[技术帖] 散装粉末物料取样规则 - 中文翻译稿 (2之2)




Types of Systems andGeneral Considerations 粉体类型和主要关注点

homogeneous systems 均一粉体

For powder systems where the attribute of interest is uniformly distributed throughout the container—so that any sample is an unbiased representation of the entire container, lot, or population of interest—scoop sampling is adequate. Scoop sampling is a straight forward procedure in which the operator,after selecting representative containers for sampling, opens a container, scoops out a sufficient amount of material from the top of the powder bed, and then seals the container. If a thin layer of material on top of the powder bed is suspected of being different from the bulk, samples should be taken from a point below this top layer. For example, in cases of elutriation segregation, a thin layer of fine particles may lie on top of the powder bed, and the operator should dig down into the powder bed to avoid sampling from this layer. The scoop should be large enough that no material is lost during handling, because lost material may result in sample bias. In other words, one should avoid the use of a heaping scoop from which material can roll off the sides. The advantages of scoop sampling are convenience and cost, and, for highly potent materials, low-cost disposable scoops that can be used to minimize cross-contamination.


heterogeneous systems 非均一粉体

If the attribute of interest is spatially distributed in a heterogeneous manner throughout the sample, then scoop sampling is prone to potentially significant errors. Scoop sampling is a non-probabilistic method because only the most accessible fraction of the container is sampled. Obviously, only the material in the top layer can be reached with a scoop. For example, a sample from the top outer edge of the drum shown in Figure 3 could be biased because, in this example, the larger particles are preferentially distributed toward the top and outer edges of the drum. Hence the smaller particles have a lower probability of appearing in the sample. As aresult, the smaller particles will be underrepresented in the sample, and any analysis of particle size will not reflect the true particle size distribution of the original population.


Forheterogeneous systems, the initial primary sample is the most difficult toobtain. Use of a sampling thief, sometimes called a grain probe or samplingspear, is needed. The advantage of a sampling thief is that much more of thepowder bed is accessible because the sampling thief can sample from differentpoints in the powder bed, thus helping to reduce sampling bias. Many types ofsampling thieves are available, including: (1) the concentric sleeve withslotted compartments, (2) the concentric sleeve with grooves, sometimes called theopen-handled probe, (3) the end sampler, and (4) the core sampler. Each typehas its own unique operating procedures, as described below.


general considerations 主要关注点

The most reliable and reproducible results in powder size measurements are obtained when the particle size ranges from 2 to 10 µm; otherwise, the powder is too cohesive and does not flow properly into the sampling thief. In addition, particles larger than about one-third the width of the slot give poor results. Samples should be taken from several sites throughout the container. The probe should be long enough to penetrate at least three-quarters of the depth of the powder bed, ensuring that material from all depths can be captured in the sample. The choice of sites should be dictated by an understanding (often subjective) of the powder bed's degree of heterogeneity, which may have been caused by handling or movement during transport. Sampling plans can call for the insertion of the probe either at random locations and random angles or at predetermined locations and angles. For example, the plan may call for the probe to be inserted at the center and at two locations near the edges. Also,many operators recommend that probes always be inserted at a 10° angle from vertical, which increases the range of locations sampled.


Some of the disadvantages of sampling thieves include the labor-intensive nature ofthe procedure. The probe must be physically inserted into the powder bed, often multiple times; the contents of the probe must be emptied; and then the probe must be thoroughly cleaned. For settled powder beds, the sampling probe can be difficult to insert. In addition, the sampling probe can introduce errors as aresult of the following: fine particles can lodge between the inner and outer tubes; particles can fracture; fine particles can compact and not flow well into the sampling compartments; segregation can occur during flow into the sampling zone; and the act of inserting the probe can disrupt the powder bed by dragging powder from the top layers of the bed down through the bed.


