1、Designation: D7709 12Standard Test Methods forMeasuring Water Vapor Transmission Rate (WVTR) ofPharmaceutical Bottles and Blisters1This standard is issued under the fixed designation D7709; the number immediately following the designation indicates the year oforiginal adoption or, in the case of rev
2、ision, the 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 The three test methods described herein are for mea-surement of water vapor transmission rates (WVT
3、Rs) ofhigh-barrier multiple-unit containers (bottles), high-barriersingle-unit containers (blisters), and quasi-barrier single-unitcontainers used for packaging pharmaceutical products. Thecontainers are tested closed and sealed. These test methods canbe used for all consumer-sized primary container
4、s and bulkprimary containers of a size limited only by the dimensions ofthe equipment and the weighing capacity and sensitivity of thebalance.1.2 These test methods are intended to be of sufficientsensitivity and precision to allow clear discrimination amongthe levels of barrier packages currently a
5、vailable for pharma-ceutical products.1.3 There are three methods: Method A is for bottles,Method B is for formed barrier blisters, and Method C is forformed quasi-barrier blisters. Methods B and C can be adaptedfor use with flexible pouches.1.4 These test methods use gravimetric measurement todeter
6、mine the rate of weight gain as a result of water vaportransmission into the package and subsequent uptake by adesiccant enclosed within the package. The packages areexposed to environments typical of those used for acceleratedstability testing of drug products in the package (typically40C/75 % rela
7、tive humidity RH).1.5 For these methods, balance sensitivity, amount of des-iccant, number of blisters per test unit, and weighing frequencywere developed in an experiment based on Test MethodsE96/E96M.1.6 Test Methods E96/E96M gives specific instruction onthe interactions among weighing frequency,
8、number of datapoints necessary to establish steady state, minimum weightgain in a weighing period, and balance sensitivity.1.7 The test methods in this standard were developedspecifically for pharmaceutical bottles and blisters as closedcontainer-closure systems. The experiment from which themethods
9、 were developed provided an inter-laboratory studyfrom which the precision and bias statement was written. Thepackages in the study were small bottles and blisters usedregularly for pharmaceutical solid oral dosage forms.1.8 In spite of the specific nature of their application, the testmethods in th
10、is standard should be suitable for other pharma-ceutical packages and most types and sizes of other consumerpackages.1.9 The values stated in SI units are to be regarded as thestandard. No other units of measurement are included in thisstandard. The units of measure for bottles are milligrams perbot
11、tle per day (mg/bottle-day) and for blisters, milligrams perblister cavity per day (mg/cavity-day). These units may be usedfor both standard and referee testing.1.10 This standard does not purport to address all of thesafety concerns, if any, associated with its use. It is theresponsibility of the u
12、ser of 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:2E96/E96M Test Methods for Water Vapor Transmission ofMaterials3. Terminology3.1 Definitions:3.1.1 barrier blis
13、ter, nblister made from high-barriermaterial, formed and sealed so that the water vapor transmis-sion rate (WVTR) (when tested at 40C/75 % RH) is less than1.0 mg/cavity-day.3.1.2 blister, nformed, lidded and sealed plastic domethat contains the solid oral product (usually one unit).3.1.2.1 Discussio
14、nSynonymous with cavity.3.1.3 card, ncontiguous group of blisters formed andsealed with lid in place.3.1.3.1 DiscussionThe card is a production geometry thatis a convenient quantity for a dosage regimen. The number of1This test method is under the jurisdiction of ASTM Committee D10 onPackaging and i
15、s the direct responsibility of Subcommittee D10.32 on Consumer,Pharmaceutical, Medical, and Child Resistant Packaging.Current edition approved May 1, 2012. Published June 2012. Originallyapproved in 2011. Last previous edition approved in 2011 as D 7709 111. DOI:10.1520/D7709-12.2For referenced ASTM
16、 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 Document Summary page onthe ASTM website.1Copyright ASTM International, 100 Barr Harbor Drive, PO Box C700, West Conshohoc
17、ken, PA 19428-2959, United States.blisters per card commonly ranges from one to ten but may bemore. From a marketing and production point of view, the cardis the basic, irreducible number of blisters in a market orclinical trial package. The blister card may sometimes bereferred to as the container.
