in spect ion and it was con sidered in adequate by FDA. One of the reas ons it was con sidered in adequate was that the firm was onlylook ing for evide nee of the abse nee of the previous compo und. The firm had evidenee, from TLC tests on the rinse water, of the presence ofresidues of react ion byproducts and degrada nts from the previous process. III. GENERAL REQUIREMENTSFDA expects firms to have writte n procedures (SOP's) detaili ng the cleaning processes used for various pieces of equipme nt. If firms have one clea ning process for clea ning betwee n differe nt batches of the same productand use a differe nt process for clea ning betwee n product cha nges, weexpect the written procedures to address these different scenario. Similarly, if firms have one process for rem oving water soluble residues and ano ther process for non-water soluble residues, the writte n procedure shouldaddress both sce narios and make it clear whe n a give n procedure is to be followed. Bulkpharmaceutical firms may decide to dedicate certa in equipme nt for certa in chemical manu facturi ng process steps that produce tarry or gummyresidues that are difficult to remove from the equipment. Fluid bed dryerbags are ano ther example of equipme nt that is difficult to clea n and is ofte n dedicated to a specific product. Any residues from the clea ning processitself (detergents, solvents, etc.) also have to be removed from the equipme nt.FDA expects firms to have writte n gen eral procedures on how clea ningprocesses will be validated.FDA expects the gen eral validati on procedures to address who is resp onsible for perform ing and appro ving the validati on study, the acceptancecriteria, and when revalidation will be required.FDA expects firms to prepare specific writte n validati on protocols in advance for the studies to be performed on each manu facturi ng system or piece of equipme nt which should address such issues as sampli ng procedures,and an alytical methods to be used in clud ing the sen sitivity of thosemethods. FDA expects firms to con duct the validati on studies in accordance with the protocols and to docume nt the results of studies.FDA expects a final validati on report which is approved by man ageme ntand which states whether or not the clea ning process is valid. The datashould support a con clusi on that residues have bee n reduced to an"acceptable level."IV.EVALUATION OF CLEANING VALIDATIONThe first step is to focus on the objective of the validation process, and wehave see n that some compa nies have failed to develop such objectives. It is not unu sual to see manu facturers use exte nsive sampli ng and testi ngprograms follow ing the clea ning process without ever really evaluati ng the effective ness of the steps used to clea n the equipme nt. Several questi ons n eed to be addressed whe n evaluat ing the clea ning process. Forexample, at what point does a piece of equipme nt or system become clean? Does it have to be scrubbed by hand? What is accomplished by handscrubb ing rather tha n just a solve nt wash? How variable are manual cleaning processes from batch to batch and product to product? The an swers to these questions are obviously important to the inspection and evaluation ofthe clea ning process since one must determ ine the overall effective ness of the process. An swers to these questi ons may also ide ntify steps that canbe elimi nated for more effective measures and result in resource sav ingsfor the compa ny.Determ ine the nu mber of clea ning processes for each piece of equipme nt.Ideally, a piece of equipment or system will have one process for cleaning,however this will depe nd on the products being produced and whether theclea nup occurs betwee n batches of the same product (as in a largecampaig n) or betwee n batches of differe nt products. Whe n the clea ningprocess is used only betwee n batches of the same product (or differe nt lotsof the same in termediate in a bulk process) the firm n eed only meet a criteria of, "visibly clea n" for the equipme nt. Such betwee n batch clea ning processes do not require validati on.1. Equipme nt Desig nExam ine the desig n of equipme nt, particularly in those large systems that may employ semi-automatic or fully