25 How to Determine the Total Impurities - Which Peaks Can Be Disregarded

TOPICS : 04- EUROPEAN PHARMACOPOEIA & INTERNATIONAL HARMONISATION  / 01General Chapter an! M"n"#raph / http://$$$%e!'%e(/en/ http://$$$ %e!'%e(/en/Help!e)-1*+,%ht'lr Help!e)-1*+,%ht'lr(.r(e,* (.r(e,*

14. Do I need to validate a method that is published in the Ph. Eur.?

The The tet tet 'eth" 'eth"! ! #en #en n '"n"# '"n"#ra raph ph an! an! #ener #eneral al 2hap 2hapter ter  hae hae .een .een al! al!ate ate! ! n a22"r!a a22"r!an2e n2e $th $th a22epte a22epte! ! 2ent3 2ent32 2 pra2t2 pra2t2e e an! 2(rrent 2(rrent re2"''e re2"''en!a n!at"n t"n  "n analt2 analt2al al al!at"n% Unle "ther$e tate! n the '"n"#raph "r #eneral 2hapter5 al!at"n "3 the tet 'eth"! . the analt  n"t re(re!% 6hen 'ple'entn# a phar'a2"p"eal 'eth"!5 the (er '(t ae $hether an! t" $hat e7tent the (ta.lt "3 the 'eth"! (n!er the a2t(al 2"n!t"n "3 (e nee! t" .e !e'"ntrate! a22"r!n# t" releant '"n"#raph5 #eneral 2hapter an! (alt te'5 % e% the 2"rre2t 'eth"! tran3er  the rep"n.lt "3 the (er%

15. Ho !an I "ind out hi!h !hromato#raph$ !olumn or other e%uipment or rea#ent as used durin# the development o" a mono#raph?

G" t" the 8n"$le! 8n"$le!#e #e 9ata.a 9ata.ae e % L"2ate the '"n"#raph "( are (n# an! "( h"(l! 3n! th n3"r'at"n% I3 the n3"r'at"n  n"t there5 pleae let ( )n"$ an! $e $ll !" "(r .et t" a!! t an! n3"r' "(%

1&. Can $ou provide relative retentions "or 'Other dete!table impurities( !ited in the Impurities se!tion o" a mono#raph?

The E9M !"e n"t pr"!e (2h n3"r'at"n5 a t  n"t nee!e! 3"r the pr"per appl2at"n "3 the '"n"#raph%

)* I have observed a sli#h sli#htt di""ere di""eren!e n!e in retenti retention on times+retardation times+retardation "a!tors !ompared ith the mono#raph. ,hat deviation is !onsidered a!!eptable?

The retent"n t'e5 relate retent"n an! retar!at"n 3a2t"r are n"r'all n"t part "3 the te te' ' (ta (ta. .lt lt 2rte 2rtera ra;; the the are are #e #en n 3"r 3"r n3"r n3"r'at 'at" "n n "nl "nl an! an! are n"t n"t 'an!a 'an!at"r t"r % There3"re5 n" !eat"n all"$an2e  !e3ne!% In an 2ae5 the te' (ta.lt !e3ne! n the '"n"#raph ha t" .e at3e! n "r!er t" pr"2ee! $th the tetn#%

)4 ,hat is the limit "or spe!i"ied+unspe!i"ied+un-non impurities?

Unle Unle  "ther$ "ther$e e pre2 pre2r. r.e! e! "r <(t3 <(t3e! e! an! an! a(th a(th"r "re e!5 !5 "r#a "r#an2 n2 'p(r 'p(rte te  n a2t a2te e (.tan2e are t" .e rep"rte!5 !ent3e! $hereer p".le5 an! (al3e! a n!2ate! n #eneral '"n"#raph =0,45 Substances for pharmaceutical use >Ta.le >Ta.le =0,4%-1 "r " r Ta.le Ta.le =0,4%=0 ,4%=?% Generall5 pe23e! 'p(rte hae ther "$n pe232 a22eptan2e 2rter"n n the '"n"#raph% Controll of impuri impuritie ties s in @"r @"r "the "therr 'p(r 'p(rte te5 5 the !e2 !e2"n "n tree tree n #ener #eneral al 2hapt 2hapter er %105 %105 Contro substan substances ces for pharmac pharmaceut eutica icall use 'a .e (e! t" !eter'ne the appl2a.le a22eptan2e 2rter"n%

)5 Ho to determine the total impurities? ,hi!h pea-s !an be disre#arded?

