;/ (. “_





hidance .ine #

“_~” _“I,

,,* ,... _

. u,.. _ x ..< w I .” ,A i ,. ;,



Documentati& is 4 P~~,ii$i%tiki itkm”Kot a filing ke~tii%i%nt: i’ ’

Remove “docutient+~” fr;m “Des&p%& .,$ “h-P,-,- Iii ,... documentation, and results”. ^.__:;

This reviewer change.

is opposed

to this

First, nowhere in the C(;MP regulations or th,e*FDC Act does this reviewer find, +ayy prohibition for the Agency’ s request for an” applicant to provide the requested documentation ,_in support of an application x II- .,.I and require it to be only reviewable as p&-t of an onsite inspection. (See alSo, review in f?pw “TQ-q$“) Second, guidance is guidance - @ requirement. Third, the docume+tion. .requests are justified because they provide the supportirig evidence (proof) that the. applicant’ s asse,rtions at-?, valid and/or CGMP . ,x, I I;, ,, compliant. For all three rea+ons, this proposed change to the draft guidance is J@ Szund~.and I should not be made. .I 6.e I _I I ./ .” ,_ ._..
Full or keduced testing by the applicant is a GI@ ~~~~;‘ X?@%%i~I; %X’ issue.


Delete “and &-e,spplicant *irki;nds to jjeiform full testing on each batch received,“.

This change should &

be made.

Contrary to the comm.en+y’ j remarks, s6 all FDA x. “L;. with ensuring that all personnel are charged ‘: -’ manufacturing practices and drug products comply with CGMP. 3I‘ ~j-~il~~-~ cis ;a‘ ‘ . y@jfiatioti ~ issue_ becauSe , the reviewer is required to ascertain CGMP 3, ,I‘ _ .&, adherence _,,. .__, prior to recommending approval. Moreover, the phrase is a critical conditional-..*_* limit (. ( _II on when the applicant may simply list the compendia1 monograph without explanation. For the preceding reasons this comment should be rejected. (See a@, revieti in Row “956.“)


Rep&e “with no additional te$$” kith “arid no additional testing is needed to ensure the suitability of the excipient in the product”.

Additional testing is- done’ fi-oti tik+ztG%ie,. I.,.. -.-” a %-ir$j%f fok /~“.*_,.j.. reasons. , This section should fo,cFs”,on attributes j ,,,.,‘ the\“.,\‘ ex. <,,..A of *i”l excipient that ensure product quality.

While the commer$er’ s first statement4hz.is true, it is a Not only does this reviewer .oppose . x -_ ,-:” II (_j_;_. “sound bite” that, has nott$ng to do with the cont&X this change hk is also don&#-@ The second .ser$ence is, at best, a red herring. because the commenters have distorted the pro.~~~~~“i;~~~~~~~~~~~ Factually, the text states. (emphasis added), it from its context. “Compendia1-Non-no,vel Excipients: 26 When a cqpendial excipient
is tested according to the monograph standard with no~a$-l$io,nal testing and the applicant intends to p&form full testing on each batch received, the ekipient (e.g., -Sodium Chloride, USP) can be listed undeii P.4 with no~detaj!gd informationr~#IL _,I.. x .~d‘ .I provided in P.4. I through P.4.4.

All that ihe preceding does is address the. conditions.^ _ ,I_ ,* under which it is Bp’ propriate to list under P.4, the excipient without providing detailed in@r.m+n, $@?r P.4.1 through P.4.4.





Guidance Line #
986-987 &989-990


. .._+/<




While this may be useful for the FDA, ‘ is ‘ it inconsistent with the organization of the CTD guideline and granularity document. If FDA disagrees with the’ organitiiioh‘ of CTD it shduld work thrqugh ICH.

Delete “%GP.4.‘ to’ 1 P.4.4 fpr esch individual II y”l-Ic”eI _“,~*-* excipient should be grouped together in the application.”

In this instance, the reviewer is of two minds. On one hand, this reviewer sees the utility of a common format. On the other hand, this reviewer recognizes that the Agency isr& legally bound by the guidance published by ICH. On balance, this reviewer will leave it up to the Agency to decide which is better.
991 Delete the &oinm&t “Additibnal CMC . ..“, *_,, ‘ II,l”x,, information can be warranted...” or provide an explanation of the type of details that can be warranted.

While the commenter’ s .,first statement is true, it ignores the reality that the gu”idanc”e” i8~~~~~“ijL‘ ‘ i~~ ICI-I is, just that, guidance does not legally bind the FDA. However, this reviewer was unaware _I that ,“ .‘ .‘ “, . ..) these ‘“; commente~rs .Ihave i standing to suggest the FDA s , .,,. _.., with course of actionvis-_,...- i vis ‘ ,-,_*., L(( ^ili%,F ,_ ^. 1 j . its “. interactions ai: -i’ ,~xri^i”(“ l”r”~lii~~,“,~.~ ‘ that international agencies - this reviewer thought such fal’ ‘ l within- the province of the Unifed @q&y Congress. If this reviewer isincorrect, hopefully, the commenters will provide the statutory language that binds the Agency to follow ICH guidances even when they conflict with US statutes or regulations. , ,>..> ,_ /,

Would that the commenters were equally concerned about accuracy. The unmangled text (Lines 99Q :, 991) states:
“Furthermore, depending on the circumstances, additional information for the excipient can be warranted.” CMC

The reviewer objects to this comment, as it decontextua.lizes and misquotes the text but would welcome the Agency providing added text to assist the applicant in understanding what is required.


removing this text. Since the Agency’ s observation is a valid one, hopefully, the Agency will ~honor this commenter’ s request and provide more detail here.

because the comment,..” ends , ~,,.,_ with ,. ‘ .“. +. the commenters are -. a,,)/. /j_ .j ,. recommending *.., ,.*a” the rest of ,the following text associated with

.:‘ :


_,*‘ .\



‘ (



.,.‘ ,


’ ‘, f ._s_ ,il:s._. < i-l, ,,A/ ~“:i”‘xl 7s. -‘,*,.“-“;i,*: i<<:r. -*,.*‘a t.“,

Delete *is paragi-aph.

This reviewer -knows ~that, th.is oaragraph should be retained an-d the Agency’ s request is rational and measured. The text for lines 10’ 1.-. 1030 22 .,_.,~.,I ._,_ .% should remain:
“In additiop to.listing all the tests for ‘ an Fxcipient, the specificatbn .,$OLIIC! ,i&@fy the ,dpg product the tests that manufacturer will rout+ely perform and the test results that ,wi!l keaccepted from the excipient manufacturer’ s cert&3te ,,of analysis (COA).27 At a IO24 minimum, the drug product manufactnrer must, perform an appropriate identification test (2 I CFR 2 I I .84(d){ I)). However, when there are specific safety concerns relating to an excipient, testing in addition to an identity test would be warranted, For tl,sv.-“m ,. l‘ example, diethylene glycol contamination of polyqls such as glycerin and propylene glycol has and ‘ the caused numerous fatalit& .”.w,_ (WI specification should ~,include &stir@ for .Ia--xL.I.xi,“. I potential impurities and contaminants .;for each batch received by the drug product manufacturer.

1, Full’ test&i xxii.& be done by either the manufa&$r’ of $I?” &ipiehi: zw the applicant. However, the issue of the applicant doing full testing x- reduced testing is a G M P issue and shouldn’ be specified in the t application. 2. If FDA wants to. make a policy statement of specifications and testing for polyols, it should do that independently of the drug product guideline. Re: Comment?er’ s”1,~~!,‘ 1..

The FDA does not reauire‘ the manufacturer’ . ._/ an of ” excipient, especially foreign manufacturers, to perform full USP-~NF testing on excipients nor does it routinely inspect such; and the USP, in its General -l$otic,es, does not require the manufacturer of_ any component to do any, much less all, of the compendia1 tests for batch release. the Thus, there is no assuran~ce that the manufacturer-;“nj;of excipient does ‘ full cpmpenai;l’ *- res+c b;‘ compendia1 testing on each batch of *each excjpient that said excipient manufacturer sellsL I ,,n_ ). Unless the applicant commit,s tgandspells out what exactly what tests wil.1. be done, on .“~ ._,-.,..*a each shipment of l.< ._ each lot and by whom, there is: No assurance that the requisite testing will a) be done and, more important, No assurance th@ the application provides W assurance &I$, th_e. sponsor’ s ,sampling and testing plans are CGMP @npliance. Again, the commenters ignore the FDC Act that requires CGMP compliance of all drugs (substances .,.,~.r and products) and compels the FDA tq>ensure that all . ” -: r drugs, and the process and, controjs appertarnlng thereto, are CGMP-compliant. The Agency should include requests for whatever information it must have to .‘ ensure that a proposed ,*^__.II “_,, drug product and its processes and ~$r$?$.zk~(=“GMP compliant - it is not limited by law to only obtaining this information, as the commenter’ s remark indicates, r.,l .-, _.‘ , by inspecting the appropriate premises Re: Comment,er% f‘ 2.7’ I. *, ,. .^, ,,_ Contrary to what the commenters ._ xI. ...//_. ttie text’ state;” on .... i polyols is ONLY offered in,. support of the “Agency’ s request for an in the e)c,ample the each lot ~ii’ additional test,.on ‘ ~~~~ee’ where there is 4s:*~.“‘:‘” a “concern” The FDC Act compels the Agency to demand that drugsafety issues, including those associated with any excipient, must be’ properly’ addressed in the -drug manufacturing process and the drug product. Since the existing CGMP incoming controls are crucial to assuring component safety, the Agency’ text s
,, : .’ ., *,

. .







&id&e Line #


_J .

.-, ., . ~

:. “,,

.:.:. S”, _l^j.,_;y_











, 1.

,,, I ; _.., _., x . . II.

, . x.




Delete the statement “-or @ ~rk>,&$W46i~l~be 1 the standard is the moco&aph st‘ [f atidard, then the iskue.of accepting 1 results from the supplier is a GMP issue. ’ accepted from the excipient manufacturer’ s COA”.

This reviewer disagrees.

1030” 1089-1094 Delete this paragraph.

See the reVi(?yS ~I’.&VII 1956,” “982-983” J and “1022on the previous pages as well as those that address the I.GM,P” issue in prior comments.
Comparison df COAs frdm t,he manufacturer +nd ,$z applicant is a’ GMP issue. Requiring such a comparison in an application is an unjustified new regulatory requirement. Such data/inform&on can be provided upon request during a GMP audit. ‘ should be sufficient tq provide a It’ representative COA from the drug product manufacturer which reflects data used for the purpose of establishing specification compliance.

This reviewer knows that paragraph should be retained is:

this as it

“A certificate of analysis (COA) from the manufacturer and the test rqlts~ for- the same batch from the drug product manufacturer should be provided for the components described i,n q.4. .The information should be for t,he materials “.Xl,tl.-.. -.. . \. “- usid to produce the batch described in the executed production record. (R. I .P). Test results should be expressed numerically or qualitatively (e.g., clear, c$l~~l~s io$ion), as appropriate. Use of terms +icti ’ij conforms or meets speciibtion is discouraged.”

Contrary to what the commen@s * ,say, no comparison is requested; all that is requested is a copy of the certificate of analysis (COA) from the manufacturer
and the test results for .the same, batch ,,from _,* “j ,“~ / j” the drug product -. manufacturer . . . for the components described in P.4” for those “materials used to produce the batch described in the executed production record (R. I .P).“- copies of information - NOT

comparisons. If, as the commenters state, these &e ‘ GMP -issues, then by law, they are CGMP issues and the Agency’ s lawful requests should not only be honored but also supported. (See also the revie\n;s .iQ ..@p,y,,:Y022~1@’ on a previous ‘ pag&%& well as those”.tl-it @i&-e& @& “is GMP” issue in prior reviewer remarks.)
While these terns are c&&@dy used in som~%r&i$ they may not be familiar to all applicants. The addition of detinitizns defined either here or in the glossary would hklp in these cases.





&&‘ +$;;”


“sunset provisions” should be more clearly

This reviewer agrees and suggests that the “Glossary” option should be used.
1153-115s Reword to Say “if a test that is ustially performed on the finished product, are instead performed in-process, the in-process results should be provided in the batch analysis, e.g. assay on a core tablet in lieu of assay on the finish&l coated tablet. Clarity I, .II ” ,,

First, in context, tly tqt


This reviewer disagrees with the proposed rewording of text that All that is requested is for the, applicant to identify the reviewer is ., clear *,. ,.-axAe ,e_- dn A~the ,~,~““those tests that can be performed in-process. grounds of “Clarity,” especially Second, in context, the proposed text would state: when the c,ommentet$,. proposal “The specification sheet shoouldalso identify: CLEARLY niakes the texts. !~SS l if a test that is usually performed on the finished product, 21bs: instead clear.

“The specification sheet should aI@ identify: l tests that can be performed in-process in lieu of testing the finished product (the results of ‘ scich tests- performed in-process should be includ$Xthe batch analysis i;?pbir (e.g., certificate of analysis))”

performed in-process, the in-process results should..be provided in the batch analysis, e.g. &say on a core tablet in lieu of assay on the finished coated table”


the commenters:


is, at best, less





hidance ,ine #
156 S e n e r a l deskriljtor of analytical @ & e d u r e s . lelete rest of $ e statement starting from “ _q,_*lj,, regulatory which are , . identifying . . . . . . . . c a n b e used,for 9,teSt”?“. _/ *,, / ./ k o m the exainpk in T a b l e 3 ’it a p p e a r s that what 5 expected h e r e is a n n - h o u s e m e t h o d n u m b e r . n e , F ? A alm,ost (but not quite) a p p e a r s to b e king for the in-house specification document. It & u l d b e s ~ f f i ~ W e ~ ~ ~ t o ? v e the specification a n d a g e n e r a l descriptor of the technology applied :.g., Assay, H P L C or Identity, Infrared. A n elec$ronic ~ ‘0s: reference o the specific m e t h o d presentation within the jsubmission could S*, e .^ ,gI l.~.l.“,,l. ,,”_:_,“_ b . / ,, S ,_,. n c l u d e d if nqcessari. It s h o u l d n ’t b e necessary to distinguish b e t w e e n egulatory a n d alternate p r o c e d u r e s in ths ,specification presentation. & i s is d o n e as part of the m e t h o d presentations.

This reviewer objects to this c h a n g e o n the g r o u n d s that a) it d o e s not a d d to the application’s sssurance of covpliance a:nd b) the c o m m e n t e r s ’ rationale. d o e s not support the c h a n g e suggested and, indeed, discusses providing this by electronic refe@ ic& :.jo “m e t h o d presentations” that con&in the requested information,

A s the c o m m e n t e r s ’ [&ip,nale‘_.j;l.r.,I _ the requested states, ..__ _ nformation ,is re@ ily available. T h e request is a g a i n just of a n annotated list - in :his instance for m eI.thods’ (regulatory a n d other) w h e n ,... , _,,,, _^.,. :here a r e multiple m e thods listed fqr a given test. B a s e d o n the preceding, the draft text, s h _ o u l d *emain as it is. , ,
being done S e e cornmerits’ above. “. $ii&. F@ ! & @ r & ? ~ r i l r ”ai :lectronically now, a cross reference to w h e r e the m e & $ a p p e a r s in the In-house,, identifiers-.LI”iiil_- I ,_^ - L L & ‘“S ., for submission c a n b e provided. ._,.L differentiation ^ nethods s h o u l d not.be part of the regulatory commitment.

1174 numbers(e.g., A P # E F G , A P # P Q R , etc). Delete Regulatory a n d alternative m e t h o d

This reviewer, pbjects to this a n d a n y p r o p o s e d c h a n g e where, as is the case here, the rationale is essentially “w e d o n ’t want to” _
1208-1221 Delete. ., .. ,.1 < ,” ”..,. Ir.. <*a

V a n e of the c o r n m e ? ! ? present a n y science-based or regulatory-based ratipnale .,fro,y the?.?, commente!: N h o claim to support “p r o p o s e d revi&% .” ‘$ih “rationale.”
This a m o u n t s to a c o + n @ ~ e ~ t to opkat6 i h a d c ~ r d a n c e viith < G ,@ P . S i n c e o u r operations a r e fully expected to b e G M P ccnnpliant, such a c o m m i t m e n t statement ,shc$d. ,F,ot‘ ,,b-F,,.< _ ‘.~ necessary in a regulatory ..,“*-. submission.

This reviewer,“, o p p o s e s with this deletion, a n d r e c o m m e n & ;the t& should be changed as follows:

) the P Q IT will b e p e r f o r m e d according to the B e c a u s e P Q IT is b e y o n d (in adcfitiofi to) the C G M P protocol a p p r o v e d in the application minimums, a firm wishihi to implement a P Q IT must l failure to m e e t the acceptance.cri[eiia & the m a k e such a cornmitment‘,~r-~the.FDA cannot u s e said .. I*i”.~ .rii~bi.~iib*li.t~iL~~i,~~~~.-~ \a*“? P Q IT will b e h a n d l e d (e.g., investigation, batch P Q IT in determining whether or n @ ,,tq rez,orr!Fepd rejection, decision) in the s a m e m q n n q as,,a application approval. failure of a test included in the d r u g product Moreover, a n y truly C G M P compliant m a n u facturer specification and, after the possible c a u ~ + s should h a v e for the P Q IT failure h a v e b e e n i$e.njifled, wishing to u s e the P Q IT a p p r o a c h appropriate corrective ,acjjqn ,,aa,,^ .*“.j_.. recognized the reality h s beer of this re~i~,~er’s previous initiated a n d the quality control un/i observation a n d w o ~ & I, ,have n o x objection to permits production to resutye, the P Q II committing to d o what they p ~ & % & % ‘?io. will b e p e r f o r m e d o n e a c h subsequent batch A n y firm w h o p r o p o s e s to d o _ anything in a n until ~ ~ w A & w & all ,data ind/cate,Jhat the application a n d w h o will not commit in writing to corrective actions I take? ,&~ye,:,:~tl;;ij identified a n d resolved the”~rpof..c,~use,~~~ m e e ting a n y o n e of the controls they h a v e elected to p r o p o s e should find h a v e their !pplication summat-ily causes of the failure. 0 a n y investigation will assessihe t$ect q n ?!I rejected. batches p r o d u c e d For all of the.. p r e c e d i n g reasons, the u n c h a n g e d b e t w e e n the & t b a t & atested, iith a passing draft text, or better, should b e inc.luded,,Jn ,,the_ final ,+ .a.<,.,*<4_* test result a n d the last bat+ S & 1C -_I.. tested . - & A . ._ ,, . -3. guidance. 0 if the result of the. jnvestigationconfirmsa batch failure or is inconclusive, changes-beina-effected a

.“, _-


‘_ _ L,~/ ,,_” “. /,. . . ,/ ,^

_ ..

I ‘ ._ “_ (‘” .s .,) .~. *a .‘ /

hidance Line #



Teed to avoid the itiplication that every clinical or developmental batch needs to be. reported. All studies and/or batches may not be relevant to Se application, for example explorkory studies on other indications.

Change to read “Batch analysis data should be wovided for all relevant batches-used for.. .“.

rhis reviewer objects to this change and would propose the following as a scientifically sound 3nd appropriate, CAMP-compliant alternative for Line% l@3~,~~‘ ~~!2~:

As an investigator having in-depth experience in investigating production process for tt@ root causes.pf tlie differences between .batcheg~. and “.W ._‘factors that .. the i”~. affect or correlate with drug-product batch ~&&“ %6 ‘ is crucia! t9 ,determining requested information * i j .> ,.~,. .&, “Batch analysis data should be provided for whether or no? a process a,nd the cpntr.oi,s ot? it are a) all batches used ip,.studies I conducted / -e_ / ) “_ . -.++.i: operating in compliance with .CGMP ?~nd-*b) capable of to assess clinical &i~cy and safety, producing batches bf drug .prodtict that are sufficiently tq the point that the data bioavailability, bioequivalence, and primary defined and controlled obtained predict that all of the .unj@ in the batch stability.” would, if tested, pass. In addition, as written, this reviewer’ s change avoids the commenters’ first copcern (“the implication that
every clinical or developmental batch needs to be reported”).

Since the comyentet-s’ second j \. ,,,i,i V.(\ .-. sentence,:g*[d @ I *’ address or provide any support for any other change, this reviewer can properly ignbre it. Further, by making the change in the manner proposed by the reviewer, this reviewer avoids introducing the obvious ambiguity that inserting the word “relevant” would create. Based on the precedi,ng, this reviewer knows that the commenters’ expressed concern has been addressed without introducing the unneeded amdiguity that the commenters’ change would have introduced. The reviewer’ s proposed alternative should be incorporated into the final guidance.

__ _I I ,, . .

,. I ,. “_ . . _ I.




Guidance Line #
1291-2 ’


It should & Ii&& efi&nt for .“. chemical, reVie*wG ‘ ‘as&s -‘ data.” .il the /L ir _.‘is-L-.(!,W ” / lii...+‘55 .%drir*.r / 4, rAeAL x% tabulation than ~4pile of %oi\<. Ha?& both COAs and collated data is 3nnecessax-y and provides no added value tq the,W~insst”gedpurpose of Datch analysis data.

Change to read “The bat& ,ana[y&s tabulatibn should include a desqiption of the batchas.“:

I .This

reviewer opposes the changes proposed by the commenters. I,,. and, I . _~” for the reasons sta@A, thinks that the draft text, “The batch analysis reports (e.g., COAs) and collated batch analysesdata should include .GI ,c@criptibn batches,” should be 3f the incorporated “as is’ it& ,t!~.e f&@ , guidance.

This reviewer disagrees with the com~en~e_r9~b~g& COAs, “tabulation” generalizations co.F$ernipg (collation) of data, and review efficiency. Factually, COAs are J-J& requested per se, they are but o,ne ex?tnple of what can be used,,for the batch analysis reports requested. Second, which is needed .depends upon what the reviewer’ cpncerns,_ are,,”and, s&e the Agency that has s .j.) ,,__ the relevant reyiew experience request is making this request, this reviewer must d,efer to tMbeirjudgm ent of what is needed for the efficient,,\” review *alri,i--ii,* ,_ i <, I.*.*.” ,+ an ,Ih, of application. Third, reviewers &her than “che,vicz$ reviewers” ” do ~ ,. ..,. x, review this i‘ nformatipn. Fourth, the batch analysis reports, when. structured as the Agency requests, do pro\iide significant relevant ^. information b,eyond’ the data.’ ; Finally, the commenters’ last remark is empty rhetoric from a speaker .that is ,o&&<~$ “gbFG$a to providing th6 information requested.
Clarity i ..^)./, .~ ,,I _^/ ” s __.v nj _vr_*ll i 2 ,“,,~,‘ ..”*l*r-i %\ *a . ”

1292 and 1328-1332

Delete the word “tabulated”.

“colla@~~ atx,,replace


This reviewer objects to the proposed change because a) the change is unwarra$t&and* bj f.h& commenters supporting rationale is not valid. (See,also Row “I~$I2”)

First of all, changing one word that has the same denotative meaning and similar Zonnc.$ative maying as another word w,ith.tbat pther y~?rcJ yay’ add clarity. However replacing one word with an~&~.er~.tl$ _ has ‘a *A r,>,b ^ similar butdifferent tiesDing does NC)T add clarity, it changes the meaning. While tabulated information, is a collection arranged in a list or table, collated information is ‘ c$irt’ -1” .’ of d‘ ibn ’ information (data) arranged in a manner ~th,?t..$J!gns the values from sirt$lar-,Q$ @sparate instances of the collection. of the co,mment$s’ lnspite using the terms “..._, ~ interchangeably, they are not the same. Therefore, the ration& propos6d is not supported factually. Moreover, it would seem to this r$vj,eEf?r t&?t$?e commenters use “Clarify” whenever these.cqmm$$ers are at a loss to present any meaningful rationale for






Zdance ine #








F. ,j _A:.,“,


.d ._..


,. ,;; ‘^ .‘ .l~.,“,..*;.l I”_‘ .“I./ ,, +\,_ _‘_ I -,

I lelete the requir&i&t I Leports,

for Bitch Analysis .,

i well designed tabulation of da& sho.$d s&ice.

’ .






This reviewer’ objections are based on;. s ) The rationales previously stated in the reviewer’ s prior remarks (see table .rbtij “i2$8,” z$d. ‘ ~17&Y’ ), and ) The fact that, the cqmmenters do not present a rationale that is supported by as much as a reference to an logical exposition based ore sound scie~F,ce, regulatory requirements, or even on some practical experience by the commenters - ali that is presented is a statement that does!?t eve!! ~in,&.@~,~,,~~,%the commenters would c,o@d,!?r a~we&@signed “tabulation ofthe data” that, in the commenters’ view, “should suffice.”
Not all of &e listed s&rkeS”bf impurities ark relevant in all cakes. In general it serves little purpose to discuss well lmown excipient degradation products for a solid oral dosage form. Notification, tha$ the applicant should consider other sources of impurities in specific instances should be sufficient.

1343-l 346

Revise to say “Potential drug-product 1 hese Iimpurities should be listed. ,J’ .. _) .. sbc&d Iinclude degradation products of the a&i% ingredient, and residual solve&s. For some 1 combinations .of drug, dosage form, and route of administration, enantiomeric impurities, excipient degradants, and/or leachables frsm the container closure system may also need to be considered.






the commenters,

“Not all of the listed sources of impurities are relevant in all cases.”

Thus, this reviewer was perplexed to see that the commenters ,proposed to change the word “expected” For the reasons _ stated, this to “potential” even if the scope of the request were reviewer opposes the cqmmenters’ restricted to the drug product. proposed changes and thinks that The commenters’ second remark is a generalization the draft ia!guage should be that adds little tq support the change proposed. incorporated “as W into the final In the third Statement, the com.me@e,rg’ [emark . CMC guidance as: seems to go against the industry’ s posItIon that “All expected drug product impurities (e.g., applications be tie&d ur$‘ fort?$ bectiuse ?t suggests degradation product; of’ ~‘ 1 “a&$$ ti% that each reviewer or review tear? should , decide .i _ -,., ” __~,.“^./ the ,* ingredient, residual solvents, enahtiomeric scope - an approach certain to lead to ,va.riab!e ,I.J@s impurities, excipient degradants, leachables of concern. from the container CI~SLII~system) should Moreover, the proposed changes would also, ii be listed in this section of the application adopted, lead to ambiguity and variable review whether or not the /mpurities are iqcluc@ outcomes for, in the case qf A,@Q&, submissions for in the drug product specification.” the same drug products submitted in different years. The Agency’ request seems -much _moye !ij@ ly to s result in improving applid%oti utiifc?E!ty, application review uniformity, and faci!itated application review than the commenters’ alter?ativgs. ,
Delete “drug s&stanCe @oEe$S’ itil%%i%:: .“. This sectick should focus oil imF;urities ‘ iX;li;& Wthe drug pioduct. Since any drug substance process impurities probably also be present in the drug product, a cross reference to drug substance impurity information should SUE@. .lt shquldT’ be“__ ,... .“, $ necessary to discuss it ,* 6.


This reviewer disagrees and thin.ks that the current language (that only requires listing them) should be retained or, failing that, c’ ross. ![gfing their referenced to PROVIDED that lisiing is in the CMC ._. _ ” of,, a,n-_a,. ,“.k, ,_. .~,_‘ section ,,_., application. ..“.

again as part of the drug prodi&ikipuiG~distiussion. ., / ,., ,


This reviewer finds the commenters’ (.“l., remarks >. -_^“lr. ““,” / ,,,._ _“A -d/ /_< unconvincing and/or distortive (e.g., turning a request for a list into one,f.Qr 3 discyssion). 2 <.,, 4, ~-_.ll~,lll.-. i;d&~ a, +,i.L_,. .;, >i. <.,A ,I2, >a _..<’ i .,,._ J. I_ _,_ .a. a ,,.20; .



. ” .,


,,a’ L.

3 _L .~ ,._....“.‘

hidance Line #


For those situations where there,are (for example) in excess of twenty potential impurities in a drug substance, this could prove really aurdensome and result in~an.e.ntire volume just for impurity structural elucidation. : The companies ‘ should. be left to, dete”rmine> the best approach to providing what is most pertinent and meaningful for the submission.

Regarding identification of impurities, the include should information provided structural fo,r-mula, empirical formula, molecular weight if not provided in S. 3.2. Providing the structural elucidation for ,a11 potential impurities and degradants should not be necessary.

This reviewer disagrees with thee commenters’ position and thinks, that the draft text shouldI_ ll;l_;,.l _( I. be kept as it is.

Since the draft text only requests information on impurities (those expected in the expected components) and, after manufacturing, in the drug product -nA ‘ potential ones, this reviewer thinks all that the number in most cases will 1 _. lessa, than“” half ,._ be j . b..l, * ,I_, of _ what the commenters suggest. Moreover, the manufacturer, by using purer components when such are availabje, can minimize that number in most cases to only a few such.
This is a good approach and should stay in the Guidance.. It would be helpful if the Agency can further define expectations related to this protocol.


Sunset test clarification.





This reviewer concurs.
1480 Interim acceptance criteria - provide further clarification. This is a good approach &d should stay’ in^the guidance. It would be helpful if the Agency can further define expect&&s with respect to interim specifications, i.-e’ what type-of submission would be required ., Also, are these interim specifications to finalize the specifications. applicable to applicable to in-process testing as well? _I __.., This assumes that freestanding stability studies reports are X%ttdn.’ The guidance should also describe the information needed in the application, and allow Flexibility in the format.

This reviewer concurs.
1570-1571 Delete “Stability study reports should also be included.”

For the reasons stated, this reviewer thinks that the draft,.text should be retained.

While the commenters are free to infer that-the draft language presupposes “freestanding stability study reports,” the text does not make that request therefore the first statemenG not factual. The second stat.ement seems to be, at best, misplaced.
This material applies to formal, supporting,- and stress kidies be better as a separate section, and would


Move the section on analytical procedures after the section on stress studies-( 1622).

This reviewer concurs.













Guidance Line #

(4‘. -_

“.s .I

.“” .,.,.‘.


c “~,~..l.,-*,_~“,


Delete: e.g. “k ight

Revis ion

Determination of weight loss change W ith a calibrated balance is a standard labo<atory procedure and should not require presentation of the procedure and validation dsta.


For the reasons ,stated, this reviewer does not agree with s imply omitting the example. this reviewer would However, suggest that the Agency could choose a different test‘ as _Is,u.l 5 .,b its example.

Factually, based on experience. in more than ,a dozen US and. foreign laboratories, there is no one standardized procedure ihaf arl laj’ otratorjes u,se ,?or, for that matlet-, a uniform calibration procedure for the balances used ,or uniformU. balances types. ,lI(^‘ ./.*a,,.,L,a.;._,, u‘ As a Ph.D. Analytical Chemist and fo[mr., Quality Control director, ,oye[s+$g the operation of the internal RM, W idatron, In.process, “‘Release, Stability, Complaint and method’ s improvement and validation lab funct.!p~s as ?t/qj!L $5 ~s,~~~~alcsp@cialized contract labs, having w&-&d with the lab operations in more than a dcizen other firms in%.the United / )iStates, United I “6, “,_II*“, Kingdom, Japan, Germany, France and China, this reviewer can attest to the need for la!+ to haye and the Agency to request proof of the reliability of even ‘ the s implest unit operations. ,,..~
1. 2. In-house holding of in-process Fnafkriils shouL$ be, c~nss&~erI~ a GMP requirement, not part of the application. This is not “supporting studies” as defined by ICH Q l A.


Delete the material ,sta&ng ‘ with “Stability data to support holding...” to the end of the paragraph.

Contrary to the position stated by the commenters This reviewer strongly opposes this deletion for all of the a-jreasons . * 1.__.v, ..,~S\in Point 1, in addition to the drug’ prbdudt (“finished .si stated - the ,draft text, or, if such dosage form”), the Agency is charged with evaluating whether or not the production processes and controls exists, an improved version thereof should be incorporated into this do, or do a, comply with CGMP.” final, CMC guidance. Apparently the commenters have ,”*.Xl_. ..._ ..*, *./_I .L_overlooked the -.,. requirements that address. the &sue”, the [Note: Lacking the data requested, an specific commenters r&e. application reviewer cannot know that the holding times proposed in an The applicable section ,is Z$&, &I&i ii.ye application are s c ientifjcally sound and limitationg on production states (emphasis’ gb%d):
appropriate - a CGMP requirement. If these hqlding times are not substan?ia’ d t’ by the data provided, then, the -$rudent application reviewer c?$dS, place the application on hold .a,@. request the applicant provide said data. Most @ms c/aim they do ti want to delay their applications. If this is $9 case,p rudent firms will report the .stability data that support any and all hold times not jtist Finally, those longer than 30 ‘ days. because this docume.pt is guidance, a firm may choose to -follow the course that these cornyenters .Ir ,”*nj* proposed _ have I instead of the, one the‘ Agency has proposed.] “W hen appropriate, time limits for the completion of each phase of production shall be est&l~~hed J O assure the. > ..“I.iil.((i- quality of the drug product. Deviation from. established .time lir& may be acceptable if such deviation dqes not compromise the quality of the drug product. Such deviation shall be justified and docum&ted:”

Thus, while the applicant is required tb establish time limits for the .cqmpletion of each phase whether that limit is one day, one week, one month or. longer. The Agency recognizing the burden that supplying all of the required - ‘ studi&. iyould impose has judiciously limited their request to a hold period of 30 days or longer.” Thus, the request is very reasonable. Moreover, were it to be removed, each application would be subject to the judgment of the application reviewers as to what the “titie-d@ay sfarf point” should be for requesting such studies - s illy me, thought the

, .209

Guidance Line #


_, ‘ .

“I) __ i *.* SW<.

_. *a:.




Rationale /_. ,.

Delete the fo&ote, or rkvi’ %gay’ se the ICH stability guidelines are the primary reference iources.

Reslators and industry have worked very hard to develop the ICH guidelines. FDA guidelines should not supersede them. FDA guidelines me only appropriate to address areas not covered ,by the ICH or unique t0theU.S.

This reviewer disagrees sommenters’ remarks..



First, if the Agency were to issue guidelines, they would supersede any guidance - because they are legally binding on both the industry and the Agency, the FDA does not currently issue guidelines, Knowing that the FDA understands ., better, jhsv+,,tl+ _ (,)_ ,..,s, reviewer what itcan and should do wjtb respect to the this reviewer will defer,, to Jheir ICH guidances, judgment and, barring an Agency-initiated change, this text should be left a.s it is in the final CMC guidance. ~./,,
The regulations reqUi<< that EPRs be provided for bio-iiva&bility, bioequivalence and primary stability lots. The provision of EPRs for multiple stability lots, for example, adds btilk and complexity, but may not always serve a useful purpose. All of the& pieces of information are ‘ included $se~~e~~: in ,je registration and should not need to be. repeated here. In the interest of facilitating any future updates, it would be important to simplify by only stating thi information once in the, appropriate place within the appropriate section.



Delete “Phase IIr Clinical” from +c s&;&c~~ The cencept of providing representative EPRs is good and should be retained. ,. Delete Name and address of DS ma$+c&+g Names and addreqsc>,pf s~~rces,,$ _ _ noncompendial excipients Names and addresses of sources of container-closure system for DP Names and address of ea+ co@r@f+&y ./_






Because the CMC, sect,io,n .is_ ,$VZJ oply section provided to the Agency inspectorate and that This reviewer disagrees with th,iz+ inspectorate needs this inform&on for,~“i~e~e~~,!~~~~~~~? informatiqn is and scheduling purposes especially in instances where unless the requested elsewh&e“ ih’ tl%‘ :‘ .C@Z the source is, as it increasingly, a foreign source. section of the application. However, given the size of an applicatibn and the need to partition it among various review -grbups, as long as physical copies are permitted the CMC guidance may, for the reasons cited, and other secti,ons may need to contain infbrmatjon in. multiple locations to facilitate the review process. In such cases, the goal of review facilitatiqn shquld continue to supersede the goal of “ONLY in one location” simplification.


Delete th; sentence that .st@s u, This ,&&l include.. .“.

Provisioti of duplicate CofAs is unnecessary. Co&@r%iiof supplier and applicant data is a GMP (ssue and can be addresSed by the inspector if appropriate.

While this reviewer agrees that providing f’duplicate This revjewer. knows that .jhis& @ -aft text or, should it come to exist, an CofAs is unnecessary,” this text makes no ,$~$b, request. improved version thereof should Since the Agency is charged with aduty to ensure ^ .._ ,,,_ be incorporated into the fin”aI CMC that the. manufacturing, controls, and drug products guidance. , are CGMP compliant, and the commenters admit that this comparison “is a G M P issue”, that “can be ac!dr+e&Jy the revjew is++ that inspector, ’ then it is also an application can be addressed ~by requesting the applicant to provide the. requisite informitibn. > (“.~ ‘ e-ir*=* +*.I 4w, ,.wP.,.k@“I .iiL^ , ,,,:---t .“+“%us -*ii
..( ,, ., ,._ r&w, ,#/ rue. t&W W . _. "_ .,:t~.~~~i~+&&~, b:&: Z ~ ;<G ,,>< j


A”entis . ‘” , ^,

Pharma~~utlica,,s : f”

sub-~iSsiori,~~~~~~,‘ ju;le ~o~~~~.~~~~~~~~~.‘ *L~~-~~~.:‘ ..il..~”~. I. ..‘ <. ,/. ..(.\ P,\. _ _

y,>2&tGs _ _ _-, _



W&z The original INTROQlJCTQpY comm,ents~~aye,quoted in a condensed font (r+rp~t~~& the quotes directly from the draft guidance are quoted in a stylized font (Lydian) and this reviewers comments are ?n a publisheis”‘ f<% (NE;$s Goftiic- M T ) 10 ma‘ it easier, for the ke reader to differentiatea,,” tl-&‘ speaker” in the various_ text passages that follow. In this ,/ d. /,“._#” review, this reviewer’ ,.ccI;~~Q~-#, are n.,l- ..I.ir”“’ ..,**- rr.>T” s commenters’ ...”comments * ,,#B rPI,. a-,‘ made after the ,i”““i,ii”‘ .?-l,, x .~*tri”-I”,r,.~,ri , ,Il-.*i,~~,...r..:and 1,-i placed within the text box contai$i?g the commenters’ comments.]