automatic clean-in-place (CIP) systems since they represe nt sig nifica nt concern. For example, sanitary type pip ing without ball valves should be used. Whe n suchnonsan itary ball valves are used, as is com mon in the bulk drug industry, the clea ning process is more difficult.When such systems are ide ntified, it is importa nt that operatorsperform ing clea ning operatio ns be aware of problems and havespecial trai ning in clea ning these systems and valves. Determ inewhether the clea ning operators have kno wledge of these systems and the level of training and experie nee in clea ning these systems. Alsocheck the writte n and validated clea ning process to determ ine if these systems have been properly identified and validated.In larger systems, such as those employi ng long tran sfer lines or pipi ng, check the flow charts and pip ing diagrams for the ide ntificati on of valves and writte n clea ning procedures. Pip ing and valves should be tagged and easily identifiable by the operator performing the cleaningfunction. Sometimes, in adequately ide ntified valves, both on prints and physically, have led to in correct clea ning practices.Always check for the prese nee of an ofte n critical eleme nt in thedocume ntati on of the clea ning processes; ide ntify ing and con troll ing the len gth of time betwee n the end of process ing and each clea ning step. This is especially importa nt for topicals, suspe nsions, and bulkdrug operations. In such operations, the drying of residues will directly affect the efficie ncy of a clea ning process.Whether or not CIP systems are used for clea ning of process ingequipme nt, microbiological aspects of equipme nt clea ning should be con sidered. This con sists largely of preve ntive measures rather tha n removal of con tam in ati on once it has occurred. There should besome evide nee that rout ine clea ning and storage of equipme nt does not allow microbial proliferation. For example, equipment should bedried before storage, and un der no circumsta nces should stag nantwater be allowed to rema in in equipme nt subseque nt to clea ningoperati ons.Subseque nt to the clea ning process, equipme nt may be subjected to sterilizati on or san itizati on procedures where such equipme nt is used for sterile process ing, or for non sterile process ing where the products may support microbial growth. While such sterilizatio n or san itizati on procedures are bey ond the scope of this guide, it is importa nt to note that con trol of the bioburde n through adequate clea ning and storageof equipme nt is importa nt to en sure that subseque nt sterilizati on orsanitization procedures achieve the necessary assuranee of sterility.This is also particularly important from the standpoint of the control ofpyroge ns in sterile process ing since equipme nt sterilizati on processes may not be adequate to achieve sig nifica nt in activati on or removal of pyroge ns.2. Clea ning Process Writte nProcedure and Docume ntati onExam ine the detail and specificity of the procedure for the (clea ning)process being validated, and the amount of docume ntati on required.We have see n gen eral SOPs, while others use a batch record or logsheet system that requires some type of specific docume ntati on forperform ing each step. Depe nding upon the complexity of the systemand cleaning process and the ability and training of operators, theamount of docume ntati on n ecessary for executi ng various clea ningsteps or procedures will vary.When more complex clea ning procedures are required, it is importa nt to docume nt the critical clea ning steps (for example certa in bulk drug syn thesis processes). I n this regard, specific docume ntati on on theequipme nt itself which in cludes in formati on about who clea ned it and when is valuable. However, for relatively simple cleaning operations, the mere docume ntati on that the overall clea ning process was performed might be sufficie nt.Other factors such as history of clea nin g, residue levels found aftercleaning, and variability of test results may also dictate the amount ofdocume ntati on required. For example, whe n variable residue levelsare detected follow ing clea ning, particularly for a process that isbelieved to be acceptable, one must establish the effective ness of the process and operator performa nee. Appropriate evaluati ons must bemade and whe n operator performa nee is deemed a problem, moreexte nsive docume ntati on (guida nee) and training may be required. 