In 2hr"'at"#raph2 tet5 the !re#ar! l't  !e3ne! a the n"'nal 2"ntent at "r .el"$ $h2h pea)/#nal are n"t ta)en nt" a22"(nt 3"r 2al2(latn# a (' "3 'p(rte% The n('er2al al(e 3"r the !re#ar! l't an! the rep"rtn# threh"l! are ((all the a'e% Pea) 2"rrep"n!n# t" the .lan) 2an al" .e !re#ar!e!5 a $ell a "ther pea) that the '"n"#raph e7pl2tl tate are t" .e !re#ar!e!% In "ther $"r!5 3 'p(rte >pe23e! "r (npe23e!? are a."e the !re#ar! l't5 the h"(l! .e ta)en nt" a22"(nt 3"r the 2al2(lat"n "3 the t"tal 'p(rte%

IB! l)e t" 2"nta2t the E9M 3"r 3(rther n3"r'at"n% Cl2) here

) The limit "or unspe!i"ied impurities in the mono#raph is hi#her than the values de"ined in #eneral mono#raph )/*40 Substan!es "or pharma!euti!al use Table )/*4.2 13 and #eneral !hapter 5.1/0 Control o" impurities in substan!es "or pharma!euti!al use.

S"'e S"'e '"n"# '"n"#rap raph h are are a$at a$atn# n# re re"n% "n% H"$e H"$ee er5 r5 the re(r re(re'e e'ent nt "3 the the #ener #eneral al '"n"#raph are .n!n# an! '(t .e 'ple'ente! . the (er a !e2r.e! n #eneral 2hapter %10% In "'e e72ept"nal 2ae5 the re(re'ent "3 #eneral '"n"#raph =0,4 an! #eneral 2hapter %10 !" n"t appl5 an! !33erent threh"l! 2an .e pre2r.e!% In th 2ae5 the 3"ll"$n# tate'ent 2an .e 3"(n! n the relate! (.tan2e e2t"n: The threh"l! n!2ate! (n!er Relate! (.tan2e >Ta.le =0,4%-1? n the #eneral '"n"#raph S(.tan2e 3"r Phar'a2e(t2al (e >=0,4? !" n"t applD%

) Ho are limits "or impurities de"ined in mono#raphs?

L't are .ae! "n .at2h !ata that re3le2t the p(rt "3 the (.tan2e 2(rrentl "n the E(r" E(r"pe pean an 'ar) 'ar)et et an! an! are are n"t n"t h#h h#her er than than the the l' l't t appr appr" "e! e! !(r !(rn# n# the the 'ar) 'ar)et etn n# # a(th"rat"n pr"2e%

) I obs observ erve e bas baseli eline ne sep separa aration tion he hen n the mon mono#r o#raph aph des! des!rib ribes es a peapea-2to 2to2val 2valle$ le$ ratio.

Een th"(#h a pea)-t"-alle rat" 2ann"t .e 2al2(late! n th 2ae5 the re(re'ent  3(l3lle! a the eparat"n  een .etter than $hat the '"n"#raph pre2r.e%

)& I !annot a!hieve the s$stem suitabilit$ or si#nal2to2noise !riteria ith the des!ribed !hromato#raphi! method. Can I ma-e an$ ad6ustments?

Pleae 2"n(lt General Chapter =%=%4*5 e2t"n A!<(t'ent "3 2hr"'at"#raph2 2"n!t"nD 3"r a lt "3 a22epta.le a22epta.le '"!32at"n% H"$eer5 H"$eer5 '(ltple '"!32at"n '"!32at"n are n"t re2"''en!e!5 an! n an 2ae5 the te' (ta.lt 2rtera "3 the '"n"#raph an! "3 2hapter =%=%4* '(t .e 'et%

*/. The mono#raph does not spe!i"$ a !orre!tion "a!tor "or a spe!i"ied impurit$.

I3 the '"n"#raph !"e n"t !e2r.e a 2"rre2t"n 3a2t"r5 t  a('e! that t  n the ran#e .et$een 0%+ an! 1%= an! there3"re "( !" n"t nee! t" appl a 2"rre2t"n 3a2t"r t" th 'p(rt%

*1. The mon mono#r o#raph aph doe does s not in! in!lud lude e !he !hemi! mi!al al re"e re"eren! ren!e e sub substan stan!es !es or rel relativ ative e retentions "or spe!i"ied impurities.