“Aventis Pharmaceuticals Inc. appreciates the opportunity to comment on the above-referenced draft* guidance entitled ‘ Drug Product: Chemistry, .This draft guidance provides recommendations on “the Manufacturing and Controls Information’ . chemistry, manufacturing and controls (CMC) i nf &nation for drug products that “should be. submitted in original new drug applications (NDAs) and abbreviated new drug applications (ANDAs). This draft guidance is structured. toe.fac&tateWW *&e.,*preparation of, applications’ submitted in Common Technical Document (CTD) format. we offer the following comments/clarification for your consideration. “General Issues”

This commenters’


by stating


Since there is heavy emphasis on excipients, especially novel excipients in Section IV. ~- , i_d,‘ ,4”.5PHARMACEUTICAL DWF,LOPM&NT (P.2) - ‘ Part ‘ PY22;1.2, specifications’ for novel excipients should also be listed in Section VI. CONTROL OF,,,~X~IPTENT~~,(P.4) - Part P.4.6 and in Section XI. APPENDICIES (A) - Part A.3. Cross references are given either to the CTD section number, or the FDA guidance hierarchy. This makes it confusing and difficult to navigate the guidance. For clarity, we suggest that one style should ). “. ..II / be chosen. Example: (Lines 332-335): For excipients (e.g., coatings, lubricants) where a range has been justified (see section IV. A.2), the target amount should be listed*inc^ompo&tion statement. However the target and range should be included &the batch.form+(P. 3.2 j: ’ In this case, Section IV.A.2 correlates with P.2.1.2, and alternately P.‘ correlates to Se.&on’ 3.2 V.B.”



,, .



Page5 Lines 161-W”?

.,“. .),_ . I’ .-.

I‘ “_

IL_ ,,,*li : ‘ ‘ ,.X4, ,,,,, ,.~j.. 1.. _,_ 1 . 1 ‘ : ,y~““” : ^_ ,,. ~

“if information, is- mot. provided in a P subsect&n a,tall,a.,. for 6. particular product presentation or or ““j a _.tlX.oI manufacturing scheme, this should be stated in the application avd a reason given.”

providing informatipn number.”

“Section IV. PIJARMACEUTICAX :, .<e.-*~&Q>~*~.*~~.~y TT:i ~E~@BP$IEFJT (P.2) ._ I I .“. .~_ -: Ii..* ~~~~,~~;6,;~~: Part A. Qmponents of the Drug &oduct (P.2.1) No. 1. DrugSubstance (P.2.1.1), a. Key Physiochemica?.CI+w$eri#iqs Page 11, Lines 383i386” ’ . . I

“Key physiochemical characterist-iics (e.g., water content, solubility, particle size distribution, polymorphic form, salvation or ~hydration state, pH, dissociation. constant (PKa)) of the drug substance%jentified in ‘ ,._ IS “<<;‘“>,3+,%w the performance or”manufacturab$ty of the drug .,,.e .I_ 3.3. I that can influence v,*., * ‘ “,;a. t,;,~,“~,I(..Br~‘ 1 .llxp(i*aii(n; product should be discwed.”


__ ._.


While this r$yi,ewgc~,cgncurs, _what is being suggested would be +?awr,if L,i,(l .*_ this corqpent.“yge 1 reworded-to.,WIstate, for exam.$e: ._ ..~_ “*~>~.Il**““jl,-l, “*“l*,.ri\o~*- i__(., __ __/, , I j . ( [ Ve suggest replacing the inner set of curyed brFck+ ‘ )’ with square brackets ‘ 1’since a _. ,,
subset is included *thin 3~ ,~~~~~~~~..”/ ”^ I. ,‘ I. < ,. s,,1,. .( ~ I -;i -: “,ebrA,r,- ‘ “Si- 2% 2::‘ ,a:.,a,&* L,X^I2*.- i *2: ~, i
“h j’ -

Section V. WVWKX-EE (p-3) Part A. Manufacturer(s) (P.3.1) Page 18, Lines 688-6~91‘ and~F~~~~~te:!9 __ 1 :- __ _, Page 19, Lines 695-697 and I&es 7jQ-712,. _

1” : _, _

,I, -~ _

,I , _i ~_ : ,, ‘ .’ ”


“Each site should . I, , identified by the street address, city state,’ and when available, the drug be _“,“e a,&, , _/i.llj_ establishment,registration number.,‘ ? 267 ‘ reg$ra&n’ requirements foi- producers- of, ,drugs. The for’ Footnote “19 - see 2,I ’CFR pati ‘ registration nu.mber !s”;he’ ~seven-digit central file number ‘ (Cm) or ten-digit‘ “FDA ‘ Estabhshment Identifier (FEI).” “Addresses for foreign sites should be provided in comparable detail, and the name, address and phone number of the ,lJ,5, agent for each foreign drug establishment as required under 2 1 CFR j, ._ ,-_ .. ,YX . 207.40(c), should be included.” . I









..,_.. ,‘ , \”

(... _

^,) .,.

: .. / Z‘ facilitate preappioval inspection related activitkzs, \“, is recommended that the ,n,ame,telephone To it a,. ‘ : -“.lj number, fax number and e-tnaj! address&of a, contact person be Rrovided “for each. site II@$ in the .. application.”
,_,._“Should 356h?” full establishment inforqa$on ,. ,‘ .


___ .__.”_I
,‘ “/.

l&n&led /.e,..in r&&-the. l.,,*^,,e l_l.,“.l”, *“a.. ,,. ..~./l/,,~ body of the application-a;;d 1

” ..,., “. the Form

,” _. .-,. FDA

Because only the CMC section of the application is provided> to and used by the FDA inspectorate in contacting sites, scheduiing the’ site inspections, and PAI audit-related acti.v.iti,e,s, providing this information within the body of the application w/II, expedite this phase of the review. This is especially important when the site is l,ocated in, a foreign country.
Section V. MANUFACTURE (P.3) Part C. Batch Formula (P.3.2) No. 1. Flow Diagram Page 22, Lines 79iX796

The flow diagram should include:



each manufacturing step with identification of the critical steps and any manufacturing step where, once the step is completed, the ~materia) .might be held for a period of time (i.e., I” “,“,._, nonc,~ntipugus process) ~~~~~~,,~~~n’ ~,iirocii~~~~g’ ~~~li“F~erf;iririid’ j_ _. I./‘ _ , . , _ “,I _. x the material bemg processed critical process controls and the points at which they are conducted the type ofequipment used (equipment model number is not needed) “, ._.~. , . . . , “. ” x” ,. I _.,(_‘ </ / _ I



“We suggest that a more precise definition of “nonc~+i~~q,~s procek” be included in this section. Inprocess material that is held muit b~~,~+l~ted~for .”*_ g;,..., j. ,. per%d in excess of the designated “hold time” in .a time the appropriate container/closure system.”

This reviewer agrees with commenters) re,marks” bWut,,+wou.ld.~_;/,_. a, ^.^ ,i / recommend’ using the term “discontinu,ous process“ as the definition basis.
^ “Section V. M*ApvFACTIJRE (P.3) Part C. Batch Foqnyl,a (P.3.2) . ’ No. 3. Reprocessing and Reworking Pa@ 24-25,‘ Lines‘887:912” “




“Reprocessing is the introduction of an in-process material or drug product, including one that does not conform to a standard or specification, back into the-pro&&and ‘ r@eating steps ttiat are part of the aRproved mariuf~.~~uring‘ process. Continuation of a process step after a process test has shown that. the step is incomplete is considered to be part of the normal process and is not reRrocessing. For general; the most ‘ drug products, reprocessing need not I. *, L-l_I “.I be de&bed* in.. the’ application. In ‘ ‘ documentation. of anddata to supRort the reprocessmg of a Rroduction batch should be‘ retained by the,~manuf$turer a$$ be available .: :. “p ,-.,3,/by FDA upon‘ request~ -However, if there is a significant ‘ ‘ for review .i !i,‘ : : ^_1. .a. .,* /_Imv,.,rr, ,, -,., : : ,.~. , _. _ ,, ., ”s., .* :..).,:ql. . : _..;hi*, ( ;: ,>“, :i ._ ,,. _’ _“( i, : :~ . _ ,, / i i *a*. . 213 ‘ -“’ . ;’ I. ”

potential for the reprocessing operation to adversely affect the identity, strength, quality, purity, or potency of the drug product, the reprocessing ope6tions should be described a.nd,,justified in this section (P.3.3) of the application. For exampler reprocessing of proteins ivould be considered. a reprocessing operation that should ‘ described in+*.;&=-application. Any d&a to. support a be justificationts shoujd, be either referenced or submitted in ‘ P-3.3. Hoyever, validation *b.I_ (j’ when “” c data,,, .x1warranter suppo”rf the ,p~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ .‘ 4w-;.,,:,~rirr;~~,~~ “i-i._*,o ’j- 1 Reworking is subjecting an in-process‘ mtiterial or drug product that does not conform.to -1_.,*,A.._ _,. --a,. a standard .,,,, ., “.I. ,/., -,,_jl*“_&.~,h or specification to one or ,more processing steps that are different from the ,mqnuf~$@g process described in the application to obtain acceptable quality in-process material or”drug product. In general, reworking operations are developed post approval, and the application is upddted through submission,of a, prior approval supplement. However, ‘ reworking operiitions are anti@pated at the if time of original submission, they should be described .in this ,seetion,,* .-\-.,,, application (P.3.3) ‘ of the2.a with justification for the _, ,,1 reworking operation and ,any data (or references to data) to support the ,_-,_ justification. Validation data, when warranted to support the reworking- operation, should be provided in P.3.5.”
“Although narrative defi@ions3.are given for reprocessing and rewcrking in this section, ?h?G&sai’ contains no definitions for $eseCtermmsCWe suggest adding these terms to the Glossary.”


Section V. iWANUFAC’ U&E J’ (P.3) j P$rt D. th~trols (.-. ,Tj_Critical *.“l~,,y and Intermediates of .,... ^.llil‘ Steps ^. 1“,.., A’ . I Page2J%Lines920-930 ~ *’ 1

(P.3.4) ” ” .,,,_ ^. . _ :‘ .. ,, ,1 _‘ _)

,, -. ,;__ .~, “In this section of the application, all critical process ‘ control&e s~~~ion’ Vc:i)~nnb’ their associated numeric ranges,. limit& or &Gpfance criteria should be identified a,nd justified and a brief description of the test provided. Any experinieintal data to support the justification should be included in. thjs section (P.3.4) as well. For critical operating parameters ’and environmenta! eontroh, numeric ranges, limits, or acceptance ‘ criteria typically can be ,based on the.experience gained during the development of the manufacturing pro&. (See section V,E for possible exceptions when process validation information.^Iis,warra.nted.) Critical process control vakres fromr&vant, bat,&es~(i.e., those I for which batch. analyses have been provided,in.‘ P.5.4) should be provided as part of the justification. Additional informat& ,,-”.*I”./-. be provided in this section (P.3.4) under the following circumstances.” should,uLI

i specifkations for product release.’ This suggestion is based. onthe ,~dersta.nding that, for most new drug products, there may be limited historical data for in-process or final release specifications at the, time of With the addition _,.ll -*“liX-hi provision, an applicant could commit to introduce. finri~ed I -.,* \,2. of this ,* specifications in a post approval submission.”

This reviewer agrees with the .commenters’ . proposal but woujd suggest _I/j ““.“I___ that the text in th,e supportiii&‘ $tatem$~t,U Fe,V_cqrjected-/ “”“to _..” ~>A,7;-“i4> ‘.(1 ‘ ;r,*.s, _it a*>‘ *,: : .-_lix *” make *,s.“,I,* x grammatica,lly cdrrect.

Analytical Procedures and asso&ted va,!ldatlon vr,” .a,*- shouldI&t&ii information I.,% i.rr*r.$.,, &i-l”*:,,be provided for biological tests.23 r,ri:e:.&~
“. . ,_ for “There is no reference provided in this bullet point to refer the’ applicant-to appropriate gu?dances ‘ establishing acceptance limits for biological tests. Several guidances, points to consider and compendia have suggestions on how to establish- fiducial hr@ts, particularly for biological potency assays, which inherently have higher variability (CVS) .”

Sectioq VI. CoNTROL, /,I, OF EXCIPIENTSi,SS’ _) .il ‘ I,.. _ *aI +:,-“>‘ \,(P.4) -I Page 27, Lines 991-995 Noncompendial-Non-novel Excipients

-ANDSection XI. -APPENDICES (A) “, ),. _.d”,. ;_I. Part C. Excipients (A.3) ‘ -“Page 49, Lines 1765-1769 Other Ekcipients

. ,, _







Depending on the functionality (e.g., complexing agent) and the route of administri-ition, of the drug -iadditional jnformation,“up~‘ and m&dkg%e’ to %!?el -iif’ Infdriiia~idn,recorii~ended for novel ,,,,. ., . ^. ,_.~.~ I^~.“I(.XI,.~~-/_X”I.,iM ^... ,&..^ I,” excipients, can be warranted for, (.I_LIIdv-,,” rroncompendial-non-no~~~ excipients. The additional CMC ,_I information or a cross-reference toXii.“, that provides tlie additional CA$.C, mformation ,*Ll,,l_l/~i*.~*“. __, be..__ . . I .*“b..- should1)*.__._ , < 3 L” *r a DMF ““Il.+&” 1. ‘ *-i~a~~ <included in A.3.

provided in different sections of,,& guidance and appears to be inconsistent. Why should “additional CMC information be included, in 4.3”, the CTD appendix for Novel Exdiijients, when an excipient is by definition “non-novel” (e.g. flavor, colorant, etc.)?”

This reviewer agrees with the co,~me,ntel;S:~,jnccSnsistency remark. I,>ix**^,\ “ ‘ However, even a flavor or a .cQrant 1,)” .ws -be “novel” jl(“Ma hasc% “ *yf$+#,*$*‘ can*a.-. .*-ir.,*ix IV,“,‘ ,~. % “>~7~~~~ if ‘its -~~‘ ~&e~* ,*r-Lv*+$,,ir~W,‘ nevef been “.** *m.‘ .*,,* used at the level. or_in the jype of formulation in _thq formulation, “I<.,s:<:r being # ..e...“erlMI submitted, Therefore, this reviewer respectfully disagrees with the co~met$e$ ‘ by

Section VII. CON‘ JRQL QF D@gG\“”VW> “,,“,i-;” ~7,.‘ I’*“,_ RODUCT .,(P-g) Part A. Specificafion(s) (P.5.1) Page 32, Lines 1153-t 155 .

-_ -,

. ,, ‘ .’


suggest adding text to this section


how “tests p&formed of Analysis - especially for extensive in-process

product testing” should be reported results such as PAT generated data.*

on a Certificate




.., _,,

___( ” r.

Section VII. CO?jTROL-OF DRUG *.PRO,DUCT j _.. ,, Part D. Batch Analyses (P.5.4) Page 37, Lines 1297


Batch identity (Le., batch number), strength, and size

In principle,

this reviewer agrees but would suggest that the ja,nguage be ,I ., ,_ .(_ rmulation identifier.” I i,*“L,:‘ “““‘. , _dl.., _,*-+ ^jj,y I ‘ __I __.._ _‘ _,“j,) “_.^.. W .,‘ . **,” ;;+,l.i+;o,,i, i <
“; ’ ’

Section VII. CONTROLOF,DRUG .( ./(,__.*_” a”*. “ia (Pk) ,PRODUCT I ,_.S” .. ,... Part E. Characte~.~atipepSl[mpurities (P.5.5) No. 1. List of Expected Impurities Page 38, Lines 1343-l 346



., _,

1 .*

All expected drug. product impirrities (e.g., degradation products of-the active bigredient, ,\ / x , _ ,,” residual solvents, enantiomeric impurities, excipient aeg~~~a;;t4~re~~~~lj‘ fr;irn‘ container closu~re ltis’ the system) shouid be listed. jn thissection of&the application tihetti.er ‘ not the impurities are included in the or drug product specification.
,,‘^. -,. .-,_““*, . __.,I,.^ _

we Since “Miscellaneous Drug Product Impurities” is defined later jn &s sectipn (Lines jZ$??-!+O9), suggest that the impurities listed- initial in Liii&< 1343- 1346 should in&de r$scellaneous ., ,$ug product ., ,,. impurities. For Example: “All expected drug_ product impurities (e.g., degradation products of the active ingredient, residual B.,.“. ,” “.‘ ,. ,esl”*l ~O+- ,,I_ i -s ^‘ -‘ “,, ,,,__ ^ /ci,.. ~‘ rW;:,,.,a ~r*/v+-.,. Gl.‘ .31”~’ 12,, solvents, enantiomeric impurities, and miscellaneous dru~‘ f;k&ct impurities * such as excipient degradants . . . )“‘ x c, . I I . ” .. _” s “. ,“.,. ” ._ ,__e _ ..__

Section VII. CONTROL OF, DRrrG,,PRQDUCT Part E. Characterization cfImpurities’ (P~5.5) No. 2. Identification cf I.mpurities Page 39, Lines 1379-1380


216‘ -”


referenced text be inclu~~,~ in,,&: guidances that can -be.accessed).

,$$t pidance

that is being reviewed,

(i.e., reference only those

In general, this reviewer concurs-vyith the/ , commenters’ ,,,, ^^‘ (.“..~ ..“.Mrl.~,~ywiii-liL”~,“irl*r,,~“:;,.r ~T.~.,/./ ,, ,c$?,Flglks. “-.,,‘ ___-_ “-,,_ ? “...h ,. .. ..‘ _
Section VII. CCW~Q&, QE~DRUG in’ i-a._r# PRODUCT /_ (P-5) >s/I +.eLv” uli.ruy:., ‘ “* Part,E., Charaderization ,,-,,a7 q&purities (E5.5) *_ .I’ < No. 2. Ilaentif&atipn of impurities Page 39, Lines 1395-1398

For purposes of this guidance, a miscellaneous-drug product impurity other than ( I ) a degradation product, (2) a residual solvent, or (3) an extraneous .conta.minant, that is *,more,appropriately addressedas a good’ manufacturing’practices.issue (e.g., metal shavings). i :. -t--F: ^>*.,~~‘ ;-,rr,e.d, .b*,:c4 n, j*,;i ,j.,i :‘*.~* _ji,;Lri” :,.* __, 1,”~ ‘ ,-._, _,_ L;-Cr* \?LI. --,i *,,, _) __._ >. _. Is*lr +&*;, , ,,_ j /

; ~(

. Page 43, Lines 1531-1537

A description of the container,c!osure system for the drug product should be’ provided, including the identjty of m~aterials constructionbi,*i~iaw~*4i ,of I ‘ iirx,.w of each primary packaging component and its specification. The , ,..A _ ., same type of information~should be provided for functional secondary packaging components ai is provided for primary packaging components, For nppfun$xd 2gcqcikry packaging tomponents (e.g., those that neither provide additional protection nor‘ &ve &&liver the product), only a brief description should ,be provided. Information -about /” l‘ suitability’ of a container closure system ,*.- the-^/i_+l .i ^ .11.,*1-+ should be provided in”P.?,% ,“_ ,._. _,,-_ _ r _ _, __“. ,, ,_ 1 ,I

This reviewer



S,ect+n X, ST&PI&IT. Page44,Line l!?Z

(i’ .8) _

’ ’ , . ^ ”

. .j,

Information relating to the stability of the drug product ashould t;e piOvidd;iditi P.S. 1

,.” Sectiw X!. AP@%?j$ Part C. Excipients (A.3) Page 49, Line’ l748-1751 (A) j ,_. _ _ . _ .“__. . -1i * _ ,_._ _;,/ ,., _ .. . .^._, ,.,, .___ i,. ,

C-i;’ ,,: T: ;:

The chq@stry, manufacturing, and c&ikrols infqrma&j @ii a,,~bvel”~~cipient.~~hould prkickd in be the same level of d+$Sqid . *, the.-*n,,a. A)_,. in * sarqe format as the infoimatidn’I” .“,.e*“_ , 1“~~-mi,n *i”e*P*‘ *Guy?>. pikidkd for a drug substance (see *.*r.r)si: r*“~~!rb*u

We suggest removing the reference to th



Uniformity of Dosage Units

We suggest that the bullet point for this item be properly indented to be consistent with the other b$$. points in this section.






idventitious Agents Satch Analysis Data Certificate gf Analysis Comparability Testing Zompatibilitjr Testing Compendia 1 Excipient +ecuted Batch&cord qon-compendia1 Excipient Vovel Excipient Xeference Standard Reprocessing Reworking Sunset Testing Validation


w. _.

.L__I_.“_ ,,


_ . _. ._ , . 1. , j, , ,,. _. _”‘ : “i , “I __ I ___

. .

This reviewey”ccpncurs is ,xli*-.%‘ but i,~~W~,~,“.~~mwA,,d adding the following would suggest also a *


DMF Standard Report of Analysis Secondary Standard

(and, to de in’ synch &it6 .th& C%$.jP‘ &gulatibns uS@.Jhis I, term in place of or witht,he phrase “%&?ificate c!f Aqalysis”)







Note: The .original INTRODUCTORY comments “n”. quoted in a con&.ns@ f~~,(&~etua), .” are ,L.X*.t,i the quotes directly from the draft guidance are quoted in a stylized font (Lydian) and this reviewers,Go.@ments I are in a ptiblishet% font (News: Gothic ,MT)‘ make it easier for the to * ^. ,._ *, reader to differe”ntiate *> the .&“., IQ thi& _ ., ,&-;/“‘ /speaker”’ in the v$$o~,~,.,.te$ passages that follow. review, this reviewer’ numbered comments ....‘ !^, ‘ imply made after the commenter’ s s -, _,._ ,.. are s _/_.“. . i” remarks. This commentey., begin by stating, “I wish to comment .,on FDA’ ,) ,_S,”Guidance ‘ &r,,+ > s draft ,,_ I.,,,, i _, .“,“*,, ,._ Industry - Drug Product - Chemistry, Manufacturing, a&l ‘ Corkrols Information w&h gas‘published on January 28,2003 in the Federal -Register ‘ with comm”ents -due- by June 27,2003. My comments are attached. This document,,is- well. ,.written 2i’ is c lear and ~*‘ confusing. It also makes many references to and “4.” .l/a* i~~“~lu~~e.Y.“,.,~not -.e e,b*\i.^** a4~e$&~&t~4y$ ICH and FDA guidances and to appropriate sections of the Com,m.on Techujcal Document: ,, (CTD) whose ,P,“j_.X_Al ” ‘ ,d-..%. format is follovved. .However, I think that the document is too long in that it contains too much- “how to” detail and can be shortened by at least one quarter. ”
“In addition, it requires firms to sub~mit more ...information than ”!wi%~,~~~s* both NDAs,and.AND,As ,. * / . .“S _#.& *.*rla<“,,,*>. r” y currently for s ince the CTD- requires information not previously submitted in drug applications in the United States.” , ,,

1. ThiS [ey igwer ,doesS” understand :-,>e,-not .-

ttie point ” this _-‘“^ of comm.ent. ‘ ,

“Since the CTD form”at ii~~not,,a&&ely required in the United States (it is “highly recommended” presentation by Justina Molzon, ICH Public Meeting at FDA, January 2 1,2003) why would firms elect to \Asubmit applications in this format unless ~,fhey plan to submit also in,, one or -bo-th of the other areas .,%I, ir”‘,x-Xr~~.?r-~.~ii.!,.~,.~r~~, z . I . ,/,,. involved in the ICH process (Europe and Japan)?”


As with rn~sj questions, the answer is ,l&ca,use:. @ , if ndthing else, doing what is requested has -been “highly recommended” by those who revi‘ s tiig ew applications is usu,~Ify’ ti good idea and b), as the coumenfer obgeyes, it fac ilitates sub,rnj~z5_ionin I.. ,_““( .,i ,,, multiple venues. _(_. %

“Additionally, s ince Japan’ CTD effort will not cover g&&ic pro&&s (presentation by -‘ s Christelle Anquez, ICH Public Meeting at’ FDA, January 2 1,2003) th e incentive for- filing in’ the ICH areas is reduced thus negating any advantage that the CTD format may have.”


This reviewer disagrees and would a.sk$he i I cogmenter -.a ./ .,_ reread’ >.,a* .own **>*’ . :_ _“_ his p ^, ,&-l’,;. .,_“‘._(-.,a as-~ &‘ (.,_ ) _a to “VI.% ” a,,, _1.a_*,an..w.~,“***~i;i,> ._ F % ._/ prior com.ment an.dLto,s .cnsider /;*,..*-_-*,,, that I~,i^i-*l~~ many NDAs are filed. I ..^t‘ / * p

“Since the CTD only invoIves format, not data, it is also my concern that FDA will require more data in each section than its FU,*ar$ Japanese partners.”


Unlike this .cq,-nmenter, this reviewer’ CX&G~~Q, 6,.,A-^,__) . 4 _/*, ^r*-*.,rrxilii*: s is that ..“..,.,**. “__and Japan IS the EU I (I ,m>:,.a may require more data than the. unit@ %&t&s a,I. *</I/ ,.guidance Ijropos^es. 4 draft

“Although I would prefer to see the CTD modified and.‘changed, the comments that follow t,alce”the CTD. 1 . ,“_“_, .“._ ,/L ” 1” as is with no expectation that it may be changed or shortened. Thus, these comments are.made,in ,the ,, hope of modifying FDA’ interpretation of the’“CTD, am&&sting s it in finding ways to shorten the

Moreover, this reviewer tends _“-to I id,ismiss any comment tha.t,,sugg&ts ‘ ” ;_I,*s _. ,+_\i.a,>,&ii l”i shortening any docuti.erit tinless the commenter ~qan”provide a sound rationale fqr th,? &ot%&iiiig’ and/or pfovides a clear a[te[t-$@i~e,,thaJ ,,a_ .,“ir ~*,,a< etisures ., * ,xllI1‘ us*\ I~ that each,,@ug application wilU contain _Ad s*m sufficient ~h.“w4~~****i to -.,L _ji ,.a_ Ia,>.ii~r‘cogent information ,/ establish tl-&, if approved or licet&d.]by’ the United States FDA, the CMC portion of the applicatibn estab!ishes full .~.”,(/ l,-l_l, U.S.C.,,‘ CGMP (21 $5_$(a)(2)(B)) .“il<l compliance for “the,methods used in, or the ,__:,_“l‘ or .._I:,-“‘ p$,f~~, its maryfacture, facilitiesl_ __controls (- ,‘ -., ,,A* l./-_l /_ &: .x a
processing, packing, or holding do not conform @,,oy- ~~e~~,~~~$&&a&!d ~&$$@~~d in” or’ conformity with current good mbnufactuiitig* @%iSce to assure that such,,dtug meets the requirements of thi’ chap& as‘to “iafity- and tias .t)e j&ctity and strength, and meets the s quality and purity characteristics, which it purpo+ts or is represetited to possess.”

As the commer$er s@u@ i !.$,I1 &IYJ~, fajlur,e .t? comply with CGMP adulterates the .drug product an& rr&~.~~, .lt SI.. . ‘“,/, ur&r *_ is illeg^al for the man*iif;ict‘ . _,^ thereof to o@[+r sale or .,*AZ products. ,~+. .u.I,“,such sell ‘adtilterated drugu”~_<_. , __\ i ./ .1.,I”_I. ,..” _ ..j\L ~~~~ilsd%i)li~ “6 .~“~,~.~“~,~~.~~~~~~~~‘ _“,. _() j ,.__( .K,ii~~~~”~~~,,, Similarly, it is ‘ equally InapproprIate for the Agency to approve an application in that -app,ication ‘ibr.~~~~-ug’ @ ‘ tiethgds, fc;(~$~:“:~~~~ G?@blish:“ tti’ ,’ controls presented the ‘ ‘ ~~~~~~~~~~~.~i~ facilities, witfi”“CG”Mp.‘ with respect to the manufacture, processing, packing, or ho’ ldirig of a drug 1 ‘, .,.. %,^, , _ the packaging, labeling, testing,.and @ ‘ f~‘ ~li’ &itrol of the da2ri., ,e*u._,_/” ~ -. x ,j .. .

While I‘::.., ‘ “ . I-I *““: “*:,;*“~;*&s1 “ >’proposed renaming the “Chemistry, have **$q; ;v; __ y,O<‘ ‘other , cointienters y; b,Z” ‘ “@Ij ._ ‘ .,Y.,,* ;-‘ secJ,!on of “..,, .i-*,;s, the “Quality” ~M&%&turlng, and Controls ..<“an-‘ sijplidationsection, it should be.,renamed -1,. )..W“CGMP Quality” section if renaming is,” the *,_/>*_,\,.*~ ., ** I,_.>1x” appropriate because that is.whaj it jt-1~1~ address++ E3ased on , \““,./,,preceding, this revi&&-, ai any o’ the cher interested ii. fX#lP r/ compliance, can only support changes that: a) do not interfere with an application review&s #,abj,j,ity to determine ti~t&h& “~~rii~t.f~~.,,~application establishes .~,X?~~~,~ c,G&@pliance and/or, b) improve application transparency vis&vis CGlVlP’ dpmpliance.
“Two avenues are pointed out, one is where the areas +Aat,j&-v?lve an increase ,,,.,rtrr of .i CI b.%<” I\r~w~;*rx~‘ requirements compared “_i*,+l. to presently submitted drug applickions and the ot&r. where \,.# . docu~~~~_~ay be shortened without the ,ra*.,,%Lii ,.,c,.I aI ” deleting the areas contain&g substantive matters. _ The .” a~; ah% contains a Module 2, Quality Overall 1 CTD M4Q ./ h”<,*;.~ Yet much of the -.I..I, d,r”L;l,,,a”& required in Module’ 2, Summary which is not addresSea,in* $.is”“guidance. ._ information ,” Quality Overall &mmary is redundant and the docuFF,?; i&f states._I..e* some’.;b//*),, ,w1_” that“,‘“““>“ of it *s be incorporated ” ,,,/may also XY. _/ that r**w” Module 2, ‘ Quality OveraIl S&m&y can be contusing to directly from Module I 3. We “.C .- believe .e,,IL7,. *#~.**“&*wi , j* firms who choose t? s&ni;t,q,application in the CTD.fo,szxt,apd ,,,,- ,‘ ~*,i”,” .ri. it ( and its redundancy in noAmentiqn of -‘ “ ,i.,,.‘ ,,. _ .”.S.S $ ,” .“~~.“i_ii~“,i* .,“,L ‘ : ;” this guidance is an error. , (_ .._ .,


This reviewer does not understa,nd,.“~~hat purpose this harangue about “Module 2” has to ,,,:1. with+ n$&&+ CMC ;*&idance and. wou,ld point out that :.. do ;.;4:* the ip$&ez ,”_ , ;y >;c:, lli _I’\ adding ~&%i&$ to discuss 11 would ” ..Increase.‘ A.” ,.,*a.+ - ‘ something the ~ s,/* &u,lr”rthe’/“se “<L”, ,./**_ .,,, length commenter has sta@dth,s, comment& ,?,^,>& is opposed to doing. .,../., ,r,.~,sv:,, *.l*.,.L,

.“It does,seem, that-with ‘ :”%F‘ information that is suggested to be submitted in Module 3. Drug Product, ” :::- all the ~~~~~~~~~,~~~“~“~~~~~ _. . “ .._ that Module 2, Quality Overall Summary could be elirninated.~:t3~~~ever, again; I take it as is.”

“Areas where more information .u,lj is, “..%..1/ requiied -.,$‘ then und&, c~r@n~,,r~quirements: (P.2), [ i.~$$~$@, 14%.of the entire . ..I.)L‘ __.. < ._ ,“_” I. Lines 362 - 678 IV.. _A^” /.,.,,j* j 1‘ . , ,,*_,”Development Pharmaceutical .,j. .I> ,/l*..-x-,,v-*l:-;;l guidance].

This report has not been previously required in an NDA or ANDA;: Lines,._ .* <. 367 lists _;_4i”&.$i ,*,./ton . 0 “364 - ” “_a ,- ‘ “ -.,&s information r,j-..,.. -, ‘ ,p&*,. the development studies conducted _ to establish that,*(Yl.rr,lr the _<“is* form, formulation, manufacturing process, dosage ,e.-.“,.“*.-,I_, .,u ‘ I.“.*_1 container clos,ure system, microbiological attributes, and usage instructions are appropriate for the purpose specified in the application’ that an application should contain,.“. ,_


This reviewer, agrees, and’ is pleased to see that a) the Agency has recognized this major deficiency in the previous guidance and, b) : addressed it. ._

“The guidance then covers 300 lines“.(377 r 678) to describe specifics about the information that should be .(_ Is.,j)). ._I..“*l,,.b,. v ,*,* _ _.l~;“e.l.wi.“4 included. The recommendation_to. subm~t,2t&isgreat amount pf information, if followed, will make such a report not only large but time consuming to prepare by a firm and to review by FDA. And for what . .. . ““._ ._.,, , purpose?”


This reviewer recommends

that the commenter “,-iv<z~::‘I.ja_ reread I.‘R@viewey’ -,p:‘ ,.,_: ,d, s 5. .,” ~-I_0 “ .“.“~II”IY2n.P~.=i-rc“ +$i,~,lp..“;~, +A7iz~._(. ,$^j ‘ $,a ril* -ii”J,ixpi ‘ ~ <


“Some general questions concerning ANDAs come immediately to mind. What kind of a ,report will a foreign firm submit ‘ who has had the product on th‘ ma&et~i,n& o*.co~untry or in Europe for ten years e‘ and has made a number:of changes since the product was developed.?”


This reviewer hopes that it wi,ll .be, one ,.that , complies with the CMC “,Si *, guid-ante ‘ and provide a historical. report that addresses the dev,elopment of that. drug product from its beginning up to the present. I’ ,, 1 1

“What kind of a report will an American firm*~make who has hadI.,li_ Wl.. .~~._l*,-l~. a product on the American m-ark& but,is /,sw,mt now required by FDA to submit an abbreviated application such as recently happened with Thyroxin?”


lgnoring the Thyroxin example cited (because it. has moteto IS,. lwith the CA _;, , / do III;.xYI.I*s”. “xxI‘ l‘ l.~,>ll* FDA’ forcing the innovator to ch,oose:“. a) file an NDA to bring a s manufacturer into, cqmpliance or b) cease making the product), if an s,ome.._, _,., have American firm ~~ne;i~.6~~‘ innovator decides to file anSA(4NDA,(as,._”about tor”.&L*_:_‘ :,<^,_ who is the done) for a ;‘ ;i;~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ‘,s :R.,.“*“:: zc-:>i .;, , _ _., .,_.1,s ^A.,,“,> expire or has expired), then that, application should conform to the format suggested in the -.*A”_ .& guidance and provide sufficient data to,.esta.bl&h off/cial .. -*;. the proposed application presents a, ~~M~#iipliant compilation of the informatipn r needed ! a,, I . *. rt **:: , for the < Agency review and inspection personnel to ,. ._ i, L<. c recommend application approval. .’

“Will such firms still have information ,I on the.development of their product?” ,- >^.L.),. 1- .,.“, ,~~*.~*~lr-em& I, *”

11. ”

lf the.firm, operates under the purvieh ofthe.FQA, it should have.much.of,, _, fh>e informatjon reQuested in the draft guidance. ib;;,*.,.“; ., :.,< >F~.,UI ,, ,_. .::j ,.. _,..). ‘ _ ‘ ‘.._^ j’I ,“,_,.( / - ‘ ‘ _a’ ‘ ;’ i; “Ici.$. > .3;;yr.i Ii j ,.I:,.:“; ,’w,‘.g,__I,>_ ,,,,:,.>‘,..h _ :... :y:;”; .,: *,I_.-; ‘ ? \..G.-i.‘;“ ,..$ :,‘ , *,& ,* :,. /:_-: I ,__ ,(,,_“”I ;,I,, )__ .i i __, I!^ _: ..-..-,’..,, _-.( i ^ -i\ “.g22- , .‘ ,, / .._“._ ”_, -:~ “_j / .* , “, -. ._’ , _ . ,, , ‘ VI, ‘ ,.I c “2.

‘ .








. . .



“ If not w h a t kind of a.report will they submit?