3. Analytical MethodsDetermine the specificity and sensitivity of the analytical method used to detect residuals or con tam inan ts. With adva nces in an alytical tech no logy, residues from the manu facturi ng and clea ning processes can be detected at very low levels. If levels of contamination or residual are not detected, it does not mean that there is no residual con tam inant prese nt after clea nin g. It only means that levels of con tam inant greaterthan the sensitivity or detection limit of the analytical method are notpresent in the sample. The firm should challenge the analytical method in comb in ati on with the sampli ng method(s) used to show that contam inants can be recovered from the equipme nt surface and at whatlevel, i.e. 50% recovery, 90%, etc. This is n ecessary before any conclusi ons can be made based on the sample results. A n egative testmay also be the result of poor sampli ng tech nique (see below).4. Sampli ngThere are two gen eral types of sampli ng that have bee n foundacceptable. The most desirable is the direct method of sampling thesurface of the equipme nt. Ano ther method is the use of rinse soluti ons.a. Direct Surface Sampli ng - Determi ne the type of samplingmaterial used and its impact on the test data since the sampli ngmaterial may in terfere with the test. For example, the adhesiveused in swabs has been found to interfere with the analysis ofsamples. Therefore, early in the validation program, it is importantto assure that the sampli ng medium and solve nt (used for extraction from the medium) are satisfactory and can be readily used.Advantages of direct sampling are that areas hardest to clean andwhich are reas on ably accessible can be evaluated, lead ing toestablish ing a level of con tam in ati on or residue per give nsurface area. Additi on ally, residues that are "dried out" or are insoluble can be sampled by physical removal.b.systems or ones that cannot be routi nely disassembled can besampled and evaluated.A disadva ntage of rinse samples is that the residue or con tam inantmay not be soluble or may be physically occluded in the equipme nt. An an alogy that can be used is the "dirty pot." In the evaluatio n of cleaning of a dirty pot, particularly with dried out residue, one does no t look at the rinse water to see that it is clea n; one looks at the pot.Check to see that a direct measureme nt of the residue or con tam inant has bee n made for the rinse water whe n it is used to validate the cleaning process. For example, it is not acceptable to simply test rinse water for water quality (does it meet the compendia tests) rather than test it for potential contaminates.c. Rout ine Producti on In-Process Con trolMon itori ng - In direct test ing, such as con ductivity testi ng, may be of some value for rout ine mon itori ng once a clea ning process has bee n validated. This would be particularly true for the bulk drug substa neemanu facturer where reactors and cen trifuges and pip ing betwee nsuch large equipme nt can be sampled only using rinse soluti onsamples. Any in direct test method must have bee n show n to correlate with the condition of the equipment. During validation,the firm should docume nt that test ing the un clea ned equipme nt givesa not acceptable result for the in direct test.ESTABLISHMENT OF LIMITSFDA does not intend to set accepta nee specificati ons or methods for determining whether a cleaning process is validated. It is impractical for FDA to do so due to the wide variati on in equipme nt and products used throughout the bulk and fini shed dosage form in dustries. The firm's rati on ale for the residue limitsestablished should be logical based on the manu facturer's kno wledge of the materials invo Ived and be practical, achievable, and verifiable. It is important to define the sensitivity of the an alytical methods in order to set reas on able limits. Some limits that have bee n men tio ned by in dustry represe ntatives in the literature or in