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Method Validation Particle Size

Method Validation Particle Size

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Published by: Sophia on Dec 06, 2012
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 Mastersizer 2000 Application Note
When undertaking particle sizemeasurements it is important tovalidate the analysis method toascertain both its robustness andintegrity. This allows the key variablesassociated with variability in theresults to be determined and thencontrolled as part of the measurementprocedure. The implementation of avalidation study is an absoluterequirement in the pharmaceuticalindustry and of growing significancethroughout the manufacturing sectorwhere the need for result consistencyis important to ensure efficientproduction and quality control.Validation is described by the USFood and Drug Administration (FDA)as “establishing documentaryevidence which provides a highdegree of assurance that a specificprocess will consistently produce aproduct meeting its predeterminedspecification and quality attributes”[1]. The FDA Guidance to Industrydocument goes on to state that forparticle sizing methods (includinglaser diffraction) that the intermediateprecision and robustness of themethod should be studied.Users of laser diffraction instrumentsfor particle characterizationapplications have a wealth ofinformation on the theory behind thetechnology as well as guidance onboth sampling and dispersion [2,3,4].In 1999 the Pharmaceutical AnalyticalSciences Group (PASG)
[5] laid downsome guidelines as to the processwhich should then be followed duringmethod validation. The work of thePASG group is built upon here withpractical examples of how validationcan be carried out. Lerke and Adams
[6] have also published their ideas onthe subject in a useful paper. Theirpaper covers both methoddevelopment and method validation,whereas this note is mainly concernedwith the latter.Note that following the proceduresoutlined here cannot guarantee thatan auditing body will always approvea given method. Rather the minimumamount of work expected to beperformed is outlined. Any additionalstudies will only strengthen the casefor the candidate method.
Method Validation
The development of a validatedmethod should be carried out usingan instrument that has validatedsoftware and is regularly tested toconfirm its performance. Validatedsoftware has lifecycle documentationdetailing its development andmaintenance and should benumerically validated using a peerpackage such as Microsoft Excel. Theinstrument installation should conformto the manufacturers InstallationQualification (IQ). The recommendedmanufacturer’s OperationalQualification (OQ ) should also becarried out at least yearly, with theinstrument performance being testedusing secondary standards on aroutine basis between each OQ visit.In the current regulatory environment,it is also essential that the software iscompliant to 21 CFR part 11, theFDA’s rule regarding the use ofelectronic records and signatures.When validating a laser diffractionmethod for particle characterization,the following main variables must beconsidered: sampling; samplepreparation; instrument range;appropriateness of the technique;robustness of the analytical method;the amount of light scattered by thesample; and the reproducibility andprecision of the measurement.
One of the first considerations inparticle size analysis is whether thesample selected for analysis isrepresentative of the bulk material. Ifthe sample is not representative theresults obtained may be atypical andthe experiment is a pointless exercise.During transit of the sample, settlingcan occur - in powders large particletend to settle at the top of the samplecontainer, whereas suspensions showthe reverse within large particlesundergoing sedimentation. In eachcase the material must be sampled insuch a way as to remove the biascaused by these processes.Research has shown that use of aspinning riffler is the mostreproducible method of obtaining arepresentative sample for powdersamples when compared with othermethods [7] (table 1). Riffling worksbest for free-flowing particles but cantake a great deal of time if a largeamount of powder is to be handled. Ifthe powder is not free-flowing thenparticle segregation is minimized andtechniques such as scoop sampling
Method validation for laser diffractionmeasurements
Table 1:
Variability Associated withdifferent sampling methods
Method Relative StandardDeviation (%)
Cone & Quartering 6.81Scoop Sampling 5.14Table Sampling 2.09Chute Riffling 1.01Spinning Riffling 0.13
 Mastersizer 2000 Application Note
may yield a representative sample.For slurries it is important to overcomesedimentation by re-suspending thesample. This can often be achievedby simple stirring. However, use ofcertain stirrers, such as magneticfleas, can lead to the large particlesbeing thrown to the outside of thecontainer (in a similar way tohydrocyclone separation) where theyare not sampled.
Sample Preparation
The PASG group defined samplepreparation as “the pre-treatment andthe presentation of the sample to themeasuring technique in a meaningfulmanner” [5]. Selection of the correctmethod will therefore depend on theinterests of the user. Where, forexample, the primary particle size isimportant, correct dispersion of thesample will be important. This may bethe case when control of the solubilityof the powder is important in definingits functionality. If the naturalagglomerated state is of interest, as isthe case in some granulationprocesses, sample preparation shouldtake this into account in order to avoidthe break-up of agglomeratedparticles. In either case, thedispersion medium – whether air or aliquid – should not cause irreversiblechanges to the particle size throughprocesses such as dissolution, millingor aggregation.For both dry and wet measurements itwill be important to understand howthe dispersion energy affects thereported particle size. For wetmeasurements the addition ofsurfactants and additives and the useof sonication for dispersion must beinvestigated. Comparison of the stateof the powder before and afterdispersion using microscopy can thenbe used to assess if irreversibleparticle break-up has occurred. In thecase of dry powder measurementsthe effect of dispersion pressure mustbe ascertained, with the correctpressure being selected by comparingthe results against wet dispersion.Dispersion parameters are normallyassessed as part of methoddevelopment rather than as part of themethod validation process. Details ofthe method development process aregiven elsewhere
