ASTM E2810-2011e1 Standard Practice for Demonstrating Capability to Comply with the Test for Uniformity of Dosage Units《证明符合剂量单位一致性试验能力的标准操作规程》.pdf

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1、Designation: E2810 111Standard Practice forDemonstrating Capability to Comply with the Test forUniformity of Dosage Units1This standard is issued under the fixed designation E2810; the number immediately following the designation indicates the year oforiginal adoption or, in the case of revision, th

2、e year of last revision. A number in parentheses indicates the year of last reapproval. Asuperscript epsilon () indicates an editorial change since the last revision or reapproval.1NOTEEditorial corrections made throughout in February 2013.1. Scope1.1 This practice provides a general procedure for e

3、valuat-ing the capability to comply with the Uniformity of DosageUnits (UDU) test. This test is given in General Chapter Uniformity of Dosage Units of the USP, in 2.9.40 Uniformityof Dosage Units of the Ph. Eur., and in 6.02 Uniformity ofDosage Units of the JP, and these versions are virtuallyinterc

4、hangeable. For this multiple-stage test, the procedurecomputes a lower bound on the probability of passing the UDUtest, based on statistical estimates made at a prescribedconfidence level from a sample of dosage units.1.2 This methodology can be used to generate an acceptancelimit table, which defin

5、es a set of sample means and standarddeviations that assures passing the UDU test for a prescribedlower probability bound, confidence level, and sample size.1.3 This standard does not purport to address all of thesafety concerns, if any, associated with its use. It is theresponsibility of the user o

6、f this standard to establish appro-priate safety and health practices and determine the applica-bility of regulatory limitations prior to use.2. Referenced Documents2.1 ASTM Standards:2E2363 Terminology Relating to Process Analytical Technol-ogy in the Pharmaceutical IndustryE2709 Practice for Demon

7、strating Capability to Complywith an Acceptance Procedure2.2 Other Documents:JP Japanese Pharmacopoeia3Ph. Eur. European Pharmacopoeia4USP United States Pharmacopeia53. Terminology3.1 DefinitionsSee Terminology E2363 for a more exten-sive listing of terms in ASTM Committee E55 standards.3.2 Definiti

8、ons of Terms Specific to This Standard:3.2.1 acceptable parameter region, nthe set of values ofparameters characterizing the distribution of test results forwhich the probability of passing the lot acceptance procedureis greater than a prescribed lower bound.3.2.2 acceptance limit, nthe boundary of

9、the acceptanceregion, for example, the maximum sample standard deviationfor a given sample mean.3.2.2.1 DiscussionThe coefficient of variation (relativestandard deviation) may be substituted for the standard devia-tion where applicable.3.2.3 acceptance region, nthe set of values of parameterestimate

10、s (that is, sample mean and standard deviation) whereconfidence limits attain a prescribed lower bound on theprobability of passing a lot acceptance procedure.3.2.4 confidence level, C, nthe prescribed overall level forcalculating the uncertainty region of the parameters from thesample estimates.3.2

11、.4.1 DiscussionThe preset confidence level is stated asa percentage, for example, 100 (1 ) = 95 %, where is arisk that is allocated to the two parameters being estimated.1This practice is under the jurisdiction of ASTM Committee E55 on Manufac-ture of Pharmaceutical Products and is the direct respon

12、sibility of SubcommitteeE55.03 on General Pharmaceutical Standards.Current edition approved Oct. 1, 2011. Published December 2011. DOI:10.1520/E2810-11.2For referenced ASTM standards, visit the ASTM website, www.astm.org, orcontact ASTM Customer Service at serviceastm.org. For Annual Book of ASTMSta

13、ndards volume information, refer to the standards Document Summary page onthe ASTM website.3Available from the Pharmaceuticals and Medical Devices Agency, Japan,http:/jpdb.nihs.go.jp.4Available from the European Council, Strasbourg, France, http:/www.edqm.eu.5Available from U.S. Pharmacopeia (USP),

14、12601 Twinbrook Pkwy., Rockville,MD 20852-1790, http:/www.usp.org.Copyright ASTM International, 100 Barr Harbor Drive, PO Box C700, West Conshohocken, PA 19428-2959. United States13.2.5 lower probability bound, LB, nthe nominal probabil-ity of passing the UDU test for a given set of parameterestimat