presentations include analytical detection levels such as 10 PPM, biological activity levels such as 1/1000 of the normal therapeutic dose, and orga no leptic levels such as no visible residue.Check the manner in which limits are established. Uni ike fini shedpharmaceuticals where the chemical ide ntity of residuals are known (i.e., from actives, in actives, deterge nts) bulk processes may have partial reacta nts and unwan ted by-products which may n ever have bee n chemically identified. In establishing residual limits, it may not be adequate to focus only on the prin cipal reacta nt since other chemical variati ons may be more difficult to remove. There are circumsta nces where TLC scree ning, in additi on to chemical an alyses, may be n eeded. In a bulk process, particularly for very potent chemicals such as some steroids, the issue of by-products n eeds to be con sidered if equipme nt is not dedicated. The objective of the inspection is to ensure that the basis for any limits is scie ntifically justifiable.OTHER ISSUESa. Placebo ProductIn order to evaluate and validate clea ning processes some manu facturers have processed a placebo batch in the equipme nt un der esse ntially the same operat ing parameters used for process ing product. A sample of the placebo batch is then tested for residual contamination. However, we have docume nted several sig nifica nt issues that n eed to be addressed whe n using placebo product to validate clea ning processes.One cannot assure that the con tam in ate will be uniformly distributedthroughout the system. For example, if the discharge valve or chute of a ble nder are con tam in ated, the con tam inant would probably not be uni formly dispersed in the placebo; it would most likely be concen trated in the in itial discharge portion of the batch. Additi on ally, if the con tam inant or residue is of a larger particle size, it may not be uniformly dispersed in the placebo. V. VI.Some firms have made the assumpti on that a residual con tam inant would be worn off the equipme nt surface uniformly; this is also an inv alid con clusi on.Fin ally, the an alytical power may be greatly reduced by diluti on of the contam in ate. Because of such problems, rinse an d/or swab samples should beused in conj un cti on with the placebo method.b. Deterge ntIf a deterge nt or soap is used for clea ning, determ ine and con sider thedifficulty that may arise whe n attempti ng to test for residues. A com monproblem associated with deterge nt use is its compositi on. Many deterge ntsuppliers will not provide specific compositi on, which makes it difficult for theuser to evaluate residues. As with product residues, it is importa nt and it isexpected that the manu facturer evaluate the efficie ncy of the clea ningprocess for the removal of residues. However, un like product residues, it isexpected that no (or for ultra sen sitive an alytical test methods - very low)deterge nt levels remai n after clea ning. Deterge nts are not part of the manufacturi ng process and are only added to facilitate clea ning duri ng the cleaning process. Thus, they should be easily removable. Otherwise, a differe ntdeterge nt should be selected.c. Test Until CleanExamine and evaluate the level of testing and the retest results since testinguntil clean is a concept utilized by some manufacturers. They test, resample,and retest equipme nt or systems un til an "acceptable" residue level isattained. For the system or equipment with a validated clea ning process, thispractice of resampli ng should not be utilized and is acceptable only in rarecases. Constant retesting and resampling can show that the clea ning processis not validated since these retests actually docume nt the prese nee of unacceptable residue and con tam inants from an in effective clea ning process.REFERENCES0. J. Rodehamel, "Cleaning and Maintenance," Pgs 82-87, University of Wisc VII.onsin's Con trol Procedures in Drug Productio n Sem inar, July 17-22, 1966,William Blockstein, Editor, Published by the University of Wisco nsi n,L.O.C.#66-64234.1. J.A. Constanee, "Why Some Dust Control Exhaust Systems Don't Work,"Pharm. Eng., January-February, 24-26 (1983).2. S.W. Harder, "The Validation of Cleaning Procedures," Pharm. Technol. 8 (5),29-34 (1984)3. W.J. Mead, "Maintenance: Its Interrelationship with Drug Quality," Pharm. Eng.7(3), 29-33 (1987).4. J.A. Smith, "A Modified Swabb ing Tech ni que for Validati on of Deterge ntResidues in Clean-in-Place Systems," Pharm. Technol. 16(1), 60-66 (1992).5. Fourman, G.L. and Mullen, M.V., "Determining Cleaning Validation Acceptanee Limits for Pharmaceutical Manu facturi ng Operati on s," Pharm. Tech nol.17(4), 54-60 (1993).6. McCormick, P.Y. and Cullen, L.F., in Pharmaceutical Process Validation, 2ndEd., edited by I.R. Berry and R.A. Nash, 319-349 (1993)。
