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D o c u m e n ts M a n a g e m e n t B ra n c h F o o d a n d D ru g A d m i n i s tra ti o n 5 6 3 0 F i s h e rs L a n e Room 1061 Rockville, M D 20852

R e : D ra ft G u i d a n c e fo r In d u s try o n C o ti p a ra b i l i ty P rb $ o c o l s - X h e m i s try , M a n u fa c tu ri n g , a n d C o n tre l ,s !~ f.~ $ l a ti o ti ~ O o ‘c K t N 6 .‘“0 3 ”ti J X $ g X ;’ g g T & & & l ” ‘“’ )’ . -. R e g i s te r,‘8 7 7 2 -8 1 7 3 ,’ V e b ru a ry * $ 2 ;[)0 3 j l (I^ * .^ -.” T o P u b l i c D o c k e t: 0 3 D -0 0 0 6 1 : T h e a d d i ti o n a l c o m m e n ts b e i n g s u b m i tte d ‘a re ”d e s i g n e d to a d d re s s i s s u e s ra i s e d b y o th e r c o m m e n te rs ”fo rm a ’l c o m m e n ts th a t a p p e a r to jb.iee m tI_ b_ dII.as *.,_/I... th e,.‘ a -;;, d ’w i thI. l a w (F e d e ra l F o o d , D ru g , a n d C o s m e fi c A d t,“a s a m e n d e d [“‘F Y D % A c t 1 ) a n d /o r th e
good m a n u fa c tu ri n g p ra c ti c e (~ l c G M p ,l ) re g u l a ti ~ n s ”fo ~ .a ru g s ~ ~ i ’C P R ’~ ‘i O ‘

c u rre n t

th ro u g h

2 1 C F R 2 2 6 ).

H o p e fu l l y , th e s e c o m m e n ts , c o n ta i n e d i n th e p a g e s th a t fo l l o w , w i l l h e l p th e A g e n c y to i s s u e g u i d a n c e th a t, i n a fe w i n s ta ’n c e s , th e ‘p ro p o s e d D ra ft G u i d a n c e , fu l l y c o m p i i e s w i fh l y & ‘F D C A c trs ‘re q u i re m & n ts fo b (? & ? & ti p-a i d ”‘i fi e * j ;~ ~ u i ~ fg ’ ,.., a d h e re n c e th e re to th a t i s re q u i re d o f d ru g p ro d u c t m a n u fa c tu re rs w i th re s p e c t to th e re q u i re m e n t m i n i m u m & s e t fo rth i n ’th e a p p l i c a b l e C G IV IP re g u ’l a ti ’b n s : F i n a l l y , th e s e c o m m e n ts a re d e s i g n e d , w h e re p o s s i b l e , to a s s i s t‘i n s p e e d i n g th e o v e ra l l s u b m i s s i o n re v i e w -p ro c e s s . S h o u l d th e re a d e r h a v e a n y q u e s ti o n s., th e ,y s h o u l d a d d_ re s s, th e m to , “.x re v i e w e rm d r-k i n & c o rn ,’ ” .‘. R e s p e c tfu l l y ,

read the comments submitted by other commenters as well as those submitted by F.A.M‘E. I SYSTEMS, this reviewer finds t‘hat so‘ e m seem to have a misunderstanding of the scope of current good manufacturing practice (CGMP [also abbreviated by some as “ CGMP”] ) as it applies to drugs and drug products. These commenters act as if CC%@ is.only an inspectionai i‘ssue and m‘ n a application submission issue. Time and time, I read some.proposed item is a “G MP”i‘ssue that need’ & be included in the Comparability Protocols submitted with respect to Chemistry, Manufacturing and Controls (‘c‘ c’j ,M, “i‘nformati.~ r&$~g-fga:~‘iig-.ein t ,waijse ;f is- a issue. Obviously, these commenters have forgotten CGMP-is a requirement explicitly .. incorporated into the United Statutes codified statutes (‘ F&d&al Fiibd, Drug, and Cosmetic Act [“F DC Act”] , 21 USC. Title 9j. These same commenters also seem to forget. _.. .that it is i‘mproper for a comparability protocol evaluator to recommend’ ny a protocol that said reviewer does not know conforms CGM’ because’o g‘a;;,~~~~t~~,‘o;ij~i;i;oduct. risk .,a. 4, .m^ I t do‘a s could athat 7, reviewer,s recommending. to the requirements.profoc61. of that‘ P -’p;idiic.;, suc~‘ a Given the requirement that each comparability protocol must provide proof that the protocol’ s proposals comply w‘t’ “a !’l ih regulatory requirements-ii.~,--.-‘^r.i.r’“, !1,. the . _’ law, and- . ii. .-:<., - --h” ~including the CGMP requirements o‘f the rDC’ ct & a‘ s ;lyeK%sb /II_ thoseiii “p ,~ legally ~iL/_ binding ,-i. ._‘ (.‘ CF’)‘~(J(and ; requirement minimums sgf y.f/yin ~l““C i‘iil‘ &f e F~~,er~-~fj-~,atrons p )> 2 21 CFR 211 as well as the requirements set~fot-th >.$ *, the,/;..,. //, applicable in .‘ other sections of 21 CFR Title 9, a CMC c,omparabifity’rotocol p should be reqiji~edl~t~“p rd;ii‘~~‘ ~~~~~~~~. j ~ statement supported by documented evidence) of compliance with all CGMP requirement minimums as well as, if it does; t‘hose areas%here” the’ submitter’ s systems through exceed 226) the governing requirement d~rLgs minimums’fthe Manu~~~~~~,‘P r’egulations o the’ %M’j7dcesi,n‘; C i (21WR 210 and .,. g pdcKing; P&ii&’ and. of drugs including the concomitant packagi’g, n “I abeling,‘est/ng t and quality operations. Finally, were the United’ States Food -~._ ,* -r.~,,i_Drug *//,s.>“, T_r,. .%. I/.:*..xli j _ ,,~, a., ^, to” and ~~ii’ ) , -a Administra”c~, l”f d~‘ ,._.. _ continue to propose guidance’hat t p‘ermits‘roof p of less than the C&VIP rnrn~~ti& the Agency, and those publishing sucti, would’ e b guiity of’ubverting’he s t regulatory process and, perhaps, subject to prosecution underth’s’ections e appertaining thereto in the FDC Act. Based on a 1988 United States-Suprei-rie’ Burt decision, the F‘ DA has no discretion to recommend or allow non-compliance with any clearly written regulation. Moreover, though firms continually point to fhe”f DA as the controllin~authority over their activities, that Supreme Court decisio’ n found that no firm’ an c validly use the FDA’ failure to enforce s any clear regulatory requirement as a defense in any legal proceeding where the firm has not complied with-any c’ear’egulatory i r requirement. Because theCGMP regulations set forth clear requirement tiinitititis,‘nyfirm d that submits a comparability protocol that does @, provide proof that their proposed : ,I .’ ;,. ~‘:, ^‘ 1 holding control ’ “G MP”

Having

.

systems 3ubmittina

comply with all of fhe requirement /_,(,.._ _tiinim$% . _“. ._ , est&bIished_ _./ fh&-ein ,- i* .a.*,., i’ kh6wi@ly i ;,.,“ le”. ~. ~‘s .~I_, _jl” a de..cient, -~-A~~~.;6ti~~’

Regardless of the’ ui~ance’S su~e$-‘j;-t~~Agency; g i’ b “w hen i‘t’inds f that a‘i,?m has f knowingly submitted a deficieriT combar&ility’rotocol, p ihe FDA F‘ h6?h 6ject that protocol for cause and ot$&stime ttieir revieti thereof when the firti h&‘ drt%dt&d d all deficiencies, and submitted a non-deficient prototi”til that con&ins a certrfication that that comparability now cor%‘lies p wit‘ all regulatory h requirement min@ums. In that regard, this;r~~~L;jsi,ivbul~siiggest that’he i FDA reqti’re,‘for i : each n& drug and abbreviated new drug applica‘ion,’ t tti~t6~‘ %z%i&$n%it t of’h~.,fi;mto,sign, t under penalty of law, a certrfic.ti.n -ff-‘f-ffi. prij$‘ict’nd-prodessks: i a “_ .. _;“,rj. ‘^.‘r‘ I. .*-*-/ ,I ,:,a ._.. “ a) Comply with’ 11 5 of the appltcable requ~rem&-$tii~&~ms set forth in 21 CFR 210 through 21 CFR 226 and b) Each batch produced from the pivotal b&h onward w;ds and, if the cor%parability protocol is approved, will be produced in full compliance with th& requirement minimums of CGMP. Such a requirement would: a) ce’tainly r be a strong incentive for firms to comply S prd;se&tion of any instance where the Agency finds nonand b) ease the FDA’ compliance.

REVIEW AND ASSESSM’ NT E

OF INDIVIDUAL

CQMMENTS

Unless a specific science-based, regul&io’-b&e!, n a word e order error)‘s i thisgrammatical, of thespelling review fdrma,. or cdii;irii’ntsio,“. ~~~~D.~~~~~“~ ~~~~~~~raised

or other issue (for example, concerning I *1(,.,_ .-(4_.,.. comment a “ thatgiven wgfe’g-&iiebT&” ,

in

_I.

electronically or by othej m eans ‘ to this reviev&r as df”l E) &idber’ 2ti’ 3), O the commenting firm’ s or indiVidu”5 1’ 5 ?&%m&%s are, “i‘n geri&al, t&?&p&i; by this .‘ / 0 ,, _. ^ i reviewer. [Note: The cornmen& labeled”C X0,” ‘ fiat? th’ % %cai?‘ &$l e ‘ ~ &soc[atien’ i&% t not reviewed because they were not available electronically~from the Public’ ockets D Web site.] Also, the review order chosen by this reviewer is descending (based on the comment number (“C -nn”) assigned to the commente[s by the Agency). Following the reviewof the forma’ com’ie&‘he 1 t t &$?trotiic comm&ts (“E -nn”) submitted by those that did not provide formal d‘ omment are al$o reviewed.

.! ,_ I /. . ‘, (.

__“. ‘. .i

2

._

o&z The original comments are quoted in a condensecj font (I+xtua), the quotes directly from the drsft ,&‘d~~ti’i~ are quoted i t in a stylized fonli’ (Lydian) and this reviewer’ s text and comments are:in j publishers fpt3 (News Gothic MT) to make it easier for t’ e h reader to differentiate! the “s peake’” r iri?h& variotis “t ext p&sages that follow.] _, _ ,>J-“. ” I f .detail on

-.
. I ,~I_ ^.

The

this

commenters
draft

Guidance,

begin

be;aus;

by stating,
-*e

keyyproblem

“. :. CEFIC/ikIC - does not find it use&l ‘to comm&t _.. ” -‘’ on the subm;;3dn -bf ;h--;; ~g.q.d;a;;;;~$.,&jf

- in.

:. 1”. L/ I,,,, _, : ..i, ,., “/ manufacturers (DMF holders) shduld be’ lvkd%rst. G v&uG$ntly DMF holders are completely dependent on their (often many) customers’ willingness to submit supplements / comparability protocols ., for their (d)NDAs in ..s* 1x. This willin&& isi inv&iably-vkry l&v. ” which the DMF is referenced.

a large extent; this reviewer agre*& with the commentet-3’ lam&t on the status for O’ F’oldie‘ swh‘ ”a rej:nbt~aIso M~ ? b t$te”m ~~~$~cturer< 1 z of the drug _c;,., ..(“_ , */.., -- . ,._,,. made from their drug &t%&nces. However, the draft Guidance provides thk DMF[VMF holder’ ith w a me&& ii propose and memorialize the/r changes both to ens&e that the changes’ roposed p are not beitig prap&i?d to reduce any aspect of the quality of their drug stibst%es and to provide the evidence “n &d& to support the validity i. d‘f’hbse t ct-&,ti@s when their next inspection occurs. 1 Moreover, it c&s~:~-I~ py$$eding ,yithout addling t‘ e burden h to eith& the Agency or the DMF/VMF’ holder to Undergo an a.@ub$$l’pi&cess * that, for p&e&es that the Agency has agreed to treat as “t rade Fecrejs,” cgu~ld, as it currently exists, present & breached - a h’ghly i risks that the “t rade se&&“ ’ status dould.I .. b’ irrevocably 1 .-,;s undesirable outcome. ,, nY ?/,_,,_,,,(__“. “/ *,_I‘._. ~,/. <..i I‘-, _:. ^_I ,“I I.., ,- j.3 ._ .’ “’ ’ _’ * , *However, because a DMF/VMF’S’ied“to‘ i t the accepted site, moving the process from one site to another sife: a) r&dk&s the approval stat& for the prod&t produced .” at the new site a,nd b) recjui-res the current DMF/VM’ F fiola&- to file a n~;y.b~-F~~~‘ ~~‘-“ ~ ~’ and have one of their customers file a supplement referenc’ng i the new’ti-F/VMF d file‘ number s review and acceptance mechanisms for the new DMF,VMFfi,e.to trigger ,”the Agency’ I - .‘~ I current products As with most things, the preceding is just 6n& 6f ihe trade offs that a LMF/VMF ,. (_‘ / .”__ . holder and the Agency must make to preserve the legal’ra~e:secje~s~~lt;;sof t a DMF qr, VMF. Moreover, because products covered by a DMF or VMF are “t iad’ e secret” products, the general mechanjsm, by which the DMF;1VM~,“~ ~ibe~~“n otif;eS “8 ” ” .‘ ” customers is a contractual one betwe,en the parties. is the case the content “t he of Agency or is’VMFl‘ ~,~~,~~~~~~~,~-~~~~~~~.~~~~-~~id because n ot f supposed to disseminate any ’ informationThis concerning a D.MF‘ trade secret status of the entire intorm&on ,iyl,,I.,,. ,,~ ,‘ “I _/I.*,Ix1’“S .-LIL\,..y-c, $‘ ’ -’ a‘.’ /:‘:‘ .,*““. *” ,+;.:‘; ; ./ -e”. : . **i* .‘$’ -: fife: . “r j,_d I__ , Ib hplcjey’ s process has When notified by the D MF’ VMF*“i h’ Id& ‘ / o tt-@ DMFNM’ F changed, the drug product m anu~~c~ur&‘ (the part~‘d‘i‘re~~lyacc’untable’o ~ ~ t the public) has the responsibility for addtessing the , .-.+,:- i” ofi a)%a”,i -.7r,r.iT * and b) __ _/^,I...‘*_ issues_,~. ..*,.>“, a-\.cdmpdr%nt;.-,-.*< comp&-ability process change not only inferrialijl but, ,to the extent they change their currently approved or l$q,,psed (: ,yfilings,‘~‘ +> i,,‘~,i~.~i~~~u~“,Agency. * i~-‘r.,,,“a rb>h<,%-v.. ,_,.:^.,l..,llz>~ -.,A ,‘a-..$* “: +L-.“.d,‘.A.j,y”. - .A, *xIil.4 t I w ith ~ the ~i,.id.:,“ . &” .,) ,1 . - 1, +&$ir &.“ ,%:I ,““Z .Z,$ .,,,, .r ibi *c* .L,. “f r _ the

To

,~._

,..

Since this is the case, it‘ is .*.,r...,..ji.,Cr product that bears the direct , manufacturer 1”_ I __ ,__* ...” 1. the drug i , re‘ponsibility s forbbt~ining Agency approval of the drug-product process changes, should Thus, bewhen the drug that the DMF/VMF-‘oCiler’;‘ hange any warranted, h f s precipitated. product manufacturer‘jndi c thil It’has z”D x~F~~fqKg”$ ;i,g.~ he ‘ changes do not precipitate any change in: a) the approved or ii&n’ & m&u&cturing process for the d’ug r product or b) the d‘rug product ma,nufacturer~s filing requirements, there is no need for the drug product manufacturer to file any comparability protocol. When the FDA’ext:inspects n (in an on%ite‘ &s) & the DMF/VMFh&der, ttie~~DA ’ personnel ,invqlved.then l&&the responsibility for reviewing the holder’ 5 records that justify the accepted site’~’ ~~~~nges“( i’~iiihing . _, s ~,, ,._ j a‘ny-&d. all personnel, equipment, .,. ,(_.. .._ method, control, SOP, work’nstructron i or other change that the hold’rhas ” .1 1.made),’ if e any, that the holder has made since thei’l’ast r i‘n’$kction.
. .i j,., . “W hat the API industry needs is a post-approval change authorization system that will grant authorization to”i mplement the change to the API manufacturer itself instead of to its many customers. Within the current system the use of comParability protocols will almost always be out , ,. _” .” _ ,,,.,i I‘... is;. . of reach for the API” manufacturing industry sector.

.“..‘X’ -’ _

_ ,,. _‘ :.

The

commenters

continue

with,

they fully

This reviewer’ oes d I@ agree say is what they want; they can disclose’heir t proces.~~s:. _I. The

with the com~ment,er~’ remarks_‘ ,, j,.because * ..,-. ,-,_rl**-,r-. if file NDAs orA$JDAs’or’heir f t drug substances ., ,_ ” ’ .” ” .‘ :

what ,, _and. i .,

1

choice of filing route has been and,stiil is the choice of.the.‘na~~-ufacturkrbf r the drug substance (active ingredient or component): The cumbersome process’ hange c mechanis’ ~s-‘ m ; burden, imposed by electing pursue a DMF,“M F filing’ather ). .^,” ..,,,G..l & Q DA, A~DA,.~~~~.‘ i~A~A’ j~?~ijing,“~ ~mes t than ‘ o C .~ ..(, /_‘.,.:““y .;.4 , L , : ~ -~“e rliii.Li,.“. .~‘.‘-.~L‘~~~ (*- r -4 ~ i- 7 -‘ **“ A with the “t rade secret”a dvanfage ‘ that a DMF’r o % !“/ ?i’i’ g ‘ in provrdes. These
FDA to resolve to be obtained

to

^

commenters
this problem from the currently

then
running

state,

for our industry.

“C EFUAPIC further efforts to be taken by po 1% e I y requests I Furthermore, we hope for a certain relief in relation to this issue FDA’ s CMC Risk Based Review project.”

reviewer would again suggest that .th.e commenters cease looking the (,_ 1, proverbial “g ift horse in the mouth..” As this reviewer suggests; the“% c.;DMF/VGF.+i*) 1‘ ,,II, e< WC “.shduid” ;*r;p;.*q&&“, holders -3, &+~,s$7z’ be help/.ng the Agency ~‘^,?.. _,” >a$.b*~*>fB+* 7; ,“r &, finalize this diaft’r;fo.~~i;~~~lixgurdance i that the DMF/V?Y(~“o Iders c%‘hen t use as a template for modeling and’ emoria.jizing m the changes they make’o t their~processes. Then these holders cdn use their guidance-compliant comparability protocols and reports (that they would’ ubmit’n’heir s it next annual.report) toi $su’port p those changes when they are next inspected and b) ensure that th.eJr post-c,ha~,n.ge product is comparable to the pre-change product, that: -i) the Agency has’& cepted” “ as being safe and CG’ P compli&-rt M a-nd”@ t‘he customers have, been receiving. * i ,. :, ” -^ I _, -_,.

This

.‘

,,

ok: The originai comm&&*$-e’ $ed & jn a,,c&&yserj directly from Ihe &-if{ guk&r$% are’ubted q in a stylized font reviewer’ s text and‘ommknts ..,,, #“” &?*‘*Iri?&y a Y_ I/ 3. c are* in publishers f&-k(Nktis *; * for the reader to differentrate the speaker*‘ in -*tt%‘arik.k v When addressing comments made in a tabular format, this required) preserve the commenters’ format and,, in gene&l, reviewer’ s remarks after fhC& 6f %e c&mmenter.] With respect to the As the COt?ImenterS
represents comparability however, attachment. guidance country’ s protocol we conclude In addition; may be enhanced. the

,fon,t (~~&&j,~the quotes and, in general, this Gothic MS) to make it easier l‘ext passages that follow. reviewer will (to the extent: appropriately place the
(Lydian)

introductory

comments,

please

say, “T he Pharrnaceuticarir;e,rchand,Manufacturers of &e$ca(ihRMA) leading research-based pharmac&ical and biotechnology companies . . . The represents a potentially useful mechanism to reduce the regulatory burden for sponsors; that its usefulness can be enhanced through the suggestions and revisions detailed, in the .>,,., / . ‘ .,,-_ c IT . ” & e’&%&~~~&&~l ‘ f observations highlight &a$ areas &herk t&?&&ir;kss of the
protocol as

_,x ....- ,..i

consider

the

following.

“ 1.

The scope narrow. The gtidance
that each process,

of a ccmpnrability suggests

curre&iy

de&bed

..,., , ; “” .” cIs.,s, __.,-- C C i :‘:,” i;*, ,_.i.. ,_ :; .;$,,I ”.;, r‘? . : :>.II i’ .L: r: ;, ‘ in the’ z&ggu&ance & 1s too

that a comparability

protoc~l~~n-~~~~~~~e
If we

,‘~; v

o;m~~~~~~~~~~~~~~s~~~ut
enhancement.Jo-the wider?‘ * regulatory

. . ._.(~.,*, ,

change be discrete and specific. the scope of the use of comparability

are to make a significant protocols must be &‘be a

reviewer finds that the commenters’.“~ implicjt , protocols to be allov$d fo. be ~o&&‘refe.arid c Moreov&, tho&‘ & they state that the proposed
This
useful enhancement mechanism to reduce the process” regulatory of the regulatory

that,

proposal is that they want non-specifk! guidance “r epresents a potentially burden’ for sponsors,” they seek a “significant as the~‘6’lo”t iiiig fl tiiil d‘emdnstr~te,.“s ubverts
I iA‘ entire & $-ocess’’ , suchas’ynthesis s in the manufacture of a drug product.”

that

process.
the protocols of a drug should &b&axe-or be made applicable a process change G~nychar$ anywhere

“S pecifically, or purification

This This products,
process “T he key manufacturing light of the

reviewer fitids This is. the tase tjeca’se u “ address
change anywhere “a ny chanie in the

- ,. comt$&t id bebisin&&-tuous. Ihe ,‘~~,~t‘;e~“~ ~~~;““e xcept d T
in an entire process” prod&t” of a drug ixotocol adequate

” .. . ._ ior‘ app,ications.,. ‘ (protein
l‘a

manufacture

for most drug substances’nd a except for protei’ n products,
is the availability substance and

to allowing science proposed

use of a comparability data to demonstrate changes.”

in such c&umstances Glerstanding of the _i A .I)_

of sufficient product in the

This reviewer could,@ agree mpre with what th’$S~fa&-n&.,sd)s. i Unfortunately, the, reality ttia‘t’his t re&tier t& seen and that the industry has proposed time a?d time, again (e.&,‘ h& t “ reck6 @QRl r‘eco&-tmendation’ concerning blend unifdrriiitj;-as~~~~~~~t and in-process testing for tablet and related prdducts) 1s th& th’ i‘n’i;stcy & d otily’iiks f a &%I @I%. ’ ” . -’ The samplirig an’( test- ~plans c that they propose and/or use in that r‘ecqrnm,et++n’ and elsewhere are not scientifically Sound and $6 ,-n’t provide d
“s ufficient manufacturing science data. ”

1. 2.

3. 4. 5.

. ), ., L.: For example, p‘harmaceutics! manufacturing firms:. Improperly use sampling plans that sa.mple one plus the square root of the number of conta’ners‘or i f incoming materials, Fail to adequately assess “i n-process u‘niformity at each stage of the production of their products for al’, variables,.th&~may l ,. 1,,, ad’ersely*$fect v tlie requirements established for the, product produced, Sample 10’ of units’ ~~m=ba~1-iks”~ ~~~e s f iJIJis’eed.to n be sampled to meet even the minimums’ eeded n for.9%%.confident ,, . _( “. decisjon making (ANSI Z X9”. - .‘I‘. or IS0 3%1), I_ ” ” Use specifications that are J& scientifically sound and have no justification beyond they are ‘c ompenditil “ specifications that are i~~~ii’e~-~o;“a ~~‘ ~ a ‘ ~ ONLY valid‘or f the prod‘ct u in commerce,+afor th$‘-eiease’~*ereof;‘ntiiori ~ a When they are-drug product manufacturers, deliberate@ ignore the’ G mP C‘ requirement to use statistical process control-for.“b etch acceptance (2i CFR

. n ~ “” ” ”

211.165@)).
Thus, process. product. these firms representative fail to provide sufficient ddta data on al.1 fa,cto,rs, th,at, may
process parameters and controls _,

much affect
necessary

less the batchand the process and/or
to make the substance or

“D o we understand product?”

the critical

Based on the preceding, the answer is, in most cases, a _ .‘resounding .?i*AmaNO - the’ _ ?“* ,Y.I.iiYl~ industry does noJ truly understand what the ,crit,$Xproc& parameIers~. ,;,.u . and ,‘ -3 .I lil 1 j,,__/ “ ,, controls are toreliably manuf&ture CGMP-compliant batches ofthe drug substance or the drug product. If they did, theie’ be-no recalls forthef&~ureof’ ny ~ ofthe$ to meet their ‘ post-release truly uri;te~“~ ~~~~~ w ourd pha_ri71F~cb~e”i a. (“~ gpj”; &?q%zenti” As all know,
“D O we understand

.,, _, .

this: i&not
how robust

th,e case.
t& substance or p~odu’t~~ d ii;‘he t

_. y, _,“^ ,,, _il,*

~_ , ,. ,x .~I >. (_,,., \‘
..,..^ <

_ 1 _ ,l.,” I .“, “” ~ ^I__, ^, “. ~ ,:. ,-~ : /; 1 ; Based on-the faii’re u to collect suffrcrent data on the-originai-process and the factors that affect it as-well as the’ecaijs r that‘ o.nt@‘;etb c ; occu-r;the answer is . again NO.
data are available, $en _ and drug product’l&&‘e s 6 more comprehensive changes to the manufacture * Li “; ,L,E-L.”i 1 -;“lii ).X,*,I-J’: ./,7‘.‘ *ia XGX~~ing a comparability protocol. ” and*control ‘r;%,,,>f$&illof I” drug i , 1 .” .,“i

face of changes?”

“If these substance

“1 . ).. i

on this reviewer’ s knowledge, the preceding statement.should have. with “I fthese da& were a$i&je.“ ’ _“a , _^/_,l. .‘* ,,,/:. This is the case because the manufacturers do,,~‘col-lkcf-sl;f~icient ~ ,,,.. Il~.-iir**r.ar”, ;r-~~~~batch i( _” ,Ij,zG.’ ” __ W representative.data at each .step in their~processes for all variables”t hat ‘ may or ._..,“( . do affect the control of their processes-or the qualjty of their produ%*for’he’r t i initial batches much less sufficient data to truly des,cribe their processes (which would require the collection of this data foreach variable factor ttia”t may affect process control or product quality for 10’ to lOO’o‘f’ atches s &&‘ :. significant a :$ b period of time). ?_^i ., :_j ,.., ; .‘ , ~‘ _ 1‘ ,+’ !“ ,‘ , ;1 ‘ _j :, :, )_i :_ .‘ _b .: j ,) II./; _.(: i .‘ i.( ., :_l_.,_ ( _,( , begun

Based

_^.,

.,

!‘Furthermore, m,a& using acknowledge circumstances’

if such knowledge ilIl -nu;l-iepb;t _s that the guidance .)”

i . . “_ . ~~ /*, x1 /i ~I .‘3bli”\ ) ..a >.A ,._,.*/ is available, all changesmade under a comparability protocol’h;;~l~~~.*‘ ~~ s ~ ., ._,I s., * ” s .,a ra*er eII _~ than .,,~g&” G ne ~~f~‘o;;“f ~wer I.-, “p > propo;e’ ‘ ~ e-z- “g --g -~~a~d~“r ”- (qy;’ .- _ “, . , “1 j., “^ -.i.a-” -,1., indicates a re,duction of more than one category is possible’ i‘n sonreV

I” ” ’ ‘“I / “‘” *^- f~ ^., L ’

Again, based on this reviewer’ s knowledge, have begun with “U fheSe d&a were>v~Mj~e?: The commenters’ statement’ is, for the wishful thinking.
.‘.,‘.‘,‘ “_,,,_,

thepreceding st&i%ent _ should I ,. ,,~_, I” ’ . ’ ‘ *I^_” . i‘ ” reasons stated’!6.&usl’; l y m ore” ‘
consistent ,. initiative. with 11 the o_ j I. “,i I, integrated quality system”

“T his being

would discussed

be

a more as part

science of the-Quality

and

nsk-based for the

approach, I? 1 St‘ entury C

preceding same refrain “T his The commenters’ odds with reality.
“2 . Additional original details submi&ioti;

The

comment reminds this reviewer of a song “, ,. would be . ..“ ” ’ statement sounds good but is lacking~in
sl;o%I-be & %&i‘ ‘ &&t

that”c ontain!s‘he t ,, ‘ ” su’ stance b and’t’ a ‘

.‘ .A .,.“. ,‘r; ‘“p .~i. .^“d k “. -I,&.,*,. . komparab&ty protocols%?aGae;

I-ii” yT_.I(u,&h&G *-s,*7*. ” ,a*<( il*i .i” in an

While we agree that comparability protocols may be quite useful in an i;;itialsubmission, severaiquestions -‘ “~ surrounding their use in that manner need to be addressed in the‘uid&%e. g F‘or exam$e; <‘fir Ithen- .‘.‘ “:use’ ~ .r”, lI.rr, ~-, j _, *,,_/ ,_ lengthen the review time? When and h‘ ow sho’ld u -the’ reviewer be alerted to Zig’ &%t‘ nce e of a comparability protocol in an initial submission?” This reviewer thinks fhat tag cM’ c lriformation”g u~~ance.istij~Ir;i~~e~~~~~.”~ ii‘.“. . ~ ,I” “a ,. ,i.ln-i”ii”. :. 2. ,,~.,~.;,~~,i*~~~.,‘~~~,~,..:~.~ r” .,,,*& ~ ~~~;,~~~~~“ ~,‘ ~~I 1 r>rW,.-G;bh ILlid$**ai*&’ .;‘ & .w :r.iri. i‘**;.l _* * - ,~~~~‘ , I./ld” ~ ii(* w r,,s b < .

issues raised should b,e addressed addressed therein. This guidance is not the place raise here.
guidance comparability should include~a protocols.

of they

have

n@

already

been

a$equa?eTy

,

for addressing

the

issues
mighi’;&@o$ i

the

c‘ o’ m e‘ters m’ n
.+ ., i*,,,( :>*-b.,c..a-‘“, .e/j_ I. _... ^. r ~ candidates
.,,”.‘“. , _ ,., * m~,..~w,j., ,.. ,. _ _, ~ (I_ as well as ” _ >_ I, .‘ .*. __

“3 .

The for

list ofexamples’fdharigks’hai ~ t
of the entireconcept ,, suggest t‘hat

Examples would ensure identify specific changes This reviewer examples and

greater understanding for considerationl” agrees but would chan’es‘ g that,.

of comparabZtj‘;totocols, i _\_. i‘hA+“F ndusfrji’

..L&6ik.6f&s,.

“l jased*‘~,,C~~P~~~~~jih”e =‘ ~~~~~~~’ ~~~” b d ~

“, ,L I . ,1 I,X

Information
“4 . Step down

draft
reporting

guidance,
can

the’ndustry i

_,, _- ,._” feefs should%e II.
protocol-tj;pically~ should capability a&w, “’

inciuded~ii7~sucl-i _, ,”
the ” emihasiie of “‘A ngle repor&g.of ,. . changes ^ .,

a ii&
x i i , _ ,I_

be enhanced.
brie’ cf ’ _i-, ,” ^. more approfriateiy in determination

The draft guidance states that a comparability category lower than normally wouId‘e*the~case. b As noted above, we maintain that the guidance product/process complexity, robustness and reporting category reductions. ”

:consfd&ation Grsus “& l&L

^’ _) “”

This reviewer does not agree because the key to any reductionshould‘ e b flitit ,. ..,<-. _I,, the submitting firm must have: ~ ’ _ ;;p;,...,^ ;,i7.:: :.‘;-..‘ .’ ” .“ : ,-,<,,:-*:,_ “ -$?. -^ - ._*,_, sound’ ndfor each appropiiate&$iy the ,ijro~ess~t~~fcTe~~~~-d”i ;m’j~~~~~~~~s~,. a of%no&edge rncludrng batch A., A~ scie:ntifically representative data Step. iii 2 )‘ ,, , -

\

_

,

I,

.b

/.

,_. :.

..,( j ). _‘.,_.

,., -.,* :

B.

that t)e fi,rm has +..@iecj e,ach product in its cur’ently’ pproved r a Established those for eac~co.mponeht adequatemonitoring‘ nd a inclu,ding

variable that & .I, ., affect state,” ” ’ acceptance1. _,a>has controls ^”used, ,,I‘.“.that ._, _ _ *in -._ been

the “the”p i’ cess _.l/_,. _^or ..,...1. . ,, o 1 on each variable, ~6Gh+6d.,.f~;flgey”f f”” yK;T”x

/,I_ ),..1” .

-I :

c. D.

process or the product, c -Estab,ish.i;d~-Sdi~~~fic~lry;sbijnd.7’jSfif~~ations:irdi~eadh;spe~‘ic~~~~n f

~~“_ ..I&“_ /,, *... .“

uses (for incomihg acceptance, .~,,,) in-process release and product c ” .Ihrelease) ,l..~_ and_.j ,“. .^ . _“. js”. pV” ,^(I. .‘ , Collected substantiating process represe;nfafi\je’ a~~~~~om “ ‘ d an appropriate _-._.*..s...,, I, number of appropriate’cale s batches that’st5b’.““, “* ,“. +b ,..*s.b.‘*ca”.iL-” th’*‘iro”p o’ sed’ p -‘ .‘~““I _ e -3,l ishes , % -;:;p”+ e /,./d ‘that change does not adversely affect the product - drug substance ordrug~ product - in any manner,whatsoever. Since most firms d’ not hav@‘ -t’hey o w t so-obvidusly .;h-6~I”$ -t~ ?spkct:.fo ,‘” -, preceding, in this it is difficult for this reviewer gu‘dance i much less more to support’ ven e than what the ttie draft

” I .

one or more of the reductions proposed proposes

“T hus, the over& process should comparability prdtocol to help appropriate .”

be a major’onsider~tion.‘~n’ad~i;;;r?o*ili;;t~~o~.~~ c ~ a the Agency determine’ whet&C a proposed

_ ‘e .i ,)a% \,:*,ti...., <#“* “a . *‘~,*zY,~~,~* ,“, b,“./es.,; “ a<* ,+:\-* jx”m , . Zanges desc&ed in Xe r,~~~~g-‘t~~~~~-i~‘” ~ ~ ’

,^,, .,,. __ / _I .I I‘ This reviewer almost.agrees with the commenter’ s statement - if‘nly o they ...a~:.. ._,x had said,.“t he’ egree d iifcharacteiizatidri ~~the’veral~‘rocess b p 1 jb.~, . ..‘’ i , . This is the critical consideration. ,IF the:; firm,,subtiifs b‘ ddy of’ e 2iG$f61;‘$iat&oii clearly .’ l’stab~iishes e that &~fpLtiuly a? pkkss-reprehintative _ understand~tff~i~~~~~~~ses, ad‘ data c on’ t ;_. _I”; 4 .,l;x j dj al, of the factors fhat‘lfecfs a that tirocess, ~vd~uces~~,,~.~~~~~c8ii-lj;l’~~t’ i .b.“c $;~c’ _ and operates in a manner that demonstrate-5 full C&Wco’ pliance~i m Agency should considerthe’roposal’n p i light‘fthecurrent o and and make an appropriate determination.
“5 .

T‘ HEN s‘upporting’ata; d

the “

The submission, review, and approval of comparability proitbcols in dMFs Gz@ire greater . clarity. As DMFs have not been subject to approv&, will’he t Agency begin & eating ‘ D’ iFs(oF M parts bf DMFs). ,, _“. _ .differently? I ,~ _.,..I ,~,. How will a DMF holder and 41 authorized users knbw w+en g comparability p‘rdtocdl h&een reviewed .I 2, / and approved by the Agency?” Though the preceding questions can on,y be anSwere&’ by”. fhgk/(g-tic); ;,, ~$&‘& . I.*-*-.‘(,..,‘. . I reviewei w..uid n‘bf&#<,iRat “T he. n.y$gfr’~’.egf 6 oth‘f‘t/,wn g: ?ybG ~‘~M.i’~fi61:d’r ^ e -.is, an

activity that the Agency should not engage in because th’s would-be’ i s violation of the trade secrete nature of the D,MF. _, I. :. .“_ ,._ i _.,(lC v_ IX “Io j_i . ‘ #‘*iv “I .+.%A.“. .___L , I. Currently, this matter is a contractual one between the DMF holder and tl% ” “‘” ,. .A.. *z _s__ ..< _s ,.. ” firms that purchase components’rom f that firm:“. “I ‘“~ “” ‘ -‘ “ ” ’
“6 .If tests acceptance and studies criteria, approved the guidance in a comparability should allow pr&k&l for reporti& ,,, do” categories not “k &t other -@&@inkd” &anPAS.”

” %” ‘

In general,

this

reviewer

cannot

agree.

.

subm”iSuch tting

findings p rdfGcd, tfie’ should

be N(jt a clear does”. and are adeclust&jc “r ed not on,ly because

flag”~ i that _. .^ Cj’;;‘~r‘Tana’$+r indicates pi;‘,cesses, the_‘ _. firm i , o that, .._L_ for a PAS but also th--body o‘f data’ .“.
?&i&v& proposed to deter&e reporting.

As such, these failures should trigger CGMP compl:;‘ nce a concerns. supporting the original submission.
“T here should be some allowance acceptance criteria are of so little appropriate. ”

trigger the need it casts’oubto.n d .1 .”

*’
if the missed category is still

for disc&sioni consequence

with %e’l&j F that the original

This reviewer dopes not agree. _ .. ;/,, It should not be left up to reviewers to’ uess _^ whether g or’not * missing ’ “I I -‘ ‘ acceptance criteria are of “x ” degree of consequence - they do ,j%&kriow~ the process and cannot, from the limited testing in the protocol studies, know the long-term consequences of the failure to meet submitter’ s acceptance criteria. Obviously, the submitters thought the acceptance criteria were important or they would not have set th*em where they did. -_In support of the preceding, this reviewer wil,l offer the follow’ng i example. A firm manufacturing a drug substance proposed”t o ‘ change their pro’ %sby & eliminating a filtration step based on the fact that the drug product stF‘I met the I LISP criteria for that drug substance. However, to do so, they had to exceed their current 5cceptance~criterion (“x . 0.x -%“) for “s alt” in the drug product. The Agency was convinced to ignore this minor excursion because‘t i was only . . .: ..I., a small change. Unfortunately, that small change significantly affected the long-term stability’ of that drug substance and the drug products made’rom f it increased the level of exposure of the public to the decomposition products generated, lead the firm to ignore “c oncordance” stability failures and projected failures p‘ n the drug substance until the, I/SPcould (_.,~...-.. persuaded be to drop those tests.’ The firm was forced to reduce the stability dating period on the drug substances and, the drug products made said drug substances from five years to .,,^ .^ two years. The result was that the negative impacts of that drugsubstance”o n the public were greatly indreased and,in some cases, unacceptable batches{& the Agency subsequently detected for a few batches) were used drug I,. to manufacture __ . -s,. “L ” ,“. products that were distributed. ,e _,_.=-,j e, _-, ,,-.i, I,.... ,” I , -‘ All because of a small change.. From this reviewer’ s viewpoint, any’ dhange that has any’ observable, reproducible adverse effect, regardless of ifs apparent iha@-Ctude, on any of the approved specifications should be rejected. Changes should improve’he t quality or, at a minimum, maintain the current level of quality for the drug substance or drug product covered by-the protocol.
“A lso, , change T&is allowance should be made f‘or &I~ the reporting category &A< GoYa n&-&$‘pply ~ for & k ‘ ., ’ .’ :

(in the absence r;vie\l;/k;

of a comparability protocol) cannot,~surjpo;r.iih~~i~~~~~~~l

in the-event it would -taf;&e;t* ._ 9

be 1.&s restrictive than PAS. ” ., ;. _.. (i 1,: “1 1 ,_i ,_i I, ._

: . .I

_^,

.