Representative Lot Sampling 有代表性的批取样

Statistically-based sampling plans are based on statistical principles and depend on the population’s spatial heterogeneity and intrinsic variability. Statistically-based plans are efficient and allow the collection of a sufficient number of samples to yield the desired degree of certainty without collecting too many or too few samples for the test method, scale, product variation, risk requirements, and tolerance for a stated product’s quality level or specification. The commonly used √N + 1 sampling plan given in Table 1 is not a statistically based sampling plan and may result in collection of too few samples for small populations and too many samples for large populations. The use of statistically-based sampling plans is advantageous because it facilitates risk management. However, in cases where prior knowledge of the population to be sampled is insufficient, a nonstatistical sampling plan suchas that given in Table 1 canbe considered.

基于统计学原理的取样(简称:统计取样)计划要基于统计学原则,且要考虑整体的空间不均一性和(颗粒)内在离变。统计取样计划应允许收集多份(既不是太多也不是太少)样品以满足一系列因素的不确定度,这些因素包括方法、批量、产品变异、风险要求和特定产品质量水平/标准接受限度。表1中通常应用的 √N + 1 取样计划并非统计取样方案,可能导致对于少量物料收集太少样品,而大量物料又收集太多样品。应用统计取样计划是有益的,因为这种方式采用了风险管理。然而,如果对于待取样品基本信息不甚了了,则如表1的非统计原理的取样计划就可以考虑采用了。Figure 4 illustrates the sample size selection scheme paths. The first choice is whether to use a statistical or nonstatistical sampling plan. Statistical plans are preferred when a variable attribute like particle size or drug content is being determined. General sampling approaches are outlined in USP general information chapter Analytical Data—Interpretation and Treatment 〈1010〉.Statistically-based lot acceptance sampling plans require a valid rationale with known quality levels for the determination of product lot characteristics. As noted, the application of statistical sampling plans, including lot acceptance sampling plans, requires specific and thorough knowledge of the material being sampled. Reference statistical sampling plans state the rationale for sampling as part of the sampling scheme. Manufacturers who use astatistically-based lot acceptance sampling method should refer to an appropriate standard such as ANSI/ASQ Z1.9-2003 for bulk materials or ANSI/ASQZ1.4-2003 for multiunit or discrete populations. These standards are readily available via sources such as the American Society for Quality ( the American National Standards Institute (

图4展示了选择样品量的路线图。首先考虑是否采用统计取样或非统计取样计划。当需检测变异属性,如颗粒度或药品含量时,则建议考虑统计取样计划。通用取样方法在USP general information chapter <1010> 分析数据--演绎和处理中有阐释。统计取样计划具体限度要求应基于有效的原理,这个有效原理建立在被测批产品已知的待测属性的质量水平上。如所提示,包括取样限度的统计取样计划的应用,要求对被取样物料信息有详细全面的掌握。还应把取样原理列入取样计划作为取样计划的一部分。应用统计取样的生产厂家可参考一个合适的标准,如针对散装物料取样的标准ANSI/ASQ Z1.9-2003 ,或针对多包装的分装物料取样标准ANSI/ASQ Z1.4-2003。这些标准可通过美国质量协会(或美国国家标准中心 (获取。

Figure 4. Sample size selection scheme. 样品量选择路线图

If one is developing a nonstatistical sampling plan for which the quality level is not known, Table 1 gives suggested sample sizes for the number of containers in the lot that should be sampled.


The Level 1 sampling plan is relevant to materials when heterogeneity does not affect the analysis and the customer seeks to sample more than one container, when the sampling plan can be proportional to the square root of the number of containers received, and when the material comes from a known and trusted source. In such cases, the sample can be withdrawn from any point in the container. For adequately homogenous systems, scoop sampling from the top of the container is suitable.


The Level 2 sampling plan involves a 50% increase in sample size when compared with Level 1 and is used when a larger proportion of the number of containers is needed, for example, when a material’s heterogeneity is suspected of being consequential and acceptance sampling quality levels are not defined, or when the material comes from a less trusted source. Depending on the material's degree of heterogeneity, a sampling thief may be used. However, if the degree of heterogeneity will not significantly affect the results for the attribute being sampled, then scoop sampling from the top of the drum may still be suitable.