清洁验证(中文)
清洁验证的实施
4. 建立残渣取样方法 5. 建立残渣回收方法
通用的残渣取样方法为浸液式和擦拭式。
▪ 在某些情况下也会使用提取法。
对设备的安装场所进行验证并针对该场所选择一种合适的取样 方法。
对表面的目测是所有的清洁验证工作的基础。
清洁验证的实施
6. 确定残渣的限量值
➢ 第二个公式是基于推荐的限量进行的计算。计算结果得出的ARL 值为不超过10ppm的一种产品存在于另一种产品中。
在这个计算中，假设污染是由一种产品均匀地向下一种产品残留造 成的。
清洁验证培训
Nick Almeida April 21, 2007
课程内容
➢ 适用规程的来源及回顾 ➢ 清洁程序的主要步骤 ➢ 清洁程序的组成部分 ➢ 通用清洁程序 ➢ 清洁验证的实施 ➢ 目前以及未来的焦点---什么是规程中要求的或未
要求的 ➢ 实施清洁验证的必要性:对一些引用规程的回顾 ➢ 自动在位清洗(CIP)的设计 ➢ 在位清洗系统---概述及通用CIP程序
清洁程序的主要步骤清洁程序的主要步骤确定合适的取样和分析方法确定合适的取样和分析方法确定检测限lod和最低检测量loq确定检测限lod和最低检测量loq包括对表面和或清洗用水回收的分析包括对表面和或清洗用水回收的分析确定清洁方式确定清洁方式自动半自动手工自动半自动手工清洁方式通常由设备的构造决定清洁方式通常由设备的构造决定通常会几种清洁方式结合使用通常会几种清洁方式结合使用对于不是按照在位清洗进行设计的设备是很难完全实施全自动清洗的对于不是按照在位清洗进行设计的设备是很难完全实施全自动清洗的考虑将设备移动到半自动清洗机中进行清洗考虑将设备移动到半自动清洗机中进行清洗在其它清洗方法都不适合的情况下使用手工清洗方式在其它清洗方法都不适合的情况下使用手工清洗方式定义清洁方式定义清洁方式在设计清洁程序时应始终考虑到清洁验证在设计清洁程序时应始终考虑到清洁验证清洁程序必须是有效的并且可重复操作的清洁程序必须是有效的并且可重复操作的清洁程序必须能保证持续性满足清洁验证标准清洁程序必须能保证持续性满足清洁验证标准优化清洁程序在验证之前进行优化清洁程序在验证之前进行清洁程序的组成部分清洁程序的组成部分化学性浓度?选择合适的化学性浓度对设备排放的限制chemistryconcentrationtemperaturetimeaction场地表面清洁剂通用清洁程序概念及方法通用清洁程序概念及方法传统的清洁方法可分为三种传统的清洁方法可分为三种
FDA清洁验证检查指南(中英文对照)
FDA清洁验证检查指南（中英文对照）清洗过程验证检查指南GUIDE TOINSPECTIONS VALIDATION OF CLEANINGPROCESSES请注意：本指南是检查官和其他FDA人员的参考材料。
本指南不受FDA约束，并没有赋予任何人任何权利、特权、收益或豁免权。
I．介绍I. INTRODUCTION自从机构文件，包括原料药化学制剂检查指南和生物制剂检查指南，大体上提到该清洗问题以来，就出现了关于清洗过程验证的大量讨论。
这些机构文件清晰的建立了要验证的清洗过程需要达到的要求。
本指南是为了通过讨论实际操作是可接受的(或不可接受的)，来建立检查要求的一致性和统一性。
同时，对清洗验证需要了解的是，像其他过程验证一样，可能有不止一种方法来对过程进行验证。
最后，任何验证过程的测试就是指科学数据是否显示出系统与要求相符和产生的结果是否符合预先定义的参数指标。
本指南只适用于化学残留物的设备清洗。
II．背景对于FDA来说，要求设备在使用前进行清洗并不新奇。
1963GMP 法规(部分133.4)中指出“设备***应该按照清洁和有序的方式进行维护***。
”在1978 CGMP法规中也包含了非常相似的有关设备清洗的章节(211.67)。
当然，清洁设备的主要理由是防止药品被污染或掺假。
在历史上，FDA检查官寻找由于对设备不当的清洗和维护和/或不良的灰尘控制系统而带来的总体不卫生情况。
而且，从历史上来说，FDA对非青霉素药品中的青霉素污染或药品中的活性激素或荷尔蒙交叉污染更加关注。
有很多药品在过去十年中被撤回就是因为实际的或潜在的青霉素的交叉污染。
导致FDA对由于不满足要求的过程导致交叉污染的可能性的进一步关注的案例是，1988年对成品药消胆胺树脂USP的撤回。
用于生产成品的原料药被生产农用杀虫剂中产生的中间体和降解物污染。
本案例中的交叉污染被认为是由于回收溶剂的重新使用。
回收溶剂由于缺乏对溶剂桶的重新使用的控制而被污染。
美国FDA清洗验证检查指南
美国FDA清洗验证检查指南注释：这份文件是检查员和其他FDA人员的参考资料。
这份文件不约束FDA，不授予任何人任何权力、特权、利益或豁免权。
Ⅰ. 简介对于清洗程序的验证的讨论，已经在FDA原料药检查指南和生物制品检查指南中有了简要地解释。
这些官方文件明确表达了清洗验证的期望。
本指南通过讨论一些可接受（或不可接受）的实例来建立检查的连贯性和一致性。
同时我们必须意识到清洗验证同其他过程的验证一样，都有不止一种的方法进行验证。
最后验证证明，是否有科学数据表明系统确实如预期稳定，并满足预设规定的结果。
这个指南仅涉及对设备化学残留物的清洗。
Ⅱ. 背景FDA对于设备使用前的清洗没有什么新要求，1963GMP规范中（133.4部分）有以下陈述“设备***应保持清洁和有序的状态***”。
在1978cGMP规范的设备清洁中有非常类似的章节。
当然，设备清洗的主要目的是为了防止药品的污染和混淆。
历史上，FDA 检查员发现由于设备的清洗和维护的不充分及不良的灰尘控制系统带来总体上的不卫生。
历史上来说，FDA更关注非青霉素类受青霉素类的污染和高活性的类固醇或激素对药物的交叉污染。
过去的几十年里，许多产品由于实际存在或潜在的青霉素交叉污染而召回。
1998年消胆胺树脂USP制剂的召回事件使FDA对由于不充分的清洗程序造成的潜在交叉污染更为重视。
产品生产中用到的化学原料药有低量的中间体和农业杀虫剂的降解物污染。
那个事件中交叉污染被认为来自回收溶剂的套用过程。
回收溶剂的污染是由于缺少对溶剂罐重复使用的控制。
杀虫剂生产过程中存放回收溶剂的罐子随后用于存放树脂生产过程中的回收溶剂。
公司对这些溶剂罐未严格管理，对存放的溶剂未充分检测，对罐子的清洗程序未验证。
杀虫剂污染了的原料药运到另一个地方提供给第二个工厂最后加工。
这对后一个工厂流化床干燥器上用到的捕尘袋造成杀虫剂污染。
这反过来导致在这里生产的多个批次交叉污染，而这里正常情况下没有杀虫剂生产。
FDA清洁验证指南
FDA清洁验证指南
FDA（美国食品药品监督管理局）的清洁验证指南（Cleaning Validation Guidance for FDA）是一份详细说明如何进行清洁验证的指南，以确保在药品和医疗器械生产中使用的设备得到有效清洁的文件。
该
指南包含了清洁验证的定义、原则、程序和要求，以及检验设备清洁性能
的方法和技术。
清洁验证是制药行业中的一个关键步骤，旨在确保设备在使用前不含
有任何的残留物。
残留物可能会对产品质量和安全性产生负面影响，因此
清洁验证是产品质量保证和合规性的重要部分。
该指南中提到了一些重要的原则，如总体清洁验证策略、验证程序的
不同阶段、适当的样本大小和技术要求。
它强调了验证过程应该是科学、
系统和可重复的，并应基于理解和评估风险。
指南还描述了清洁验证程序的各个阶段，例如验证计划的编制、击中
关键因素的确定、清洁程序和剂量的开发、样本收集和分析等。
它还提供
了相关文件的要求，如验证报告和标准操作程序（SOPs），以确保验证结
果的准确性和追溯性。
此外，该指南还提供了一些实施清洁验证时应考虑的额外要求，如定
期审核验证程序、定义验证周期、报告异常结果、记录过程参数和审核活
动等。
总之，FDA清洁验证指南是一份重要的文件，为制药和医疗器械行业
提供了进行清洁验证的详细指导。
它对于确保设备在使用前得到有效清洁，并遵守相关法规和要求起到了重要的作用。
制药公司和设备制造商应该遵
循该指南的要求，并根据需要进行相应的验证程序，以保证产品质量和安全性。
FDA清洁验证检查指南介绍 杨仲元
.
who is responsible for performing and approving the validation study, the
acceptance criteria,and when revalidation will be required.
析方法的灵敏度对限度的拟定很重要。
.
原料药生产，尤其是激素类，如果设备不是专用，应考虑副 产物的检测（如用色谱法）。
其限度设定是经科学证明的。
6 其他
.