15、es.3.2.6 multiple-stage acceptance procedure, na procedurethat involves more than one stage of sampling and testing agiven quality characteristic with one or more acceptancecriteria per stage.3.2.7 representative sample, na sample that consists of anumber of units that are drawn based on rational cr

16、iteria suchas random sampling and intended to assure that the sampleaccurately portrays the material being sampled3.2.8 sampling plan, nscheme for selecting dosage unitsfrom locations within a batch for testing purposes.3.2.8.1 DiscussionIn this standard, a single dosage unit isselected from each ba

17、tch location.3.2.9 uniformity of dosage units, UDU, nthe degree ofuniformity in the amount of the drug substance among dosageunits.3.2.9.1 DiscussionThe requirements of the UDU test ap-ply to each drug substance in dosage units containing one ormore drug substances, unless otherwise specified. The u

18、nifor-mity improves as the variability decreases.4. Significance and Use4.1 The methodology was originally developed (1-4)6foruse in drug content uniformity and dissolution but has generalapplication to any multistage test with multiple acceptancecriteria. Practice E2709 summarizes the statistical a

19、spects ofthis methodology. This practice applies the general methodol-ogy of Practice E2709 specifically to the UDU test.4.1.1 While other methods can be used to estimate theprobability of passing the UDU test, they are outside the scopeof this practice.4.2 The UDU test procedure describes a two-sta

20、ge samplingtest, where at each stage one can pass or continue testing, andthe decision to fail is deferred until the second stage. At eachstage there are acceptance criteria on the test results as outlinedin Table 1.4.3 The UDU test is a market standard. The USP GeneralNotices include the following

21、statement about compendialstandards. “The similarity to statistical procedures may seem tosuggest an intent to make inference to some larger group ofunits, but in all cases, statements about whether the compendialstandard is met apply only to the units tested.” Therefore, theUDU procedure is not int

22、ended for inspecting uniformity offinished product for lot/batch release or as a lot inspectionprocedure.4.3.1 The UDU test defines a product requirement to be metat release and throughout the shelf-life of the product.4.3.2 Passing the UDU test once does not provide statisticalassurance that a batc

23、h of drug product meets specified statis-tical quality control criteria.4.4 This practice provides a practical specification that maybe applied when uniformity of dosage units is required. An6The boldface numbers in parentheses refer to a list of references at the end ofthis standard.TABLE 1 Uniform

24、ity of Dosage Units Test ProcedureNOTE 1All measurements of dosage units and criteria values are inpercentage label claim (%LC).At each stage calculate the sample average,X, and the sample standard deviation, s.StageNumberTestedPass Stage If:S110 |M X|+2.4s 15.0, where M isdefined below.S220 (1)|M X

25、|+2.0s 15.0, using all30 results (S1+S2).(2) No dosage unit is outside themaximum allowed range of0.75 * M to 1.25 * M.M is defined as follows:If T is less than or equal to 101.5 %LC, and(1)IfXis less than 98.5 %LC, thenM = 98.5 %LC.(2)IfXis between 98.5 and101.5 %LC, then M = X.(3)IfXis greater tha

26、n 101.5 %LC,then M = 101.5 %LC.If T is greater than 101.5 %LC, and(1)IfXis less than 98.5 %LC, thenM = 98.5 %LC.(2)IfXis between 98.5 and T, thenM = X.(3)IfXis greater than T, thenM = T.T is the target content per dosage unit at the time of manufacture, ex-pressed as %LC. Unless otherwise specified

27、in the individual monograph, Tis 100.0 %LC.E2810 1112acceptance region for the mean and standard deviation of a setof test results from the lot is defined such that, at a prescribedconfidence level, the probability that a future sample from thelot will pass the UDU test is greater than or equal to a

28、prespecified lower probability bound. Having test results fall inthe acceptance region provides assurance that a sample wouldpass the UDU test with at least the specified lower boundprobability. This procedure does not account for any decreasein potency during the shelf life, which could affect the

29、abilityto meet the UDU test requirements.4.5 This practice can be used as an element for processdemonstration or validation, continuous process verification,in-process testing, or lot release (acceptance). As the circum-stances and available information vary in these differentapplication areas, this