Table 1 shows the number of containers, n, to be sampled for a lot segregated into N containers. Note that the value of n from the formula is rounded at 0.5 up to the next higher integer. For example, if N = 6: for Level 1, n= √6 + 1 = 3.45 rounds to n = 3; for Level 2, n= 1.5 × √6 = 3.67, which rounds to n =4.

表1展示了样品包装数目,n,代表整批分散到N个分包装。注意公式中n值逢5方进位。比如,如果N=6,则根据水平1,n = √6 + 1 = 3.45 ,修约为3,根据水平2,则n = 1.5 × √6 = 3.67,修约为4(译者按:全进位法则在国内是可取的,适于口算而不必精确到小数点后一位).

Table 1

These initial decisions, as illustrated in Figure 4, are often difficult and sometimes must be made without sufficient information. If there is uncertainty about which method or level is appropriate, sometimes a quick, small-scale informal test of the system may help determine the best way to proceed. In addition, for some systems and attributes, the Level 1 and Level 2 sampling plans may result in over sampling. For example, when one is sampling for identification from the same lot, the suggested levels may result in collecting more samples than are statistically needed; in such cases, the statistically-based sampling plans referenced in Figure 4 canbe used.


Sample Collection 样品收集

Acquiring a representative sample from a lot of bulk powder is a difficult procedure that requires special consideration, and the basic procedures for acquiring are presentative sample are discussed below. Note that every situation requires techniques that are appropriate for the given population to be sampled. The methods presented here are applicable to the sampling of static powders stored in midsize bulk containers such as 1-ton super sacks, 50-kg drums, or 50-lb bags. These methods are not necessarily applicable to the sampling of liquids, large storage containers such as train cars or silos, or in-process systems such as blenders or moving conveyer belts. In addition, the procedures described here are most applicable to particles in the size range from approximately ~1 µm to approximately ~1000 µm. Significantly smaller or larger particles require special procedures that are not covered here.



Lot acceptance samples are generally transferred or delivered in containers. To collect a representative primary or gross sample (see Figure 1), the appropriate container or containers must first be selected from the population of N containers; second, a representative sample must be withdrawn from each of the selected containers.


Container Selection 包装挑选

To avoid bias and other sampling errors, the containers to be sampled must be randomly selected. To make a random selection, first number all containers in the lot, then use a random number table (or computer-generated random numbers) to choose from which container or containers to withdraw the samples.


For systems in which containers are grouped together in such a manner that many of the individual containers are not practically accessible (e.g., 50-lb bag sstacked and bound in shrink wrap on a pallet), the sampling plan may need to take into account the larger container, in addition to the smaller container, as a sampling unit, in order to ensure a representative sample.


Withdrawing Sample from a Container 从包装中取出样品

container types 包装类型

The three most popular container types are the bag, drum, and super sack. Because bags are generally closed and not resealable, special sampling thieves, sometimes called bag triers, have been designed to puncture the bag. If the system to be sampled is heterogeneous, the samples should be obtained from the bottom, center, and top of the bag; and, depending on how the bags are stacked on the pallet, they should also be sampled from the front and the back. When sampling from bags, particular attention should be paid to the corners, becausethey can disproportionately trap fine particles. If no bag trier is available,use a knife to cut open the bag for sampling. When sampling from a bag, be sure to clean the external surface sufficiently that the sample is not contaminated and foreign material is not introduced into the bulk material. Once the sample has been taken, place a compatible material over the hole in the bag, then fix this patch with an appropriate adhesive tape. Depending on the heterogeneity of the drum, a scoop or a sampling thief is used. Super sacks are large sack containers that usually have a fill spout on the top and a discharge spout on the bottom. For adequately homogeneous material, scoop sampling is appropriate;but if there is any concern about the heterogeneity of the material, a thief should be used. The large size of super sacks makes the use of a thief more important for representative sampling than in the case of a drum or bag, in order to limit potential delimitation error.


Sample Handling 样品处理The samples collected can be either assayed individually or combined; then a subset of the gross sample can be assayed, as depicted in Figure 1 and described below. Sample increments should be combined on a clean, dry surface or in a suitable container or bag. All containers with which the sample comes into contact should be inert and should not chemically or physically react with the sample. In addition, samples should be accurately labeled and good records kept. A portion should be kept for possible future analysis.