（1）无效对照
.
用无效对照物相同条件下生产检查有无污染，结果不一定可靠，因为污染物分布不均匀的
问题
.
（2）洗涤剂
3 通则要求
.
FDA要求药厂应备有成同品种药品使用一种清洗规程，而更换产品时，对不同品种药品用另一种
方法清洗，要求有成文的说明。
3 通则要求
. 药厂用一种方法清洗水溶性残留物，用另一种方法清洗非水溶性残留物，成文的规程均应
FDA清洁验证检查指南介绍
GUIDE TO INSPECTIONS VALIDATION OF CLEANING PROCESSES
杨仲元
2009.8
该文件是作为参考文件，内容
包括：
1 引言
2 背景
3 通则要求
4 清洁验证的评估
5 限度的设定
6 其他
.
应容易完全冲洗掉
.
（3）清洗至合格为止
.
说明方法未经验证。
谢谢
management and which states whether or not the cleaning
FDA清洁过程验证的指导(英译)
一般要求：FDA专家已经为各种设备写了SOP细化清洁过程。
如果一个产品的不同批次有相同的清洁过程，产品变换时用不同的清洁过程。
我们希望这些不同的细节能被写下来。
同样，如果一个过程用于清洗水溶性残留，另一个过程用于清洗非水溶性残留，这些过程应该被写下来，并且要判断这个过程是否实施。
散装的药品决定了特定装备的特定化学生产过程，很难从设备上清洗的残留物和胶状残留。
流体干燥床是另一个常用于特定产品的难以清洗的设备的例子。
任何清洗过程中的残留（溶剂等）要从设备上清洁FDA专家要求有一个清洗过程的书面流程要被验证FDA专家当可接受的验证和重复验证被要求时，希望验证过程确认谁为过程负责，并推进验证研究FDA 专家要求准备在确认样品过程和包括这些方法的敏感性在内的分析方法的每一个生产系统中或单一设备在样品生产过程中的在进一步研究中写下验证参数。
FDA专家要求对应于参数和结果研究文件的验证研究。
FDA专家希望有被经理推进的和标明了是否清洁过程被验证的最后的验证报告。
数据应该支持残留物已经被降到一个“可接受的程度”的结论。
清洁验证的评估第一步聚焦于验证过程的目标，一些企业已经在发展这些目标时失败了。
在看到企业使用清洁过程的特殊样品和实验过程没有真正的评价在评价清洁过程时一些问题要被提出。
例如：一个设备或系统在何时变干净？需要用手清洁吗？是用手还是用溶剂清洗干净？主要的清洗过程一批到一批，一个产品到一个产品很显然吗？这些问题的答案对于检查很重要对于要决定过程的有效性的清洁过程的评估时很重要。
对于分辨提高有效措施何公司资源的结果的步骤这些答案也有帮助。
决定每个设备的清洗过程号。
一个设备或系统有一个清洁过程，然而这将依靠生产的品种，和是否同一产品的批次之间（在一个大的时间段或不同产品的批次间清除干净了。
当清洁过程在同一产品的不同批次间（在大的过程中的不同批量的同一中间体）最严格需要为达到一个标准，设备的“明显清洁”。
这些批次间的清洁不需要验证。
WHO清洁指南中英文
WHO 最新清洁验证指南中英文A p p en di x3C l e a ni n gva l i da t i on清洁验证T h et ex t o f t hi s a ppe n di x w as p r ev i o us l y p u bl i sh e d a s:本附录的文本以前以下列形式发表:■■A pp en di x3: C l e a n i n g va l i da t i on. In:W HO Ex pe r t C om m i t t e e o nS p ec i f i c at i on sf o r P h a rm a c e ut i c al P r epa r a t i on s, f o rt i et h re p o rt.G e n e va: W or l d H e al t h O r ga ni z at i on; 2006:An nex4 (W H OT e c hn i ca l R e po rtS e ri es,No. 937;附录3:清洁验证。
在:世界卫生组织药物制剂规范专家委员会第四十次报告。
日内瓦,世界卫生组织;2006:附件4(世卫组织技术报告系列，第937号;h t t ps://ww w.w ho.i nt/m ed i c i n e s/a re a s/qu a l i t y_s a f e t y/q u a l i t y_a s s u ra n c e/S u ppl e m e nt a ryG M P V a l i d a t i o n TR S937A nn ex4.p d f?ua=1).1.P ri n ci p l e原则1382.S c op e范围1383.G en e r al概述1394.C l e a ni n g v al i d at i o n p ro t o c ol s an d r ep o rt s清洁验证方案和报告1395.P e rs on n el人员1426.Eq ui p m ent设备1427.D et e r gen t s清洗剂1428.M i cr ob i ol o g y 微生物1439.S am pl i n g取样14310.A n al yt i c a l m et ho ds分析方法14511.E st abl i s hi n g a c ce p t abl e l i m i t s确定可接受标准1461.P ri n ci p l e原则1.1T he obj e ct i v es of go od m a nu f a ct u ri n g p r a ct i c es(G M P) i n cl ud e t h e pr e v en t i o n o f po s s i bl e c ont a m i n a t i o n a nd c ro ss-co nt am i n at i o n o f p h a rm a ce ut i c a l s t a rt i n g m a t e r i a l s a nd p ro du c t s.药品生产质量管理规范(GMP)的目标包括防止可能的污染和药物原料和产品的交叉污染。
FDA清洁工艺验证指南中英文对照
FDA清洁工艺验证指南中英文对照FDA（Food and Drug Administration）是美国食品药品监督管理局的简称。
FDA的清洁工艺验证指南提供了有关如何验证食品加工设备和工艺的清洁性的指导，确保产品的安全。
下面是FDA清洁工艺验证指南的英文全文对照。
FDA Cleaning Process Validation GuideIntroduction简介This document provides guidance on how to validate the cleaning processes used in food processing equipment to ensure their cleanliness. Cleaning validation is an essential step in preventing cross-contamination and ensuring the production of safe products.本文提供了关于如何验证食品加工设备中使用的清洁程序以确保其清洁度的指导。