W h a tever, th e firm in q u e s tio n & id th e A g e n c y a g r e e u p o n is available a n d s h o u l d b e s u b m i;tte d“i “l< In“,l*_.t~ .~ “.il*~isIII_ e c ~*.,~ ~ *. a~ ,i-. a II th d ,.) -the s a m e j~sih l,*,.x.cl~ a s e to‘-;e*d . d ”i& ii~ y . _. __.’ ,.,^

“A n d for w h a t p u r p o s e ? ”


T h e c o m m e n ter,is

a g a i n a s k e d to r e a d ;Revi$wer’sj.,
.” , , . I _ . _ ” _ _ , _ __; _ _ _ , _,* ^ _

) ___

_ 1 ;’ _j (_,_ ”

“S o m e specific c o m m e n t s follow:

.A . L i n e s 3 9 $ - 3 9 9 inl+ate~thatifdcl~g s u b s t a n c e particle size is e x p e c t e d to influence dissolution, t h e n d r u g p r o d u c t testing s h o u l d b e p e r f o r m e d to test the a p p r o p r i a t e n e s s of a c c e p t a n c e criteria for the d r u g substance. This s e e m s b a c k w a r d - G & e the-,kky for a g e n e r i c firm is to d e v e l o p a f o r m & & o n k & h the A P I .. (./..L ,.. < ,_ ” _., .,_. I- x .,I ,. particle size a s s u p p l i e d b y the v e n d o r .” ’


First, c o n trary to th e c o m m e n ter’s assertion, th e g e n e r i c firm is r e q u i r e d to d e v e l o p a d r u g p r o d u c t th a t“i^s’~ ~ o g q u i v a /e n tto th e innovator’s p r o d u c t. T o d o this, th e g e n e r i c firm m u s t first d e.te r-m.I_ e/._b*) th e .-,.,. a particle size i “M N _ ‘.I*-Iei*“,*,& .*i n if r is . e ffect for th e .,active, v,.-.s L * +a .n d,,‘: ~ ~ w . th e r e is, th e g e n e r a l type o f particle w ^ or actives .l...~ r ~ h e n .E “y ‘“4 s o size (“a s o b ta i n e d , from * .sjowa*recry% ifizaf!on,i’ ““aI_ “*’b ta i n e d from rapid .,, N C a .*,bill‘ - / crystallization,” “m icronized,” “a g g l o m e r a te d n a n o p a r ticle,” e tc.) a n d , in m o r e th a n a .fe ,w cases, th e exact crystalli-ne unit structure.,o.r sttuct,u,re,s~ f l _ _ o _ _ I. //-““ th e active or actjves,in th e innovator’s p r o d u c t. t yneric tir^+ m u s t: a) fin d a S O U r C e ;._ :A r m e d withy th a ” - .& ;;+-;?-;-$++ “.~.,.<.“m I . 1 Ix.,.“* th a t c a n supply th e n e e d e d ~ s tructurally equivalent A P I or b), ‘in th e c a s e o f I. m icronized m a terials for: w~ljic,h,,. e ~ ~ .Zo~nly a i l a b ~ l e sources X 1 .,-d* .,*,,~ ~ i ei~ “+ _I ,1 th av r I aI.Ie ~ for th ^ . * ;ej. crystalline m a terial, i) d e v e l o p ’a n in-h.ouse process fbr th e m icr.o,niz~afjon. f o th e A P I or A P ls, or ii)’ fin d a s u b c o n tractor , w h q ~ c a n p r o v i d e d th e n e e d e d o p e r a tio n (in th e lafter”case,‘*‘th e -generic firm is r e q u i r e d to receive, test, a n d r e l e a s e t.h e s ~ u p p l i e d bulk to th e processor [m icronizer] w h o , u n d e r C G M P , performs th e m icro,njzat,~o~n n d , a fter inspecting e a c h m icroniied a lot, releasing a n d ship th e niicronized,I,,AP!”b a c k .& th e g e n e r i c firm w h o m u s t receive, inspect [sample- a n d , test] a n d ‘r e l e a s e th e . m icro,ni,ze,d, .I p r o d u c t to th e g e n e r i c firm ’s m a n u facturjng o p e r a tions). A ll o f th e p r e c e d i n g n e e d s to b e appropriately d o c u m e n te d a n d s u b m i tte d . . S e c o n d , since this g u i d a n c e applies to N D A * s a n d A flDA s ,-‘this-reviewer is certain th a t’th e ” c o m m e n tJer<.kA o * .~ ItlV a t .“Y?ll,i(.“n~ ~th e ~ ,.~ ~ ~ ~ ~*:”z,,~ “~ “~~ ,~ ~ i~:,:1 :;;~:>i , ‘i . o L .d a , n - w s Yth + firmb \i< d o - ,“,~ studiesm “xl l u ~ ~ ~ ~ to ~ .,,~~ ~ ‘:,“!~ ~ ,e”s rl& i m ,,~ . d e d ~ ,,~ a s a part o f th e p r o d u c t d e v e l o p m e n t process else w h y w o u m so, m a n y ’ o th e r w i s e ’stable aietjves b e Ifo *I”+ala..Ir ,>ixr,ir.*)xir*n. . 1 ”.b ,C,.__., - *,.. - ‘/I x./ j .II_ r m u a te d l,\j s “salts”? a _^ + ^.“” I\ ._ ” _, , “. . ~ 1l.l.lll-.T1l.

“T h e formulation _. d..,.v,_ l o p e d with the particle size of the A P I ,wi~l,effectclis~,~lution _b n d bioavailability a n d e e - .bl i....% .iul”L.a,pllwr-rw*i&. **.> a d ,i if the firm c a n get these to c o m e within t]r?ee x p e c t e d o r r e q u i r e d r a n g e u s i n g the particle size a s delivered. ,_ b y the v e n d o r , w h a t testing must b e p e r f o r m e d ? . ”


lf n o th i n g else th e m a n u fa o turer .m u s ttestfto n *d e.x+r.o iiu e_ I*.;\a~ ~ th e particle ~ ~ ~ ;“. “IJ te m ). , . th t ‘is,;~ ~ //x _~ ~ .~ L~ ~ ” _ size distr/butio.n ,, o f,.~e a c I.. s h i ._m e n t o f e a c h “lot @ th e . A P_ . ,**S,> ,\,a s a m e .r-.r~% .I;. h ,.,“._ p I IS th e a s n -, _ “),..,l< ,+ * . ~ \< ._ , .) ‘,- ., T -L..‘“.*ii*\a4ur-h-r ‘1

that of the, lot shipments used, in,the’.I_,i1h.b alluded to by the commenter stud~ies ). ‘‘ _.v- ..~*,“.‘i~-~~,.ir ,#,*, :” *wvII~ v*-li(~ *cs~‘ as well 33, for the ‘ iaT‘ $3’ iot,s, ‘ the other te$tjrig in the USP monograph (to confirm that the API X.rl -.lr-,-. grade) as well as other,tests”that,the;sqClrce __ _ ,” is USP -,_.I (microbial testing on APls .from ,. ferment&o,n), production process l__,“i**_L..I, _/ (residual solv.ents,, toxic impurities) or method of, ho!ding or shipping (contaminants, product, mix:ups, and substitution, of counterfeit:b,P~!s) may .j ‘ .., .‘ indicate _),~“~~f~,~l~-.a*, ,,_r .s~@&~.:&,*,,*i,rw*,.‘ ,..,,,,.*-“&, ,:_. *i :’ ‘ $.^ “” . ”,., h .$ _ ‘ to .,I *tie**““s** be - .s ““..,“a “. need “m”*“. conducted ,, ‘ * --*-,.-“4,. r%l,, * :” ,+, ,a”_11 *-,,~^; ,%..iiir , ”
“B. Lines 422: - 430 concern excipients and a discussion ,re?,at&.nqt only to the role of each excipient but to their characteris@s ,that can /.*._ drug . l>l”.influenceI,*eI’ product performance. What is “required at present is that ~w.“FA-n*uxI,d the role of each -&pi&it be listed. How will a veteran formulator who has been .~a/ ~s*adY products l--*.-“._l .” -*rr*r* ~~i^ir~~.i,i~,*~.r.r,ll-llr_~.lr ,-,,,a- formulating *i “44”~. for 20 - 30 years help his firm answer this?” ., “” i _ .. I. ,._


,” The obvious, an,sv$er bell this1” xp to +)‘ w’ question “is that’ ldepends on “who that’ ,@ f .-y formuiat$is” a,nd,,,,,,~$$ “.L.,s, ”,.m‘ A”-/,understands ., about@,&J. to detect, 2,,,.,,,,,” , he or. )I,,. ~-%~-r~~..*~~Li~,~~,~~~~,~~~~~~:~.~ . :‘ she “ *ir yM3xW&. ,I #a _,._ #,. +~~,“* ho& ~?&i&sad.W.~~, “( __ measure and specify such. In some ca.ses, the firm will neied)*“.\,I s _.~__.. _)** to^‘Ihire*,+someone: .” 2 L (employee ‘ or < .i*“*;*fl*s .W.r*jxr~>,~ consultant) who has the requisite knowledge; training or combination thereof.

, ..,,

“The role of each seems to, already do that. The formulator “knows how ear& ex,$pient affects drug product performance and so should thenFDA re%iewer. “ I_ )^:,_-._ I*~ “W -“11.11 ,, _.,,, ,, 1*“1, __l ^. .,/_ _


Contrary to what the‘ cornmenter”scare’ ,” “;I, (_,.* form$ators, ,on~ysbme’ know ~ aboutill,“xI_“xIx”_ , .A‘ ~“u*d+,,” % exactly how each excipient affects “drug product performance and even fewer understand .how-.-.-“7”‘ e.*“ *da.-a of the excipients,,___,~I_ formulation, , the,interactions 3 9% ‘ -.a-\ _ i*~“~~~i~~~~,.~~‘ jl __I__ i__, I‘ ,wq*&w~~~~: in the c*e&ew_ r with each, other and the =..“ d.w~~w~r~~l*u*~,.w.*&~~*&& performa.n%~of‘ active +r* ***&yw* combine-to affect tfie ttie -.,.*a *,,I_ ‘ “**I II /./ ~“p&&++~,~ drug product. [Note: This reviewer’ sjafecent IS ,ba.sed’ ~‘‘ xi,..xiiwx‘ ,\l_ tyI, <~, s c;n‘ ~~~“ ~Ran ttieii’ ““’ ‘ %*.,“*a, “ --+, ,A;‘ years of off again, ‘ again coi-Es~lEti‘ ~iti;“for-~~~~~~~‘ ., ““.“_SL,,&, cogently <ri*‘ iji+ T~~~ cannot ;rix,,*,O& even discuss the effqc$s+pf,gca,leon$,xcip/enf”berformtinde much &s,explain what the critjqal , interactions are.B”.L~~iS,,b~,,excipietitk and“_ API-X P;P,l.s: . .aI&t. _ %%&$i _the thk tfiaj, _...,1.-.*.*.,“-,.u,~s.;*~~~.,~~‘ BI ‘ I-* i product performance.] Moreover, since m.ost”EQA:rev/ewers ‘ ‘ comment”er f,~e!.~.that such revi;GGr;“ are ,&OT.formulator,s, why doesmost ~~;;;*I~,‘ bw’““~~d;e .,an _ the ~;;‘ /,,“1., ,. ,r I> rrr Ijl ,.,~_j.j”.L-,_. b,,) , ___,~.,_ .,:,*..+, & “$_ i’“,~.<,>$., ,~ .“.Y^ .-. _(. ,,,, _ _hlj, s, x,*a,‘‘ -’ I-’ “I,/\ ;;, ‘ VI_ .,.l,SC .formulators seem .toII know? ..~,1 ‘ *-I”.,-i.:~- __, ,_ ,“..) I,. ,“_ 0 “ i.^ *. ~ , , _, _ B’ .,_ . ‘



“The formulator’ job is also how much of each, excipient gets put into the formulation to give the desired s formulation icharacteristics The UA, _ reviewer probably doesn’ have that type .,of (I . (, t knowledge or skill and ,_“_ x ./I\_ .*-d.Y-~ FDA lird,-*,*+ ,“ii ,i** “. i)ortant is t&t the formulationbe presented it shouldn’ be needed.. to I review.,,+ application. What is im’ t ^ x, and if it works, what further discussion is .a.“. ,,a~“.* The “4 -r,q.,d&v-ir~R *I*i#.,+s the selected formulation. ,“ needed? ,,I.I ““(. firm is now bound by *i*i,rl*:,i


Now the co,mmente&argues that the FDA rev,ievvers,~do,not have . the same _ ^- __.-.: x level of knov4edge as the applicant fi&s~:fo~imulators - il /.-,,... *,*,- I I ^) . ..l _\ .- ,.,, ,. i j ^“_-,.a.* Ir Since the Agency reviewers ‘ ark $ci&tjsts, regardless of their skills .a? formu/af.ors, the application reviewers. 9)sII”_LU><‘~,~,‘““,,.~,“.“‘“, :such infortiation shou!d“11be ‘able ! tihen “.. .‘ ~~, .~“ is provided, to review this type of info~rrr#&n aqd cllj&nirJ~Pwhether.or,\,‘‘ l.\‘ .“.x? r%~..‘._.A not “8 ,d.e :-c ,.,h. J it is sufficient to support the applicant’ claims, s I. __ ,(,. L/ ‘ 9,__^ i _I_ ,. _ .\ ), : ,I,, *‘ i .: ~.-i_ ,* j . ,_- ‘ _ ‘ > ;: -- * .* ,(,.’ :.,: _, : ,( i . _ ._ :I .‘ 3 .” ,.._, e






,Y )_ I _






I ., I . :_ _, ,, , ,

Therefore, the guidance’ s requests In this area are, ‘ vajid:*,and. ... _ J-e ..j. ” _ . ),.” the applicant should provide th.e information ._* requested. _.r ,L ,$,,
“C. Line s 492 - 493 discussesthe development of the release_.“~-~ch,~~rsm,*?f ./ / -4. .,n” release product. It a modified -a*,.- l”i, _a ,“.W seems that this /.“, .1x bx ._., be’ should’ nec&&y when a novel or patented release system is used such as the CIT$ s. ‘ only & systemwhen initially used. For other.vvell”known controlled ./^^^>*~_~“..~j~ I.S.,~ ..,. “C releasing agents this should not be necessary s ince their mode of affecting release is well known.,: .,


ThisHavingl‘ reviewer knows4 that this commenter.‘ . *‘“-;: prob,ems :, ,,_ j *.,on its face. s remark’ :~;~,,.~~;l”*~~~~~~~-~.,~ *i;~~~~-i;;*t‘ j~~~~~~~ly~~~~~~~~~~~~~~~~ is specious assoc.iated. with getting lots of Hydroxyprdpyl .,s, Methylcellulose, USP”{Hypromellose, USP) . ,_.. ,s ,. ,” j ” from DdW that’ were” the sawm.eas ~.- ._I>.lots -**“l?“l_,,*,<.‘ the .)fi, used .,,\* “.* formulat/gn upon in _.,,. the ,: *,,, , which approva, and thG ‘ t:DA-accepted specifications’“~~~~~~“~~~~~~~~‘ a f~~ I -- .^.“_ ,_j__* I~ .^“(l”, generic 450.mg sustained-release Theophylline, this reviewer can attes t that the EXACT mode by which ‘ these affec t release is NOT ‘ known, [Note: In the .ins tance c ited, “even with the complete set of parametric mea,surements
that D O W ,was, able ‘tow‘ . “ai, provide, and the creation of a special grade based on , feedback of which &~~s~,produced acceptable drug” *uni% the generic firm .was forced to receive preshipment samples‘ of those three,: to .“. ,,. ,l, lots of .i”,l_I_, ’ ei, ‘._, _, five .il ./+*~I...*~ O W s . D .._” I 4/..s_ production for the m_onth that matched the D O - Wcriterra ( ,. O W “special ,,, _^.____”), = ’ isf>.7P:?$.. , .._._ _. grade x D ,, prepare lab scale batches .~?‘ ~~~~~~~jc ’ “~~~~~sS~~~~’24~sampfes from ea”ch lab:, . scale batch”(of about 100 units) in the generic firm’ &SQ?5,.cpmpliant lab, and, s based on the !ew/Q o”/~ja&e$~hy that-lab, and authorize ,D.&.% ship those zero to three lots that gave acceptable drug product using the pre-shipment samples (yes, 0 % to 60 % acceptable each monthfrom -. _,,^ **~*;I. (3 to 5) of the‘ O s of lots the feti lO percentage of D O W ’ monthly s that D O W produces monthly - a very small ‘ .~ .- .”I . production of lots of Hydroxypropyl M&hyliAlulose {Hy’ inello.5e}). So much @o’ for the commenter’ “t&r mo~e~,~f‘ s ?~~e~~i,~greIeask kno+n.“] is well

“D. Lines 537 - 539 states,.&at 1In general, use of an overage of a drug substance to compensate for -d egradation during the manufacture “of a product’ shelf life, or to extend the expiration period, is not s appropriate.’ This statement is basi.cally correct in that overages are not to be used ordinarily. However, this would-be improved by adding the following statements. The word “considered” should .,_, .,_.ji “~ be added j ) -8” ,I The thought should be expanded by the following sentence. ‘ However, before the word ‘ appropriate’ . certain important drugs would not be marketable unless overages were used, for example epinephrine solution. “’


W hile this overages _“.._ /” ‘_( 6-gcommenter ‘ reviewer,,and the ,~~~~~~~l”~~~““~~~~r agree in princ tfiaf such seem to I.’ arbitrary shou,d iecbgnizes. iple that
included 8 ..v,:_ ,e ensure that 21 ,CFJe I@l(a)'s formulation to* a) requirement of “not, les,tha_n..ipO percent of . ...” b) make up for los s e s during must be

production, and/or c) compensate-for unavoidab<!,e. ,de,gradation during production and s low ,degradation in the,, re.leased drug product unit ,.,., c A,. occurring within the drug product’ lifetime. s ^ A
“E. Lines 662 .- 663mention ‘ *-, mix- - .~-.r-~‘ reference to footnote “r~rr~.~~r~~s~~,~,~~~~*a5i; of di-2- ‘ ‘ ‘ :, 17 The level >&&A’ -*‘ , l leachables with ~~~~,~~r*a,,~i,.l(~~4r~~~~~ which states: ‘ * r’ .“+.W --.-<I s ”ji*,**,& ~~~.~,~~~~~“~-~-~~~~ :.r, x ~,& ethylhexyl phthalate (DEHP) leaching from polyvinyl chloride containers should be ass,,essed,and appropriate reference to DEHP leaching should be included in the product labeling.’ Again, this seems to make labeling requirements more stringent &n what is acceptable presently. As far as I can determine, _. ,,(, . _, ./^? .1 ._ ,> P “’ i j ,A ,, ,,: 1. I ^_ ;” \ _:<.I i .,^- ,\ , .1,I _) ~_ ,_ . .; 225 “,5.. j_





not all drugs packaged in DEflP ‘ specifically in LVPs packaged in polyvinyl ,,,_“.b required to contain suci;a reference,.-L..., ,, ,i __~ ...““. n _-_. l.>,li. , . .(. ,.“..

chloride IT

containers are _,, (, _ . _~ i

* ,_” ..:


The commenter’ _,. re,mar,ks“ here “seemB’ ignore ‘ the ai ,.h -,.l. ,, s r5asses, the *_industry and’~~~~.~~jy&%j, to .-?++ ident.ff,, realityin that, as timea this caSe, .‘.-_. ., (. i (, “-“^ ’ weakness in the drug-product s.afety controls. If the commenter *.(I_ 1,._*,wr.\< was‘ to- review the’ .Agency’ s recalls database, the ,: c0mmente.r would .find‘ that r*/lj “‘ only identified recently and, /i i.lm_,,*, thrs”&r%%m”&as ^/\ W/C’,,s“k . therefore, would not have-even.. thought of, much fess addressed, prior to the discovery of this ‘ broblem. As with all of life, the Agency’ regulatory ., “) I. s framework .) _a living and/ , :, _ is adaptable framework, The draft test offered v. ”InI>.,li,.I ‘-be,,,Iincorporated’ into the*‘ final CMC -s _.,I .I .,l-lj,.., should .. ,)i,, ‘%friw, -,-L” guidance because the,. problem it addresses”@ reaj::, “__ _ i ).. : . ;. ‘ j _, ,V :.:,,(3..)_‘ j -*“.‘ !,,, ‘ ,, ...-,” ,. b,
,) .(,.‘ ,. ^.


“Shortening the Document We recommend deletion of the follo~wing in the, draft guidance:

1. In IV. Pharmaceutical,De,velopment (P.2) that lines 377 - 6’ be deleted, about 7.5 pages. Allow 78 firms to submit what.mey believe should be in such a report (section) without instructing them as to what should be therein or providing them with a ‘ how to’ guide. After all, the i%ms have developed the product and should ..“.(_ ~.-, ”best. .*IxI_ , know it ,,,., /~_._ Depending on the drug that was developed, there is no reason for such a report to be in the same format or cover ldenticalareas,f~~,~~~“~ntgs.” ,.,i.

22: _,This reviewer disagrees because: is.”in a) iogically ’ ratid~~~~;;v”-.~~~‘ ~~~~~~~,~~~~,~,.~~~~~’ the commenter~brovides the ndindustry’ kee,p-ing with either i) s “-1.1,. , “ii‘ ‘ ..“* ,...,,*~a.q,~>“~~~* / ;_:, avowed goal of uniform r&iew‘ or~.ii) the Agency’ go&l of receiving u-niform s applications that’ provide proof of -compliance to all facets of- CG#lP; and b), based an this rey@gyq’ qperience, this section is a must. $
“2. Delete Attachment 1, lines 1856 - 2 116, about 6 pages. Leave it up to the ICH and individual firms to recommend/select spedific’ tests for specific dosage forms such as appear”inlCHg~dance Q6A for solid and liquid oral drug products and parenteral drug products. As noted in the, draft guidance, the universal tests have already be stated in Q6A Allow firms’&e responsibility to select specific tests that best “ describe and control their products without tqo much rote instruction IC,,.I-.~\__sI”~~ ,_ 1,“, __ _. from-FDA.” i, ,.2d”““l*l i”~ :


This reviewer.,.._ ,-,, .,_;/_ _^_ illcommenter’ .,*~e:F&.“y&. have little to do with the I.::<*,_/ finds that the s 1,w ii I,,&+- u aremarks ,dw:, fact a*! I ,;S”~~~~~~~~~~~~~~~~~~~~~~~~ _‘ S‘ reporting requests of the Agency justify (establish) scientifE5ll~‘ shnd and appropriate specifications, standards, sampling
plans, and test procedures designed -to -assure that cqmponknts, drug product container& ‘ closures, in-process materials, labeling, s“*ea., -* .“. and drug products conform to appropriate standards ities ctinnot be of identity, stre$$i,“’ k$&ty, and purity.” - these resbonsibil’
“L eave it up to the ICH and individual firms to recommend/select specific tests for specific dosage forms such as appear in ICH guidance Q6A for solid and liquid oral drug products and parenteral drug products,” this WspOI’ Si bi I ity t


delegated Contrary

to the commentei’ s

first remark,

is the firms’ ejone, it cannot be delegated‘ the to‘

ICt(l nor does”thgAgency’ s

_,\_ a: -, . )(

;,,- f



by asking that the applicant ,,draft guidance, information, in any way usurp that responsibifity.


‘ the


3. Delete all references*hat, appear in a” number of places in this‘ draft guidance to additional futuredraft guidances. The latter have,^I: ^ ‘:,a.-(a”1 ‘ .,~.:~,‘ or at least are not supposed to have status and. therefore a- no real status at WA ~~i~.‘ :‘;e@+&#&+p&~~ ,I. “ ._ .‘ % #9 ~l,~‘ ~*~~~~* “ ~lines. really cannot be factored into “&is, particular draft guidance. Th.is,“wj@ ~~~~~perhaps”l‘


This, reviewer, agrees that reference.s ,to .non-existent .bii;r.*-ul*Yn*, should “am??~* * IS” .e. rc1 *,sl,.-. documents u*~~~;:~~“.~s d.. - ,i*,**_*..jl ‘ ,-a. .<i B‘r,N$“.$,‘ $“** &<,,+“y,- be ,‘ removed, but thinks that, the, Agency‘ would do well. to incorporate some specifics from eSach ~I_)(<_,, .,,., **.“+ .l*i,“li$ idance and, by adding, “When into I<~the : CMC’ gu‘ , published, the guidance in the specific guidance will supersede the general guidance currently bein,g provided,” allow the.CMC guidance to be finalized and issu,ed irrespective of%ie future guidances. ““ ’ .,. ,

“4. Delete Table 1: Example Target Composition Statement and “fabik2: Proposed S&h Formula (no ‘ line numbers a&&& wit& these‘_<“&I _l_, of _^X. ii.<* “in(Xtablesj. Will save at g G@murn~ .a__ 1 page. Firms know how to .Lq +,r “>,-a prepare’ batch formulas and coniposition statements.”


This reviewer strongly ,disagrees because’ on more than qne occ&@n, this reviewer has found that the formulations i**<tid”““*,”._. for sub.mission and, in (’_WWi~ developed*, ~!i’ ap<L&>,i,, ’‘ -product batches ‘ having,,’ on average, some cases, approved, ^.’prov/deddrug a batch level of active _thatwe._.d&* (.,ii significantly than ‘ was..r, .I/L_,*,,* less !t8fqi (down to 96.5 .,,a i .a. yO in one case) of their label cla.im.,“or targeted level. Since the proble*riis~~~ij;i~~‘ s~~ral in‘ firms, some firms ,not~-only do not know ~how’ prepare CGMP-com’ to ijliant’ ~~ias fd;‘ but’ they ar”so “do & do so. Therefore, this com,menter’ proposal should. be rejected. g
.‘ : “_ _,l . I, , :


,. _‘. _: .; _.

_‘,/ : ~-.; ,

\. , I .)



.’ .,: -, I’ .

Note: The qriginal INTRODUCTORY &jt$~~&n~s e” .-is are quoted in a condensed for$ (&&&a), ““A.,>. the quotes directly from the draft guidance are quoted in a -$ylized font (Lydian) and this reviewers comments are in* 9 publishers font (News -Gothic MT’ to’ make 3 e&i&’ for the)‘ reader to differentiate the “speaker” in the various, text passages that follow. In this review, this revie;;;e~s~;7‘ U;;1bere~~~c;~~~hts-~Fe~^s.imply made after the ~~,~.~~e,tIfers~,,, _ *l..I 1*.-- ,a6,l, z,;?x*i*-li*il x1* j .. _.( \ ;. remarks. .~i”,_” _, ,,. ‘. . ,.

, ,


This commenters begin by stating; “Aegis Pharmaceuticals Inc.” submits these comments on me,.Dr-aft j-b SW, .~‘.-*si Industry on Drug Product:. Cbemistry,.Manufacturing Guidance j,.for and Con,trols .* ,.*>.**,*< ,,,, a”-,bd Information; Availability in response td the Federal Register notice of’ January. 28, ‘ 2003. This Draft Guidance addresses the information‘ ,lJLabe--submitted--ii;*,p9.Fh “~-““‘w?b‘ “1.c_>(to. _.. _.,, “,‘“$33 in ANDAs and NDAs for drug products to ensure ,,,I * l~ -qz+ “Micuf i;~;rz;~~-~.;,~c,,:~~,~~~ ~.*y h continued product quality. Recommendations are provided on the mformation that should be,in&$ed for (1) description and, composition, (2) manufacture, (3) ‘ control of exkipients; (4) ‘ control of the drug product, (5) reference standard materials, (6) container closure systems, and (7) stability..‘ Information is also provided on the type of pharmaceutical development information that should” be in&.&d in, an,, ,. application submitted in the.~ Common j Technical liCC>~“,v,.I~I)(CTD) format.” ..‘- . _**,xi.a*.; Document @A .p*.a;*,>
._ “Aegis finds this draft guidance an unnecessary escalation of requirements’ for the submissi& of.,WD&As,, and NDAs. This escalationis most >. obvious.”in the requirements for ,the Pharmaceutical. Development .x *, “1._x_.II ,,h>..*,?wn/ ,*?xv,.o^rr Report (PDR). Currently, the information described- inthh_P,DR_ is reviewed>~.a I &1.1.%, :*p:*q%.““~ .,.~. .,” ,_ I?a.. ” with a FDA investigator d,<l<rl..~,,d%~a~ during an FDA audit. Indrug developer collects this informationas the process is being developed and it content and format.:fs sped’ to the SOPS of the developer. This new requirement for inclusion in theific AND A and NDA- ?nd ,me, prescriptive guidelines presented, will burden the Agency and restrict the development activities of the find’ ,, _ _. _*_,(, . ,_, II) j_. . “_ I. _/ “, , 1.



First, this reviewer finds, that_/ _.I ,,*.“(“-“q I_,. ‘ ~~~*w*~~.~w”^of ~&ds~. word ~~~~~~~~.‘ ~:~ _l..l this commenters’ :i> use^*h, cri”.,-i*i “ I&1% *.-*, “-“pf the ,aa~~,~-?,;,,‘ i’ .’ ^j,, ; ._ h ,.. : ,‘ i “ escalation” for “increase”, @,eifh*er:! a) an unfortunate ‘ choice or b) an indicator ,of the?, ccxmmenters’fy* predisposition to resist any change in .) ** T<p~y~~,~.~ -. _ guidance in the C&lC sectjo”n, gf,an‘ aijyjlic;ition. Second, the commenters “vociferously” object to~having to file the RDR I._ _.. . *,*a ii..^_, _ section on the grounds that, “Currently, the information -described, in the PDR is., _j Ib_.,,l ,,..
reviewed with a ,PD.A,m,vestigator during an FDA audit. ”


In‘ ma,king this comment, the comm,enters, ad”mit ,that, that~,‘ ~s~,m.e’ __” ” : burden is curre.titly on the FDA’ inspectorate. s Thus, by requesting that same /nform_a_t~ionto &submitted there w,il! ,~,,, -, __,, be, contrary to the itiplication borrimet$e?f “rqt$a&.s, no additio~gj-‘ ~Z~~e;7‘ on ’ the Agency. In the commenters’ words, the burden,wiII just be reapportioned so that the larger review ,staff ,“,$i”l] just be relieving some of the red,uced inspectorate’ s burden. On that basis a,lo,ne, the review process should be no slqwer and _ probably faster than is currently the case. Moreover, by requesting the informationJnazti~standardized >N_I .*IJ+ _ ,it format,_( -e .i :.a<ll,. _ “l.r.:,“*.*I* .y Al will be easier to revjew&and, unli,ke the current *, I,(“1-x+-“-. .,, state~of . _^6 affairs available so _., ,rilirx+a~,*J _,,, _ _ilif there iS,* question, the FDA auditor WilJ not have to hunt through a that il., d’ :.: “a d, \ ,.i:I” .I I’ “ -; >: ‘ ,‘ _*_ __‘ “. ‘ .... , I,/ i .:! .>:‘ ” L

‘ -: ,

large mass of unstructured vh--s.d-*~b.,*,~,_l.~,*‘ ,,,L&.&L%d%-<pi,.>+. ,&~:$A~“& / .:,’“-)/,l_., ” :to find ((^*,,. the to j i’^”1.“-.-1 s .LIii records :ln*,,*;*&“b*;~ information ‘x needed ‘:r, laW\SUIL~ @ ,,‘ .c;:.,::~?: ‘ :xr ; C% $ : ‘ r_,, confirm_. .compliance. __; Therefore, the com~menters” I WI o--RI1 with ~~~~,,.ir/~r.~.~ ‘ u--‘ ‘ ,” ,__,_ , * are -~i.~~~,~~~‘ the nebulous objection, j, _ “-‘ left. i:,~,~.~~;~~~~;n*l~~ .,_l/ w$&a&!.** ,
“inclusion in the ANDA .,. I** w-,m and the prescriptive’ guidelines ._-and NDA presented, will . . . restrict the *~.,*i*,~~~~.,,~-~~. ,:> j development activities of the, f&m.‘ j _ :

. 1.

Apparently; -the ‘ coriimenters choose +yo i~60t??th6 “posit:% bene-fits.of‘ being provided an activiti‘ ‘,I/* .i~.~“~‘ es documentation ?A,,, wJ-bw%~ to providing _/__111L roadmap the ~-.-lx” ..“““, _.>A. ,*irl.~““r\_;*._ .,/,&_.“./ x ., _..-*. II ,‘ ,\ ., _ Agency with an easily reviewed submission, since this guidance. only applies to the:‘ jnfor”mation Moreover; requested, it does not in any way, shape or form “restrict the development activities of the firm’ ,” provided, that firm’ s”, c.~r~“~“~~~._systems are.~,,c@?!,p ,- .1,”. ., compliant. ;is ‘ guidance, ‘ simply outlines what jsneededand .A* requests-that it the ” ib.ll-ln_~.4 _,>. needed information be provided in aWdefinedrstructured manner.‘ II ,.., _ _ __ ,.-,..- l-~.I~h-~..l.,“% I, </_, Iwl~k*.ririr ** “_,._,,” If, as the commenters, assert, the firm has the )N,. %xjS .,.b_,>a..* files in a _ information .-” its -“I”*L,I,II,,,~“~I*“, ,i “*“___‘ in **u,mrrrs ,&,& format different.th”a,,n that~requested by the guidance, the firm may elect to submit it. in. its, original format provided’ truly ?f‘ does meet the requests strictures, note the format differe.nce*, ‘ and provide a-simple statement that the alter.nat.jv,e format 1ib4,,i..1*,, is equivalent to that .in ‘ the guidance. I,.“_re.*,* *,/ -_I
“Aegis recommends that ‘ sectiijn~ ,of .,“2m”l.,ia<,*r.CI~%~~Lr&~~i,\,.m,. the requirements are escalated be __ __ this Draft Guidance .awhere 2..j ‘ \ ~iv”;.d:, L. ~“..~~~.~~~~~~~ addition? eliminated or changed. These sections are detailed b&x,,..- In,,.* lT~,~i.-l,x, Aegis recommends that the 8 _ pages of the PDR be replaced with a list of topics that the ANDA and N,D,A applicant should consider in. ” the process development of a drug product.” .



For the reasons eoutlined *aka.bhi?l~,~~~~~~~;~~~~~.x,~c.~~~’ ~~.. (7 a. ** _ :...,,e s, ._, I) , in s ;.,..,_sl~. 4,sr ,a***.; Reviewer’ 1 this ll,___ _ l-il,il^-.& ,,-,, a* *,_ reviewer~‘recommendsthat.,p M ,^ ,‘ _),_ 4,. ‘ the comt-nentera’ remarks .*.be qi rejected. - ._,“_ _,,+-/_ “.,_.*\
-.“-.m, ‘ _ ,

. _,.-


., , .I ..,_,. _ Aegis finds this, draft,,guidance an escalation of requirements for the submissi~o,nof ,AED,As, and,,ND&.- _ This escalation,.occurs ,in>the Pharmaceutical Development Report (PDR) section and other sections of the -.!a. “*ai <r+,* ir”i.* ,*,&.~,4m,~“.“~*.& jinxr ,6 draft guidance .”


For the reasons -.~(-*..’-‘ -;xil.l^l.<.i.v.Y” s .:.+ this ” reviewer recommends ‘ ^”-; : outlined in Rkviewek’ X, ,,.rj,_ __()“( -I a .‘ -.*.,:,-,.*%d.;, ,, ._ ‘ : that f.^ ‘ ., the commenters’ remarks^“,_j,I,/ .. 4,,,”*. be ignored.

“Presently, the information requested for inclusion in the ”PDR is *a /(/A< ^^_ vi., FDA investigator during / +---/il”,_,. .*a-,*,-7 a #S.-l 1 reviewed with iTJ,,& “.~~“^“#+aq!*~4 a FDA audit. The ilnformation .~~~~*~~,~.~,-r~.“.:~-r”*...i*i, is being developed and it is specific to the SOPS is collected as theprocess i_ a,“., ._“;, +a‘ -. ‘ i*,>;_l.* the prescriptive NDA and‘ of the developer. This new requirement for inclusion -in ,me ,ANDA __“,X.S>“~ .~o-“,),,r*wr ,- I and I”‘ guidelines, will burden the Agency and restrict the, developmentactivities of,& firm.” _


For the reasons out!ined , -in/ . Reviewer’ ‘ this, revietiei s 1, .- x+ 4i1~e.q,*,&,Mi.(ir_* ,, -. I ““n* the commentersr remarks,‘ I) , \ ignored. be ... ,) lj “_.

recommends _,_ ,’


I ,

:‘ :o,;

:x _


_. ^‘


-1 ,

‘ ,<.

j‘ ‘“..




“Thev<..^ .,,c “d.*i,‘ &e 3, to Agency will be in slowing the rev& .mdi a$r&al ,b..l burden- .I-.-..in;-u*. will be a large and concentrated report addressikg chemisti-y, formulation 5.

of ‘ ANDAs and NDA. +pe and analytical inform&ion.

FDe’ “

Base-d of re”iewing‘ burden on the +qq-qenter’ -;;yf s

own f$kJy!g.@ , ‘ h-vz b\gency already has the yjji“ inform~fion~.~R~~:.~~~‘ s.“~~~~~~f_,~~i;d~~nci! ,is, .(., _

requesting” be” su%mitted and, because it is jn an u,nstructured -ljI.ii,.“,c_i,,‘ ‘ mas.s .+x. of, 8. .^ rec’ ords, the Agency currently has the a.dded burden of ferreting out and piecing together the inforrn&o,n ne,eded, .._“_r.,i -*, from disparate records. “me_ “__ Accepting the commenters’ rema.rks, $3~ PDR ‘ @II/ reduce ?~e~&[t&? , , O~I the Agency-d increase it.

“The typical review


does a

have the, skills neqe:$ry resources

io assess t&


bf t&e diGelopme;t ,. “,.

activities. This.will.Zi * lea-d, $0 -slower reviews, ,additional * .,. . ,* I~*~L~~“,.,>~~-**l guidance.”

and $p+~t~~,t .‘

implekentati’ o6 bf the I, ? *.~: ,. ” ,_


While the typical review ,chemist may ‘ exist,’ this?eviewer, *for o’ ne; has never met or conversed, iv(j$ t@$ persbn. Moreover, while the FDA investigator may have as’ little as the equivalent of a degree in some area of science, like Geology, the personnel that review ap@ications~are persons’ ~typicaIly fhaf’ have degrees and often advanced, degrees in the relevant sc[en~ce.s.~, (e.g., chemistry, bi,ology, chemical engineering, physics,‘ ph,armacy and the like). To be a Chemjstry Reviewer, you have to be a bonafide Chemist. Moreover, such are more !ikely in today’ FDA to have the skills to s assess the quality’ of the ~devek$%nent activities ina firm than some II,,I.w*IL ,.. who _j ^I _ ., +p&r’ additign, this &.l;t~&..> ,_* expefi&+cg “is ‘ iii “lh:~~..cjrj&j reviewer,s’,~;/ ,;.i ., In tKaF, ‘ ‘ y;&yp; -the “Re,/ie;ij -& a Chemist,s..(wqrking in the same physical”/( location as their supervisors): a) r _I ” ,,,*b*.,, a, tend to adhere to’ th:eir~c’ klist~‘ , Iil4, “-d@ * b)are”able, ‘ ~ed’ 6eZter. .ir and by-looking at the &u*“m . information provided in the forma‘ t~requested,~ to ascertain whet,her “r-not ’ the information requested has be”en’ provided than an equally qualified investigator at a site can by digging through disparate records. As Sam Clark, now’ an’ % -FDA ..investigator ‘ the ‘ in’ area of software, _ t validation said, “If I ask .and you aren’ able to provide the- documents requested, I need go no further.” Thus, by requesting the informati.on provided be furn@ed~: ,in a particular format, even‘ fiIing’ ~clerks’ and coni~uteriied system’ can be s’ trained to recognize when requested information is missing - detecting mis.sing records in a submission ~i.sn.ot :r.ocket ,^,I” (*-km‘ .I *I science.”. ,1^1 .i n * ‘ “” _, /&< j;, For all of the preceding reasons as we’ fl,as:those s.tated in ,Reviwg’ i, ,s‘ the * this reviewer. finds the ,comm~enters’,.,*...,@of .woes .%\.‘. \* “I,<%% , * .,“ list *,.. -., ^< to $,, ,Agency”not*only ,,“, ,,_/,I _,.‘ unconvincing but also at .odds with,.reality. I

,, I_ ““~“~“‘~“.~~. /;, .y, “The restriction’ in -me dev,elcpment ‘ process% ‘ Krm~Gr1~ come. from Ime developer s tendency to the’ ~ ., ..,.,e”*, _, 1, _ _ , .,L, /. : /(.. <~ I., satisfy the prescriptive reqmrements of the PDR and not ,fully explore the process parameters. This. will result in a less comprehensive characte,riza&nof_me process.”


