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outh !frica
Pharmaceutical Development
Analytical Method Development
Presenter:
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April 2007
Analytical
etho! De"elopment
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April 2007
!nterchangeability "!#$
#()*&+HA(,*A-#.#)/ 0#+1 #+ O2 3.)#4O3&+* 2PPs 5 0*44*()#A. 4# #.A&#)/ W#)H #((O6A)O& 2PP1 2PP 5
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April 2007
Pharmaceutical e%uivalence
2PPs meet same or compara'le stan!ar!s 0e.g., mar9eting authori:ation, analytical metho!s1 metho!s
% % % % 4ame AP# 0chemical an! physical e$ui"alence1 4ame !osage ;orm an! route o; a!ministration 4ame strength +ompara'le la'eling
Pre%ualification re%uirements
Analytical metho! "ali!ation is re$uire! 'y WHO ;or the pre$uali;ication o; pro!uct !ossiers. (on<compen!ial A&6 AP#s an! 2PPs =ere>are teste! =ith metho!s !e"elope! 'y the manu;acturer. Analytical metho!s shoul! 'e use! =ithin , P an! ,.P en"ironments, an! must 'e !e"elope! using the protocols an! acceptance criteria set out in the #+H gui!elines 7?0&@1
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April 2007
6ali!ation o; analytical proce!ures: text an! metho!ology 7?0&@1 #+H Harmoni:e! )ripartite ,ui!elines, 0?DDJ1
http:>>===.ich.org>.O->me!ia> *D#AB@H.p!;
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April 2007
&eneral re%uirements
7uali;ie! an! cali'rate! instruments Documente! metho!s &elia'le re;erence stan!ar!s 7uali;ie! analysts 4ample selection an! integrity +hange control
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April 2007
68.26%
95.46%
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April 2007
avera e ! mean
LSL
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April 2007
#apable process
Almost all the measurements o; a sta'le process ;all insi!e the speci;ication limits USL LSL Cp E K @D @?
EB ppm
http())www*itl*nist*gov)div+,+)handbook)pmc)section-)pmc-.*htm
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April 2007
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April 2007
'(a#mace tica"
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April 2007
#mpurities
7uantitati"e .imit
8 8 8 < 8 8 8 8
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Trueness
Precision
$2andom errors"
4ystematic errors
!ntra6assay variability
!ntra6laboratory variability
!nter6laboratory variability
2epeatability
4ource: #4O. @FFB. #4O JH?J @<E: Accuracy 0)rueness an! Precision1 o;
!ntermediate precison
easurement
2eproducibility
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April 2007
!naccurate : imprecise
*recise
Accurate
April 2007
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:ean 1.909 1.908 99.9 1.88 "$e data s$ow t$at t$e recover# of anal#te in spi(ed samples met t$e evaluation criterion for accurac# /011 2 3.1% across 51041% of tar et concentrations5.
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April 2007
% Reco,e#y
2ed line( ;A
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April 2007
)he precision 06A&#A-#.#)/1 o; an analytical proce!ure is usually expresse! as the stan!ar! !e"iation 041, "ariance 04?1, or coe;;icient o; "ariation 05 relati"e stan!ar! !e"iation, &4DL.1 o; a series o; measurements. )he con;i!ence inter"al 0+#1 shoul! 'e reporte! ;or each type o; precision in"estigate!.
'R-&ISI.%
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April 2007
&epeata'ility expresses the precision 0sprea! o; the !ata, "aria'ility1 un!er the same operating con!itions o"er a short inter"al o; time. &epeata'ility is also terme! intra<assay precision.
R-'-ATA/I0IT1
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April 2007
'ea2 a#ea 57935 57833 57497 57617 57778 57231 57649 257 0.4% 270
April 2007
Im*1 0.301 0.301 0.299 0.300 0.301 0.298 0.300 0.0013 0.4% 0.0014
)he repeata'ility precision o'taine! 'y one analyst in one la'oratory =as @.?JL &4D ;or the analyte an!, there;ore, meets the e"aluation criterion o; &4D M?L.
#nterme!iate precision expresses =ithin<la'oratories "ariations. N@, N? an! NG: !i;;erent !ays, !i;;erent analysts, !i;;erent 0manu;acturing1 e$uipment, etc. &epro!uci'ility expresses the precision 'et=een la'oratories N@, N? an! NG 0colla'orati"e stu!ies, usually applie! to stan!ar!i:ation o; metho!ology1. 0)rans;er o; technology1
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April 2007
5Assa# /m ;5ml 50.8 50.9 54.1 53.5 53.4 53.8 53.4 1.49 1.9% 1.50
April 2007
-ombined values :ean S"7 6S7 -. 95% 53.5 1.49 1.9% 1.40
53.6 53.0 53.4 53.9 54.3 54.0 53.8 1.44 1.9% 1.46
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4pecificity "selectivity$
4peci;icity is the a'ility to assess une$ui"ocally the analyte in the presence o; components, =hich may 'e expecte! to 'e present. )ypically these might inclu!e impurities, !egra!ants an! excipients. excipients An example o; speci;icity criterion ;or an assay metho! is that the analyte pea9 =ill ha"e 'aseline chromatographic resolution o; at least ?.D minutes ;rom all other sample components 4ta'ility in!icating analytical metho!s shoul! al=ays 'e speci;ic.