^ ; ,(_‘. .

;. “

_.

.

.

.-

For this rev@yer’ ,‘ _> .,I point of view, all changes in the process, _,. ^‘ s . of component or raw mater&f; and/or changesto the”f i’ ished n product, including vendor source for packaging components, minimum, require the submissian of a suitable comparabili‘y t Having addressed the commenters’ g‘eneral examine thosejn,the 25 pages of lSbulated‘ pe’ fid s & submitted to the public docket. komments, comments

., including padkaged should, protocol.

source drug at a

this revietier~will now that this dommenter

.

^

,‘

be

defined

in

the

acceptance

critei-ia

of

the

Contrary definition

to the commenters’ of comparable should

remarks, be independent

the

“c omparable”

as follows:

Thus, no process or drug product should bej udged comparable if its produces product that has any safety or other standards or specifications that are materially outside of those in the currently “a pproved” process or To be comparable, every aspect (variable factor) of the safety, and the identity, strength, purity and quality of the drug substance and/or drug

Thus, changes that reduce product quality should be unacceptable. Based on the preceding facts, this should be ignored.

safety comment

or

The example clearly illustrates the nonvalid nature of the commenters’ proposal. First of a//, a new process is comparable to the accepted one i7and on/ if the changes do not increase the risk to the patient. Second, a new process is comparable to the accepted one if and only if the changes do.~@ decrease the purity of a drug substance or the

An example of a criterion comparing related substances from two processes could be that T‘ o demonstrate the compatibility of the processes, the total related subkance’krage a from process 2 cannot exceed that of process 1 by more

Based on the preceding, the primary criteria for related-substance impurities wouid be that the acute and short-term chronic toxicities of the related substances should be no greater than

This reviewer is an example

finds of:

that

the preceding

2. A widened specification 3. A non-comparability

In other specification

words,

less

safe

and/or

less

pure

> , <v ,_, ._ .,., _>_/ .;/ .,.. “li” _ “~~,_ ./_ ,: I%-.IV*“,r,, -ri.,,* j.~~ ,~ ‘“_,” _,. /_. _j

iection

hidance he

Zomment

/ Observation

Rationale 3verall

/ Justification format consistency.

ieneral :omment

a‘rt V, B-G should have their own section title section VI for example) “S pecific Protocol Issues.” jection V, H & I should also be a separate section section VII for example) “A dditional Issues for Comparability Protocols on Master Files” (for :xample).

This reviewer suggests that the Agency consider the commenters’ oroposals, but“w buld suggest the last oroposed title be changed to %sues Specific To Comparability Protoc& For Materials Controlled By Drug/Veterinary &faster Files.”
Zeneral :omment
The usefulness of comparability protocols dictated by how easily they fit into overall :imelines. 1. reduced comparability [rather than FDA protocol 4-6 month will be project 1. In some cases, it will be faster to call the FDA with a specific pestion, documenting the teleconference, rather than waiting For the approval of a Comparability Protocol in a PAS, and then zompleting the work and submitting the application (with reduced submission reporting) to FDA

approval timelines for review and comment current PAS requirement)

While this reviewer agrees with the “t imely review” sentiment expressed by the commenter, the reviewer would cast Point 1 in‘erms t of.“r edu,ced.KJ review timelines. for comparability assessment and comment”* and leave,jt up to t,he Agency to set time!ines based on protocol complexity and length rather than those based on arbitrary dates.

Though the reviewer finds the commenters’ remark not directly pertinent andjnteresting, this reviewer would strongly recommend that no FDA official engage in such practices - all questions bearing on any aspect of ICGMP^ shouldbe submitted in writing (e-mail bi‘ FAX) % and an appropriately vetted response written response (e-mail, FAX or letter, as appropriate) issued. Since it is inappropriate for an FDA employee to give advice that does not conform to the requirements of CGMP, the Agency would be better served by a) written requests (by e-mail or FAX), so that what is being requested is clear and b) written response (E-mail, FAX, or letter, as appropriate) since, unlikeverbal discussion, it is: i) much more difficult, to distort. by taking passages out of context and ii) easier to track in existing database structures.! -,
2. Some evaluation points such as impurity qualification or dissolution include FDA groups in.addition to CMC reviewers.

2. inclusion in protocol response

of other FDA groups (Tox/Biopharm) to assure completeness of

FDA

rhis reviewer agrees and would nclude Statistics, Manufacturing and r‘oduct Quality and the Fie.ld nspectorate as groups that should be nvolved.

This reviewer’ agrees “a nd notesthat. some changes in equipment, process control point, or inspection plans (sampling, and testing or examination) would benefit from the input from :he Field Inspectorate, Manufacturing and r‘oduct Quality, and Statistics.

i‘

-

~
“. ^.

:;.:
.; “,_

:
-_ ”

.

_, -

12. ,
I. k.. ,. ““,, *_

ection

hidance .ine iection titles constructed as questions this construction should be avoided. guidance in the form of “y ou should” md uncommon in Agency guidance. !4 botnote &em o& Provjding is also pdd

Rationale

/ Justification
of other Agency would be,qpre

ieneral :omment

Iuch headings are inconsistent with the’ format suidance documents. Shorter section titles )eneficial and easier to scan and use.

2

Jse of the same term “p roduct” to mean anything tom drug substance starting material to finished kug product allows for excessi++gbiguity fn ater parts of the Draft.

n parts of the Draft in which thk FDA x _recomm&&m~W~ight .~Z .j I .I,.. _. ^,‘ .Z “ ‘ . apply to more than one component, more speckic’ b~a~e”t o % ;pecify drug substance, intermediates or drug product ih;hbuld Ised.

be

Nhile this reviever understands the zommenters’ remark, the reviewer has IO problem with the Draft when the term product isused to. t$c;“z $( either the drug substance or then .drug product. Further, the @viewer found no instance in the guidance where the term “p roduct” could be taken to mean an intermediate or in:process material. For example:
l

This decide :hanged

reviewer where, in the

leaves it up to the Agency if at all, the text needs to manner suggested.

to be

For clarification footnote to read:

of

Footnote

2

change

that

In lines 40-41 characteristics products only;

and lines 98-99, appear to apply

GMP-type to drug

“2 The general term productas used.in this guidance means drug substance, drug product, intermediate, or in-process material, as appropriate. In general, the use of the

l

It is unclear if lines 476-520 .refer n$e!y to biological drug substances or also to the products made from them, and- how the SUPAC Guidances (drug product processing) would be applied

However to address the commenters’ concern, this-revi,&wer propos8s to add clarifying text to Fodtriote 2 as shown in the adjacent column. 1)
32-34 FDA Draft notes that “s hould” (in t&e” text) indicates an Agency recotimendation, rather than a requirement. Please add clarificat& igd&ting the wording that w)ll b&’ us%l for -required elements.

term “p roduct” for an intermediate or an inprocess material should be”r @ricted to: a. intermediates and in-process materials that: i) are isolated from the process and ii) w be held for extended periods of time before being reintroduced into the process in a subsequent process sfep, or b. intermediates i) purchased .from dr ii) supplied by a facility other than the facility used to manufacture ,the ,,tjnaJ product produced by the process.”
Clarification of required elements “m u&” Vs. “s hokd” vs.

This reviewer disagrees with the commenters’ statements. is clarification requested The guidance in a inappropriate document. __,“,,

Guidance documents do not and should not set requirements. Guidance simply provides the Agency’ s thinking on one way that the:rTgulated in$$ry can meet the requirements set fortii in the [‘ C D Act and the CGMP and,, other applicable regulations regulating the conduct .of the pharmaceutical industry. /‘ _ ” .~, .,

:-

/

;ection

hidanck. he

Clomment
3ackground glossary definition Jreparing

/ Observation
or Introduction Section needs, a to provi&.the’ sponsor with a clear of regulatory and technical terms used in a comparability protocol.

Rationale
slossary needed

/ Justification

for a glossary are: Zxamples comparability comparability report, analytical arotocol, related CMC changes, -eference standard, Jnrelated CMC changes, drug substance, drug aroduct, isoforms, orthogonal‘ te&g,“p ;dauci‘ rpecific, process-specific, current protocol, obsolete protocol, qualification or validation lots, PAS, reportable categories, me’ od m v alidation, ‘ process validation, FDA review period, criteria for non-comparability, stability-indicating assays.

This reviewer agrees with -the commenters’ suggestion for aglossary but thinks that a key defrnrtion that should be included in this Glossary is that of word “c omparable.” This is the case because the goal of a comparability protocol is to show that the output of the postchange, process is comparable to the output of the prechange process.
Change “( the act)” to “( the Act)” Typographical correction

This reviewer agrees but would prefer the use of the com.mon abbrevjati,on “F DC Act” and change “( the act)” to “[ FDC Act].”
Indicate protocol the difference between a comparability (CP) and a validation protocol.

The use of brackets is typographically over nested parentheses.

preferred

This reviewer suggests the obvious,‘ a CP determines whether or not the post-change product is comparable ta the pre-change product; a validation protocol establishes that some thing (system, process, method, equipment: performs as it is intended or required to perform. Thus, a CP compares product Ai,,, tc product Ai.l,, when process Ai,” is known not to be the same as. process &.I,,. .. . ., /I__l. ,i,

Once a CP is approved: a) if the change is small and evaluation is being performed on commercial scale, a validation protocol should not be required, b) if the change is significant and the evaluation is being performed on ,a sm,all, s.cale batch under,the CP, then when the change is implemented on full scale, a validation protocol will be prepared.

This reviewer does comrnenters’ remarks made in the comments

not understand apply to the section.

how request

the they

The read as follows:

change

proposed

not

only

properly

In footnote 5, clarify category is ensured and how the between the agency and the applicant

agreement is reached

While

this

reviewer

supports

the

If the matters raised by the commenters are important, the text of the guidance should address them. If they are not important, then they need not This reviewer leaves these decisions up to the

IV.D

for a potential

exception).”

“F urthermore, submitted

because a detailed plan in the comparability protocol, to provide input earlier and is less likely to tion to support changes 01 (see 1V.D for a

will be FDA has in the request made potential

less likely to request additional support changes made under 1V.D for a potential exception).”

information the protocol

to (see

the effects of the change earlier in the process without the use of a Comparability Protocol.

than

would

occur

“F urthermore, because a detailed plan will be submitted in the comparability protocol, FDA has the opportunity to provide input earlier in the change process and is less likely to request additional information to support changes made

distributing comparability protocols that cross FDA disciplines, and providing a consolidated FDA response to the NDA sponsor sooner, or would the sponsor need to send copies for binding

cases, reviewed by, FDA example Biopharmaceuticists

groups

in add&ion to the Chemists or Toxicologists).

(for

_,

.

-, _‘,

concurrent with CP approval. ,x __“. “” _..,_ , , _,:.., , _“> . “. ,. ..‘ ,<..

-a__

,_j. c

,,

*

.

j

,,

i

-.

-

,.

I-

.,
/ . .”

.,,.

I

:

I,_

‘,

$

-

,,x. .

, .

-

.,. ..,

.,_.. ,.

\

..,

,

_,,

.,(

/,

.,

I

. .

“_

I,.

,

.,

,_

_.

I

iection

-‘

hidance .ine 27-143

Comment
idditional dissolution )ioequivalence

/ Observation
FDA or ICH Guidances addressing testing, impurity comparisons and should,be cited.

Rationale

/ Justification

rhis reviewer only partly agrees with :he commenters’ remark., ._ rhis reviewer concurs with the peferencing of other applicable FDA guidances but would recommend, that guidance explicitly :his nclude/request: 1. The appropriate sections of. th.e CGMP iegulafions contained in 21 CFR Parts 210 through 226. 2. For valid comparisons of drug product units, the miilimuri7 inspection plans set forth in IS0 3951 or its American equivalent 2‘ 1.9. 3. For valid cornpat-isons, of, ,dyug substances and other non:~d.iscr@% materials, inspection plans that provide proof that: a. The samples sampled and tested ate batch representative b. The samples sampled are of sufficient size. and properly handled in a manner that the sponsor establishes .enSures are batch that they representative and’ each is of sufficient size to provide 10 times the amount needed for all chemical testing or, when physical properties testing is required; 1 five times the size required for all physical tests. c. The sample aliquots used for each chemical test are unbiased by the subsampling procedures used and not significantly larger than the size of the dosage unit.
Add a bullet for BACPAC documents,’ and a fdot “B ACPAC (Bulk Active Post Approval note: Changes)” .I _. .._. l,. _l”x .. ,-,.,.\“/ ~V” .i. “”

ZMC elements such as comparative dissolution are influenced mnd in some cases, reviewed by,‘ DA F grodps in addition to the Chemists (for example Biopharmaceuticists or Toxicologists). merefore, other Guidance reco~~.e~&+c~~s c~n~~r~i~g d‘emonstrating equivalence” should be provided.

This reviewer is opposed to referencing any CH guidance that is _not been”explicitly adopted 3y the FDA and issued as an FDA % qui~~l~nt.” ‘ In addition, this reviewer is opposed to any guidance that does not ap@o@riately recognize :he requirements of the Fedeiaj,Fopd, Drug and Cosmetic Act (21 U.&C. TitleIS, the “F DC Act”) , :he cu.rrent good manufacturing practice :“C GMP”) regulations in 24 CFR .‘F$rtS: 210 ~ :hrough 226, and the applicable recognized standards and principles of sound science. The listed items are minimums,that should be given to industry to assist them in developing the jcientifically sound data sets and “C omparability ?otocols” based thereon that these commepters :laimed the industry is interested .in doing in their general comments. The listed items are also the m/t-jmums that should be given to all FDA personnel that are involved in any aspect of the’ FDA’ review s and Inspection processes. :

“A comparability protocol prospenively specifies the tests and studies that will be performed, analytical procedures that will be used, and acciptance criteria’hat t w’ll be l achieved to assess the effect of CMC-ch&ges.

“A comparability protocol prospectw+ specifies how the effect of the CMC changes will be assessed (i.e., the analytical tests and studies that will be performed,

While the commenters’ revision is an improvement, the reviewer’ s suggestion changes it to the “s hould” format suitab,l,e for guidance and adds the critical “n eeds to establish @rove) CGMP compliance, includi’g n the scientific soundness of the proposed changes.” For drug products, the comparability protocol should explicitly include. a reQuirement for with 21 CFR

While the prop’sed o improvement, this propose the following:

change reviewer

is an would

“A comparability protocol should prospectively specify how the effects of the proposed CMC changes will be assessed (i.e., the tests and studies that will be p&formed, analyticarproces that will be used, and acceptance criteria that 6411 be achieved to assess the effect of CMC c&inges)“a nd supply the scientifically sound basisdata that establishes the proposed changes‘ ) s will maintain full CGMP compiiance, b) are scientifically sound, and, for drugproducts, c) comply with stkistidal quality control requirements set forth in 21 CFR

:, 4 . ., L

_‘ :

!. ,.

:

-‘. .

i ”

one

category

is possi

reporting Additional guideline

category

is ensured.

reached

(i.c discussions).’

detail should be provided in the to explain how process complexity,

While

this

reviewer

would

agree

that:

a) the

Specifically, a non-complex, robust, process should be able to readily utilize
level reductions, even for comparability

capable multiple
protocols

If the commenters want a valid example of a process that might qualify for a single reduction in the level of reporting required, then this reviewer would propose the following as a

have not defined (e.g., “n on-complex,” “r obust,” and “c apable” and/or ambiguous (e.g. “s everal” To address the fuzziness commenters’ remarks, the proposes the alternative based criteria stated in the

are land

of the reviewer scienceadjacent

Unlike the fuzzy baseline proposed by the commenters for a multiple-level reduction, thereviewer’ s proposal is a detailed, CGMP-compliant, science. based, criteria set that firms that are truly interested in science-based compliance and improving p‘roduct quality should welcome.

scientificaliy sound and appropriate acceptance inspection plans (lot-shipment representative sampling, testing, and process-appropriate physical and chemical property specifications) are used for ail incoming materials, b) batchor lot-representative inspection plans are used for each phase (step) in the process and the plans cover/monitors any and all variables that may affect the process or any aspect of the safety or quality of the product, c) ~h~-;‘~~~~e,~~~i~~on ~ process includes batchor lot- representative-sample inspection plans for all controlled variable factors, that, at a minimum, are based on IS0 3951:J989 or ANSVASQZ 1.9 and use statistical quality control (SQC) for the drug product or, for drug substances, batch- or lot-.representativesamples are tested for all critical material variables including the principal physical properties, and d) the effect of changes in the variable factors on the process~are well defined;

,,

.. . . (^ .*. : I ,.A”, I , ‘ (,”

19

are one category the case (e.g.,

lower than normally from PAS to CBE-3d,

would be CBE, or

“T ypically, categories designated for reporting changes under an approved comparability protocol are one category lower than normally would be the case (e.g., from PAS to CBE-30; from CBE-30

qualify

for comparability

protocol.

comparability

protocol.

This

reviewer

believes

that

the

The

commenters’

rationale

simply

restates

comparability

protocol

rests the

with changes

the

As the guidance stands, do have to be related.

example could qualify While each comparability protocol, it is up to the Agency decide when a) multiple protocols are needed b) multiple changes may be combined into

for to or the

supplying substitution

a starting material of a material

may that has

result the

in the same

+

Modified

a component(s)

for milling

equipment

Or, a change in the source of a raw material may introduce or remove an impurity that affects the crystallization rate in the process necessitating an increase in the hold time for crystallization completion. ” may-require a Or the change in raw material

+

Used a low container/closure

extractable polymer system component

for

This

reviewer

finds though

the

commenters’ grammatically

Therefore, if the “u nrelated” changes, should require the changes are tru.ly before accepting because they are relationship between

does decide to allow the guidance provided applicant to prove that the orthogonal - non-interacting them as $‘kelated”simply in different steps and the them is’ot n obvious.

Agency

I ,,” f,, ,I .,I,,,,; . .I. .,... ,__.,.( ;.. , .x^ .“. ,.. _. _. ‘,

A

comparability

report

would

have

to

strength,

quality,

purity

or potency

of the

drug

This changes

omission is in processes

e,specitilly egregious that produce bulk

for drug

specifications for the analytical used to release drug substance produced withoa the change.

reference or drug

standard product

This reviewer finds the commenters’ remarks, at best, incomplete. The reviewer would suggest that

In addition, the commenters fail to address CGMP-compliance in the areas that are critical to establishing (proving) that batches produced by different processes are truly comparable - not just that the samples tested give comparable To do what CGMP require’, s sufficient batch-

the

to establish @rove) proposed process unrelated) had no

that the sum of the changes (related and adverse effect on the

sound, appropriate specifications established for the baseline (unchanged process) batchesnot just that the samples tested gave comparable results. Only when the preceding constraints are satisfied for a sufficient number~of batches (and, unless the change is for a single variable, three (3) batches, are not enough unless nominal,and worst-case change levels show that the changes have no adverse effect on the process or the drug

scientifically

batch

should

be

not

less

than,

twice

(2 times)

the

duced

number

of batches.

Should the firm wish capability, they should follow minimum capability approach in PharmaceuticalEngineeringin

to

estimate process an approach like the published in two parts iate 1999 and early

“T he use of the Comparability Protocol for technology specific changes (e.g., change in filtration process) that broadly apply to multiple products is also appropriate: Process complexity, robustness and capability may help determIne the related appropriateness of including multiple changes in a comparability protocol.

The commenter’ s rationale simply restates the first sentence in the proposed change. Moreover, the need “f or each change to be discrete and specific is obvious. A proposed change should not change a pH limit from n‘ot more than 4.0’ to n‘ot more than 3.5 to 4.5.’ - a limit should be a discrete Similarly, process that acetic acid’ one should not propose changing a states a‘dd 200 L of 1 N aqueous a‘dd 2‘00 L of a to one that says

This reviewer that changes

cannot agree with t‘he comment&-s

the are

should,
discrete and

as

the
spec$ic:l

draft

text

states, remarks

‘“b e

In addition,

the commenters’

With respect to “t echnology specific changes,” let us consider the two examples, the one in the commenter’ s “C omment” column and the other in their “R ationale” column. Obviously, changing a filtration process to a new one that improves the “q uality” of the filtrate containing the active in Rrocess “A ” could

The

example, second is more of an

“n ew

bottle

for several

oral

item

change

than

a

cheaper

bottles

not

better

bottles.

Also, the guidance should describe situations khere multiple related changes are appropriate for a comparability protocol.

,_,

_-.

“.

adverse effect has change. However, that the purpose of be to demonstrate Demonstrating adverse effect

occurred as a result Sktion II D line 134 the acceptance criteria equivalence.

of the implies would no

equivalence and demonstrating are not the same.

This reviewer disagrees, fhe definition of an adverse effect is independent of the protocol any process effect that reduces the safety, identity, strength or potency, quality and purity of the products produced vis-&vis the original FDA-accepted, CGMP-compliant process is an

remarks the definition.

have

some

define the term comparable as, “C omparable: For the pu@oses of this 2. accepted process if and onljr -8” &e alternatives and their prod&s have been shown to meet all their existing safety parameters, and identity, strength,‘ quality, and purity specifications as well as all of the (see Glossary).” Lines 127-128
“0 .

should

be changed
Pdsta~proval omparability

to read:
Chaiiges Be

and

Where Can More Inform&io<on Dembnstration if kq&&~-C

postapproval

changes,

and

(3) the recommended

reporting

Thus,

CGMPxompliaiit

processes

that
“A comparability stability studies . protocol should include a plan for the that will be perfdrmed to demonstrate the comparability df pre- and postchange

increased potency,

safety, quality

identity, and

strength or purity when 5.

e@+&xx Lines

418-420

should‘e~changed b

td state:

Those processes that produce products that have decreased safety, identity, strength or potency, quality and purity when compared to the inand finished produced by the original FDAaccepted CGMP-compliant pro&s are “n onxomparable.” A CGMP-cot-rip&%$ p,‘c&s o that generates comparable products is

“Y ou shouldinkludethe acceptance criteria (numerical limits, ranges or other criteria) for each specified test and study that will be used to dsse&8ie effect of the CMC changes ori ihe product or other material and/or, demonstrate eqk&nee comparability between pre- and postchange material.”

6.

Lines 462-467 shduld “7 I&J&&W Comparabijity
the Approved Comparability

be changed
NotlBJemonstrated Protocol

to state:
Using

It is anticipated that some changes in the manufacturing process will result in a postchange product that cannot be demonstrated to be eqtkakt comparable to the prechange product without more extensive bhysicochemical, biologkal, pharmacology, PIUPD, efficacy, or safety testing or in a pi+oduct that does not meet the prespecified acceptance criteria in the protocol.”

vis-&vis the products the original FDA-

a

proposed

process

CGMPcomplaint products by the original FDA-accepted compliant process. Corollaries are:

produced CGMP-

As this reviewer has defined it, an adverse effect is any effect that renders the product produced non-comparable to the product produced by the current FDA-accepted CGMPrespect to safety, compliant process with

produced cannot

is, by law, adulterated legally even be offered

and for

First, a change cannot result of the change can’e b

be.., an effect an effect,

- only the favorable,

The commenters’ remark taken out of their contexts; seem to be contradictory. This reviewer agrees with the

is correct, wher the ttio passages

comparability
Lines

“g eneral”

protocol. 211 through impediment,

213
“A <t$

s‘tate
change

a

studies more total In that

whenever the level of one or are included impurities increase even in cases where the level does NOT change. this reviewer’ s experience, the only time such toxicity studies would be superfluous

changes, designate

but FDA may be limitid iii tis ability to category other than PAS a reporting

However, since this reviewer knows that safety must be an overriding consideration in all cases, this reviewer would change Line 1‘ 83 to
“T he effect on safety of changes k--the

xd”

and

Lines

211

through

213

in the process. improvement Finally, this reviewer-would again recommend that the Agency consider including a specific bar to the use of a comparability.protocoI approach unless the sponsor has established that the current process and product is fully CGMP compliant, the sponsor has CAMP-compliant data that s‘ubstantiates the p‘robable nondeleterious effect of the proposed changes, and the proposed changed process has ( . been . ^x,I,_,, proven ,.,, __*_“ ~,“

The preceding change permit comparability the change only affects

is needed to protocols when the level of the

or

However, reduce

one that proposed to change the tes the number of samples from tha.

. -f. ‘:-’

r :.

Section

Guidance Line

Comment

/ Observation

Rationale

TJustificatidn

We recommend Lines 190-194 of the text bc moved from the end of the section to the beginning of this section, so that it appears more prominently to the reader.

Proposed will emphasize that comparability protocols shoulc L ).’ 7‘” only be considered when changes associated with product. specific and/or process-specific attributes are well known capable of being detected with established, validatedor @aMed analytical procedures, and expected to m eet previously ‘ approvec saecifications. Such a change of excipients shouid be p&3&m a comparability protocol. (e.g., switch from animal-based magnesium stearate vegetable based magnesium stearate)

27

Add “F or sentence.

the

APL”

at the

beginning

of

the

tc

In the context in which this stated, this reviewer disagrees the comment and supports’e&ving l text as it stands,

line

is witfthe

First of all, the commenter’ s example is no1 relevant to the text because, unlike the, “. ) text Xc itl j I .I Line 227, “A change-from s~nth&.dGi:ived to naturally and vice versa,” the example is a sourced material change from one naturally derived source (animal) to another naturally derived source (plant). Given the differences in not only the impurity profiles but also the physi‘al c ~~io@Xe~“o i synthesisderived materials vis-a-vis naturally. sourced materials, the Agency should keep the draft text as it is for both safety and process performance considerations, and, for the drug dosage product, performance consideration5.
If the downstream possible to handle purification such a change process under is extensive a comparability it should be protocol.

11i.c.224

226

Change

the bullet

to include

the underlined

text:

A change ‘ from plant, animal, or multicellular :e.g., algae, macroscopic fungi) source material tc L different one (e.g., different plant. species, different tissue and/or plant part, plantto animal): leaending on the extent of the nurifm -.

In the context in which this text appears, the modifying clause is not’nly o superfluous but also introduces unneeded ambiguity. The bullets are “S pecific &&ii$% o‘f’cli%i~~~ x ftiat
may be difficult include. ” to justify under a coniparability protocol can

n context, this reviewer again opposes adding the comment&% ohrase.
111x.227 Change the bullet to include underlined $koe s text: to naturally &;;‘ D on the

Therefore, this bullet does a-warrant depends” ambiguity that the commenters seeking to introduce.
If the downstream possible to handle purification such a change process under is extensive a comparability

ttie’t “ i are
it should be protocol.

A change ‘ from synthesis-derived ourced material and vice versa, . ‘ 2i.kn.t of the purtflcanon process

n context, this reviewer again opposes adding the commenter’ s lhrase This reviewer also notes” that the :ommenters apparently made ^,., a - ,, :onscious decision to separate the two :hanges they were seeking to make to .ine 227 and would recommend that he Agency seek to find the reason for he separation.

In the context in tihi‘h c this text appears, the modifying clause is not only superfluous but also introduces unneeded ambiguity. The bullets are “S pecificx~~~~iilesbif’E~~ihat c
may be difficult include.” to justi+ under a compaiability protocol can

Therefore, this bullet does‘ d warrant depends” ambiguity that the commenters seeking to introduce.. ” ’ *‘

the

“it are

231 new paragraph:

review division. GMP status, the Manufacturer may implement change without delay in acco&&e 4th approved Comparability Protocol.”

the &he

suggested

changes.

this The

approval “s ignifies.” commenters’

Further,

the commentek’ ,
GMP &t% the change

of the acceptable may implement

“U ponreceipt ,^‘he Mkufa&$e~ t without delay

in

Therefore, be found compliant” even offered to be before any for sale. “fully product

the

proposed

changes

are

both

CGMP
may be

Section

Guidance Line 238-252

Comment
Where placed is the within

/ Observation
comparability the structure protocol (and report of the CTD? -*-” l‘.’

1V.A.

Would comparability protocols (CP) be placed as region-specific templates in‘he t specific sections under which they directly apply, (i.e. if a CP is for a drug product manufacturing process change, the template would be placed under CTD section 3.2.P.3.3 Description ofthe Mfg Process)?’ Ifthat is the case, what would be recommended for those CPs that support multiple changes?

1V.A.

238-240

The Draft notes that the cover letter for the application should state that a cqmparabihty protocol is in the submission, to properly direct review. It is unclear whether this is. also the case for original NDA letters; which typically don‘ t get into the specifics of what documentation is in the _‘ -_ -’ submission.

fhe administrative process x-iginal NDAs needs‘larifica6on. c

and

cover

letter

annotation

for

W.A.

244-245

Indicate why or CBE-30.

a CP can not be submitted

as a CBE

The answer from this revieweris that CPs need careful Agency review of the requisite supporting’ata d provided or referenced to en-%.ire t‘htit.U~~tt% proposed CPs are fully CGhiPcompliant. To permit this, the Agency has rightly classified a CP as a PAS and p‘roperly treats it as such.
Why k& not make he nature the submission of &;&&ge-;s than making format consistent spk;~~~~~~~j all protocol

A CP is supposed to propose changes that the sponsor has an appropriately large body 01 submitted documented supporting evidence that establishes that the proposed changes: /. _ 1_ .^ . ,Y a) Will, if implemeiit‘a,.“E ji;6d’ce e u comparable product where I the definition , of “c omparable” ,_. ___.‘ x -,_.. is the same or better and b) Are themselves and the products produced are fully CGMP compliant. _“ _1 ’ It seems to this reviewer that tlie commenters’ -emarks are deliberately obtuse )_ andintended ” d.~~~6~~~~~~~.~~~~~~~s sromu,gate a positibn that /.^,. to

guidances submissions

rather PAS.

The answer to the commenters’ question is obvious, a CP’ is not a change, it is a protocol submitted in support of a proposed change that itself requires different’evels l of notice IF the prdtocbl “is a‘ccopted’ y’ e “% b Agency.

3 protocol in support of a pio’osedcliange p with 2 document submission requirement f‘or the :hange itself. Moreover, the commenters’ remarks are sresumptuous, at best, because they fail to %ddress’he t case where the Agency rejects the >P because it either proposes changes that: 3. Do not comply with CGMP’ r‘ “ o ^. 3. Are not adequately’usti’ied j f by the body of supporting data submitted as evidence that the changes will produce’ i$~m$3~&7e product.

Section

Guidance Line

1V.A. (Cont.)

244-245 (Continued

Comment/Observation

(Continued)

Rationale/Justification

(Co&inued)

.

There needs to be clarity on how long.FDA wil take to review a comparability proto&ol:^^W& submitted as a PAS 4% ii$ilica&on”i s ih%G~%GWi. up to 180 days like a PAS for all protocols.

The Draft clearly and pt@%ily c‘lassifies a’ *F C as a PAS. As such, the timelines are cleaiand r% additional clarificatioti iS iie<d&!i.^’ -‘ .” 1.

Based on the commenters’ remarks i. is clear that the commenten understand how long the F‘DA. ma) take for a CP and need” t-6 furfhel “clarity” on this issue:
The intent of th e protocol is to bbtain consen& with FDA on docdm&t&Gn &&ii;~~ to s$p$ the change and ehe filing str&egy/pl&?In eks%iij; proto,cols are submissions without data and shoglc track with the categories already defiLeaiti FDA guidance documents.

Given the name assigned bjl t‘ie Agendy, t “C omparabili’y t Protocol,” it is.-& s’ irld % be Dbvious that the Agency is providing a mechanism by which a mariirfacfur‘r‘ ri e& have the validity of a proposed change determined by
the ToAgency. obtain FijA’ ~cL&Lfa;ce;. i‘”~ 6*~~cp’&sl .

Again, the commenters atf&rn@t Yc assign their own view of ci;hat the intent should be instead of tihat’he t intents of the CP should b& &?d, i‘r fact, are. The most egregisus statement made by the commenters is their &se&on that “p rotocols are subniissions Nithout data” when, in fadtyfhey are supposed to be submiqions 01 sroposed changes supported by a 3ody of information and data. 3ased on all of the preceding realities, :his reviewer would recomniend t’5t h :he comments made here be disregarded.
146-250
<e-write ZP. to indicate that the PAS “c an”i r&ude the

srovide a detailed descriptiori 6f the’hange c and ts projected effects, if any, and t‘e b”d dy h 01 evidence that establishes that the proposed :hanges, if implemented, are predictedto sroduce c‘omparable (the same or better) 3roduct and are fully dommenfe.ers”“,cot%pliant. h‘ jstatement ,_., CGMP i;_,“. ~,._..s~.*l Thus, . the zharacterizing comparability p’btocols r as S ubmissionS ‘ without d‘~tita”- ~s pateii~r~-fa’~~~n ~ is face. The text should remain a.s it is.

rhis reviewer finds no need for the juggested rewrite. [his is the case because, in the “T he :ontext stated (Line 242,
ubmission :omparability can consist of protocol in”) , the propoied

h‘e way it is stated may lead to an expectation thatI a p1Zoco1 Iso needs to t‘ie &bmitiecI tb’e&r“% $ g ~~~;o$ds&dXG~e vhich is contrary to the intent that’ e & CP i.$&%al (& 10’). 3

the

draft

ii

:lear

as written.

This reviewer is surprised that the :ommenters have again ,obviously failed to read he statements made in fh&ir:‘,r(ipeY i &i&t. -lowever, even if a PAS dbes ti dbnta‘n i S~CP-is should contain a body of facts and data that substantiate what i‘s pro@sed “is’ .CGWlP :ompliant and will, if accepfed by the Agency Ind implemented by the $o%or,’ ie&ilt in )roduct that is the same or better ttitih f‘he urrently accepted, approved or licensed ,roduct.

.
Section Guidance Line

Comment

/ Observation

Rationale

/ Justification

1V.A.

This is the best way for a CP to be submitted tt result in time saving when performing the change

If the CP is submitted by itself as a PXS, the only benefit woulc be if the data can-be generatedin ,~~lla’ i~-~~‘pprova w a process, and the change implemented as soon as the &’ is approved.

The commenters’ rationale is again flawed and again overlooks a) the reality that a CP _.,A. . may be rejected-by the Agency as iYelj as b) the post. change submission requirements that the sponsor must adhere to. Moreover, there is no prohibition to the sponsor’ s collecting the data from post-change batches before the’ CP submission is made as should be the case if the CP”-is subnWedasan original “C MC” application (governed by the Agency’ s current “C MC Info~rm;iist$? gui&‘ce). n IV-A.
!54-259 Guidance approved r‘otocol described. states prior review that to the protocol implementing times are not must be the change. defined or If the reviews are more lot of time (i.e. getting the change. _ than 30-45 days, the sponsor stability studies started early) “; will lose on making a

The commenters’ first remark states :he obvious. 1 Fhe commenters’ s‘econd remark is ~ISO accurate but irrelevant. The commenters’ rationale remarks 3re observations presented without iny supporting facts and, in g‘eneral, ire, at best, -peripheral ’ to. . the observations made. these 3ased on the preceding, ,emarks should be ignored.

This reviewer again finds it odd that .the commenters are making observations that have little to do with the text in question. Since the review tiinelinesare properly stated as those for PAS, nothing more needs to be said. If the sponsors’ overriding‘ ori’et% “ c c is’tie t potential time of the review, “,.l, t,. __ then’he sponsors I._. should do all in their power to see t’i‘lt’tiati o t a) their CPs are for changes that &-e’omparable, c and b) the supporting body of evidence clearly establishes that .wiII,changes “i miSle-~~~t~~~..p~~~~iTlce CAMP the proposed are compliant and if product that is the same as or b‘etter than the product produced by the CGMP-compliant baseline process. Moreover, except for the cost, there is nothing that prevents a firm from mak/ng fhechangefor a few batches and proving that the changes do, in fact, produce comparable product prior to the submission of a CP as the guidance clearly indicates in Lines 246 through 250.
Comparability protocol review for post-approval purpose for a reduction review should be less that the agency sup+ments;‘therGise o it def&Xthe in reporting category.

For all of the reasons stated previously, this reviewer knows that this remark has no validity. Moreover, other than their words; the commenters provide no supportingfactsfortheir statements. ., ,_ _

_
Section
Guidance Line 254-259

i.l ,,,r,*dl i ..I ,‘. .. ,i.-:-...a .“* .wmh~,L,‘.,e.,*. j.,. ,.,.:” “ ,.._ : )_., / Observation
made‘ de1 G &seGeht the following

Comment

Rationale

/ Justification
of a submission. ne purpose of having ar is to reduce the regGlatbry Sling requiremen category. If, for example, a P A S change car CBE-30 under a comparability protoc& ther (should notj be distributed until after the 3C the concern is, tha<:the parakaph’ akes m nc

This paragraph su&ests that product the change can be distributed &er’ e & The paragraph should also contain information.

The applicant must assess the effect ofthe change: . . . and submit the changes in accord with the reporting category designated in the approve< ,< 4”: <protocol prior to dlstnbution . . .“ ’

There is no mention approved protocol by (possibly) one now be filed as a the product cannot days. Therefore, mention of filing.

While

the heading

in Line

236,
Piotiicol

“A .HoM
Bc

indicates that the sectior only addresses submission issues ant the heading of the neit s&ion ir Lines 261 aiid 282, “B . FiGAGChaiig&
and Study Comparability Results Submitted .’ After Protocol is Approved?“, .2

Should a Submitted?“,

Comparability

indicates that th,is section is’ he-rstl$ w commenters’ irifeired concerns are addressed, this reviewer would agree “F urthknore, ar that the last sentence,
applicant who is using an approvea comparability protocol to in$emenl postapproval CMC changes must assess -the effect of the changes on the identity’ stl;etigth, , quality, purity, and potency,.-,. ;,... tI. pr6duit._ a‘s of ‘he ^I, “. , these factors relaie to‘he t safety or efficacy 0‘ 1 the product pt$r to distributing product mztjle with the change. (Se&on ~OGA(b)WfG G)),”

Since this section is intended to only address of a CP and, @&i fh’! lasl i the submission paragraph, when the CP is approved, how the results obtained for the prodirct pi-OduCed .“, by”N ie . ,“.” . .. ..^ changed process should be’tialuated, d there IS na need for this paragraph to address submission. The preceding is true because the next two sections (“I V. B.” and “I V. C.“) address how the outcomes of the evaluation procedure should be handled. This reviewer can o‘nly hope that the commenters, on reading this reviewer’ s remarks argbktter addressed will see that their concerns by the changes proposed by th”e review&r. After referenced the suggested paragraph changes were would read: made, the

needs that
product 506A(b)

to be revised’;t b would GggGI the clause, “p rior to distributing
made with the of the act),” should change. (SectiQn

be‘i-toved t to and “I V. C.“) address what a sponsor should then do with the next section and a sentence added regard to submitting the resul^ts of the sponsor’ s that states: “T he~following sections (“T V. assessment and proceeding beyond the assessment.” B.” and “I V. C.“) address wfiat‘spoiisbr a should then do with regard to submittirig the results of the sponsor’ s assessment and proceeding beyond the assessment ’ In addition, this reviewer suggests*...,,s that . ,.,*_a “. ~.,.i,i,,* the title of 1V.A’ should . be changed _,/ __, to:,” ,”
“H ow Should a Comparability Submitted And, If Approved, The Changes Be Evaluated?” __ Protocol Be R&Its of the

“I n all cases, a comparability protoc<l would bk+ewedand approved by FDA prior to an aptjlicant implem&& a _.‘ ,,. change under the protokbl.. Fiitihermore, %a~~liGii~ kho is using an approved comparability brdiocol” to im$Giknt postapproval CMC changes must assess the effect &i-the -.--i‘i-” changes on the id&i&y; str;?ngth;“q ualtty, purity, &d _.. p&ncy of the prod& as these fG3oYs relate to the sifetfety or efficacy of the product. The.f~ll~~~ng’ections’~~“l B;.” s ~

, i , ._ ^._

31 .,

.’ _x _.,,_.,._ ,” . _., . ),” ^ ” ‘ .. . 1

._

,..,

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II”,

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.Sli

r..“..“,<,

,::.