The cornmgnters remarks are inconsistent w.ith~i‘ processthat .&gqt..>~ _,I~ _, the ,*; *,,#z *ws* the fact ‘$*<*~r& ~$si,guidance I 4 _ pushes the dev~~b;er’ ~~~~~~-~“~~~~~~~~~~~~ *,i* the *&?g***& ;yap;‘ parameters (1 but also to gather and re.port the documented evidence that~,supports the development process’ validity. Since the guidance ‘ addresses areas,;(such as physical properties and physical property interactions) that the current C,uC guidance does not, it is, or should. be, obvious that the, opposite will happen - a guidancefollowing applicant will provide proof of a much_more, comprehensive ,,characterization of the process than is* done at present. Thus, Ghile warning of “Agency ‘ slowdown and burden, the commenters are actually transfeirfng the‘ firm ’ s concerns,<,.,of” the jmrjacts on its submission schedule / to ,,._ “. the .a,,. ...“.,Agency. Based on the preceding realities, the comm.enters’ remarks should be, discounted or, in the least, taken-with a large grain of-:.,: ,;-. salt. .’ ,.

“Aegis recommends.that the f3 pages of the PDR be replaced ;?lith a list of topics that the ANDA applicant should,consider ,_..II~. the process development of a drug product.” .<, in “.

and NDA


This comment is. b-utan .I almostc,/.~~~.~.*‘ repeat of _I -.,li, exact ><.,*C,~,,” a remark made ,earljer (in _^ the se.ntence preceding Reviewefs.2): i I .I ,;,’ : : J ‘ ,_ .j_, ; .
examples of requirements escalation are listed @o-w: x1 3 A. Lines 68 1. : ,970 V. .May&~~~~e 0’ 3) . This section stageqlrat a flckd~agram should be included for the rnanufacmring process. Previously, many, but not all submissi&s:j,ncluded ,.“““,“ln c j.%,diagrams. To require such a diagram is requiring more flow .._ information in the application.”

‘ Additional


This reviewer agrees with the comment&’ first,statement,,, _ I _,_ /_ 1,, Then, the commenters. state--that,- ‘ many, but n&all, submissions included flow I‘<...~” ‘” reviewer accepts-’ ’ diagrams ” - another stat.ement this ,i.. //, pi,.._..‘\*x~i.4xLy-.i-,.~.~ .. “ ’ es*, I* However, based on the commenters’ “, ..*“....__.,(A,) first*“P ;‘ .t”*s*s”~&>‘ remark, a “should” is !@I a “ * “must or a “shall,” and, therefore, this draft’ gurdance, contrary to the commenters! .thi.rd statement, imposes no re”quirement. / ,-_~,*I _., Moreover, again accepting ‘ the commenters’ _observation concerning ,‘_1..*_,A*, ,. 1. ,) I. today’ submissions, many already include flow diagrams. s Thus, flow diagrams or their equivalent have”beco,me ,a de,facfo~ $XMq requirement even though- they cannot be set forth,. as .,,a guidance and cannot _ be‘ made to be requirement - by definition, guidance isnd .. synonymous with ~equiremenf. / _.




-; “ .” i

‘ , A”.. ,^_ ._

‘ ,_


, ,;




* .,



“a. The’ flow diagram is discussed in-lines i82~7961des~~~~s ““*.I *‘ in detail the information &ua~$*& should*( -, i ‘ ~“<h,l(-,~irii Ii _r;‘“,G”i s that LT. 7’ & ir.t ,:>.s&&;x, be ,F,..J>‘ included. These.include. weights, critical process controls, and the equipment used. We believe:“‘* j --,” _ that this is not _”necessary information for a flowchart )_ and-“m,8.P.i-““.,i informations. already exists in other .” II X,“ar% the -‘ _14i*xi* ,\.ii*i,,+,,r I 1.-1 A.“. .“,- .. .;C WA> sections of the application.”

..*( ;” ,





This ~~,~.~i,ewer-:,respkctfully disagrees with, the 1 com”mente$ 1 re,m/r~ks,~~,~ ., concerning what the’ requested” frow &giam should cover and thjnks, that to cover all steps that fall’ under CGF-R, additional steps should be included. That information exists _,has *.. ..“ .,%(l,.,_“. on’ whether’ or ‘ not ‘ flow a’ II, no ‘ bearing /-.i, .. _ diagram should cover that information ‘ ,)^.,I ,,“. , .‘._*., ., “. **. s.““,i-“^_l.i 3” ..*,-,., A “, /,I.I^x, . ‘ _* &I‘ ./“, how can anyone” generate ‘ .(. a flow After all without,, any information, .^ diagram? Aren’ all flow djagrams high-level overviews of jnfor,mat,@n~., x .,l,, I”,“_ t ..,^ Based on, the.. preceding .reaf%es;“this reviewer not only supports the ” . scope of the flow *diagram currently requested in the draft guidance but also thinks that it’ should ,,I be ,:_expanded to cover ,>al[ aspects of -_,+_I ,, . ,V”,_ ( 1 “^/ manufacturing from incoming, through in-process, to release and .. distribution.
“b. Lines 8 16-822 discuss>&e, desc-ription of the manufacturing process and the difference ,.that ,, .,,, “. i , r_X., exists between requirements for an, ANDA .and._^.i, 4 .s,....“”Both of Ix”,p:., applications should have the same ., -_ NDA. J1_ _.lxir~ill these reporting requirements for the manufacturing process.




11,. First of all guidance does not establjsh requirements; it si’ mply provides an ‘ ‘ apbroach to satisfying requirements that the proposing Agency, \ the .FDA in ^ _^ this case, thinks is appropriate. Second, the lines in question state: “ForNNAs, the, description of the
manufacturing process can be either ,a d”etailed narrative ,“*_lyl*(__s or a’proposed master d&$ptiori “,,_. ,S‘j..\__l*“.j /,” “<, production .record jMPR).2z -However, CDER and 17”“. prefer that a detailed narrative be CBER -, provided for .an ,NDA. __ ,A@&, the proposed MPR should’be’ For submitted, A: narrative description should be subn&ted to.-suppleme.@a M.PR when ,appropriate, for example, when novel processes or technologies warrant ‘ description in greater level of detail. Executed Production Records should, be,provided in R. I .P.” .,I .~ _‘

Thus, the text cited i addresses &‘ .y_\*+~‘ . _ .“A.//“.” “e-4 ,ll* .,/,.” .differences.,in the presentatio,n of the i_/ informatipn requested and NOT difforences~?“n”~ inforr@tion -.r&w..“rli/ ,#S,\ is j_ _., being ,,j sm.3 . j , , ”: I ),, . _, ‘-*”, /,/(_. ” requested.“ Third, all such application CMC sections do, have, the/ .. same’ reporting %* A ,\. ,+<.,,*.<,7r requirements as set forth, in general, in the CQVIP., regulations 2%. CER.2tC. and 21 CFR 211, and, in specific, in 21 CFR 314 thro,ugh 21 CFR 320. Based”. on the preceding, th’ reviewer thi.n,ks that. the com+me,nfers’ is remarks should be discounted. ,e- /,. _ , _^,_o (“) *‘ /‘ --aG_ ,‘ a 3, *_,a% ,,,>,__ ,“. . >../. .”I ,./ ,._ r _.
“B. Lines 975 - 1126 ”VI”i: ControlA”“*of I”ir-xr; Excipients ,I* .‘ ) ,*,.” (P.4)” “a. Lines 1984 -,, IO87 list the criteria ..d.d..i. “,.,ir* justify proposed excipients specification for non-* ,.._ needed.to I”, relevant * _I_“1 data, batch kalyse~, data compendia1 excipientg . The crite+include,“i. -l”,“l/_/ ;I,~,“wl development ,l,*/jl,, from drug product stability studies and informa+tion,,that,-is presented in other parts of the . +, .:, application. The statement that this justification should be as recommende,d*for a,d-pg substance : - . “_ d. .^ ,- ~, _ ,., ^ .,_ A .r .1 . . ,“). ~, ,1”..1 . _,_^ __.” I . __ _ * 232

j. ;_

guidance) is a substantial escalation of current requirements (which will b,e g iven in a forthcoming it is up to the &-m.to justify the chosen specifications for nonwhere, per current practice, compendia1 excipients according to their own SOPS.”

First of all t~is~re~,~~~~~~,,agrees with Me. co.~menL~rs~~ ,,@vlied objection to draft for “*d*i.,,_ ,. references” _.. .^^“a“.(” L__l~_c, guidance” th:at is not ,even _“,” ,““ir-ixrii-h^i*xx;r~~i~wr,~*CI.. “~,,v)ji,, _ to .,., forthcoming ....I available 1.‘in *i”c _“_ae.*) ,&eai_l. ,x .^,__,,d_ nL review.

excipient specifications should be provided where* appropriate. For compendiaf excipients, justification pf the acceptance criteria for testsbeyond those in&d&in 1 *-L, monographs is the .,MIa.,._*.*yc The specifications for recommended (e.g., particle size, flow properties, impurities). noncompendial excipients should be justified as recommende~d, the drug substance for, (guidance will be provided in the discussion 6,, section 3.1b. “v.of the forthcoming drug substance of ,ILcs.*%-. ““ir~*“~~“u~irn~uc,,~~~~~~~~ S.4.5 ” *“I guidance). The justification, should be based-r.r-6.. I’ ;development data (P.2. I .2), batch on “.“W”“‘ Li%a:r**.“% relevant -w-Y”%-. .c.-,_ ^..,*.* “,, analyses (P.5.4, R. I .P), and any other relevant data, such as,data from.drug product stability studies (P.S). The discu&on in -I i I.cil,,.. ‘ IS this section .“&eyJ””unify, either by reference or in sum.mary, x. % should AV+,Jg&b& dataReviewing )_ this ,.“,.e4A**rlocated in other sections,of the application.” and informatibn that are _ ,,_i* __,li par~~~~~~~~~~~~~~~~n~~~~~-~~~i,~~~~ “lIxI1 z, nbP6g is, thaf Such


.are /,only


@h.ere, it





(“Justifications for, the proposed excipient specifications should be provided where appropriate.” [with underlining added foremphasis]. For compendia1 excipients, the guidance simply requests a “justification of the acceptance criteria for tests.beyond those included in the monographs.” ^ _- -/ >, lX1~-rrirur.-.*rii.~r^~rrrr*-“~ For noncompendial excipients, the guidance requests the “specifications for noncompendial excipients should be justified as recommended for the drug substance”

which is th’ protier ‘ eir tretitment because. by law any component of a drug product, including excipients, is.a drug. Nothing in the proposed text conf!icts with the,co*mmenters8_._, remark, “it i l_V. ,,,.“< ,”; **! ” ~
is up to the firm.to their own SOPS” justify the chosen specifications ,for n&compendia1 excipients according to

provided those “SOPS“ a@ QG,M,P qynpliant. I this‘ reviewer fi,nds that .II...the%‘ only objection ’ ad., that the 1/“. “ .~LmM I ‘ c commenters make i that l.l is valid@ “X~~’ implied one concemng the . ._, ~.W~~,‘WC”~L-es “, “r” is the ,.a-+~*<: ~ -8.~~~;,.~a,~,,~?,;~‘ ., referencing of non-exi.stent dcs,uments.~.,. ,_/.,_.. ,. I \ ^, , ,‘ _ -’ ,’
“b. Lines 1121 - 1125 for novel _(_, h.‘ k&ate that full .deta& of “f manufacture, ).“_^/ ,_ .I*lb_l. x, “. I.jas excipieuts _“X_l characterization, and controls,,.with ---^cross-references to a,#**qr The .,, ^ “9-.-i “,-. ,“_l .l-.“.“.l,,*sj*safety_,_Idata should be provided. .,-, disclosure of a novel e,x,cipient’ manufaciuring’ s Process to a drug product developer is rare. This To require ‘ the applicant to include, this. .in information is -most likely to be in the D&IF. application is unreasonable and-~an escalation,,..,of , ,,, , . requirements. I_ ... (X .a,.,.-ii- ,__^,


The commenters ,,, .,c-dl,J .‘concerning __,_ ~ remark- “ *Y-&s.:rsP#-.:. information “in a DM,F is a red, herrj,ng ‘ I .‘ ., i, 3“ ‘ ,_ because, as the commenters should,,,\l.“.k _.ll _ . such contingencies are ‘ ,‘<, Iknoti, ~ %I l .tia “.!’ addressed. by the applican’ s’ referencjing the ap$icable c’ ~ portions of th.o DMF an&the, ,Dv,F ‘ .,,vdvs-. ,,,,~ holder‘ providing s a .“l$Jer of authorizatjo.q, j ,, )_ ,_ FDA .-a, ,_ for,,!!-& “a., ‘ I I.“.,& .W.~ _ j )<.” .,. to review”.that portion of.the ”filed r DMF ?I *,*_. . __” .~ ‘ ,.,.o *. ib j ‘ ,_ .. . .‘ , _ . . ‘ _, -- ,. , _: j. : ) ,. ‘ ; ~ ‘ I. :- _’ ‘ -:,s_ _‘ _,_ , -’ _ I 233
,_(,_ .,-



in some cases, it may- add to the body of unreasonable though, informatiqn requested. Finally, because the informatjon., request is conta,ined in, a-guidance, it establishes ,_ .. ~_ no requirements - only provides an approach to establishing / “.ll . j that a firm operates in compliance with Cf3.M‘ p(,z Therefore, the remarks made by these commenters: shoujd,‘ be ,, ,/ discounted.
“C. Lines l! 29 - ,I 509 W.. Control “.-...>rir-,*i:d,.:. .I . I” j”<,l of Drug Product (P.5) Items a, b, and c represent an escalatipn of requirements.”

_, ". .,_ .:.: I" .""^ . .*.-"_ :I,,. ".i.: *::,,, x .% ~_‘ Based; the' prededlng, +-is\ rcj.i&K+' on thg n~~a~d'li~forinsfion.is..N*i L.."a .j,_, ,,^ _ .,s,*.,, MI _,_",

~~Fo~ALCOMMEIC~~~'T~PUBL~C~~~CKE.T -.., .c,-.*;?=.;~u"'sxli~~ -<*.%. qs XW' sx ;*" r,~~~'~~~,.~~~~~~~~~~~-~~~~~~*,~~~;.;"~~,~~, \~~“,~,~,";,;^.,"~~~.,‘ '(/,_ ._ ":‘ z 02D-0526 ~~,~~~~~,~~'~ i,‘




Because this text “%“a/_,. itd’ ~d does not attempt , S.d is .‘ guidance dacu~~ri~~‘ a~nbt.a’ _/ a,“#li to change requirements. It simply modifies the portion of the, requirements addressed .in. t.he CMC sect.ion of ani .n*.application for whi.c,h th,e ./?gency is requesting the ,-, applicant to incjude~ supporting documentetjqn that /establishes,v , ,_,.-.-“_ ., Ij,L1c.,“‘“;sl”,‘ ., ~, ,, ,,_,.. ..$” compliance with CGMP. ^_
“a. Lines I 153 - I.I5$ s+q‘ ES%‘“that certain in-prdckss t&s be performed in lieu of @shed product tests (such as,hardn+ss.an$ tablet weight) and should be included or~eeCQ& ...%%$“a 1., ,.*/ ‘ ,vm*j/ standard practice and it does notS gppear in the GMP regulations. This is not con.@tcnt with current requirements and should We.,,<” .s . -,I be changed.” .,,ll..&ll _ ,_


15. &,the followjng will show, the commenters’ ..S”” Y vI...It.l., /.i ^4 misconstrue remarks totally _.s. -, ’/^ the text‘ andthe factual,**“, i-“: ‘ .e?ere?r; *“yx*“pk,~ the text, “.*,* ,--,-9.i y,) ,I..4: __;_ _$) * l_l realities associated with. I”ye~w~lhli ,^.“__ *_ *,,.di iwwi.Y%‘ msl*(**> “l-“.“lw ” -:.,. *” *:.;:* I ,_,,_ In context (Lines_l‘ .P4,-1,~), the text In question states:
“The specification sheet should lkt,alt~tests-Ito r..eeaw~ hai”.,.ir*,i*ur,.~~~,~p\‘ drug C * which each batch of a ,.A,‘ product will conform &ire**.. & and the associatedacceptance cr?eriaq.a.nd. shouldz,..“._ .A,,”I%.~~>,i.li+-“.<.*-i.*.>:<- analytical a.lso.include a,.i #lib> to the$7; * ., .F‘ >d reference y&.aTS’ I ;:s&sq”,~~* procedures that .wil?.be used”jo”,perform each test.,,j!cceptance criteria are numer@a,J: @nit& ranges, or other criteria-for the tests“,” _.ri%Y.el<u-an analytical procedure will be,used-only to described. If *a.,,;*,* -_ - -I. 2 *,-_/ “;x.a, .* generate stability data, the analytical procedure should be described in .P18.?. Justified interim acceptance criteria and tests, ^_” >,, with ,, sunset’provi&%k should be included, in the ., .e,“. I”II.._,IIL,~,X~\ specification (see section ,V!!.,F): Presentation of infortna@on. .a.tabu!ar.,format is suggested. jn i “..\W1 i,irr”“.~“,*.~~xl The specification sheet shouJd.,alsp identify: * tests that can be performed in-process in lieu of testing the finished product (the results of such tests performed in-process should be included ,in .the “,.,iI <.%-.f’ #“, batch; analysis report (e.g., ” ‘ A”I certificate of analysis)) all analytical procedures that wiJl be used for atest;.identifying which are regulatory,.and which are alternative _.- <. analytical procedures when..m,ujtiple analytical procedures can be “. ,,_._ .) ._ .,,_” ,_ _ “_ used for a test3’ . acceptance criteria for the, test using the regulatory ana&&al ‘ procedure and alternative -’ analytical procedures when~the ‘ cr&ria‘ .-se”mb,,l..+F**_l conformance to a~spectruin for different (e.g.,‘ _.are “Ip/ ‘ vii* near infrared (NIR) or retention tjme for cjPJ&) releaseand .shelf-life.,acceptance criteria when, both are used.“. .1+17,‘ _, ‘ _) ““j (^ ,” _, _, ,_c.” <_-I _ ,*.,~*.*(* \~*-ls”+c I__
l l



1155). _ s., .._

The fiist ‘ bullet

contai,ns the, text -,_9.es _i/m* cited _ lines ;,,* (Lings,e,&~T$~3a,)_<“<from the , I, rri*+ ;~~~“*~:L,~\s,%8,7 "',~i,-:_"l_" l%m; .~>yvr.;*.r: iT.p-*?%L, _x.,".


,, ., " ; _ni_.. ,\, *_,.._/_



( _ 1,
_. ^ .,


All that is requested here’ for~the ab$E&nt to’ & identify which tests on the requested global sljecifications’ sheet’ ,II /‘x_.., of tests that that,“<gn_be, s 5 iisting’ ” ,“< . “) performed in-process in lieu of testing the finished product” with the parenthetical request that “the results.._),.*b .*~~,il*_*..,~“l, . A_,“ ofI such tests performed in-process shoula be included. in.the.batch ‘
analysis report (e.g., certificate of analysis)).”

Again the text ma.kes,requests.- it does not establish requirements. Moreover, the text does not request, “certain in-process tests be performed in lieu
of finis&d product tests.”

However, factually, the test “tablet +ight” is required by the CGMP regulations (23 CF@ 2&&$0(a) and 21 CFR 2fi.ll*g(b)on each inprocess batch tes:f’ _.+.I”./l.sui=h ll,*.alm. ,.“*#*. where ..,(r**.-,. test “<<‘ is appropriate. “~‘ .%. _,, . ‘ . j,I. -, The cited passages state (emphasis added): “” “*. ‘ ;(
To assure batch uniformity and integrity of drug product& written procedures shall be-established and followed that ‘ describe the in-process controk‘ and tests, or’ examinations to beconducted on, appropriate samples of in-process materials of each batch. Such control procedures shall be established to monitor the n output and, to..,validate.,the performance of those. manufactutjng I*. processes that may be responsible for causing variability in the characteristics of, in-process material and the drug prod& Such controj procedures shall include, but are not limited to, the_. .,. .,. .s following, where aonronriate: ^ (I )T ablet or capsule tieipht variation; (2) Disintegration time; (3) Adequacy of mixing to assure uniformity and homogeneity: (4) “Di&olution‘ fime and ,rate; ”

procedures where audronriate. Examination a,,., testing of samples shall assure that.the~ drug ‘ and __ product and in-process material conform to specifications.

Based on the preceding, tablet weight (for variation) is a test that is appropriate” is explicitly required for tablets because - 1,s a jx;I*..\,~.-*ii_.,l__7j.,~..,: the .l.,. clause “where _>> .,.. ,/,. *, required to be taken, to mean“ unless’ ~“~.‘ test is inappropriate for the drug ‘ ,‘ye,-,.* the ,~*‘ . ,: , 9 ,~~,,F-i~~~~.~.~~“~. .&*+*4@*m* _, an product in’ question i.e., for examfile tablet weight variatio,n”for ointment product in tubes. Moreover, when tablet hardness variation is : IS‘‘ y:”to _ variationr*‘ ;in the i -:,, , “” linked *he. ..,,+u.~~~*‘ a,.*,,*, L “*.y, ,a. *i$,r?i ,.,!*l.. release of ‘ the active.brlactives~.~~~m’li,~~~~~t >.a,>_(“A product, then hardness drug ..*:j_ ,l~li*,~.*l,L_ ii\” a., /-_, “.a‘ ~‘,, ‘ _,>/ Il.v.--“r.,*,a, *%w monitoring is also required. Thus, contrary to the com,me_nters’ remarks, such in-process testing is ,e” 1_ .~ ,. required by the CG~M,P,regulations on batch representative samples (21


CFR Zrl.$etJ(6)(2)):
While requesting such to be reported on the batch analysis report (e.g., COA) may differ from the practices of these,^,__ I *,.. -,i,“.,*- ,wal I,,“>~, the tests firm, ,/ commenters’:..a .,^a /. *<*a themselves mo.$ certainly are “consistent,*@ cKgn:,requirements.” Based on all of,the preceding, the‘ text simply QQ,!Yrequests that CGMPrequired testing be reported on the batch analysisre~ot?‘ when?hat~testing is done “iu.li”eu oftes$iug ,,the finished product:”

,, “ b. Lines 1286 - 1305 require that batch &dysis bd”prd’ lded for ALL ba~~~~~“ .~~~~~~r,,~~~~~~,. _..” ‘ ;‘ ‘ _,,j .__ efficacy and safety, bioavailability, bidequivalence, and primary stability studies. TO include ALL batches used f& ,&kik~~~ $i&,$ kd safety, bioavailability, bioequivalence, and primary ‘ stability studies will, i&&e a”huge amount of data of $9’ i;ypk described in lines 1297 i 1305, ,I T&i;* .j requirement should, be-changed to pivotal studies only.”


This reviewer disagrees with the commenters’.1.te.. ,..., ‘.because the Agency , ._” d.t^.-,,_X”_, ,d*-, ,“b-*e&a . .- remarks /r,_* ,,,c..*-,“, +#*w”uut~:~ n’ inie;pretations eeds th,at information to determ-ine .wh,ether ornot, th.~~~rmk_s,,conclus/ons ir4 yx x&42 .. es. ‘ and “.~~~~~~~~~~~~,~~~~~~~~~~~~~~~~~~~~n~ prer& ~Aa@~~,w thaf ~J~~~,;)r”~~:,%\&.~, the * ._I1,. *,-l*d.“m”~s..l 3,,_(_s “,,_ i .a-;i ,eliV1. “1*.;4J.e l.~. firm’ manufacturing, s. processing, packing, packaging, alabeling, testing** / il) 4, , _,a r^r*““~i-,./-~mi\*-l,.i~r. . and quality controi%perations are CG,~P:,cb~~~piia‘ n~~~‘ .’ Applications that-lack any of the requested infor~mation~rnay be rejected or placed on hoJd - thus..dejiaying the a~~licafion’ s approval. Thus, it would seem that firms woujd.~.,be1,,*-“.‘ ,x,j-,, provide all of the .I j_anxious to * dr.~r~*,~~,“~.~ data requested and .more tox^ ensu’ re~,that an *x overlopked ‘ study will not hold .,.. by ^.S,.d IIl-*,,a..*, * 1y_, l*,,,,_/ “._, “,V^W j. up their application’ s review. ‘ ._ _:- , e *i
“c. Lines 1339 ,-: I”334 presentation of assay, impurity results, degradation products and residual ni;; reqi;~rw”m~iit should solvents results fro,m ALL, batches *.will v.,* involve iPI.huge amount of data. .S)P I_.,/ .I,h/i,*e a,,“ be changed to include pivotal batches only .”

identified as~^‘ pivo&l batch” or “pivotal’ batches:” ;‘ In an’ ANDA.application, the key batch is called the bioequivalence batch. In such ap’ pli~&b;‘ ni, &‘ th~i$ ‘ term pivotal -is-‘ w used nor would it be ,,,,. appropriate to do so. _ ., .‘ I _. P^. _ /.* ...x ,.. : ” ._ ,j
“These examples of requirements escalation are the strongest cases where the draft guidance has increased the requirements as compared with the current guidance and practice. The above references illustrate <. <, *.” ,_. ““S.~‘ .“,,%.. ,%~ ., how and where escalations ofrequirements occur and. should serve, as ,examples -to change the draft ,+,^I”, j ./(..i. /,F, _^, ,, 4, L (, @dance to betier -&yt ;;;;r~~“reg;;;;~“E~~c “_ _.,..) .._” ‘ I-, .,_.. (. “i ,^.__ , _ ..IAL ,* ,$ \ 1 _,:^ ^” _x__LI:,....; ~_ :_;__ ;. > : * *. ,.aI._^v. ‘ ,.,. ‘ Recom mendati.yy -..Aegis PharmaceuticalS,recc?mme,~~~ ~that&&,e*t,pages of the PDR be replaced with a list of topics that the ANDA and NDA applicant should consider in the process development of a drug product. We also recommend that the examples of escalation of,requirements listed above.,b:echanged to reflect current approved guidance and practice. In addition, the draft guidance should-be reviewed.&-, additional,.. examples of‘ escalating requirement; ~&I’ they should also be,reviged.to reflect cqrretit “approved guidance and practice .” i “Aegis believes that fojlow’ tig the recoinmkndations ngde ,:A*... >, eliminate the increasingre~uirie~~~ reflected in the draft .” ,._ _‘ . ^“. , ‘ *_ 1/ , 236 ,* in. gurA.ccg+++ .wjij reduce and potentially l.‘ ..,,*i.,iAJ ,./, guidance .” L.,,., ,. ”_s> )/“” . ^.__I. . ,’,a:*,.__,.“, ,f I”. ,_._ _,,,, ._ ,;’ . 1. “.,_ _,., , _^ ; I’ . .’ ,:

* _^



I -

_, _ : __, 1 .,. i” __ _ .

,, -li’ ,_ .’ ‘. .-.



_j : i



:,“- ,













Note: The original INTRODUCTORY cc),m,ments are’ w - ~.(l_‘ _,_ ,,. quo,ted in a cond.gns@ fgnt (Pwpetua), the quotes dir&ly from the dcaft gui&ric& are quoted in a stylized font (Lydian) and this reviewers cornme!+ i,, ;, _,.,,-*^_w are in a publishers font (News.Gothic”MT) to make it easier for, $!‘ I?, reader to differentiate“._-:the _1 “syjedker” in the variqus text passages that follow. In this ,. -.I ,- II _..b”‘ review, this reviewer’ comments “._ a,re made after the commenter’ .b 3.i’ ‘ _,:: ‘ &+ “*,,:y.,,‘ A’” s ”.**, 1% I ‘/,, , / ~.“&~::K$ie” s remarks “& and, when :,, --‘ r~P !‘ ~>~<~&““5~* wa.+ 2 i the commenter’ rema,t%s,grf; ~‘ s :,b~,~x~~,,” &<*ipi%%a ;ns~@ethe bpx.

This com,mw-dq

begins by s,ta~ing,”

Thank you for. the opportunity to comment on the .&aft Guidance A._<> for”In&&-y, - ..\-.,.xi..‘ i.“~“” _I_*a.,_j Drug @duct, Chemistry, “,‘ ‘ ,.., extensjve, document ..v, j I.clearly represents a that Manufacturing, and Cqntro& Information. This is an ‘ I,“*.L-**.iT /m. .ehr*D,. consideral& investment j,.,*r/_ l.i ,,.,,8;..<>A ‘ *.*,ai,* contains some important considerations for presenting the jl ,”I,r,s’ of FDA resources and *p&w 4W.>j, ,~“*. * 2s:“ ,g&-<, ‘iu “,&@CS&&>~ I j _ .1 -.,,*I .-l;..*l *_.* (I drug product section of an application. Although comments on draft guidances often focus on ,the parts of the guidance that the commenter would like to have changed, I would like to highlight a few important points in the guidance that that I believe are very helpful and which should be reta$ed in. the,ftral guidance. These are the.folJ@rg:” Line Number

. *I , ^Ib s . I ‘ @-,. i (?> -vi ‘ /A,_. _. ;(i/_ ..__ #l, c*.yypl:,‘ .; ~*a.: . . y+“!

The concepts of sunset test protocols and interim acceptance criteria are very useful. Having them in the In some instances, the use ofsunset test guidance may eliminate some barriers to their implementation. protocols could streamhne the regulatory processes for both F&A ,and,~ndustry while ensuring the delivery of quality drug products to the marketplace.

In general, this reviewer agrees with the commenter provided .~ full CGMP compliance is established a_nd.mainta/ne,t, Similarly, this reviewer is a strong proponent -‘ &e&&al/j of ‘ sotind and’ appropriafe predefined contingent (hierarch,ical) sampling and testing plans in “I applications. ,,._ “,, ‘ _,” .,: ~,,_, _”, ‘ ’ II_“.”,/.s,/“,~_ , r ‘. L_ //, : c.G\- * LI#A ~ j_ 4-xr:/ b ,-.,. ..“, ,7,-“(: ?..:‘ “,,J.&.q x i_ %-I ‘ ?.S? q$f”.‘ ._, ;, ”
The discussion of reprocessing is clear, concise, and provides a very reasonable approach.

While this reviewer agrees, this reviewer also thinks.that the “Glossary” should define this term and, firms electing to include such ‘ their applications should in provide detailed-explanation (justification) of the reasons thattheir process could not be developed to be robust enough that such is not-required. (,.( ,‘ 1* ., *Ir*x.e,“,c*,“, d..“I,l:-.~.-,~,-*n-.“~~~~~, d<,. ” >p .*.,~~.rh~~~~~,.~~,~~~~~~~.~~~~~~~~ x1. .l %)a
The concept of providing EPRs for representative batches is good and should be retained. ihe provmon of EPRs for all stability and BA/BE lots, adds bulk, and complexity to the application, but may not always serve a useful purpose.

This reviewer agrees with the co.mment,er’ . _,.e _.”>i \ _“_ * but takes exception s first statement, .,,_ _I to his be, the Age’ second.because allun;ier;ta;;“.~~~~~..~‘ to increase, or _I *;i I .“,,11_ ~#.g.ation such data serve ,~~~~~~~e~ may ;cy;;’ ‘ or decrease, as the case not .!be, .” ,,I.,, Is,... presents a CGM.p-compllant picture of the ‘ proce~<es, controls and systems that will ensure the safety, efficacy and quality of each RELEASED unit in each ACCEPTED batch >*, ~.“~‘ be i,.,i,rl* -u?.a~r~“..~.wL..,) .should*Ir.lil safe, effic6cious, _ and, if tested,,, meet ttie drug ~~~, “+<* “.w.“,product’ established post-release specrftcatrons for’ s that unit. . ‘ .



I “I have several general comments: I.



.I. .V~”,.j..s,. .,,,, _ , ,.. i” * In genera),’ this reviewer agrees that, for harmonization with~,th,e.el.CH, Y$lC” could.be replaced with “Quality” wh’ erever possible, but, upon reflection and in consideration, of ii.i-+.r the ...“Wf” importance of. n*ames, would recommend thatit be replaced wjth. th-12phrase “CGMP Quality” so that ,it i,S harmo,njzed~both .yIwithI#1_)<_ >,b, _ the “A*xr,,*_. l,_ ,. s for CGjMP that the .... CMC %** a*__‘ s..,I;*_, _ section’ -~,.ri^.5~~i ICH and the ,,FDC I, ~.“_.. lxlmv .sc- /I +*“*%_I __I- Act’ requirement (_^x ,iR’ s documentafionis.supposed to demonstrate. 1 _. ,, ,~ 1.
“2. The use of the. ou,tlin,e.”numbering for the CTD headings (with CTD numbers in parenthesis) is , ” 1 <. ,, cumbersome. If FDA “needs ,. ..w*.4’‘ id.,**,iid”ii-i ii.,& numbering system for the guidance, perhaps it <. to maintain j-8” ”outline’ .l!‘““.+~,~“b’ “.‘ the ’ _L6iH.l ** could be-used fo,r Sections_I.”and ,I.. of . the guidance, then the rest of the guidance could be presented in II i* *c<.*,s, *I.” the CTD fwyt,“. _ ,~ i 1. _ -~‘‘ )“ ‘ 1 .” _, , I . ’^

For consistency 64th ICH, replace “CMC” with “Quality” wherever possible.”

While this review,er ~-agrees with the com.menter’:,_,,a,_W>,“. ,cji..rr.‘ .i”;,~.;-,l-.~~.,~2‘ ./ll I^ Is observation ,iq# the , i 1&, >.,“/,a-, that. ~“. outline (and referencing) system used in, th.Js.,guidance is cumbersome, this reviewer woul,d, as others have, suggest that the outline simply use the CTD referencing system.
._ .“,’ I. ^. _

“3 . There are several places where this guidance calls for information “..i”->,,..i-”more properly a GMP I^, “.~. that is F*v/I^ These include provision of duplicate test results (supplier and applicant) for requirement. ._,_..,. .I /. components; in-process stability “reXts; and strpulation of different requirements, depending on whether the applicant or the supplier performs full testing. These should ^continue, to, be .G&IP requirements and not be added-& the~~applicaiion. This, information~~should .be re$ked, during an inspection, rather than in a registration document. -,

This reviewer \ r,ejects this commenter’ s, reco‘ ” .(^~//a..,, ,*~.l$*1,*,_/_/.“,~,*,. s mmen,dation .a.-. *L,,. on several ; .I,i^.,,S,.. grounds: A. Nothing in the statute (21 U$C. TN!?,?, Fed&h *Fdod, Drug, and Cohetic Act, as amended [commonly -abbreviated .as “rt>C &t”]), the CGMP


211 and bj by statute or regulation to be ava.ilable,for i,nspection.
6. The responsibility for establishing that processes, controls and drug products comply with CGMP. ,is not borne solely by the FDA’ s inspectorate - all FDA. personnel ,directly or indirectly involved in the review of, an application have a duty to ensure that what is approved does comply withCGMP as it is defined in 21. U.S.C. .***w_*1x ..I ,_.V_,_.a‘ l?d 351(a)(2)(B) and r*.,_I “r; reiterated in 21 CFR. 210.1(a). The Agency ‘ ther&%e?ias the., .d[sc-etjon of ,*~requesting any such document th”at isrequired to exist be submitted to the,Agency or having its personnel inspect that document in,a,n,o.n-,s~ifea,udj$ _


The providing of the informatio”n’ lj~~~ed req’ in the form,ats requested will not only reduce the review ‘ burden upon the inspectorate (a dwindling #, d... ,.l_ ‘ ,.L^,I,I~LElll~“~l,,i resource‘ in the+ Agency) but also speed ,the review process by: a) ensuring that the requisite, CCYVi~ compliance is supported in the documentation _e* submitted(eliminat]ng review ho/ds when a,~ “PAI, ._/_y= inspection finds’ ~~~~~~~~~ienciencies ,that v&&$ 1 .“.,,I. ~.,.S_ obvious have been’nl\~,u.a,r~-.*,rilil., _l_ (__. .. had . *,‘ (.“a .,+,(,__,q the Agency requested the, info,rm,atjon,,* in.2the~,,submiss.ion) 4 and b) :”.,,w* >9.&‘ *y+;xp+ providing the inspectorate’ (com’ m!tted to using a systems approach to ,”“. \.,,(Tinspection) with a clearer picture of which,systems‘ need theemore 1m,_,_,, ___ ,_ _ focus.~, “_V [In essence, the additional infolmat~..~,r?,~.,e~~titutes,,: -“a: in-depth,pr.e-audit S” “.,A& ““V**%\ “*cam”an x, survey of the sponsor’ sites and systems. ,-,./_ j.l s In ad.dit,ion, by askrng the information be provided in a structu.l~~~~~~or~.at ^ pI,‘ ~”/,**w-v ,review, : that * facilitates’ < .‘ . lv. *Lh--i~~~i~l*,;“* c.:ir~;ir, the Agency will ‘ save those person-days that the inspectorate has been spending assembling and col-lating that same information -_ thusallowing the Agency to increase its, review efficiency by minimizing the clerical -burden on‘the-inspectorate.] ” mis,*< ,.+“..,</_ Based on the preceding factual realities, the commenter’ s rem-arks should. _, ,. be ignored.
“Specific suggestions for revisions are in the attached-table-. , __, ,. j >.) , ,, -., If you have questions, or if I can be of assistance in any way, please*feeI free io contact me at 5 13-83 1: ., ” ,_ /;_ , ,._.,”,_,._ _.I. 5802 or hl~reg;@fitse.net.”
Line Number 55-74



. I __

Rationale . _ ,_ I .,
This is a drug product guidance. in the drug substance guidance.