PRIMARY SAMPLE SIZE REDUCTION 缩减一级样品量As mentioned above, the primary sample typically consists of multiple samples taken from containers and mixed together. To obtain an analysis or measurement sample (Figure 1), the gross or primary sample must be reduced to a size appropriate for the analytical method. Gross or primary sample size reduction is an often overlooked as pect of a sampling plan, but it is an important step. The factors that cause segregation in a container can also cause segregation in the primary sample, and any bias in the size reduction method for the primary sample will lead to erroneous results. The advantage of secondary samples is that the mass has been reduced to a point at which it is much easer to obtain are presentative sample because every element in the powder bed is readily accessible. Such accessibility makes it easier to adhere to sampling best practices. Generally speaking, sample measurement takes place under either wet or dry conditions; the choice is dictated by the requirements of the analytical method. For example, the Coulter counter requires that samples be uniformly suspended in an electrolyte, but other methods, like sieving, are typically performed with dry powders.

如前所述,一级样品通常由来源于不同包装中的许多样品混合而成。为了获取分析样品(见图1),总样品或一级样品必须缩减到合适的样品量以适用于对应的分析方法。总样品或一级样品缩减经常是取样计划中被忽视的一个方面,但却是个重要的步骤。在包装内导致离散的因素在一级样品中同样可能出现,一级样品量缩减方法中的任何偏离都可能导致错误的分析结果。二级样品的好处在于重量已经减低到容易获得有代表性样品的程度,因为每个粉体的部分都容易获取。这种易获取性使落实优良取样法则变得简单。一般而言,样品检验在干或湿的背景下进行;这种选择由分析方法本身的描述限定。比如,粒子计数器要求样品均匀分散在电解液中,而其他方法比如筛分法,一般以干粉的形式被检测。Before dividing an agglomerated sample, the agglomerates should be broken apart by asuitable technique such as sieving.


Dry Analysis Methods 干法分析方法(的分样)Many laboratory devices are available for the reduction of the primary sample to ananalytical sample. The three most important methods used in the pharmaceutical industry are: (1) scoop sampling, (2) cone and quartering, and (3) the spinning riffler or rotary sample divider (manual method of fractional shoveling); see Figure 5.


Figure 5. Two procedures for dividing samples. Top: spinning riffler, in which a circular holder rotates ata constant speed, and the sample is loaded at a constant rate into the containers via a vibratory chute, which is fed by a mass-flow hopper. Bottom: cone and quartering. (Cone, left, is flattened and quartered; quarters can be formed into cones and further subdivided.)

图5. 两个分样程序。上面的:旋转槽分样法,其中有一个旋转槽以恒定速度转动,样品以恒速从漏斗中流下并从斜坡振落到旋转槽中。下面的:锥体四分法(左边锥体摊平后四分;每个四分体可以再形成锥体二次四分)。

scoop sampling 舀取分样法

Scoop sampling is done as previously described, but generally with a smaller scoop orspatula. Great care must be taken when removing material from the primary sample, because this material could be highly segregated as a result of handling. Scoop sampling is appropriate for homogeneous or cohesive powders. However, if the powder is prone to segregation, scoop sampling can introduce significant errors. Moreover, scoop sampling has several serious disadvantages. First, the method depends on the operator’s deciding from which part of theprimary sample to scoop the material and what quantity of the sample toextract, which are features that can introduce operator bias. Second, in scoop sampling, operators have a natural tendency to withdraw the sample from the free surface, which is highly prone to segregation and is not representative of the bulk. Third, operators need to avoid creating a heap where rolling segregation can occur, because material could fall off the edges of the spatulaor scoop and bias the sample. Ideally, the operator should make some attempt to mix the primary sample before using the scoop, but this too can exacerbate segregation problems and should be done only with great caution.