Section

Guidance Line 265-268

Comment
Change from:

/ Observation
Not all investigations and devi‘tions a change being made. For example,‘ & contamination must be examined, issue, not a registration issue. may b; per&& to the presence of’xtraneous e but is a c%MP d&$&e

1V.B.

By definition, all investigations and deviations occurring during the study-of the “c hanged” any other pertinent information. ” process are pertinent to that process. To introduce ambiguity” in what’ should b‘e Change to: submitted is,!etlbest, - anti-quality. ^ ,. /‘^-_I “T he submission would include (l)‘he t results~of It is and should be the responsibfli’y t oftt?se all tests and studies specified in your comparability Agency personnel to assess the pertinence and protocol, (2) discussions of any deviations-&k import of any and all aspects of the submission e,fF-not the sponsor. stfffffff8qL6fBty investigations-: aid W Contrary to the commenters’ assertion, all any other per&ei&nformation~ pertinentio?Kz review personnel inciuding tli~‘ie~~‘~~~~~~~~te F ~ ch ange being made.” have a duty to ensure th8”~ll’ anufacturing m This reviewer cannot agree with the practices and the products. they product are commenters’ suggested changes here CGMP complikit.~ .‘ . . ” .x because to do so could be a Obviously, it appears that‘ the commenters subversion of the regulatory process. wish to conceal certain facts from the reviewers ensure thXthe“r eview”e is approve The Draft text here should remain as it and thereby their submissions in support of process cti%iges is. even when those process changes .‘ ay “n ot m comply with CGMP and/or produce product that may not comply with CGMP.
276-282 Current statement: Ifthe studies in a Comparability Protocol lead to an unpredicted or unwanted outcome it appears that there are only 2 choices: not implementing the change .&d/or submitting a PAS.

“T he submission would in&de (1) the results of all tests and studies specified in your comparability protocol, (2) discussions of any deviations that occurred during the tests or studies, (3),+,a summary of any investigations performed, and (4)

er&e&+ If this oc&S, y‘ou can ei‘ & not e implement the change. If you decide to pursue change, you should submit a prior’ approval supplement that provides the supporting data justify why the change will not adversely affect identity, strength, quality, purity, and potency the specific drug prod%as these f&tois relate the safety and effectiveness of the product:’ n

to the to the of to

This reviewer agrees that the guidance permits the two-choices-the commenters found to appear to be the case.
However, different modifications change should to the protocol be permitted. to provide I ”

OMLY have
for a

This reviewer notes commenters omitted sentence in the passage indicatethey are commenting

that the that on:

the first they

This reviewer cannot agree’ i‘~“f Fiisjj^~~~osaI w~ because it attempts‘ to Co$ert’ 6 “ e~l%Xied ‘ k regulatory process into an undefined one. This is the case because the’ommenters c propose no limitations to the “m odifications” to the “d ifferent change:”

or

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,,_

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.

.,

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_1

. . ‘”

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,a

,,. . . . . . .,

^

Since

theapproved

accept&ice

criteria

are the

devoid of any substance. The CGMP regulations already require the investigation of any “u nexpected” results vis-a-vis the product. Provisions should be made that if the acceptance criteria are not met, the change should not automatically be bumped to a‘ AS. P

The results should be reported to the review division prior to formal submission of the data and, with the approval ofthe review division, may be submitted under the previously agreed -’ submission requirements: _

Provisions have been made. The sponsor has two choices. The flexibility allowed in fhe’ raft D should be kept as it is because introducing more flexibility is not Warranted.

This this

reviewer provision

does not support adding because it is a‘t odds

sponsor and/or

does not the existing

truly understand process controls

the process tire, at best,

implemented

as For the same reasons as stated in this

treat found

the submissions were compliant.

as if ttie results

There should be some reviewer to determine

allowance for discussion if the missed acceptance

with the’ DA F criteria is of so

established in other related the filing requirements guidance, if applicable, or as determined in consultation with the review division.’

This

guidance

need

make

no such

provision

as

ecifications

as the .,._,x

Draft

states.

Before
have they any way become of tracking these to determine whqn obsolete - or is it strictly up to the

commenting,

the text cited

needs

to be

reduced

value.

manufacturer

and not necessarily

at the pinnacle

of

reviewer”

finds

This

reviewer

would

suggest’

the

text

be

scientifically

sound.

The onus

text is

clearly on the

indicates firm that

that h‘as

the the

studies, analytical procedures, and acceptance criteria described in your approved comparability protocol are still appropriate prior to implementing and submitting a change under the protocol. If you find the aljptoGed col;iparab&ty protocol is no longer correct or adequate, the current approved protocol should be modified or withdrawn. You should submitted apply similar consideratio?s to your but, c‘No*k:,“ as yet, utiapbr”o.*aci;;*-~i<,+.t. ved comparability,-a, ’ mx ~d‘ &

.’ )‘_ I__
34

7,)> , , I .‘ ,
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1. ._

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;_

, _,.^

; .._,

2,’ ’ ^” I. ^

Section

Guidance Line 284-296

Comment

/ Observation
intent.is cldar--?o main& protocols-the w ording’ ‘ I./ i <. . FDA policy” witl i:

Rationale
“P olicy”

/ Justification
I ., ._ ,., r _j.~.~

1V.D.

Although the Agency use of appropriate ambiguous.

is an overly

broadterm

“- ” not

‘ “ : ” restricted

,

“.. to CMC’ssues. i

.._I

.

.

.

..(

(,

,,-

Line 219-Replace c‘urrent “c urrent FDA Guidances”.

This reviewer does oat agree the commenters’ unsupportable.
Line 295~specify how a protocol

and finds rationale
is withdrawn.

This reviewer commenters’ recommends submitted .oi reported in the To accomplish would recommend (Part “1 V.F.“) :

agrees,“s upports the recommendation, and that withdrawals 01 approve‘ d -c’ s P be firms’ Annual Review. this, the reviewer adding a short part

“P olicy” is the correct term because are but a subset of Agency “p o&).” guidances Thus, for examp!e, if the Agency were to issue a policy that proscribe’^~~~~*~~~~~-~~~~~~ d acid from animals sources -and the sponsor’ s previously approved’ CP included t‘he change stearic acid from vegetable sources to from stearic acid from animal . “1 ,.“I _. I sources, then,,whether the CP is simply pendrng or has been approved, the sponsor should withdraw or modify that CP or, if pending, modify, that CP.
(I _, %../ LX“m l 7 * ,_ . ,W”) Draft states that a protocol may be mod&IFy a PAS submission (Part IV.E), but does not state how a protocol is withdrawn. PhRMA recommends the use of the Annual Report to w&hdraw protocols.

“F . Withdrawal O f A StibknStied“O r ‘ Approved Comparability‘ l;‘;;t6~ol. .“a- ... .* P b .. .
A sponsor may withdraw a submitted or approved comparabil8y %y submitting a “w ithdrawal” ~~~ei’d‘fie ‘ ft I appropriate review division and,‘heG ~ appropriate, should report the accomplishment of that withdrawal in their Annual “R eview:“ ’ ^‘’ .’ - ’ .‘

This reviewer agrees that ttiere is a need for a and would suggest that the mechanism be similar to t‘h’a~f.ij’M~‘ g b y-,-in mechanism application and, where the product is su~bjed to annual reporting requirements, appropriately the withdrawal o‘f the CP in”W ie ffrm’ include . s I” formal “A nnual Review-:” The mechanism for withdrawals need to the cases where t‘he‘ P % Wks submitted include but not approved and where, though th-e CP tias been approved, the underlying , _. app‘ication x, has l _,” .” “” X,~/. approved or, for the- DMF case. t‘he not been
The commcnters provided no rationale.

V.D.

286-288

Screening for new infectious biological source is a‘j?lamic-state. d occur constantly as new technology are acquired. Cutiently, there

agents

from a Changes and methods are no current

compendia1 test methods available to quantitatively assess BSE/TSE risks. Would the CMC information required to obtain EU CertiBcate be satisfactory for EoA, or .~~uld’ ~‘ ~~2~~T~~ additional/different BSE/TSE safety “C MC information for assessments? , q_ I( .&,CS,,l, Jo ,“x _!“i ,,,,., /,1”_ “* _ In..,_ Clarity

The wording is awkward-. Is the FDA trying to state that when a parameter in an’ approved xotocol is changed we can get the kha&e approved and the protocol approved in the same xbmission, thus not having to get approval f‘or ..~ _..__. j .,. . 10th the parameter change and the protocol :hange separately? I’e use of a decision.tree h simplify the presentation. or flow chart would

,I.

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iection V.E.

Guidance
Line

Rationale,
To avoid revising a protocol, it is recommended different that, when predictable’ or possible, options be submitted in the protocol. Veed

/ Justification

for flexibility.

This reviewer disagrees. IF different outcomes‘re’redicted a p for THEN the process is a change, obviously not adequately understood .and/or controlled. When Predictable In such cases, the sponsor should not be using a CP but rather conduct& studies are. needed t‘o whatever understand and control the subject processes. When Possible Even though it is always possible to submit different options, changes be specific and have a single should predicted outcome before the definite use of a CP is appropriate. This guidance clearly establishes’he f need for the outcome of a change to be predictable. Thus, the CP process should not consider the commenters’ remarks as viable for a CP.

Need for protocol speciffcity, regufatory certainty, and CGMP compliance. If the changes proposed are predicted to have more than one outcome, perhaps a prior. submission approval or a supplemental application approach could be used. However, such are not amenable to and should not be the subjeczf”a CP:

V.E.

Changes to the protocol that provide increased control should be treated in the same manner as any CMC change that provides increased control. These should be filed as’ CBE-30, s not a~i%S.

Consistency

and burden

reduction.

This reviewer cannot agree. In such cases, the commenters should pursue the CMC change option they alluded to in^their remarks.

the Since the use of a CP is optional, :ommenters can, and, in such cases probably a) not use the CP approach and b: should, pursue the change by other suitable Agency, recognized approaches (such as the CMC change process alluded to by the commenters in their remarks).
Need a system to track (modifications/deletions) the status of comparability protocolr

1V.E.

Revisions to the comparability protocol tracked in the annual report, similar to This would be a sub-CMC index. changes made to the protocol over the protocol.

should be the CMC index for life of the

Section

Guidance Line 316-317

Comment

/ Observation
Clarification category compaibility to of procedure to be fdllo~ed’nd a be used -for modi&atio& protocol. to -an submissior a$Gvec

1V.E.

It is stated that the notification of editorSchanges to a comparability protocol can be provided in the can be AR. It is not clear what type of changes made/characterized as editor& and~thuGG!r be >. _/, ,,,, -> provided in the AR. A clarnkationis” req&ted. Examples might be included, ’ .‘

- ,- . _, This reviewer agrees; To clarify what w as ‘ intended; this reviewer recommends replacing li,.,l”x -the ._“A _ _,*_ “e ditorial” word with the phrase “t ypographical, spelling,’ and grammatical.”

_ i .‘ Since a CP is a technic24 document, it IS “n oJ ._ expected to and should not contai-nmu,ch iti”t he way of “e ditorial” content.‘ .I’ -‘ i’ ’ Given the preceding reality,^‘-,.Iyc,.“.-..“~ L : “i seem“‘x *~~*~thal it-would -.‘, x . *< the Draft’ s intent “h ere IS to. -,.provide . ./ a defined “ 0. j mechanism .for correcting “. ,a,,.*.c -,“, .,d_^“. . , _ _ typographic4 (e.g., “T he . . . p‘rocess’ , . . . . ” tihen the proper format%&.& is b‘rocess,i *:l”y .Sljel-ling “‘r . .. “T he “0 omogeneity” when “h omogeneity” is. the _ ” * correct when spellrng) and -is.gr~rii.~~‘”i~‘~lfji‘,c‘~~~~t) grammatical ~ ~ (e.g., “d ata “d ata is” f are” errors submitted discovered after’ to the Agency. -the f‘irm’” s %p““is _,,

.
$23 Change to include the underline text: .‘ protocol be of exi&;ig “W e recommend developed and change control that a comparability used within the context procedures at&&m:”

Clarification

This reviewer has problems both with the Draft’ s text and- the commenters’ proposed addition. To address both, this revietier recommends the following:
“W e recommend that a comparability protocol 1 -.. lL1. /‘___” . be developed and used within the context of tfj& existing CGMP c‘&‘ge-cont~ol^‘ kedkes n @ and the “C GMPrequirements

The reviewer agrees’ that the text needs clarification. Further, this reviewer agrees with the commenters’ placing of the control procedures within the responsibility sph-e~~~‘ffhe’irrng”~ rm o ~ (sponsor). However, the guidance needs to ensure that the sponsors not only have such procedures but that the procedures they have. are CAMP compliant. This reviewer’ s alternative addresses botlissues.

compliant sponsors

have

procedures implemented’ ?

that

the /

;ection

Mdance ine 125-328 Allow writing CpS-ii ie&&bgy ~~&%~‘ &s & several products, or to address .s_ a change .&it .,” affects the manGfactu;ng 01 several or n&&&s particularly when t& “G h&ge is products, necessitated by new FDA or ICH g&da&es.

Rationale

/ Justification
specifid, &%~se<er~ only for industry but j%&%,;‘ ll & also for the FDA

Writing a’ CP technology result in time saving not reviewers.

For the reiisons’ stated in the reviewer’ s previous “O bse”r vafiori” arid “J ustification” remarks on this issue, this reviewer cann‘it t support this repeated att,empt b) the cbnimenters to subvert the clear. and proper use of . a CP. While a “c hange” may affect sever:al or numerous products and may be precipitated by a change inI%II‘r d ICH guidance; the”eV~l“~ ~~~%‘i?&” ‘ l ~ required be for’ll&j a and the “cmay not m~‘y the same han~.pr~p~~~~d.‘ result in acceptable outcomes Therefore, this t‘-etiiewer w ould ‘ recommend that the Agency the commenters’ unsubstantiated unsubstantial remarks. forx again ignore arid

This revtewer cannot tigiee with the blanket assertions made cpncerning the saving of‘Ri& ~ For example; w&e. the preceding to be allowed, a failure in one cds8”w ,~iildreqijive“t~‘e Agency to reject all since all are in the on& CP and require a PAS be initiated. How would this save time?
It would be advantageous to obtain FDA agreement on how to Fo’; &n&, o the file changes thar: c&la &pact &any @d&s. improvement or development of a new method for evaluation of /residual solvents ked in the production’f o ,@G: ’

If the commenters’ goal is simply to obtain agreement on a single ch,ange (as the eitatible states) multiplei products, all they need do impacting seto~C~~;^o~i;‘;j~-~~~~~.p~~il~~t, is fi,e.a as a group.
Often the same methods and same $pes of t&t data be generated for multiple APIs each of’ lkh w &aj be <sdd in multiple products. As the comparability proto&l’s i c&r&tly conceived such a change Co&T rG$& a ~~~&~~ ~r”& ~~i~~~~e ” filedas; PASfor eac~d;ug’roducl.“-.’ p x _‘ .

&Ii

This reviewer--distigtGs’ tiith * w&8 commenters’ supposition. “, * . ,,*.A..I ,,,. . There is no need to allow f‘or thi’ s Since -the cti&@e .in’ i‘s tiG.%Prs, ” the firm cross-reference between protocols as manufacturing the APls would only... ._Ineed.^ _ to file a ..,., the sponsors are free to submit or CP for each API that thk change Impacted. .”Ix.,“x ”- c *em.“v I”” e.. data packages in reference submitted As long as-eacK’fi53 r change lP?%??$y any other of theft- submissidns. “c omparable” to the “p re chailge”A PI,‘hg’ ~ug t “ ~ Thus, if a firm wereto submittwb CPs product manufacturers would $ riced to and that were interrelated, they could product are not required to file CPs for their drug ,, ,_, /“. _ reference each other’ s dati %.‘h‘oii) s process unless the change in the API process support for the change even general generated product that;’ -thoughI, -.- producing “is comparabI<““d &a though the comparable drug substance batches, 3% ” ..“d riig .‘. be that supporting ,,s-.,, .,”ttie substance would is somehow not a~e~ab’ti l t‘o the drug,,j-i__ “c hange” proposed in’ e‘ach separate product mariufacturing. p&e& arid, t‘hus, CP. requires them to change souZc& or theii drugproduct manufacturing process. Moreover, this request has n‘&thing that this revi& dail s‘&?%do with the cited text. Based on the preceding, this r&iewel would recommend discounting the commenters’ last remark in thfi case c

Allow for cross-reference of pr&ocols betwe& Indicate a mechanism for this to products. happen. .,.

Section

hidance Line

Comment
Proposed protocol registration

/ Observation
change and the data to support should be in the context’ ”& tGl X commitments. it in z The example ciied implies &that^‘ &&iE&~‘ s ~ p;oGGT‘or f change in a fdriYnent&iofi +oie.& Gouh simple raw materials result (in the FDA’ s mind) in the need to assess aran ge o fermentation and product’solati& i p&met&s that ark ndi like13 to be registered or for that matter wkll enough understobd tc discern equivalence or differences beforeiaft;l^;^fl;e-~~~n~“. ~ ^-

, ._ ~‘ u1

This reviewer d&&e&, al’ @-b‘dsgd 1 p changes and the data to su@%-tW’i% ~ in a protocol must be considered -in the context of CGMP compliance and not, as these commenters .rem&-‘ k states, “i n the context of registration
commitments.” Example cited is not a good one.

This revieweifinds the <omm&te’s’ r remarks very revealing. From the reviewer’ s experience, such thing as a “s imple raw materials
fermentation process. ”

ra‘ioti& t there
change

is nc
in ;

Beginning text being
“F or

at Line deprecate’ d

328,

the :example &tateC *

Furthermore, commenters’
range of fermentation not likely

this t%G;ijEr remark concerning
and product isoI&n

g&es

w’ti7 “tfii i
ar;

“ theneedtoassess; procedt&s’ t &

example, a change’ in a feknilntaiion medium component used to produce an antibiotic can result in m&e Padid &ll growth, which, in turn, causes a higher prodiiiidn‘+ate i 3f antibiotiL Changes related io ~hii’%i&Gn 3 culture medium couldkltide modiEi&%in the length of cell fermentation, increase in iarvesting time, and/or changes to purificatiiin :olumns. We &omti&d tGt i;bti “& Giit separate comparability protocols for unrelated :hanges. ”

to be registered”

Firms have procedures However, that remark,
mderstood ihe change,”

there is a need and some not reported the ranges ant needed f^o Bs-Ce‘$ dbrn’~~~aI.%Ti’y.‘ s p I ~ this reviewer finds the other part oi
likely to be .,. ~~11 enough or differences before/aftel

“t hat are not to discern .equivalence

3ased ?eviewer’ s n this excellent
Intire e&on 334. .35)

on

what is- said and .fhis knowledge bnd &xij&%$iice area, the example is an one and shduld‘6 b ki?pt’ ,
. .*I, woulXG$Zy for validation development

“r ea^ii’~: t to be at odds%iI!h Remembering a certain‘irin’ f s chdnge ina rah lnaterial that resulted in a new impurity that the firm even attemljted to conceal fl’jtithbse c iri the ndustry that burchased th&‘estilting‘ r API; fhis ?eviewer can’ see why the Agency chose this example and why it is on pijWan?i GGid~S the appropriate message to the industry.
Several ccincep& are presented in “d e&e” t&xi.

Jse of a decision tree or BowTchart he presentation, in particular .equirements of release and/or haracterization testing.

This

reviewer

agrees

with

the

comm,enters.

lhis reviewer a&ees that th@~i’Ycftisidh .L*“. t ,,...,x.*>,,,..* ,, If a flow diagrat%“a tidE? declston free subsection might assist the ,‘reach o reader in determiningBxacI?fwhat “is required. However, this revieweddiG@+GG’ i~h G part of the commenter’ s rz&onale for the adding said decisipn tree or fldw diagram (the te.rm _y “f low chart” ’ 15 ,. usually more appropriate to an outline 3f a computer programming 9roposal).

he appropriate extent of validation information to be provided n the CMC supplement (in particuIa+ f6r ch&%feri&&&ing ,educed in a comparability protocol) is unclear and may be :xcessive.

This reviewer disagrees assessment concerning
information to be provided.”

wifh the commenters the “e xtent of validatior

It is clear tihat is being requested just as it iz clear what CGMP requires i~“t hi‘ X gdrd~~‘ S’ . Unless the c.ommenters’ dkfinifibti oi “e xcessive” is simply “t iore :t‘ati‘tieq h t vi;dnXtc provide,” the request to provide only sot%e oi i&quit-e .,I .wmpLI --t c.,“,. ttie~~‘ iFm’ Y ,... what the CGMP regulations lave gathered and ^‘maiii”t a’lii~~“is‘ ertaInly i “ c no1
axcessive.

,,.

. ;, *

_

.;a,. ix,,

.

,,>,

Section

Guidance Line 368

Comment

/ Observation
information into $e

Rationale

/ Justificat;‘n o

U.A.2.

Inclusion of stability protocol comparability protocol.

Since the preceding is the fiidt‘f o the two options provided in the guidance, this reviewer agrees with what is stated. rl.A.2.
Add the following 373: after the sentknce ending in line

Cross-reference to an approved st&iIity protocol &&d be adequate [Comment:“.. It is nKt “c lear *_ to ..,me I what. ;y‘: are e _ recommending here]

Since this is one of the this reviewer a‘grees remark here.

options with

fhe

ih fhe guidance,” 1._1 _-‘“ , commenters’

,

“G enerally, data submitted implementation comtiitmetits the FDA as a component of the .;__ the product.!’ / ,,.

as part of post may be provided’o t Annual Repoti for L ^,1”( “_ ..i,< . . _-

Not all ofthe data will be collected at the time that information Is provided in the follow-up submission, e.g., re&time stability data.

This reviewer sees a need for some type of statement along tliisliKe (.,^j_ to,I, be . included in‘f6 t text. However, the commenters’ statement needs qualification and shbuld be placed at the end of the sedtioii. 1 Therefore, this reviewer w ould ‘ recommend the- following be added after Line 380 in‘he t Draff~“~ eti&+li~, post-implement&ion, cbmmitment-related data, beyond that required to be submitted as a part of the change implementation notification subt%i&oE:
7 component may be provided of the Annual Report from: piocedures pro&e&& ’ be use the to the FDA for t&p&duct.” as g

This reviewer agrees with the commenters’ statement about the “r eal-time stability data.” There are two types of post-approval commitment-related data: A. Data that the s‘upljorts the initial comparability of the “c hanged process” product and related datii ?ecjr$st6d ^‘fjy‘lie t Agency that needs to be submitted witfi*the “c hange” notiKx%bii s’it%nl&ioii i an^d x B. DgtB,‘ ,ikb .stabiliti .$-$-“ ti5iaf ‘ f wi”i y.-bf necessity, have to be submitted at later times. Based on the preceding, this reviewer proposes the changedI 1 *.*yu.u .~*i.mws”, _-- .‘rl~.YI~-.~~*~~““y -’ wording provided or 6etter .“ language 56 tidded a”t the end^oi”flils sectIon.

ll.A.3.

397-398

Change

“V alidation of new modified an$tical or revalidation of existing analytidal should be performed, as appro~riatk? Change to: “M odified validated, Validation manufacturing

analytical procedures should as appropri_ate; “6 ; & %%$&d ‘ data’ should be retained at site for all methods.”

Generally, only limited analytiLa1 pJodedure <‘nfo&ation is provided to the’ DA N for raw materials~“s &t$naterial$, drug substance intermediates, excipients, and packaging mat&i&. This section should no: req&, r%~“% &de inform&ion to support a change’ that what is required for a new drug. Analytical procedures are validated as appropriatd for their use. This information* should 6‘; ~~~~‘^ ~~~~~~~a~~l~~~~~~~~e “ manufacturing site.

This reviewer does not agree with the comm&ters’ prdposed %tig&. .‘ However, this reviewer proposes,jI*.,, _ the “_ following altertiative: ”_ “ -The initial validation ofnewmodified analytical procedures or W the on-going validation or verification of exist@ &+&a1
procedures should be performed, as appropriate.”

The CGMP view is that validatid’ h journey and not a destination.

i‘s a‘

Apparently, the commenters have elected to ignore the draft guidance, “C MC liifoi+r+tipn: Availability,” issued zXKbotit”t t% Xatie‘i’ X tK this Draft, which does require the same ?or the CMC section of all NDAs and”A N’XY l as well as DMFs/VMFs that address drug stibitance, drtig products and drug components submit&d titider the DMF/VMF process. _ _ .. . , ,“, ,~11-”*“),... Since the d‘omm&Yfers’agree that this Info must be acquired and maintained (shouldbe held md be availablt at the manufackrin~ site), ttikil it should be providea’b.th&‘ @tiy t A ~ofor’tisp*&Xion i in the mant-ier that the Agency asks. .. ...- .,.‘,~ ._ ,,/ ? .)(

-.

_,_

,_,,“..“..

.

..,

-

,

.

.

~

__

,

I.

.

Section

hidance 2ne

Comment
Change’b t

/ Observation
include the u&&ned ,.*,,.* *~“% .~r....“.“~ *:* aa, u._. text:

V.A.3.

“T he protocol would specify that“& )“n ew o‘r revised analytical procedures and the approprike validation or Galidation i~f&i&ibn GoUld b‘e _ provided &P.: m A.& or CBE$ w hen ‘ a postapproval CMC change ik&mentgd using&e approved comparability protocol is reported to FDA.”

This reviewer c‘annot support the commenters’ p‘i%po& ’ change because it does not cldrif$j7~‘ &%~k % to limit how th~infbi?%i%ijii -67li be provided. If any “c larifying change” E’kedk~, n then, this reviewer%quld a,te;nGyiyg‘ sug&t that ” ,,,, &Ee the reviewer’ s considered. V.A.5.
MO-444 Revise this paragraph to read as follows: , .j/

The unmodified sentence already tells the sponsor when to report the i?formation, “w hen a CMC chkqe itipleme&d’ ng & the approved postapproval protocol is reported -.” _) ....\\,_** to FDA,” so‘ the comparability addition of the &use suggested IS a) %$%ed, b) adds confusion, and~‘) c itipropeily ” I... litiik’he t “w hen” to reljorf the data:” __-‘ For all cjf ttie prededirig reasons,,, I 3 ,Jhe s i <,.a%., commenters’ suggestion shoula”b e Ignored or, failing that their modifitiafioii klauke’hki’d s l be moved to the end of the sentence and changed to -‘ include all possibilities as ElIotiS:
“T he protoc6l wotki should specify’ th& any n-m or’ revised analytical procedures andlhe appropriat; vahha’i& t &k&&&&r and/or verification information would be provided wf%i a CM change implem&kd using the. approved postapproval comparability protocol is reported to FIX4 (i.e., rkport8ii7an i .*--. d*.,,e. i-,,,..‘~‘ “ + AR, CBE-0, CBE:3Q or PKS‘ ~$‘$p~qprrate). ,~I .“.. , z The sentence is too long, leading td c&f&X

“T he comparability p‘rotocol should identify the following information, which will’e b sJ&mitted to FDA at the time a post approval CMC change’s i ox A,/II,.1 .,,.._ implemented under. t‘he FbA-approved . _” comparability protocol: 1. 2. 3. the type accelerated (e.g., stability release, long-term data) of data accelerated prior to . where category or

The

sentence

being

discussed

stares,

“Y ou

the amount of data (e ,g., 3-months stability data). the data that will be generated distribution of the chang&prod&t, appropriate (e.g., when the proposed is a CBE-30, CBE-0, or ARj.”

should identify the type (e.g., r‘eEk~“l &&~&k or accelerated stability dat8) and %‘&% I d d‘ -le.&, & 3-months accelerated stability data) that -1 will - b&bmitt& a . 2 *<‘ih&&e a .,. y/..b, “x .*~*da” “. ~ ~,kur.d+&d.ev CMC change implemented usmg tLe approved postapproval comparability jxotocol is reporkd to F‘DA and;. when appropriate, generated prior to your distributing the pro&t made witK”‘t hk -cliange j&g., when pk$osed reporting category is a CBE.30, CBE.a;cr^*mf: ‘ ” I“ i ._ i “I

but
“T he

This reviewer aggress’ would suggest:
comparability t approval protocol

with
should

the
identify

commenters
the #‘ ?&e&q

information& time apos FDA-approved

that

will be submitted to the FDA at the CMC change is implemented unde; an

In general, this reviewer agrees with the commenters’ proposed khanges but would suggest the improvements presented in the adjacent column: , “.

that

comparability protocol. At a minimum, information $iould, include’he*foI^C~~‘~~ t ~ 1. +&-Type ofdata(e.g., in-process, release, long-term accelerated stability data) data’e.2:; ( “. ^ . --

or

2. &Amount-of (2)full-scale
3-months

and
Of accelerated

three

release data, from (3~i4il’ Sc~~~~~~~~, X
data) prior to dist&ution

two

stability

&-Data
changed

that product

will be generated

o‘f the

(e.g., in-process and release data from not less than three [3] full-scale‘titdhks, b or 3 months of accelerated s~abiTi~~‘k8a ? &i8% month’ s long-term-+&%-age-Cotiditi&“ % ‘ & %I ii.& _ ..“_ _.._I “. less than 3 ftill-~~alg P~bZ%K%>~~Xe~e appropriate
t??pOrtitI& category is a &E:SO,

(e.g., when the p&posed CBE-0, or AK).”

hztion

Guidance Line

Comment

/ Observation _L
an a

Rationale
Most reporting sponsors

/ JustXidicjn
would probably

“.
not go to the trouble of preparing

The first sentence states that “.. .use of approved comparability protocol may justify reduction in the reporting category.”

a comparability
category.

protocol

if they

would

not get a red&i&

in

Although the FDA intent that a protocol~does not automatically result in a reduced reporting category is understood, thjs reduced’ regulatory burden is a primary motivator.to the effort’f o submitting a comparabrlity ~r~t;;d~~s;~~l. [Comment: Is there a suggested’evision r here?’ If not, this should be’el’ted:] a e i

This
comment

general

revie%r and reality.

f‘ails “t o rationale ~“.

see” the point”3t‘his - it simp’y~‘Y,Xs l s

a

This reviewer agrees embedded “C qmment:”
460 FDA should for reaching clarify what “a greement”

with

the
be The commenters did not provide a rationale.. ’

the mechanism would with the applicant

This reviewer following:

agrees

and

suggests .

the

A. The sponsor. submit -‘a ~wriften~~&% outline, B. An appropriate reviewing group then evaluates the outlinea gaitZt’CGMP, * the changes proposed, _’ &d”‘ Yik w sponsor’ s compliance history, C. Based on the Agency’ s assessment, the Agency should: 1. Decline to suggest a reporting category, 2. Suggest the standard reporting category’r o .‘ -’ 3. Suggest o‘ ne category 6‘e’iOw ttie normal filing category f‘bi-‘ tne changes proposed, and the _ D. Send sponsor their recommendations and the rationale used to reach the recommended category. E. The sponsor could then either: 1. Send a letter’ accepting the Agency’ s recommendatioii’r,‘ ’ d ~ 2. Submit md~~.‘~~~il~~~(~f~~iiT‘~fi6ri ~ g that, in the firm’ I I jllq.a WI‘“, ...A s d‘ p’nion i supports a different repor%-rg category. F. When the )_“‘s pbnsbr ob[&A!i’ *“* .w#J,.., ^‘ *the Agency’ s formal disljute resolutibii process should kick in. G. At the end of the’ay, d the Agency would then send the spctisb-i af%t?$r’ t;;;‘ir % l that” assigned category _ .%&gtit the t(3D&‘GifG-.e ~-!$.& pro.eii with .or the q .$.& product to meet any ofitj: @ept%k ci%ria nullifies any -category ” ._..^,_,, .,‘.^ *^,*s*_, reduhidn , and &ii r_ require a PAS to address the actual outcomes observed.” _, _,” ; “,:,.*.““: ’ :I-.‘ .~ :- -,.;-. __.“I 1 .., ,,.: ,; .

believes tt%t the mecf‘nismhe 2 can meet all of ,the preceding and for the purpose stated. this reviewer’ suggests that this contained in “b fi :q$g~~;*;~d ^ “. I _. _ l’ y “( ^ ./.i‘j ^ -‘ . r referenced in the tekt of the guidance .i_ ,,. as ,-., and .., :‘,’ where the Agency sees fit.

All formal mechanisms All formal straightforward At the end en-sure CGM,P by the FDA. This reviewer has proposed is appropriate Moreover, procedure be

procedures need formal to govern them.’ mechanisms shouldm,,.. .- I be * and self~docurrieniing. of the day, thefin&l”d eci’ n & m *‘ _ ,,.__. i. ust compliance-arid should be made

Section

hidance Line 163-469

Comment
Delete

/ Observation
this paragraph.

Rationale

/ jiistifikatih

-

This reviewer disagrees with the commenters. The fundamental premise for a CP is that the sponsor has amassed sufficient data and, basedonfhatdata, understands the process to the point that it can prospectively project-tihat the effects oh the process of the product that each change will probably have. Thus, this reviewer fi$s ,the commenters’ first “R atio~al$” statement disingenuous. If a sponsor can’ t project a course of action because the sponsor-&% &t ‘ understand the probable process outcomes, then the? ~&bi~ld @ submit a CP. With the replacement df the wbrd “e quivalent” with “c omparable” previously proposed by this r‘eviewer and minor changes d.esigned to improve readability, the paragraph should be retained and state: in the “It is anticipated that some changes
manufacturing postchange I. Cannot process product that: be demdtistrated will result in “a

As it is difficult to determine prospec&Jy (without the actual data in-hand) what steps would be taken’if &q&alence‘s ^ i not demonstrated, this p’ ra@$h a should be omiited.

Apparently, the commenters think” that a CP be submitted even when the sponsor has should no idea of the effects that a change may have on the process or the product produced by that process. Their thinking completely ignores ^ the reality -I,. that a CP’s an bptidnal i firocedure’hat f a s@%or should only use when the sljonsor has a good understanding of the process and the &%d of factorIn such~c~~zs; changes on T‘~gs’~~.“d.‘~hti”$ a that process. j .6g”5 Erg” o ‘ t project the actions they plan fo take if, in spite their understanding, the r&Its are not expected. As the commenters stat&hi the other remark, the sponsor may elect the PAS option. However, what a firm plans to do is left urj them. The Agency just ex@cts th&I to-uticieistzihd their process well enougti to p%jekt what Zttions they will take if a given acc6~tati&critk’ioh~ i not-met.
Moreover, if equivalence isn’ t protocol? Mb% Bpb;nsol;s’ b;uld w md request approval based justification).

of as

to

is

demonstrated, why refer to the I... ..I ,,. .d I ,,: merely submit a “s tandaid” PAS on T‘ Xe iii’ludkd~~ c &a .‘ (With

comparable

to the prechange

without more extensive biological, pharmacology; or safety testing or v

to bi eqG&kA product physicochemical, PK/PD, efficacji, acceptance the steps you

2. Does not meet the prespecified criteria in the protocol. You should identify in the protocol will take in such circumstances.”

Apparently, the commenters have gotten the proverbial cart before the hot-se, the request is what the sponsor plans to do in the event of failure before making‘he~ch&ge t - n’t’t‘ihaI%ie o sponsor does after the problem has occurred. There is nothing to prev&Xthe sponsor from sleeting to do as the cqmmenters suggest after the fact. Further, if t‘his reviewer tie?e i6vi‘li;iti~‘ ’ e Y CP for acceptance and approval, this is one area where this reviewer would tise the sponsor’ s zontingency plans to assess, how well they do Jnderstand their process 2nd the probable :hange effects as well as the firm’ s approach to CGMP cotipliance.

The

presence

of a new

impurity

that

is not

downstream steps of the CP envelope

renders because

the products the products

outside cannot

words from the change completely However, the text it is but changed safety oriented as

text they wish to out of context. should not be left as to be more patient follows:

“W e recommend that attention be given to demonstrating the absence of any new impurities or contaminants, or that they are removed or inactivated by downstream processing. Any changes in the impurity profile would meet the “p redefined criteria (see section V.A.4). The predefined criteria would indicate when qualification studies will ,be” warranted to

“W e recommend that attention be given to demonstrating the absence of any new impurities

Moreover,

to

be

equivalent,

the

changed

“, -.

. I ^ I_ ,, ; /

,“.

.

,,,

.”(I

.,,
Section J.B.1. Guidance: Line 184-486

Comment
Change from:

/ Observation

Rationale

/ Justification

/_
of physical i‘s demon&rated characteristics i: after the fina

“A comparability protocol would normally include a plan to compare the physical characteristics (e ,g. polymorph forms., product produced using the old and new processel when these characteristic? are relevant to .ths safety and/or efficacy of the product.“” Change to: protocol would normally the physical characteristics
pa&clk ~&~‘~~~&i~~~~~f&&

As per BACPAC I, a‘n examination .” required only when equivalence solution step.

@&i& “& ~2~~i$~tT~~~~~EG

A comparabili>y a plan to compare
polymorph forms,

include (e.g.

111 comnar&&tv 1s es-d Ion sten of the &up su&tance f2LthdBW~&~EIkWh&; and/ortioftheDroduci.“” This re”i ewer aig”g ~-ees

when

.

.

.

.

.., -.* svnb

after

the fim ,_ .

*im”“- -y~;

This “R ~tidnale” st&Zii~nf’as h iG bearingor the Draft’ s text because the-st~ted’ompariso~~i~ c for the product that, in thii c~~~~~~;‘i~~~~~~~~i~ ~ the drug substance. The BACPAC I gtiidance is designed to resft?ci the comparison to the fi~al‘5iodiiS j ~XXh’he I statement has already done. However, the examples list is incomplete and should be expanded to ensure that 6‘th6”r key physical properties of the drug S’bstahce u are al least considered. . Moreover, as written, the text only apljlies to a solid drug substance (a/k/a active ii-@-ediX or active pharmaceutical ingredient~ ~~i~re~f:‘[API]).’ - j Given the preceding, ~~eij”iiiy‘ i ~~~on the commenters e‘move the phrase
Jld

commenters’ proposal. However, the reviewer would change the text slightly to reflect the-other common physical propertiG.‘W t c&n be critical to the comparability of t,he drug substande us&d. foe produce drug products: comparable
“A drug substance compa&bilii~ piot&ol Gould normally include a plan to”c otipdie tl%~~ptijki&l characteristics (e.g., for solids, polyti%ph’ ii%, % particle size di&ibuti& bulk aiid~‘“% p~dd

proposed
the

the
prodkt

change
produced

was
usi&

to
the

density, flow, permeabiiifjl,‘ . inttinsid solubility; for iiquidb, tiijcbsity, iefractive w*“.*:” _), -^llixi index, color, density) df’he ptkiiict t produced
using the old and new characteristics are relevant efficacy of the product. processes to the wheti, the& saf&y and/&

and the new to pertiit‘hthe t f‘ii’iis’ to r ~opase comparisons of the product from the iew process to other than the old process (for example, a comparison to some refG-&ice naterial) even though doi@ such is not in teeping with mqit$aj$ng ’ the postchange 3roduct’ s comparableness to the prechange lroduct. For all of thk precG#itig E asbtis, ‘ .- fhe zommenters’ proposal should be rejected. Moreover, the text needs to be augmented to address the CPs for the drug prod&t aXits various common dosage forms

“o f processes“

Similarly, a drug product protocol would normally include a plan to compare tiie physical characteristics (e.g., for. ..._”,,,“. , ..’ solids /, hardness, friability; for serii’s‘ollds, r color for suppositories, softening density; : temperature, density; for suspensions settling time, coloy, @@y; for Iiquids refractive index, color, d&sit<! viscosity, particulates; for solid ae[osols, particle size distribution, dose dispKi;‘bn i ijatt&-n; and for liquid a&osols,‘ di6ljM si& dose dispersion pattern) oi distribution, the product produced using the old ahii new processes when thege charadte?isti& are relevant to the safety and/oi efficacy of the prciduct.” ; . . ,, “. _I, * .. _“. ,: ,s

Section

hidanc Line I9 l-492

Comment
Change from:

/ Observation

Rationale
As per assessing

/ Justification
BACPAC I, demonstration residual levels of existing of andany equivalence includes ., ._./,” ,,., new solvents.