Th '"n"#raph '#ht .e part "3 "(r re"n pr"#ra''e t" ntr"!(2e 2he'2al re3eren2e (.tan2e 3"r pea) !ent32at"n an! relate retent"n 3"r pe23e! 'p(rte a $ell a an e7pl2t a22eptan2e 2rter"n 3"r (npe23e! 'p(rte% Pleae 2"nta2t ( 3 "( 2an (.'t 3(rther n3"r'at"n%

*). ,hat is the di""eren!e beteen a pea- area !omparison and a %uantitative limit "or  related substan!es?

In the pat5 the a22eptan2e 2rtera 3"r relate! (.tan2e $ere e7pree! relate t" the area "3 a re3eren2e pea) "3 )n"$n 2"n2entrat"n >l't tet?% 6th"(t pr"!n# a n('er2al re(lt5 the 2"'par 2"'par"n "n "3 pea) pea) area area lea! lea! t" a pa/3a pa/3all !e2" !e2"n% n% @"r 2"'parate 2"'parate tet5 the appr"7'ate 2"ntent "3 'p(rt t"lerate!5 "r the (' "3 'p(rte5  n!2ate! n .ra2)et 3"r  n3"r'at"n n3"r'at"n "nl% "nl% In '"t 2ae5 2(rrent '"n"#raph '"n"#raph !e2r.e !e2r.e (anttate (anttate !eter'nat"n: !eter'nat"n: a 2al2(lat"n "3 the 2"ntent  ne2ear t" eta.lh 2"'plan2e $th the '"n"#raph%

 **. In the !ase o" a harmonised mono#raph0 is it possible to use a re"eren!e standard "rom a di""erent pharma!opoeia?

N"% N"% The The (e "3 a E(r"p E(r"pea ean n Phar Phar'a2 'a2"p "p"e "ea a '"n"# '"n"#rap raph h re( re(re re  the the (e (e "3 E(r" E(r"pe pean an Phar'a2 Phar'a2"p"e "p"ea a re3eren re3eren2e 2e tan!ar! tan!ar!  that are ree$e ree$e! ! an! appr"e appr"e! ! . the E(r"pea E(r"pean n Phar'a2"p"ea C"''"n%

*4. Is it possible to per"orm a t$pe o" measurement su!h as 7T83 di""erent "rom that des!ribed in the mono#raph?

In prn2ple5 "( 2an 2h""e "ne "3 the 'eth"! !e2r.e! n 2hapter =%=%=45 (nle the '"n"#raph pre2r.e a 2"'par"n $th a re3eren2e pe2tr(' "r an e7pl2t preparat"n%  Alternatel  Alternatel55 2r"-al!at"n 2r"-al!at"n $th the '"n"#raph '"n"#raph 'eth"!  re(re!% In an 2ae5 "( hae t" appl the a'e pr"2e!(re 3"r the (.tan2e t" .e e7a'ne! an! the re3eren2e tan!ar!5 (n!er the a'e 2"n!t"n%

*5. Do I have to per"orm all the tests des!ribed in the Identi"i!ation se!tion o" a mono#raph?

N"5 the tet "r tet that 2"ntt(te 2"ntt(te the @rt !ent32at"nF !ent32at"nF 'a .e (e! n all 2r2('tan2e% 2r2('tan2e% The e2"n! !ent32at"n ere  n"t nten!e! 3"r (e n an "ther 2"nte7t than phar'a2e% It 'a .e (e! "nl 3 t 2an .e !e'"ntrate! that the (.tan2e "r preparat"n  3(ll tra2ea.le t" a .at2h 2ert3e! t" 2"'pl $th all the "ther re(re'ent "3 the '"n"#raph%

4. ,hen should I appl$ Chapter ).&.4/ '9:I;O8E 9:ITS(?

@r"' a phar'a2e(t2al (alt p"nt "3 e$5 the appr"a2h ta)en n the har'"ne! #eneral 2hapter "n (n3"r't "3 !"a#e (nt >=%%40?  2"n!ere! e(alent t" $hat $a re(re!

n #eneral 2hapter =%% an! =%%*% Th(5 the !e2"n "n $hat appr"a2h t" ta)e  le3t t" the (er% Ether =%%40 "r =%% an! =%%* 'a .e apple! t" !e'"ntrate 2"'plan2e $th the Ph% E(r% $th re#ar! t" the (n3"r't "3 !"a#e (nt% @"r '"re !etal5 "( 2an al" 2"n(lt the (et"n & An$er pr"!e! . the (alt 6"r)n# Part "3 the E(r"pean Me!2ne A#en2 "n ther $e.te