30、 practice does not prescribe a specifictarget, sample size, lower probability bound, or confidencelevel. These must be prospectively selected by the user andmay be different from those used in the acceptance limit tablesprovided in this practice.5. Procedure5.1 Generating The Acceptance Limit Table:

31、5.1.1 The general procedure that generates the acceptancelimit tables is described in Practice E2709 and the specificprocedure for application to the UDU test is described in theliterature (4). A simplified description on the construction anduse of these tables is given in this section.Acomputer pro

32、gramis required to generate the tables given a target T as apercentage of label claim (LC), a lower probability bound LB,a confidence level C, and a sample size n.5.1.2 The first step is to determine the acceptable parameterregion. On a two-dimensional content space consisting of thetrue mean () on

33、the horizontal axis and standard deviation ()on the vertical axis the upper boundary of this region is definedby a contour, a curve that is concave downward and depictedby the solid curve in Fig. 1. The contour is determined by theLB probability and the Target under the assumption that thedosage uni

34、t content is normally distributed. The acceptableparameter region is the set of points on or below the contour.Any (, ) pair in the acceptable region would pass the UDUtest with a probability of at least the LB.5.1.3 The second step is to generate the acceptance limitcurve. The sample mean (X) and s

35、ample standard deviation (s)estimate the population parameters and within C %NOTE 1All points below the lower bound contour have higher than a 95 % chance of passing UDU test if mean and standard deviation are known.All points below the acceptance region contours pass the associated acceptance limit

36、 table for n = 100 and n = 10.ULS is the upper confidence limit for .Z is a standard normal critical value.FIG. 1 Example of Simultaneous Confidence Interval with 95 % Lower Bound and Acceptance RegionsE2810 1113confidence limits as chosen by the user. The joint confidenceregion for and (5) has the

37、shape of an inverted trianglearound a (X, s) pair as depicted in Fig. 1 with the lowest vertexat (X, 0). A value of Xis selected starting with s = 0, then theconfidence region is expanded by increasing s until one of theupper vertices just touches the acceptable parameter region.The size of the conf

38、idence region is determined by C and n.This value of s defines a point on the acceptance limit curve at(X, s). Additional selections of Xthen generate the acceptancelimit curve, as depicted as dotted lines in Fig. 1. Acceptancelimit curves are shown for n = 10 and n = 100, illustrating thatthe accep

39、tance limits approach the acceptable parameter regionwith increasing sample size.5.1.4 Computer programs have been developed for generat-ing acceptance limit tables, but these may not be available toall practitioners. This practice contains four acceptance limittables for many practical use situatio

40、ns.5.2 Using the Acceptance Limit Tables in This Practice:5.2.1 In each table acceptance limits on the standard devia-tion are given for means ranging 90110 % of LC in incre-ments of 0.2 %LC for sample sizes ranging from n =10 ton = 500. In all tables the target is set at T = 100 %LC, so theacceptan

41、ce limits for standard deviations are symmetricalaround 100 %LC. This target is also required for interchange-ability across the ICH regions (6).TABLE 2 Acceptance Limits on Sample Standard Deviation (%LC) forT = 100 %LC, C =95%,LB =90%LCSample Average(%LC)Sample Size (n)10 30 40 50 60 80 100 120 15

42、0 200 500100.0 2.91 4.36 4.65 4.84 4.99 5.19 5.33 5.43 5.54 5.66 5.9399.8 or 100.2 2.88 4.31 4.59 4.79 4.94 5.14 5.28 5.38 5.50 5.62 5.9199.6 or 100.4 2.84 4.26 4.54 4.74 4.89 5.09 5.24 5.34 5.45 5.58 5.8899.4 or 100.6 2.81 4.21 4.49 4.69 4.83 5.04 5.18 5.29 5.40 5.53 5.8499.2 or 100.8 2.77 4.16 4.4

43、3 4.63 4.77 4.98 5.13 5.23 5.35 5.48 5.7999.0 or 101.0 2.74 4.10 4.38 4.57 4.72 4.92 5.07 5.17 5.29 5.43 5.7498.8 or 101.2 2.70 4.05 4.32 4.52 4.66 4.86 5.01 5.11 5.23 5.37 5.6998.6 or 101.4 2.67 4.00 4.27 4.46 4.60 4.80 4.94 5.05 5.17 5.30 5.6398.4 or 101.6 2.63 3.95 4.21 4.40 4.54 4.74 4.88 4.99 5