清洁工艺验证是防止交叉污染和确保生产安全产品的关键步骤。
General Principles基本原则1. Validation should be based on a scientific and risk-based approach, taking into account the specific characteristics of the equipment and the product being manufactured.验证应基于科学和风险评估的方法，考虑到设备和正在生产的产品的特殊特性。
2. The validation process should be well-documented and include clear objectives, acceptance criteria, and a description of the methods used.验证过程应有良好的记录，并包括明确的目标、准入标准和方法描述。
美国FDA清洁程序验证检查指南1 9 9 3年
美国FDA清洁程序验证检查指南1 9 9 3年I．导言 (3)Ⅱ．背景 (3)Ⅲ．一般要求 (4)Ⅳ．清洁验证的评价 (5)1.设备设计 (5)2．清洁程序的规程及文件 (6)3.分析方法 (7)4．取样 (7)ⅴ．确定限度 (8)Ⅵ．其他事项 (8)Ⅶ.参考文献 (9)I．导言自从包括《化学原料药检查指南》和《生物技术检查指南》在内的一些政府文件简要而明确地表示希望对清洁程序(工序)进行验证以来，清洁程序的验证已引起厂普遍的重视。
本指南旨在通过讨论一些已被证明可行(或不可行)的实践来建议连贯一致的检查。
同时，应当认识到，清洁验证和其他程序验证一样，可能有诸多种的验证方式。
但对任何验证的检验都取决于科学数据是否表明该系统能始终如一地按预期的那样运行，而且产生的结果能—贯的符合预定的标准。
本指南只涉及对设备中化学残留物的清洁验证。
Ⅱ．背景对FDA来说，要求设备在使用前必须清洁并不是新规定，1963年药品生产质量管理规范(133．4)规定：“设备***应保持清洁有序的状态***。
”1978年现行药品生产质量管理规范(211.67)也有类似的关于设备清洁的叙述。
当然，要求清洁设备的主要原因是防止药品的污染或掺杂。
历史上FDA检查人员曾发现由于设备不够清洁，保养不当和(或)缺乏合格的灰尘控制系统而引起严重不卫生的情况。
同样，从历史上来说，FDA更关心青霉素对非青霉素药品的污染或药物与强效类固醇或激素类之间的交叉污染。
在过去十多年中，有许多产品由于存在或可能存在的青霉素交叉污染而被收回。
1988年对一种药物的成品——美国药典上的消胆胺树脂的回收，增加了FDA对因清洁程序不当而引起交叉污染可能性的警觉，用来生产该产品的化学原料药受到来自生产农业杀虫剂的中间体及其降解产物的污染。
这次的交叉污染被认为是由于重新使用回收溶剂造成的。
回收溶剂被污染是因为对重新使用溶剂桶控制不利。
溶剂桶曾用于储存杀虫剂生产过程中的回收溶剂，然后又被用于储存消胆胺生产过程中使用的回收溶剂。
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《美国FDA认证与申办指南》权威资讯系列清洗过程验证检查指南GUIDE TO INSPECTIONS VALIDATION OF CLEANING PROCESSES正大资询清洗过程验证检查指南GUIDE TO INSPECTIONS VALIDATION OF CLEANING PROCESSES请注意：本指南是检查官和其他FDA人员的参考材料。
本指南不受FDA约束，并没有赋予任何人任何权利、特权、收益或豁免权。
Note: This document is reference material for investigators and other FDA personnel. The document does not bind FDA, and does no confer any rights, privileges, benefits,or immunities for or on any person(s).I．介绍I. INTRODUCTION自从机构文件，包括原料药化学制剂检查指南和生物制剂检查指南，大体上提到该清洗问题以来，就出现了关于清洗过程验证的大量讨论。
这些机构文件清晰的建立了要验证的清洗过程需要达到的要求。
Validation of cleaning procedures has generated considerable discussion since agency documents, including the Inspection Guide for Bulk Pharmaceutical Chemicals and the Biotechnology Inspection Guide, have briefly addressed this issue. These Agency documents clearly establish the expectation that cleaning procedures (processes) be validated.本指南是为了通过讨论实际操作是可接受的(或不可接受的)，来建立检查要求的一致性和统一性。
同时，对清洗验证需要了解的是，像其他过程验证一样，可能有不止一种方法来对过程进行验证。
最后，任何验证过程的测试就是指科学数据是否显示出系统与要求相符和产生的结果是否符合预先定义的参数指标。
This guide is designed to establish inspection consistency and uniformity by discussing practices that have been found acceptable (or unacceptable). Simultaneously, one must recognize that for cleaning validation, as with validation of other processes, there may be more than one way to validate a process. In the end, the test of any validation process is whether scientific data shows that the system consistently does as expected and produces a result that consistently meets predetermined specifications.本指南只适用于化学残留物的设备清洗。