18、3.1.4 cavity, nsee blister.3.1.5 container, n(1) bottle that contains multiple units ofdrug product, or (2) a card of blisters formed and sealed withlid.3.1.6 quasi-barrier blister, nblister made from low-barrier materials formed and sealed so that the WVTR (whentested at 40C/75 % RH) is greater tha
19、n 1.0 mg/cavity-day.3.1.6.1 DiscussionAn example of this is 250 m (10 mil)poly(vinyl chloride) (PVC) formed into size zero blisters andsealed with aluminum foil lid.3.1.7 test specimen (or specimen), n(1) for bottles, thebottle is the test specimen and (2) for blisters, the blister cardis the test s
20、pecimen.3.1.7.1 DiscussionFor blisters, more than one card (orspecimen) may be grouped into a test unit for conducting thetest.3.1.8 test unit, n(1) for bottles, the bottle is the test unit aswell as being the test specimen and (2) for blisters, the test unitis a group of test specimens (cards) proc
21、essed together fortemperature and humidity exposure and weighing at each timepoint.3.1.8.1 DiscussionThe purpose of the test unit for blistersis to gain the advantage of additive weight gain resulting frommore blisters than are on a single card. Detailed discussion ofthis point is available in Test
22、Methods E96/E96M. The termtest unit when applied to bottles is simply to maintain congru-ence of naming among the three test methods.4. Summary of Test Method4.1 In Method A for bottles, desiccant is placed in the bottlewhich is then closed in the normal manner including anymembrane (tamper-evident
23、or otherwise) sealed in place. Thedesiccant-filled bottle is stored in an environment at 40C/75 %RH. The desiccant-filled bottle is weighed at prescribed timeintervals until steady-state weight gain is obtained. Oncesteady state is obtained, the bottles are weighed at fiveconsecutive time points.4.2
24、 In Method B for barrier blisters, desiccant is placed inthe blister and the lid material is sealed in place usingequipment that is capable of filling and properly sealing thecontainers (or cards). The desiccant-filled blister card is storedin an environment at 40C/75 % RH. The card of desiccantfill
25、ed blisters is weighed at prescribed time intervals untilsteady-state weight gain is obtained. Once steady-state isobtained, the blister cards are weighed at five consecutive timepoints.4.3 WVTR for Methods A or B is calculated using linearregression of the weight versus time. The number of blisters
26、tested depends on the barrier characteristics of the material, thesize of the blister, and the sensitivity of the balance used in thetest.4.4 4.4 In Method C for quasi-barrier blisters, desiccant isplaced in the blister and the lid material is sealed in place usingequipment that is capable of correc
27、tly filling and sealing thecontainers (or cards). The desiccant-filled blister card is storedin an environment at 40C/75 % RH. The desiccant-filledblister card is weighed at zero time and 48 h (two days).At thistime, the difference in weight (the weight gain) in mg/cavity-day is taken as the WVTR. T
28、he number of blisters testeddepends on the barrier characteristics of the material, the sizeof the blister, and the sensitivity of the balance used in the test.NOTE 1For this test method, the requirement of five consecutiveweighings is waived because the desiccant quickly becomes saturatedwhen packe
29、d in a quasi-barrier package and stored at 40C/75 % RH.During development of this test method, it appeared that after the secondday the weight gain displayed a curvilinear profile typical of approachingsaturation of the desiccant. To obtain five weighings within two days is anunwieldy process and is
30、 likely to lack precision.5. Significance and Use5.1 The purpose of these test methods is to obtain reliablevalues for WVTR that can be used to discriminate amongbarrier packages for pharmaceutical products. These test meth-ods will establish a WVTR value that represents the watervapor transmission
31、of the container closure system beingevaluated. They are intended for use in evaluating or compar-ing, or both, the water vapor barrier performance of alternativepackages for use in packaging of pharmaceutical products.5.2 While these methods were developed for a specific,limited application, they s
32、hould be suitable for most types andsizes of consumer packages.6. Apparatus6.1 For weighing the test units in Method A, use a balancethat has sufficient capacity to weigh the total of bottle, cap, anddesiccant throughout the period of the test. The balance shallhave sensitivity adequate to measure s
33、mall differences inweight from one time point to the next. The balance sensitivityshall be smaller than5%ofthedifferences in weight from onetime point to the next. (For example, during development ofthis test method, a balance with capacity of 110 g andsensitivity of 0.1 mg was found to be acceptabl