44、.10 5.24 5.5698.2 or 101.8 2.60 3.89 4.16 4.34 4.48 4.68 4.82 4.92 5.04 5.17 5.4998.0 or 102.0 2.56 3.84 4.10 4.28 4.42 4.62 4.75 4.86 4.97 5.10 5.4397.8 or 102.2 2.53 3.79 4.05 4.22 4.36 4.55 4.69 4.79 4.90 5.03 5.3597.6 or 102.4 2.49 3.74 3.99 4.17 4.30 4.49 4.62 4.72 4.84 4.97 5.2897.4 or 102.6 2

45、.46 3.68 3.93 4.11 4.24 4.43 4.56 4.66 4.77 4.90 5.2197.2 or 102.8 2.42 3.63 3.88 4.05 4.18 4.36 4.50 4.59 4.70 4.83 5.1397.0 or 103.0 2.39 3.58 3.82 3.99 4.12 4.30 4.43 4.53 4.63 4.76 5.0696.8 or 103.2 2.35 3.53 3.77 3.93 4.06 4.24 4.37 4.46 4.56 4.69 4.9996.6 or 103.4 2.32 3.48 3.71 3.87 4.00 4.18

46、 4.30 4.39 4.50 4.62 4.9196.4 or 103.6 2.28 3.42 3.65 3.81 3.94 4.11 4.23 4.33 4.43 4.55 4.8496.2 or 103.8 2.24 3.37 3.60 3.76 3.88 4.05 4.17 4.26 4.36 4.48 4.7796.0 or 104.0 2.21 3.32 3.54 3.70 3.82 3.99 4.10 4.19 4.29 4.41 4.6995.8 or 104.2 2.17 3.26 3.48 3.64 3.76 3.92 4.04 4.13 4.23 4.34 4.6295.

47、6 or 104.4 2.14 3.21 3.43 3.58 3.70 3.86 3.98 4.06 4.16 4.27 4.5495.4 or 104.6 2.10 3.16 3.37 3.52 3.63 3.80 3.91 3.99 4.09 4.20 4.4795.2 or 104.8 2.07 3.11 3.31 3.46 3.57 3.73 3.84 3.93 4.02 4.13 4.3995.0 or 105.0 2.03 3.05 3.26 3.40 3.51 3.67 3.78 3.86 3.95 4.06 4.3294.8 or 105.2 2.00 3.00 3.20 3.

48、35 3.45 3.61 3.71 3.79 3.88 3.99 4.2494.6 or 105.4 1.96 2.95 3.15 3.29 3.39 3.54 3.65 3.73 3.82 3.92 4.1794.4 or 105.6 1.93 2.89 3.09 3.23 3.33 3.48 3.58 3.66 3.75 3.85 4.1094.2 or 105.8 1.89 2.84 3.03 3.17 3.27 3.42 3.52 3.59 3.68 3.78 4.0294.0 or 106.0 1.86 2.79 2.98 3.11 3.21 3.35 3.45 3.53 3.61

49、3.71 3.9593.8 or 106.2 1.82 2.74 2.92 3.05 3.15 3.29 3.39 3.46 3.54 3.64 3.8793.6 or 106.4 1.79 2.68 2.86 2.99 3.09 3.23 3.32 3.39 3.47 3.57 3.8093.4 or 106.6 1.75 2.63 2.81 2.93 3.03 3.16 3.25 3.33 3.40 3.50 3.7293.2 or 106.8 1.72 2.58 2.75 2.87 2.97 3.10 3.19 3.26 3.34 3.43 3.6593.0 or 107.0 1.68 2.52 2.69 2.81 2.90 3.03 3.12 3.19 3.27 3.36 3.5792.8 or 107.2 1.65 2.47 2.64 2.75 2.84 2.97 3.06 3.13 3.20 3.28 3.5092.6 or 107.4 1.61 2.42 2.58 2.70 2.78 2.91 2.99 3.06 3.13 3.21 3.4292.4 or 107.6 1.57 2.36 2.52 2