V.B.2

“T he studies would assess impurities and process-related including, if applicable in-process catalysts.” Change to:

product-related impurities, reagents and

“T he studies would assess impurities and process-related including, catalysts, if applicable ;iod solvents.” sentence in-process

product-related impurities, reagents+tn& ., It is necessary to confirm that the demonstration oi comparability at a certain step will not require complete processing from the modified step through unmodified steps to __; the drug s&tat&e. ’

V.B.2.

Add

as the next

on this line: orofile can be e uxrguntv : .’ aanroorrate Isolated . ” __,j ‘ the chawe or the drug

m termediate -

followk

This reviewer does not agree with the commenters’ proposed addition. However, this reviewer would support the following modified versio’ n of the preceding:
“C omparability established bytesting of the impurity profile can be

the drug substance or the drug product, or, provided a) no new impurities are foun’.>tid” d b). Se levels found for @ of the existing impurities in the postchange process intermediate are ti greater than the levels found in the ~$65 p‘&chCi@ process intermediate for a drug substance process, an’ appropriate isolated
intermediate -. ” following the change e+k&&&g

The commenters’ wish to minimize the processing of the intermediate to the final drug product needs to be balanced,against the reality that intermediates that co.ntain ne% im‘ut%e~ p or increased levels of existing impurities need fo’e b processed further (through all-of ttiepurificafi’n o steps in the process) to ensure that the resulting drug substances are camp-arable.“ ’ . .- ” ‘ ” This is the case because the carrying-of new impurities or: higher leve!s of the ‘ i .,... ..*~:~,-. existing .I “ / . impurities into the post-dhange’drug ~ substance the post-change drug substance’ J# makes comparable to the pre-change drug substance. In addition;the.issije’ bf i-.p~$te&-.i,+-.fiA-& product should only be assessed at the the process that manufactures the fini’hed s product.
., ,-_. ,,,, ..~. .,_,

end drug

of

“,

.,

V.B.2

Does exclude

reference to a “r elevant ICH Q7A? ’ “

FII)A‘uidan&” g I ,.. I

,“.

The

commenters FDA, of

provided

no rationale. Tfi” T;lye

Though this reviewer;cannot’ answer ._ _“ ._S ‘ . for the Agency, this reviewer notes that the FDA should-only reference guidances that it has issued. Thus, if the FDA finds a given ICH document to be the same ,as the Agency’ s current thinking on a subject, the FDA.” should publish ‘t’ “s i and own- version -of that -guidance reference it.

The statutes

bound United’ theSta.g5 l M‘“,r;i3 by fhe “d FD%“ “,a sFi.-Gla*“.

reference documents that are either “r ecognized American standards or their IS0 equivalent” or ones they issue. This is the case because other agencies, not governed by the FDA, can change’~ei’-gliia~~‘~ t r ~ documents in ways that renders them at odds with the FDC Act; the’ GMP’eguIatlons, C r and/or ’ ._ . FDA’ s current thinking. ,*, _.... The a consortturn “ 3) ‘ ( pharmacopeial ICH is organii~~~~~~.i~~~~a~~“ii”i i~~ire of “t hree not controlled by the FDA. -’ As such, the FDA should ~dir$‘”[ y t .I -. ICH guidances. /.*. .., _\_ / rX?ence _

I : ._

:/^

1

-:

-^, . . .

Section

hidance Line

Comment
ch ange from:

/ Observation

Rationale

/ Justifhtion
in all cases. Each case

V.B.4

“W e recommend a statement be included that controls, including those,that have been validaikd to inactivate and remove impurities or contaminants, will be revalidated fdr the new production Change to: process, if appropriate. ”

Validation may or may not be appropriate will require individual evaluation.

This The that

reviewer a drug

FDC.Act

“W e recommend a stat&m&it I% %%&Xih~t controls, including &se that have be& v&&Gd to inactivate and remove impurities or contaminants, will be msessed for the n&w producnon process: and revalidat&d, if P, m.

“jf it i a-drt& and the methods used in, or the facilities dr conlGl$ Gd%T;~‘ts i manufacture;-pr#cessing, packing, ii holding do not conform to or are not operated or ~dniinist&d in ?orif&mi$ with current good manufacturing practice’o’ssure > “. “^ ,-..I.. such drug la that meets the requirements of thi4”c h+GFas to safety and’ 4 & <he identity and strength, and meets the quality and purity characteristics, which it plui-ports -‘r is &pie&$eX‘a o t possess. ”

disagrees. at 2IXJS’ ; X is adulterated

%T@@)(b)

states

This reviewer disagreeswith @I@ the original text and the commenters’ proposed revision. This reviewer ~~6ptio~iifS the f&lowi&
“W e recommend a statement be included that controls, including those that h‘ave been validated to inactivate &id i&&e itipuritiG or contaminants, will be ~MG&IBI validated for the new production process for

Though the regulations governing the substance ha\ie not been puIjli~hed,,the.Agency rightly p&lish&drtig’regulations‘ t * “ & forth in applies cFR the^Paifs ~~~~~t”l jy?-6~~~-~~~~~~~h 21 drug 21 substances and’rug d pt%dticts.: CFR ,~tt;~ar~f-~r~~~~t~~~,~~~~~~~~~~~~~~~ls sets forth the’ regulations t?at controls. F, 21 CFFl21ZKl.3’, 0 In Subpart
testing of in-process materials
of dru &y&

drug

’ process

goverri

and

both drug substances and drug products to at leasf*“ h& ‘ f kZ?‘t i required by CGIVTP’ as set,. .,iforth :,/_,,_/< the ,. in ;,i 21 (TFR 21~,“1 -4):““ .‘C ^ “

(underlining

emphasis

added)

“$ &i$@‘“a n‘ d d’ ,,, f*‘pSl&~~” ._,.,,, I_ ?$i&“_ , XI & g *-, .%.II WI “, ,h

at (a),

unifor it and i t rit b es mbliYh d. 1 y+,,&

rodu t ,w &en ;&5=+&

ToassuRm r&c & G“k h&l ‘ P.;c:;;-;;-~d

tests, or examinations to be conducted on aDorooriate sat&es __x” inof process materials of each batch. Stich c &&%I br&&res “I “) _ shall li be . “. ,, established to i&i&~ &e output &d to j%iaaththe performance oi those manufacturini Drocesses that may _,,,,_ .“, ..#> “: _I-,>-r c‘.L. ks+” & tG~b&ible ._ “fdr at&g , ..-, variability in theeharacteri&Gs6%-trocess material and the drug product. . . . ”

Therefore, a firm is required to evaluate each of their process controls in‘ach e i‘teration 67 tlie process [IJ a manner that validates ttjat cor$r$. Thus, the A&e”n cy shoijldiib”fj’!X~&<& and the sponsors cannot do, less in this case. [Note: As the regulations so clearly indi‘&~ c GliX%?r?Y‘ n ~

i22-548

Since the regulatory filing requirements for the analytical changes would still applj-; * axGl Se’ science surrounding analytic;1 Gl2ati& requirements is well documented, it is doubtful that the use of, ~omp&ab~lii) p‘&&~ls”& I -.‘“.“.. j,.l‘ “, 1 , analytical .changes wbuld$~o&IF slgmficant sponsor benefit. ,, ,. ._;_, , // _ .. ,” +_>.,yl,_,,.II /l. ,‘

Time required might approved comparability

exceed timing o‘f protocol, with’ittle l

submission in&e&d

without hsk.

..

,

j

,

:

,,

Section

Guidance Line

Comment
SUPAC Add guidance

/ Observatidn
should of line be cross-referenced.“ ’ . 579: I ,.

Rationale
The commenters

/ Justificatioti

i_

” ,. ,* I ,“.l,. “- .__>.,,a~_j.‘. *a.,,^ >%/,,” ,/,“

to the end

“If a Site Inspection be initiated by the supplement, the insuring that the inspection in the implementation of commitment to Protocol.”

is required and would typ&liy submission ,of a p&r approval applicant is responsiblk for site has a satisfactory cGMP type of operation prior to a change in accordance with a the approved Comparability

provided no rationale. “, S. ^, ,. ;..,“,.. ,. ,., i”, _.,_ , ,j_ j,“_ lI “~ I Ix,.L~uIx, ,, d.” ~._“ We suggest that the Manufacturer shduld be-able to work%& the local FDA office to schedule inspections related to tht implementation of the comparability protocol. The Guidance should clearly state whether FDA will permit z supplement in a non-prior-approval reporting category for i change to a new site which has not been inspected or does no1 1 I. “. .^ *,,,.^_ , ,,., * j have a satisfactory cGMP inspection, smce prror approva inspections are usually prompted by, or requested via, the PP supplement process. For instance, standard packaging site changes require CBE-30 supplements, unless the site does no1 have. a satisfactory cGRP .&gi+g;g6;:“A ; .‘m.<;;;e‘ . Comparability Protocol could allow a packaging site change to bc reported in an annual review along with a statement (Lines 570. 573) that the movewill be implemented only when the s&has 2 satisfactory cGMP inspection for the type of operation. Thir Guidance, as written, does not necessarily provide for the use OI such a Comparability Protocol, ;yhich places&e responsib&‘i o insuring completion of a satisfactory cGMP inspection without a PA supplement.

,11*‘a> -.,a”_*d ...s-a>“, . The FDC Act is quite cle&- with respect tc requiring CGMP as a precondition for the manufacture of a drug. ,,,~,._, ,__, In 1988, the US Supreme’ ouit C ruled that%‘ e FDA administrators have no I&itude tith’especf r laci/ity that does not have to clearly written statute or regulation --that ,, ..,” inspectional confirma%n of governs the pharmaceutical industry. .‘satisfactory CGMP complia’ce1 n In Both the la% &nd the regulafi%-i’Zl ( CFR2%j) cases where a new facility is both make CGMP compliance a prerequisite for proposed, the review_er, ?!I’ aswif h‘ , the commencement of manufacture . .‘ any other type of PAS, .“^ vei-‘,;1 .-,’ the “. i %jLegally, the Agency can do no less. proposed facility’ s CGMP compllanc% Thus, the .Agency.., should’.ot’ _m,,_/.-_ approve any “h n .. _I ,I status. In cases where the proposed submission that the Agency knows does not meet facility (not the-$) d‘oes-~~~‘ ~ve R a all of the prerequisite CGM^P minimumssef forth history that supports ~ ~~~r satisfactory CGMP compliance;~;~~~““~ ~$~~‘ in theFD C Ad and the implementing CGMP .~,;c*u~.,“, -il~~~~~~~~~~~~ d44ra regulations. will notify the FieTd~*fnspectorate and work with them to Xiedule’ ~ the needed facility inspection, ’ F‘irms should not submit a‘ P % unless they know that the faci,ifl’~re’il~fijr’P~~ i a ~
_ “_ ,..S”/ facilities at whiMl-i~‘ gency A si%%~~&@ finds unsatisfactory CGMP‘orripiiance o the facility named shotif& ifribi~acc5epf&d, be rejected and, i‘f zT’ @%d c or%ppt%ved, should have their acceptance revoked approval suspended untilthat f’?iMj%a6 a satisfactory CG,y’ p $~~~$I”’ . ;. __,. ,._ ,.. .^,., -I

o~ppbsas*“. .~ -the This reviewer commenters’ addition. It does not conform to ’ the expectations. of the FPC A&t t‘hat the Agency only approve submissions for processes in facilities that are CGIWP (21 U.S.C. 351(a)(2)@)):‘ . compliant Since the preceding is the case, this reviewer would propose . . ,_. SI_. . ,” the adding following after Line?39, “G iven the requirements of the Pb% Act, the Agency cannot approve .a Comparability ~yd-f--y-qc.py~t-~;

inspection submitted.

on

the [Noief,

day the’ CP i‘s &js *,.t%igf n‘ame af
or 6 ./; .

Section

Guidance Line

Comment

/ Observation

Rationale
Clarification

/ Justification
needed.

If a change in manufactu;ing’iteSis s pronosed’orar f aseptically processes product, wbuld‘hk t FlX4 sanction the site change 1% the‘peciii~~ility s 0; area had successfully met a cGMP impectibr within two years of when-the comparabiky repok was submitted? If not, would the successfulWmedia fill:(3 lots)‘e b satisfactory evidence if the last inspection perioc exceeded two years at the time the comparability report was submitted?

) ,., . .I . . .~” ,._..,. .. . Given the high risk ;toe the public associated nl,._n” ll ‘ Nith faciIities”“t hat u*.,* asept~~~l~.“ r~~s~,~~~~~~t, ~ the Agency should do al-r “~ ~~.~~‘~~~~~~~-~~~~re ~ “ an . that such ..facili2i:;s’“^ ‘ have.I _i ‘ /_^“. ^% .up~‘&-te g satisfactory CGMP-compliant~ inspection status.

Though this reviewer cannot answer for the FDA, he’ would recommenc that, to be approved, the’ aseptic facility should have its C GMP ‘ compliance history updated to a date appropriately close to the -. SubmisSion .- \ date before the%P is approved and; ii; the approval, sh~u)~. .ywire I 1 j,_ .the. ” ,, sponsor to initiate use of that facllrty within one (1) year of the approval ana submit the required CP report, including the results of at least tliree (3) media fills, within 18 months oi the approval or the approval should be automatically suspended pending a facility inspection update.
,. ,.

;81-586

Add to the ends 586):

oflinesII.B.,

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1,

“C omparability Protocols are not needed tc provide a list of supporting data that the applicant ,; ^.-A&.-*_ r_~“ll~ll-, -._li,^/ Lr ^ will provide to support changes that current guidance classifies as annual reportable. This information must accompany the change when it ir reported in the Annual Report.” ’

This reviewer cannot agree with the proposed insertionl _,- .- _\<lpc ~,4~-~,v‘.~~,+‘ the because ~ (1) .,T,I_‘ . submi‘sion s of a CP IS an optlon a’d n (2) if the sponsore‘ects’o’urS‘% l fp i this option, CPs have the, .sa.me jnterna,l reporting requirements as a PAS because the Agency classifies them as a PAS. Moreover, the commenters’ rationale seems to be derived from unpublished guidance discussions that l%ive no currency. Therefore, the commenters’ @-oposa1 .. should be rejected. .‘ “ ‘

War to I l/99 PAC Guidance, application included a form of Comparability Protocol or interchangeability protocol which lescribed changes that appeared to reduce the reporting category kdm CBE to AR (based on 2 1 C FR 31$.,70 ‘ requirements). In Jignment with the allowable changes in%e l’”@ $I?%C I S&dance, there is no need to describe n%or,‘niiual a reportable :hanges in a Comparability Protocol, except to provide a list of Lupporting data that the applicant &ill provide. FDA should itate that they do not expect to see Comparability k%otbcbl<for Zontainer/Closure changes that are described as annual “. _^ “, ..,,.,. . .,,” , ,eportable in the 11199 PA% Guidance to simply provide a list )f supporting data,

Vote: As far as this reviewer was able to ascertain, there is no official packaging PAC 11 l/99 PA%) guidance ’ tin&” “t ne”“‘~ ~~” has xrblished as the commenters seem to indicate 3nd a search of the enfire‘0A‘ ite f S for “II‘g9 l A C Guidance” ‘ found no matches. This revietier *did find “k v!dence that such P ACPAC” ‘ guidance was“d iscusSed” - and p‘lanned” but nothing more. .‘ On this basis alone, the commenters’ proposal should be dismissed as wiShful thi’kii7.g n on their Iart. .“. “.,.

.,,
Section Guidance Line 581-586 yhntinued)

Comment

/ Observation

Rationale

/ Justification (Continued)

Comment/Observation-(Continued) Please clarify the use of the word line 585. Does this mean e
l

Rationale/Justification
“r epetitive”i n to numerous

a single applications

change or

applied

The alternative choice was included because ii seemed to this reviewer that the section I II.and context logically pointed’o t an alternative that the commenters somehow missed.

a series of changes that have predefined acceptance criteria but which may extend beyond any single change?

Or does it, as the context, indicates, simply mean a‘ single change, like‘ s bottle source or a .packaging site change, that applies to several different packaging”f orm~ts” fdr’ e % same drug product? This reviewer leaves it up to the Agency to respond as it sees fit.

V.H.

ws-606
/^NADA/ANADA holder responsibilities communicating with one another when comparability protocol references a DMF/VMF *at is not, held i b) .‘$-- L.I&f,~~A~~~ , /NADA/ANADA rhis reviewer FDA has any holder. && ri”f .ftii’k.~KgrfE.? . atithb~~~t~~..~~~4.:~~~ to a

This section sought

needs

clarification.

reviewer disagrees because the clarification is ~outside df bij@‘hAg r ;eg~f$(jfZ~e“~ ~~$& : __ ._ .,,. I snd the FDA’ authority. s To condiict a re\iiew t‘ri~~~~“~ ~~~i’~~~i~~i~g ~ nformation in a DMF/WXF( tlie“ %‘&r ‘ n $ & iust ‘ obtain a letter from the’ D~F/VICil~-‘~~~~r” i;~at ~ ‘ ~ authorizes the Agency reviewer to review the specific part of the DMF that bears on’hk t sljotisor’ s i_ ., , “_ ‘ . . _. ; submission.. How the sponsor deslsw~~~~~‘3i~~7~~~~~~~~r I IO obtain the requisite DM~/\;IMF” eSie;j;-““‘I”~ ~~r,““~ s ‘ r strictly up to the s.pcGisoi. . ”

This

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should not attempt to get‘ilvolved’n i i vYhat is purely a contractual matter between the sponsor and, if-different, the DMFNMF is.16EaPea ;;u~y@&..cf.t.Re holder, o‘r iih&T 'Vi& DMF holder .. US territorial - b‘ound&E, DMFNMF holder’ s agent. t‘he “I

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Comment

/ Observatibn

Rationale

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The protocol would include a com~mitment~ ^ _ tj provide a letter authorizing the FDA to review 1314 master file when a postapproval CMC changq implemented using the approved comparabilit protocol is reported to FDA. ’ Change to:

new information to the’ D needs a new letter to permit it to review the nev information in the file. Moreover, the control of the quality attribute: This reviewer cannot agree with the of a DMF-controlled drug s‘ubstance, other change proposed because the component or container closure system< rlr..ri*.rr is 2 commenters who proposed it are contractual matter betinjeenPh*e~DMF/VWholde~ obviously unaware of the trade secrei and Thethe CG.M,~iegirl;~io”d ~ drug product manufacturer. “; l~;~{h&-tiurd~~ :.. or provisions appertaini,ng tc I: DMFs,“M Fs th-“f -‘p-&~flf “t he Fqq the manufacturer to only acce’t p incoming.item: from monitoring theircontent.“ ihat are the “s ame” ai those that the Its contents are ,.<d,&rrwq*: secrets” and i-0 used to obtain Agency approval OI i,:... “t rade :*ii~~~~,~~i.,.~~.~~rii-~;,c-~i nanufacturer not a‘vailable ,etfer’ r-.m review f‘fg without @ an for icense. authorizing “ f b”) #~p),“ Therefore it behooves the drug produci , ) Jl”_ lr,i&*.. * holder or,’ if the “D f$Il%/‘# f holder is nanufacture to have clear contractual provision: located on foreigir sdi!;-fhe~@‘@~ . :hat ensure’ ‘ x/ that /, ;., the _) “I. ,-1),, manufacturer is kepl c, I,~ ,,,. ji”. holder’ s j legally _ empowered nformed of all‘ changes ma&%~;“i ~DMP h$der representative (agent). This the ease because, while the DMFIVEl”F The FDA bnly’ tF?.?cks *,&. ;g~-‘.~ + Iolder may be-fifingthem annually, the Agency :annot, except in the inspection process.(PAl, annual DMFNMF “u pdate’nd a simply files all other DM,h,~/J~s.&-‘~on~~ ; ,iannual or for cause) review the changes being nade unless the ~DMWV’ IF K I‘%3?E?pro$des E Unlike the drug product AR, i‘t, is & etter authorizing the Agency to do so. [Note: IIautomatically reviewed nor is it ight o‘f this i&lity, perhaps the industry shoufd‘ e b automatically reviewable.
obbying 1oi;rers.l for q-t~$@ inspections fdr all” DMF7V’ F’ M

The DMF holder should confir.m*;&at$$g$ a: properly reported to the FDA. Additional u$ate may be provided at any time or during the annua update. This information shouldn&dk ui;dat~ reference citations in the DMF. TheDMF hold%) /,; ~ j. .,“,.,.a_ may unilaterally expand the infsrmatror supporting the NDA holder by irmlusion o ,, . ,* /,,*.*,m Ic additional reference Information in the update.

indicate that a new authorization letter is. required whenever a change is made to a specific DM’. F However,’ this’ sectio n appears to require a NEW letter of~aulroriiafion If there is a n NDA change which may reference a different file or, perhaps a different portion of a master file. However, this se+on, a .S written, implies that the NDA holder has intimate hnowledg e about the content of the master file and must understand that th e initial authoriiation did not grant access to the existing section S of a master file.

new letter is the A cp,~ fh.* ~‘~~~~~~~ needed’

_.,“.. - ,.

Moreover, if the Agency finds a problem with he drug product’hat t come$.from a ,change in he chemical or physicai~proper&s of the ~drug ubstance, the Agency holds the drug-product nanufacturer most accountable because they Ire supposed to ensure that components that are lifferent than the c‘omp&ents listed for’ the irm’ approveci s or licensed drug product area ised to make dtug product, The DMF,VMF h‘d,~er~~‘esponsii;/llty ; in such :ases is clearly”s econdary._, (. ,j;,“,,^ . _ ~> .,s -. ,.,.,. ..,*..,- * (,.<<.1 -i‘ ,, L *,~*. “ v _ L ..” : . . . Q-._

Many master file holders to provide are very reluctant details about their master files that would allow “f or or facihtate clean, clear references. Please clarify why t&FDA needs a copy of the DMF authorization letter from the DMF when -the ._.” ho&r regulatory file is reviewed for a change contained in a DMF (e.g. container resin change). We believe that a new authorization letter is unnecessary since the FDA must have recejved,the D@IF letter at the time of the original review of the regulatory file.

The prior letter only authorizes a. “o ne time” review of the file for the sole purpose of “initial acceptance” that the file supports a CGMP compliant material component, container closure component, or other material.

process material component, affected submit a appropriate

is changed and the cha,nge has a effect on the drug substance, other or container closure system, the drug product firm nee,d.sto obta,[,n ,and letter authorizing the FDA tb review the sections of the D&IF. ._

As DMFs are not “a pproved” documents, how is the Comparability’ rotocol P to be approved when submitted to a DMF? How is notification of “a cceptance” of the Comparability Protocol received?

As the next Draft paragraph indicates, that is a question for the FDA tihose exact-answer. has not yet been formulated. Under its existing policy, the Agency would simply “a ccept” a CP filed by a D~F~Vfl’hdlder F and not review it until a) the holder’ s riext inspection or b) it is referenced in ,a drug product If the NDA/ANDA/NADA/A,NADA h,older submitted a CP protocol referencing the same DMF/VMF process and product, it would be either approved or rejected. In Case 1, review during inspection, only the DMF/VMF holder would be notified; in Case 2, both holders would be notified,(DMF/VMF hojder in its EIR letter, and the others by an approval

be needed authorizing the Agency to a) review the appropriate DMF/VMF file,sfc$rthe~~P $ic] b), when the CP studies havebeen completed, again review the up-to-date files as a part of the Agency

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Section iTi

hidance Line 508-617

Comment

/ Observation
a’

This section implies that changed using a comparability

Di%F/VTi@‘ n &
protocol.

be

Clarify

the section.

Discussion 1 This section does more than imply,. it Further, because DMFs/VMFs are “t rade states that a DMFNMF can be secret” documents, except for cause, the Agency using a comparability changed does not ordinarily have ,.any “1 7*4& .,,_ a,.,* t6 **1,*. . ~, a “. i&%v *h-“ .^ authority -~ protocol that the Agency would not CP so submitted unless a drug product ordinarily review. manufacturer explicitly-files a‘s‘ ubm’s’i6^n’t’at is Lh the CP and p‘iovides’ie t A geincy’ ‘ a Thus, determining the’afidify v d’ CPs addresses f review authorization letter from-the DMF;/‘;/F;EIF i submitted by D M F N M F holders falls holder. on the inspectorafe’iid a “t hoSef?rms The drug product manufacturers do’ave h a that use the product produced under compelling interest i-t-~, seeing‘ to i‘t t‘haf”% e the DMFNMF. changes implemented 1 produce comparable We would like to see this clarified. Changing a product. DMF/VMF under a comparability protocol is This is the case because a change that.leads another of those changes potentidIiy i‘mpacting to a postchange productthat is‘bt’omparable LX”, ,,._” n c multiple products manufactured I$ muhiple drug could put them out of‘u5ine~s~they b are not product manufacturers. approved to use such APls. This reviewer ^agrees .’ with the Thus, to ensure that .,,“. _.~_.i, (_<”, ,,.(*- ..._,“. ,%./^ ^, ---I* the-components supplied . commenters’ remark. by a DMFIVMF holder are the ,same as the components supplied in the submission _/ _‘_ I. , Would the DKWVMP ” &g. ” 'XPrj a nd ‘ documents, the drug product Wmanufacturer corresponding NDA/ANDA/NADAYANDA (e.g. needs: Drug Product) protocols need to cross reference _. 1. Strong incentives for plea& the one another? DMF/VMF contractual to d61r.$6.~b~g”; ;f~~ holder for proposed changes and Specific identity testsuites that aie’esigned d to detect undisclosed changes._‘. I”x .,_ .~ ., I,.~/~.~~r-. *”.” j _ 3. Rigorous specifications for aTI vanable column). factors (chemical and physical) that can affect the safety, efficacy, and conformance Sometimes the drug product manufacturers are .*“A i~~rrm9e,*hi ..*,*e*, to CGMP of the d‘rug products made with unwilling to divulge the useofan API produced each such component. under certain DhIF1VMF.s. In the reviewer’ s experience, most fii-ms’ re & Failure to disclose the true sburce”o f willing to do whatever they can tb satisfy their an API to the Agency “a dulterates” the customer provided the customer is ti[lling to pay drug product produced Gid make~‘he t for the added costs‘or f doing%. offering of said drug product for saleya For example, Dow was -more than wi)iing-to violative act that subjects’hose t wti‘ o provide a small drug product manufacturer of release such drug products to criminal sustained-release drug products with a. very penalties. special grade of “M ethocel” atan additibnai%ost Hopefully, the commenters will work of only $US 0.03 per -kilogram) VA.* ..I t hougti, even’ on _ ,.,_ / with the Agency to identify and excise average, only 4.5 lots/month of thei?p?o’t.i”d tion d such persons from ttie d‘rug~$6duct s special release crkeria’nd a only 2.5 ,, met Dow’ industry. lots/month of their production lots met thedrug product firm s’ rigorous acceptance criteria. 2. The DMF/VMF‘ has no need to cross reference any of ttie firms that purchase the DMFcontroll‘d e products (see “D iscussid” p ).. ii;-‘“g qw~-~f

‘_,

-i

Section

Guidance Line Recommended verbiage: are uncertain of the benefit that a DK’P i providing a Comparability Protocol, s‘ince regulatory “P rior Approval” issues with which
We

The provisions for submitting a comparabihty protocol to a master file Will be the subject of future revisions to CDER’ s Guideline for Drug Master Files and CVM’ s Guidance for tndustry for the PreparritEbK and5ubmission~ of‘ et%n&y V Master Files. Until thkse revisions have +been made, comparability protd”c ols”f d;‘asterfiles ~ are not included within.the context of this Guidance.

holder thky“h % to contend.

& ii%% ‘
no

This reviewer does & agree with the commenters’ proposal. Comparability protocols are a valuable tool that the DMFNMF horder can; if followed, use to: themselves with the 1. Provide assurance the holder needs to have that, as “c omp&-&le” i‘s‘”d efii?&?I by the FDA, the dhanges’hey*i’ plemerit t m do produce postchange product that is comparable chemically and physically t6 the FDA ?ii%‘~~d” ~ ’ product, 2. Ensure thzit the hdlder Will h‘&e ho change-related inspectional issues in CGM,P,i&pection, their next general and 3. Ensure that their custtimere cbt$i,fiue
to receive comparable FDA the customers drug product that is to the prechange prod&t “a ccept&Y’ .-‘ So .- fhat . have little or no risk of

The commenters arecoii’ect. r .” However, DMF/VMF holders do hav”eC GMP ‘ compliance issues that should compel them to only make changes that do @ change the,nature of their product in -q.-~-f-&~ $+-y* “I _’ I ~. _“,,.t,_.._ ,_ “ Since the Agency’ s method of auditing for cGMp comp,iancG is, *$--Lg~;ty, .--pe~tion, I,..“. _--,,.*>_\* the DMF,VMF hold& aKd.“a g~gi-Ef both have much more at stake in an inspection than -.nonDMF/VMF holders do. ‘ ” In genera!, the finding of non-comparability in an inspection, should it-%rie~ateTyXuspeiid the holder’ s “a cceptance.” * For ,holders located on” US territory, *“t he Agency can, should and has, simply had a local health official or, in some cases, federal marshals, padlock the facility and issue seizure ” .‘_” ; ._ orders for lots-in commerce.’ *dj For foreign holders,. the Agency need only issue an Import Alert to custo’is n and ~initiate seizure actions for any bulk component in commerce.
Do you intend this to say that the NDA holder comparability protocol in the D&fF- and be additional work? can reference the re;i;ired t‘”d & %o ‘

The text does NYJ state whatthe commetiters’ remarks state. to usf;;‘jci&%i@~ i Moreover, nothing could b‘e fufther from the their approved product in truth. drug-product processes. What is iritended?s to notify the drug’roduct _ ,,.h”. p A( .,,. In this reviewer‘ s experience; there manufacturer to have a strong-cohtractual and have been several cases where’n a working agreement with theii”D MF/V@F’i?older I innocuous change by a DMF holder suppliers and work with them to ensure thatthe has resulted in postchange Apl” lots changes the component manufacturer makes do that their customer’ could hot convert not adversely.impact their drug product. into acceptable drug product using This could be one of “t he’ geiic~?s A not s‘o the drug-product manufactiirer~s subtle ways of reminding “_ -i<.‘. /I, \-se SI,W. ,.., ._. _,.,,,m. the “d rug’ I product * .1 approved process. manufacturerfhat’hey, t not the Agency, bear the In every case, part of the “r oot cause” responsibility and accountabilify--for ther’ . isks , solution was to improve the working they elect to’ake. t and contractual rel’tionship~between a If a DMFNMF holder will &, for a-fair price, the parties and, at a‘Tight s increase in agree to provide the information needed by t‘he component cost, appropriately tighten drug product manufacturer and work i‘vi’h that t the incoming,contractuaIKacceptance firm. to address change issues, the drug product criteria that both should 5m‘ly‘ p not buy‘ that ,_ _”parties “, , i’ agreed._.~.I_ manufacturer “_ _.,_, should be met. _ component from that source and make other sourcing arrangements. .1,,,, I _,,“, ,,.,. _, .,_,, “, ^, ,,. II ,. . .“” ,‘_ ,. ii‘ _‘ : *: , __-a, 2,: , ,” :: making unacceptable when they &tempt drug product

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“B risto%yers Squibb is and personal care company with $ncipaI business’s’n e~ pharm&&icals~ con’ mer & medical devices. We are a leader’ m the’ research ana’ deveio~ment of innovative . ._l_ll-l metabolic md infectious diseases, ,neurologica dis.-rd&rs; an~onco~o~y~-“~ ~~~~i^~-~~~~~, dedicated $ *. 2 .billion for pharI;iaceutical research ana;i”, ,ky;~Gg;; ;;~~;~~es~ q(jo scientists afid doctors committed~~o dis;.‘&i v -‘-d d‘&vel;-‘est b &‘;;s-&;r;-‘;~& ~ ; that extend and enhance human life. Our active development. For these reasons, we guidance for industry entitled C omparability ‘ Specific comments are provided’ bullet G . Reference is made to lines 2.88-Jol:

These

commenters

begin

by stating,

/_ .a diversified’ orldwide w he&h ,” “,j ,_. 1 -.,._ ~,il. .I,. ^- .~.)_I., I. . >.‘ ” medicines, nutritionals and , lli *..z_ _^_i. ,: thera$es’ for cardiovascular, B;i;t;f;Jj;g;; g----fg i‘ >tTg”a &.+;~~~~~~~~;; i‘-%;&. / i‘ _ ;~~;~~--;;~;;--~~~

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current Fipeline comprises of’ph;roximatefy a J?‘ com@&& U under . are very interested in and well qualified to comment on the FIX draft Protocols L %hemistry, tianuf’cturing, a &rndCont~%ls h&&m~t&~. -, ._.I)j \,.I ,. ,, .~ L /. ^ ^”,, .~.” _., L” ~ format below.“ ’ .‘-” ~‘ “- % *” -~;jjifica&o&s‘ to a ,’ compa;~bilif~ protbc~~,sf;o;l~~~‘e~an$ r a” F’ %” ‘ / _’ ’ , ‘ “ . . n,_ a‘l e*_l ,a* .-.. .x_ ~~,_,,. . ._ . . 1.,.1,- ,-., , .,_ (*-*rrrji.nln,,~x^r;C’rr b *)b~_cI”- ~e.^. approved according to the appropriate reporting category*fG-the change. For example, a change in a test method to comply with an.offisal co.~i~nd’im ~ wd;ld i;G-fir;&& .a,-p;~~~~;~~~~~~.,~f,~~~~ange intest’ j _ -,. / -s ..,“_ ,d,- “_ , .” a‘; “. ,, -wa** i*; S *‘ s _^ 1; rolllu.*** r&r ,v>/.hY*Ic/ w**‘ .1 _“. -14‘l.*.Il-LNI “,..“i(*l.....“, ^I./_. ^ “W /. ” “1 1 . method also affects a.na$proved cornpara~~l~~“; ;~~~~~~a~~~~e protocoTrs referenced as part of&e request .,.1 -_i” .^_/,i._ ._. to make the change, the modified protocol should be a‘cceptable for use be~tuse~~-~~~~~-~.~~~~~~~~~~“ ’ I*.’ “” “ l‘-“^ ’ i>.,ml_l,_ ‘ n” .” .“d -. “, -I , _.. ,..‘l~l _ ,.,d ,i , _‘“, minor .” , ,. ” ._

This reviewer does M-agree tiitl-i the commenters“ proposal. ” ’ If nothing else, it is too, si,mplistic. : % ” “ ’ For e,x,ample, it does not differentiate betti.een:’ a‘)’ v&at should b‘ e d&i’ ”~ to e _-~ I;u‘***i_. : ~~-w-k”u..j” ,, ., ” *ia,x” ^,A . change a comparability protocol when’he t comparabii’ty i drbtocol’~‘ ~‘ ~~~ed i~~ but J-& yet approved and b) tihat should.be done _’ when ., the j: _;’, ,. sir change is to an approved / _ . ^ .L comparability protocol’ : I i*, A., ,n caSe ,,,),,, this relriewe‘ r would agiee wirh‘he,,gti;he~~~repo~~~~~~~~~~~~ange t ,~~~n,~~~~.~~,~~~~.,~~~?”I,* I , -,.. “I . z. ‘ i . (in the Annual Report) but would suggest that the sponsor”s ubm~itthe ui;date’o’ ta protocol under review-a-sari addendum. ., &-.>- , ‘ ,. / “. ‘ I In case,,‘b),” t this ~revie~er’S.ild’ 6r6tbd’joroljose” ttio’Eave ,_,f~a&on.” yet bgeri‘ ~i&cufe~, k c ourses‘ ^.not ,,._x. o ).+ ,._, For a‘ p~oved p c6mPara6ili’~~ t i j.5*‘h.t t ~a;, ,j_,-.., .I, -,, Agency shou,d require the sponsdr,to’onsider~th‘appi-~~~~~mp~~~6ii~~~~~~~~i;;coi~.~~~ c e obsolete and to su bm.it / a ,..” ._ .” (‘ mod,fi~~‘ ” ,,.. ~~~~~~~~~~i~~~,,-~“~ ~~~~~~~;.” ~~~~.~~~‘;r’. ~,~~~~‘’ ~ “ l ,i _.- ,.. *.* .‘ _1 _ modifications, coula be-given expecritea:“~ el;ie.~‘fafijS.’ s . *(‘ .I ^” A.,, *r **~,“e ..* _. .,>AjC..‘ -i..__ ..*.. , p/II , . ,_... ”

detailed description of the-proposed’hange~cEarljr ~ ;. 1 .-I .*y.T+60 GTETK~i&GlG~~~~~ --II. ~.. ~... -. y.. iilA,,“,_.\_(I .. “. ., ” “..‘.,.-.““l .sr*,r*nl.i-i _//I 2: .x : will limit the usefulness bf a ~ven~prcZ&& si&e.X &ill 6Gl&uIt to antlclpate the precise nature of every “. _” If.. I; Ij / ^ * , ._ ~, >. d-I .,xn%r>,,, . dAb,.Y .. <** h.l change that is to be made in the future as a result of development work.-’ FG;;“e $@G; ‘ ,-~A&$$aE$$~ ^, ^ ,-s, /_^I ,. ^_.. protocol could be filed” for “t iO;liG~~GbG$ -to ~W&GpIeGfermentation procC& **G&&t detailing w hat ‘ components or conditions would be changed:”

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._

.‘

_,,;; ,&;“>;~~~~~~~!~~‘~~~,~~~~~,~~~~~,:~,~,2‘ .^, ,“. .s“: f ~ .b c&ld‘k$i~~%~j/ e %& that, once submitted, the ~“~ -~p~o~oco, as a who,e regard,~ss of the I ___,. ~..,&,+i ,_..._ LIXI,4(“. : ’ “A ” nature , of this ma~n-er, the’ umbe’ n r o &,ga; Impacted. ~ n the deficiency-or the A~~ticy.~ti~iy”h ifie~it of ~f%‘ducts ~~at”b lj;ld,.ing,,~)‘ dr;bouraged-and ” <,> ,&,,,,*;‘-* i’.;)(;:w <1,wi,, ,ead to the Agency’ s rej’ecti;ng th~‘rotdco, e p for a,f o” t~~~~~~~~~~~~~-~t~~~~~~~~~~~ .‘- -. -^ ?o..z+ist the”A gency, the guidance Agency wij-,. ~itti~~~~~~~~~~or~“~ ~~~~~~ one change is’ eemed d to probably generate _ Ir$&4!>~a;<-L 9.;;a b le a non-corn-para’ product. : Further, should_. *,., . .a _Ijl“- ,t~‘i~le~‘ 5&ct mui’ ~*~>,+w,‘. @ r,.n*~-%a-~&-.#w~ir.*c**m~tw”: -*-~yYs+ $-otocol%e approved and $nyone product *n”& j s .I (.. lx._i/ ,‘ found to be lion-comptirable InThe post-approval studies; t‘he Agency%I’l^reject l all of the products in the comparability protocol. ’ This is the case because the’ Agendyapproved ; the protocol cont&ge%upon its ._ producing comparable prod&in affcases: Thus, a failure in one product”I /n a multiple-firoduct comparability protocol would, at a rni+$~, triggerthe PAS .. re’orting’eouire~ment p r for all products in such ).,,. / protocols because theira~‘u*ltip~~-p~d~‘j’ ~~~~~~~a’~i~~~~~~~otocol. is tied to the protocol and not ,.to__, the_ individual products in ~ reporting ; ~ status ~ ’ *’ 1 1‘: /_I_ ,; -,,- _, ;, _” ., ,, i _. I . when-any

,‘

,.“ ...~_~“ , ,. ._%“. _,%“/ :‘“. /_W” a.+.. __.. .-, _ ,* ,.” _,* I_“n f. -l.,,x, “. ._ .,~,iill(,Rli”l L-..C- ~ .i~. -_-L, ..L.il, *,..riT , ,#I I *y1 “S ection 1V.A. How Should a Co&p&-ability P&%orBe SubmItted? ip ,*(l*,,~“r Ie;z liifrequest t‘ .‘\- .:;r, -‘z”c !’ :‘ ” “r ~.‘“~ “_a‘ . - -.~ .j*‘,,&-, for review : , - ‘ The Agency should dkfine .~,i~~~~o~~~~~~~~~~~‘~~~~~~~~~~~~~~~~~~e ~ SPOnSOr,S ,i ._ _ .,/_ II .’ and approval. ” . - ^^ .....)_. _I, _ _ ._. ~ .) ., ^

.^_ ., ( )

-‘ .

