STERIS
Rin sampling for Cleaning Validation Studies
清洁验证中淋洗取样法的研究
Destin A. Le Blanc
Rin-sampling procedures that draw from the final rin solution can provide upper-limit estimates of potential contamination in subquently manufactured products. The process can be improved by parating the process rin from the sampling rin. This may result in more accurate actual estimates, more flexibility in lecting analytical procedures, and more flexibility in choosing a sampling rin solution that is different from the process rin solution. Procedures for such determinations depend on adequate rin recovery studies. This article describes the studies.
野外玉石原石的鉴别
从最终淋洗溶液取样的淋洗液取样程序可以提供后续生产产品中潜在污染物的上限评估。该程序中也可将淋洗工艺和取样工艺分开。选择不同的更加灵活分析规程、选择与淋洗工艺不同的取样淋洗溶剂，均可以得到更准确的结果评估。这些检测程序均基于充分的淋洗回收率研究。本文即描述这些研究
Validation of cleaning process ud for product contact surfaces in pharmaceutical manufacturing is
required by FDA. The 1993 decision of US v. Barr Laboratories gave FDA the right to mandate that cleaning is a critical process that must be validated (1). Although this decision focud mainly on issues related to retesting after
out-of-specification results, it also held that FDA had the right in this ca to mandate validation of cleaning process. In July 1992, while this ca was being litigated, the agency’s Mid-Atlantic Region staff developed an internal inspection guideline for cleaning validation (2). In July 1993, the more official and still current “Guide to Inspections of Validation of Cleaning Process” was issued (3)
FDA要求药品生产中对于产品直接接触的表面清洁工艺必须进行验证。1993年美国Barr Laboratories案例（注1）的判决结果中赋予了FDA将清洁规定为关键工艺且必须经过验证的权利。尽管这次决议主要关注的是OOS后的复测相关问题，但仍可认为FDA在这次案例中获得了清洁工艺验证的授权。1992年7月，这场官司还在诉讼期时，中大西洋地区部门开发了清洁验证内部检查指南（注2）。1993年7月，更官方的并且现在仍通行的《清洁验证检查指南》发布了（注3）。
The 1992 Mid-Atlantic guide discuss three types of sampling: direct surface, rin,
and placebo. Direct surface is rated most desirable, rin is considered less desirable, and placebo i
s considered generally unacceptable. In the 1993 guide, although not explicitly stated, the relative ranking of the methods is assumed to hold —with direct surface being most desirable and placebo being acceptable only if direct surface or rin sampling is also done. Two reasons support the less-desirable designation for rin sampling. The first issue is whether the residue of concern is soluble in the rin solution. One analogy is that of a dirty pot. If the concern is whether or not a washed pot is clean, does one examine the rin water or the pot itlf? The cond concern is the analytical strategy ud. Some pharmaceutical companies previously analyzed the rin water and tested it merely for USP compendial specifications for purified water or for water for injection. FDA argued (quite rightly) that manufacturers should have a target residue and measure that target residue. It is possible that the rin water meets USP specifications and yet may not reasonably indicate contaminants in the rin water becau the target residue is prent either at a level or as a chemical species that cannot be adequately detected by USP water specifications.
1992年的中大西洋指南谈到了3种取样方法：表面直接取样、淋洗取样和安慰剂取样。表面直接取样被认为最优先考虑的，其次为淋洗取样，而安慰剂取样一般认为是不可接受的。在1993年的指南中，尽管没有明确的规定，但三种方法的优先级可以这样认为：表面直接取样为最合适的，安慰剂取样只有在结合直接取样或淋洗取样进行的情况下可以考虑。淋洗取样被认为次级可取的方法有两条原因。
第一个问题是，残留是否会溶于淋洗液中。类似的问题如：“脏点”。如果清洗点是干净的，是否只检查淋洗水或者清洗点本身？第二个问题是使用的分析策略。一些公司以前只检测淋洗水是否符合USP关于纯化水或注射用水法定标准。FDA主张（非常肯定）生产商必须确定测试的目标残留物。淋洗水有可能符合USP水的标准但不能表示其中的污染物符合要求，因为目标残留有可能在USP检测标准水平以下或未经充分检测的化学种类。
The 1993 document does offer some guidance on acceptable residue levels by citing a paper from scientists at Eli Lilly about their procedures for tting residue limits (4). The residue limits are bad on the possible contamination of product subquently manufactured in the same equipment. The Eli Lilly scientists propod limits in the subquent product that would produce 0.001 of a minimum daily do of the drug
爱眼征文residue in a maximum daily do of the next drug product. They also propod that if the calculated value bad on the 0.001 daily do is more than 10 ppm, then a default value of 10 ppm residue in the subquent product should be ud.
1993年的文件中引用了一些残留物限度可接受标准，这些标准来自礼来科学家在生产中残留限度设定的文献（注4）。这些残留限度基于使用同一台设备生产可能带入后续生产的污染物。礼来的科学家
建议，后一批产品最多日治疗量中允许带入的前一批产品量不得超过前一批产品的日最低治疗量的1/1000，以此作为确定残留的限度。他们同时建议，如果按0.001日治疗量的计算值超过10个ppm，则应使用10ppm作为标准。
Bad on possible contamination of the subquent product, it is then possible to calculate — using parameters such as batch size, surface area, and sampling technique — items such as allowable contamination per surface area or per swab sample. Although swab-sampling residue limits have been discusd in numerous papers (5,6,7), rin sampling has not been covered as rigorously.