This guide is intended to cover equipment cleaning for chemical residues only.II．背景II. BACKGROUND对于FDA来说，要求设备在使用前进行清洗并不新奇。
1963GMP法规(部分133.4)中指出“设备***应该按照清洁和有序的方式进行维护***。
” 在1978 CGMP法规中也包含了非常相似的有关设备清洗的章节(211.67)。
当然，清洁设备的主要理由是防止药品被污染或掺假。
在历史上，FDA检查官寻找由于对设备不当的清洗和维护和/或不良的灰尘控制系统而带来的总体不卫生情况。
而且，从历史上来说，FDA对非青霉素药品中的青霉素污染或药品中的活性激素或荷尔蒙交叉污染更加关注。
有很多药品在过去十年中被撤回就是因为实际的或潜在的青霉素的交叉污染。
For FDA to require that equipment be clean prior to use is nothing new, the 1963 GMP Regulations (Part 133.4) stated as follows "Equipment *** shall be maintained in a clean and orderly manner ***." A very similar section on equipment cleaning (211.67) wasincluded in the 1978 CGMP regulations. Of course, the main rationale for requiring clean equipment is to prevent contamination or adulteration of drug products. Historically, FDA investigators have looked for gross insanitation due to inadequate cleaning and maintenance of equipment and/or poor dust control systems. Also, historically speaking, FDA was more concerned about the contamination of nonpenicillin drug products with penicillins or the cross-contamination of drug products with potent steroids or hormones. A number of products have been recalled over the past decade due to actual or potential penicillin cross-contamination.导致FDA对由于不满足要求的过程导致交叉污染的可能性的进一步关注的案例是，1988年对成品药消胆胺树脂USP的撤回。
用于生产成品的原料药被生产农用杀虫剂中产生的中间体和降解物污染。
本案例中的交叉污染被认为是由于回收溶剂的重新使用。
回收溶剂由于缺乏对溶剂桶的重新使用的控制而被污染。
用于储存杀虫剂生产过程中的回收溶剂的溶剂桶，后来又用于储存树脂生产过程的回收溶剂。
公司没有对这些溶剂桶进行适当的控制，而且没有对桶中的溶剂进行适当的测试，也没有对桶的清洗过程进行验证。
One event which increased FDA awareness of the potential for cross contamination due to inadequate procedures was the 1988 recall of a finished drug product, Cholestyramine Resin USP. The bulk pharmaceutical chemical used to produce the product had become contaminated with low levels of intermediates and degradants from the production of agricultural pesticides. The cross-contamination in that case is believed to have been due to the reuse of recovered solvents. The recovered solvents had been contaminated because of a lack of control over the reuse of solvent drums. Drums that had been used to store recovered solvents from a pesticide production process were later used to store recovered solvents used for the resin manufacturing process. The firm did not have adequate controls over these solvent drums, did not do adequate testing of drummed solvents, and did not have validated cleaning procedures for the drums.一些被杀虫剂污染的原料药后来被运输到另外一家在其他地方的工厂进行最后加工。
这导致了由于工厂的流体床干燥器被杀虫剂污染而把使用的包装袋污染。
结果导致了在该工厂地点生产的很多批次被交叉污染，该地点在正常情况下是不生产杀虫剂的。
Some shipments of this pesticide contaminated bulk pharmaceutical were supplied to a second facility at a different location for finishing. This resulted in the contamination of the bags used in that facility's fluid bed dryers with pesticide contamination. This in turn led to cross contamination of lots produced at that site, a site where no pesticides were normally produced.FDA在1992年对使用普通设备生产的活性激素产品和非激素产品的国外原料药生产商提出了进口警告。