__

.‘ Y’

.‘

:

-2

Since there ,is nq ?ucJ~ dat+a,se (toxicological and cli?ti%l j'6r I ii& pbijulation ‘ risk for non-comparable product, the Agency can only‘ ccept a the change when the product is comparable an-d reject LyLi/y& ~ “i iiiit”-i‘-i’~--tjased ‘ s dec.i<o’i”f ;naking i is not supposed to be based If the Agency
who

administrator

vaccine becaus&Glmost 100’ s of thbse w”h 6 shortened lives.
“S ection

decide-&‘o< f ,‘i‘rfh--.rize” a ._^,.,_“:,._, ,j_l,- ...1,”s rLr^’-*_‘ __*.j_ -* _

on speculation. needs a’ cigar

example,

; ,_- “~ r t .,_ ‘ -0,..,* iI ,‘ -.. .I,j\,>, “;‘“.,“‘.met ~“/“dthe **,-. .‘ 1 one lim it fot’ NiCd*“‘& “ vi’ us~‘tiat .,. ” ,”(.” d&Z%i‘“i ii~ur~d L- ^ .,,., . stage i-&etved that lot ,and put s6’ii‘r n r g’ Iron,lungs for the rest of their .^ _

t&^;&i&.‘e s $ f’ ‘g rjarficuiar’af& L . “~ “ ” / .,”s-,,*. ,, ^.,+*^..&l(,,a,y.‘:*

let

them

t%metib&-

ihat

$

FOA p;ii.

lV.D. When Does a Co@Girabili’~‘ r&c& tP Become Obsolete!’ ’ ~ ’ ._’ ’ ’ ’ ’_ Clarity is needed on what is obsolkte and what is not, If a process works and is validat&but & es‘ot ‘ n use ,‘ ,., _( I. ” new technology (software or equipment), is it obsolete? Who makes the.&cision about when it is or becomes .‘ 1,... ~ , “_ _ 2‘ -* ,. ” Ia.. , obsolete? What is the d&e&nation df co&parab&y”p rotocol that is obsolete?”

While this reviewer recogni%&s the coi-nhetite’k’ ; e-t,:7*37+.. : <2:.. I the context r ., doncern,*:-, OJ& <.--,* ‘ applies to the compatibilify proto&l”a tid &t~t< the process, the techt%$gy, or the equipment. To clarify this, this re{,iew&r again ~&dot%--$ier&U-iti~ ff-$ Itel;f‘i-i;‘ ~~:~~~~~~~” l ~ through 296 be changed fd.read,-r<$, @ I’ + ~ --‘ ; 1 ’ I”:,“’ ,.‘: ;:r~ “’ “_ I ‘ ‘ I‘ __ .
“N ew regulatory requirements, identification of a safety is.&(e.g., screening for new infect& agents in materials from a biological sour&$ identikiti~i _ ,i ,.“, _/ ne%&%k%%~ *~“. **l a\.:*:_,‘_. :,&.a ii(> of h &technoibgi&l a&ancem&t . r((_ / * :<.I-, ‘ after the comparability protocol;h&‘ eG b z$p.roved can render a protocol obsolete. We recommend you review ihe tests, studies; analytical’roceduies, p and acceptance criteria in your approved comparability protocol to ensure they remain current and ~, consistent’ it6‘ ~he;~~~%~~d application Gid curt&E FDA I_ “. G policy. We recommend you detkrtiitie whether the t&s, &ii&, analytical prbceduies,‘ nd a acceptat$e fo&app?o$%d &jrnp&aab;ilky pkoioeor*ar;?&li appropriate prior to implementing and criteria described’n i ._“,.*“a .*i*,“. >_j.l<,” *,<m.,/,^i(l” :,<:_,._.* ),_. ., I ., ,?” .*.;.* ~ ._, submitting a change under the protocol. If you fitid the appi-&ed comparablllty protocol IS no longer correct or adequate, the &re?tappioved protocol shodId”& tik$ied @~~i~hcir%.k~~ Y$.~,$&juld

apply similBr considera~~~ns:~~,~our subrr$tEd,,b& as j&;‘ n8ppt&& ~ compdrability [Note: FDA can.rsquest ad&k%&nformation i;;‘ suppo% * a change that is implemented protocols. using an&seke approved protocol that the Agencj/ &t%&entiy finds, ttirough’ eview r or inspection, to be oljsoI;~te*bkcau‘i;‘t”i s s i “b ut d f’ y”* &+ ‘& respB;ftij .($GFsIp;; ,cu;rent . +(cij_~:~,,*ii,-‘ G ,%4 1 ,q * rd-3. applicatioy, or I$ense, Agency policy, and/or the^ firm s ,.** ,..*.-I”. j /I,,_petidtng ’ or approved _, (\/< curt-&t or its current pending or accepted D.IG7FIVMF.T‘ ___’^ ” ” _.
~ ,._, \ , -,“ x_ ~*, “^ r ___I, 1V.E. How is an Approvgd Comparability Protocol Mbdif&l? when it &o& for a’ re&ion that is:L minor; can the Clarity is needed for using a’o&+arabiiity’ b ; “r_ a +,,p;:r~. -“, I i”” I :e~ l*.. _.,i^“. ~:dcer,?$p~‘i 2+ I,<I)%. ,‘*- -or*;-*;I,i‘, ,,L * ._ I ~ 1.. I submissIon? revised comparability protocol be reported as a CBE-30 rather than a prior approval “S ection ,.( ,‘ _

protd

.,.

_ ~,-.The pro”ides:p;o~~‘~~~~~~~~~-u~~~~~~~%d’y ~ b the resu,ts obtained by’ t;/-g--fy;d‘ reduction in‘ crai’i.+~K~ti r i.“..u*i’

.,(. “& .& “6 6~

,, .,

.^. -.-.%“l;ed ;jen” are‘dh,parab,e d of the’ nowih; sp;nsor to

c,. ,-,-j ,&,- .;,;the ;‘: ,xti:.:.4 Usp~re”r s~~~mgf~~~,1 .. “, ii&d f0r The.

.. 1 rei;iew‘nd~.ai3p;o~~,’ ~

comparability protocol. _All other revisions.. to a‘n approved compara”b il/ty~ protocol should be because they indicate a lack of process under+8ing u$on the dart ofthe~submitter. suchrevision, revised its comparability protocols should triggera‘ o on,y the Moreover, broposed supporti.g dafa‘ andjirsf~ic~~~~~l’~iiiei~~~t”~~ r evieti’f ~

approved

.PAS not yut. .’

also a revisiting of the original approved comparability protocol’ s submission package to ensure the overajl, Subiiii~~ion:.a)~~~~~ii‘$SS1:ij;*doriipliant ~ andl’ ./,.l<*xIy. that), , -,&, ~.*sr~~*~~;.~p ;edicts =A ” ,,,.j.ues ~ ~~stiil’ ,* i the post-change @ roduct ~~i~i~~~-clb~rnp;arabie to the$e-change product.
“S ection Define V.A.8. Commitment ^_ ,. _ ’

obsolete.”

dictionary,sThough “O bsolete:

need to’efine d~ ,‘ut this o‘f reviewer b date,,,-th.S sees&no revie\;i~r:ie‘o.r;;~~~;js‘~~~~~;~~~~~~’~’the term d ~ ~~~iti~~, out of date with the firm’ pending current current s respect f‘o~Ci;iVi*ij, current pending D m’T(mi:F a ppllcatiori or’pproved” ~ or acc~eptea‘ F
dbou< . C%&q&

“o bsolete”

beyond ..” ” the. ,.

“S ection Addressed facilities.

V. E. Does FDA Have “S pecific Conceks in a Comparability Protoddl? Clarity is need&d abdut the ne&Jfior,a’om$axability c ”

,.I . 4 .I Manufacturing F&ties^That ,.I _ (., I_j “” ,^ ,.‘, ; ,_,_,, protocol when using or changing con&act (_..,. ,,” ..,

Agency {oiicy, and/or ;i or license, ,*,. ,>,.\ or its >.-,-l 4 ’ ^‘ ls~,lf. -‘ “ .*.-... ; _‘ ^’

,.

Should Be . I ,_ ‘ ., ” analytical ., _I

As a Ph.D. Analytical‘ heniist C and sometimes auditor of cot-&act laboratories, this, reviewer is all~too‘$a$e:,ofa a need for so’ e’ echanism mm for&e f?r’ t‘o.verify’hat m t the results obtained by one lab are valid and’ruly t com~ara‘le b to the results’btained o previously. However, because a comparability protocol (CP) is’a‘n . optional a‘pproach to satisfy the Agency’ s need to know that a firm’ s rnan’~~ctijringsjistems, u p’ocesses r and -products are in compliance witl-i C$@F),‘lie~use f of cp tcra<con-$&h this‘s i upto each firm. ,,*:_trc,.-i ,’ _ i j _L_.*_ ,( /* .’ . ; Whatever a firm elects to do In this regard;‘ e % Agency’o’veiri~ing”g oai’s s i to ensure that the post-change p‘roduct batch is combaraple to the pre-change product batch. Changing testing laboratories can impact batch comparability especially given the batch acceptance requirements set forth in CF#-~~~l:T1;~~d);that.require.that not only musf the tesfresu,ts fdljyd irieet.specifi;gljo; i;l;lrf x;;fhat stati.tical quali‘ y ,-m+r$;,~,.*;,y:‘,t. can.,: , be -iA, * r :‘ “., . ‘ “ .‘ : contro, (sQc) muSt ,rj~~.~~~t~~~‘~~Ij~~~7, ~ .s-g-w;g~fP6ik before :,.‘ p” ^ released.

gi

If the overall result uncertainty’ in the proposed laboratory is m‘re o than that found in the current labbi~~~~y,-‘~e-S~~-accepta~~lilify;;of t the batches’ ill‘ w not be comparable and, for the same acceptance criteria, -.* *“I/ ,.l;_ .&,< ),“,V,. Lt,+++.^\li.-I’‘meet .*, the more batches t. w-ill fail’o *v.“ _”_.,‘ t * .>~*;y” ‘ .‘I‘ ,“ _ *_ _.”4x, ,_ .~__ : _- ~ ~_ criteria. Convers~ely, if the overal\ “” II result uncert&int) inthe ~ro+sed GborL3tory isless ., *” than that of ti-ie current laborat&y;“t he laboratories are, by definition, comparable . (,. 61 _ : / .I.. : ,.

V.F. Can a Comparability F%oto& Examples of acceptable compkabiiity products) would be helpful. ”

“S ec+n

<_,,._ ,““. “f.. Be’ O&d for Containe”; protocdis f&r hi&&&t

L

*i

‘, ).

-

,.-

I

,; _ .‘ >,.*. ;, , . and &&al-

, -) .‘

,-

8%&e d&~~‘ rn~ G

$&em dh&gesi )* (‘ LcludGg i&aI&oti

This specific.

section states Clarity is needed

&at.ccomparad;ili$ td &deGtaAd”h dw

protocols are product a’omparabilitypro;ocol-could c ^I, (_

s‘pe&&

yet a DMF is not always c l&$ I’i&: h ”
I. ., I. ,,

product

[Note: The original commentVs a^re quoted i’ a c‘ondensed n font (Perpetua), the quotes ~~~~-~~~~i~~) and, in general, this directly from-the‘ia~~‘uidance ~ g are quo’ed’ri t i aS$$yi&d reviewer’ s text and comments are in a publishers fonf(r\ieb& Gothic MT) 6make it“% i&? for the reader to differ&nti&k the “s peaker” in ??I; V$i~t&” f&t‘ p&sages that follow. When addressing &mn?ents made% a-tabular f&=6&, this ieviewer wilJ.(to the extent required) preserve the’?pmmenters’ , fst(Fgt and, in general, aljpr%$?iately place t‘he reviewer’ s remarks after those of the com.menter’ ”j S ’ .‘ “, _‘ ._

been

As of 18 October 2003, the comments made available to this ieviewek.

made

by th&e’ nkk+-$ C

h&e

not

,“..

_._.__”

,_,..

_

.,,.,.

~.:

,,/.

/..;

1. ., I ;

_,

ote: directly

The original comments aye from thy d~~f~,~u~d~~~~?~~~~~~~~~~

quoted

in a condensed in d‘Siiz;d’ s f;;t

f&$ (I+~~cu), the quotes (I-ydian) andl in genera,, this ”

reviewer‘ s text and comments are in a publishers font (News G o~tiicMT) ‘ tc%%&?‘t‘ dua~& i; for the reader to differentiS’ -% % “s peak&” ‘ in -l!hs‘ ario$ C text passages that follow. When addressing comments made in a tabular format, this reviewer will (to the extent required) preserve the commenters’ format and, in general, appropriately place the reviewer’ s remarks after those of the commenter.]
\ ,_,, (. ,< 2 , . (, . ” -

These

commenters

begin

.‘ by’ stating, ;

Comparability Prbtacols--Chernist~,‘~~u~~~t~ring, ~ . scientists at Johnson & Johnson Pharmaceutical consideration.”

referenced ,FDA draft,* guidance ? entitld -______and’ or&ols, C issued February 2003 has been reviewed by Research, LLC. The “.. following_ comments are provided for your _\,~ .;;._,. .( ,, i ,

’ “T h e ag ove ‘

“G eneral Comments .. .,,.’ “. . .This draft guidanceW’ttempts a tobe responsive to industry’ s need for more predictable, resource-efficient, and scientifically sound regulatory pathways for post a‘pproval changes made to pharmaceutical drug substances and products. Our scientists appreciate the potential benefits of defined protocols‘ut b have the f&&g majbr __ ._^_ -, .).“‘I concerns: , “” .Z”..) ,-j ,j_ ,. _I_ * .“, .,,L“(.‘,, , In order to enhance the usefulness and effec&ness” of comparability protocols to industry, a‘ higher level of protocol review is requested at FDA’’ We recommend . that a “C omparability Review Committee (Similar to the SUPAC Review Committee) be established~to oversee p&to&l practice in order to, ensure consistency across divisions on’ various issues, to I shorten “,-(, approval times and to provide I , further . ,, guidance such as Question and /, _., j ., ,. . , ,.,I.. :,c<#~,”j ....~~,.hj riL -,+, ~~~ Answer documents, for the benefit of industry.

This revjewe,r does If better consistency corresponding guidance Given the level of scienceand/or regulatory: committee would increase and contribute to the ever
“T he requirement for early container-closure component early in the review process: provide. ”

submission of highly dehned protocols seems to suggest that all process changes, changes, analytical detection requirements, etc. are anticipated at NDA filing or In fact many- changes are not anticipated and detailed information impossible to

agree. . is sought, then the AgencysClou’ d,be.;eq.~esfed’o.is;ue ~ t a to its review and inspection personnel. competence ,demon$rated by many of the supposedly based committees”w ithi~th~~~~~~~~,‘ bding ~ another such the’ lready a excessive bureaucratic overhead in the Agency lessening role that sound science ljlays in Agency decisions. “‘, ..I,..’ , \, . . . .,

not

If a firm does n+-J truly” understand their process, use this alrea.dy optronal approach to demonstrating another route. .

tha.t firm should C A M P compliance .‘ .. ,) j

simply and \_,.,.

&$ use

,_, (, ,_I. ,- -,‘ , If “If provided, the level of specificity may define the protocol ~sonarro%ly as to,:diminish future usefulness. I _ /, , ~“, _“. i,,.~^x, ,l ,,,..a*-...,+/“/ ,, ” specifics are provided, protocol amendments would likely be required later as additional information and This wouId, diminish the usefulness/benef;ts -_,_ .‘. of using protocols: Further clarification and experience is gained. guidance is requested ,_ _) from :x:FDA. to ” achievei Qi ~:.“‘: ?‘~~~~r:.~:;<r~-‘balance .‘.*$&~e, ,‘“i &.j ;r,i:h:need -,*-for _ specifics and the realistic a ; workable between, the ,s Ib a__ /.. _j ,“_ I\ .. ;.y*‘ ~ .‘- ** +,, $ limits of industry information and experience. ” ” ‘ .’ _ 64 _.j .. I ,_

_ “. j ;,_ . “i , >

_ .. I’, “_ I 1s .

‘,I‘.

,,

.’

‘.’

. This revie~~.~,ajs~~rees with th e corn’r n ~ ~ ~ ~ ~ ~ ‘r ~~$rks.,,.“< .> “.‘< ,j_ ,< . ” e’ _” , * ’ I ,3* ,,& ;,, Firms‘th a f d o n o t tru,jy~understarjd th e ~ r ~ ;b c e s s e s . a h d th e p r o d u c ts produced’ b y th e s e processes should I-& u s e th e , ~ c o ,m p a r a b $ “ty ‘p ~ ~ tdcol”.‘.apljroach’ to ’ regulatory complitince u n til th e s e firm s fully u n d e r s ta n d i ” 1 C a M (and com *.. W hG t P consti~utksso’u pi li yd ~ ~ ~ ~ ~th ce er e to), n (grid,‘u s e so;nb insrjecti.; s & y ’;e ”i.th ;i; st;b(;; ” I .I , . e: a n d specification setting), and . ‘/ ..(. *, ,,/ .; I’ 3 . Their processes a n d p r o d u c ts. T h e reality is “t‘t& t”fh k iirii’i ts’ o f industry ignorances are’ almost al’v & y s self imposed. /. M o s t firm s s e e m i n g l y d o n o t w a n tto k n o ,K ,b ,e c a u s e :if th e y k n o w th e n th e y will have no excuse for their n o n - c o m p l i a n c e .
“S e v e r a l comments > more general comments a r e offered.for b y section a n d line n u m b e r . As noted reduction changes in Section,111 B , reporting of a relaorting’c ategory. where this reduction may changes This apply would “y o u r consider&non, ‘f ollo*wedhya _, under ‘o u t c o m e an approved protocol valuable. ” would and normally result of the in the types of is~clearly^benefi&l b e extremely examples listing ofmajor and minor “’ ” ’ ”

p

_I.

_

“T h e draft g u i d a n c e states in Section ., III .- A , that protocols container-closure system and other changes of a repetitive When multiple related a n d repetitive changes a r e involved, ..:_ , 1 > ., changes, m a y the r e q u i r e m e n t s of the protocol focus o n ,. the _ o n the smallest Container, etc?” . “W o u l d lines? !f ) .(, I., ‘^ ^ I (1 :, .: : it b e permissible to c B u n d l e ’ protocols to facilitate

m a y b e u s e d effectively for c h a n g e s to the ,, 1. ., nature. ‘I particularly with container/closure system ” .,. ,._ c , .( ), ._ L I “worst-case” ..,,,I,_c h a n.’e s g s u c h a s a n e w closure 1,, (. :,“% 2* ._,,I _, mult$&Yrelated “i+ :-.‘- ’ ( _ /I, -,’ ., .I. _ ~ 2 _,i. ,a’., ,. , ,/ ..~ “/ill”“,“~ ,._ .,31. A , ./ ,-a* b ”b _ ‘c h a n g e s across products ., (‘, .$ ( I; :’ ; (,

7, 7 _ _ x >

In general,
“Specific Skip Testing

.I this
and other

rev,@ ver: ,._,:\.h 7 /_“.th.‘“, ;. Draft, d .o l n + o.’ s;u p p o r t’this - _ ..% i, ._ pj p r- o a c h . ,/, e /, t a __ and ,_ I, ,: ,. : I.,_ * ‘, .. “. ” _ ” 0
to ( a n d more detailedexplanation theories under of) the potential the p r o t o c o i 8 j ; ~ t ~ ~ ~ . ~ ~ u i d testing requirements for S u n s e t Testing, ~ - :. b e extremely valuable:i’

1

,r

reference

and not

,‘ < [ *.:< ‘! ” &i’,“2’’‘7.p ~. .,.,: “*. .,.‘,:.;2i:++“& +:A .. .;;-2 ,::’ .‘> ;A.” )-*; ,‘/“I,‘: . ‘_ . I,- + ‘, * .“‘,p ,.” .,‘. *W ” U ’n d e r C G M P , ‘S k i p ‘c iestrng IS vrola~veldftheexpllclt representative sampling testing from k a c h i h i p m e n t, lot, or .b a tch d e ~ e n ;j+ g u $ ~ n th e -;-‘;~ ~ - & s h o u I,d b e discussed. ‘,S u n s e t testing” is a C M c iS s u e .th a t required LnbE -herigge jo..$ ,--& ;ai;;ility b e for dne .’

# p r o tocol because th e c o m p a r i s o n tests th a t a r e o .u tS i d e b f‘~ ~ ~ ~ ;‘~ e ~ ~ ~ ;e :

(without testingto % ith testing) m u s t K ”~ ;~ ~ ‘.~ ? & ‘. -;;~ e diopped i;,“‘b f‘n k d e ;sity,

th a t is in a d d i tio n to th o s e r e q u i r e d b y ‘C G l@ c o m p l e tio n o r across e a c h p h a s e /ste p /sta g e

( i n c b m i n g ’a d c e ~ ~ a n c e , in-process a t th e sta r t o r in’th e ’ jS?kess, & % g ’p r o d u c t f6 r release; drug

substance inspection

aa nn dd dcroum p ,a p.i~oTd u c t h 2 5 .dlli;igj:jt release$$i!‘~ t~ 2 g r for p o s *^*> I -*-,.

& 5 ’o ~ t--g _ _p .r o d u/_t.. & $ :re-i’& % c ‘. ‘, I_

annual

.

.

L,

.I

,

,.-

I

,_,

:

I”‘

is r e,d ..,. “.-,“_ r tibilityP ”c~-~ij‘~ o ~ ~ - .‘,,;~ & ‘g.,, A s t~ far~ ~ ~a ~s ~ ,~this~ ~ ~ reviewer 1 .:I“‘““, tha ew‘,ai:f,rm cto m pdao_.-l.ClidMi”.r”,l”-,bl‘ i~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ (asraem p ln iontg , a m e n a b l e ~~ ~ ~ ~ ~ u ,re _ protocols “,I ~ a n d testing or e x a m i n a tio n ) for every a s p e c t a n d . stage
“Specific g u i d a n c e r e g a r d i n g also b e greatly appreciated.

to

.’

o n ’b a tch-repres&&ive’s a,mples o f th e process. .^ .
the potential requirements

from i’
for c h a n g e s

each

lot or b a tch

-”

.products would

to B C S I category

,“,,.‘_ O u r scientists h a v e expressed a g e n e r a l concern regarding the benefit of ‘s ubmit&g’ comparability protocols versus a potentia!increase in the n u m b e r , ;& $of J ysubmissions “q& ry& 2 , required to g a i n approval of a post W_ j:“‘ . .>-**-~r% & ,*i>r_i.‘0 . -1 ,“, :: _x.-.. approval c h a n g e as described m t h e S U P A C guidance, T h e benefit of a r e d u c e d reporting category in : s o m e cases m a y b e o u t w e i g h e d by the n e e d to submit the comparability protocol in advance, k e e p it “, u p d a t e d or alternatively withdraw it.”

th e

This reviewer a g r e e s th a t it is’u p b e tter o n e for their o r g a n k a tio n .
“It w o u l d submitting * The b e useful to include,further a n d maintaining protocols mechanism for withdrawal

to e a c h

m a n u fac$rer to d e c i d e ~ w h /ch ,I _(,~,, ,-.,~I) .> ‘/,_ s_I , ,r j

p a th I

is

of the benefits to industry b a l a n c e d with the “C O & ~ ’ of the product lifecycle, addressing the following issues: ” _. ._ ._ ,.”._,.. of a Comparability Protocol”

discussion throughout

This guidance.
l

reviewer

a g r e e s ’th a f

this

is a topic

th a t th e A g e n c y ,. .,.

s’h o u l d

include/n

th e

, ,.

., .- ,

LC.

“U n d e r Section IV .A ., if a comparability protocol‘f or a n u n f o_r)e_,,es_ n.I c h a n g e is not submitted s e in the N D A , a n additional Prior ‘A p p r o v a l Supplement w o u l d ‘b e required. P l e a s e provide clarification r e g a r d i n g the a d v a n t a g e s of submit&g protocols via the PribT’A p p r o v a l Supplement r o t & ~ W h i l e it is clear~that submittinghrotocols at the tim e of filing’m a y d e c r e a s e the future regulatory filing burden, submitting protocols via Prior A p p r o v a l Supplements (with or without supporting data) ,~ .“” ,,,,_ a ‘, _,..,, ^ “.,-c<,“...” -*,/I*:‘.“. ‘, “‘;,, ,dl” offers few filing a d v a n t a g e s a n d is essentially similar to current filing practices.

S ince a C P is a fo r m o f P A S , s u b m i ttin g it with a firing or in a P A S is e ffectivelyW ._ .,./ th e s a m e from th e viewpoint o f a timelines.’ ’ Moreover, all C P s a r e s u p p o s e d to b e s u b m i tte d ’w ith s u p p o r tin g d a ta . A ll a C P is d e s i g n e d ’to d o is s p e e d th e 7 i P A S i ’ r e & w p r o c e s s by ensuring th a t th e s u b m i tter provides th e ’n e e d e d ‘b o d y o f e v i ~ ~ n c e ,‘th $ ~ ~ ~ ~ ~ a r C y ’e stabii~ties,the CGMP” compliance o f a n d th e p r o b a b l e comparability o f th e p o s t- a n d pre- c h a n g e p r o d u c t. For th o s e w h o truly u n d e r s ta n d their processes,“a C P-.should’b,‘< f-.i:u/,‘,.,I. -ijustify ; ,: > +/aI -.,/ e .,,. easyto when during d e v e l o p m e n t’o r’a fter’a pproval, l\cen?e, or-acceptance, th e firm fin d s a b ~ e tter tia y to m a k e ’th e s a m e p r o ”d u c t or a w a y to ’m a k e th e s a m e product b e tter a n d w a n ts to i m p l e m e n t th a t c h a n g e . ~ ,, (.,,:,....a“,~.?.“,Z^‘_ I”-.--‘ . If th e c o m m e n ters d o n b t see-the a d v a n ta g e to ’th e m s e l v e s or th e A g e n c y ’s submission reviewers o f h a v i n g a-well-defi’n e d o u tline or r o a d m a p to follok;‘th e n this reviewer w o u l d s u g g e s t th a t th e y c o n tin u e u s i n g their_ ,~ ._ _ current _ ..-a p p r o a c h e s . ,_ __* : .~ .I’ _. e “T h e m e c h a n i s m for discussing comparability protocols with the reviewer prior to a n o n - a p p r o v a l
letter or other adverse,r&ng so‘m a t approvals are&t negatively m&acted”

::

, . -_ y, ; x,, .~ ,‘ , .” ,,,. i, _

._~, /,“. -‘ “ ,:...,” : “I . ‘

_^. 1, _,.-_.

___,

-,

^I

‘“

^

,-

proceeo.though”a &.rpervisory change his or her findings.
l

dhemist$

reduce

the dir+3

pY@ui-e

on the

reviewer

to

.,_*_

,...

.,I
is weak, t(.; /‘ .‘’

“I f protocols are used aggressively, there may be a p‘erception’ that product ,. ., thereby jeopardizing dossier appioval” This re”i ewer agre6i<ihd‘ buld w add thii;‘h i his;~~~~~i~~ce,.percepti~~‘.;;i s

development

often not far from’eality. r However, the preceding.is just another one of‘ hose 1 .,,, .things t that’f’irm a must j (_j weigh against its haste td get theproduct td ~ma&etI , If nothing else, thisaraft’ndthe, a comments-made to;-,it (.Ii_i‘ _L(/ greatly should y‘ :; assist the ,+,,“. ‘ review chemists in their effortsto determir;e~~~~‘~~~m_isslpn: ~ a) IS U%If~ compliant and b) ensures that the prod&s, c&t&, and product are, with a high degree of certainty, CGMP. ., 1 : ;1 4 “C hanges reportable under an Annual Report or Changes Being Effected Supplement will take
longer to implement when reported under a protocol”

sort

are

Other

Comments

“P art II A * Line #97:
changes safetyand

bv Section; ,I

.‘.

I
deta&$ , ” w&ii $afx potency of a specl$c drug &es& product

_‘ ,

“A comparability protocol is a uGll-&j&d, _. in the identity, stret$, quality, purity, and $&veness of the product:

tlk’ &t~~f &
as thesefactors _”

ipec$ic relate ,-..

,.. CMC to the

,.L

This~defin%ion’ef&en,ces r drug substance -bhotilcl:ge

ihe d&g i%!tide‘~.i, d

prod&t

and “. not “. , the -,- *‘ s ubstance. diug’ _ _ _,i_, “Z . .‘

Reference

to the

(Lines

This reviewer agrees 97 through 99)i

and

wou’d l

again

propose

the

following

alternative

text

“A comparability protocol .0 .I..,a wel!:ddfGed, is a changesk on the identity, st&gi&, &$y,

material,

intermediatoy;‘
of the final

drug’ ubstance-or s
drodtict‘” .

,,_, __ _A _‘_>,. ,. . I. ckzl~~d,~~%~~~ ~l&&&&sing the effect of specific %C purity, and pbt&ncy of a’pekic&ttgprod& s (in-process drug l%ocjuc.F) i! &@?$j&y@‘ei~te k to the safety
,I k

and effectiveness
“P art 1I.B.

0 Line # 109: “F urthermore, becauSe~adetailedplan.~ll “. is less likely to request additional information potential exception). The term l‘ess likely’ is vague. T&sentence
the FDA protocol.“’ would not need to &ques~~&litional

/_ _ -_ ,, be &-ovided in thecom$ar&&ty protocol; the FDA to support changes made under the protocol (see 1V.D for a .^
,‘..it / should ,r,*‘ .*l;i”u r Ili./i i.,._l> u, to-read ,‘“_ .‘ % be revised information to support chanies is anticipated made under that the

This reviewer disagrees w ith the commeriters. ‘ Though “l ess l‘ikely” .may be vague, it properly of what may be the‘ ase. c What will be the case &&%-rotbe’ nown k a‘t&the be knowabi,e..;nti.lr~tti3T”~ fi’~‘~~~l;’;’ ~an’ e”i ~.issu~d ~ ~~ c with the CPs submitted.’ “*

conveys

the Agency’ s and,

perception

pr&ent time, an.d the’ gency A

if ever, will not gains experience

The Agency’ s anticipation, is that it is %%s lik~~~‘”~ %id’~ hat t “
0 “L ine product #112: T‘ he in distribution

based “a w*i.?> their&%rience$th / ,*, i,,L,.s,*.+ on */lj,* ~,~~.~..a”& *<. .-. shou,@ be good _; enough
_ ,‘ _j _‘.,

.

other it tt7‘s’ihe.’ it
. 2” 3 .,. ,

such .‘
I^

._ guidances, .,,
and place a

.-’

use of a comparability sooner than with-xt

protocol could allow an applicant to implement t,he use of a compkability pro;ocol. ’

CMC changes

The “T he and

word “c ould” should: be r‘eplaced by .“will “. The sentence’houhl s be revised’o . read ,7.~.;..~...-~i~.,~~*..‘t!? \ )‘k’ ,*5::* ._a use of an approved comp$&bility protocol wjll;;!id~an~~,i~~~~~rnplement CMCchange& _ (_ . ,“” .,_ ., place a product i~‘i’ but& d& kbo&& than without the ,gs,f a comparab&!y proto&” . : ” i ,.*.*“lle”p .a‘~ 5s.. “& ,” :/. *,<1” .I _ ?‘ .

Gf

s‘-j

Again, this reviewer can’otagiee n with the commenters”p resumptuo;s If an app,icant subm;ts a deficiefit cp “f $e,L’whgp$,, be t~yasel~I,, *&,. &&- ‘ i The uSe of ,‘ou,d,, ,-” ..&;, “. *“- a:’ &.A**“) *cI* I,:,‘ ._ h ~s~no,d/reEI c ,s approprrate becaus~~~~~~~~~~‘ the su’fiie?cy f bf the c~~~~~~~~~~~~~~~~~~~~~;lb experience baseto frame properly
“P art
e

change. con;r;,‘v;r o draw -qn to ,yhen it is ,,-.,.,, “

theirremark As with shy used.
KC

ariy more positively ~~b‘s’i’r~~~t~~~~‘ v~~ r ~

here

th% ta-yi#

%e &$i&y onjyfacilitates

h&.

the task a‘ _

wifh -in other qf aid’& action -itsA,suse is ani fhe.cont~y similar of guidance fi;“~ documeri$, i us~.~~it’~s...~’ ~~~~~o no course the th~t“v ;iShe~,.t’ it mandates~ : _~I_, _.~_...^ ,x.. compliance activities. __ _.” I_ “, ; ,< ..r. .,: -,.I -I,” i i _, Since the _ use v,, of *a . C,P’s b$h,.@,ption& i and donsidered as”~ .a;,@junct prc&col, ., .<,.“ no other guidance IS directly a‘ffected by this ~uYd%$~.~” ’ -‘* * Based on the preceding,’ fhis ;e;/ie%br &I$$.& foresee any’ uch s problems because this guidance does not establish any requirements. ~(. ” “* , “_ .. It simply provides a path that a‘ firm may, ,or I may?%t,~ dhoose to use, as all guidance documents do. and
“P art
l

#117: For many years; )‘ap”p licants (upon FDA approval) have used protocols to _ _,... -. * a..“; _ . _~ * (expiraiion:$at~~g’kribd ~ extensron, con”t &&implement certain types of CMCchanges closure component interchangeability, etc.) .v-.2c,I..I. ,_ ..A . Would these protocois need to be updated or withdrawn to’bmply c &h there$rirements I/,< ?, ,, ; ,,,I,,‘ .Ix-i.$^ ,i,,.i”i e I, s. )(_L .L.._1 _ >+;p a‘w;?(:“t ~+,zs’c; ” set forth in this draft g&dance or be grandfathered? ., ._ j..” h.‘.~, .‘j y-,;,:“, ~; .’ (1. .-,,I ,. : ;,, ) _ _ ., r __ ,, :a...-. . . *, ._ *A. , , i_.*
^ _, $, :‘-,, :, :. I. .” .: _ ” L ,’ 7 “.

Line

,\ ,_ ___,_

III. C
Line ofthe #2 11: “A ,CMC change that requires effay, change (e.g., certain formulatioii i‘haijei,’ safety cli&cal

._I;1 .-,

_, ,.”

“,..
the e&t

> “, :a _:. ;‘ “p ”“- ‘ :. .,_., The’ dra‘~ li;nfcai”, ~~o~~~~~~~~~d. w “ The ./,’ sentence shoul-d be.revise$ to r&d (‘ CkC change A I .._: thgt requires &i&l kfl%@, SC $‘&!~ (&ical ‘’ or no&~&l), or PK‘PD 7 data to evaluaie the e#ect .c; . I ofthe c‘hange’ (e.&, c&tq$ formulation changes, cii‘jiCal oi ;:..‘:‘ .,+.a(&r*,..%s&j&~ ; noncllnlcai to &&& hew rw+&%.f~*% &..^:,, *_ : -1. used for Thei~~li;udt~~;;‘;om~~~~sc;tion-g~that f a protocol should not be impurities).” BABE studies. More specific i‘nformatioh“o n ‘ of CMC changes that- are ~ .i %“t $k”“& pes ( ‘ “I;, inappropriate for protocol use would“b e .,... very helpful.” ^ _, I _-. ,” , ^- , . __ ., :, .. : ;, ThiS. reviewer‘a.g;ies;..:v l ,(’ ^ .’ ; -: ._ ”

(clinical or nonclinical), -. or PK./,PD data to ev+e;e “I . or n&&&al studies to qualyy new impurities)”

.

.

_.

0

“L irfe#217: S p ec if K examples ‘ (list of examples):’

af changes

that

may be d$ic&

to just&

under

i .) a camp&ability

r

pro&

can include

Please protocol
I‘

provide use.”

specific”i tifdrtiation

0;

t‘he

.,

rat&aie‘ ._, __.

for t&ch$l~,n~ &eie &$m$&’ y-v. j i i e __._l~ .,., ” .* , .; I ^‘* _ ,.

SS& . _ . ,,__

Part

1V.D
#283: “W hen Does a Comparability Protocol Become Dbsohke?

Q Line

Clarifitiation anticipate be added approval

is r-eqtiested z$$a&%ng &w a protocol & d$$Gned .:>,,, .( &king &iS d&&mina~ion‘ & assignihg & kxfiiration to permit the “ ~vikwx6f’ ~~~~~$“ ~lrotodoi~~thout ~__ a ~ ,_ .‘ suppleme’ .“’ &

b Ddes FDA 0 tb’e -._. obsol&. date? A”$ &&&&~hb~~d &&tting it as a prior .“,., ,,, lb,

reviewer sugges%‘he”c ommenters t reviewer’ In both s proposedcases, alternative. *” the calf cleai,j;‘x determ ining From
determination

This

sfates

when an approved the Draft’ s t&t,
0~ assigning-ati ,,I

CP is “o bsolete” it i‘s clear’ that the: F’Al~~~~-~“‘a I;tic~~atema~ing b
expiration da‘e t .”

shoL;‘d . ret-&i * ,I the currenttext and the _” l rtiae $& ~i;dm itt&i:“i la~“,f ~~‘.~nus;‘f ‘ . o ,,P. ,ih’ ./ .. __,“.i I .‘ . (out ofdat?$ ”
this

and that

The comment&-s last statement should a firm takes.a’ fssk be ignored; ,f r and-subm itsa ,\.~ _, ;._: fyg-y&; firm shotijd’..~prepared ,

is inappropriate

in the

context

of this-section action w’ en h

~~P.~~~~~~.it’ij‘ ;d$Jstsnds~‘tsprd~eHs,.then’ . ; r thg ~oSt‘ ;~~~~~i~~~ij;ecipitous o

they find t-hat the process must be changed again or that the, praposed c’ ange‘s h i (.. untenable. .,.x1 “) (* As was stated eat-l&~ the oniy a’ea where r the Age‘ cy’ h~$id’ cor n s ~ 1 .._1_ flexibility Gould be for method changes that*the*‘“hj_,,*. ._),/i*<,..c.~*<i.-- theci-”I__approved older ; d . “. of. -“, i CP ig . . ” _ij) . compelled to maket o ~~~i~~““‘~ ~““‘o irfsli(e ‘ non-governmental, organization’ s reauirements (like the US/%. ”
“P art
0

V.A
Section stability Please

2, Line #374: I‘n some cases, no stability studies may be warranted or u commitment to report resultsfrom studies in an AR can be suzicient. Ifno stability studies are planned, we’ ecommend r that this be stated clearly. ’ ._ .,Gi . , ,_ prov;d& an ex;&iig &fh& &&$ty &=g& Gould ,L”. “1 , not *; be _* needed*” ,j i .,s” * “‘ > ” . . ,< _- : .I -: --lyy I .;‘~,,“, ^‘ ” “,” ^*__ (” . -._,“) Example: The proposed c‘ hange is to, iric~~~s~.~t.ti;~~~~~~~~~~~~/I~~~~~~-.~~~

“_

,,.

” .;.-

., I.