,.“,<,1,_.1*_ ir-i .e,i-.li. _I,, /. li.& c.,* (,, ,*..
should be addressed

Eliminate the reference to drug substance requirements.

Drug substance requirements

This reviewer disagrees with this commqnt.


“Components that are used in the manufacture of the drug product and,do not appear in the finished drug product . . . should be identjfied as _ i processing aids.“.

In the context presented (an introductipn to the, CTp), the comments made pertaining to the drun substance are be oSe~tt;;add;ess.~. -deleted,, without” some cannot and appropriate misrepresenting ,.~ .,_~~ “._,*” ,. 3 _is supp _*jl/^C‘ *(_ what ,,.. Module the _. ____ ,,1 ,__ 1,” ,u..i~li;4,ti.r&. _I, *“.\ .% AL..‘
This is very prescriptive. about these components. Wow is it that At times it may be useful to provide other information




“should be id&ied


This reviewer agree.

does ti

the applicant from providing other information about these components? Since the guidance simply suggests a “name” for such components, nothing other than the ai;$icant’ decision prevents the application s from providing other information about these compounds. In fact, the guidance suggests that a specification should be provided for each such processing aid (ii&s i(iCB’ 1‘ -‘ 010).

processing aids” prohibits











. ..”

j .:.

*a (“,

-I. ”

Line Number 362-680

P r o p o s e d Revision ,,
pharmaceutical Delete the d e v e l o p m e n t section in the F D A guideline a n d refer to ICH. : ’



.j. i ,, :,.i * , )_ ^,

This section in the:,FDA guideline is very detailed a n d prescriptive. My understanding is that there m a y b e a n initiative in ICH to d e v e l o p a h a r m o n i z e d guideline o n pharmaceutical development. F D A s h o u l d not p r e e m p t that effort. If ICH d o e s not d e v e l o p a h a r m o n i z e d guideline, the C T D g u i d a n c e serves as a n a d e q u a t e starting point for this section a n d ,the applicant s h o u l d have. s o m e flexibility in presenting the data. ’

This reviewer disagrees.

R e p l a c e “study n u m b e r s ” with “appropriate cross reference identifiers”.

T h e F D A is c h a r g e d with assisting the industry to operate in compliance the requirements of the F D A & t, and, C @ V IF,.,, W h a t the ICH may, or m a y m , d o in the future is not certain. G iven the requirements of C G M P , the C T D g u i d a n c e d o e s N O T serve “as a n a d e q u a t e starting point for this section.” B e c a u s e the doc,ument!s g u i d a n c e a n d not requirement, it does & , as the c o m m e n t e r implies (by using the terms detailed a n d prescriptive) restrict the flexibility of the applicant. P r o v i d e d the applicant’s alternative “prescription” is equivalent to the F D A ’s guidance,‘the zppircant should h a v e n o p r o b l e m with it. Thus, t h o u g h detailed, the g u i d a n c e offered .is, rational; n e e d e d , a n d sh,ould,,be reta,jned-(W,.. . r .c a I.a5, “y”‘, u-sde_ It ‘as the , ,(.,. ICH - n then *_.; ..“1 ~ /.. _;“j, -, *4**,, basis for their initi-ative w h e n a n d if they d e c r d e to undertake -. l.,“lll. ,.“,I _,/, such. _.-- s._..*... I” I^ i _,“,.i._“_ _ _-s,” ‘.-*~.rlv.;ru” & b“(_, ,, ,14*1, ,-.*a *,;;jC, ,.,~
A s written, this implies that there will b e stability “reports” with title pages, etc. in the Quality section, such as is d o n e for the Clinical section., % T b i s not js necessarily the case. M o r e g e n e r a l w o r d i n g s h o u l d b e u s e d to allow for differences in approach. ,_,‘ “. ” ,_ I_ ;_ “3 .._ P e r s o n n e l information ,is provided in the d r u g establishment information attachment to F o r m ,356H. This fo,rm is, u p d a t e d a n d submitted ,with every registration ‘tiled. It’s h o u l d not b e necessary to repeat this information within the b o d y of the Quality m o d u l e . Duplication in the quality section is redundant a n d the information there b e c o m e get outdated.

710-712 Delete this section.

This reviewer disagrees. ‘) ,, -_

T h e c o m m e n t e r ignores the facts: a ) u p o n submission the reviewer is s u p p o s e d to b e r e a d y for inspection, b) the applicant is already required to k e e p the referenced information u p to date, c), since the inspectorate gets a copy of the C M C “Quality” module, providing this ‘w o u l d expedite the review process, a n d d) the A g e n c y h a s n o leverage to e n s u r e that the c o m p o n e n t suppliers k e e p that information . u p to date. B a s e d o n the p r e c e d i n g facts, the A g e n c y h a s properly included a request for this information.






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ine hmber 784-785

‘ reposed

Revision ,i (_


_ “.>”./ -

;._^“+^ 2,. 1. *ah:.&i”,C_ ),_.%. ,(, “W *,.> ,iJ.z Ih

Ielete “(e.g. weighing of :omponents through finished moduct release)“.

Requiring basic plant operations such as weighing and release to be shown in the flow diagram adds to the complexity of the diagram without providing useful The flow diagram should focus on the major manufacturing unit information. operations.

his reviewer respectfully ) disagrees with the renjarks ommenter’ s bout what the req$e$e; OW diagram over and b) knows, that 3 cover all steps that fall rider CGMP, additional teps should be included.

sentence ,,as._ a _mixture.“;‘ I;,_ of Discounting the initial *b, -“,,” _I;, unsubstantiated. ,claims.,,and **“,‘“ld-.;i-*~,rsi-..“iil,“,\n,~ revjewer ...“l irrelevant. facts, this, agrees with the commenter - “t+ fJoy diagram should focus on the 2 :.. “i,:. ;
manufacturing unit operations.

However, regardless of the complexity, or the lack thereof, the routine manufacturing unit operations addressed, by CGMP start, v#hi a)‘ receipt of components; b) sampling of c) testing of components; d) release of components; components to production; e) allocation of components for a given b,atch; f) start of production of a batch; g) charging of components for the first phase of manufacture; h) in-process control of the fi.rst. phase of manufacture; i) - k) sampling, testing and/or examination, and release of the output of the first phase in the manufacture of a _I. ..is. ^ :,-*I “.“,,Nni batch to the .w,p*<t~~ next phase; and ends wfth,‘ unit operations: . ia) - IC) the Inspection (sampling and testing and/or examination), and release of the finished packaged batch, of, drug product; and id) the the, * reJeased, batch,., from / .manufacturing transferof *tlnl..~X-3’ ?,*L1I,c4.,*/* to , warehousing or distribution. Therefore, the requested diagram (which, may ” be composed of a ,series of “sub”. diagrams) should address al! ^.“,‘“.“,;‘ “b‘ : regulated manufacturing unrt operations. Since that is the, case, ttie preceding should‘ be included in said diagram or set of,“sub.” diagrams. . . ,. _,, .‘ ., ‘ j..-‘ _ _ l. ,/. * ,_-,, -,, _,i.,& * “,,,..d-rr *\*
This is a US-specific requirement and not part of the manufacturing process To have the requested statement here introduces US-specific description. information into a document that otherwise would i*n,eqi,,, <*~,‘ for ‘ use *,,., most be -: b_ r,YL..rlc. suitable+ r > $,+in“%>,*w~‘ . geographic regions,’ ‘ R~~~~~~~~q~~~~~~~~~~ould be addressed r-n klodule, 1”or the Appendices to Module 3.

paragraph or Move the ruminant-derived materials : tc the regional information.

Provided the the Appendix in this reviewer

mpve ,is~.to appropriate Module 3, concurs. “.. I ._j,,m _
the the

Though not bound by the ICI-i guidance, the draft “CGMP Quality” guidance’ format should parallel that of the,ICH to s the extent that it legally can. . .. ,; -,, > ),.. ,, >,,” ~*sy __“..a ,_i,Xl<rI iir”i;(:rr--““*r
tmay or may not be critical” is suffkient. The general statement that a contra! ‘ The applicant should not,have any trouble in interpreting that. If FDA thin!zs more detail-$ neceesav, a discussion of the principle involved in deciding if a process is-critical would be a better approach.

Delete “as illustrated in following examples:” and bulleted list.

This reviewer disagrees.

This reviewer recognizes the power of providing examples as an aid to the un.d.ersta,n,di,ng of what is being requested. Further, this reviewer knows that those ,v$p_fill 1 ,> .V”<. out any a%..;,. information request appreciate examples and bulleted I@, that they can use as “check lists”. to .ensure $&applicable requests are satisfied.



_ < ,>


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j. ‘_





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? r o p o s e d Revision ,-,


I\dd a statement su& as ‘A l t h o u g h they a r e considered ,roduct critical process coritrols; : o m e tests o n iqterrnediate m a y lot n e e d extqsiye, justification if h e y a r e consistent with cuv$nt ndustry practice or c o m p e n d i a 1 standards, for example, h a r d n e s s 3r assay of a core tablet prior to zoating.‘.

,,,,. .,,”#. ... ,~(//,_,/,. ,. ...a. “. “~ ,. s I ,_(. :DA h a s defined Jest-i d G .pg,,qn rmedi,a!e products as critical process controls, @ lowever, the acceptance criteria fors,qme, of these a r e well + + l @ & $ + d ~qee$, 1 0 further for justification. T h e c o m m e n t e r ’s statement is, false. Factually, the C G M P regulations defink the types of control a n d p r o c e d u r e s (tests) to’ b e considered tot’ u s e “e=*.>.” .. ~“” o n a ac,F e h ,L. batch a n d specifies, “S u c h control p r o c e d u r e s shall b e ,established to monitorthe output a n d to validate the p e r f o r m a n c e of those m . a ~ u @ $ u j n g
processes that m a y b e r e s p o n s i b l efor catising’variability in the characteristic+ ” Df i n - p r o c e s s ~ m a t & $ a n d + e , d r u g product.”

This reviewer disagrees.

Thus, w h e n e v & % firti: finds @ @ t,any of these a r e required to control e a c h b S @ ,t& y bkcor% c&ical c o n t ~ & If they a r e not such, then they should either not b e b e i n g u s e d by the firm or tt?eif~.~ses~$~l~ b e justified in as P Q IT. the C$$P regulations require each In addition, m a n u facturer .to ezJ&j.jsh ,(justify that) that the controls they u s e a r e scietitifi&fy s o u n d a n d appropriate (21 CFR 211.160(b)). A s the A g e n c y knows, factually it h a s b e e n established that the requisite controls a.re & t those in th,e~ S P q r N F , b e $ a y s e U these a r e O N L Y $cientifical/y s o u n d a n d appropriate for d r u g product in c.qmrnerce- - not necessarily for in-process m a terials. In addition it h a s b e e n .@ a,blishe@ ,,.that (<II.” ,a.ru_.^“‘.e _ u the s a m p l j, .,..? n u m b e r s and/or u $ e d in -ysny cases by the Industry, including most published exa,mples, d o not, as A g e n c y m a n a g e m e n t is aware, m e e t the requiremerits of 2 1 CFF! 211.160(b)(2) and/or are, for other r&asons, riot scientifically sound. B a s e d o n the p r e c e d i n g it is, or should be, obvious that: a) This a d d e d text should, b e rejected a n d b) b ) E a c h submission. sh~~!~~~itivid~ a regulation-compliant, scientifit@ ‘y sound, a n d appropriate justi ficatio,$ f pr a n y in-process .controI that i,s required to b e u s e d o n - e a c h batch (to .ens,uTecompliance with 2 1 C F R 2 3 1 . 1 3 0 ) . Factually, most firms d o & , perform tests or e x a ”minations w h e n they k n o w that these tests- qv ey$#tions /contribute‘^-““” .bI,. “~ ,~ UInothing to the their j requirements for product quality m a n d a ted by the g o v e r n m e n t or, for a p p e a r a n c e , by the c o n s u m i n g public. If tomorrow the cons$,rn~erwereJ&Jyagically stop equating physical a p p e a r a n c e a n d $ & % a n c e uniformity in a coated tablet to the drug-product’s quality, then the r n ~ ~ n @ $ r e ~ ~ w o u l d d r o p those attributes ,from its current stz$isti@ attributes inspection plans the very next day.


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.ine hmber

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Revisi,on .^” _~j( *s j

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, ., _, . .\ .^”,, .*,. ,.-s.~_)* , ei..<.,, ,, ., ,.,,,. a,, “\

Delete “and t$e applicant intends to perform full testing on each batch received,“.

Full or reduced testing by the applicant is a GMP issue, not a registration issue.

This reviewer this deletion.


First, by taking the phrase out of context~aQd,makjng a tangential. jssue jnt,o Ithe‘..-1, A*“,““” d._‘ the proposed change, “rationale’ for~~-‘““~u : * )i .I -,..a, ‘ As_-*. the commenter deli’ .w.IV)” drstorts what IS being said. berately s d”ew,llj., The text in question (Lines 981 - 997) states (underlining added):
“Compendia1-Non-nqve! Excipients: When a compendia1 excipient is tested, according to the monograph standard with no @l@ty!+,Q&~g and the amAicant intends to oer&i;mfi;li testi% on each batch rec$vkd, the,@pient (e.g., Sodium Chkjide, USP) can be listed under. P.4 .-~~t$:.,no,‘ ~~~~~~,, information provided in p.9. ! through P.4.4.”

Deleting the second condition,-..*_ . ,. . ,,. subvert’ xri.+a...L‘ of would the _ .A& lll*.--l-“* intent. *.,> _u ‘ *y”.^ this text - to insure-that, the*,,.‘ .b “““~“-“ -‘ x”*.~*‘\ ”get detailed - FDA reviewers WIII ,“I_ ‘ :‘ ^‘ information in P.4.1, through P.4.4 whenever the applicant does not perform full testing - regardless of what testing the ’ supplier may perform. Thus, though wrapped in the language that .,, _. would lead one to believe that ~this is a,n.,issue /.,: 2, % _ a CGfvlP requirement between * and a registration requirement, this co~~e:i;~~~‘ ~~~~~~~~pting to have the,text, modified ,,*,“,*4 to escape having to report exactly -. what testing the supplier and the applicant are doing. Moreover, the commenter’ s rationale*has I no basis _,,. fact. x ,, in _ “3%” I**,.*%“/( _li(.h_~l” (“_S,_ Nowhere in the C(;MP-regulations or the FDC,&t doeqthis reviewer find any prohibition for the Agency’ s-request for an applicant to provide the requested documentation in support of an application a,nd require it to be only reviewed as part of an inspection. Contrary to the implication of the commenter’ s remarks, all FDA personnel are charged with ensuring that all manufacturing practices and drug products comply with

The current tqd .simply a’ rightly z__ nd stiites the con.cjitjqn$ _I&“. under w.hich.the sponsor can I$$‘t&$~cop?pendi&l references to the ingredi$S 1testing it is proposing without any additional information ..: %+,-

Thus, this is a registration issue ,because the.,rev,jewer is, required to awe+@ CGMP. * ~Yz2x-c~ ,,,,, srior to recommending approval. Second, guidance is guidance -not requirement. Third, the documentation” requests are justified because they provide the supporting evidence- (proof) that ,.the applicant’ the phrase are a,val.id .and/or CGM.P cbmpliant. when s assertions is Finally, ‘ &y~j “-=~~~g-$“*~ on the applicant may’ 3imply ‘ li??t’the”“co’_.“_^.”__,,__ monograpti “ mpendiaj “ ‘ __ without explanation or justificdfion.~ For the preceding reasons this com~m~enter’ suggestion s~ should be rejected. ,*.._a”*,r,ai,n./4%. ~>,-*;“lqi r&a;< _.~_ ,%.’ .w?, ,,;l r.-,# .~~~.~~~~,~~;&~*~~s w-p ,~* ,‘ <+” “jiit. r I(~~~a,~,,~~~~~,~~aP~~,~~js* &; “I$, .; $.g.$$do’

ine {umber ‘ 82





Revision . < “./,

Rationale . ,, I . I_ __,x .,., -.~;ll‘ _“rl~~_,,~~_i~~, i”:-di
Additional testing is done from time-to-time for a pariety of reasons. This section should focus -on attributes of the excipient that ensure product quality.

no additional Replace “with testing” with “and no ad&onal testing is needed to ensure ,the suitability of the excipient in the product”.

This reviewer must and does oppose this change.

Having proposed removed half. of what, the com~m,e,nter,,,, must really feel is an onerous request, the commenter turns his attention to “adjusting“ the first restrictive,clause.,tq his ..,.. _ liking. Again, by taking the phrase out of context, dividing the changes suggested’ for the same text passage, and making a tangential issue (what “Th is sectjon shouid’ focus on”) into the “rationale” for the proposed. ch’ ange;’ the commenter again deliberately distorts what is~,bei,ng said. The text in question (Lines 981 - 987) still states (underlining added):
“Compendiai-Nonkovei Excipients: When a compendia! excipient is tested according to the monograph standard~‘ with no additional testing and the applicant intends to perform firli testbtg on Gch batch receiced: the excipient’ (e.g., Sodium Chloride, USP) can be listed under P.4 with no ,detailed information provided in”P.4. I through P.4.4.”

The current t,e”xt simply and rightly states the c.on,c!it@q under which the, sponsor can list thi cpmjieiidial references to the ingredient testing it is proppsing without any _ additional infortnafion, .1 :, However, were this change and’ previous the‘ change to both . -- ’ be made, the text would be reducedto: :
“Compendial.Non-novel Excipients: When a compendia1 excipient is tested according to the monograph standard with--no-dddi+iia+-testmg and no
additional testing is needed to ensure the suitability of the excipient in the product and-the-applicant-intends to-pe+&m~- fuR testmf -i~-+&-bateb

feeeked, the excipient (e.g., Sodium*Chloride, USP) can be listed under P.4 with no detailed information provided in P.4. I through P.4.4.”


As proposed, the applicant could simply list the excipient whenever any one monograph standard test ,js performed because this commenter did not ins,ert”the.word “8 ,.“full” ; before .,.a-_ _“% ,,1//.“..S ,_“,i.-ix and all compendial-nonnovel “monograph” the word excipients would simply be listed This is the case, because the applicants would continue doing what most are doing now, they ignore the strictures of 21 CFR 211.84(d)(2) that ieauire doing af least one specific identity fest before the supblier’ s report “of-analysis can ‘ be used in lieu of testing. Instead they claim to follow 21 CFR 21$.84(d)(l) that only requires an identity test, but instead of an [de@ify test, they perform an “ldentificati,on” test. x Then, the use the results.,of that-‘ ;ldentifilc~~~?n” ,s,/, test l.<.<i/ (, ; s;r to justify accepting the supplier’ report of analysis. s Finally, based on doing periodic cross checks, of the supplier’ s results with theirs on’ melot, so’ they falsely claim that they are operating’ in compliance with CGMP.. Hopefully, the Agency, reading this reviewer’ comWments, s_ will crack down on th”isviqlative practice that, as this reviewer has pointed out, seems to be widely used. . _M 1.. ”y,*;.* 7. M :?_ . I,, ,,: .,., ,,,” ai* -.L,,l, 1Pb >,,_..~,.,j,*.,, ,“,_ I*xl,,/ a. Is
: 245 ; ’

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This organizational detail has some. merit, but it is inconsistent with %e, organization df the CTD guideline and granularity document. If FDA disagrees with the organization of CTD it $ould work through IC% tb change it.

Delete “J$q p, ,,, . . to ,/.,* .. ililil 1.4 _I P.4.4 for each individual excipient should be grouped together in the application.“.

This reviewer disagrees with the commenter’ . ,‘ ,“b _ s proposal.

As the Agency of a sovereign government, the United States of America, the FDA is, in’ no ‘ way,. constrained by the guidance issued by the ICH, a nonsovereign body (“NGO.“) Whenever the FQ& chooses ,it~~ may ignore such guidance and should in this, c,ase because, grouping the data by excipient makes it ,.easier_fpr.! the., application reviewer to understand SwhSether_or., ,not3,$e .,-specifications. for a given excipient are adequate for the use of that, excrpient‘ in that formulation. Frankly, this reviewer thought the industry was all for doing what it cou!,d”tp expedite the review process but time and. time again comments such as this remi,nd this -J.+ “P..w.>_<,. 3, . reviewer that .*e .. “” 1,,,,.” the industry’ agenda seems to. be .other thanthe -.vj_one they s ..s,<ejL‘ _J.L.jl espouse in public. Therefore, this reviewer again recommends that the Agency leave the draft !anguage as it is and ignore this commenter’ s proposal.


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Rationale ,~_1 “.~3,..”‘ .I_A./,,_/, Y ), *, i(<,ii-“ ..*i , :.a,*(,, ( I.II-ilt.r’ 2 .“_ ‘,r”*lr~i,(. ,, l1, Full testing must be done by either the manufacturer of the excipient or the applicant, However, the issue of whether the applicant does full testing or reduced testing is a GMP Sue and should not bepart of the application. 2. The statement regarding specifications and testing for polyols is important; however it should be.addF,ess+,j,$dependently of the drug pioduct guideline.

Ielete this paragraph.

rhis reviewer not only also but jisagrees this that 3roposes saragraph be corrected :o fully mesh with all,).of [he applicable CGMP for ,all requirements components as shown on the following page.

Before consideriDg the commenter’ s avo\?ved rationale, the ,, ,_. _*_. ji. .,(, text needs to presented so that anyone reading either the comments or tliis reyi,ejv&s, appraisal thereof can know what was stated. The text in-question states: “In addition to listing all the tests for an excipient, the specification should identify the tests that the, drug product
manufacturer will rqt$iyely perform and the test res&s t!$ @IA&, _acqepted from the excipient manufacturer’ c@fic@q of analysis (COA).27 At a s minimum, the drug product manufacturer must perform- ah appropriate identification test (2 I CFR 2 I I .84(d)( I)). H owever, when there .aye specific safety concerns relating to an excipient, testing in addition to an identity test would be warranted. FLir exq$e, dietliylehe glycol contaminrition of polyols such as glycerin and propylene glycol has caused ,n~k~~r~~s,fat$es, and the specification should i,n&de’ t@&g ‘ i;ot&tktl impunties dnd contaminants foi for each batch rece@qd..by the drug product manufacturer.
” The drug product manuf&tti~ei”&sf%kablish ihc, refiabjlity of the supplier’ s analyses through appro@iate validation of the supplier’ test results at appropriate s intervals (2 I CFR 2 I 1.84(d)(2)). Tfi e reliability of the analyses need not be estabk%i at ‘ time the application is submitted. l-@v&kir, the specification the should in&ate t6e,t~~?‘ t&-@ji! be‘ performed 6nce the reliability of the supplier’ s results has been, established in accorcimce, with,V.cyr@ “good manufacturing practices.”

Thus, the first thing this reviewer noticed is that t,his paragraph has nothing to do with “full testing” but rather with 1. The identification.of who (supplier or manufacturer wil! do each test), and 2. The need for* safety related tests w&n there -/s-a? i.t$z+$ “concern” (such as: potential toxic impurltles, microbial or BSE contamina.tion, product mixing and mix-up in an integrated facility) dssociated with a given excipient. Based on what’ fh’ p%a$i[jh e says, it _”.,., r ,) that this is obvious . -(_I :ext needs to be retained. It is equally obvious’ that .this. ~cprn,~~r$$$,.~ @@?a,@ jeems to have been crafted tsiniply thit the paragraph dealt Nith issues ot@- thazpth_ose that it does. olil.*f..,.” .,.“ht. For all of these, reasqns, ~hi~o6%$%~?~r*{t-?$‘ ks should 3e ignored. Moreover, as written, the text misstates the, @.‘ !A? *equirements for the ..a$ceptance of the supplier’ s report of analysis (COA) in lieu of full.compendial testing and, where required; t&s& for 6t.her cor?c”ert-jSat~d properties. To correct that misst&n@.nt, this reviewers again offers the alternative testthat is presented on the next page

,ine kmber

Recomqwxxlalip (._“_,~

>>l_,i ,Iil,\“,ab,,.+ j :,Eir4sry-,>*~*,* I “4. In addition to listing ai ;he‘ &i f% 3; &$&it, ‘ specification should the identify the tests ttiat the drug productmanufacturey wilj routifiely perftirm and the test results that wi!l~ be accepted from the excipient manufacturer’ s 27 ‘ Xi”“a. mininig;;i”,*., $“; .cjr”.diict ihe’ certificate of analysis (COA). manufacturer must perform at least one specific identify test (21

1030 [cont.)

Change the’ t&t a -‘ *a; adjacent in shown column so ,that~“it fully meshes with all. of., ,-t,he CGMP requirements for component acceptance.

set of ‘ satnpies CFR 2 11.84(d)(2)) ori a lot-representative from each stjpment of each Iot27a when the ,“_. manufacturer ,)/t .“l._.‘ .~^..-.“~~~~l”.,“,~~l..ix elects to use iqfqrmajioq,from , *.I*~ Li _” the- supplier’ s COA in lieu of __” . full testing. HoweGr, ivhen there‘ are specific safety concerns relating to an excipient, testing in addition to an identity test would be warranted: For
example, diethylene glycol cqnt$@-+ti~fi of polyols such as glycerin and propylene glycol has caused numerous fat.alities, and the specification should include testing for potential _impurities and contaminants for each batch received by the drug product manuficturer. / __ .%d j. i .r.sr+/,r?‘ ..% ~.,“-,i:.,‘ iU,r:. ,.CI-r ,, 27 To elect to ruse .this option, the drug product manufacturer must: a) perfurm at least one specific identity tes‘ on lot-stiipmeni i;kpi&&‘ t &tive samples from each lot a?4 b) establish the reliability of the’ supplier’ analysis through i appropriate validation ef the supplier’ test results at appropriate intervals (2 I s CFR 2 I 1’ .84(d)(2)). The reliability of the analyses need,liot, k etabj/shed at the time the application is +bmitted. &w&er,“” thk specificafion-she@ in&ate the I* tests that will be performed price the reljability of the supplier’ results has been s establishedin accordancewith .curr<pt good manufacturing practices.” 27a The drug manufacturer must comply with i &e’ X+qwir&nents for component sampling set forth in 2,I (3% 211.84(b), “Representativesamples of each shipment’ i&i Idi ‘ of hall be coll&ed fcit ‘tisd~~ or ‘ &Wnation. The number of contaipers ~9.be sampled, and the amout$ bf~material_tpbe7taken from ‘ .‘ h.;-.‘“r“” ; each container, shall be based upon appiopriathcritefia Such es ,&@s&$ c+er~s for component variab/lity, confidence levers,%d degree of precision desired, the past quality history of the supplier, and the quantity needed for analysis and reserve whew. requiied by Sec. *21 i:l70”* and 21 ‘ Cqa 2~~1.16~~)(1), “Determ&ajion” of confoimance - to appro@ziE wiif.6 ‘ specifications for the ,ex _ *.+*v, ,.. **a. “,‘ acceptance of each lot within each shipment of components, drug product containers, closures, atid lab+ng u%d in the manufacture, processing, packing, or holding of drug products. The specifications shall include a “dcs<iption of the sampling and testing procedures used. Samples shall be representative and adequately idetitified: &I? pl;ocedtii;es “&III a6o icq*uiie app@%iati! retesting of any component, drug product container, or closure that is subject to deterioration.” [Note: When the fu1.l monograph option’ is chosen for excipient testing, there is J-I-Q need to cite 21 CFR 211.84(d)(Z) and when the 2X CFR,211..@$(d)(2) optidti is‘-eIe?Aed,., . . ,.”... / tl,... _* citing 21 CFR 211.84(d)(I) _. - _ would be incorrqA. Tj-teyefore, the guidance should refrain from citing 21 CFR 23&8,4(d) (I). Thus, the Agency shpuld cite‘ CFR.?11.84(ii) ~l’ when-addressing full monograph testing and 21 CFR 211.84(d)(2) when addres$.ng either &$ect of the ‘ Ac&ejjt-WA” option: -,.+ _ a G At least one specific idm titi- ta.4 f 6 T b. Establishing the reliability of the supplier’ s analyses tlwough appropriate validation of the suppfiei;‘ s~ A&t results ai appropriate int&w3/s.] _‘ _I’ _- _ ‘ _ I







Line Vumber 10891094

P r o p o s e d Revision .
Delete this paragraph.

“S ,”* II..~ l.l, ix. I_*, .. .),‘ x* ,*.*sjl*.*l e., wi”. o.,a&, ,..,..,.. -a\, “L, vs _ s--k,, :?i
C o m p a r i s o n of C O A s from t& .m a n $ a + y . e r * a $ tj~e”applicant is a G M P issue. Requiring such a c o m p a r i s o n in a n application is a n unjustified n e w regulatory requirement.

This reviewer” disagrees a n d r e c o m m e n d s ,that the draft text b e retained “as is.“.

B e fore p r o c e e d i n g to review the proposal, the text n e e d s to b e considered. “A certificate of s*,,T** T h e text reference, & @ ,es..: I,,j+,A ~ - ,,,*+ /, ,*..>a,nalysis( C O A ) from the _ x 1 ‘,,y., ,
m a n u f a c t u r e r a n d the t*est results ,for,ttpsa~m~e batch f&m, the & u g p r o d u c t m a n u f a c t u r e r s h o u l d b e p r o v i d e d for the, c o m p o & k d e s c r & e d in P .4. T h e information s h o u l d ,be for the, matejals u s e d to p r o d u c e the batch d e s c r i b e d ~ in the e x e c u t e d p r o d u c t i o n r e c o r d (R. I .P). Test results s h o u l d b e e x p r e s s e d numerically o r qualitatively (e.g., clear, colorless solution), a s appropriate. U s e of terms such.as c o & w r n + o r ~ ~ & e c i & t i o b i ~ discouraged.”

The COAs of the same

first thing this reviewer sees is that n o c q m p a r i s o n of is b e i n g requested, all that is b e i n g r e q u e s t e d is a copy supplier’s C O A a n d the m a n u facture.r’s resujts for the, batch. M o r e o v e r , the request is that the information b e provided for the m a terials u s e d to in the kPS,b.atches. S i n c e ni, c o m p a r i s o n is requested m u c h less required, this rationale is specious o n its face’g n d n e e d not be.“addre.ssed further. B a s e d o n the preceding, this‘text .should’ be: retained, A n d y incorporated into the final “CCflP Quality” guidance. -











ine umber


Revision Clarity. In context (Lines 11&d - lJ62), the text in question states (with pertinent text underlined): “The specification sheet should list all tests to which each,-b;lt& of,,?“.drug product will conform and the associated acceptance criteria and should alti incl&le .a r&<cfl& &!he
analytical procedures that will be used. to perform each test. Acceptance criteria are numerical li,mits, ranges, -or other criteria for the tests ,+@&d,., If an analytical procedure will be used only to generate stability data, the analytical procedure should be described in p.“g.3. . &#@_ $&rrm acceptance criteria and,@@ .@h ?qy+ provisions should be included in the specification (see section VILF). Presentation of i,nform&pri in 3, ta@a!: format is suggested. The saecifktion $h& ._. . . ._(“_._ .‘ should also ideptifv:

Leword to say “if a test that is usually performed ,on the finished moduct, is instead performed’ injrocess, the in-process results ;hould be provided in the batch malysis.

rhis reviewer objects the reasons stated that this (news Should be retained into incorporated final guidance.

for a@ text a,nd the




tests that can be derfi;ed in-process ‘ ~‘“6~s%-~esk~ ;he finished product (the results of such te&s tiel;formed inorocess should be included in the batch analvsis redoit (e.g.: &iii&&e of analysis)) all analytical procedures that will be used for a test; identifying which are regulatory and which at-e alternative analytical procedures when m_ultiple ~,. . “’ ’ ’ _ analytical procedures can be used for a tes$e acceptancecriteria.fqr the test tjiing the regulatory analytical procedure and altern$i~e ,ag$%ical $icedures when the criteFa:z!$f. @f&r&? (e.g., conformance to a spectrum ,foy cpar./nfrared (NIR) or retkntion titik for _)/’ HPLC) release and shelf-life acceptance criteria when both.are t@.”

The first problem that this reviewer has is .the.” one of grammar - “the specification sheet should:alG ?&My” “if a test that is
usually performed on the finished product, is instead performed in-process results should be provided in the batch analysis.” in-process, the

How can a -specification sheet identify a future condition in a given case? Obviously, it cannot. Since the co‘ mmenter SW%! that the, ratipa~J.e..u~~d...~~~, clarity, it is also equally obvious that he .falled, to add any clarity with the his substitution Based on the preceding alone, the present text ,should be retained unless other .better,,$& that preserves the request. Moreover, this commenter again attempts to turn a simple request “tell me which in-process tests, if any, can be used in lieu of testing the drug product” into something else apparently because, given his suggest6d ‘ %i$e6ktive, this commenter is se&king to cb~~~ai”“ftie“~~~ct~:~~tu~re~ C$ .t.JIe applicant’ inSprocess and release testing programs. s

i he (umber 174




Proposed 1





“_ “.~, ,,,. -,)~,>,$.t *I),^.,,ll.,,*L A\*,.+-.

I3elete the reference Jo ,in;h,ouse Inethod numbers jn,tjte,table.,

n-house numbers are not necessary for method identifkat~on.. Alternative nammg :onventions could be used, for example Reverse Phase HPLC Determination ,of Compound X. With e!ectron~~,~qss,referSnces, this is clear and concise.

This reviewer disagrees Nith this co.mm”ent and would suggest that the table ‘ be example modified to, ,conta,jn, x.a that states, footnote “When the firm does not use any formal system of identification, method other than the name, of the method, that full name should be included in the table.

: ,

First of all, while technically true, the commenter’ s first remark is disjngenuous because the reality is most all firms Jse formal identification systems to name, track and contra! their methods. In almost all cases, that identifier is considerably shorter than the full name of the. method .and,~ is, therefore, more suited for inclusion in a physical ta.bular format. Moreover, even if the applicant submits an electronic submission, where physical width is not a ‘ ~concorn; the primary electronic links .in that su!?-issip? are Ee; p,g$pg, identifiers. When reviewing an application, it facilitate,s the review when the primary and alternative method or methods, if any appear next to one another. Second, contrary to common. sense, this reviewer states f’ !With electronic cross. references, this is clear and concise” - a sentence, that begs anyone tc- know for,, sE3.i”raln,.~~a._is -IX.clear, i(_s~.,.*yi tj~.n.*dr and _:*, concise and “to ‘ what, if not an identifier, do the cross reference refer? Based on the preceding, this reviewer accepts that, to allow uses for the possibility that some firm somewhere Q& method names, a naming alternative should be consjdered. . ,; ^_, A”_., % 8.I,.._“. #,.,‘ ,
All studies and/or batches may not be relevant to “the application, exploratory studies for other indica&ns,., j j, for example



Reword to say “Batch analysis data should be provided for batches used in relevant clinical efkkacy and . ..” -.

I‘ Batch analysis data should be rovided for all batches used in

This reviewer objects to this change and would propose the following as a scientifically souna and appropriate, CGMPcompliant alternative for Lines 1288 - 1291:




in As an investigator having in-depth experience investigating production process for the root “causes, of the differences between batches ,_,~/l the .i facto:rs that““3’ ~ ”.. ,. Ij_lr,jand . ic xwM.I^*<‘ & affect t‘ .aTti’ s. e”ciF;‘ ,,,oL ed correlate with drug-product batch values, information is crucial to ~.determk&g whether or not a process and the controJs o,n”it are a) operating in compliance with CGMP and, b) capable of producing batches of .drug product that ,are sufficiently defined and controlled to the point that the data obtained predict that all of the. units in the batch would, if tested, pass. In addition, as written, this reviewer’ change partially s addresses the.~commenter’ s. concern (“studies and@r batches may
not be relevant to the application, for example exploratory studies for other

lssess clinical efficacy and bioavaiiability, afety, sioequivalence, and primary tability.”

indications”) beca.use the data, from a!l suchsfu~.i~.s,~~liS”,~~.!,~y~-~~ to assessing the performance of the applrcant’ systems. . s Further, by making the change in the manner proposed by the reviewer, this revi’ ewer ,avoids. jntroducing the obv.ious ambiguity that inserting the word Vei&%%l;” wou!d create+: because what is relevant depends upon the “person” making the “relevance assess,mentl: whjl,e, the. designed purpose of each study is supposed to be clearly defined before the study _” is initiated.

~. .

Line Vumber


Revision . . .. . jI ..“r ,_i, ., , 1 ,-*.,I, I. .” >.I_ I , _^*
for This section callsfor CofAs fqr.all batches_& ,coJlated batchtanalysis data for some tests. Providing tabulated batch analysis data on all relevant batches would~ be a clearer and more practical way to present the data. The use CofAs is not a clear or efficient way to present data on multiple clinical, safety, BABE, and stability lots and they do not add anything useful to the application. Documentation should be checked during inspe’ &bns,” not ‘ ‘ % $art of the rei;ie$ of the application.

Eliminate the requirement CofAs for all batches.

This reviewer opposes ttie changes proposed by the commenter and, for the reasons, stated, believes that the .* *_ draft text, “The batch analysis
reports (e.g., COAs) and collated bat&, analyses data should include a description of the batches,” should be

After stating what is requested, this commenter ,begins by -: making an unsubstantiated claim, “Providing tabulated bat&h analysis
data on all reIevant.bat&es the data.” or,e,$cjent .vvay to present data on multiple clinical, safety, BABE, and stability lots and they do not add anything useful to the application.” would be,a &u-er and maore practical way to present

The commenter cont.inues claims, “The use CofAs is’not’a‘&+r

with more unsubstantiated /n* _..“-. ).,~_ I..c ._ 43 ~‘ l~~i?l‘ ”*. /, “ _,Q. $i”“‘*“:**‘ i

incorporated “as is” into the final guidance.