cone and quartering 锥体四分法Cone and quartering is done by pouring the primary sample into a symmetric cone on a flat surface. The cone is then flattened by a flat surface such as a spatula,and is divided into four identical quarters (Figure 5). One quarter is taken as the sample. This procedure can be repeated (e.g.,quarter-samples can be subdivided into quarters) until the desired sample sizeis obtained. The theory of this method is that when a symmetric cone is created, all the segregation processes also occur symmetrically around the cone, and hence symmetry is used to mitigate the effect of segregation. In practice, it is very difficult to actually make a symmetric powder cone, and the method becomes very operator-dependent and often unreliable. Differences in how operators form the heap and subdivide it can lead to a lack of precision and significant errors. In addition, if the method is done more than once, errors can propagate each time the cone and quartering is performed. Some experts do not recommend this method.


spinning riffler 旋转槽法As pinning riffler (Figure 5) includes a series of containers mounted on a circular holder. The circular holder rotates at a constant speed, and the sample is loaded at a constant rate into the containers via a vibratory chute, which is fed by a mass-flow hopper. Once the material has been divided among the different holders, an individual holder can be removed for testing or further sample division. The angular velocityof the circular holders and the amplitude of the vibratory feeder can be controlled to accommodate powders with different flow properties. The holder velocity and feed rate should be adjusted so that the containers fill uniformly and so that a heap does not form on the vibratory feeder. Spinning rifflers are available in different sizes, making possible subdivisions of powders ranging from a few milligrams to hundreds of grams. The only drawbacks of the spinning riffler are the time required to process the sample and clean the device, and the capital expense. Despite these minor disadvantages, the spinning riffler isby far the best method for subdivision of free-flowing powders.

图5旋转槽包括一系列在旋转器上放置的小盒。旋转器恒速旋转,样品以恒速从漏斗落下,再通过振动斜坡落入小盒。一旦物料被分散到不同的盒子,某个单一的盒子可以被取下作为样品,或进行进一步的分离。旋转角速度和振幅是可控的,以适应粉末不同的流动性。支撑器的旋转速度和漏斗下料速度应调整到合适,保证小盒被均匀装料,且振动斜坡也不会堆积样品。旋转槽有不同的尺寸,可以适应几毫克到数百克样品的二次分离。唯一缺点就是需要时间处理样品和清洁装置,并且价格较贵。除了这些小缺点,对于流动性强的粉末这是远胜于其他的最佳分样方法。Fractional shoveling is the manual version of the spinning riffler. In this method, scoop samples are taken from the original sample and placed into a sufficient number of aliquots, and then subsequent scoops are taken from the original sample and placed into one of the aliquots in sequential order. This process is repeated until the original samples are gone. Then one of the aliquots is randomly taken as the reduced sample. As is the case with all manual methods, operator error and variability can be significant factors.

片段铲分(旋转分样器法)是旋转槽的手工版本。本法中,从原样中铲取样品,平均配置到足够的(旋转)小格中,然后再次从原样中获取样品并同法按序配置,直到原样分配完毕后随机取出一份作为二级样品。由于本法中所有操作人工完成,操作误差和变异可能成为重要影响因素。Wet Analysis Methods 湿分析法(的分样)Wet analysis methods require dispersing the sample in a liquid suitable for analysis, and then withdrawing an aliquot using a syringe or pipet. Effective secondary sampling requires making a stable homogenous suspension (i.e., the sample must be stable from the time of formation of a suspension to the time when the analysis is complete). Some important factors in wet analysis are sample solubility in the dispersion vehicle, aggregation of sample, the use of suspending agents, and deaggregation of primary particles in the dispersion vehicle. Even though a uniform suspension is created, the sample should b ehomogenized, typically by shaking, immediately before withdrawing the sample with a syringe or pipet. The diameter of the syringe or pipet should be large enough so that particles are not excluded and clogging does not occur. The diametersof the largest particles should not exceed 40% of the syringe or pipet tip diameter. If for practical reasons the amount of material from the primary sample is too large, the sample size should be reduced before a suspension is made. To reduce the sample size, use the methods described above in the Dry Analysis Methods section. As a precaution, collect and retain enough sample to repeat all tests a minimum of five times.