,,. ,

__

;

,, r ,.j ‘_..: ,** T :

:

..: I,,

,*

_,1

,

/ . ./. .I,. 1,.

film -coated immediate-release tr,.Q 5 “, ..A..--‘ir .“,.3.bto .Grd,* *..J.**, tablet appearancethat, “; “$ 2 ,c‘‘,,,,>based a, > -4 on: “5/a6 tablet improve I ‘ _ . *+,:‘ i *“ a~” ..$ ‘ , of scale studies, only slightly ,.),_,/;_..i..._._ *--a). 0.3 ,.,yO -., .i.Taverage~‘ he’nrtral changes (,,. (c-,,,, 1/.1 on* -“* p ? r Drssolutron I ‘ the tablets. In this case, the only comparatrve studies, -required wou’d l be . “D issolution” studies on the’iriish’dtablets. f e ‘ ’
* “S ection 418: Y ou should include ‘ the acceptance criteria (numerical limits, ranges or other criteria)for each ,,a.n*,z,,$ .+aw,>, ~:*~~.:r.f&*i;,_ ,_ j L ,, _. .,\ /. test and study that will be used to assess the eflect of the CMC changes on the product UY other “m ater& “. _ demonstrate equivalence between pre-. and post-change mater&l.’ specrjed and/or

Further changes (I

clarification can ., be included :

is requested iti the

tar this &me “_ .-

para&@h’i.e. ( :1 _‘~.j.l_ i ; i‘i /j

whether

speci%ation

protocbl).“’ ,_.. .69

and .,

process I’ 2‘ li I-

I_ ! _. _,< -< _, , _

_~_ ,_,“...._ ,- “,b.. ,,.“: .*.. L ,),,I 1__,:, * i,__ ,I^ I ,~ -,_ %i;.. .; ;# ., ::,‘..“;:;,-a I .,t _,l .< (~; j .. ^ _ .,1r r ..-: 1 ‘ .\ ,,” ,. ,. .I j” ,., _ ”

.,

~._

..)_

_.

(

.

procedures improve or do not sign$cantQ of analytical procedure (e. fl:, accuracy,

j I. do Got. ;jixl+-,;lj ;~-hnse’-sti”o .u;*.~ * b‘e’ anged X .to (...does_“_ not I advei;ely The phrase ‘ .. . . i l,..I”> .“T se. L &-j&j re& & .fol]ows ‘ &,+&&ii$, ~&~~ol ;‘oul$j.,e se n .t &ce change’ : The d&s;gned to demonstiaie that the proposkd chasie i;; Be~~~i~~i~~~~~~~~d:ct;resin;p;rove or 7\ w, s.*.. al.*n_ do not adversely change ch&acteri&s used m method&%dationthat are relevant to the ,av%,r~ri*.. .“, . --.v_.\q_&.*,‘“.;‘“‘A ~~““i dll --r*a-ri ;*a&,?- “; *“, .::g;-‘-< ^‘ $“ +.“ ’ T-..‘ type of analytikal ’ proce’~re*‘e:g.~~~~~~~~ ~ ( preclslon, specifkrty, detection limit, ^,i., “* )j *~,I-) “., quantitation limit, Iinearity, range)‘’ ? This re”i ktier: agiges ‘, +.ifti’ ke’~;otimgtife~ij. “ . su.!g-.do~n a.nd” .notes chat it is

change precision,

characteristics SpecifYcity,

useain;neth~~v~~~~~~~n detection limits $&titatlon’&t, l

XZrFAJ&‘i ~ linearity,

to thk’yie t ranje), ’

;.

refreshing to see that a neti test method is cdm@ab~ieto a previous’es’m ethod t t’ andotq/yifif improves ordoes’./ . ..“. .... adversely_‘ n ot im~a’t’he’est ,, ~,” ,“. ~., I b.^. c_: c t _,t method’ciiti’al:-ilZlity I ^I.‘ ,“. attributes. , ,“_ .>. / This reviewer only hopes that a post-char&? product will i&&&e’ recognized as impact comparable:to,a pre-change v ali~i%.a~~ii~~~~~‘j;sji~~~~iii~~cy,change’m’ roves fj’o’uct‘het--the rd k T i p not adverse,y th’.product,s ~ drltica,‘ “/ “_ _. i , .^ stren@ h or potency, qua~f);;,-purify;:~~ci st;i~~l$y~~’ ._ ._
l

/f -‘ ._ only be or does i;lenii.$,’

“L ine
deletion

#545:

‘ when usedfor of a test or relaiation

release or process of acce@nce’riteria c

control, use of the new revised analytical procedure that are described in the a$oved application.’

should

% “k k&‘n i
following and ihaf . _. ,X’

text should aSSUreS the

be added,“E xce$ sasety, ;mcacya;d

where the new method ii;;dl~~~~~~~~~~b~~.,,,

provide better T~~-J~p-‘,“I t.is e

The orequiv&ntQA recommen$ed

the sentence shoiId.be new revised analytical acceptance criteria that method provides I .. better _, ,, a product.“ ’

revised tpre~d,~Whenus~d~oilbr rerease‘r o @kdess Co”% %d,~& of the *~&a& ,, .A.,_ pro”~ eduieh;i~~d~ddt”r ~~~~~~;; ~~etron”o fa”te‘si ‘ o‘r re&@X&Gn”“o f’,, ~ ,.&. ,~, *-*,& , -*“, e .ii. ,~~.;&ci*e..:$d _?,, +&&; . :j.&~CL$&!&, .~ * are described in the approvedapphcatlon, except where the new or equivalent QA and assures ,. the ,.” safety, effki~y and quality-ofthe ..A_ ,,s\ 1, “_ .-l_ -, . -.

This reviewer odds with reality. change Theperse “r elaxation and

does_nofagree

with the’ d~me.nters”s uggestion‘ ecause c b do

it is-at a,,< .-_;,_.,._ “+ .. .,I.,<,.,‘..*-.“” .*i.:: 110 ,‘ ,a,>,+ p‘

“a ke@Mke a) has?-ioth?$“t o ‘ b) ofcannot Y prro;;;‘ebetterore;iui;;gikntQ;i.j~:. ‘ crite&“i b

with ^‘.‘the .:.e / meth,od test -. / , ’ (r

/

However, the addition of’ neti test may be’ ermiss%le a p in cases there the new test measures attributes in one test’;;o]cedure’t haf’reviously ; “ p required’wotest ,~. t i.. I. I procedures Thus, this reviewer ,aand sound science,bd’h.suppb~~th~.~~jibi;;i~~~a.,tera~ion r bf ;., . ,” .*,< _,/_.,__.. _,. /-, the text: L. “V.i*-, ~.k_.
“W hen used for release or process control, use ofthe’ew~~~se;~anai~t~~ n ~~&&%e should @ b‘ &&‘~:’ i 1. De,etion 6f a i&i fhat7s”~‘~~~~i6~~7’~,~~~‘lj~~~~~~~,,~.~’icdnskd i ~ , i~pjr~af~;;~“b r _/_^,, I‘,.,r” ,_l”“~ #^Irj_“..I_. . ” I-X-;It,-Is+~G”. C accepted DMF7vMF”i r’lg5s n .I,.I gn ” *

..

“. “& ,-) .. i ,A.,_r._i‘ ..l,. . _\. i, a. The new revised mmimeasures multible variab&ina single test that were’ previously measured using multiple tests and’ _-’ b. The new revised method’ easures m those va%&b!es~~,$fh at“l easttt@ same limit‘ of quantitation, precision, and accuracy% the test niethoc’the k new revisecl‘ method is superse~ding, or ._ .(__. -,:,_ I .( __ ., :, ) , ;_,_( __ /I _.’ ,‘1 * ,. ,_
“,“_:F ,,_, .:“, .<,,&:‘.” i. I jl_,s-...,b~ c’ ..,: .;*:‘ ,,_, $ -i; ,. I , ,- .” *

~‘
,- _

_‘I ,_)

, ,_

__

‘*, ^ . . ^_.

. ,-:
_

_,.

‘_

, _ . . i

.._.

ate: The original cbmments are quoted in a condensed font (r’:rpctUa), the quotes f directly from the draft guidahCe ai-e’tioted q in a-styliz~ci“~ ~~t’ii;jianjand, i in-general, this reviewer’ s text and comrrie%ts‘re a iti a ptiblishers ~~n~~~~~~‘oth~~ ~ Mfytd mdke’t i easier for the reader to differenti& the”‘peaker”i“‘r4‘~e’vdrid:us’ext‘assages e ,, ,.,a.,; “i’ Z,’.‘“. s ~ ~ t p _ that .” follow. . a e1 . When$Adi-+sing c&nti&-i~~““t %a& in S’abular f format, t%*h,s reviewer tiill (to the extent requiredj”p reskrire the cbrbnenfers’ .fbrmat &id, i? get-&St, ~~~p%~~~e~y place the reviewer’ s remarks after those of t‘he c‘oib-&%&?]““ .‘. : )_ L- _/ j .-_

These corn menters, begin‘y b stating, “N ovartis Pharmaceuic,als Corporation is a world leader in the research and development of products’ & protect and improve health and well-being. Nova&s researches, develops, manufacturers and markets leading innovative prescription drugs used to treat a number of diseases and conditions, including central nervous system disorders, organ transplantation, cardiovascular diseases, b\, dermatological diseases, respiratory disorders, . ,I_‘ __.*r:.“( ,~ .I and arthritis; “p I‘ Th:e, company’ cancer s mission is to’ improve I -. ,; people’ s lives by pioneering’ovel n healthcare solutions. As a global pharmaceutical corporation, Novartis is _Ij” .I “( , . b -~“, ,” _ ,‘ -“* .“ ~‘.‘-‘“~ “, “~ ,~-“ ‘, . ‘ _~I / x>III,e- , I . .’ supportive of efforts to improveand to harmomze the techmcal, requirements for registration of pharmaceutical products. We appreciate the opportunity to cornkent on t‘his -guidance m. accordance with FDA’ s Good Novartis supports the concept of comparability protocols; basedon the,, _.successful ^, use. of Guidance practices. /_ ,. _1 ~^_ .:_ ). _ I such protocols in past FDA interactions.” , General Comments
that the usefulness of comparability proto&s~might ;‘;,;-;,Lor P;pprot;alSuI;plkments ”

:
be dictated-by done wi*out

” i/ :

“H owever, Novartis is concerned &ey ~~~~o,,,r;r6j~~~~e~~~~~,~~~~~~~~~~~~~~ comparability protocols. ”

how well benefit of

Since, as proposed, . _..- a comparabi’ity’protocol isanoptional adjunct to a filing or .., _ l ~ this e reviewer is ~~~~~~~~~~~~~~~~.“~ ~~~ai: does Q$ share the commenters’ opt,onal, ^/,concern. r^6,:-; ,; ” can”c’h;os; a PAS, Becaus’.it ;” i*;,,:.p’:, **“o .:(%?,jr. firm ” # ,s each tb u;-e this approach to addressing Agency concerns;-or”n lbtrue ~‘~~a~ ~h~t“iir~‘~e’ ~ s fit.‘ Like the propoSed “. ~eve~opment Repd~t,,~~iltl~~‘om’anion ~ p hra$fguid^a--; on _. CMC Information,‘t i is’uf b one’ eans m that a f‘irm can’~~~‘p‘rovid~‘tie . tp t information needed by the firm and th”e A sency ‘ to ensure: >. ’ “ 1. The firm’ s proposed changed process &d/or controls are projected to be and will probably be CGMP compliant before‘he’~~ii~es’g’kinitiated .I .. .. ;‘ ,’ .*;~ t c . “, ,. ;c..y;. ~; .and _l” *. The rirm,T~.~~~~~~h*~~~e^~~~~-~~~~~~ a. Be CGMP-dom.pli.nt’ degree .&; of assurance, probably be “c omparable“ 5 .“S _,
clearly %c.at% how ,*

b. With a high’ product.
“N ovartis protocols is also concerned

,I__._ ,. th*epre-change .to .‘ I^ .
complete FDA input into

~
the

that departments

the Gi”;i”d& .rce; ‘

by all involved

w hen ‘ fin&zed~ ..) > .* .I _ :, q, will be obtained.”

think -“for

Whi,le the that the this reviewer to’i,‘i‘iiti;~is*~C;;e comment&s’ & tich coxern,,:this -j_ .a..~ reviewerd -. oes guidance ~ shares ;t p~l~v&:y’ commentary:‘-‘ sj.., ~~ “ ‘ ~ .) __*I,_^ ,+” .^ _ Therefove; this rev,ewer.suggests .- -^” _ .~r that ti7~~~~~~~~~~~~“~ ~‘~~panion ~ guidance Agency personnel or update a current
..‘f2 ,

@ t fit to

such’uidanceas g ,‘ , _

;

j the’ Agency

sees

address the campsrabi.ity
“T hese points ” are

commenters’ pioyoco,;:’
elaborated and

concerns -““. ” -‘i’“.^‘*’ _additional

about theL ,._, i”n t^eC-Gl r‘r.*.*“i wdrkingS 1°F’ +lJ .^ ,.,_. .(,R;~*>I*.,rx,.)“,,.L-- ,_* _,_ “I , ;.,
comments are’rovided p in’he t attached

6f’fie i‘&ie\;;l f __ .” ., ,:
tabular format, for

o‘f a ,
ease of

FDA, use.

Major
Locati,on In Draft
General

comments Issues in’ guidance/

Reviewer’ s
The usefulness will be dictated overall project be addressed: reduced FDA comparability comment (rather PAS requirement)

Corqryqj
of comnarabilitv urotocoh by how easily $ iy, fit’md ‘ i timelines. Two points d&d

Comment/Reviewer’ s

Remarks .I ,-.“/b,icc;L%*.,l.~~ ;s:iri,.,,tr W ’i * .%‘,,.*&/j,, a.;,., , .,.l”

Comment

In some cases, it will be faster to call the FDA with a specific question, documenting the teleconference, rather-than waiting‘ for the approval of a Comparability Protocol in a PAS, and then completing?he work and submitting the application (with reduced submission reporting category) to FDA.

Approval protocol than 4-6

timehne for review and month current

While this reviewer‘grees a with the “r educed . . .timeline” sentimeni expressed by the commenter, the reviewer would cast their’ first point in terms of “r educed FDA review timelines for comparability assessment and cotnment” and leave it up to the Agency to set timelines based on protocol complexity and length rather than those based on arbitrary dates. 5
Inclusion of (Tox/Biopharm) assure completeness other FDA groups in protocol review to of FDA response

Though the reviewer finds the commenters’ remark not directly pertinent and interesting, this reviewer would strongly recommend that no FDJ4 official engage in’uEh’ra&%s s p -all questions bearing on any aspect of CGMP should be submitted in writing(e-mail or-FAX) and an~approp&%ly vetted*r&ponse written response (e-mail, FAX orIet’er,“a s t appropr%$‘sued. s Since it is not appropriate f‘or an”F bA e’ ployee m to give advice that does r& conform’o t the~req‘irements u of %GMP,‘ the Agency would be better served by-a) written requests so that what is being requested is clear dnd b) written response since, unlike verbal discu~s”i ~n,“~ ~‘”is‘~‘uch t ~~ more difficult to distort by taking passages out of context and,b) easier to track in existing d;tabasg gtrii;fu’i;s, r ’ * _ /”
Some groups points such in addition as impurity qualification or dissolution ,; “. -\ *..,s I to the CMC revrewcrs. evaluation .x . ‘ mclude FDA

This reviewer agrees and notes that some changes in equipment, process control point, or inspection plans (sampling, and testing or examination) wouid’enefit b from the input from the Field Inspectorate, Manufacturingand Product
CMC elements reviewed by, Biopharmaceuticists Clarification agreement suchas FDA comparative gr’ ou- p s in’ or Toxicologists). dissolution

Lines 112

1 lo-

Would the FDA Review Chemist take on the role of distributing comparability protocols that cross FDA disciplines, and providing a consolidated FDA response to the NDA sponsor, or woukl t &sponsor ‘ need to send copies for binding to -._comment other FDA groups?

;adzo;;

are influenced and in some cases _ *.*A.*. a II.%‘ ,,_ ~ .t a--to ” the-“” Chemists (for example

of the administrative on the Comparability

process needed Protocol is requested.

to

obtain

a binding

FDA

Location In Draft
Lines 296 284-

Issues
Although maintain wording

iti guSdance/
t he Agency ‘ intent’ use of appropriate’rotocols p is ambiguous. “c urrent Guidances”. how a is clear - to -“t he

Comment/Reviewer’ s
“P olicy” is an overbroad term not

Remiwks SL. /,a*I_ ~a_~,“x ..* ,,*,,*,/ r*2<. i,>l,r:,,I x ,, .,., ,_ ,* ,.,, “;
restricted to CMC issues.

Line 291 -Replace with “c urrent FDA Line 295-specify withdrawn.

FDA . ‘ protocol

policy”

is

This reviewer the commenters’ action, and withdrawals approved CPs firms’ Annual

agrees; supports recommended recommend,s that of submitted o’ r be reported in the Review.

“P olicy” is the correct term because are but a ..,_e ,,d,(S guidances subset of Agency “p olicy?’ ’ “” ’ Thus, for example, if the Agency were to issue a policy that proscribed the use of stearic acid from ahim& sources and s previously approved‘ P’ C included the change the sponsor’ acid from vegetable sources to ste&-ic acid from from stearic animal sources, then, whether the CP is Simply pending or has been approved, the sponsor should withoraw or modify that CP or, if pending, modify, that CP.
Draft states that a protocol may be modified does not state how a protocol is withdrawn. Report to withdraw protocols... -. by a PAS submission (Part fV.E), but Recommend ,). the use of the Annual “.

To accomplish reviewer would “F : wj~~drawa,

the commenters’ recommendation, this propose addjng a short part (Part “I V. F.“) : Of A”S ubmiiiga .‘ir*xibkbl t .p6spi>ib#ii

.,

,“,

.,

,,,,.

_*

Protoco/. A sponsor may withdraw a submitiedoiapproved comparability by submitting a “w ith$awal” letter t‘o thk *ap’ripriate p review division and, where appropriate, shbul~?&pd? th~‘~don$ishtient a of that with,drawa( in theirlA,nnuai‘eiiielni:” ~ “l ” ,:a : I,. j,,, _“_ _. ___i j
Is the FDA tryin”g6 %ate ’ that &hen a the parameter in an approved protocol is changed we can get the change approved and the protocol approved in the same change submission, therefore’ot n having to get approval for both the parameter

~

Awkward wording; flow chart would

use of a de&ion tree or simplify presentation.

This
Entire section V.A.2,3 & 4

reviewer

agrees.’

. ,. ,.,,,
Several concepts are presented in “d ense” text..

.

Use of a decision tree or flow chart would simplify the presentation, in particular for validation requirements of release and/or development characterization testing

This

reviewer

agreeswith

the

commenters.
to be provided in the CMC referenced in a comparability

the This reviewer agrees t‘hat inclusion of a flow diagr$r and/or decision tree for”& &‘ subsection might assist t‘he reader in determining” exactly what is required. However, this reviewer disagrees with part o‘f the .‘ommenter’ c s rationale for the adding’ d ” sai’ _...,, decision tree or flow diagram (the term “f low chart” is usually more appropriate to an outlinei. .‘x‘” of ; a “computer programming

The appropriate extent supplement (in particular protocol) is unclear and

of validation information for characterization testing may be excessive.

This reviewer disagrees the a “e iy&iifi Owith g-&y+; commenters’s,sessment ‘ f. .“i ;f;;ii;ation to be concerning the provided.” It is clear what is being requested just as it is clear what _ CGMP requires in thk?egard. Unless the commente,rs’ definition of “e xcessive”i‘s simply “m ore than they want to provide,”I ,.& tfier’q’ue<t $ ,,-,* _ Ito$rovide only *-3,,,, / ,<,/., ,,**,~,“,“e -“. _s I”. ‘ ~ ,*>... some of what the CdMP regulatrons ._,hii‘ ,~,~ require the f~rrri”t ohave i” ., , .- ,,,. gathered and maintained IS certainly not excessive.

In Draft
Line 455

Issues in guidance/ Reviewer5 Ccygtntgn~
The first approved a reduction Although does not reporting reduced motivator Equivalence the approved

,

CommenURevievyer’ s
Most sponsors‘ould k protocol if they would

Remarks ,._.., ,‘. ill.,i _( /, .‘.‘~S,., r u.u*u.-imp.~~~~,~~~~~~ . ,j***r;~~~“, ./ -.,,./ r~im~“ -6 “~ .‘,~~~~~~~.‘ 16% ,
probably not go to the trouble of preparing not get a reduction in reporting category. a comparability

sentence states that” . . .uSe of an comparability protocol may justify in reporting category.” the FDA intent that a protocol automaticall) rest% &‘r edu&d a‘ category is understood, this regulatory burden iH’ a ’ $imary ‘ to the effort’ of submitting a not being demonstrated comparability protocol usihg -

reviewer fails to see the point of these comments simply state the general reality. Since preparing a comp’ra.bility a protocol is optional, each firm has the option of not preparing one, regardless of ttie I .1 ,I . .reason. they ,,, . l,,l.. \\_ ^S” _” >-.,_<~,,> r- “c ,>.-?.,s,k_-.“.. ,.,.,/;,,l ,.,..I .,’
refer to the and r equest ‘ Same point as line # 455. If equivalence isn’ demonstrated, t why protocol? Most sponsors would merely submit a?stand~ai-d*‘ iAS t approval based on theincluded data (G&h just&cation). ” .( ‘

This

Lines

468

Apparently, the commenters have gotten the proverbial cart before the horse, the request is what the sponsor plans to do in the event of failure before‘ akingthe m change-not what the sponsor does after the problem h’s occurred.,, a There is nothing to prevent t’e‘ponsor hs from electingto do as the commenters suggest after the fact. However, if this reviewer were reviewing a CP for acceptance and approval, this is one area where this reviewer would use

I

i . . .

,,,:.. . .

.,

,”

_Y”

_,/

/;

,,

,

,_,

I

i

\’

, .”Mint yI ”/ ./_I
Location In Draft
General commeni Overall format

Comment/Reviewer’ s
,_”

Remiir@ ’ *,, III/r**,,,*r; **.-“ ,d”? *l*iwi.i”li, .‘y&.:,-.. t: /,‘ _ i$>J, . &132; ,‘, “_ ..,+;,s,a,“,,*&; I*r.( \ *r*#*,& “

Parts V, B-G should have their own section title (section VI for example) “S pecific Protocol Issues” V. H & I should’lso a be a separate section (section VII for example) “A dditional Issues for Comparability Protocols on Master Files” (for example).

This reviewer suggests that commenters’ proposals,, but would title be changed _ tb . . %sues .z;i_ Specific
General commenl Line 24; To 2 Overall ,, Use of the same term anything from drug material to finished drug excessive ambiguity in Draft. “p roduct” to meal substance ,. ._( ,.._^ ^, + start&l __, ‘ product aIlows fol later parts of the one component, drug product more specific should be used. verbiage format

the Agency consider the $uggest ~,;d.,Gr..y ,$.““‘iast -”proposed ” the ,.,, ,.“
T$‘I,j * h y C omparat’ Protocols

Gr

to specify

drug

substance,

intermediates

or

For example: in lines 40-41 and’ines l 98-99, GMP-typ characteristics appear to apply to dru; products only; it is unclear if lines 476-520 refer mainly tc biological drug substances or also to the products made from them, and how the SUPAC Guidances (drug produc processing) would be applied

While this reviewer understands the com’ enters’ m remarks, the reviewer has no p‘roble,m with the, Draft ~whk‘”t ho‘ n term product is used to mean either the drug substance or the drug product. Further, the reviewer found -no instance in the Draft guidance where the term “p roduct” could be taken to mean a non-commercial intermediates. However, to clarify the guidance, their ieviewer’ ould w again recommend cha,nging’ d%&e F 2. to read: “2 ihe generai Je:& product ai u&&‘ k<$dan& t means‘rug d substance, drug In general, the use product, intermediate, or in-process material, as aj$ropn’ie.’ a of the term “p rbduct” for& intermediate or an in-process material should be restricted to: a. intermediates and in.process materials that: i) are isolated from the‘rocess p and ii) mav be held for extended periods of time before being reintroduced into- the process in a subsequent process step,01 b. intermediates i) purc’ased h from or ii) subplied by a facility other than the facility u&d”t c “h iz$:ufacture the final product produced by the process.” In addition, using the term “$ -oduct” reduces the need to repeat text that could apply to both and, 5s the comment&~ remarks indicate, the ambiguity seems to be contrived. Therefore, his reviewer would leave it‘p u to”% ie”A gency to decide where, if at all, ttie-\Noi~~ing~~te~~nee‘s d to be changed “d rug to restrict the “p roduct-rei%rks to “d rug substance,
Clarification of required elements “m usty ,. vs. “s hould, vs. “m ay”

.

,II

_

., I 1.

e,.,:*,

_.,

i

r

I

Lines

33-34

FDA Draft notes that “s hould” (in the text) ndicates an Agency recommendation, rather than a requirement. Please add a clarification indicating the wording that will be used for required :lements.

This reviewer disagrees%‘ih‘he‘ommenters’ i t c statements. The requested clarification iS inappropriate in a guidance document. Guidance documents do and sho&-not‘ set -not requirements. Guidance simply provides the,Agency’ s thinking on one way that the regulated”i ndustry c‘.an .‘ _“\,, meet, the requirements set Forth in the FDC Act and the CGtip‘*r?d a o‘ther applicable regulations regulating the conduct of” the pharmaceutical

In Lines
143

Draft 127-

issues in ,guidance/ Reviewer’ s Co.m,mt@
4dditional ddressing comparisons :ited. FDA or ICH dissolution testing, and bioequivalenke

_ ~~,
&i&&es impurity

Comment/Reviewel;‘ q
CMC elements such -eviewed by, FDA Biopharmaceuticists othe; Therefore, equivalence” should

Rem&kg ~. ) -, . ,..,_,.., --“a ” ~.__,, ,_-\., ,s . . ., ,~
to i‘re influenced and in some cases, the chemists (for &ample concerning “d emonstrating

sh&Td be’

as comparative dissolution groups in addition or Toxicologists). &&&.z~ rkommendations be provided

This reviewer only partly agrees with’ the commenters’ remarks. This reviewer concurs w ith ‘ the referencing of other applicable FDA guidances but would recommend that this guidance explicitly include/request: ” ’ 1. The appropriate” sections of the CGMP -‘r egulations “ contained in 21 CFR Parti 210 th’oughZX’’ r ^ 1 2. For valid comparisons of drug product uriits,*the minimum inspection plans set forth in ISb “3 %1’r o its American equivalent Z 1.9. 3. For valid comparisons of drug subst%ces and.other-non discrete materials, inspection plans tf&t provideWproofthat: a. The samples sampled and tested are batch representative b. The samples sampled are of sufficient size and properly handled in a manner that the sponsor establishes ensure that they are batch representative a‘nd. each i‘ of s sufficient size to provide 10 timei the amount needed for all chemical testing or, ,.,(.~ e.. .-, physical when p‘roperties . testing is required, %&times the srze required for all physical tests. c. The sample aliquots used for each chemical test are unbiased by the subsampling procedures used and not significantly larger than the’ize s ofthe dosage unit. This reviewer is opposed to referencing any ICH guidance that is not been explicitly adopted by the’DA.and F issued as an FDA “e quivalent.” In addition, this reviewer is opposed to any guidance that does not recognize the requirements of the !%deral’%dd’ ! , Drug and Cosmetic Act (21 U.S.C. Titld 9, the “F bC A i%“) , the ‘ current good.manufacturing practice (“C GRTP”) regu’ations‘n l i aiid the applicable recognized 21 CFR Parts 210 th-rough”& & standards and principles of sound science. The listed items are minimums that should be given to industry to assist the’ m i‘n developing the scientific&l’y l sound data sets and ,~~omCja.rab;ility~^P*votijcols’,’.~~~~~~~~~~on ,~ f/L& these commenters cl+aimed the industry is interested in doing in their ,isted items are /,* , “” / fh6ie’ i;iii”ii‘ti,.tii general comments: a,so ,..1 The i “t ila~“s h.~;la’~~“~ ~. , given to all FDA personnel fhaf‘ireInvoi&i’ t in’ &iyaspect of .~r., ’

,,

Loc&i& In Draft
Line Lines 213 183<211:

.;_

.I

‘”

,c

_”

.; ,*.;N

,, :, j

,_;_

” 3

Issues

in guidanckl
seem‘ontradictory; c please

Comment/Reviewer’ C
The Draft evaluation appears to be might or might

Reka’ks r
, * ,_ ,__, ,;.*,.,_ ,,.._ II,. 1, 1 jl ./,, *./,; -,.,. /._ ,,., ;IF1( rs. /; \

T’e two passages h clarify

stating that a change in impurities requiring a safety ..” .,I ,/__, not 66 amenable to a CMC’ omparability C Protocol

This reviewer agt’es~ e “W ith the that fhe two commenters statements appear contradictory. However, in the context stated there is no conflict. Line 183 simply lists-otie factor, the applican? should consider when devkloping a comparability protocol (CP). Lines 211 through 213 state “g eneral”
impeairrient;‘ lr~”

“T he effect impurities,”

on safety

of changes

in the

that

a

The commenters’ remark is correct, when faken.out of their the two passages seein to be contradictory. contexts, In their contexts, the passages cited by the cdmmenters are obviously non-contradictory. However, to ensure that all comparabi‘ify l pt-otocols explicitly consider ~561~; %is*’ re&%ei ivoljld iecommend _( removing the “i n ihe impurities” restricfidti k5i?‘i’ti~ L %%: In addition, this reviewer wotil‘ d restrict comparability protocols to only wl-%n’o n new imljui-iti& are found provided the appropriate acute’ and ihdrf-term chronic non-clinical toxicity studies are included whenever the level of one or more impurities increases‘ evg6 ;‘g ci;gg-;y-g t‘h-‘ ytgl g (eiel: doei change. In this reviewer’ s experience, the only time that such toxicity studieS would tje su~erfl%%%iild be‘he t case that the change intrpduces no new impurities and?E?fti&%the_ .. ,,. ,..”ie$ of all of the exi~tti‘g‘”~ :~irriti‘s.‘ ni e ” ,‘” -‘ ^I .i/ (. (3. S” Thus, process
recrystallization

Cli;lc

safety change that requires -efficacy, (clinical or nonclinical) studies, or PUPD data to evaluate the effki bf the chat&$ (e.g., certain formulation ch~i@e$XiZJ or nonclinical studies to qualify & w ‘ impurities),” that the Agency sees to

NOT

using the CP approach. Lines 215 through.‘%7; 2 I‘jio$de the possibility for the sponsor to overcome the impediment when it “I t may be possible $3 de$$ a states,
comparability protocol-fk’ ome‘fihese s b CMC changes, tGt FDA ~iky~&%i&d its ability to designdte a relG&g category other thaii“ PAS” “f b;i“~ hanges under such a rjrotocof.” implemented in

a truly iinproved, that reduced
step t’haf

all

nofsimpl’ y changed, impuri%%~6r V i& ‘
si‘gii‘i~ic’a”li‘t”1’)‘ieaiides~’ali‘iFn’p.~~if:ies’

cryS‘aliization’ t %I&tidn df’ g

Since this reviewer ~&IV.% that must be an overriding safety consideration in all cases, this reviewer would change Line 183
to “T he effect on safety of’ aii~~~ &

introducing new o‘neswdUld be drug substance without examples where no extensive safety-tests would need to-be included in Ehe protocol. However, -a sponsdr’ ay‘ z$nt m w to include a simple toxicity evaluation to assess the le$cXdf i~hiij?o$$n&li”ti’n‘ Ihe process. Finally, this reviewer would again. i&commenr that the Agency consider includinga specific‘ bar to t‘he use df a protocol appr&%ch tinless th:&,‘ sp&so; has comparability established that t,he.curf&nt *p&c&s c$p.ati~~li~~f’ at&product is fully f Ki”i CGMP the sponsor has *“$ .ti’ ‘ “ compliant, the probable non-de‘eterious l effect bf’ the substantiates proposed changes and the pt%pos&i & t‘iged* ‘ i;i-&& has been proven to be fully CGMP compliant. Thus, a cornparab~iliI~~‘~~~~coI ~ that, proposed to drop a CGMP-mandated%-+idtiess‘olitrdl c sh‘uld o be proscribed. However, one’hat t projjosed’o t ch‘ti& g t& test or reduce the number of samples from t‘hat recjuired in the current FDAaccepted CGMP.corri~lia~~i~~~~~~ a-T&se?, but still C%MPnumber shpuld be considered. compliant,

CMC change that requires efficacy, safety (clinical bi n&ciii%al) studies needed for new imptirifies, or PK/PD data to evaluate the effect of the change (e.g., certain formulation clinical or noklinical studies to changes, qualify new impurities).” [Note: The preceding change is

iq~&&” read:

and
“A

Lines

21iG?T,3

fo

needed to permit comparability protocols when the change only affects the level of the exiStilig kriown impurities but, in generai, prbscribe this approach when any new impurity

;.

.

._

i

:,A

“,

- 78’ ‘ “

“, ”

,..” ,‘ . _,,.., _:

.

L i.r-_, , , _ . :;:- -i i_\ I . ,. _\

-, “ :i -i ’

.Locqtion In D&f”
c

Issues in guidance / Reviewer’ s Corqtyent
The Draft notes that the cover hatter for the application should state that a comparability protocol is in the submission, to properly direct review, It is unclear whether this is also the case for original NDA cover letters, which typically don’ t get into the specifics of what documentation is in the submission. [nclusion of stability into the comparability protocol protocol information

Comment/Reviewer’ s
The administrative clarification. process and cover

Remarks
letter annotation

_’
for original mEi; needs

Lines
24.0

23%

.,_
Cross-reference to an apptovedLstability protocol should be adequate.

Line

368

Since the commenters’ suggestion two options provided jn the guidance;this what is stated. However, as the Draft states,
to confusion. Proposed wording: , ,

is already the first of the reviewer agrees with the
_,

stability

protocol

Lines 444

MO-

Sentence

is too

long,

leading

This reviewer agreescornmenters that sentence is too long

with the

the cited

In general, this reviewer agrees tiith the commenters’ proposed changes but would suggest the improvements presented in the adjacent column.

The comparability protocol should identify the following information, which will be submitted to FDA at the time a post approval C M % change is implemented under the FDA-approved cbmpakabihty protocol: 3. the type of data (e.g., release, long-term or accelerated stability data) ,u ,, .I”. _.x” 4. the amount of data (e.g., 3months accelerated stabiht) data). 5. the data that will be generated prior to distribution of the changed product, where appropriate (e.g., when the proposed category is a CBESO, CBE-0. or AR).

This reviewer’ s “T he comparability that
will be submitted under implemented

proposed wording: protocol s‘hould”i d~~~f~~~~.‘‘ ~
.i. ,. j ~ to the FDA at the’ ; % an FDA-approved comparability

i,f;;,&“- +f& ‘
a post’ ppro~a~dkC”c hange;s’ a protocol.

At
or accelerated

a

minimum, 1. &-Type
stability

that
data)

informatiori~should, of data (e.g., in-process,
of data (e.g.,

include
release,

the-following:
long-term

2. &-Amount and three
data) 3.

(3) pilot-scale

releasedzita batches,

from
3-months

two

(2)‘ull~~cale f
stability

of accelerated

&Data that will be g&rated prior to distribution of the changed product (e.g., in-process and release data from not less than three [3] full-scale batches, or 3 morithk of~accele?&& st&ilEy data and 3-month’ s long-termstorage-condition data’n o not less than 3 full-scale”~ i~~ti~~~):‘~e~e ~ appropriate (e.g., &hen the
of subm&!on without approved comparability

Lines
548

522-

Since the regulatory filing’ equirements r for he analytical changes would‘till s ap&, a&d he science surrounding analytical validation eequirements is well documented, it is doubtful that the use of -comparability >rotocols for analytical changes would >rovide significant sponsor benefit. 3UPAC -eferenced. Guidance should be cross-

Time required might exceed-timing protocol, with little increase&&k.

,) I

,(

,.

.‘.j

Lines
557

5.50-

79 ^.“.. i

_. * _ ,_.<.

_ _)

i...

,, .__ ,. .” .,_,

_*, .‘~

_.

l3@ei /*;-*:: ;“~ .?<& .“; “: a&.&dorpchation’ l,“. “x -.w , Su~m’ssibn,‘atea.~~~~,~~~~~~~~:~~-,, i HealthCare *_ -‘i,,,& .“. a/s “ .%“,#*Ix @ e &sL.Jzy*“* ,-,,p ai- ‘ a “X --*‘ a ~lytmj~~ yg,(rc$JI:.~ .‘~‘ -QT,~ .“I I” “1 ,>,d “ -.! [Note:

,;.j. *.a

The original comments are cjubted in a’c ondensed “ f‘dnt (‘ $&), & the’ quotes directly from the draft guidance are quoted in a stylii~d-i~iit~(C~jan).a‘il: n irYgen&-5l;‘hiZ t reviewer’ s text and comments are in a publishers font (News Gothic’&)& ! make it ea$ier ” . .,_ 1.. ,_“_ .‘_ x,, ..” __‘ L ...”,,_. _,, ,~. .“, , .. , ,.. .d,.“ / for the reader to differentiate the “s peaker”?‘ n the various text passages that follow. ” When addressing comments made in a tabular foriiat; thhis’eviewer r wllf*(Zo’he‘xfenf t e ’ required) preserve the commenters’ , format a-nd, in generals app‘opriateiy r place- the ”‘ . reviewer’ s remarks after those ofthe commenters.j “’ .” . 4.1 ..,/ I . “, _ ,, * , ,._~~r _; ,“.

1.

These
following Information’ comments

cbmmenters
published in February

begin
20‘3. 0 ”

by stating,
for C omparability ‘

on the draft guidance

“B axter Healthcare~ l%tocols~Cheiisky, ,>_/ ,

Corporation is submitting the ..-._. ,. *+ 3 Manufacturing, and Controis _,. . ,.. protocols ,_ _ associated , with / -i .;j, _ I , 1

“C omment 1 Please clarify how a bundled submission approach changes affecting multiple regulatory file&(line~!J~)”

may

be u‘sed

for comparability ....

.h~ ,.,,,,./c_,. ,., .*_ r:,,ll -ii ,~, )’ 1. I’:-‘\‘ I,*-“ * .

provide

a pathway

for “b undlin&’

subinissions.’

^’

2 The draft guidance stated that if the study results do not meet the criteria specified in’heapproved t Comp&abihty protocol then the applicant can decide not to pursue the change,~ or to submit a’rior p approval supplement. X‘” ,_ ” a.t+l ,>- j‘ij .__ _ ,A, H,owever, in cases where the deviated criteria have m inimal ‘ potential to impact the product, &e”r ecommend using the reporting category that would normally apply for the t‘ype of chGige%&ead of being ~~&red to submit a prior approval supplement. (line.278)”

11Comment

* ~‘ “ .

.

This we,,-defined

reviewer cannot agree with this proposal regu,atory .pf$&s. ifito’fi a ~ndefin-&&d”+ *“ ’

be^daus& *‘*‘^’ *

itattkr;;‘fs’bconve;t-a‘ t (,, ~.,”~ ~j., I

This reviewer does &t supp&Y&!lding ~h~i~‘ ”~ &?$dn’ kda~se p b it is at”& & with’ ” establishing a uniform, fair t@,eti”o f all CPS 06 an’qual e b&isatid’ @ks s tb p&-tiit processes that are ndt com’arab,e p to be imp,e~;$;f;d is .ifthey .&g+-.inpaia’1e: 6 When th,e outcomes are m as the sponsor projects, it is or should be obvious “, _ ,b*.* .,,~,~)_ .e,,,,. .I (. ,.,. that the s‘ ponsor does a truly un?lerstatYd the*@oc&S $td’ tii Y the exlsttng process controls are, at b,est, marginal. 1 In genera, the acceptance crit;& f&, into.two.j;~im.~t”. .claBses:. .I”. . : .\’ When a higher level is better (fbr Gxdm$6, a‘ ‘ higli&‘ i$%$j ~ th~‘ ~~~t~t-i~e % I *‘ * **.,/t 9” “. >d*~.a&Z.?.,.I -r” “, in a CP shotild‘ e b S&z &‘r iot “ less th$t-“# 6‘c’ u~~ent~y perrnlssibl~~~~~~~“~ ~~~~~~.‘ ~ a,,lower @+I ( for j ‘ ?o’ $ r -the acceptance Conversely, criteria _ when a Cp.7&‘b,~Gw.b.~f’ s is better”not XImOre ~x&‘“.?%*v*dJ,*e%?“a d-u’$-tij;; i”h pu’iij/), in i a *‘..-&:” ..‘ *.*/*.b, s.f‘ + than h^ ~ 4.erm.issitile’ . criteria highest renders level. Thys, a?y real th” post-change excursion beyond the bounda)ies”~ ~p~~~tl:by material noJ.coTpartibl&.to the pre-change _) .,. I* ,” ~” I, .,_ _.” _ _ __,,, . .‘_” ._,., )i ,80
. 1 :
.._..