Then, the commenter again plays-,anofher verse of his. favorite tUne, “Documentation should,he checked during mspe&ons; not as
part of the review of the ap;plication.”

This reviewer disagrees with the cort-trnentet-:s%. broad of generalization concerning WAS, ~“tabulatfon” (collation) data, and review efficiency. Second, which is needed, b&h analysis records or data collations, depends upon what the reviewer’ ,concerns. are .s and, since the Agency thathas the relevant rev&$ experience and is making this request, this’ reviewer must defer to the/r judgment of what is, needed_for,,the efficient ”review a., ~nan of - ,Xr,‘ ^,q -<_* ,“,‘.,.” _I_ m..l*. .x application. Third, the batch analysis reports, when- structured~ as the Agency requests, do provide significant relevant information beyond the data. Further, the commenter’ s “last remark<‘ -‘ ~con.undrum, is a . ./“/._ since PAI inspections are integral parts of application review, what does, “Documentation shouJl:be checked during inspections, not as part of the review of the.application” really mean? Factually, by requesting that pertinent documentation be submitted with the” application, the ‘ Agency” is: a) ensuring ‘ that the data they need to properly review an application has been requested and hopefully provided and ‘ ‘ 6) conducting an effective pre-audit survey of the components, systems, controls, and the drug product that are to be .auditeo during the PAI inspection. In the first instance, conforming applications should generate many fewer “data” holds than at present. In the second, the FDA inspectorate will be much better able to generate targeted site-specific audit plans and, relieved of much of the &.p@n~o[,&jn& what is being“x. ._....,_ ,,.. ,.,, requested of the submitter (col,lating the information from different. batches, for example) should be able. to perform more. ,inspections focused PAI inspections of shorter durati_on: In sum adherence to . the I proposed guidance‘ will shorten the ““,1 review period #-ri-vis submitting a current application. .,, “2-I /i( u+.i**,& -1, ,I.:“; *;-;I ,r.,?^:l 5”“-. ‘ _ l’ “.<*ap I 1 - _,* ..a>“*.I/ Il-l/*d^in<~~* ,,<l*py .,, .r”“r /,...






C~M~IW~O I .,.. “a ~3 , ” 2*,/*

~$~&jC;$+j, .,/ * .XII, ,./I ,. 1 (\ .*,“r i,_,.l -A.., : j (,

@$@6 “~‘.:-I r.*.: . ,.,‘i< . I‘ I *.; 3‘ ,j -’ ;:I. 1 ,* ,_

,.,,~,“\rl ,.*j



Line Number

P r o p o s e d Revision
Revise to say “Potential d r u g p r o d u c t impurities s h o u l d b e listed. T h e s e s h o u l d include d e g r a d a t i o n products active ingredient, a n d residual solve&s. For s o m e combinations of d r u g , d o s a g e form, a n d r o u t e of administration, enantiomeik impurities, excipient d e g r a d a n t s , a n d / o r l e a c h a b l e s from the container closure system m a y also n e e d to b e considkred.

Rationale ,. .,, . ...,w_,/ .,I?* s--i S F ,”
Not all of the listed s o u r c e s of impurities a r e relevant in all of the cases. In g e n e r a l it serves lisle p u r p o s e to discuss well k n o w n e x ~ $ i i e Y i ~ e g r a d a t i o n d products for a solid. oral d o s a ’g ‘fckm~’ ~ o t& a & & t&.t .~ >2 * applicant s h o u l d k ,, ‘$.., , , c o n s i d e ro t h e r s o u r c e sof impurities in s@ ~ & c instances h o u l d b e s&cient. s

134313 4 6

First, this reviewer a g r e e s with the c o m m e n t & , ‘ “Not all ofthe
listed s o u r c e s ’of impurities a & & l e v & in ail’cases.” ’ ;

For the reasons stated, this reviewer o p p o s e s the c o m m e n t e r ’s p r o p o s e d changes.

Thus, h e w & s p e r p l e x e d tb” s e 6 ‘thai‘ th6 c o m m e n t & p r o p o s e d to c h a n g e the w o r d % xpected” td‘“pot&ntial” e v e n ii the s c o p e of the r e q u & ti~ r e ’& % fii’ct~d to tfie’d ? u g 6r6duct. T h e c o m m e n t e r ’s se&rid E E i a r % ‘is a iefie/aiizSiion that a d d s little to support the c h a n g e proposed. In the third statement, the c o m m e n t e r ’s remark s e e m s to g o againsfthe industry’s pdsifion‘thtit appticati&is b e treated uniformly b e c a u s e it suggests that e a c h p e v i e & e r ’br r&ieti’ t e a m should decide the s c d p & - an.appris&h c@ & I,~ ~to IFad to variable levels of concern. Moreover, the p r o p o s e d ‘c h a n g e s w o u l d also, if -adopted, l a S of A N D A s , a n d s ~ ~ ~ ~ ‘~ ”~ ~ ti~ O & “$ I% ce a de to ambigtiity s u b m i f variatjle ~ ireSeti- s gL % ~& ? Sfo”r, in the prijductj submitted in different years. ’ * T h e A g e n c y ’s request s e e m s m u c h m“o‘;l;plication 5 res‘tilt iri r 6 like&% iin’lformily; improving apbiidatiori ‘review uniformity, a n d facilitated’” ‘application ‘r e & $ than “t’h e c o m m e n t e r ’s alternatives. .,” ‘ ,jlj,.,. ,,;I 8 I,

134613 4 7

C h a n g eto r e a d “D r u g s u b s t a n c e p r o c e s s impurities that carry o v e r into the d r u g p r o d u c t s h o u l d b e identified h e r e , k w d not b e dIscussed further s tbev a r e also d e g r a d a n t s . ”

Discussionin the d r u g s u b s t a n c e section-issufficient.

B e fore commenting, the text n e e d s to b< I,.Viewed.‘7 r ”%_,j,j _ j *-* e i L S‘“~ *,~ & & < d8 T h e text in question (Linei” 1 3 4 8 : 1 3 4 9 ) states: For e x a m p l e ,
d r u g s u b s t a n c e proCessi ‘mpurities that c&Id c a r + o k t6 i’h h d i $ p r o d u c t s h o u l d b e listed h & e e v e n if thev‘.$&&mallv controlled‘diiiin~ d r u g s u b s t a n c et& tine a n b will not b e i n c l u d e d in tfie‘& u h d i % ~ 2 ‘s G & & o ~ . ” A t first’glance; fli& e .!G e ‘m s td~be~lietle diffet% n d e ‘b & $ & e n the eff fkt of the two teif.i- “& c d u s ~ ‘ “listed h & e ” ‘a n d -“identified h e r e ” a r e effectively the s a m e thing.

This reviewer‘ p r o p o s e s that a simpler alternative w o r d i n g considered, “For
example, substance dw p r o c e s s impurities that c o u l d carry o v e r to the d r u g p r o d u c t s h o u l d b e listed h e r e ” since, upon reflection, this

However, the difference b e t w e e n “carry o & r into” a n d “could carry o v e ‘r into” is significant. In addition, the diff&% n % b e t w e e n the ‘c o c a & applicable modifier, “e v e n if they a r e rrormally.‘.. “‘$ ? d ’fl?g t% o r e ’ $oballi reaching modifier “but n e e d not b e c $ & $ s e d further” unless...” is alsd significant. reviewer sees n o n e e d for the modifying clauz2.e; B a s e d o n the preceding, &is ?kvietier will di@ r’6 ’th&‘I% A “e v e nif . . . ” with respect to the c h a n g e of modifier * Claus’& but “ie.+ “,-*:m e““1 ~ rae _. ..i.h*aw.a”, c o m “.% id: :._ n that the w o r d “G o u l d ” ‘b e t% C % G I’“*% d the modkfyulng clause 2 b e r e m o v e d as superfluous.

.le -





‘ -



,‘ .’ .,‘


5.,, :


Number 15701571


Revis ion


I” / ,, ,.-^j_ ,. ,I..,I‘“ */, ,

A’ /* .,~ :.

Delete “Stability study reports should also be included.“.

This assumes ‘ that freestanding stability reports ‘ w&en. are The g&dance should describe the information needed in ,the application, and allow flexibility in the format.

This reviewer disagrees; Each CGMP-compliant stability test generate< a report. The guidance text in question should be kept as it is.

The c ited statement does ‘ nijt, as the commenter states assumethat any particular type of stability report is written. It s imply presumes’ C@VlP compliance. ‘ . : * 21 CFR ‘ 211:194(a) outline$, all ‘ the’“ite’ of, ms that a lab I_ record must contain. Sec. 211,194(6) requires: “A statement of the rekults~of tests and _,_,.__,.“_*l..“; IF”,. how the results compare with established standards of Identity, strength,
quality, and purity for the component, drug productl container, c losure, inprocess material, or drug product tested.” ’ ’ 21 CFR 21$194(ii)’ requires: “Complete records shall be maintained of all stability testing @&for& in accordance with Set .._ _ 211.‘ 166. .^ “,. ,“. ,,“..~_ ., ,_” i / ,j. a,. “fy .; / ~ ,.,, / ,. ~ *_. Thus, all stability records contain a report, A statement of the results of tests and how the results compare with established standards of identity, strength, quaky, and ‘ f&ty for ‘ ‘ the ,comijonent, “drtii*~~&&ci container, c losure, in-process material; or drug d&duct tested.”

Thus al stability studies generate ‘ reports and the commenter’ s remarks are, at best, unaware: v$at CGM,P. requires v is-8-vis stability testing. _.._ “_“a“.*~,,,//, _. .^l . ,
Move the section on analytical procedures to line 1623, after the section on stress studies Information on analytical procedures may apply to all three: types. of’ smdies~ (formal, supporting, and stress studies). A stand-alone section on analytical procedures would be a m.ore.straightforward way of presenting it, rather than j including it in the formal studies:


This reviewer agrees. ^. “,
Delete “(e.g. weight loss)“.’ In most instances determination of weight change of a product’ &h a calibrated balance is a standard laboratory procedure and’ sho,uld not require @&en&on of , r the procedure and validation data.

For the reasons stated, this reviewer does not agree with s imply omitting the example.
[Note: this reviewer would suggest that, in the future, the Agency could choose a different teSt as its example to nip such in the bud -this reviewer would suggest "closureopeningtorque" because most don’ even t presume to know how to do the test much less how to do it properly and, in many cases, the test is critical to ensuring lifetime c losu?e integrity, especially for drugs packaged in unit.bfuse containerdJ

Factually, based on experience in more than a dozen US and foreign laboratories, ‘ there is no one %ndardized procedure ‘ that all laboratories use nor, ?%r’ ~that” matter, a uniform calibration procedure’ ‘ for the tjal&icei used or uniform balances types. ’ __ ” As a Ph:D. ‘ Analytic& Chemistand .former Quality Control director overseeing the’ operation of ‘ the i”nternal” RM, Validation, in-process, Release; Stability, Coktplaint arid method’ improvement and validation lab functions as well as s several specializ,ed c$ntract‘ l~bs, havin~‘ ~~~~~~~~~~~~.‘ iab operations in more “__ ,. II_/ a&Y~..’ic.:.,.*~>iau.‘ Ithan dozen other firmsin :, .rul~.-~’ the United States, jXYted”K‘ ingdom, Japan, Germany, France and China, this reviewer can attest to the need for‘ labs to have and‘ the Agencyto’ requesf proof of the reliability of eventhe s implest unit operations.
* i,^ .! ,. * ,





Line Number

Proposed --

In-house holding bf in-process materials should 6e cokl&ed a GMP requirement, not part of the application.’ In addition, +Tse’ :re not “suppbrting studies” as defined by ICR QIA.


Delete the words starting with “Stability data to support hold&g .*. *to the end of the paragraph.

This reviewer strongly opposes this deletion for all of the reasons stated - the draft text, or, if such exists, an improved version thereof should’ be incorporated into this final CMC guidance.
[Note: Lacking -‘ the __ data requested, an application reviewer cannot know that the holding times proposed in an application . are scientifically sound and appropriate a CGMP requirement. If these holding times are a substantiated by the data provided, then, the prudent application reviewer could place the application on hold and request the applicant provide said data. Most firms claim fhey do ti want to delay their applications. If this is the ,case, prudent firms will report the stability data that support any and all hold times mt just those longer than 30 dtijs. Finally, because this document is guidance, a firm may choose to follow the course that this commenter has proposed instead of the one the Agency has proposed.]

Contrary to the position stated jl. by the commenter in his ”,.., ”.., , first statement, in addition to the drug product (“finished dosage form”), the Agency is charged tiifh ‘ evaluating titiether or not the productipn‘ processes- 5nd controls do, or do a, comply with CdMP. Apparently the commenter has overlooked the specific requirements that address the-issue ‘ fhe~~ijiiime~~~r’ The ap’ plicable section isbei-T‘ 2~~~~~~~~i~~‘ ~a~~es.’ r^i~~fiaf’ ii‘ i‘ iis

on production states (emphasis‘ added):

‘ when $prop;iat’ e,


limits for the completiori of e&h phase of production shall ‘ Ablished be to assure the quality o&he drtig product‘ ‘ ueviation from &a&shed time limits may be acceptablr;‘ i{;h ;i<~a%{~~~j~~~ h~~~~o;i;p{“~is& tji;p: ;;liiiitY if^ihe if drug product. Such devktion shall be jui&&l &id d&utii&d.”

Thus, the “the applicant .,. phase~~~~~~~~.~~~~~~~i~‘ ‘ isV’ est~blish time limits for while cqmpletion of .each “.required “to’ i~ one day, one week, one month ‘ longer. or The Agency recognizing” the’ %urden”ttiat suijplying all’ of the required studies would %%pose has judiciously limited their request to a hold period’ 3O’ of‘ day$ orlonger.“. Thus, the request is~very’ reasonable. Moreover, were it to be ‘ removed,’ each’ appl!‘ cation would be subject td the judgmentof the application/j / _., 1/ . _ reviewers as to ,“, what the %rne-delay st&?~~oi;it” “should be for requesting‘ && studies, - silly me, thought the inijiistrj was fo?i$fc%ti revikws. As to’ the commenter’ s second remark, cohcerning ICH YlA, the folIowingS real$ies,a@y: _ , _. 1 No ICH gu.idance %fnijf *: The guidance IS perfect. tiinding”updn ihi,‘ qjA Recognizing this deficiency’ tiopefu’ fly flie”ICH tiill’ adjust their :understanding of su@porting studies to include those required to support ;I in~process holdtim%. “ ’ /, ._; ).” .~. Of course, ‘ firms can avotd having‘ to ‘ submit this information simply by holding all of ‘ ttieir‘ in~f%%c”ess materials for less than 30 days (as measured from the date and time of completion of the preceding step to the date and completion of the next step). ” Of course, they will still need to do the studies on ‘ to beyond the maximum times projected betG%i” steps and have those stud@s ready for’ t,j‘ ~~l”~~v’ e ‘ ~evj~~~~~~~~~~ct. 3.



Line Vumber
Delete the footnote, or revise to say the ICI-I ’stability a r e the primary reference sources.

.1 *


This reviewer disagrees with the c o m m e n f e r ’s remarks.

ReguIators a n d industry h a v e w o r k e d very h a r d to d e v e l o p guidelines the ICH guidelines. F D A guidelines s h o u l d not s u p e r s e d e them. F D A guidelines s h o u l d only a d d r e s s a r e a s not c o v e r e d by ICII’o r ~ & a t a r e ‘uniqueWto-the U.S. (-2 First, if the ‘A g e L . & *Geri:: td ‘“issu; gui~e.,in.~;~-t~ey &-;;ifh

s u p e r s e d e a n y g u i d a n c e - because,fh.ey a r e legally E n d i n g o n both the Industryand the Agency, the F D A doef ,@ c’urrently issue guidelines, K n o w i n g that the F D A understands” better ‘than “‘this reviewer what it c a n a n d s h d u r d d o with r e s p 6 8 ~ to the ICk guidances, this revi’e w e r wi”ll“defer ‘to their j u d g m e n t and, barring a n Agency-initiated~change; this’te{tshould be.Ieft’as it is in the’final ‘CtiCgukz!ance.‘” . ,” ,__ 1. I ,.., < ‘_
T h e regulations require that E P R s b e provided for bioavailability, bioequivalenck a n d primary stability lots, not P h a s eIII Clinical lots.

Delete “P h a s e III Clinical”


Delete the sentence that starts “This s h o u l d include . . .“.

This reviewer k n o w s that this draft text or, should it c o m e to exist, a n i m p r o v e d version thereof should b e incorporated into the final CMC guidance.

Provision of duplicate CofAs is unnecessary. C o m p a & o n r of supplier’ a n d applicant data is a G M P issue a n d c a n b e a d d r e s s e d by”& inspector if appropriate.

: W h i l e this reviewer a g r e e s that providing .“duplicate cofh is unnecessary,” this text m a k e s n o such request: * S i n c e the A g e n c y is.charged with a duty to e n s u r e that W.d - ” _ “_ _the_ m a n u facturing, controls, &-id d r u g productS‘ a r e C G M P compliant, a n d ’the c o m m e n.‘ r admits that this c o m p a r i s o n te “is a G M P issue” that “c a n b e a d d r e s s e d by the inspector,“’ then it is also a n application review issue that c a n A b;p -*c d r e s s e_dry ,Lby e a d ,*dl..“+ a \ jd requesting the applicant to p r o v ~ e ~ & e ’&$isrte;rnformatron. .,/. , -, .‘_. -Uniformitj‘of dos@ ~ G & G $pliia6ie to individbil & & g ~ ;;niCs.


Add after included “if p a c k a g e d in single uSit containers.“.

This reviewer cannot a g r e e with this reviewer.

This reviewer k n o w s that it is importanf’foi’thie semisolibs that the maniifbc~~rrers~-de’t~ i ~ ~ ~ ethe uniformity regardless of the packaging. This is the case b e c a u s e ttiis reviewer h a s - b e e n Involved in several product k-rvestigatidns ~involving hydrocort&-re creams a n d triple antibiotic ointments. T h e p r o b l e m in all‘ but’ o n e ’ case w a s ’ significant n o n uniformity across ^i’ii;fijr~giiiiidh’.~ ~ 6 ~ ,~ e A ‘scigtirtQ’c & d /j. ,.:“-the batch F n theafilled tubes. Obvibu~$~,y.thi‘s d ;: T h e draft text shaG/-rd ~ .,~ ~ ~ ~ ~ ~ ~ ~ ~ ,~ ~ ~ “~ ~ ~ ~ ~ ~ ~ ~ l ~ ~ ~ ~ “e ~ ~ ~ s ~ .‘ti781 ~ c o m m e n t e r h a s failed to present ‘a n y rationale,’ m u c h less a substantive scientifically s o u n d rationale,‘for ‘the c h a n g e the c o m m e n t e r h a s proposed.

Note: The original INTRODUCTORY cor&ients ‘ ar6”quijt‘ ifi “b‘ kd’ conden$d fc&t &&&$, .,, +-,,”$.L” a^,X,/$~~:“‘ i .,x ..u, -~,~~.d~~~~.~.‘ .~ the quotes directly from the draft guidance &-e’ $%t&d iti a stylized font (Lydian) and this reviewers comments are in a publishers f6nt (NeKGolhi? MT) ,to make ‘ ea$er for the it reader to differentiate the “speaker” i’ “fh< V&%.% ltkxf.p^a$+ges ti th8 folroiv. V$h& quoting from the USP, a %-n&-N&w’ dijtia? fdk‘ &iil”bE! t‘ used. In this &view, ihis reviewer’ s comments are’ made a‘ .&E ft&‘ &5m’ r%%te?‘ r&r%rki ~‘ {nd, ’ when the commenter’ s remarks are “b,oxed,” are’ l%&d i&k% .the b’ p’ ox;’ I. :.. ., These comments begin bitti ‘ ITS * .,,r~..., ,.‘;. .,:i.i, is.jl :. i,..:.. 3_*. ,‘ , .(i_-; 1,. &.&
e corrn.rZ&s based on a second reading and‘ &v&w being provided’ to IS&k&

of ““D&t

Manufacturing, and Con&& [G : i 127 5dft. doe L _ i ,,*.“, . .e:., ;,“*i+-%. 12/ 16/02]’ that attempts to add elkments ihat&%e~~~$ts issues ?n the_draft prov&d’ by’ &cAgen$ to the CGMP regulations upon which they are supposed to be based. The‘ current comments embody slight revisions and grammatical corrections from the origina] comments submitted earlier ‘ (p&tea: on 8 .-, April 2003).” Chemistry,
: shoufd be stated:” s~oul~‘ be

G’ ti&&e Itif’ orni&&j


i’ tidu&ry kv&labiiity

.j; .~,Z 9;. 6;’ Drug Prbduct:


Line “331” - “In general, to read as follows:

a fixed amount

for e&h component

,,. ,._i_” d -._ I _I. -, ‘ In general, this revietier a&-e& wiih the_b.,__ I ‘ i s commenter’ proposed revision but. x ~ b would modify it slightly to’ )_ “. “._(. s read: “” ‘ or‘ qy+fo; if;; active ?j;ed;e;ts’(;;; filler ~~i~e;;t‘ “ the !;~~~‘ t~~‘ t ,:,t..,i-:./‘; . 5,.,..^ I;.-, ta.~~~~~~e’ theweisht the ;i;,~;je ‘ in “ . of _

,.. .,*ji-I- , TI*‘ ?:*, a _) ~-:.,“,.,.“~*~c:.‘ :*i>:, .:.., .”.,-,r .: :.. /. .,4‘ .+,, :~4 Exceptfor the active‘ ingredienti and thefii I er U&d to balance t%i &&@;n the weight of the weight of each, “Drug substqce”neqded to ensure that the ie&iremetks $21 ‘ Ftr” r$“ol(a) a& mei, a fied’ amount _ _.,,.>,, .,“x , --. t for each component should be stated. (__ *. ( [Notes: To satisfy the requirements of 21 CCR “itl.lOi(a), th e amount of active should be determined by adding a small amount over the label claim (ty$ally, 0.5 % to 1 %, or, if there are sign&ant losses in processing, 0.5 % more than the worst-case processing loss) to the label claim amount and then- dividing that “_ x>,L -$“~*, *.*ai: j $“Ai ,_ of HcGe in the lot or batch of’ the active pharmaceuticaf. ingredient weight by the “as is” weight-fraction pi&~ 1 ** ,.(__i jl I. _a / /..~” I., iwr^a:&; i ^ weight should (API; “Drug substance”) assigned-to be used in a ‘ $ven batch of the drug product. The resulting ‘ be rounded to the nearest 0.01 % of the weight calculated. Then; “the -weight of the largest “Filler” or j ,x, ...” t .,,...*,. .‘.. “ “D&tent,” or the one first blended with the’ drug &b&&eshould be appropnately reduced so that the weight of the drug substance plus that”fiIler or diluent is’ constant. @or egample, IF: a) the label claim is 1 mg, b) the a’ firm adds a lob overage, and. the weight-f&&n ‘ p&y; of%e.‘ fot of- API”& be used is ‘ i)876 ‘ T&N, the formulation would need to be adjusted toX 1 .01/0.$76 2 1. i 5i‘ 968%i3’ or, rounding &Ythe h,;est “O:‘ 1’ 7 d ,&,a,,~.,.^<l.- ..” ~ ” r %,” 1.153 mg. Then, 0.15 3 mg”should be appropriately subtracted ‘ from the weight of the’ approP&te “P&r” : or “Diluent.“]

: . /

-7. / ;; _


‘ -


o~‘ %k&



wei& fmed

of each ‘ Drug substance’ needed to ensure thjt the requiremks

oy21 ‘ @lk”ilv’ (a) l.lbi’

a’ mit; -a’ ie’ ^

amount for each component should be stated.’ In cases wfiekthe $pllcant is ‘ *1 J, i :.,_ ._(*...A;;sc*.\:;j_i $4 ,lr ‘ *i I required weight of SOme weight coij7’ acttve or actlves or ctiti )k$f~poi~i+nbf to adjust the of/$.r 6f The a’ rat$ge ^ for the P;Oi7ent;::tiiet~~~Iq~~~~~~~~ ‘ fhe’ ii ,a., j., .*l_ -, i ‘ . ..” * a d&fin&d formklafibn contalnlng the, activ$%ii&iti “be’ constant.” ’ s ~.; )” i , ,_. ” --. i, I

2.1 2.2

First the weights

in the table should be‘ &f&-mi~

,@sseaf’ &-

‘ &h

,,,, I.‘ “>I <;.s, . -, ” ingredient as, shown in the ’

’ ”

‘ (Revised

Table 1” shown on the nextpage. .,

do this a slight overage must be added &id the drug substance ITAG &$Tecorre&ed for its “as Il”_.,i_ll ~, .p ,j [k&e: 21 CFR 2!?.8a(d](2) req&es the-I;u;itY‘ ~~-c~~p~~knts to be .’ is” fractional weight @&$I.

,>, ..A*: vcomponents that dilute actives by some integer multiple. ‘ kA&&r, ‘ level oft&- %ller” the must be reduced by the amount the correction for purity increases the weight of d?ug substance so that the total.“(;lore Tablet Weight” is maintained without changing the level of disintegrant, : 4. ,, binding agent or lubricant. ‘ “ f,&l ’’ 2.4 The changes proposed in “T&l& j” &e’ & a ,.&$‘ This re”iewev agre “Excipient X” is a components that dilute actives by sornk integer ‘ m X” is a ‘ Fillkr’ ‘ andnot a ““iMuen


I.. __ determined, “Ea&“component shall be tes%d fbr co~fkrnity WA all appropriate written specifications for purity, strength, and quality.“] J . ->:<***.:,,,., i term ;.;.,~?*~~,~~.j.~ _,..applies ho strictly, “Excipient X” i’ a “Fi~er”‘~n;i s I;dt ,;-“aj~i~;l~~~~ Gecause the ,~~.,.I‘“‘~hiluentn L,A, .fL’. ‘ ’ ” _ ’ “ “” ”




re+ictpd” to ir&tqnces the actives’ level:‘ ”





“Revised” Table 1: Example Target ~ompositi’ tin”Sthe~enf


. .s


Core Tablet
\ ,%,S. /,

Drug substance


standard I

Drug Substance


166.65 mg’
59.00 mg*

88.35 mg2 66.0 mg

15.0 mg
IatTnesium Stearate INF ILuWcant .’ ’ *I
1.5 m0 3 T

4.5 mg 340.5 mg

,. urified Water [ydroxypropyl lethvlcellulose dolorRedTM’
lolor B1uem3

e. I .

D M F Holder Y

13.5 mg

I standard
D M F Holder Y

I Standard

0.45 mg

itanium Dioxide otal Tablet Weight

354.45 mg

Print Ink Solution

Equi”alent to 50, * oo, and * so.mg,‘ ;~~.~eai~e,y;

on~~‘ ~ll;t~d;;~~~~~-~~e~~~~~~~~~~~~~~~~~a~~~~~~sing

o”erage of .. % I j, j,~i ij.” h-_,x.L*._ 1 ” he>Y --‘ X1?

and corrected for purity by dividing resulting weight by “&:is” fractional weight purity and rounding result up.to nearest 0.01 mg. For example if the “as is” fractional weight purity is 0:9,&%, andthe actiye is to be formulated’ as a l,Oq mg tablet, the drug “ 7,.#.....: :“” .I‘ . 8, substance amount would be 112.45 mg.

The weight of filler is adjusted by subtracting the e&ra weiglit’ of l&g* ~c;bsiahce’ ~d;I~~~~~~~~~“~‘ ~~~~~:‘ i”fiii DGg Sibstance weight in order td keep the total;vkight co&&t. In thiexample shown, in e&a 1.45 &g of’ 1 would reduce the weight of “Fill&” fioti ‘ c~9.i)onig)) to “57.65 -rn&”
The qualitative and quantitative composition s‘ tatements’for the two co&-s are incorporated by reference from”DhG 99999.’ The information is located in the January 21,200l amendment to the’ Dh4pz ~olirme itpage l-&$‘ and l-05. Seetheletter of . authorization from D M F Holder Y in I$orju!e 1. : ‘ ” ‘ ” .-. ” . Th e qualitative and quantitative composition of the ink is provided in Table XYZ in the anplication.
(Si_. ‘ I. ,(,I

SF ,.

This re\iiewer cdncurs witlf the” ci%&S

pro&se+ .” 1

in‘ this t$bk. ‘ ‘ __

“ ’

.‘,._ .i (i

$ I

, I



‘ ,,.


..,.: Page ’ 10” Lines “364 - 367,” “The Pharmaceutical‘ l%elopinent section should contam information on the .;..*,* 2:.&a development studies conducted to establish that the -dosage ‘ form, forkulation, manufact&&g *-“ ’ ’ process, container closure system, microbiological &Gb&s; and’ usage instructions‘ are appropriate for the purpose specified inthe appii‘ catidk:” he’reviikd .‘... ,.:‘,~ \_,,- ,x &;;‘ iild ‘ fiAlowS: aS .’ I’ 1’ ,,,i ,, I ” :: i,,; _,4s.l, “ .:‘ +...“F .-.~.‘ cc.” .:,, &,: (((. L.5~ “/ _ _- ,j should con&n mforrnatron on the development studies The Phartiaceutical Development s&ion i :. conducted to establish that: i. :’ specijca’ t&s, a) Components, and their identity, purity, quality and 111 in%, 1, ,, ,a*‘ ,,_“_“..xi_i. “).I ‘ ~ i* , _, *( ~ -1 ., batch-release specijcations, b) Dosaseform and its statistical-quality-control-based C) Formulation and the overages of actives added, ?,> d) Manufacturing process and its representative-sample-based in-process control specijcationsj e) Container-closure system and that system’ acceptance and performance specijcations,’ s ’ ‘ Microbiological attributes, includinj; as a~p~upriate,’ tiinil, and/or endotoxic attributes an’ d*.!I ,s.,_*. ‘ ..; g) Usage instructions . ‘ ’ ‘ ‘ . ”* are scientijkally sound and appropriate for the purpose specified’ in the applications ” ’ .! [Notes: Component identity, ptirity, quality is required to satisfy 21 CPR’ 211& and “compbnen’ &ntrol t’ specifications” are required to satisfy 21 @R’ 2mi1’ :i16.’ ” ’ ’ ‘ ’-.- ’ .. Dosage-form statistical-quality-controEloased’ release sp&ific&ons are reqtired to satisfy 21 . CFR 211 .I65 (specifically;‘ 21 %FRZl ll’ lb$(dj a&I; f or d osage f%riscomainmg ” ingredients that control (accelerate or retard) drug availability, 2fC!S 211.^lW[o). ‘ .-’ ^’ “ ’ : Component overages are required I&-&Y%’ a&?e’ &+&lie& $6 r&t the “&oti~I~‘ le& not’ thh “CY . >,.&,I.,) ) :. XTl‘ ‘ _..;: /’ _. (/ ). 100 percent” requirement of Fr‘ FR ~ll.lOl(a). teking’ is recj&r&d “at commencement’ or completion of significant “4” Representative-sample in-process ‘ .“-’ “->i.“ __, CI/&.. (2.1 ~FR 211,1~~~~)~ (‘ ‘ 1 */ ,I, ._, phases” to momtor the output and to da~date’ ‘ ~ihe”~~rforn;eince of those manufacturing processes that may be responsible for causing variability in the characteris& of in-process + ( material and the drug prod&t” (21 CFX 37 :\‘ fti(ij j .I’ . satisfy V Container-closure system‘s acceptance and performance spec%catib‘hs are kquir&d’to --~.~~~&jng 21 CFR 211.84 and the implicit requirements 6f ‘ 2~~“C~k??‘ i.~3*0 go;e;n&g “yra@;i l’ operations.” “he phrase “including, as appropri&,’ @ion%; v&l; knd/‘ or endoto&c a&.&&f) should be added to ensure that such are considered‘ and; &here such dan’ ~affectSpr&lu&I safety, ‘ reflected ‘ the . in submission documents. I j . j^ _. “? 1‘ . &,p /,,, . , .!“.,i V% include. W” “are s&entifically ~ sound. and appropriate”II -“‘Ti*‘cFR sil‘%ti’~ *, . .. ^co&&_,..“,II&ail “,. .*._?I--_ the .’ ” .I j ,, .. .*>&*.& establishment of s;;dn; ~ h~speciKcanons;’ standards, samphng plans, and test & ie ,“, . /_ ^ ‘ .,._, . ,. procedures-designed to assure that ‘ %omp&knts, drug product contamers, closures: m-process materials, labeling, and drug products confdrm to appropriate standards‘ ‘ of identity, &en& quaky, ‘ and purity,“ ‘ ,“,.. ““,_,^ . . _ _. ‘ ..,. requires all” cdntroIs ‘ be,*“first, ~S’ ‘ to lkKGKiiy sound and, second’ appropriate - not just”“appropriate” , ^. as the text currently reads.] ’ ’


za)” “b),,














! Gl









This reviewer agrees with the cort&ents


‘ .


Page “10” Lines “367 7 368,” “The studies included”in‘ this se&& are dis&$hed from r%ine dot&d tests eond&ed‘ ac&r&n~ - ti,-_,,.r, .” , *v il.. ,a, I/ to specifications (e.g., release testing, stability testing~.wsho&l’ be rev%l as follows:,
_I ,, i


The studies included in this sect~cn are~dism$&&l sound and appropriate specifications (e.g., incoming the resultsfoundfrom the testing if the appropriatefull-ichZe


‘ from routine co&rLl tests conducted according to the scierkfcnlr): in-process release testing, and stab& testing) wfrom

‘‘ .“ i’

‘ ,


^ _)_“,i,_:c . .. /,,* x ,,~ %::i?(,*22. .& :.; ,. ,_/ ,‘ ‘ _” / ,,


or %t- representative &m&s

during thefinbl


of development.

This reviewer concurs.


: .” _I -’

-4 1*,_1 ‘ :, ..l>,

_‘ il

d. j

~_ #”

,,~ ‘ /!_ > b

_, .^


” !‘ ! ‘ )... 1 .^ . Page “11” Additionally, .&i~“u..on ‘ ~~o;*h^=ideG;ify: ;,a- Jescrice .g ‘ t;;&;lb+n, ‘ ’ ._ &d Lines “369 - .371,” “ process attributes, including critical parameters, that. can ‘ influence batch r~pro’ dldib’ ility; product “<I’ ~“.I_, ,... \ .) : _ ,.. performance, and drug prod&t ~Galit$” &G~ld &~rGGisZTas foUows: _,.i. i”,. .. -1 , _(.,I; i :I”’ r ....?’ :. ‘ .’ “ “Additionally, th& s&tib~ shou‘ identify and describe the component, form&&on” and ‘ lh. p;oc&s attributes, including critical parameters, &.ich can influence batch reprocJucib$ity,’ product performance, and drug product quality.” ’ ; This re”iewer concul’ s; the impa;is &the -. _ p;~~e~t;kd’ of t/h;,-;;m;o.i&nis, ofi’ j ”



the manuf&Yuring addressed.
Page”ll” .,

* #,‘”“ .~.,“. 4.‘ .. “‘::’ .l_. r&prod%it?illty and drug




























Lines “383 - 390,” “Key physicochemi&l*&-acter&i& (e.g., wker content, solubility, particle size distributiqn, polymorphic form, salvation Idr?iydr&ioti &at& pH,’ d&so&&n co&‘ &t .(pKa)) of the _“.. .,., drug substance identified in S. 3.1 that can infl&ce $e perfbrmance”br’ ~a~~act~~ai;iiity of the *^r., il”3~“. _c product should be discuss&d‘ ff‘ . %e’ drug -s$Z&&‘ is ‘ . .. ,,.” . sG$G-~fi~GGd&ed from an active moiety ._j_ *c<*(e.g., salt, endogenous protein) and the modification afJec~.ey physicbchemic~& <e.i:, sblubi&y) and/or biological characteristic, this &ould’ ge diskksed. These’ &&&ions should cioss-reference ‘ .*, j,.‘ . + .liidi,~~Ib’ il?,,;..;-lp, -*‘ .~,~.,~i*r.!.-)r-,i- .__ ” *‘ : .L<. \#, any relevant stability’ da& in S-.7’ .” &oti@~j+< ‘ :s) r~~~~~*d*~~~~Iows: __ ;, .SI e_j,a ,&‘ P i *..+..i., ,.<..t.*,., ;& “Key physicochemical characteristics (e.g. ; water c&&t, s&l&y Gart& si$ distribiCon, bulk : .,_, /_.,. “., 1,.” and tap density, fr,, surf& .aj‘ @(, haid&& ‘ @ol~o$& form, solvati& br hyd&&n s&e; pH, ^,. .z_; dissociation constant [pKa]) of the drug sbbstance ide&ified in S.311 that’ ‘ can $-&.$n~e” the * performance or mtiuf&tu;abilit; of the c&i p&d&t ~;o;ld’ ~~ii$~~cu‘ be’ s;sed:- thk dr@ stibst&& is .. If I* .,,.i, s~~J-L+II$I~ modified’ rom l’ & active m&kty’ (e.g.;’ salt; ‘ endo@Gx~s prdtein) and the’ tiodification ,a_/ “~.s>-;.. \ .,,,”_. _ ., - ,, ,./. ~. ,a . affects a key p~ysicdchemica~“je.g:, ‘ “““““a ‘‘ i i’ “:‘ . solublhtyj &d/or bIological characteristic, &is shduld 6; discussed. These discussions should cross-<ef&~~~ spy i-eleCa&t stability ;lata in S:7.‘ ’ ” “-. 3).“


This reviek& coricur’ physicai pkoperties ofher t;h‘ s;an..“partfcie“si;e,~istrib;tioh” 1, ‘ . , 2 are important and need ~67%‘ r;i&$“i6i@d~ : “* .: ,, ~ ,^ : * ,: _

Page “14” ” ... ” ’ 1.’ .” Lines “51 1 - 5 12,” “Data to support scori~~i &o& &cl&k con&& uniformity ‘ dissok& and ”’ studies comparing split versus whole tal&k’ *” should he revised as‘j;bll~&vs: ‘ __ ’ _, .,” _,__ .~_. Data to support scoring should include baich-Fepre&dta&content uniformity and d&ohhon sampie I * .“. y. . “.A ,,^I ,_. _,...I_ studies comparing the batch active-un$xmity and batch h&e-riieuie properties ofihk split tablet fractioni ‘ ‘ to I the corresponding batch-represent&e samples bftt;e”Ghdle tab&t.”