Detection Limit and Range
Assessment of the detection limit ofthe laser diffraction technique is notrequired as part of method validation.However, it is important that thedynamic range of the particle-sizinginstrument covers the size range ofthe sample being tested. Thisnormally does not present a problemfor most pharmaceutical samples asmodern laser diffractioninstrumentation can cover a sizerange from 20nm to 2000µm in asingle measurement. Olderinstrumentation, however, may haveto use many lenses in order to coverthe same dynamic range. Here thelens that covers the largest proportionof the particle size distribution shouldbe used. Alternatively the result fromtwo lenses can be blended together,although this is not recommendedsince the result depends on themathematical efficacy of the blendingroutines.
Specificity, in terms of whether or notthe technique is appropriate to thematerial under analysis, should beaddressed as part of methoddevelopment and does not have to berevisited for method validation. It is, ofcourse, true that different sizingtechniques display differentsensitivities and will therefore providedifferent results for the same sample.Selection of an appropriate techniquedepends on what is of interest – forinstance is the detection of a smallamount of over-sized materialrequired or does the technique needto differentiate between differentparticle types? Laser diffractionprovides a good method for assessingsmall changes in the size distributionin this regard. However, it is difficult todifferentiate between the different
0 2 4 6 8 10 12 14 16Measurement Time / sec19202122
   D  v   5   0   /  m   i  c  r  o  n  s
Figure 1:
Variation in the Dv50 as a function of measurement duration. Theerror bars represent the COV over ten measurements.
 Mastersizer 2000 Application Note
components within pharmaceuticaldosage forms using the technique.
The robustness of an analyticalmethod is an indication of its ability toremain unaffected by small variationsin the test parameters and soprovides assurance of its reliabilityduring routine use. The methodrobustness should be consideredbefore repeatability, reproducibilityand intermediate precision areassessed.Measurement duration andmeasurement stability are the twomain variables to be considered aspart of a robustness study. Others,such as air pressure (drymeasurements) and pump/stir rates(wet measurement) are normallyconsidered as part of methoddevelopment, but are briefly describedhere.Measurement DurationThe duration of each laser diffractionmeasurement should be set so as toensure that representative samplinghas been achieved. For narrowdistributions or fine particles relativelyshort measurements time can beused. If polydisperse or coarseparticle size distributions are analyzedthen longer measurement times maybe required in order to ensure that arepresentative volume of largerparticles has been sampled.The suggested procedure forassessing the correct measurementduration is to carry out ten repeatmeasurements using measurementtimes of 2, 5, 7, 10 and 15 seconds.The individual and mean readings foreach measurement time can be over-plotted and any shift in particle sizedistribution noted. The appropriateduration period can be selected bylooking at the coefficient of variation(COV) for the median particle size(Dv50), Dv10 and Dv90.The COV should be within limits ofacceptability laid down in ISO13320[2]. This states that for samples with amedian size of greater than 10 µm,the COV should be less than 3% forcut-off values close to the centre ofthe distribution (e.g. Dv50) and lessthan 5% for cut-off values towards thelimits of the distribution (e.g. Dv10and Dv90). For samples with amedian size of less than 10 µm, theCOV limits are doubled. Theincreased variability allowed withinISO13320 for fine particles reflectsthe fact that dispersion is importantwithin this size range. Note thattypically COV values of less than 3%are achievable across themeasurement range if both dispersionand sampling are controlled.Figure 1 shows an example of howthe Dv50 reported for a lactoseexcipient varies with measurementduration. In this case measurementduration of 7 sec was chosen.Although the COV is low for the 2 secmeasurement, the Dv50 issignificantly smaller than for the othermeasurements, suggesting that thelarge particles were not correctlysampled using such a shortmeasurement time.Measurement StabilityIn order to determine whethersamples are stable over the period ofanalysis and not subject toagglomeration, de-agglomeration ordissolution, it is necessary to monitorthe particle size distribution at knowntime points.A sample should be prepared inaccordance with the method underinvestigation. It is recommended thatat least five repeat measurements atthe previously established duration betaken at varying times after sampledispersion (1, 3, 5, 7 and 10 minutes).The mean and COV for the Dv10,Dv50 and Dv90 values should then bedetermined and should be shown tobe within the limits of ISO13320 [2].Typical measurement stability resultsobtained for a lactose sample areshow figure 2. From these results it isclear that the lactose sample is stablewhilst in suspension. It was decidedfrom these results that measurementsshould be taken after 1 minute inorder to give the sample time toequilibrate.An example of how the dispersionconditions can yield poor
0 2 4 6 8 10Time / min020406080
   S   i  z  e   /   M   i  c  r  o  n  s
Figure 2:
Lactose sample stability measurement summary.

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