./ .‘ ” “” .) ’ ^

xc .:*h, Ob” w: .; +sr$.*;r, ,%>.. 1_-4 , ,,‘ dB- ::.” *; a ,,C,” such crlterla material. .__
I. *.
I _; I , .__ /, , / ^ (j _.. ., ;

._.
,.I,.

..
.: _. .

-,
., ,-

,. ;,

Moreover,

neither

the Agency

nor the sponsor

know

for certa/n”f hai.~~thedkviated

.

seemingly therefore

“s light” increase in asingle frace~level~impurity has translated tnto (and can translate into) significant public safety r‘isk. Therefore; this reviewer recomm’ nds e that the. Agency , rejectthis and’ all’ uch s proposals into the guidance. *+^,. , , (.. .,...,, ,^__I”. ,-, ._. ) ^ “i “_ x : ) ” .’ /I , 1‘ Comment 3
-

’ __ .1

Per the draft guidance, modifications to approved protocols shouid be submitted as Prior ApprovalSupplements.’ In order to”f urther reduce regulatory burden and streamline thg SubmiSsion~rev& process, we recommend that he Agency cohiide; using‘ e & repo~i.~‘ ~~~a~i;isln m “& Tin&a & j& i,+KgGikS t&;n Appr&v<;l M)-,x or kN~+p guidance document for modifications to approved protocols. (line 298)” ,,(

Unless by.a.ctiange a) the osed‘ “ ‘ is dictated obviously by an FDA

modification i ;~al~~~~~~~~.su.~fi:fr~~~ri;cogii~~e~ is a sponsor’ s analytical in”a d‘ij;iii~e” regulato.~y. c,hange, a’r-~rr=lo;‘ ~~~~~~~~~=~~’ l d

test

“m ethod change “~ ~ s‘i;,t(....d,a.a “, cps aie

.‘yv$-w6~

PAS changes. This is the case because they are being’ . made based‘ on an :improved understanding of the process or because, in reality, some’ tudy s tias shown that one or more of the approved changes wii’-probably l leadto post:change’;od’ct’tia”~ ~‘is’ot p ~ ~ n _i : . r*.,&.I* .: : I.: .‘,d..,& ,* ,, .” I_ l.. ; /‘“” ;. I” 1 . comparable to’ pre-change product.” ’ Firms 6ecome.awa4e on their .‘K gt;fR% initiative, do not, own change ;b‘v;l of any kind u;less ihey t’ .pr~focol [i,go.ti~et’ approved..protocols invalidI % In the cases of second and third-par~~~ariil~~~~ch~~~~~;“th‘is ievlevjeiwbilJ - “r .x/I,*I..,_,./ . ._.*s‘I(u*l‘,_ ,., , , ,,, ~._*j*‘ . ,.., x propose that such be treated-as CBE-30 submissions‘q‘ ~grve f the Agency time to makecertain that changes br proposed bafty.mand’fGg:’ in ~t’;~~.si;~~l~~~~re’niy _‘ %,,> .-, _ changes ., imposed o .-,i . by legally binding the seco”d thjrd $i ” *. . ^, ., i Furthermore, i‘n such &s&this reviewer would recommend that-the Agency should request the sponsor (,,I,,,.to provide -al>- the r appropri5te ,, Gr~~~iii~bsta’~~~o~“t liat t such .a ,__ /L/ j hp._ ^__/,, -,-** i,”./‘ _1 ,. modifications’ ave h the same or better prob,abrI!ty of producrngcompai”a ble product as -‘. , the changes in’he t approved CP. .~ _ ,I.. ^‘ . . I‘

Comment 4 1_ ._ : /,_. ,/,(-,,I_ .‘.I7 .,“ .) .! a:. “,, Please clarify the intent of Lines 426-436 (‘ revision ’ .’ of a drug. product ^‘ .‘ or drug substance specification). The statement is: “If the recommended reporting category for the specification change is the same or lower than the designated reporting category for changes made under the comparability’ protocol;‘ the specification can.be updated and provided when a post approval ClX~ chiige i&@&&d &ng”t he‘ approved comparability protocol is reported to FDA. ” ,_

Based on this reviewer’ s reading of the t‘ext; .%&, “‘intent of Lines 426-436” is to provide the submitter with a, clear understan’ing‘f?he d o impact o‘ n” the”r ep~o,rting ’ cate.gory As when Draft indi.gtgs, the sponsor’ s changes r jii an existing a n~“~ h~~Ir~Ijo~er;if*i,~ speciflcalIjon.“” ” j-6paE^fs ae key / “ ’ the Specificati‘ ~~~~~~~s” -. _“. j factors in: a) determining the reporting status of’he t comparabil’ty i r‘eport and 6)

-

.,

,‘/

_,.,)

81
” ,

*,:,

,y:,.p,

.(

,,

^

-2-c

(‘ _

.

_

In general, ,( from -_ “n 6f,,,ti6i’ ‘ e

changes than ov2

that,,-,,improve b Fe quality t~anO:i (e-g;, $& fb”e ”i idt,,m ‘

changingi ,sji“G

the n for inim u m changfji‘ glim it the.*mImpurity ‘

A

purity from “n ot less than 98.5 % by weight” to “n ot less.,.?-than ;, 98.7 % ,.by weight”) are supportive of lowering the reporting category. Conversely, ctianges‘ that, ,adversely i‘ pact m the product (e.g., c hanging ‘ the allowed tablet weight range from “1 90 mg to 210 mg” to “from 185 to 210 mg” or adding Ina fact,it if a anewnew im:piiri’y lim for impurity) is gkner~ted;“t heii:th~-~~~oiting raising are supportive of the‘eporfin’ r ~&tt;gsi;j; category. g t .g~bul$& PAS and conducted.
definitions

.I.

appropriate
referenced for the reporting

acute

and

short-term
and

chronic

toxicity .. s“tudies “b ._)< ,, s hould; ,l, ‘ . _.S.. ‘ y. - ,

be. ..__
(. ,,A ,(

The

gujdance‘“C hanges , categories

f. an’ pprov~~ A NDA brAi~~~‘“. p’b~~~s’~e r f esta~l;~h~~.~i”da’;‘ k”‘f ~.~~~~~~’~oii.~~rcari ~ ~

use

to assess

which

is the

correct

category

for‘ a

g iven ‘

proposed’ hange: c I.I ,

“C omment 5 ). 1. / Please clarify the need to provide a copy of the i3MF Gthorizatioh letter from the DitlF holier when the _. I_ I~~-.,‘/d e ~.i(.*&uw&&>>i.__ ., __^ >* 1.x , **: i .%~*,A,,_ ._ % a*, regulatory tile is reviewed for a &.ange contained in a DMF (e.g. contamer resm cbnge). We believe that a new DMF authorization letter is unnecessary if the FDA has received a DMF’ &G-%f C kk&a6on at‘hk t time of original fihng of the application. (line 61 i)” . .,

This reviewer cannot agree with the commenters: statements. This is the case because each DMF/VM,F~authori~~~~i,qn letter,only review of the file that exists‘t a the p oint in time the letter is wt%‘ ii”“a nd ‘ E the Agency-to review revietier specificuntlers‘a-nas’if;“; d~de the D M F fh.Kggncy’ a uthorized’n the parts. of that are’ i Thus; as this t co~pr$&.5

perm its the only perm its ythe ..ie;iew ‘ h’ letter. e

_

..

,./....,, j..~ *.a- .,.. a,uthorized, by said authorization letter, the Agency ,cannot, except’ for -‘ ause; c I subsequently review that D”M F /VMF file without beingprovided with ati authorizing letter from the DMF/VMF holder or, for foreign firmsthat have agents~emp&ered“b y the holder to grant access, the holder’ s legaIly.authorized agent. This level of control is required because DfvlFjPMF:fiIings are“‘t rade’ecret” s filings that require thishigh level of access restriction:. -’ Therefore d new letter is needed for ttio’ &sons: % a pre-existing letter cannot give perm ission to review documents that 1. In general, were not in the D M F N M F file when the letter was issu,ed, and secret” S~~t~s:‘ f’ PMFrVMF”, OI ~ll~s~is:ina’ntai?ed i “b y ma’ ing k each 2. The “t rade letter a restricted “o ne time” review privilege. Thus, unlike other filings with I‘ ,/ the Agency, all that tiie,Agency can routinely do ._ with each submission is file it and keep track of i‘t.‘’ --“‘. To b iicsa‘et~ any informationi ssije)~‘eq’ iie.~‘ri files for‘ ny‘ eason review in such a r i;ti;o.&E~./Arg~tz~;~” tha’ “for I”.%I , ..i*r*‘i-% .__ _..1. -. j other n cause” . (an actual pij‘ f or’ ffiCgcy’ ~ r ~ ~ r..-“ -\ “^ . .. In a “for cause”, case, this reviewer thinksthat’he t Agency m ightneed a court order before proceeding.

.‘
82

A REVIEW OF

[Mott;: directly

The original comtients from ttle dratiguid.ijh-ce

are quoted are qLj;ted:

in a condensed ina.~~ii~~~‘~~~~~~~;i~~~ ~

font

(Perjxtua),

the -.‘l.,‘n;ggneii,, d j

quotes this.

reviewer’ s text and comments are in a publish& fotil ~~~~~~~~~~~“~ T~ to mal%‘t’& &ikr i‘ for the reader to differenfjz& the “s @eaiiei” in thk various‘ r;ri,a:WI_,F.” $&sages text /, .,),->*, that follow: .i When addressing commenti m ade ‘ in a‘at.$fa‘“f &~~t(~ ~ ~ this revtewer w~liq(6’i”G $ &&$$ required)s preserve t‘after cqm’enters’ of & c.ti~~;;f~;s*l.he y f6~mdt”& d’~ , ii’ g&?e?~i, i‘~“~ t?@%iefy > ,; place the reviewer’ re.marks those ‘ _ 11.1 ,
“P D’ i ispleasedto provide these’omments c on the Ch&&r$, !&-$Kcturin& a~d~i%&%& InfdrmatL~. t‘h;;; 16’o;bQ- ;na?;;d;;y ; *ie‘r;b& r -?;ti&;‘avi”g h ;, .;.,,; “r x, ycs1.‘‘ d, *,ji “i 4.“. ,‘/“,“ ~ _ interest in the fields of pharmaceutical manufacturjng’ b. & qualie. ?hk 6o$Z&b&ty protocol represents a useful It &our assessment that the utility of the mechanism for facilitabg registration of certain manufacturing changes. Comparability Protocol is prim&y limited to pl&ned~ ~sigX&t & a@$ ‘ &de‘ & ,&$eG products (e.g. It does not add sigr&ant value p those pro&cts and Z&eZ&&ges already proteins and sterile products). covered by a SUPAC document. T&s though useful; the proposkd Co&p&ability Prototiol al&e does not realize We believe that the objective of FDAMA to ease the regulatdry burden on registration of post‘approval changes: the clarifications, modifications, and scope redef&&n proposed’&& b could make the com~ar&ility protocol a I .;ri%s .>., .%, (il-.._ ,& s,,56% i “. +i * -&&!*,~~~,r,i;r.cl *,_. more useful tool for tLe ihdustry and the FDA:“; *O~~~~~&~‘~S ~ were prepared by a committee of experts in this field. “T he committee believes’hat’he t t draft guidance is aL’ d~l&‘s’~e~ & Z 6%~‘ & &he &v&p&&t~ofmea&gf& guidance on comparability protocols. It has m&y excel~eent.f~~~u;es~airea;ijr:” Draft Guidance-For Industry on Co;;iijarability I%ot&ol& PDA is an i‘nfel;natid.a] profess~o~~~‘ a$s;;iatioh of‘ore k “T he committee concluded that the documek would be &ore p; tisefui’f: i -v+ -*t .‘ .~.,.-.*.,~..,~,..,,,,2~-,~“* ~~~:~~-~,~~~~“l ~ *pa. ‘ .*<.-, u “xI:’” *:-)‘*irr,- -w&,*3 ~ C’ ;’“,j ;‘ “-_ y’ .t*,*rii.&&~~- )‘-i &>LZ . . raft guidance 1s broadenea. It is unnecessarily limited With respect to “ G “G &p& &be ‘ Y current product types, in that it should include biological/bioled~~lbi~~“~ rad~~~s (‘e.i., $&fied~ bio&fi With the consolidation of biotech products info’ & C e&! ‘ for b‘ig Evalu&on and Research, products). _ ,.. ,, ,*; / . a‘”--*;,, *p,:.*“V .,_r an opportunity now exists for meaningful harmonizing of regulatory mechanisms. This document . . . “_ “_ *_ represents an excellent opj%&ii~y F‘or stibh’armonizing. h ” Fur&&, “ ’ the contepts presented in this document This also generally re”i ewer appiy does to biotech not agrke products. wit)i ” wh.at foe co”s +.k.+&eiss~hAvk h&$-& -‘

These

commenters*‘e&i’ b

by stating,

i.

^ -’

^ .,

First of all, this reviewer notes tt% tt%S‘ -S?“ ,“r5”&&.‘6ntt-&& ,~. ... _“. ..~“,.,,-, t heblanket “:-* ..,. ,I. @ ’ ,‘ ,,P~ , ~ ;..,, to’ ,‘j; .^,._,I..._.._ ;, ^~,,~‘ AL . assertion of the commehters, already pet-h% GYch bio~o~caI/blotechnologicalproducts to be addressed in a ~omparability’rotocol”“e xcept p f&applications&pr&ein produb”

(Line
unique presents,
“2 . Explicit changes

24).
Based on this, this prob,ms that would
guidance in i-g

reviewer wou!d~~~.~~~,~-‘o’h~““F [IA tt e.stabl.shi‘g. ~ the c-,‘~-;f~f~‘-~f’ + + r the .‘ text: @‘?Sti r -. ;y

ti;i.;<, ie$ognizihg the p;bteii p‘roducts
_ &r&d . or active as +&li~ process successful. a dRc 1 of the

recommend’hat t

is provided in the dod&&nt for c&pa&& &it 6% to i&&de 3’“, + >“ ii;it;a’ I‘trjfjygBTA l &jy--lsslons~ ,a& ,*,.*A<*.-li,i:l..:c’ I Cqmpanies o&h-need to b~t&~z~&mfacturing ,, ( I” ;x. i_.., pl-ocessessoon after approval of the NQA/BL/i -ipl%o+ai: -Changes to a d&g product ,.^ *._,*_ _* ,,*““Ar’.‘ ” w &a.a*m.r,~l ._ _.,~ pharmaceutical ingredi&;li’ i manufacturmg process serve: ,.,,r‘l.Yl* I L%rie$ OK&&i1 @-,os&; s&h etc. The ab:&y &reasonably pr&lict‘he t improvtment, waste reduction; efficiency &&ncem&t, will significantly improve implementation by providing a pre‘ictible d timeli& for Based on *& chte;ia f‘;;r” mhken’ ‘ 3 fiTght “g 6b,,a;a$m{y Prot;;;l &Ju;g&%; implerLent&ion . _” ,..-a Jr>.”-is:i*i*e6%;‘i*,~ ;i); “, &*i<%“-.* ..0r _ il /“, x L, ~ JFZ Zh&gk” d‘e<&&ed m SectionIIIB., we suggest inclusion of a se&ion ,&at discusses the submission

.‘ 6s if is. ” ’ _‘( ‘ ,. . -; .: . .;L

)

.

.

;. comparability the review for changes protocol in the initial (new) , cykle, location of the‘morrnation’n i i to approve a Comparability submission. ,, the Protocol It &uld provide information 3 _‘,._ ComSmon Techni~c.$ I&&&nent’ , a. i after the initial Lrbmission.”

.. .. regarding impact and the”m &hamsms

on ;.

In general, this point where it st%te$
initial submission. ” ~This ~~~teirienf

reviewer agrees “8 1 e me<hanismsfor
i~problematid‘bedau-flk, ~

with’he-: t
changes as

,..‘ ..,. commenters’.rem a’ rksup ., 1 to-approve ;J:;itten; for changes a Comparability it is i‘llogical, to approve Protocol

“t o the
after the

What
Protocol . . . “?

do the commenters this
“I t

mean would

by

“m e&anismS

aComparability

At best, statement to
information in the

’ revjetier

s‘ uggest

could Common

provide information TechnicalI%&nent,

i_‘I.__o .‘, ~,~‘“‘” .,~,,/,, ,.;, 4,, *_. __ :_ :-. I _/ ~>*.%,‘“p d.,_ .,. II_ > x , >‘ regarding impact on the review cycle, location of&e &d?hem’ e&&&ms *for changes to a&re& a‘

chang/ng“

the

commenters’

last

1

ComparabilityProtocolafter&eitsinitialsubmissioni~

filing

for a new drug.” Provided the suggested commenters’ recommendations
to “b und!e,” provided: we

i, the‘ ClviC’ i*,” )“ & ct@n ~ changes are m ade, ‘ this reviewer in Point 2. ,I.I, ;i\_
related agk;cjr &an&% J‘;jis*ion

ofan would

” ‘ ANDA or NDA support the
i‘s .

“3 .

.I. i‘ protocols for multiple unrelated changes to a single prod& However, ” ’ 1‘the guidance I” ** i &ould > “. , ,,, ,_ ^ , 1 allow for making the same or related changes to multiple “r od&s, i.e., bundling, wmch ~hould’ e b _,x xI, /N,?“> >. ,--.n -- *_. In BUCK cases, the precedent for “b undling”‘~ multiple for changes affecting multiple regulatory files. * . % ,,__s- I__‘ -,,~a. j “C .~.*.u .?.,b>.-?‘ .‘,,q*,- “_ j &L “1 -j .‘ . -. I‘ -. .’ ,submissions together is well established. E&-$i& include changing multiple sohd oral products packaging system (e.g., from‘ one H bPI! ‘ bottle to another IKjPE’ottlej b or m &ing ‘ a change technology-specific multiplelproduct &anges (e:g. ., ,, ,’ new

The ability explicitly

ihe same o‘r ,;,;;ki&‘he t

for-‘ne o & k%pi&‘~6d&ts p ~Or*~;;^j;;,r~;i~“p rovision

fo; geneial
explicitly applied .

-” ”

1

to a new to allow

,.

bo&

&~ .,,*-.-7, &%&~“&...I,-.,“” I’ .” _^for ._, *: -, “ %d’ $i~j ,, _,

,

reviewer has problems simple example that’ as h little to to buy into. Moreover, the commenters“r emarkS 1. If the commenterz? goal‘ change (as the lexam-ple need do is file a set of product, as’ a group. 2. Comparability “b und,ing,,

This

with the g‘lib lti@uage used do with what‘hey-are t seeking’ ,., f oget _,

that I .(__ - I/. ,I a , presents the Agency -..

L‘a:_ ., ,& ,,._ ,I #. i c^,,._ i‘gnbre~the folk$$‘g~real~ttes: n is 5imply to’ o‘btain agreement on ~‘ a single states) imp&tit-@ multiple” product’“a l~~ ; they comparability protccols (CPS), one for each a (Z,to ~I”j ~,\“* cps ,‘ f%Zh~ay*for .)I pt&vide’ wir(,larg*i~wf~n8Gid ,, .

protocols (CPs) are not intended ~ubmijsitins.~Thei~~~~~~~~t~~~~~~general,

* _

to a) be process and product spedific‘ nd g changes in the process or its contrcls~that have a high pr”o ~babiI‘.y i of pio-&~lng comparable tb the pre-dhange /oduct:‘ : 3.

b) address the~subm~tterh& .“~ ~~~:cl;an~e’,product I( +. -‘.“. *T,-’i_’

sbecific. related’ e’ bli!sIied & % .,<*:a-_ ;i;,**,,_.,*A,;*_,> ’ .( ,s that /

If the preceding were to be.allowed; a”f aiiure in one j”, “.~‘case would ,,* (,* require ,,)-;.u~alii~~~~,cv~~,,~, _I the Agency to-reject all changes. T‘ his Gthe’ gs‘ because&-‘.+*-~.,.\Z~ ;~#i,,6;~. c .~ .>.,“* ; ri \~> all :,,would be in e one CP and require’ s PAS be initiated.* T‘ hus, a failure tn one~“p ro*dbc~ It-’ . a multiple-product co>mparability protocol~~~~c~~!d, % a I-%%&$; ‘ trigger the PAS,reporting’equir~~ent’or’fl~I;rbducts i f a insuc~‘p ^rd~~cb’s,because “ i their repot?i’ g / ,,.s‘tatus n is~‘ied t /to the prctb;dcl’_/. L . ,> not .t”o “L .:. .,_ .“^individual’ * and .I:_), .“ the” I_“_ j., ,

Thus, to make ambiguities the very . products
“4 .

the Agency “i e,~~~~.:~h’ nges”iin general, should, a n reject comparability mu,tip,e r‘;lu,tip,e‘ products in re”i ew~~d’ eviewtim~~~~‘iies~~~~is~~~sit~~~ionls~~~~s.~ r r real reality th;it”a ” in the protocol. 1
related to ,Drug
is inLolved a DMF should

protocols b‘ ecau’e‘ j fails’ the

that df a} seek ti;e and @ &?$-e’ et S .‘
_ i^ .,

failure ”
Master Filings

in an$one .” ’
(D&F)

p‘roduct .
i‘s in&decJ.

of

.,.
The use 2

Informatioq
Protocol when

a Cornparabilky

be described.

This reviewer disagrees with the commenters’ proposal because the use of a DMF or VMF is the same as the -use‘ in &I’ &her filing caseS - to provide a mechanism for i‘ti detail data that the proposed changes describing ^pidauceco;mpara’jTk arid’ providing .wil’ j i proa;.%& supporting Nothing proh%‘t~~q’ i D’ %~/‘ \;rMF hold&- from fi’ihg ti”i dtib&ra’i’i$ f V l bf proposaI (CP) or, after making thedhanges’in”t ~‘~‘P ,‘~‘~~~.a . k‘ ~ CP report to their DMF. However, unlike most qt,her filitjgs, th<AP;g&dy is not p&%&d, oh its,own,, ’ initiative, to do more than fi’e all~s”u b’ i’s.$ibn$. l m This is thFi.c?,se be$ay2e8$l!. ~LIJZ,~ filinks, inci$hiiig. thk’ nnual a a;e I report” _ &titled td be and ~$6 t‘keated as “t radk:!$$-ets.” Thus, in general, the CP and’he f CP r&port at-6 oniy‘ sub&t inspectional review triggered by a biannual general CX%‘~tiud‘t*~~r ~ i ti “f o:O; cause” (product problem) s fi,ir;g.fasu’ m’s~ion‘ ~~~~~~~”~ ~~..~~~~ r&4$ (triggered by a‘ manufadturer’ inspectioni a or authorized b apbrdpriat& drug-product D”M i,vM.F permission letter frbm $6 ~Qlf~V~~w’~f~~r ~ df theii~‘egaliy’~~thbrized j ~
agentjs

I

Thus, in general, D M F’ ~VMFh&%r~ ‘ ne6d”n o’d;b; i pre-sanction to implement their process changes and, ?._^_rr”,ei as the batch-repi;&erita&e‘ te&aata on th,e _L., .,. .I as long .a,-.._.I *‘I*- ~*::‘.‘. *q I product indicate t%<jIhe post-change product IS comparab’6” l to fh’ ~r&~hti@ & % product, ship postxhtinge p‘bduct’o.th~i~‘ ~~tomers: r t ~ This is firms reason the that ~ this reviewer hasn long t-ecommended that purchasing in;djude ss-~i~~“ ~~~Eo*n^tSac~~~r~~~~~et4i’ ~~~~~~~~ .Dh&..tii: the holder changes to disclose no mater (‘naer u a sujta’jr& ~‘o~~~~~~alifj;“a gree-~ei7i,, l how “t rivia,” and b) suffidient,.~~,rigorous a‘i”l “p rocess j”,,_._.phd~pji6.-grf; ,,. -’ ”

acceptance specification : -,*.>.,:derivedirI,^,t,.,**“‘r yi(”,\.*;: : ,.“- ,~,r~,,“~the’-‘ #$Y,+k:;%c$~; ii-*;“n+ &nts of :&‘m:.otg used’n i ,d, from thos6 ^.,‘ :.; l r f‘6f i:i.Q * . conipo’ 1 \” b+4 the manufacturer’Yflirng . to”o btaln rnttraj product approval or li&ns& on pred&.Kig‘ l :j ~ w&Id ;ecoriI&$dvis-&is cps Bas@ Drug the Master.,Pi,esr %iii%$’,(n”o MFs a “, .ii”“””~ his”ris-,-ti~r ~ ~~~~~~~~~~~2.~~~~;~~~i%” and )’ ,s t~~~~i;~“ ’ _ll.e,.;‘ ~l’ ,** ~vi’ inc,ude DMFs. Vete.rinary Mc;last.r . il’e’ s l (ilwrr;;lFs’) ~‘ hene~~~~~~e‘cir‘ ent:Zext , c S ;os.~esses

:

, 85 _ ..+I~.,“‘>,, . . ,. _” :_ <,/ ’ , ‘. ,” ., _/,” ,_ ,” ‘, ___./&/ ’ _. ,.” ^. c i ,1

I” .

“r .: 1. ,-:” (. I

‘.

_.

,. .,,

;.

i. . ,’

industry needs to $u’po-t-t p decresSing;th~~,inslj~dfld’i‘nierv$j-fdr n “5 . inspection timing coul;d

funding

this sudh igky&&

program “a nd, sites to annua,, ~~~,,~~~~~~~~i~~,~~~~~

-perhaps,

l‘obby . at ;i_ !l <_:, q ue;p*f the re‘

for :

be coo;$inat&d

the Manufactuiviri in a non-prior-approval not have a satisfactory

~..,..-,,*,~,~~~,~-~~l,.*~r,~..~r~r~~ ~..4-.~:..*.~.;‘ ^* , * - >.((“, ,_ ?;h~‘~ida~~~~i;(;i;;I~~~~~~ ~ aearly state whether FDA would 2 permit a supplement i reporting category for a change to a’ew-site n that has not beenII*.*r” inspected or does :I,-,$:” ’ __ ,)- .,* C-~~~~~~~~~~~~;~~~~~~~~~ &s;;ection,. L.-,“.is usually,,+“. “ pr;r;;pted\,..-““,’ f-,‘-&\ ,* ieqbestid v;a,

the PA supplement process. For instance, standard*p&kaging site changes require CBE-30 supplements, An approved Comparability Protocol could unless the site does not have a iatisfactory CGGP inspection. allow for a packaging sitte*change to be reported in’n annualreport, a along with a statement (Lines S7O573) that the move will bdm$ement$i oni) when the”s itehas a satisfactory CGMP inspection for that This Guidance, as written, does not provide for use of such a Comparability Protocol, type of operation, which requires insuring completion of a satisfactory CGMP inspection without a PA supplement. We propose language such as (line __ 579 j: “If t‘h e submiss+ -.. of the prior approval Comparability Protocol supplement would require a site inspection, the applic&t is’esponsible’f or r “ insuring that the site has a . satisfactory CGMP’nspection~for i the type of operation prior to commercial distribution.> of a change in .” __“. ” ,” accordance with a commitment to the approved Comparability Protocol.”

reviewer finds the comm”e nters”i ntroductory’,entence k &~**q**~.n*i+.+xn ,“, _.“_^j 1 /. .idto,,,.- j at :, be a odd-s with _I i*o*. should~& d-one vis-g-~vis~‘~‘ ~~~‘~‘:_j~spectlon, ~ ~ AaS .w.ith current fijiing.$.t’ e h *‘eviewing r division needs to do an overview assessm‘nt e before any inspectional action, wculd be appropriate. After all that assessment. review lcould find that the changes are ,not comparable and trigger the rejection of the’ P C’ withdutthe’n eed “ of an inspect& or, based on the fir,m’s proposed , site‘ s having an acceptable compliance status for the changes proposed and an acceptable acceptance-review, indicate that no inspection is needed. _‘. ,“_ ,‘ j _ ,_,_* ITS,. ..::,s.. “, Therefore, inspection timing */jr“..llr.^lll”“‘i ~~,i”‘“. Ibe”c oor&n’ted %se->;,S‘ ,j,through shouid‘ a xv\>***“ the review *r I**““* 4 *..~~,,ir,uwr/*r, divisions and not di,recfly th’ ough r the FDA District Office. Moreover, to prevent the submission ~f.‘~n-paijer”“c ~an~es ~ or site;, the Agency should require the .propo%d’ s‘fe’ r i % s‘ites ~‘o be fully functional t and CGMP-compliant before ” a .“, ., is’..a. / -“s lir.“i -;” /..I CP ...k ubmitted’as:the l Agency does for ANDAS‘ nd a = N DAs). On the secondary issue of “s ite change,‘ ! this revkwerrecommends that the use‘f o a CP in such cases shou’d r flCT be encouraged. Moreover, it should be ,,proscribed for c‘ hanges to sites that have no acceptable compliance history because there are other mechanisms ./ _. by which such In can and should ~ ~~~~~~~~~~~~~olji~~~ be addressed. addifion, CPs,‘ &o”e s f;c;‘.‘eifei g di;e;;c,;under FDA what re”i ew because definition, product to sites sites any produced that fa,l unaer a,.MRAo;~~‘~:~~~~uid:‘ng~~~~~il-i;e ~ i proScribed in such product under countries’ are not r‘ equked to meet CGM’ ” thus, P by produced (be,ausein suchon,ijf*~h~=~Pe~;;;n6io~.cd‘;;parabi,ity sites cannot’ ; b8”“c ~‘~‘araij;le~’ ~ to CGMP is _ I.,:A. _‘ ;-_.I under ‘ : ~‘.;. ~ . / < ,I*-# ,. that ___.__,deemed. .._ is / . _a to cG’ ~“~ ~“. “~ ,‘~‘CGIVIP’n‘ij~^“u n~~r”~ ~q~~~ysystern _ ~ case unless that “c omparable” quality system in:procekk material and batch: or lot- release that meet or exceed: _. _ . _> ,i //. > ., .i :‘- ;;I ~* .‘,_ : :_ _., _/ ___ $6 .’ i. 1:. ,‘ be the

This

that be to be suchomparable’ produced c‘ I

The preceding should incomingc’ mponent, o ,I, ,,, j‘._ establishes ~ oon~~o;ls :+,: s~d”~ ojt:r,l-~~‘ VI.-. )‘ *.

-

the.

e5st,,shipment

Of

each

,ot

repres~ntativgsa~ljie”ib~ntit~,tesiii;g,

.‘-

‘a_

in-process

re,5rgg~~fgfy;g

~~;~yLs

.&’

cacti”

bsf<$at

-adh

stage

(phase

*r

-

step) material ass’ ssme’t~for e n a-II‘ &it&f character&tics, drug-product representative units~~test:;ngredluire~~~~t~ of statistical quality control for release, and scientifica‘ly l sound and appropriate sijec~ficatio’ s’for n( the “n jfed sta*es ~h~r*~c;oP~~?i p’~~j:e~~~~I’s~es ~ i that are article” procedures. derived (reverse specifications _. .>“_ , ;_,__, ” i

‘ “ “ ’ that include “, .,~,, I all factors‘or‘yhi& f i p‘o~t:release’ests) ~

the use

engineered) from the post-release by the sound use ,_ of/_^ -appropriate ,, ”^

U.!WIike “a ny statistical .-

“6 .

Data

requirements

manufacturers capturing the manufacttning dating reduction potential data

for *,common “ii,*,r,.ir..i’ :: changes. Comparability Protocols would be more useful to _ ^ _il ~)_ ~ if FDA could provide data requirements for some common changes. Data requirements expected information for common changes such’ as alternate API supplier, API I ^._ I” site change, alternate te&ng’abor%$ l product line extension (a new fill size), expiration or stopper changes could be very useful. W e have~ai!tached~ihree ‘ examples of such
requirements in Attachment 2.” ($ee A ff;6’l%$t$$ ‘ ~

Requirements

fbr Common

Cha~&%~‘ j

:*~’ .‘

“”

.,

2,”

l‘i’ 6%b~n C

Data

First, because guidance does not set requirements and the’ uidance g requests, as their examples clearly reflect the’ commenters understand, more than data, thisrevie<er recommend!to,the com.menters th,at they change _I,.would “. their first’ remark to read “I nformation,. recjuests‘or f some corn+? changes” and ..frarne thei-r t+ i‘ ter~.s”o i~h~~‘~r~~~~~~al n ~ term “i nformation.” Second, this’ rh~,eiver:‘greesthat a detailed ex&6ples can always’elp h the users of guidance in formulating their d‘ p’ roach b t‘oproviding the information requested in a guidance. ^_ :. ,c-~*\i”, ._, / , .,> -.,1 ,r--,_a I,, With the prec&~~nAn ri;‘cb;f<“s - ‘ -xg&;; will,now ,“_ .review“2 “ .“+the ,, comment;;-,’ “A ttachment 2.”
“b ttachment “C omparability

.
2: Data Protocol * Set Requirements &&a
rubber

,
fdr . . &ti‘$on i

_‘ ,
Changes” - #l”
as an product .e”

.

Sample

! flfOrt?latlOfl ” 1
stopper would

R equirements ‘

“t i
alternate line.

A stopper
to the current

fabricated
approved

from
stopper.

a new
Such

a change

W“G eneral
e
l

For

such

changes,

the

supporting

compound “i s being proposed could b‘e applicable across‘ n a entire zr.;*.* ,,r”s .,r.3.. ,,,. .,. II ) .,. jl “. “I .o informatron package should include:‘”

Information
for the new evaluation Cytotoxicity stopper including USP Biological Reactivity, LISP Systemic ._, and Intracutaneous ._

Specifications Material, Toxicity,

of the stopper, and

information for the firm or firms data collected, and the,djsposition , ~ (” __ _ “I “. . I/ -, ,.,;

tests, ’ the identity:’ location and contact performing the evaluations, copies of all of the of “a il 6% examined; 1 “. 1, j _‘ _ ..“ ,’ :“ ,, .,“. -.,I_ .: ,~., ; .;“- ,“y i- _ ,& I ,_“_ _(: , 1,/ _. 1,..j,;.2.:. / ; ; ,“- :;,. ( .,,” * I.,j~re,Lc, ;, ,‘; -:.,\,‘ ._.r ---*. -; r ,‘, %~~. .^ ,_ .~. ,. USP P hysiochemical ‘ 87 4‘” ,_’ ;“. ; L_^’ l’ . I .‘_ ,I_

A REVIEW 6‘ ~
,,, : : _I”’

A supplier statement that certifies that th,e supplier kili manufacture ( , ., each lot of Ij^ ,b< the new storjpersunder a quality system that%5inform,s, ft the, eppl’cable l ,,. ,, ,” I.,/ requirements of CCMP. ” ‘ The description df aiid spe”i fications fo; +&mG d ~fi~in~,ri;w‘t’ w ~/c~‘ the ‘ i h‘ . new 9.‘ : stopper is to be used
uses .to obtai’i t Zhe ;‘&“; rf& r‘ wg~ 6s; ,;thgir “.;‘;y-;$fi;af; o‘ & :’

Copies of the methods: a. The supp,ier

b.

c.

The data

Analysis”< “% “O A and contact certificate; The Pe~ffij:i;“m t^fie i-‘ qui.r,d spdnsor’ sed u e to: ,‘dknfifica~i.~rt’. anci l ,‘ (..I’ . . s .^ i. ii. Validate “B ie &&~bilit~<f the-suppiier’l’est’ e~~~~~~’ .I,_ ,-j- ~&*~:. 4ur*‘,:.ii,‘z,.:,:;,‘ ,2 1. ..2 i s r as well ./ as Tr,_ ‘ : , ., iii. The identity and location ofttie firiti~that dud each; and The sponsor ~ro~os’ s e to use for evaluating e&h b&h along with the identity, location and contact information for the firm or firms that[tiill do each evaluation. ._ ,., sponsor’ s “s u@pl‘ervalidation i p ackage” ‘ including I* all of the results and . .“, .__ obtained. “v alidation p&%age for stopper evajuation”. j<‘, i,nck.&ing aI‘ of the. f _.. ^.^* ‘,,.I \ ‘ ‘ ” data __obtai’ ed,. “‘* _I^i 1( .,y. ^” _ “<’,, ?I._ ., ” wz; j” “< ,“, ? -. . ^ ^.,,- : l_.,ji(i’,. _ : n -,,I, __,. ‘ / ,_.,_ . ‘ j, or not, the sponsor
“w ith

, __ ..- “i, ._YUr.l%**~5*ir*.c ),,,, s?&.g: .*‘4*“* ::4z-$qp./ <~>,,:;‘“. A ~B*4&~**‘ .13 “, *A_ :r ~,.+?,A w “F _.,. ,.;r .,..‘ c ‘ i ‘ +‘ , :.;p. : ;,,,; or Report of Analysrs ( ROA ) and the identrty, locatron for‘ each firm that, performs each evaluation l‘k’ ed t on said

The sponsor’ s results and
0

A statement as to whether, each lot 211,84(d~~3)). for compliance If the sponsor does not plan

intends

to test each
-(ii

shipment
21

of

ail adproprike“( :‘/ ^‘writ& :* ~kc‘k du~es” ,%. ,, ,, _‘ ,- __( .
sh,@ment assessment

_; b‘ &r

CFR

to do each

with all appropriate written e,apsed-time interva,.for

procedures,” l‘approprlate

a stat$ment ,&$& Lljbnsor’ ’ s vaiictatfon of thesu~~i~~~,‘testres;i~:“.“~ - :’ s ‘”

for “f orcdnformatke
es;a~g&-.d “.(I‘ ’ “’ ’

“S oecific
Copies

Inform&ion
of the Certificate df A&lj&‘ or f

e /& s”t ogipper ;eck’ved i by the spbnsor each lot of‘ I & ‘ to date along with each lot’ evaluatio? s yesyltsfbr 6&h evaluation performed to comp,y with the require,nients Of 21 CFR *11‘ 84~~X~~, , q5;);.~~~~~~)S1‘ ”n d‘ a the d,ispoSifion (BcceF~,&~‘ ~~ b rejectedy;f e aciif.3;;,;+ ‘ ,ote~. At least
one commercial-scale co&noditi& batch of drug product at the approved fa&ty, filled “” and . finished with

the current approved number (or fill size);

that

includes

at least
.

one *’ .’ . commercial-scale - _“~ ^__I. _._,

batch for each list ,: I ., .. ,“. -.:

generate

Certificate

of Ar$ysis

$i;&eitifi;;l-;

for

e&h
, ::

kuch , .)commercial-sc& . . .c ,-“, -_,aslong bkch’ ..l.% ,,, ‘,, ~ u
-, _, r,.

with
,__

the
,_

data
,“.l.i..

used

to

.,,

..__

;.,

“,

?,.,.

\(

~

A

_(

,:

Y

__/

,.:

,_

jl_,j

i

b

Stability intervals’

protocol/testing

matrix;

include

upright

and- inverted

via??-% .?“c

as we’l a s, l ‘
batch record

if a ny; ‘
drug

“a t a”n y o ther ‘
product list number

i~ntervals‘ hat t
jor’ill f size) for

& and 2s”c at standard “‘-:‘. .: ,/..‘,‘,& i 1 ,‘’ / ). , t-he sponsor’ s protocol

specifies;
Blank for each

ttie “n ew
_i r _. l... __. “>:I ,+.’

stopper”
. . X1/_ ‘. -,”

.lots -’

produced

for the

stability

study;
__.