.” “,1__” ‘ ; .:.



Page “14” Lines “521 - 524,” “The amount of oveif$‘ &yld’ ~i

&I&&~~~~~ &I$

&ii &&s&kd’ d&ge

form meets appropriate pharmacopei’ al t&s (6.g.) dniteh hates PL$copeih @I~P)“&&I chapters < 1 > Injections, <698> Deliverable Volume, <7!W kf mirnum Fill.” should ..*., s reviskd’ ,~,, ,**” _ : be a ,.L.*z~follotisas‘ /*\\a ,,-.. x Full-scale-batch-representative sample testing should be ustd,,;o ~&hit +a! ,$e min;*rnurn spec$e$ ‘ ok$li is .-,,/”,u.,a. suffkient to ensure that each and every artic& of.tt;e~~h~~h~~d~~~~~~m i;l’ that the ‘ b&ch meets the .. ,.,_. , ... .__x “V-..,W_‘^_ ?r ./i ‘ ~~~~~~~ &” minimum CGMP batch-acceptance requirements ,skt forth in 21 CFR 211, and, ~“~~~~~~“ ~~i~‘ appropriate pbarmacopeiai tests (e.g., U&d”States <698> Deliverable Volume, <7555 MLAizu~~~~l~
.__ : ..~ %

. _, ,“. *. _.( l./l/ _,,, i -

IV ’

l%w~~cope& ‘ @Sfi) ‘ &&al ,>,,._ . ,. a

‘ Chapters 2 1 Y‘ fnjictions, ” ., / ,).‘ .

This _ reviewer cyyp, but would correct :I .“(, *. ‘ *; ” ._ Mini&m-Fill).” and a& the following sentence:

‘ ~75~ -Mtirnurn xI.I:_I _/, , .I?,i.““._ ~755> kill” ’ to “,:“r’ _I(*,“*rrrl~: ‘ i.i,;;~.,z”.<~-,~*4 I” s,


4~ ”

“,n caSeS where no fu,,-sca,6.‘ ~.tche8 ;ha”k‘ be&h Y--dA’ “ d;“Qh& ‘ G”~~~~s ie’

I-..,1.. ” / ,Mll*1. ,a_, I ~ from the testing of the largest scale ba~cch,‘ ~aving’ same formulation as”tFie’ _ .~:.$.&~..~>;4.~~?r .; , ‘ I ,. :.“i\,*: the proposed, formulation shoulh iixlude fii~~‘ ~~~~ti~~“~~=ttie lesser of: a) twice the number of batch-representati;~~‘ ~~~~~~~~~ cdmp,iande with ]$o’ “^ 3951 (or the equi”a,enf> ;4meF&‘ rVlafiG/6r,Standard; a. s9 ,eiti“ ,“-lr,&-i. .~Ns~7A~Q~2.~>~~~ ... % < “”1-_’ .” ‘ ill < would require, or b) represeqtative required scale batch.”

at least threk Kri& by those _,, ^ standards’ /.” foi _

‘ #ti& numbers’ ~8 “l%&chtti6I :iie of* tkk “lai;@st ,, ,. ^



~ I, . 1 .

i;.,. ,,”.J,i. ,>L _ 1 ^,” of the drug sub&a&e in t&e dosage form that is added + excess of the libel ciaizrnT A”ny overages included in the for&&&o& dk&Zbedk’ P. 1 should I,“__ ^^ E-” I:~, c_ I ,I .- ‘ ). ,_.,, . be justified. Info~mati’ on si;oGld b-G‘ proGdYJ ‘ the: (l’ am&&‘ on, j &f kerage, (2) reason for overage (e.g., compensate for expected and docuke+d r&&$uX~ i&s~Z’ &~~e prop&r && G,‘ Clkl&e;y), and (3) justification for the amount of the &&-age: se overage should be included in the amount of ,drug substance listed in the composition statement (P.l) &d the reprksentaiive l$t& formula , ( 3.. (P.3.2).” should be modified as fOlIbws: .An overage is a fxed amount of the drug substance (kive ingredient) in the dosage form-that is added in excess of the label ciaik. kny “oieiage, ihcluded in ‘ ‘ the for&&&& ‘ &Gibka 6 P. I should’ be ; _ ,‘ : ,;. () ‘ G!‘ \i.,” ‘ si*it-:rq ”(I” “c‘ .Q .ri .‘ <, 1, -‘ .q ;‘ justified, includir$ the o&age added tb satiqy .t6e’ reqznrement set forth in 21 CFR 211.101(a). Information should be provided on tE;e:’ (1) amount 6f o&age, (2) reason for &e,ge (e.g., ” ““I=.,,.~,” compensate for expected and’ documented r&&ki4&ing losses, ens&-e proper dbs& dklivery); kd . ”,_,.. a,,*, I (3) justification for the amount 6f the oSerig&. ihk G$eGage &&G’ &cluded in the amount of drug substance listed in the cornpoSition s&&e& ‘ 1) aAd ihe representative batch L&CIa (P. ‘ s‘ j.’ ($. :? , “,..” I^*/ ) [Note: For ov&;agks a&ink from the variation &the weight of ‘ “l&s than 100. % pure” API necessary to then provide the required weight of active ingrediest (d&g substancej in the’f&$latiok, the amount of API listed in the composition statement (P. 1) and the representative thatch formula (~.3~2~“~~edd~“~o ‘ a$propriately i;d! increased based dn the weight~f~~d~~;;““ptntyn of&e ktive in&&dient (&-ug~s&ta&ej in ‘ APi. &g -I The formula for computing the required weight of da&Ai)I shbuld be: -’ . ” (Required weight of active ingredient) / (weight-fractional purity of&A&)’ It is neither scientifically sound ~&r appropiiatk td use ‘ ?OO %” d&idkd b; & &a; in‘ &a& of ‘ w&&k: t&i fraction purity (“100 %” d&ded by the Wefghi-per-d,$ @&ity); 1 ?$& !&< case ‘ because thd repo&& “Assay” of a given lot of API is NOT a”valid measure 6f k.& lkri~y of &t’‘ “iot d”~iii.‘ -~“~B’ “~e~reason is’‘ 21 CFR 211.84(d)(2) specifically requires, “Each compo&% shall’be test&a ?or~~o&%$~ w&h ‘ &&r&k& written ..“. , _ specifications for m, strength, and quality.“” aili4 & ihe’ iaii b’ el%d XT purity ” ~s’ thi samei& Apj stiebgth “*“ . kt ’ (typically measured by an Assay). In‘ addition,’ t];e weight of the appropriate “Filler” or “Diluent” in the . <. Ii/ “4 ,. I( 1 ; _ IL * I‘ / / ,, ; ,I,. j _, I ., i

Page “14” Lines “531 - 537,” “An overage is a fixed amount



i ,.



‘ : .‘


‘ ..; ‘ ii,.<.y_)~I,.c ..F .!,

‘ 1

I 4: pi” ‘ i,

i. .y



c!mposition statement (P. 1) and the representative batch’formula (I? 3.2) needs to be red&ed IGi the additional , i I:* ” wkight of API required .]

: I

$, a

This reviewer concurs.
10 Page “14” Lines “638 - 640,” the indent
as it relates to preventing





system .-


._,^. For protein-based components and products’dekedfrom animbl sour,:, ‘ he;.proof that &h iGod&s dre free of prionic contamination including any transmikible sjongi$orm encephalopathy (TSE) ‘ . .,!_. _.. “: ” For components and products derivedfrom kimal tissues Abject to contamination by &uses,“the pr&fs ;hat such product arefree of viral contamination For components and products that may contain endot&ns, the riat&e and kvel of such contariinants in such components and products and the pathways and levels of reduction by which are reduced to acc&table levels ii 3 ,_, thefinished drug product. h”_.”,_,/ , ‘ ‘ .I I_ i *i ;“. ^ >. > I


“ for stei-ile pro&ictC~ the i&e&ty’ oGhe contamination”‘should be ftiHoW&l%j: 8, -._ ’





In general, this reviewer c&b$;‘ ~t$t would recommend phrase “free of viral contamination” to free . fd; .I ac@#itip.ti~ ti~al~cpnta++io+” .,
11 Page “20” Lines “765 - 767,” “Expkkatory
notes should be ir&luded’ & notes should be used to, +.l~~t$y components “&that‘ ai;e^&&&d inert gases used during the manufacturing ~rckess.“~hould%& Explanatory notes should be included- as ipiwbpriate:
i. , : .; v”, (r 1 i : +: 1 _ i*, :y,: ;;.; 1; ;;;




kp@bp&ie: Foi’ exim$d, expl&toG d&&g jkocekng” or t& purpose df

,, -“For example, ek$a&ojr ’
1 ‘ \ . . ‘ ,;,:,;;;,i;,

&vi~e’ to read: d
I. -. :

” jS
r&&‘ sKould
: I,,~.~ :---;.$.‘ .

be u&d ’




Explain the adjustment $ the weight of iW’ ~eq&ied to ensure that the weight” of&&e ingre&&‘ (drug. substance) added is su&ent to meet the re&Gemenis of21 ‘ CFFUl i ;‘ (zi li)f ’ ” ., / .J ;,-~>.. . ” i ,“*, ., ,, ,.,~ .,“_ Ij;...” -il., Explain the adjustment of the weight of the “Fiber” ore“Diluent reduced to ensure ihit ‘ Le totalformulation i’ .“ki.” , / . _ . _ weight is of the active ingredients plus thk adjusted “Fill26i “Diiuent” w$jIht I:s i’ constant. ._,-)/ + I(, . ^i.L ?i.s<,-~ *Y i- *“.-, ). _..>>/, ..,. >A, %,q.~)-“. .., ;,* &.?i Zdentfi components that &“r&n&Gd ,&u&g processing or the purpose of inert gases used &&g ‘ I’ . .., the manulacturing process.


This reviewer concurs.



_‘ :I


,” a.



‘ jl



Page “2 1” Lines “769 - 770,” “Table
Table Core 2: proposed

2” should

“,.“, __*

as’ follows:
,.. _” I_.I I_ ,” 41,_ .,” .~ !;




2.50 mg TrademarkTM


Table? I Reference to Oualitv Standard in-house Standard
National Formulary (NF)

Component Drug Substance Excipient X ExciPient Y Excipient Z Magnesium Stearate

Amount (kg or L) 505.0 305.0




280.0 kp
50.0 kg


15.0 kg (range

14.5 to 15.5)

(200 L) 4

Film Coat Solutionf


“not less than 100 percent” requirement of 21 CFR 211 :lOr(a) is met. ’ The actual amount of APL to be weighed out for a gi~ed‘ o~API’ gi6en ldi’ is’ hj;thef&i&: s~:iiRg^~~~~~L~i’ ~ght-fra~ti;bn ~w’ . I” I _I / 6% ..” _$,\ ,,. i *_/ , purity) with the result rounded to the’ n&est 0.1 kg. ’ The actual amount of “Excipient X” to be weighed out is’ 3bS.O kg minus (~PI’ kg*vGeighi~co~mputed &Poop 2 minus#.o . / 1 , j. ,4. - _,, : ,’ kg). p,

Water iSremoved

during processing.

Film coat weight may vary between

6 Solvent evaporates TNote:

80% and 120% of target coating weight. after ink is applied. 2 I ,<,; __, ,,,). .“._



:. ^ i :_ ^ __._1 _‘ /-;._.i ,,^ (d.“,(lm,,l *, ~ _,.

Then rationale‘ for changes are required:

‘ preceding -chang&(in the

bol’ il)

should be s&G&ddnt. ,V” \’ /;,

Hoikver,’ & s, ., /


‘ ~ 1. ‘ ‘ :+& “1 I, : To ensure that 21 CFR 21i.!Ol(a) !’ ” ” ” is met,a& overage ‘% be added f+ the active’ ingredient. ?<y’ . : 2% ;.,x>,.,‘ ,,..&i because . :” is 9,. : was &nd ad ,__ ‘ value :~<‘ selected :../.a, i/nl*:. this_^ 1the * typical minimum value’ that permitsa v&d (&@c$j ,&..t\ i appropriate) determination of the &II strength (us re&red bj 21 Cl% 211 ;l&S(a), “For- each batch of drug product, there shall be appropriate laboratory determination of ‘ satisfactory confor’ mance ‘ fmal ^tb , jy‘ ,.>S _..~ ,._d ,mi%.*“ ). I.,. ” specifications f or the drug product; i&luchng the rdentrty and stre~ngthof k&h active ingredient, prior to “ /,“( ’ I,_ .I ~” ^..,i , ! : , , 264 ,‘ ?:,, d. : a ~‘I ,. ‘ >1 j I. ~)__. ._:?,., ,, i.<* .. ^_/o ,?>. .q, I 1,,.). I I” ,.

r .,


: _(,j






~1.. i.



.?.,.C /,_












,als,j ,,,,’ at“? release. . ..“)b a s ed o n the “Assay” testing ‘of g “fe w y e( < ‘“2 % h e 9 5 ‘% *c o n f i d e n c e level) a j i q u o & ‘from”a n 6 ”. I, appropriately h o m o g e n i z e d b a t c h - r e p r & n ~ a & e composite sample.. “_ I . . , : :,:.:., <’ T o e n s u r e that. the weight of a g i v e n I& of A P I a d d e d to this formulation is’sufficient to p r o v i d e the r e q d r e d & e i g h t of active ingredient,’ d e A ”iii’t;ki~ h t’;nust”b e a d j u s t e d ’“~ ~ .“div:ti~~~~ ;;;;& ;n”-l W e i g h t *
,. ‘i* ‘I _*I,, ,,~ : _‘

r e q u i r e d b y the weight-fractional‘ “purit);‘) ofthe A P fwith respect to the‘active. This is r e q u i r e d b e c a u s e _ “,,. “i / I II,,_, .... .1 .* n o A P I is 1 0 0 % p u r e b y weight; typically, % e “a c & e H S p u r i t y of most A P Is’is less than 9 9 % a n d in s o m e / “I *.’ _ 1 .“, instances ( w h e r e the active is p u r c h a s e d diluted in‘a carrier).may b e a s little a s 1 % *of”th e c o m p o n e n t ’s weight. ;j) T o e n s u r e that the overall weight of the formulation is approximately constant, the weight of s o m e 3. ‘excipient” that d o e s not affect active availability ( a fill’e r ~o r a ’diluent) must b e r e d u c e d in weight b y the a m o u n t a d d e d b y the adjustment of the vveight of the APlieqnired. ‘~ : T h e weights of materials a d d e d ‘b y weight G & e f o l m u l a ~ o ~ ~ t a ~ ~ e ’“~ ~ o u l d b e e x p r e b s e ~ to the ‘level precision that the b a l a n c e u s e d to w e i g h them. Fb; ‘ingredients ‘d i s p e n s e d b y v o l u m e rather t h a n ’ weight that d o not r e m a i n in the formulati& after’.& e completion of the” p r o c e s s i n g steps that .a& them, the v o l u m e (weight) a d d e d n e e d only b e e x p r e s s e d to the n e b e s t ’hter ( k $ o g r a m ) unless less t h a n a liter (or kilogram) is to b e a d d e d (in s u c h cases, the v o l u m e [WZght] a d d e d s h h o u l db e e x p r e s s e d !. to the n e a r e s t 0.1 L [O . 1 kg]).

This reviewer concurs.

! ,. /

.I,, / i ) -. 1 3 P a g e “2 1 ” -- , L i n e s “7 7 4 - 7 7 6 , ” “T h e description of the ~ m a n u f a c t u r i n g p r o c e s s a n d p r o c e s s controls s h o u l d include a flow d i a g r a m of the m a n u f a c t u r i n g ~ p r o c e s $ a n d ‘a d & h & I des&iptidn of the m & n . & c t & $ , ./ . p r o c e s s ,& p r o c e s s controls.” s&,ul&.,& &+-&d { & ; < & a ; “.’ “ ^*. ‘“‘- .I-_ 1 ” se, j g - -! h description of the m a n u f a c t u r i n g p r o c e s s ’a n d p r o c e s s controls s h o u l d m c l u d e ~ ~ : ‘I ” T/ae r’ = L, _. ,-,--. ,‘ 8, ,‘_ ^. 2,; I d 0 F L O W i a g r a m of the m a n u f a c t u r i n g process,
l l

Detailed des.cription of the m a n u f a c t u r i n g

a. Detailed description of the p r o c e s s controls that includes the rat&ale that establijhes t& t the p r o c e s s controls s p e c $ e d satisfy: a ) the in-process controls ( 2 1 CYf?k Z”i.‘IW ~ d b ) thk batch r e l e a s e controls ( 2 1 C F R ”2 1 IAN, -r”l’ C F d - 2 1 - 1 ’.1&, $I’ 2^f ‘e @ I$ hclrigTj $ ‘$ i h in the m i n i m u m c G M p reSu*htionsforjrinish~d p h ; l ~ ~ ~ ~ c ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ,,~ ~ ~ .* - . .‘, ‘rfqi iha*. .!I -.

process, a n d

‘2 O m C !? X ’i~ o j’~ n d


This reviewer concurs; th e C G ‘M ’P m a ’n i 3 5 d tiuFiti~ ~ t% d & ~ b e g i ’% ‘& ith th e ” ,/ . I p rb e ,in g , c p a c k a g i nogf , anncd m i n g m aaterials ‘(ccjmponents, c b n tai&is, e’ Zl&ures,e i i -. oper o n trol i o process u x :i,iarie’s) hria.“..n ,j “eii’il~ ‘w ~ ~ i i ”t~ ‘,‘d ~ ~ r o v ,a P,^ *A , u ,oraj.‘ ,./,*,,, ,,, .(I..b ,~ ”p & 4 .,3 ,+ ,**I es; i~ -, ‘~ur*,.ril,t~ ).. fin i s h e d p a c k a g e d d r u g ”p ? o d tict b a tch leaves % Y i% i;~ Z ? $ ‘? % i% ? c,ontr$. s
: ,” 1 4 P a g e “2 6 ” > A . r // ,a’, ,‘.,. , L i n e s “9 4 8 - 9.50,” “W h e n the s&n.5 analytical p r k e d u r e i s ~ & e ~ d ’f~ ~ “b o & the’i&jprocess test a n d t h ~ & ~ h ~ d , product te’st, ’ the a c c e p t a n c e criterion for the in-processtest s h o u l dbeidentical to’% tighter t h a n 4 % a c c e p t a n c e ’criterion the finished in * . / ^ ” .^ , product specificatibn.” s h o u l d b e revised to r e a d : ..), 4 ) (,, ‘. .a “~,,I.__ _ _ L d. .,.$ ‘i the a c c e p t a n c e criterion for e a c h scientfiallj s&&l 6&h-representa&kknple-based i&process test bI / ,, “) “‘..)_;..._ a > .?, s h o u l d b e appropriately ‘tijhtk t h a n “.the bcckptance crit&ion in the finished p r o d u c t b q t c h - a c c e p t a n c e specijcation & the p r o c e s ssteps’s u b s e q u e nG .said in-@ o i e > s test caniot adversely affect the variability of t 1;; s u h ’case~, ‘~ e ’a c d e p l t ~ n c k c~~te~i;;;;“f~ i;r’~ . e ~ ~ ~ ~ r d d e s stest‘~ a n b e identical to the finished‘product. .,.s.. _ S L ,I /*,_._. ..~ “‘,r “‘vy ** ,“1 + e a c c e p t a n c e criterionfor the f& h e c i p r o d u c t specficanon G & S h e s u b s e q u e n t stelk’a o not affect batch un&Fity, or, w h e n s u b s e q u e n t ’ i n $ b c e s ‘s X $ s ’a r e k & G Z t o G p r o v e ‘batch uniformity, ,,,,, ._^ .,^“.,I .“j . ;_ ~ */_ , . .I ._ I’ .< ” . I_ .s; “-1. ^: .I *^ ‘~ - c Q a ~ ~ r o p r r a t e l yw i d e r t h a n & e a c c e p t a n c e criterion in the fimshed@ o d u c t specification. “’ ’ j .’ .’



_ -.



.,. ( ,.s, :) 15 Page “28” Lines “lo?4 -- 1026,” “At a minimum, the d&g prod&t manufacturer Gust perfbrm & appropriate” J ,“,_ ,*_“iir **,~.4*,*^~.,~.(_,... .,+ $. ,_3.? ideritification test (2 1 CFRZ Ii .84(d)( 1)) .” &&iId b; ‘ &%sed to read: ,, // At a minimum, the drug product manufacturei- must per&& & $pr&iate iden&$a&& t&i an&$” spec$c identity tests exist, thej’ must be z&ed“(2~??F&2~1.84(d’ );’ ~(i’ “Ad east on&‘ shallibe cbnducted test’ to verify the identity of ea&h component 6”f a‘ ?&$ @&ct. Specific identity tests, if thiy exist, shall performed ;;;^‘ b&Kr+$re&ntative a set -oS;.Sam$es (21 4&R be used.“). Moreover, ,ail, testing must be ‘ . 211.160(b)(l), “Laboratory controls sh&“in&de: (1) ‘ D”&k~min&io~‘ ~f co;;fd;l;l&ce to appropriate “ written specifications for the acceptance ‘of ‘ e&h lot- within e&lXip&en~‘ ‘ ‘ X &f;;poGe&, drug prdduct containers, closures, and labeling us&d in &he nGntiG&tiiZ, p;ocess&g, padking,’ or h&ding of drug products. The specifications shall ~&IL& a‘ de&i:ipG&Y bf^& &n$ing and ‘ testing procedures in “a&&&, **& J&j p&&t used. Samples shall be remesentative ancj idk&i%kd~ 1: .“).

. ’’


manufacturer must appropriately determine the purity, not the Assay, of each shipment ofe&h 1:; of component that has a discrete chemical composition. ‘ Each ‘ p&y de&&&ion must be performed bn & apiropriate batchrepresentat;ve’ sampI ;hTf;i:‘ tz;z,” ,,., v.1‘ *~r.i”a.li:,.#.X.‘ -r.,ir9. _,- *..-, ‘ II.i , 1‘ M .., . ‘ ;. ‘ I >, p, ~; ;i ,x\‘”.” ,I/:“-~ ^.“ _/y <, : __ .:-



{- _I*‘ _(

In general, this reviewer concu^k$ but notes that the pt-irase “an appropriate an identification test“ should, at a miniti@jT, be changkd”tb “‘ appropiiatei’

identity t&t” components or, ;s ~h”e’ w-“iewer‘ yas- -8bte‘ ‘in, fiie --review oT tKe i PhRMA d’ ..,Z,‘ ,,” .. “. _.^” .__. i I.;,.i- I.^ : .,*;,__.:,>;iji;. " ." "<P".,,- ( _ cotilments, more ‘ properly, the cite ,$tould be~‘ ~l?lli~‘ ~“?~ $i %'211:84(d)(2)~
~~z~Lzs~~~ *ii,.j . ,~tien the us the regu!+ory text is con&ruct$d, “Iif”CFR-~~i.8~((;d)(ij;~o~lj;‘ 3 m”ai’ ;~~$~fti*~~r rs”aoriig”7u,,* .(, *t’ ._._ test,ng. ,-.*:a< ,I.,‘ : I,,“. i* ,., : 2 $ppjies If the mariufadtur6r elects to’ &e a report of antilysis (or’ ckt?ificate’ of analysis) from the component’ * 1' i,s I,,. *#.:LL,., ;&L '&Re21i184(d)(2) hp$'&'*" s ,I_ r-L iit% I;c- : __ ,,.- mahuTacf:&&m,n,mum, IIi,p "-*,u a~.:‘.r,>**>cr*.,'"e\*.and the true, miniMUm "Ibec6ses the *a~“:th&-2~Y estaST;ifiearri-;iyRI CFR' ’




Based on the preceding regukitoiy ,.“,‘ ,,“*‘-_l,i th”is~~~~i~weu‘,x(” 4:l.A.I,_(, ~ej,‘ ”/,I,, “. I ._(i-li/? reality, “x:.‘ “”.”.,&A x. .‘r%c&-ir&tibs~thdt “‘ ; x:“_.1., _, ,,.. the text in the guidance be changed from, ,+f a rn!vJmyrn, the drug pro$ct ‘ ;nanufaqurqr
mu+ perform an approp!iate ide@ic+oti t$s?-(i I CFR 2.1 I $$l~(ij)2Y.’ 10 “At a niinimum, the drug product manufacturer .must perform at least ‘ ;6ne siiekific identity f{&’ (1 I* C&

2 I 1.84(d)(2).”

‘ ”


‘ : .


* “” _, ._ _ ,.


_ .,_ ~., .,. _ _,., a ,J”*.. :‘ y~z.~,r” : .-..w,“;“h-ir. _.. ? ... : ii. :. I,_ 2;.“.y afirm’ im);rementatidn of an analytical procedure changes It In any wayfrom the current FDA-recognized revision, i x *“. , 3.\,.o’ ‘ *, f ,A ’ thefirm must include a copy of iis Z$&caI procedure jn’ ;GJ%j. ““. . . *_ ‘ .I,,/” .,<‘ I , I‘ /a? %e9 -“.l:>IT(,i,<*,-, ,<.c- ,ai;.n,“< ‘ r&t.$:&s,,-, ;*:, ‘ uI-I*-Lp(.l~~~lr! ‘ $,“, lL,l*pi +*A%*~i”’ ., 31:., :“I+-./‘ ,-, ., ,( “. J. ‘ ,.,,, I. t,-+,‘ .‘ _ ^ ‘“” l. i 266 : . II ,, j, ,, .L 1. 1~ ,_: j ._. .,

15 Page “29” I? Lines “1053, -~ 105i,h “Whew th e’ &alyt&S’ +GG.u-e use’ is in &e &rient ie&ion ‘ & offidial & of’ cbmpendium or another I%A&ecog&zed~ standard’ reference (e.g.; AOAC Inte&&i&al Book of Methods) and the referenced analytical @Gedure is~ not‘ modified, a ‘ statement i&&&&‘ ~the analytical procedure and ref&-ence can Ge ‘ @b;vidid’ &l&r &G-t& -$&$&~l” ~~&{du~e ‘ itself.” sh&uld be r&&d to r&d; _ “.’ “’ 1 ‘ _ .,I~_ ,.,, . \., I” ” I&“.~, / When the analytical procedure used is in th, &.n-reht r&&n ~o.~,~~~~~~glc;dn;pdndiurn or another FDA-recognized standard refkrence (e.g., AOAC Internatio&arBook of Met&o&> &d’ &e ‘ ;efere&ed ^I I./ , analytical procedure is not mddified’ &&&ed , or &t’ ex; &a+! $11 fn-v wq a s&&&%&&ng the :,,~,,~~,,i,,-,r,,‘ ~~ analytical procedure and refer&c& cant L;e IJrovided rather than the a&&t&al p&kcl&?iG&. of the





l-his reviewer concurs. - *__ ..

. ”

,,_ j _(.

i I I.

’ : -?. .

. ,


16 Page “29” Lines “1062 -

1066,” “Wh en analytical procedures from the current revision of an official compendium or other FDA recognized” st&dardref&endes (d:g.‘ ,“Ab‘ AC %~&&&a1 Book of “, ,L ( Methods, analytical procedures from EP or JP that are’ int&&&geable with aUsP.~;;n‘ ~~~~~~~~~~~~“~~~“I used, they should be verified,to be suitable under a&ual condi.tions of use.” should bk revised to : ‘ _ - 3: /I r ‘ : ‘ !, _’

‘ ,‘ When analytical procedures from the current revision of an of%&1 compendium’ or other FDA recognized standard references (e.g., AOAC International Book of Rethods, an2ytical procedures , .L^, A”..,,-d.+ ,, from EP or JP.that are interchangeable v&h’ aUSP ‘ Gk%il’ Chapter) &k- “u&d &h& in) kodijcation, change, augmentation or interpretive languaie, they should be verified to be suitable ‘ under actual “’ ^ “. ’ conditions of use. Otherwise, such analytical proceduresmust be appro&at.$y v&d&ed..


While this reviewer thinks that’ the commenter’ s suggestion is’a ‘ good,, thisreviewer thin.ks that, to enhance this guidance’ ‘ s immunity to’ the need for technical revisions caused’ .by agencies ‘ outside of ‘ tiie”control ‘ thei I%fi; the’ of,” commenter’ s text should be’ further:revised: to:
“When apalytical procedures from the current revision of an official compendium or other FDA recognized standard references (e.g., AOAC In~ernatibna’ ~~ l’go& bf M iihodk, analytical .oth-i ,FDA-iecogniie‘ d pharmacobeiij’ ” -,^I^ procedures from EP &i ?P . i _3 ,, _ . ^_ : are used without any modijcation, change, augmentation or -1 they should *be ’vef%d k~ ! b<~&ii&k ’un& ‘ actual &n’ di6ons .of use. interpretive language, ‘ :Cjdedse, ,;A ,,i;ti,ai<;~c~dti;gs .s.g31ui$be ap~~~~h~~~i;Yalidated.nhi” -A’ ,‘ .’ -*“*~“-’ _ ’’



This reviewer understands an”d .agrees with.‘ the ‘ commenterJs need for ‘ the restrictive language,‘ ”are used without any mod$cation; change, augmekzation or intkpietjve language, ” ” ..^ on what constitutes an analytical procedure’ “.__ , “l>.,i ?i”’.x* j/_ ,. _.j Lfro’ .,1( ~*-i m’ anTDA-recogniiedsouice but ,,,_,_ ,*“” knows that the inclusion of the restrictive phrase,, that are mter+angeable’ v&h a. ‘. than the ,u,nderlying regulation’ s language and ‘ General Chapter, ” is more restrictive ’ therefore should not be included in thi’ guidance document. s Similarly, the use of the word “must” should, in general, be avoided in guidance because: a) its use ‘ inappro’ is priate’ ~there/n ‘ and b)’ those in the industry to whom it is directed are responsible for knowing and doing what the m inimums in the underlying regul~tion’ require of them . *.s
/ ,.” \ .I , “// i ,/, . . ‘, /

‘ ~




Page c‘ 30” justifications of the acce$&e cr$er%*for tests Lines “1079 - 1081,” “For compendia1 exdipients: ‘ beyond those included in the monographs is recommended (e.g., particle size, flow properties, - _I_, .,_” ___I _ ./(.~_.,” -* _,1,.* .,$% ^ ,. ,,._ ,,..r, ,.~? impurities) .” shoiildbe r&vised to &a’ _-.“’ ” I ~: For compendia1 excipients, justification of the scient$c soundness and appropriateness of the acceptance &o~og$&S or reqtz&eTiL 21 CM ‘ I:84 is req;ired 21 criteria for. tests. beyond those~ included’ in’ t& ‘ _,, i , _ .._ ^( (e.g., particle size, flow properties, impurities). * .(, a., ).“.^ “.,

Oli‘FOI$ij’ lL COikJ&tENTS:~6PT$LIC*A ‘ l’ DO&E+ , 0) ._” +, .,_ ,- I bq~&k$ _) /_ -‘ ‘ ,,. /.>,( ..;,.L*al,wr,~ri .‘ /_(Q/ ,j. . -, ,, : i. ,’


This reviewer con,curs with thk gram ’ m8tical construction is awkward:

rev&& :


but “‘t&&& -that’ its’

I > 18 Page “30” ,. I” *_ Lines “1093 - 1094,” “Use of terms such is conformS ok meets spec$catjon is discouraged:” should ! i revised to read: , ‘” 1 / Use of terms such as “conforms” or “meets specijZation” is proscribed.


This reviewer disagrees, but,’ to address the c&ntne$er’ ~ genuine concerns, proposes to revise the guidanck sentence tb re’ ad, “Us& of &ms”such as conforrdnsor .m,eets sp&ific&n is discouragkda,nd, when these. fei;t% ‘ ~&?iki%i,‘ tii’ e report containing them should iii&de.“the (, /““*.,d&&d I..2.’‘ sptkifk~fi~,~ . ttiat”‘M ie J-.-sr>,“. , component tested confoyni 80 or. ~~&jts.” $ II /.i, ,‘ __I .^ , I I
19 Page “31” _ 1 ,.s,i Links, “i lOO,-~~l~lO6,”“Exci$ents of human or animal origin should be idenfified. The gem&; species, _,,, , -.,, country of origin; source (e.g., pancreas),’ and manufacturer or supplier should be clearly indicated. ”,.>I I.& ,;< Furthermore, for excipients “derived. from r&in&t materiaj$ the application sh&Sd Ftate’whether the materials are from BSE countries as ,defined by the U.S. DeRarfment of ~g&ulture (9 CFR 94.11). Guidance is available fidti FDPi ?$The&u&ing and Pro&s$j of Gel&in to ‘ Reduce the Potential Risk Posed by Bovine S@giform Encephalopathj (BSE) in FDA-Regulate2 Pioducts for Hum&- Use. Use of _ _,_, l,_L terms such as conforms or meets spec$cation is discouraged.” sh&ld be rev&Xt6 &$a& ’ _ ”

c ”

Excipients of h--an or qqi.gql origin ‘ &kld de identified.’ !lYh& genus, speciei, Co&G of origin, ~source (e.g., pancreas), and ma&fact@er’ supplier stiould 66 6le&-ly indicated. or Furthermore, for exci@nts derived ‘ fr%? r$&& ‘ ik&&ls ’(OY mat&Liis’ ZjheL ~j% & susceptible herbivores), the application should state whether the materials ark from BSE countries as defined by the U.S. Deptirthent ‘ Agriculture (9 ‘ 5f CFg 94.il). ‘ Guidance is available from FDA on The Sourcini and PrOcessini of’Gelatin to l&&e ihe Potential /” ;. Risk Posed by Bovine Spoiz~iJor%Eri~e~h~lopathy (B$@::‘s:, -_ *?<~~~-R&&&! I_ @ % & & yor ..^ ‘ ,_. .’ /.. I. . / , Human Use. ““,,, ~ Cd _,‘ i” ,‘_o.).. ‘ . . j _ i-*_*. . _> This reviewer concurs w’ the wii’ itti ~of~t%-@% p?op&s&d. .’‘ ’ *. e,:s” ,... .( *:_ j., *s,., / r


: ._: ,. “.’ , Page ‘ (31” Lines “1108 - 1110,” “The potential ’adventitiqus agents should be identified,; and general’ information regarding control of these adventitious agents (e.g., kl!&ifications, ’description of the testing performed, and viral safety data) should be irovided in tis section.” should bk T,ised to ,:,s )”b._i,‘ ,..,.,. .“,.“I .; /.” ,,-.~.,, _ / > .- _,,. ; “, read: ‘ , The potential adventitious agents should be identified, and general information regarding control of these adventitious agents (e.g., specifications, descri$ion of the testing performedj’ and viral and priori -i..f safety data) should be provided in this section. “ ’ -! a,,. ,\‘ _^ * ” 1.,“,., _’Y” “- _



This reviewer agrees with the text added by th” {orqmenter. ,II.^_

-’ ^..s ’ :

Pages “31” to “32” for the drug product should be piovided. The Lines “1133 - 1142,” “The proposed specification‘ specification estalzkshes criteria’ which eZkh,$+zb hfg;ug’ to pro&i& shbkld Co&foG to tf. c&sidered that the drug prdd&t,%wh& tested acceptable for its intended use: Conformance td spe@cation mkans ‘ according to the listed analytical procedure;, will meet the listed acceptance criteria. A {pecification is one part of tlk krate~ tb &%ol drug ‘ product \Uality.’ They are lkoposed ahd ju%ified by the manufacturer and approved by the Agency. Specifications are established to confirm the-quality ;if d&g products rather &an to estal$sh, full’ c~aractt$iia~&k$ sh&j,d “foeus on t&se $-@racte+ics found to be useful in ensuring product quality as it relates to safety and efficacy; %formation on periodic quality indicator tests is proirided beioh.“‘shouid be rebise’ d,to: read:. ^’ i The proposed specification for the drug. product ‘ batch should’ be provided. ’ The: specification establishes criteria to which each batch of deg p~odtict &should&nfd& to be co&derkd.acceptable on for its intended use. “Conformance to specijcati’ “ineans that batch representative samplesfrom the drug product batch, when tested according to t&e: ksted analytical procedures, will meet &&form to the drug product CAMP reqtiretiek‘ s kstablishkd -in-l%^ %Ffi ‘ 1 .“f@,-. 11 ^C@R !2rf;%ti,. ‘ CFR 21‘ 21 IF~j~“‘,~*b.s,-,.‘“*a 1x_11, * (.” li” I 21 II.165 and, where applicable, 21 CFR 2! 1 ii67 an< ‘ &?hs$l ,%zc,eptance criteria. A spec&&i& is one part of the strategy to cpntrol drug product quality. The manufacturer propo;es and just$es their
scient$c soundness, appropriateness, and confoOrmY&e to &e ‘ ~p$icable”CG@ re q ui~eti&tsfb; t&e drug product batch. If and only if the Aaenvfindi that the kp&ijicati& proposed complies with ‘ s&d ~&TP’ ~r~quii~rn&i~s, the u iem; .Co;rt;ruli.g ii3~iAoyi~~‘ ~~.(488 .~~‘ Agency can then-approve itfor use. [Note: Ai ,er G i988’ 0. S’ p S US 531, 100 L Ed 2d 531, 108 S Ct 1’ 954}), the Aiency h as no authority to appiove >pec$cations that do not comply with any of the clear ;e$uir&e& >eL$r ir;‘ rr%~fZ~~2’ f~.~U~_ijecifications k-e kstablished to cbnfh-m the quality’ bf drug’ product bakhes’ based’“in ihe”iesults’ obt&ed f;om the teiting of batchrepresentative samples therefrom rather than to establish full charactkrization and’ uId f&&s on those sho’ characteristics found to be &ful in ensur&pro&&’ quality ‘ is.& re%&s’ safe$& $bstGed~‘ ihk‘ io b> batch’ drug product identity strength, and leY&‘ the~i~~u&zs) s of aGd efficacy (as me&&ed by the batch’ s unijkmity with respect to the active and the a@~ releaie or release r&e). Information -n periodic q&lity

indicator tests is provided below.

