ASTM E2810-2011 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 11Standard 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, the

2、 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.1. Scope1.1 This practice provides a general procedure for evaluat-ing the capability to comply with the Uniformity of Do

3、sageUnits (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 virtuallyinterchangeable. For this multiple-stage test, the procedurecompute

4、s 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 defines a set of sample means and standarddeviations that assures

5、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 of this standard to establish appro-priate safety and health p

6、ractices and determine the applica-bility of regulatory limitations prior to use.2. Referenced Documents2.1 ASTM Standards:2E2363 Terminology Relating to Process Analytical Tech-nology in the Pharmaceutical IndustryE2709 Practice for Demonstrating Capability to Complywith a Lot Acceptance Procedure2

7、.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 Definitions of Terms Specific to This Standard:3.2.1 acceptable pa

8、rameter 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 the acceptanceregion, for example, the maximum sample stan

9、dard 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 parameterestimates (that is, sample mean and standard deviation) whereconfi

10、dence 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.3.2.4.1 DiscussionThe preset confidence level is stated asa p

11、ercentage, for example, 100 (1 a) = 95 %, where a 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 responsibility of SubcommitteeE55.03 on General Pharmaceutica

12、l 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 ASTMStandards volume information, refer to the standards Docum

13、ent 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), 12601 Twinbrook Pkwy., Rockville,MD 20852-1790, http:/w

14、ww.usp.org.1Copyright ASTM International, 100 Barr Harbor Drive, PO Box C700, West Conshohocken, PA 19428-2959, United States.3.2.5 lower probability bound, LB, nthe nominal prob-ability of passing the UDU test for a given set of parameterestimates.3.2.6 multiple-stage acceptance procedure, na proce

15、durethat 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 criteria suchas random sampling and intended to assure t

16、hat 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 batch location.3.2.9 uniformity of dosage units, UDU, nt

17、he degree ofuniformity in the amount of the drug substance among dosageunits.3.2.9.1 DiscussionThe requirements of the UDU testapply to each drug substance in dosage units containing one ormore drug substances, unless otherwise specified. The unifor-mity improves as the variability decreases.4. Sign

18、ificance 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 aspects ofthis methodology. This practice applies the gen

19、eral 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-stage samplingtest, where at each stage one can pass or con

20、tinue 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 statement about compendialstandards. “The similarity to

21、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 intended for inspecting uniformity offinished product for l

22、ot/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 batch of drug product meets specified statis-tical quality c

23、ontrol criteria.4.4 This practice provides a practical specification that maybe applied when uniformity of dosage units is required. Anacceptance 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 tha

24、t a future sample from thelot will pass the UDU test is greater than or equal to aprespecified 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

25、 account for any decrease6The boldface numbers in parentheses refer to a list of references at the end ofthis standard.TABLE 1 Uniformity of Dosage Units Test ProcedureNOTEAll measurements of dosage units and criteria values are inpercentage label claim (%LC).At each stage calculate the sample avera

26、ge,X, and the sample standard deviation, s.StageNumberTestedPass Stage If:S110|M X|+2.4s # 15.0, where M is defined below.S220(1)|M X|+2.0s # 15.0, using all 30 results (S1+S2).(2) No dosage unit is outside the maximum allowed range of0.75 * M to 1.25 * M.M is defined as follows:If T is less than or

27、 equal to 101.5 %LC, and(1)IfXis less than 98.5 %LC, then M = 98.5 %LC.(2)IfXis between 98.5 and 101.5 %LC, then M = X.(3)IfXis greater than 101.5 %LC, then M = 101.5 %LC.If T is greater than 101.5 %LC, and(1)IfXis less than 98.5 %LC, then M = 98.5 %LC.(2)IfXis between 98.5 and T, then M = X.(3)IfXi

28、s greater than T, then M = T.T is the target content per dosage unit at the time of manufacture, expressed as%LC. Unless otherwise specified in the individual monograph, T is 100.0 %LC.E2810 112in potency during the shelf life, which could affect the abilityto meet the UDU test requirements.4.5 This

29、 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 practice does not prescribe a specifictarget, sa

30、mple 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:5.1.1 The general procedure that generates the ac

31、ceptancelimit 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 programis required to generate the tables given a ta

32、rget 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 the horizontal axis and standard deviation (s)on

33、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 unit content is normally distributed. The acceptabl

34、eparameter region is the set of points on or below the contour.Any (, s) 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 sample standard deviation (s)estimate the popul

35、ation parameters and s within C %confidence limits as chosen by the user. The joint confidenceregion for and s (5) has the 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

36、 is expanded by increasing s until one of theupper vertices just touches the acceptable parameter region.The size of the confidence 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 accep-tance limit c

37、urve, as depicted as dotted lines in Fig. 1.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 table for n = 100 and n = 10.ULS

38、 is the upper confidence limit for s.Z is a standard normal critical value.FIG. 1 Example of Simultaneous Confidence Interval with 95 % Lower Bound and Acceptance RegionsE2810 113Acceptance limit curves are shown for n = 10 and n = 100,illustrating that the acceptance limits approach the acceptablep

39、arameter region with 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 situations.5.2 Using the Acceptance Limit Tab

40、les 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 theacceptance limits for standard deviations are

41、 symmetricalaround 100 %LC. This target is also required for interchange-ability across the ICH regions (6).5.2.1.1 At the confidence level of C = 95 % used often inthe regulatory arena, three levels of the probability lowerbound are provided: LB =90%(Table 2), LB =95%(Table 3)and LB =99%(Table 4).

42、These provide 90 %, 95 %, and 99 %coverage, respectively, of the population of dosage units underconsideration. The usual coverage is 95 %.5.2.1.2 Table 5 is provided at C =90%andLB =95%forcomparison with Table 3 to demonstrate the effect of a lowerconfidence level.NOTE 1Tables can also be generated

43、 for other choices for ranges ofmeans, such as 85.1 to 114.9 %LC, or for other sample sizes.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 80 100 120 150 200 500100.0 2.91 4.36 4.65 4.84 4.99 5.19 5.33 5.4

44、3 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 4.43 4.63 4.77 4.98 5.13 5.23 5.35 5.48 5.7999.0 or 101.

45、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 5.10 5.24 5.5698.2 or 101.8 2.60 3.89 4.16 4.34 4.48 4

46、.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 2.46 3.68 3.93 4.11 4.24 4.43 4.56 4.66 4.77 4.90 5.21

47、97.2 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 1.06 4.24 4.37 4.46 5.56 4.96 4.9996.6 or 103.4 2.32 3.48 3.71 3.87 4.00 4.18 4.30 4.39 4.50 4.62 4.9196.4 or 103.6 2.28 3.42 6.65

48、 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 4.6295.6 or 104.4 2.14 3.21 3.43 3.58 3.70 3.86 3.98 4.06 4.

49、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 3.48 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 3.35 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 2.98 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.