‘”
:

^
,” . . ..~,lj_

Executed batch-record the “n ew stq~pe;$qo{s Scientific report

a hd’ 4 p~.~;-ed”f bflghe l’ ected I I” d&i co r
” (‘ ia.. _ . of three a minimum

^ i,&or ,eacl&rug .study’. product ;tability ;
.I_ /.,.... ,‘., : . “- ‘ *

list number data

(or fill size) for

containing

months “L S.‘ /_/W.,.~‘ ~rj~.~“_ ‘ stability _ j of, Saccelerated * *+/ ,-. , . ‘

produced currently
Sterility

using the new stopper accepted s topper;’ ‘ .
assurance package including

as well as the hjstorjal ’’ .
study of the proposed

report

and

-,-..: for product data for the )

stopper; and .._, ..~. ’ Specifications and methods referenced in the above studies for the products produced using the currently approved stopper and, if any are different, the new stopper (if different, the rCtio,nale’ for changes shall be d iscus$ed’ ‘ tindthe changes justified).” depyrogenation

After a few,changes and t&appropriate additions, this reviewer agrees with the commenters’ general example layout but finds that”‘m uoh “m ore, informati.n should be, sub+Aitydd befbrG Kg j‘4gen*c)~~~‘ eviewer’ ould S c a) as’ esss I the sc;enf#c soundness of ~ ~y-‘ jods,” ‘ & data; i~.uli~, *and _,_ .__I, ., I is certifications, b) determine , compar;at;ig ,j6 and c~irenxtly the ac.iep.fed whether s ioplje;; or’ not,_t~h~e’ ,.new _ stopper ‘ Should that should addition. the Agency be inck&ed find that this revie~e‘ overlooked r I’ the exampie’“t his n ; r&$&r any ~tiould information support its

“N ew would

API (drug

substance)

vendor

could be applicable across information package for M licensed bulk drug shouldinclude:” “G eneral 0

as an alternate or replacement to the current approved an entire product line. The & ‘ post-change n6vi;’ venbor sfi\cbm:~~k~~a,~t~~AacceF;ted, ^ _ -‘ ”

vendor.

Such a change --roved, ., or

API supporting
_.

:.. ”

Information ,.__ ,,,. >._ .~, .) . ~ 1 If the API vendor is located in a foreign country and/or the API filed under a DMF or VMF, cOver Letters of 4uairiqa;ion from the DmF”“& f v@F*“K c’a$f”$ s$j i i‘C+he ” firm has one, its legally duthdrized .“- s agint aut~~;;;i;ir;g”h e‘ gency’ o A ~ review ” Y 2 “. W”,,“. of *, ;~*,,L~...~MI:-‘i*dld. ‘ q,i- the DMF filggtid i the comparabiIity~“j jr~~o~~i’“~ ~~.~t~~”~ est ; h”~ ~‘ s‘ ~~~ni,:i ‘ u. a.,, )j . ir,~.‘ ,.__ Ye .T a . d..%“j;,&- ,,e”* ,ed”i pc ,*,“,-2ii e >r;~~*A“h d% ,*,*‘I ‘ warehousing facil.ities,‘f i such?%ist~‘ or ,.,” -,-/”_,,1 and a’ 1 Information f any C bearing on the API and the‘ API i‘j;bc~~~e~~‘ nci~prbcess a changes, including a brief description ofthe new API manufacturer’ s facility or facilities (when different sites.are _I. used to ._ rn.a.,~~~~,~.~fure.al~~y i riter’ ediate), m GMP certification letters .) debarment certification letter (if _.^ _
and Central File~Numher.‘ ,,,. \ *’ * ’ ,_ ” ;_, ,,,“, E )?, , ‘ ,‘, : ‘ -( : ( I. ” __ :, .-. r l.~,\. _‘ _ is , r @ : ,.^‘ ^ . .‘ *, . _^. * ._ L,^ ..,, _, ,,, . _: _.,“_ _ ,,‘I^ ,I ,,I/, j, y .? . : _,, , _,- .: ; , ^ _)” /.a ._,, I.>.), . , _x,/,_

apphcable)

(_ ,. z *

information

may

or may

not be available

from

the new

vendor.

Typically,

where

such

EIRs

exist, a copy Of the unexptirgated version ~~~conta$edinthevendor’TypeiIDMFk-V&&F s I+, because it is proprietary in nature some vendors may be reluctant ,f not’ ava/!ab@ j;s-$ the‘ i‘end& the sp;;sor to p;ov/de’ this infbrmation. shou,d obtain exp;;gated Giei cder Fre;do&-..;--, rY-i;;tia2‘.& i Ac-$ ;i”F O.,A”) If the 2nd include those- co@‘ ,“_tb’,,.facilifateI ,-~*, the A<e%$‘?l&%tin~ & ch; &@nals. _,.Mh, ! x ,;,i ,j”_“ ,. existing.ElRs ar&*‘i$‘ f-date, b % do t& coyer ,the~ si$e t‘hat the vendor uses to manufacture the new API, or the proposed Get-tG”$ r~has never been inspected, the Agency should be c~~~u!t~d,’ cn”g &nePar; ‘ rio cqmparability protocol should be submitted when’he t vendor’ ,,”..II_,,‘o-.,l”x ~.l never ~ _i II”“I c*v.,ls-.L1” s site~ has been ,.,” inspected (such changes should be handled via th&‘ P% ~ approachj. *=“_ ”

0

&&hangea.nd’ o&p change vendor are the same~firm or cooperating v&dbrs, the current pre-change process versus new vendor process-)with the differ~ncesexplainkdbr, when ttie “b bst-change vendor does not have access to the pre-change s prdcess information, .~.. vendo/‘ the identity, r6cat;br?.~~~~--c,~~~~~~ ,i.nfoymz$on fo~‘,h;at‘&idot-j,” ? v ” ” , . ..^ “S pecific Information
Ove~iewofthemanufactureof;hedrugsubstance(inju~~~when-~he stage for ;;.,,“, .,,I__, the.” ,-,*_ ./~,__l. II _ ‘ ._,<-, post-changei-w ,‘ a,‘

,_

-

*

in the Acute

pre-change API. and short-termff~

.’

.c ,: .” r ,___ .I, .,._ ) , l. 1 safety.

.‘ ,( -‘

... &

impurity fractib& exist in differ~rit .)

-.. ,,_ be provided td support%Abj ?hou@ diysta,,ine”f arm~~‘ii~~o”m parijori’ s~ou,6 t ~

When_,., the API can ,. estab,ish “, ,. _ .that. g; of the pr&

solubi,iity prbp%ies of the p&f-change change API. Fo’ -a*c$%ge’ r ut?de; the 90 ,_a

AP\ are comparable to those c&&l x 6i th&‘xistin’/“, ” ,. v &dor, 6 ,“, ” <, g ~&%&p~&$‘ ,“* ., .-.

the,Tomparison

should

nonconsecutive m the post-change reproducibi,ity).

be of II&xH&& pre-change API (minimum of &ree B >..“ .,I *.P*. \+ . six,“.‘ (6) * ~I, , ._ j,h,*_. _I“a &,A*,, * ,,+i , .” “i x,*,,,: -*i*sr.q--b ,:w”> ,-ir) 8 , lots’eprese‘tative r n of‘he t observed ranges of ImpurltIes)versus API (min.imurn,of three consec&L l&s to’ demonstZafe.~prdd~ss When. the post;chinge aiiil’~~.,~~‘j~~,a’;ei7~.c;“io‘ ~~~~”t hani i \ ge

currently accepted‘ne,‘.,ots o t he (3) consecutive

b ; d’ cjf‘ the,comparison ve’aor shoulds“& . Apy ,. etween at u-‘r.a.~-A.b e ”e ~~~~~~;idn-‘ three new, n ” _*_.)“ ._’be’ _ ,‘to) ,A*^ir..i,east”. min&&mof - a ‘ ~~~~‘

’ -,

consecutive representative lots of the previous vendor’ s API (see Note 2). To be comparable, the post change API m -u& have w ‘ safety, purity, particle size cl&ibution, polymorphic form, impurity profile a&d otf& $$xhemical properties are properties of the pre-change that API. the ” same ., / orI, better than’he ,( L”“. corresponding ,_, ._ t I_ ;‘.“, %‘.,(, I [Note 1: rf the post-change API is produced by a’i-dce$*that p
@ Iiany level that are not found in fhe piGhang& approach should @ be us&d. -” Note *: When, in a n&ydrug situd40n’.“f hie’c oop~~~~~~ l “ the API has post-change in~~oduc&nipuriti&s ti--@~db~ti~ar~l%l’~j; i Ijve:;-nge’ a‘t P~otk%i of

;C;g--ja-“& u;er

not produced
vendor should

more

than
su’rkit b

tri’ee’ i>” r @
-5’ l8’ r~,of @

ldts arid-does

not intend

to do so,’ the

ce~~~~~~tion’ib’~the“l jre’~~ange f ~ -

l

e For each post-change API batcti used in any’tudy,certified-copies s of aj the API manufacturer’ ” s coi and, if not in ; American “‘f :x A#/^, 2 Irr ” I. certified(_ I English;. ,,:&z-,-#$ :$i L ,, * ), translations thereof, b) API spec&ations ” x in’ m&can A English, c) the ihentity, location and contact-informat%n for eaich”l aboiator-ythati‘.. I’ used s to en&e that the API m ,eets specification, and d) al.1 of % G lata ‘ and reported i’formation n f& each lot of the post-change API manufactured by the.new vendor, including spectra and
chromatograms as we,, as, bf not in Arnefici6 .~~gri~~;‘“~ ~~~~~~~i‘ ~h~ ~ . \l ,y i ‘ wa;+ B<ii&,. ,.,( g fi$ */,= of aT, i narr’

*

remarks.
e

including d‘ esta~blishes i ‘ .the ,;,_ ata < :‘-:.“, ,a-,?;“~ :.+A.“, “; ,%.‘ $> t t‘hat-.y “, ,each1, *.-,‘s ;,,, *~.~i.y.“ ;that’ a.:; . :> A validated, the’dentity, i addi&s< andcontact lnformatron for each facrlity.other than the manufacturer that has-,-done any ofti% testing &longw”? th”t he tests they have been authoritedto perform,‘ nd a a certifi&tion’hat..a.*.“r-. .1L e&h I_,methodwili .. . i . have t. ,. - ..A i^‘,__w~l,,,*l its validity i urid‘ of use,,prior to, during,‘ . arid.,$t ttie appropi-i~~~lyvei;‘fi;ed end of, &d.~.i; usage* -,”~ . ,,_. _- ~~a~~~~~“i co?d!tl,~ns
Analytical methods for the API Stability protckol

.’

a

*

__ ,. ... 1. .., “b atch of the post-change or “n ew,, API ,isted in’~‘~--Cdiiipara6i~,~~~‘>‘~~;jcdi: c i~ .“y Kg Ij;ot~~z~,~~shOu,~ abdress ,“_ ,_lf _,,iy I ,..,I-,i.., I_,, “_ ^Lu~^,1_..^*,~, ,I II*<_.__‘ . “3 .-L_-i.(“‘f ;” ‘“E d-- ***(“b “a .’- ,(,, . x‘ i _y,, .~I_j ...ir-i X ,“ ., -. * * a) rang-term storage at warehouse temperature” and b) an “a ccelerated” condition (‘at -3‘ ”c , b 40~6, or other temperature, as appropriate). _I . Stabilityeka&-eport with copies of‘fl-data a as,. 5f‘o,llows: .. ,, ’ *I. ‘ , 1. When-the the-nges are in the same process’ in the same facility, a &-day ’
withG~est&g
& Zn~a~d &GGak^f6k

each

i. ._ ‘.._ ,^ ”

r, .~ ,.

,.

pre-change

,o~

a’iid

dt

reasf.three’~~~,iS:~~~c~ang~

r6ts

*

.lir,rr*.,, (twq

.-ti.,, of

*“-‘*,g,.*. wh,ch

:,

r:-*

i‘k., may

dW”.r*

be “:‘,

.‘:

pilot-scale lots) i , ^.,*g-*,.,A>,.\‘“~ ,”~, ..,,. :’ j” ...Y.. _.;,.,* .-a . When the change’s i a move by‘he t same firm??o’ one m srte to another s!te,. a,, go-day stability report with lot-representative data from the last three (3) pre-change lots’ nd a the’i’st fr three (3) post-change’ots” i When the change is the cooperativea.‘rj~~~~~~~~~25ie”“~ ~~i”“p ri;dss the pre-change i ,u * < (,, API a;;iotcer^.,‘ transfer of from one manuf8dZui;er “t o . from.’ process .., ”iy*r$aw “:,b.* ‘ ,* manufacturer,-~ili~~~ystab~lt~ @$sff wi~~l‘t-i-e”l jresentatiue d data forth& last appropriate number and type of pre-&tinge a > lots’ nd I,- *., the _ first _ three (3) post.s ,_i,... I ..i_l& -* .;, change lots with a commitment‘ % I?~&‘ ay d testtng and reportrng intervals for the “a cceler@ed” testing protocols. 4. When )‘,. the! chan,ge. new is ,,,, the .co~MIjara6iEfp and/or ~ 6%w~~‘~;6~~tiof the impuritiesa”, ndt in’he b‘ e non-cooperative any t l,new &PI ar.A,‘ p’ & tii’ ‘ l used. 5. .j :I .,_.: 1 ,-I .:“ _I :_ J .j :,. -_ - A<“3 ?) z.b,v-‘ “.i”;;‘i” ~,‘ ‘ ‘: .‘y,.*,: -::*i, _, .‘;,i ,,‘_‘_). “: ,. In all cases, the “w arehouse interval must be submitted Comparability Protocol as the fuII’-tjom.teriiperature i storage” stability data for the 3-month’ s for a’f’ poSt-‘ hange l c lots covered by the a part of the ^com’ itment m to carry all such stab’l~ty’;b‘^d’ o’~ i p t ci _ .” -‘*‘ _

I +!

-

through

population APls and

projections API processes

should being

be used compared;.

t,o establ$i
,*

the

comparabrlrty??fS’lfie‘ t
I

<’ ‘_ ” “

First, the example was revised to limit it to the’rjfor~mafion”p ackage i the API rather than the information package‘or f ,” ,,,,the “, API,‘and * products made from the API: ” -’ . to focus on the-, use of a,comparability sole,yThis for change ~pI was m‘ de a.ddin~fhe”~ bmplex;ty^~~~“~ u~~~~~~~ei7ttiischarige the .&.Ktita ‘i“ is a part of _ a” ;. .1 ~i,+,<~,_i_ ,.*,,l.-6.. g,ven drug-prod~iict’ aiSufdc~~~~~~.$‘ ~~~~o~~,~~.~~~~~~~ m ~ suppliers. most API manufacturers’ .manufactuie.,th%~~~~~~~~~~~‘~~~~~~,.~.~v~~i~tj;^.a~ ~ manufacturer ~ ~ who’ ses u <ywn c‘ ~~~~~r’ ~i~~~‘ ~~~~~ss~~~nts .“, _.

for the d‘rtig .“< ,“. ,#...I\. protocol up, j‘

,. “.

markets and purchasers. Though needs each to drug-product SOUrCe‘ per’;eri; f

“it‘s

any,,,AP’~from.~‘~p,*p”. ...if i‘t l^-,,’ .;,:, !,“ and,agiven

.

elects to change sources or to use API or”@ ) oth”e ~dru^g’omi;;dnent c from one of their approved vendors*‘ter’ha’ $ t t “v endor c‘ hanges the process for that component, these need their o,wn co~mparabifity protocol. In such cases,, the 1^“, , Comparability Protocol’ i‘nfo”r maf’ on ~ package ’ . . /. l f “. dii~‘ described ii-\this AP,. ..Comparabi‘i’ji-Protocol ,. *-p.1,,/c;l.w* l;“ii’ie,~~S;~%~~~~~eddecl in -~ their :,;,yDrug-PrGduct’ om~arabliity‘ r’otdcbl. j ” ,,. C /~‘::‘:‘* P ,: “, ‘, ;‘.. “ : ?“ ^ 1 ,. . ,. I /

,After chanies

remo”ingthb,bui,ets.adaie~~i‘ l~~~~~rugp;;oducEa;~~c~~ ; a’ d’ n nisrk’ n”@ ; fj+6:a~~ropr,ate ,. .~‘; -?:$“- ,l:‘ ,‘

’ & ) add+$io.s;-Athi;; rei;.iewer.agrees

,; of’he. i with

_I c

the commer$ers’ general example laybut buf finds‘ th&i%Eii rr?O”? e information should ^“I % sti’ ~i&d b before -an &$‘ $zy t ~ evi&~?‘ & lb ‘ c’ a) assess the .scie$[fic. .,.. ~s@%&&s &of’ th&,:&,. &hods.i;-~% ? !W ildata, I . results, . % . ~“.,;.‘ ‘ and .&‘ ~ ” .I. ,).I , (A certifications, and b)“d eterniir% ~&$~$~~y p$ tf7e Ned A.PI IS comparable to the currently Agency accepted firid API. this. ~ re”i 13v;e;-,o~~~~~~ked.~n~.~~i;j;~~tion ” Should. the that that Shduld. be includea in fti&‘ 4a;;;,ra;;~f(& e r&yg&gr - o‘ ;ld ‘C support ,. .-,i -_)2
- #3”

~..

its a.

addition.
“C omparability Protocol Sam$k D&a
~n’ brWlatiOn f

. I II^.,.. ,- ..“I
Re{uirem&ts :.

“T ransfer currently possessions)
company pt.‘ Note:, [ manufactured site;

of the manufacture of an approvebor -licensed Drug Product from the approved US“@ idl6ding P&rfo “l %%‘ % & $11’ 6f. its territories and &&&&e’ manufactuiin’ -side’ & to a n.‘ ‘ * ^_ .,._,_‘,,_ ,‘“( ! $ _;. ,, .,- ,:+,, m~~ufac;;nngsite’ alternate , *. . iCII ( -_ or from a US contract mawwJ~rerf0 a ir . a~ ,-**~‘v site, or vice versa) e, .‘ .“,...&” US .i company n[e, eyarnple sample data’ requ&ments reflect a drug that is _ ,I,>. ::,.a.*:0 ,‘a !.V pro&ct
at more than one product strength.]‘ he T data pickage should include:

“G eneral
l

Information

__ .‘ /

: : ‘ I ?e&rt&

,., ,_,..~

1

.

w and

A copy of the last three FD*‘ Est~~lishm,,-in,e,on’^, , ii rhey exi& z .:; ; ~ the firm s ’ res’ o&e*s b to-&hi &%&vatlons for fli’ $rti~osed e newmanufacturingsite ., and& fhe fi;~‘ & i& s’ c o m @ iance~ &d de&Gment L&ficatio~ ...1>1-1.‘ 1,-,.;;;-y:*;,. th’ ”p rdposed ,,,, letters ”(if e , site has nevera manner j‘ns-petted,cc?mpliesa certifi&fi&~ appii~~~~:~~~~~‘~~~i~~ibnS);. * regi&&d bee;;’ thXthe i sate is’ iid‘ operated in th,at withiajl bet;een $6 -.~ijo;-&
the . .

~

A comparison for the
in&&&g

;“d
manufacturing

the cu;re;&

__,

, app;;;;d~;; steps; e

li’ ensed ;

site

facilities,
components,

systems, labeling, and drug-product the: a.

e quipment’ ‘ , w padkaging handling
,

pro&&

formulations, m contain&/closure & and labeling systems, rati m a t&-i$, ’ intermediate, and warehou&ig; aniriprocesscontrols, including 4: _. _.__I^ .

Incoming components, testing and examination) specifications that comply

containers a:nd closures inspection (sampling, plansa,l “c ~~~~I’ sii’i~~enis~~~~~.~~~~~ sci@ntifical!y at--$ i establiShed’ ii;it‘ h e thatsoundl ot ,‘

shipment representative” san-ip~les are taken and,appropri&ely in’ pected, s ,b. In-process etich-b&h, b afch.r$.%entative ~,> ^ .~ .*,.~..~--~,~~~.;“-.% i x i ,II, plans ‘ inspection and i.jL.,, . +,,., _,, I ,,~;~ established scikriti~ica’lj;~$%id l speclflcatlons that comply with $1 C%M*P requirements and ensurethat $$dfi ,represetita‘ iv$ t samples are taken. ./__,*.. I_ j . and*,* appropriately b .i,~ify.” inspected adversely the-^I* end ofaK5ch;ty”o f~tiei@ at“. t 6?~&% &..odess Z%ble hateriil, factor 1,._.&. 1~~“.. ~~~~~~Ti;~~~‘ a’ 3t’ whose var.,,‘ ~i
C.

and the drug Drug-prbdu~t scientifical!y and er$&

product, and b atch’ re~resentative ‘ :

inspectio~.,~plans

.‘ n‘ ad

e s~~l;i’shed. ‘ i

souiid specifications that ?omply’iith t that~ “‘b %$ repr&eritative” <ampIes ., ,: - ~93
, ^. ,_ _, :. ,

aI”1 ~~~~P”i e~-li’remen~s i are taken and appropriately . .. ,.,.,“,-“~ ,,7,* ,I
r _; , _ _I “..

.

_ _,

ii _,

,:-

.,” , ,,

’ ,(”

9 “* “- /-a

.,

:x

_~.

:.

. ..inspected for each vari&le property.,“, _ . .that -;t.w :.I.../e&‘ y -*-,I the USPagainst their _ ~_ is add”; ‘ wa-flb. _,~^ rd b established specifi%tioniz%ti6llas against the appropriate batch statistical quality control acceptance quality lim its set in compliance with 21 C’ FR S m icrobiology, ana sterility assurance&stems used in the the that the ‘ pr6ducts as appropriate, their meet app,icaljle proposed n dards . facilityI*/.,. _to~ ~~~~~~~~~~~~~~~~~~~~~~i.ncludi~g, d itig sta’ ,,~,> of *clea” ensure ”a,,/, lim its on total bislbad, fre’ dom e fr&ti obiedtionab,~~organisms,‘ nd~~steriIity. a is ’

211/165(d). 0 v * . The cleaning;

l

A copy of the test dn,d exami.natidh m &o& ‘ i$iud&$$& b&a that kstablish the methods used’ are valid and‘ s statement that at a m inimum, each verified as suitable~or.ue’ nder u condit~~:nsbf.actuai “. .^.,il,‘ l,~,._ I. , &,.l~ihriing’ nd use affl?e’ @ ) ~ ..1, ,.. _ ,_/ end of each @sage:

l

l

A copy of the justifidati&s @ % $ i ~c&~~ta~l~~~ the v$lid8yy6f’ll a i‘&omi@, ifiprocess, and drug product acceptance plans, incl@iiigth6 i;alidity of each of the firm s ’ test- .%a “e j;ar;ri:inafi;& spec’fic,atibns‘ i . ‘ .-* <‘I ‘ _.\ _.~,. .,,jI. _.-_,._.., “> _‘“d ,” .I ii* L_ , ,. ,. *-/,~, /.,I.:,, Commercial stability study &mmitmentt to put the first th ree commercial batches fq- each product strength in a sta bi I ity test program utilizing the approved marketed p&d&t stabitiiy protocol;.
b ,. __ ,,. i I ,,- _p,

,,

l

=A . v

statement Propdied

of’ he t

expirafion

date proposed

for the proposed-site /
USA.” ,- ( ,, _ “.. “,/, ,)

.*
drY&nufactured by XXX:&>;, ” >

.,) --;,. ,.,(
%Z&-, ZIP Code, _

drug. _._,-

l

City, State,’ ZIP Code,‘;[@ i

revision -:,, ;‘:1;1’the 3‘ ” labeling’ocorrectlyreflect“M anufacturedforXXX, of ::. x t t I,

,i

.,

I

_..

“S pecific
0 0 Blank

Information
master batch records

. .

for each proposed s’1) _ ,* -, ,_of drug product.; t reti~h “. ,,,,. >,,~1,. ,: for each batch, produded in sup&wt of the’ change and all Executed batch’ ecords r . .._. supporting I&&, @&dj, inv&igatiohs at-id ofher.~o~ir.~en~~~ltioi;an-~incorning ,. I ^ .. and in-process data appertaining thereto. [At a t%inim,um, three (pilot)bat&recor& ;’ “’ .” ’ for 3 62 d h product strength;.] .:.,+ , _ _Certificates of Analysisfor each lot of finished

0

comparability thereto.
*

protocol

ai$al]

l”> ~:,:;“% .>lr.~.,,“b , ~, ,~ ; .. h. ‘ of the suppp$ng re&%& -)
%-ee

drug’

prG>uct

p?Ga

u&&d’

ih

.&pbort

& t‘ he

&%i b’ -& a <.’ I

appet%aining

: I ‘

Stability data, records, and supporting information bracketing approach can be utilized for the stability s&&es. strength, one (1) batch of edch intermediate of the highest product streng& should.~,~,-~~t~~~d,~~~~d

~fo~,.~~~.fi~~~~,dosage form:. [a A (pilot) batches of the lowest product

product

strength,

.,,

placed” fin is hed packaged solids: l‘oh$$%im studies under the r@&r’ of”t he’ labeled +tQrage conditions or 3O”c /t;ip ~ti and $F$term a$;.e!Frrated stud@ at 4O”C /95 s RH or, if the drug‘ roduct p is u’ ~$~l~ & .z~f,,E$ ~3~,~~~~~~~~‘ ~-~~~~~‘ ~~~~s~ed ~ . packaged liquids:.‘dng:term-.~tudles “j b _ ,__z ,.;,“l .*~“. -~~,“.the l&ser’ f~ .+..~~“, ~~,~~~~~~2;,*.~;‘‘.~,~ storage l o /. i”l ~ -“ ‘ ..<.~.. under ~~iir,~;~~~~i:r~rr~r~~~~, the labeledx”‘-i” isa~ , ((I ~,~-conditidns or 25 “~ /9~~l?Hand short-term accelerated....>/,l , .studies . I~.=,~*\I1 at 4OW30 % >_ .4 ( j( .* \, ,/,U,?_ = ..“- .A-\.“.j i \i / _,.._S’_,,-l-,l . ^ 6, .,/ .I( 1 ._ ,,^ 9‘ 4

and&-e? &‘ aG~l~&“& ?~~f6~ G

(pilot)batches

data

&

pilot

for the batches

drug

$rodGkt

froxn

pro&&d

, I .,_ ” , , . 4 _,,. _” -. .,‘): ” ^ the current approved facility and the iar& d& frdm “, a”, ,(^j.“il<,. /,..I .^ ,,1,_ ,,._~ L .”, ,**..4:*.\_” _ at the pr,oposed new rnan+&~i$“* ’ ‘ l‘”- *~‘~~b~” y

t‘he _. ,‘

After making some changes, this reviewer agreeswith ttie comni&titers’ + _,.f>,‘ (._ j l,*..ll,ll _< general exampie &out but%tih’?hat s n‘ %$ md’e i‘tifij?matlon r should’ e b submitted before a~ Agency. revi~~~;‘~‘ o~‘~“~ ~~~‘ s~e~s”~ ~~e’ , i ~ scientific soundness of the t-qethods, data, resl;‘ts; l atid .ce;ti~ica~idnsl’anh t5) determine wheth”e r qr not the process&d product-“, &.~~~,L~ ,_..., A,*s .__, 3,‘ ic,.n,. , representative ..~ data .*I, ,be>/l ,^Ii from the new drug product i‘s cbtipdrat!% & “f he ‘ processand productrepresentative the Agk‘idiiii.d datar from the th;f*fKis.reviewerap‘roved~oi’ ~lcknse~.d~u’ currently p ~ dv%rlq’ g product. Shoulcl ~ a;i;informatibn that should addition. Having “A ttachment remarks.
“M ore specific ” .Df.& Guidince comments

be

includkd

i‘ti fh& exzimple,’

th.ci % &%$ ‘

& %~ld ‘

stipcoit

its

addressed the examples provided by the comment&s 2,” this reviewer will now address the commenters “_ . .-, _,,
are in .foi jndusfrjl+“n the attachment.

in their’ other

Controls

lnformatior?y)
Comment


Recommendation

” (See A$~achme&“ P c __. “; “. ,; n/lanufactur,ng, the FDA ;c.~mpar~~~iit~~~~~~~~~~~~~~~~em,s~r~,f?IA’ 6mments~onj i: :&b&j.“: I li :,“ I .:’,. , 1 \andJ ’ _ _... _‘ .> ._ _; .‘ l.. . :

for Revision

Please clarify how comparability for changes affecting multiple change to a container/closure filed via a bundled submission

protocols can be’pplied a regulatory fife‘, %I& as a s system. Can the change be route?

For all of the reasons stated in the general comments, , _ .“A p” thisr,.Fil, ,,b:_L. .,s+x%X~~%.*I., ot _-. general, eviewer in Hs& doesn,‘ z? .k* agree with %uyd!lng unless the ctiang%.are for a single drug product except 6dr The &se of multiple strengths of the satie drii’ ~Eiict”d osige g

This

reviewer

agrees

with

this

change.

Clarify footnote 5 to indicate how the reduced category is ensured and how the agreementbetween agency and the applicant is reached.

reporting the

additional protocol

information to snpport (see 1V.D for a potential

changes made exception).”

under

the When using a Comparability Protocol, the applicant benefits by

“F urthermore, because a detailed plan will be submitted in the comparability protocdl, FDA has the opportunity to provide input earlier in the

Changes)”

since it is applicable

to this guidance.

This reviewer agrees that BACPAC should be referencedthinhing as pri,or theguidance that Gas h s at t‘itie .~tE.$,gGii‘;gbEgt’6 FDA’ d .y,i best
Add a bullet for BAC-PAC

i

.,,, *;,a

*i.

a*,^~

i

Section IfI &Line # III. A. Line 152

Comments

regarding

text
,,“.,

Clarification is needed in this sentence i’ determination f category for filing will be ider&ied~ ” Comparability Protocols will~be most useful if FDA declares filing category for each proposed’ change covered.

of the

Change

from:

With a comparability protocol, the FDA can determine if specified cha nge can be reported in a category lo-w&‘h%‘ i a category for the same change, were the khkge t”o ” 1 implemented without an approved comparability protocol Change to:

While this reviewer agrees with the first sentence of the comment&s recommended change in the text, this reviewer does oat agree with yet another of the commenters’ attempt to enlarge the guidance beyond’ts i proposed bounds as embodied in the setitendk they attempt tb add. Based on the preceding, this reviewer would recommend the commenters’ proposed change be revised to: and data submitted by the “U sing the information will be able to determine if manufacturer, Fetl the Agency proposed ,c hanges submitted t the M in a Comparability Protocol will reduce the reporting+ and/or review requirements &F vis-&vis the k changes submitted -via an Agency-acceptable

Using the information submitted by the manufacturer, FD will be able to determine i‘f -&’ change ’ subnutted under z approved Comparability Protocbl’ *%~ll ” rkd&e‘ ?I ‘ reporting/review requirements for the change submittc without an approved comparability protocol. A&o, &&I multiple changes are in&d&l, the agency will be a‘le-1 b provide information on each bf the Bpecik changes.

The Agency’ s responsibility should be to judge the comparability protocol (CP) & a tih& and’o t base their decision on that whole. “’ If, in the‘ gency’ A s review,‘ ? particular change identiiied as b&t-@ problema& that is information should be included’n i the Agency’ s initial assessmG-II c6m’;iunication. i However, to preclude non-productive “n it picking” and minimize the’ burden bn the reviewers, tee Agency shduld & spec’fically i address each and every change in their assessment responses. It is and should be thesporisor’ s responsibility to assess the probable regulatory impact for each bf the changes in 6‘” CP that they choose to

III. A.
Lines I.56 154-

Change

from: The current example is confusing. i;o CBE to an AR would normally reduction. Going from be considered a P A S to CBE30 a three-category

T ypically, ‘ categories designated for reporting changes undo m approved comparability protocol are one category lows than normally would be the case (e.g., frotn,PASto CBE-3( CBE, or AR).” Change to:

T ypically, ‘ categories designate2 forreportingor-reio&ng chan& &d an approved comparability protocol are one category low than normaliv would be th&& ie.6:. fk% P A S to CBE- 3

This reviewer agrees with the commenters’ revision of the text. It does clear up the confusion that the Draft text has apparently engendered.

In some category

cases, a reduction of more than may be possible (e.g., PAS to AR).

one

reporting

This

reviewer

supports

the

commenters’

In

general,

this

reviewer

is

opposed

to

“G eneral Comments.” In cases where a single change not only affects multiple products but also the existing information and data clearly indicate that the
General Concept for the Section

o the

submitted

changes

would

cause

for

a

“,,..

*

“-

,I

i

8 ”

,

/

:

..&L.,

*:u

_,_,.

a*

L

___~X.

,>ax”>,.““-

‘,d

.”

i. \”

,“(

Sectibh &Line III. Lines
164

“ilI # 163

Comment
Current: discrete Proposed:

Recommendation
we recommend

for ReGsipn ~” ,,,.; I-)kI -. ., i‘
that each change be Wording multiple specific broadly

Comments

regarding

text

“H owever, and specific”.

should product

be broadened changes (e.g.,

to allow new bottle

technology-specific for several products)

The use of the Comparability Protocol for tec$nologY changes (e.g., change in filtration process) which applies to multiple products is also appropriate.

The need for each change specific is obvious. A proposed change should limit from n‘ot ri7cir~ t~ari

to be discrete not change 4‘.b”~ ~~fiidf

and a pH mdie

This reviewer cannot agree with the changes that the commenters are proposing because, regardless of the number of changes, each change “‘t ie &Crete ant as the draft te’t states, x should,
specific. ”

than 3.5 to 4.5.’ -a limit‘houidbe s a‘iscrete d number. Similarly, one should not propose changing process that states ra&.j 2oO.C <f”f-r;;i’fi-j~~u~ ‘ ~

a

acetic acid’ to one that says a‘dd 260 L 0f.a suitable 1 N acid solution’ L a c‘hange &%id be specific. to “t echnology specific changes,” let US With respect consider the two examples, the one in the commenter’ s I‘.. Recommendation . . . . “c o~ir& ‘ and the other in th’ii e I‘... regarding text” column. Obviously, changing a filtration process to a new one that improves __.,the L I‘“q uality” of the ”-: .. ,. filtrate containing the actrve tn Process. “A ” could adversely imij.$t. tf.ii; ?~q~~i~f~;?~j’ f‘he _” ,.,..exII filter cake containing the active i’ Process n “E j” The second example, “n ew bottle for several oral solids, ” is more of an item chan~e~than~ a technology change. Similar caveats applyc in “. that ,I-**.- protectice ,i .w.-l,n the ?ffect of the new bottle may not be the same for all of the different “o ral solids”t o ‘ W%$“$ is
Liz---

In addition, the commenters’ remarks are not even self-consistent. The first example (“P roposed:“) speaks tc technology specific changes applied to multiple while the second’“n ~~~bottle”) ( speaks to products multiple related changes in a comparability protocol. Changing the example fMiation process to a different filtration process might affect different processes differently and, for that reason, should not be proposed in a blanket protocol, as the commenters would suggest. Further, the commenters’ example did not even suggest that such be limited to cases where the proposed fjltration process change is known to improvethe quality of the desired fraction [filtrate or filter cake). * Moreover, though current technology exists fo ?7ake plastic bottles impervious to the diffusion oi deleterious gases (such as water vapor, oxygen, carbon monoxide and dioxide, and nitrous and nitric oxides) and /igtit,feG fi?^k seer% wiWing ti adopt such bdttl+ b&k& df th&‘i’&ts.’ r The industry seems to-prefer instead to use 3verwraps”“a nd adsortients”. to “c ontroi” or m itigate” ‘ the problems. I ,- ,. ,, ,. _‘ - ., I ,.,.,.,._ / I
it %en if the downstream purification process is extensive, bould be possible to handle such achange m ad&a ‘ comparability rrotocol

Lines
126

224

-

A change ‘ from plant. Animal. Or multicellular nacroscopic fungi) sotirce material to‘different 8 different plant species, different tissue and/or Jant to animal)” Change the bullet to include bolded text:

(e.g., one piant

algae, (e.g., part,

A change from plant, animal, or muhicelhtlar (e.g.,‘lgae, a nacroscopic fungi) source material to a different one (e.g., lifferent plant species, differ& tissue at&or plant part, ,, il / , ~. _^_ ,.. rlant to animal), dependmg on the exit&t of &e

This reviewer again opposes adding :ommenters’ phrase. In the conte$n t h~s:text appears, (which’.Y ..a,;) nodifying clause is ti only superfluous but ntroduces unneeded ambiguity. The”b uflets are “S pecificexamplesof changes that
>e difficultP to j‘&if nclude” - difficult under a comparability protocol

the the also
may can

mrifkation

process.

Therefore,

but not impossible. .th~~ bulief ~~;;s ii”d f.~~r’ant r t‘h&t the%mmenters ., _._

the

“it are

depends” \
, ,. . _,_‘,, j) ~,a,$ :.) _;* ._i.- .‘ A i’,.le ,,,( 1 ,.,L,~‘ W .j j .,,,,,u*~..:*A*, ,

ambiguity
/

:

L.

Change

the bullet

from: synthesis-derived to naturally sourced

“A change from material and vice Change the bullet

versa”
to include bolded text:

In the context in which this text appears, the modifying clause is not only superfluous but also introduces unneeded ambiguity. The bullets are “S ~ecificexai$es of changes that may
be difficult to justify under a comparability protocol can

purification

process”

bullet does not warrant ity that the commenters

the

“it are

Delete

lines

229

- 231

as currently

stated:

A move to a manufacturing site, facility, or area when a prior approval supplement is recommended because a current‘ood g manufacturing practice (CGMP)“i nspe&n ‘ iS‘ %&ited w (e.g., see examples in guidances listed in 1I.D .) Insert a new paragraph:

“W hen a Manufacturer moves a process to a previously uninspected manufacturing facility, the approval of the Comparability Protocol signifies that the Manufacturer should notify the field when the facility is ready for inspection status. The inspection should be scheduled prior to the submission of the agreed data package to the review division. Upon‘e’eipt rc of the acceptable GMP Us~tus’ from the Field, the 1Manufacturer may implement the change without delay in accordance with the approved Comparability Protocol.”

reporting category without the need for the increased regulatory time constraints for implementation. Dishibution of product would not be allowed prior to-the receipt of the acceptable GMP status. As written, this represents a significant increase in the regulatory burden that is contrary to the spirit of the Prescription

Though commenters phrase the question so elegantly, they attempt to confuse the realities that they pose as an implied “w hy” question. If, as th’y e initialljl state;’ a Comparability Protocol would in this case require a PA”S , then why do they state, in their second.,) remark, “t hesite
change could be reported at the reduced reporting category”

In context, this reviewer again opposes making the commenter’ s suggested‘hanges. c .‘” Moreover, the proposed paragraph speaks of a

when, second

if their statement

initial statement is true, is, at best, illogical.

their

The commenters’ proposed text. ignores the reality that the protocol may be rejected and, in such cases, the existence of a submitted Comparability Protocol is of no significance. Further, the commenters’ , “U pon receipt of the
acceptable change GMP without status, delay Protocol,” the Manufacturer in accordance may implement the with the approved

the obvious answer is that the-Agency sees that such approaches should not be allowed. Moreover, tlie text does allow for the possibility that such a Comparability Protocol may be allowed in some cases (Lines 217 and 218,
“S pecific under examples a comparability of changes protocol that tiay be difficult ” to justify can include.

misi’entifies d the standard required of the facility as “a cceptable GMP status” when the FDC Act and the CGMP regulations require the site to be found to be”fully CGM’ P compliant” before any product may be even offered for sale.
Comparability

text

In the context should be

in which this text appears, the kept as it is and the proposed

changes

are

both

100