基于后续产品中可能的污染物，建立残留限度时可以考虑批量、表面积、取样手法、单位面积污染物量或每擦拭量。尽管擦拭取样残留限度在很多文献（注5,6,7）中都被论述过，但淋洗取样仍未被严格的讨论过。
Bad on the author’s experience, manufacturers have often made assumptions about acceptable rin water limits without adequate consideration of the potential for contamination of the subquently manufactured product. In many cas, a rin water limit of 10 ppm has been automatically lected and assumed to reprent an acceptable residue limit in the rin solution. The rest of this article focus on the critical relationship between rin-sampling results and potenti
al contamination of the subquent product. Issues covered include rin sampling as it is currently done (i.e., grab sample at the end of the rinsing process), rin-sampling process that may provide more scientifically justified residue limits, and methods that may adequately determine rin-sampling recovery.
陈伟霆女朋友根据笔者的经验来看，一些生产商经常在设定淋洗水限度可接受标准时，未充分考虑到对后续生产带来的潜在污染。在很多案例中，10ppm通常被作为淋洗水残留物限度可接受标准。这篇文章的其余部分关注淋洗取样结果和后续产品中潜在的污染物之间的重要联系。涉及的问题包括淋洗同步取样阶段（比如在淋洗工艺的最后一步取样）、淋洗取样工艺应规
定更加科学的和合理的残留限度，淋洗取样方法同样要充分测试其回收率。
SINGLE-POINT FINAL-RINSE SAMPLING
单点最终淋洗取样
In this method, manufacturers obtain a sample at the end of the final rinsing process. If the rinsing medium is water, then this is obviously a water sample; if a solvent is ud for the final rin, then this is a solvent sample. The volume of rin sample taken will depend on the analys done but typi
cally is in the 500–1000mL range. The sampling point is usually identified as that point at the end of the cleaning circuit at which the water exits the cleaning circuit. Assuming that a specific residue is targeted, as FDA recommends, what does it mean if a chemist measures a target residue in the grab sample and measures a level of, for example, 5 ppm? Can it be reasonably assumed that a level of 5 ppm in this rin sample corresponds to a potential contamination of 5 ppm in the subquent product? The existing literature for cleaning validation does not provide a ries of calculations to go through, such as with swab sampling, that can lead to a scientifically bad correlation between rin sample analysis and potential contamination of the subquently manufactured product.桃树的介绍
制服英语通过此方法，生产商得到最终淋洗阶段的样品。如果淋洗介质为水，那么这明显是一份水样，如果最后淋洗使用的是一种溶剂，那么样品即为溶剂样品。淋洗样品体积一般按检测用量来取，不过通常在500~1000ml。根据淋洗水流经设备的线路，选择淋洗线路相对最下游的一个点为取样点。如果残留已知，根据FDA建议，如果化验员检测的目标残留水平为，如5ppm说明什么？淋洗水中残留物水平为5ppm是否相当于后续产品中的潜在污染物也为5ppm？不像擦拭取样，目前关于清洁验证的文献未给出淋洗液残留和后续产品潜在污染物的相互关系的详细计算公式。
How can this relationship be established? For swab samples, factors such as batch size of subquent product, shared surface area, area sampled, and amount of solvent ud for desorbing t
he swab must be considered to obtain an accurate relationship between the analytical result in the desorbed swab sample and the corresponding contaminant levels in the subquent product. What are the corresponding factors for rin samples? How do the factors relate to what is really of interest — that is, potential contamination of the next product?
这种相互关系怎么建立？已擦拭样品为例，后续产品的批量，共享接触表面积，取样面积以及用来溶解拭子上残留物溶剂的量等因素在获得擦拭取样分析结果和后续产品相应的污染物水平相互关系时必须考虑到。相应的，淋洗取样需要考虑的因素是什么？这些因素如何和下次产品中的潜在污染物联系起来？
不言而喻是什么意思>我们再也回不去了对不对One way to establish a relationship is to make assumptions about what rinsing reprents. The first and critical assumption is that the target residue as it exists on the equipment surfaces is solubilized in the rin solution by the rinsing process. If this is true, then the levels found in the rin are indicative of the levels on the equipment surfaces. The cond assumption is that the rin process adequately cleans all surfaces and any sample measured is therefore reprentative of the entire system. It should be noted that the notion of worst-ca locations does not apply to cleaning validation rin sampling becau the entire product contact surface is sampled. Several more assumptions that depend on the types of rinsing process will be discusd later.
写老师的诗
建立这种相互关系首先要清楚淋洗的前提。首要是存在于设备表面的目标残留物在淋洗工艺中是否可以溶于淋洗溶剂中的。如果的确可以，将淋洗液中污染物水平表述为设备表面污染物水平。其次是淋洗工艺是否充分的清洁了所有表面，并且测量的样品也是整个系统中具有代表性的。应注意，最难清洗点概念在清洁验证中的淋洗取样是不适用的，因为整个产品接触的表面都已经被取样了。基于其他一些类型的淋洗工艺稍后讨论。
Two scenarios of interest are possible. The first ca involves a continuous rin process, such as would be found in a CIP operation. The other process involves discrete rins or batch rinsing. Batch rinsing is considered first becau it is the simpler of the two. In a batch-rinsing process, the manufacturing equipment is filled with rin solution, the solution is circulated or otherwi agitated until it is uniform, and then it is dumped. For rin sampling, a portion of that final rin is sampled, and then that sample is analyzed for the target residue. If X liters are ud in the final rin, the subquently manufactured product is made with a batch size of Y liters, and Z ppm (adjusted by a recovery factor that will be discusd later) residue is measured in the last rin, then the level of residue C that can potentially contaminate the subquent product can be reasonably assumed to satisfy the following limit:
C≤ (Z)(X) ÷ (Y) [1]