34、e for a 60 CCbottle.)6.2 For weighing the test specimens in Methods B and C,use a balance that has sufficient capacity to weigh the closed,sealed blister test unit throughout the period of use. Thebalance shall have sensitivity adequate to measure smalldifferences in weight from one time interval to
35、 the next. Thebalance sensitivity shall be smaller than5%ofthedifferencesin weight from one time interval to the next. (For example,during development of this method, a balance with capacity of110 g and sensitivity of 0.1 mg was found to be acceptable.Test Methods B and C may require that the bliste
36、r cards(containers) be bundled in multiples to achieve periodic weightgains of sufficient magnitude to use the balance sensitivity.When so bundled, these cards are called test units. TestMethods E96/E96M specify that the weight gain in eachweighing period shall be 20 times the sensitivity of the bal
37、ance.6.3 For exposure of packages to the test environment forMethodsA, B, and C, use a chamber capable of maintaining 406 2C and 75 6 5 % RH. The humidification should beachieved with de-ionized water, or equivalent means, to limitcontamination from water impurities.D7709 1227. Reagents and Material
38、s7.1 Purity of ReagentsReagent-grade chemicals shall beused in all tests. Unless otherwise indicated, it is intended thatall reagents conform to the specifications of the Committee ofAnalytical Reagents of the American Chemical Society wheresuch specifications are available.3Other grades may be used
39、,provided it is first ascertained that the reagent is of sufficientlyhigh purity to permit its use without lessening the accuracy ofthe determination.7.2 Desiccant for Method ADuring development ofMethod A, anhydrous calcium chloride in granular form wasused as the desiccant. Other desiccants may be
40、 suitable; forexample, a molecular sieve or silica gel. If calcium chloride inany form, including anhydrous, is used it shall be pre-dried at215 6 5C for 714 614 h to ensure that any hexahydratepresent is fully converted to the anhydrate. Cool the desiccantin a desiccator for at least 2 h before use
41、.NOTE 2It has been shown4that anhydrous calcium chloride maycontain calcium hexahydrate, which loses water only when the tempera-ture reaches 200C.7.3 Desiccant for Methods B and CDuring developmentof Method B, silica gel was used as the desiccant. It was usedin a molded form to fit the size and sha
42、pe of the blister used.Other desiccants may be suitable, for example, a molecularsieve. If silica gel is used, it shall be pre-dried in a circulatinghot air oven at one of two conditions: 155 6 5C for 314 614hor1506 5C for 414 614 h. Dry molecular sieve in a mufflefurnace at 595 6 25C. Dry the 4A an
43、d 3A sieves for 314 614h. Dry the 13X sieve for 514 614 h. Cool the desiccant in adesiccator for at least 2 h before use.8. Sampling, Test Specimens, and Test Units8.1 Method A (Bottles)Use 15 bottles and 15 closureschosen to represent the package form to be tested. Reserve thebottles for preparatio
44、n at the time of testing. The bottles andclosures should be stored such that they will not be damaged;particularly the mating surfaces of bottle and closure. Preparethe test specimens by filling each bottle23 with desiccant thenclose the container in the appropriate manner as quickly aspossible, inc
45、luding any membrane seal (tamper-evident orotherwise), if appropriate. Filling of bottles shall be done in alow-humidity atmosphere (as low as possible, but not greaterthan 50% RH). Close screw caps in accordance with the torquerecommendations in Table 1.8.2 Methods B and C (Blisters)Fill with pre-d
46、ried desic-cant and seal the blisters on equipment that is capable ofcorrectly filling and sealing the market or clinical trial package.The desiccant tablet should fill the cavity, but for practicalconsiderations, multiple fragments may be used. If fragmentsare used, the total weight of desiccant sh
47、all be enough to meetthe quantity required to avoid partial saturation of the desiccantbefore completion of the test.8.3 Filling of blisters shall be done in a low-humidityatmosphere (as low as possible, but not greater than 50 % RH).8.4 Desiccants shall not be exposed to room humidity formore than
48、30 min before sealing.9. Calibration9.1 The weighing balance used to weigh the containers shallbe appropriately calibrated.9.2 The environmental chamber shall be appropriately cali-brated.9.3 The oven(s) used for drying desiccant shall be appro-priately calibrated.10. ProcedureNOTE 3All samples shou
49、ld be handled in a manner that preventscontact with skin or skin secretions and contaminants. Tweezers, forceps,and powder-free laboratory gloves have been used successfully.10.1 Method ABottles:10.1.1 Bottles shall be received in the test laboratory, filled,and closed in accordance with Section 8.10.1.2 Mark each container with a unique identifier. Markwith indelible ink on the container. Do not use a label.10.1.3 Weigh each container at ambient temperature andRH. Record this weight for time zero.10.1.4 Place all containers in the t