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April 2007
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April 2007
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April 2007
T(e#e ;e#e no *ea2s in t(e *"ace!o c(#omato4#am at t(e #etention times o+ ne,i#a*ine 5%67 * met(y"*a#a!en 5M'6 an) *#o*y"*a#a!en 5''6 *ea2s S m o+ %7 M' an) '' *ea2 a#eas. T(e t(#ee in4#e)ients can !e assesse) in t(e *#esence o+ 5non< = e:*ecte)6 )e4#a)ants. T(e *ea2s a#e (omo4eneo s an) * #e. T(e met(o) is se"ecti,e7 s*eci+ic *an) sta!i"ity<in)icatin4
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April 2007
.imit o; 7uantitation 0.O71 .imit o; Detection 0.OD1 4ignal to (oise &atio 04(&1
*ea( = L<,
*ea( A L<7
(aselin e
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noise
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April 2007
Im* #ity 1 0.D 4176 3608 4196 4303 3932 5238 4242 548 12.9% 0.086 0.017 0.= 7235 8099 7950 8166 7847 8415 7952 402 5.1% 0.171 0.033
Im* #ity 2 0.D 3497 4258 3275 3464 4008 4702 3867 551 14.3% 0.107 0.019 0.= 7892 7791 8292 8050 8368 8284 8113 238 2.9% 0.214 0.039
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April 2007
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April 2007
;inearity
Meas #e) mean Rea" mean
'#ecision
.inearity expresses !i;;erences in precision at !i;;erent points o; a gi"en range. A)he linearity o; an analytical proce!ure is its a'ility 0=ithin a gi"en range1 to o'tain test results, =hich are !irectly proportional to the concentration 0amount1 o; analyte in the sample.C
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April 2007
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April 2007
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April 2007
Dissolution testing: O ?D L o"er the speci;ie! range. #mpurity: ;rom the reporting le"el o; an impurity to @?DL o; the speci;ication. 03nusually potent or toxic impurities, .OD an! .O7 shoul! 'e
commensurate =ith #+H re$uirement.1
#; assay an! purity are per;orme! together as one test an! only a @DDL stan!ar! is use!, linearity shoul! co"er the range ;rom the reporting le"el o; the impurities to @?DL o; the assay speci;ication
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April 2007
Sta!i"ity
:easured means
N@ Q 2irst measurements N?, NG, NB, Qn 4eries o; measurements o; the same sample wit$in a relativel# s$ort period of time.
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April 2007
A#ea 72079 71574 71740 71960 72352 71573 72322 72310 72312 72670
April 2007
An analytical solution prepare! ;rom (e"irapine JDmg>Jml Oral 4uspension =as spi9e! =ith #mpurity<@ at speci;ication le"el an! store! in a cappe! "olumetric ;las9 on a la'oratory 'ench at uncontrolle! room temperature un!er normal lighting con!itions ;or ?J hours.
+onclusion: the sta'ility o; the 0.3%< analytical solution o; #mpurity<@ is 0.3%< not a source o; "ariation.
0.8%<
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April 2007
2obustness
t6 :et$od parameter S"* )low @avelen t$ ?ariation of mobile p$ase -olumn temperature pB
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?ariation ' 01%' 01% 5nm' 5nmA 3%' 3%A 5o-' 5o-A 1.4' 1.4A
.mpurit# 0 1.94 1.94 1.94 1.93 1.94 1.91 1.94 1.93 1.94 1.94 1.94
.mpurit# 3 0.91 0.90 0.93 0.90 0.90 0.99 0.86 0.91 0.90 0.90 0.91
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April 2007
% .imits o; !etection an! $uantitation % Accuracy or reco"ery ;rom rinsate 0S KDL1, s=a's 0S FDL1, an! process sur;ace 0S HDL1 % &ange 0lo=est le"el is at least ?x higher than .O71
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April 2007
6ali!ation shoul! !emonstrate that the analytical proce!ure is suita'le ;or its intente! purpose. HP.+ systems an! metho! "ali!ation !eser"es special attention !uring the assessment o; !ossiers ;or pre$uali;ication.
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April 2007
T@A/A <O5
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April 2007