! , , es I

c ,, _ ,__


This reviewer supports the cha;ges and additions ~?nade; a?tb &-I&&S thatthese should: a) help the industry t&%hd&S%iid what ‘ fh6 re&Iatioi%‘ ~6itqijire of’ them in this area as well,gs: b) reduce the’ Agency’ risk’ haf s’ t’ @ i6~‘ i%$-@P:~o~e an application that is violative in ?h&6ited’ &e&S ~f’ C~M’ th~‘ P’“regu’ lat~~~~. ’ .:,,, 81, 2j .. ; t ,’ ‘ ,

‘ ,

^.. ., j ,_.-,,, 2 _, * .“i< ./. Page “32” 3 I ._ Lines “1144 - 1,162,” “The specification sheet should list 41 tests to which e?yh ba@ of ? drug product will conform and @e associate’ d.acce$tance criteria and should also include a reference to the analytical procedures that will be used to perform e&b test. Ackep&tnce criteria are G$&idal limits, if an~,analyti&l procedure will be ,used only to ranges, or other criteria for the tests d&&bed. generate stability data, the analytical pr&Lre’ should be .descGibk;l‘in ‘ ES. 3’ Jus&ea interim . , _< *,,\;. -,.,_ . , ( .=\ +.i acceptance criteria and tests with sunset pro&ions should be included in the spec&ati$ ‘ (s&e s&&n VI1.F): Presentatibn of information in _a t&larL_,( f&&at ,)is., kigked. -The spkcifificatio~ sheet should q,.,“I :, ,_ .i ,s,. , I), .. / I, Y also identify: ” ’ ,” ‘ l. .,” . tests that can be performed in-process in lieu bf’ testkg tl;e f&Gd p;od& (the &sulk of such tests performed in-process should be included’ in the batch qajysis report (e.g.,’ certificate of * analysis)) j, / i 1, ” :,,_ ‘ ._’ . __ *; d ~;,i . *‘ ,:. ‘ . ” ,: ( ,J : : ‘ ‘ . / :. j....! ._
269 ’

., :’ :

8 . 1,.,


“i-. “ -’ 4 1 analytical p r o c e d u r e s that will b e u s $ ‘f6rW,a;j,es<~‘ide&fykg w & i & a & ;egtiiatdr>; a n d which a r e al>ertiat.+eanalytical p r o c e d u r e s w h e n multi$e analytical p r o c e d u r e s c a n b e ’u s e d ’f% ‘8test3’ .- . ‘a c c + t a G e ~ & t& a ‘ for & k t& % ing t& e & @ lat6+ arialytical pi-ocedure & d G e r n a k analytical p r o c e d u r e s w h e n the criteria a r e differei$ (e.g., & & % r n a ~ c e to’ a & p & r u m tbr ‘& k G ‘infrared (NIR) or retention tim & for‘H P c % ) . ’ “’’ . release a n d s & G ,life+ac~eptancedritekia & h e n both a r e used. T h e p r o p o s e d spkcification f& r the d r u g product should b e provided. T h e specification establishes crit:eria to which e a c h batch of d r u g pr‘o d u & should conform G b e & & d e r e d kce$able for its intended use. C o n f o r m a n c e to specijcation m e a n s that the d r u g product, w h e n test<cl,$ $ k d j ~ g ’to the listed ar$ytical procedures, will m e e t the listed acceptance criteria, A specification is o n e p & t of the strategy to control d r u g product quality. .Y l G y ‘ark p r o p o s e d a n d ju&ified by the’rn*kkfacturer a n d a p p r o v e d by the A g e n d y : ‘S ~ & % & m s ark k $ , a M ~ ~ ~ ~E G - c & $ i & 6;” { L a G i of d k g ’ p P o ’dGcts d rathe; ““,,_i ,.‘, . _/ “‘.,.,,. _/. ~ .,. _ “S 9, ., than to establish full ~ h a + a & & + ti@ a $ “ih@ ld-fo{us 9 ~ & o ~ g .@ x~~z~,~stxs f o u n d t? + $ ,(useful in ensuring product quality as it relates to safetj; a n d e f E c a ~ “G formatio~ ok p e G i o d i c iuality indicator I_ , )) s b o u l . ~ b e ~ e v ~ ~ e d : f o ^ r e ~ ~ ~ ~ , * ‘(_“’ : “. “1 1.’, ( , ., tests is provided below.

T h e specification sheet should list&‘~ e k $ $ ‘~ L ~ ~ k & $ & $ b f i & u ,.firock& w!ll”& & o r k a&d&e associated acceptance criteria for the b a & ~ e p r e s e n ’~ a tG e s a m p l e s tested (as required by .21 C F R 211.160(b)(3)) a n d ‘t h e i a h z h e d bhtch stat&&l quality controi val& d e & J J ~ r o m the‘. batch-representative ’ Y *. ,.*.> ,,l, s a m p l e results (as required by 2 1 C F R ;?~l~fiS~(il~j~~ T he sp ccl & i & iheet shoiJd‘a & o irkiude’a j” reference to the analytica p r o c e d u r e s thk W ill bk u s e d to ‘perform. e a c h test a n d t& e recognized statistical standard u s e d to evaluate the s&istical a & e p tability of& b & h : A & k $ a n k e ‘criteria a r e numerical limits, ranges, or other criteria for’the:Gs described.. ti:.q &aly&J ‘@ r & G & d &W ill b e -e u s e d only to g e n e r a t e stability data, the analytical p r o c e d u r e s h o $ d ’b e d & & i b e d ‘in”P .8.3. ‘Justified interim acceptancecriteria a n d iests with s & k & p;o+isions should ‘b e i n d l u d e d in the specification (see section Vi1.F). Presekatibn ‘of informatiqn $ ‘a tal&lar format is ‘L&jested. T h e ’specifkation sheet .’ ,^( should also identify: l Teststhat c a n b e p e r f o r m e d in-process in lieti of testing the finished product (the results of such tests p e r f o r m e d in-process should I;k ‘Irkltided in & e X & h ’~ ~ a $ & ‘r & p & t (e.g. ,“^certificate of 2, 9 analysis)) l All analytical’p r o c e d u r e s that,wi!l b e usid for a.Jest;‘identifying which a r e reblatde a n d which a r e altq-native ana$t&l j p r o c e d u r e $wl;e~‘~ ~ u i t i ; ; ~ ~ ~ ; ~ a ~ ~ ~ c a i ~ ~ ~ ~ c ~ ac &; - e ’s G & Y l fbr~a tkst3’ G bZ

A c c e p t a n c e criteria for the test using the regulatory analytical p r o c e d u r e a n d alternative ‘&alytical

p r o c e d u r e s w h e n ,the criteria a r e diffk$ (NIR) or retention tim e for-HPLC)* 2

.*& & & ;&al;ce’ t& a ipe&,& ‘f’& ““~ ;a+“i;ared .(e.g., ... , I_ I,,9,^ ,,-.s.“,< ‘j* . ” *: ‘. “i* _

R e l e a s ea n d shelf-life acceptance criteria, w h e n both a r e used. ,

T h e p r o p o s e d specification for the d r u g p r o $ ~ V ~ + ~ ~ $ $ ~ x provided. T h e specificatiori ‘G tablishescriteria ,,b~ to which sach .b$ch of d r u g broduct sh&[d conform to b ~ % % isi&@ l ac~~~iatile~“fiii:‘~ ~ ~ i n t C ; nuse. ded C o n f o r m a a n cto $ & ~ ~ ~ ~ i 6 n m k a n s that the d,iirg prtidtict, w h e n tested according to the l&ted analytical e procedures,wilr m e e t ths lisled acceptdncekritkia. A s p e c & & i is o;i;?$% o f thh .& r & g y ko control d r u g product quality. T h e y a r e p r o p o s e da n d ~ G tified‘by the m a n u factcrer a n d a p p k v e d by the Agency. Spkifications a r e “established to .confirm..lhe.“qualitjr ~dlfIG $ p K & c ~ < ratli&‘ thin t$ e.$ablish full’ characterization a n d sh,ould,,fcjcus those ~ h ~ ~ a @ ~ riisti.~, n d to b e usef$ in e n S $ t$ $oduct quality ,on, fou as it relates to safety a n d efficacy.lnf onnation’ peribdk quality i n & & ~ ~ e s t s is proiiided below.” bli a. . . ,/, . . , .5.‘“^ > ,“>*,.a,..5 i. ,.,.. / .,;v .,*i.: .s l,.-:> .““, ,, ‘ r.L”~ .’ < ” ,.*-, .,. In general, this reviewer c o n c u i 3 ’b u t n o te s that th e a d d e d p a r a g r a p h n e e d s

to b e i n c l u d e d in ttie revi.sion for c b m p l e teriess.
2 3 P a g e “3 2 ”



: ^ .: _ j






L i n e s “1 1 4 4- 1 1 7 0 ,” h e IC H g & d a n c e A S p e c $ & i o n ste s t P & e & $ & d ~ ‘% e p n n c e & r i ~ ~ r N e rkk g k u b s tn n c e s “T @ : Cr a n dN e w D r u g P r o d u c ts :h e * m i c a l b s ta n c e s S i d e ~ & ~ & r n & c & & % ~ 6 ; & & ~ ~ th ~ < k h d u l d n c h i d e d nb e s p e c i fi c a ti o n 6 Su p ro s %i ‘i fb r s o l i do ra l d & g p ro d u c ts l, i q u i do ra l d ti g p ro d u c ts ,a n d p a re n te ra l(s m a l la d l a rg e v o l u m e ).S o n i cte s ts th a t a re s i d e n ti fi e a sa p @ d $ ri a fo r i n c l u s i oi n t& e s p e c i fi c & %c a n b kp rb p d s e a sp e ;i o d i c u a l i ty‘i n d i c a tb r& w h e n th e re a re d te d i te s u ffi c i e ndt a taa n dj u s ti fi c a ti o n . e c o m m e n d a ti o6nnsi e & s fo r b -th e d o s a g fo r & a ;e i ti & d e d i n A tta c h m e n 1 .” s h o u l d R ; e t

b e re v i s e dto re a d :


T h e IC H g u i d a n cQe6 A S p e c i j c a ti o n T :e s P r o c e d u re s d A c c e p ta n cCer i t e r i afo r N e w ‘D ru gS u b s ta n c e s d s t an an N e w D ru g P r o d u c tsC h e m i c a lu b s ta n c p ro v i d ere c o m m e n d a ti oonnste s tsth a t c a nb e u & a s th e b a s i s fo r : S es s th e te s tsto b e i n c l u d e i d th e s p e c i fk a ti o n ”foor l i do ra l d ru g p ro d u c tsl ;i q u i do ra l d ru g p ro d u c ts a n d n s , p a re n te ra (s m a l a n dl a rg ev o l u m e ).S o m e s ts a t a re i d e n ti fi e a sa p p ro p ri a fo r i n & & n i n th e ls l ‘te th d te s p e c i fi c a ti c a nb e p ro p o s e a s p e ri o d i q u a l i ty n d i c a tote s tsw h e n th e re i s s u ffi c i e ndt a ta.to s u p p o rt on d c i r
te w s u c hp e r i o d i ra th e r th a n e a c h a tc h e v a !u ,a ti o n v i d e th e f u rn c a n d e m o n s tra C G M P c o m p l i a n c ei th o u t c .b p ro d , e t p e rfo rm i n g u c hte s tso n e v e ryb a tc h . In g e n e ra lth e te s tsa m e n a b lto s u c htre a tm e n a re th o s p ,t,h aet v a l u a te s -. ; ;-. ,,i1 j fa c to rs , l i k e a p p e a ra n cth a t h a v e .n d i re c b e a rq o n th e ’s a & y a n d e $ i c a o fth e d r$ p ro d u c t.In g e n e ra lth e e, o t cy , l ) e rm t b C G M P fo r d ru g p ro d u c (fi n i s h e p ha rm a c e u ti c a 2s1; C F R ‘2 1 1 ~ ‘d o e s ”n o t~ p o m i itti n g& V s “th a t e a r t d

o n th e i d e n ti ty ,p u ri ty , s tre n g tha n dp e rfo rm a n cqeu a l i ty f th e e a c h ru g b a tc h .‘l & o & n e n d a ti o n s o d o n te s tsfo r o th e rd o s a gfo rm s a re i n c l u d ei d A tta c h m e n 1 .” e n t > ,_ *,

T h i s re v i e w e c o n c u rs ,b u t w o u l d p ro p o s eth e ,fo l j o w i n g l i g h tl yre ;i & d t& t: r s
“T h e H g u i d a n c e 6 IC Q

AS p e c i fi c a tiJoensP rq c e & ~-? n A ,c c e p ta n c ete rifo r N e w st :: e $d C ri a s D ru gS u b s ta nacn d e wD ru g~’ro d ~ & ~ ‘C h e$m ? & ‘c +pe;io v i d ere c d m m & d a ti o n s eN s u h s t& ;? i s o n te s tsth a t q n b eu & a s th. et- ,j .-. k,., *._ _ /, k s b e i p + d k d‘i j $ h e ,‘s h ;e c i fi foar ti o n i d b a i fi r% %te to i c s l ,, *
o ra l d ru g p ro d u c ts i, q u i d ra l d ru g p ro d u c ts ,‘~ ~ ~ p ~ ~ t~ ~ ~ ~ i ;m n d ll a rg e o l u m e ). l o a al v S o m e s tsth a t.a re d e n @ fi e a p p ro p ri a te i n c b i o n n th i s p & i ‘? i c a ti b i i ’c$$i % 6 O S e i l te : ,i Z II-( fo r i ;o p a s p e ri o d iqcu a l i ty y d i c a tbte s ts w h k i th e re , i r
s u p p o rt u c hp e ri o d i c th e r th a n e a c h s ra C G M P c o m p l i a n c e th o u tp e rfo rm i n g u c h s tso n k v e ry % a tc h ’“~ ~ ~ ~ ~ a l ,“~ e ’~ e s ts ’~ ~ e h ~ b l e wi s te “In to s u c h a tm e n a re th o s eth a t e v a l u a fa c to rs ,l i + a p p e a ra n c ea, th a v k o d i re c b e a ri n g n tre t te th n t o a th e s a fe ty n de ffi c a c y f th e d ru g p ro d u c ‘a i ti e 1 1 s th o s e t& s fs th a t ti t% b & y & d ’th e a o t

C G M P ’m i n i m u m s ,l i k e i n -p ro c e s s X a ti $ ti c abl ro c & s ,6 o h tro l ~a n d & $ i !r~ l z
, ’,~ ~ c h a rti n g . In g e n e ra lth e C G M P fo r d ru g p ro d u c t(fm i s h e d .p h a r;;l a c e u ti c a l s ;‘2 i 2 1 1 )~ d o e s o t p e rm i to m i tti n gte s tsth a t b e a r n th e i d e n ti ty p u ri ty , s tre n g th n d -p e rfo rm a nqcuea l i ty n o , a .fo n & $ ? i d o f th e e a c hd ru g b a tc h . R e c d m rn e ’n d a ti ~ ~ ~ “~ r o”Zee!:& fs + j e fo ti s a k i n q l u d e n ’. _

A tta c h m e nI .” t
2 4 P a g e s “3 2 ” - “;3 ”



z _ ,. _ ** _ . i_’
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L i n e s “1 1 7 2- 1 1 7 5 ,” A n i l l u s tra ti v e x a m p l o f a s p e c i fi c a ti o n e e its p ro v i d e dn ‘T a b l e .” I) “ e sh i 3 _ ( *, “T a b l e 3 ” 1



T h e e x a m p l p ro v i d e d n T a b re 3 i s d e fi c i e nm s e v e raal s p e c ts c l u d i n g ,i l u reto : a ) s p e c i fy e i t in fa th a t th e s a m p l te s te dm u s tb e b a tc hre p re s e n ta ti vbej ,’s p e d i fy en u m b e o f s a m p l u n i ts th a t e ‘th r e i b -” m u s t b e te s te d fo r b a tc h,.a c c e p ta n c c ), s p e c i fy f th e te s ts s h o u l d e o n ,e a d ;:*u n iot.r:& a e h o m o g e n e ocuosm p o s i te -(a in d n th e c o m p o s i te , w m a n ya l i q u o ts ). fo ho In a d d i ti o na, s m o s t d o , th e e x a m p l c o n fu s essp & f& & i o n l i m i ts a p p ro p ri a te ‘a ’g i v e p o s te to n re l e a s g ra b -s a m p te s t (th e U S P te s t’* r a n :a rti c l e ) w i th s p e c i fi c a ti o n s p ro p ri a .to b a tc h e le fo ‘a p te a c c e p ta n o r re j e c ti o n r th e a p p ro p ri a te ”te s ti na b a tc h -re p re s e n ta s a e p l e . ce fo of g ti v m F i n a l l y , o u g h p p e a ra n te e ti n gu s i n g N S I k 1 :4 (o r th e o b s o l e tk k l S td i b 5 Eo r < 0 5 F i)s a n th a cs A i n te g ra p a rt o f th e te s ti n gu s e db y a fi rm fo r b a tc ha c c e p ta n cneo; m e n ti o n s m a d eo f i t i n th e l i e x a m p l ta b l e . e i /I, .*.L ~ , ‘;; I ‘I”~7“:. r. ;;..,,;,k .-.,. _ ,,I -’ ‘. p ,,,;:“,l -‘,,“,> ..].~ :. : -1,_ ,,” ,’ ” : ,./_
2ii I I ! j . *,




e re ere;ce sta;d&d, fS ”b ,-h5.1’;@ ss a n d ’ .‘ & 4. For compliance with 21. CFR. 2!1,&$(d), k’ ” > ‘-, acceptance’~ ~ terianeed to--be.addressed h e n?-”tat?i$tEal .~ 3 control acceptance,decisionsa r e , S quality ).‘,,I ;i,/~ .h 0),,li,w .” ,i ,.,,i~ ,,,,l,.““,~ .i. % \ to b e m a d e (typically required for active ‘uniformity (“content uniformity”) a n d the uniformity of the release (“disso@ @ o n ”) the rate”of release (“dr’u grelease”)of’& active ingredient or ‘I 8 / -., : ,; .;:’ T o address the p r e c e d i n g issues, the follo&ing alternate T & e 3: ~ s h o & n o n the next three ‘pages,is : : !_I_ , proposed. d., ,. “> 1, . ,.. i..” , I ‘..S(/“~”. ,. h ?, ,, , j :..

This reviewer cqncurs

2 5 P a g e “3 3 ” L i n e s ‘tllT$ ,,! I,@ !,” “T h e C G M P regulations require that for e a c h batch of d r u g product, there will

:’ -, _ ? ,, ..,< *d _ I.# ,,a _ ,.,. ~ ^ _ ,.,,~ /_ , ~ ‘ -1I ,

1 ;.,.. !I

._ ‘.


.,, . b e appropriate laboratory determination of satisfactory ~ c o n f o r m & c e to’ the d r u g product .. _, ,_ . -I ., specification. ‘D r u g ‘product E & g to m e e t es’t~ b l i & d standards,or ’itt specScation a n d a n y other relevant quality control criteria must b e rejected (2 1 C F R 2 11.165) .” should b e revised to read: ,I ,& , ,.,i lW,>~. “. ,~ .,” ‘” ss 1 ,_, .:. ,^“I .: _.).,,$’ .X :x’.‘“.., /Isill.“-‘ _I.. ,:‘ ,, *. _f‘. :: ‘-: :* .j,’ :’ For e a c h batch of d r u g p r o d & b e i n 2 evaluate;ijibr b&p&rice, the C G M P regulations r e q u % y ” ““. *’ _ ” I T h e sampling a n d examination or testing of batch-representative samples ( 2 1 C F R , * , _. :’ ” _ 211.160(b)(3)). T h e laboratory evaluations to b e p e r f o r m e d o n said-batch-representativesamples to establish the satisfactory c o n f o r m a n c e of said samples“‘to fin a l sljecifications’fo rth e d r u g b r o d u c t, including

th e i d e n tity a n d strength o f e a c h active,‘i n g r e d i e nprior to r e l e a s e ’2 ‘i‘ .$ $ 2 @ 16s(aj).’ t, ( C Appropriate “l a b o r a tory testing, a s necessary; f e a c h b a tch o f d r u g firoduit r e q u i r e d to ’ e . o b . . ‘lbl.ll‘y, . “_ I

.,, .I


_ 1 .‘

Acceptance criteria for the. sampling a n d ‘testing conducted by the quality control & t shall b e a d e q u a t e to assure -that batches of d r u g products m e e t e a c h appropriate specScation a n d appropriate statistical quality control criteria as a condition for their approval a n d release. T h e statistical quality control criteria shallhi&lude appropriate acceptance levels and/or appropriate j’i rejection levels ( 2 1 C F R 211.165(d)). ’ *- ’ . ’.’

T h e accuracy, sensitivity,’specificity, a n d relkoducibility o f test m e th o d s e m p l o y e d b y th e ’ firm & a il b e e s t a b l i s h e d : a h d , d d c u ~ ~ ~ ~ ~ d m lti Y lf% @ kjj’: (2i --’’ ’* jr D r u g p r o d u c ts failing to m e e t e s t a b l $ h e d ’sta n d a r dosr specificationsa n d a n y o th e r relevant ;_” ‘. ’ quality c o n trol criteria shall b e rejected( 2 1 C F ~ 2il.i6.#):
,! ” : I-.$‘-.” ‘W; .+ ~ > .( ‘-: : ; <, , ,


This reviewerconcurs

Representative Sample Number And, Protocol


Being Evaluated

(Individual IIRIwNI Or Homogeneous Composite [with testing of%” aliquots] {HC-N-n))



Regulatory Analytical Procedure

Alternative Analytical Procedure

Description RI (normal inspection) [RI - 125 (reduced inspection)]

White, biconvex, 11- m m diameter, 4-mm thick, film-coated tablet, with “identiiier code XYZ” on one side. 800 2-p 0 [0] Broken,; NMT2 5 [I] Chipped; N M T 7 [l] Film holes/bubbles; N M T 21 [S] Other minor visual defects 10.5 - 11.5 mniindiameter 3.9 - 4.5 m m thick

Visual ANSI 2 1.4 Normal Inspectjon: Single Level o uH u 25 & t.s ,,,0 . ,* A P 3 # DIM3A ANSI 2 1.4 Reduced: Inspection: Single Level Same % A P # ADMO9



Core Weight Hardness4

and Core

RI - 9 or more sets of 23 tablets (1 from each of 23 stations in tablet press used)

Weight Setup Targer: 443 mg Setup Mean: NLT 442 mg Setup Range: 44.0 - 446 mg Run Range: 437 - 449 mg Run Mean: NLT 440.5 mg

Hardness NiT’ 9.5 K P ’ NLT 10.2 K P 8.7 - f2.5 K P 7:5 - 1410 K P NLT 9.0 K P


A P #AWTl 1


Test #l


Retention time of the major peak in. the chromatogram of the assay preparation corresponds to that in the cbromatograix of HPLC, A P # EFG2 the standard preparation obtained as specified in the CISP-based Assay. Responds to the tests for sulfate $S 211.101(a) Comnliance @lease) Mean (2): NLT 100.2 LC6 (200); ” [NLT 100.0% (75)] @ 211.110 Comnliance (Release) Range:90-112%LLC;RSD:‘ <3.7% 192 - 110 % LC; RSD: < 4.0 % @ 211.165(d) Comoliance (Release) SQC Acceptance Using‘ IS@394i The “s” method, n = 200, AQL 0; 1% Accept:(]112-X]/s)&(]~--‘ ~s) 9O]‘ ’ 2 2.73 .“s” method, h = 75, AQL 0.1 % Accept:(]112-R]/s)&(jX--90]/s)> 2.55 HPLC, A P # EFGl USP <191> I HPLC, A P # EFG2

A P # UVR19


Test #l

HC-200-l RI - 200 (normal test) [RI - 75 (reduced test)]

Active Uniformity in the Tablets (AUT) -Content Uniformity (CU) .: Post-ReleaseUSP Article 30

A P # UVS29


USP Comnliance (Lifetime) NONE outside of 75 - ‘ % of LC, 125 N M T 1 in 30,outside of 85 - 115 ?‘ of LC ~ RSD N M T 7.8; Mean NLT 95 % LC _“_,,Z _. . . 8. I. .” I” LI1,_,. “< t,-,.



273 , :

Property Reing Evaluated

Represeritative Sample Number And Protocol (Individual {RI-N) or Homogeneous Composite [with testing of “n” aliquotsl-{HC-N-n))
RI - 60 (correlated
test) [RI - 42 (correlated test)] (Release) normal reduced



Regulatory Analytical Procedure

Alternative Analytical Procedure

$S 211.110 Comoliance
NLT 8s $ LC (60) [NLT 85.5 % LC (42)] Range: 78 - 97 ?$ &C (60) [SO- 95 % LC (42)] Me&:


4P # I3CD2

b 21 l.lWd1 4ctive Availability 7 Stage 1



SQC Acceptan&St&k&~~ i’ Gf&hce Using “s” Approach, n = 60, AQL 0.4”% Accepf: (197-RI/s) & (Ix--781/s) > 2.22
.Using “s” Approach, Post-Release LISP Article n = 42, AQL 0.4 % ,. .I Accept:(j95-XI/s)&(lji--8O\/s)>2.04

4P # UVS28

4P # BCDl


on 6 units

USP Comaliance


None: L? 80 .?+LC (or MT9. 100 o/, LC) ,” Mean N&T 85 % LC

Release has NO intermediate Qctive Availability Stage 2


Vo Test Defmed 4P # BCDl

rToTest 4P # BCDl

USP Article
on 12 units

USP Comoliance



LT 65 % LC (m&IT 10s 9,! K> Mean NLT 80 % LC (corrected)

RI - 200 (correlated
test) [RI - 75 (correlated test)] (Release)

normal reduced

&$ 211.110 Corn&and&
Mean: NLT 85 % LC (200) [NLT 85 % LC (75)] Range: 75 - 100 % LC (200) p’ 1- SS;%LCT75J]



4P # BCD2’


‘ ”

$6 211.165(d) Com-Dliance 4ctive Availability Stage 3


SQC Acceptiri&eSt&istikal infkrence Using <‘ Method, n = 200, AQL 0.4% s” Accept:(llOO-RI/s)&(Iji--751/s)> 2.33
.Using ‘ Method, Y Post-Release USP Article n = 75, AQL 014 % Accept:(l98-RI/s)&(jji--77i/s)>2:12

4P # UVS29

A P # BCDl


on 24 units

USP ComDliance


None: i? 55 % LC (or .$I? 110 r/oK> N M T 2 LT 65 % LC Mean NLT 80 % LC (corrected\

RI - 200[75] (mean from ADT test) or HC-200-8 (test NLT 8 _I ?‘
ahquots ex. HC-200) Post-Release USP Article - Assay 20 ” . . w>/..y.lI

S 2i f ;lOl(a\ ‘ Comaliance
Mean:‘ NLT 10012’ (200); LC [NLT 100.0 % (75)] -orMean:,NLT lC$O &c (8 aliquots)


Result from “ADT”

HPLC, A P # EFG2 4P # UVS29

Tablet Strength (Assay)

USP Comaliance


(homogenize and test duplicate aliquotsl

Mean: 90 - 110 %LC (2 abqUots) RSD: NMT, 2.0 %





/.” __,I .,./ ‘ -.. .

,- .““.‘ ;‘ .,” “

..I*, .:,:.iI:,._


.“;,.* .‘ :<v.,.y” ,“;“.: ‘ ..._ .;,.;.

: ,.:, ,, __, :

. /” :. x





3: Specification

for TrademarkTM’ T&lets

(100 mg

) [Continued]

Property Being Evaluated

Representative Sample Number And Protocol (Individual (RI-N) Homogeneous Composite [with testing of‘ n” aliquots](HC-N-n}) HC-200-3




Regulatory Analyti’ cal Procedure

Alternative Analytical Procedure

NMT 0.7 % by weight - RSD NMT 1%



Post-Release USP


- grab 20 units

NMT 1 .O%

LISP <921>; Method Ic

9P # PQR7

(homogenize and test single aliquots)

Depradation Specified Prodti&s Degradant Degradant De&ad&t

Products Degradation >_.. A: B: at RR?’ Xx


representative units and

HC-200-3 (Take 200 batch-



Lifetime NMT 0.5 % NMT 0.6 % NMT 0.3% HPLC; AP # EFG2

Unspecified Degradatiori Individual

homogenize them; then, test 3 unit-dose aliquots, weage the results & compute the RSD values. Batch is acceptable when all impurities meet the release criteria set.)

NMT 0.<3%; RSD <4 % NMT 0.4’ RSL) 43 % %, NMT 0.2%: RSD,G %


Post-Release USP.


Total Degradation Products:


- grab .20 units
& test single


0.07%; RSD <8 % _S~.

NMT 0.1%

(homogenize aliquot)

NMT 1 .O% HC-200-2 Release.

NMT 1.5% Lifetime NMT 200 ppm” / ._ ,,,.“,,. ._* *,, .i GC; AP # XYZ31

Release: Residual Solvent A Lifetime:

Post-Release USP Article-grab 20 units (homogenize & test single aliquot)

NMT 100 ppm; RSD,: NMT 2.% L “.. I /.,I ,_ _I &,_ <11(
to provide

1 2 3 4 5 6 7

,*,,,,s .I .^“. .“. I,>,
claim or established amount’ ‘ :.

This product requirement NMT


a 1 % f~rm$ation

overage to ensure that the ‘ lintent is met.

not less than 100 % of the Fber

set forth in 21 CFR 211.101(a)

= not more than Procedure


AP = Analytical

The Core Weight and Hardness tests are performed NLT = not less than LC = label claim

“in process” as the tablet cores are being produced.

The process is designed to pass at “Stage 1.” However,

8 9 10

if a batch in release testing or a p&t-release USP article fails to meet ihe “Stage-l” criteria and all _ _,(.\_ ,*.I”.^, ..i_ “,, ^ ,._ .I wr? ix c ‘ IISPrS ‘ lifetime linuts that, for &is @o&W, reqtiirer valid results are within the appropriate release range for the batch (60 % to 110 b/‘ ofl ab e1’ 1aim ) or the ‘ . all tablets to have a dissolution value that is NLT 55 Vj of LC ?I$ n~,ny~ than 2 in 6,“+..*, a. /,.*.*w“*““~‘ less than x~;.,~ $&.thi-t$ %, plan should revert to full. ,“*_.-,.-. tablets teited are*.,~i”d~~ 65 #A, ..d.” sample testing (200 for the release test and any “12” [6 more] and “24” [ 18 more] for the post-release USP test). 8 LT = less than MT = more than RRT = relative retention time , ” /. / , a ,. _ x. I, _, .,”,,, , I__ :_ ” 8 : , 1

4 ! ,;., y,, -,a


In general, this reviewer finds the proljoied alternat extirqple tiuch more comprehensiv6 and t%th$“poi‘ d -‘ tti~,h’ .~,li-‘/ 8ri~~;al; at% frkt~~thk:fi$l, ‘ guidance ..3 will..) include , it.. j^ ,. .” . ( ,“_ )_





6,. ._ ; j ,.

lj,” .: /

i ,.*,. ^“i . . .. .i/.ll. ,(1” _; ,. / ,, L‘ ,L,FI I_ 1 ”

, ,” ., ;, _1 _( I, I .I

_;) >, (” ,> _,.. .

I ,.1(,, i:+l.&ii. ,_ (p. , ai . ,/ , _, iI ir

+: ,.;.

y.’ 4’ ,’

5 6 ,. :-, ‘ i:” ( . .-


< .,> ;” ‘ il.’

I. _j :._ : f.-‘ ,,\.,



..: /.

‘ I







CoMMENTB~~P~~iiC.~OCKET.~~~~~~~~ -“. ) ,I i “SS’ .“, Io/ , *, ,.. _,_ o ir:i.-z ,\.,* _., lll”;o. ./a. .“ !i ,‘ ,,“I, J. I, e.. ,,,.

,_, ‘ . .j , _, :,, ~ I I. _‘ _j..


_i ‘ ?, I” ;.

: ,s:*

_ ,,.a’

1 /_ -, , <^ i:, -2 a.,>:

,.a i, ,,.



‘ I



Page “3’ 5” , Lines “1250 - 1260,” “If the analytical .procedure used is in the current revision of, an official compendium or another FDA-recognized standard reference (e.g. ,. ACAC Int&iati$ai” Book‘ of Methods) and the referenced-analytical procedure is’ not modified, the analytical procedure need not be provided. A specific citation to the analytical procedure is sufficient. 32When a general chapter or monograph included in an ,official compendium or othe; FDA ^recogXed standardreference allows for the use of more than one analytical procedure for a test, the specific analytical procedure that will be used should be cited here (P.5.2) and i;l$e sped&&% (P;5-.“l).“flcr example, when using USP <921> Water Determination, the method, should be specified (e.g.,’ Method Ia). If ;an analytical procedure is based on .one of-these sources but has <been:mpdj;fied, the analytical procedure should be 2 /_ /.( 8.. J”^ provided.“‘should be revised to read:’ 1 ‘ _ :’ 6‘ ,/ .. _

If tine exact detailed written a,nalytical procedure, used:’a) is available In, b) has been copied -verbatim from, : and c) uses the exact equipment specijed in t%e current revision of :au ~oft%al compendium or another FDA-recognized standard reference (e.g., AOAC International Book. of Methods) and the referenced provided. A analytical procedure is not modified in any manner, the analytical procedure need not be‘ specific citation ‘ the analyticai procedure ‘ suf&ient32. When a general chapter or monograph to is included in an officialcompendium or‘ other FDA recognized standard reference allows for the use of more than one analytical procedure for a test, the specific analytical procedure’“that’will be used should be cited here (P.S.2) and in the speci&ation’ (P.5. ri;‘ For example, when using USP-292 15 :’ Water Determination, the method should be specified’(e.g., Method Ia). If an analytical procedure is based on ones of these so,urces_ but,,has>~Wb;een_x--irr*..,*~(.w’ manner, the detailed w&ten validated any ,_‘modified in *>.. .. ” analytical procedure and its supporting valid&oii’ repo&&st .~ be provided. _, 1, : In general, this reviewer co&&-s, except that the added phrase “I... must be I sti6ii,d. ,b6 ;;kp,ac&~:J$ifKi ,,.:. ‘ sK6G]d’ “~;~“;r-.-videh *,**i,!.;ije~,use, this, .< provided ‘ .: ” .


is guidance.



Page “37” Lines “1307 - 1309,” “Test results should be expressed numerically or qualitatively (e.g., clear, colorless solution), as appropriate. Use of terms such as ConfoOrms me&s spec$cation is discouraged.” ‘ or , should be reSi&d tb read: _ ,. ,:. i Test results sho~ld~~be,*expressed numerically or &litatively ‘ (e;g., ‘ clear, coloriess’ solution), as appropriate. Use of terms such as ‘“conforms” or “meets s@sc$cation” ii proscribed; In ad&on, where the value reported is the averageof several indGdua1 results, &her an ordered list of aIl.of the in& 2 ual results that -* ;l-~”



,.“T1.“. _. “, . . ,. were used to compute the average or, if the distribution ,of the results is at ‘ ieast pseudo-‘ Gaussian, the ranie, “.d.“&.” ,,- ,‘ ,,.( .,., ,_ ,, /(. number of values, standard deviation, mode, and media+ va~ues”&uld”“aEo be “retorted.’ ‘ In cases where the distribution is non-Gaussian and an, average is reported, in addition to the reported average, ‘ &the; an ordered list of valuesfound, or the number of values, a valuefrequencyhsting and the ranjel mode and median’ the data set of ,, j should also be reported.

reviewer- again disagrees’ witti ttie-’ ,change from “‘disc&waged” to in the seco?dC Sentencel,a,~d.-again recoetiends”keeping’ that word and adding the constraining text ,a, 3, .,, __ ijreviously proposed ,. by this r&Viewer at Commenter’ 18. s The added ,infprmatjon shouldu ?, 4 i~ a more I ,” help firms to report theii- res&lts’ uniform and .informative _* ,,_\ _“”,.. ‘ ,‘;,;,/ unlike,_the common cur&t manner that, prabtice of only reporting the average value un’ l,& .r$bl;e is requiired, is als‘ sdientifically o Sbtin~d and helpful to ~&vidirig’ th& t&i&wet% a./ truer ,picture of the’i Ilr,? ts tound. ;’ ,:‘ restil‘ ‘ : ji ~‘ ‘ . I ,, ;r., <,,j“
276 ‘ ,^/. ’ 1” , ,,: : ., ‘ It. ,, j .1 i ,? C’ j’ j I





0~~FO~A&CO&I&IENTS To PUBI& .<,,.:.-. :.,-@D4%26 v ,i .,i,Cr‘ D Q ,L, .,I% . ::_, i ::::: . \ ‘ ‘1 ..~_.I “.a,~~~-.,‘ I;,‘“.““““,‘C I@T 1‘‘ j .‘ ““. ?-



il_/ , I _,. 28 Page “37” L \_ ~. , . _r/I.lw*,l-*~ _. -‘ /*. “; ..(._._ ,, __., %_/.S.T,p ‘ 1 I ,,.,” Lines “1330 - 1334,” “Presentation of resu$from iall-batches,for a particular test in‘ tabular and/or Collated batch arkiyses data are graphical format is often helpful in justifying the acceptance criteria. not warranted for, all tests.“*l$A&er; ‘ collated’ data shou,ldbe provided’ f& assayand imp”urit&(e.g:, degradation products, residual .solvents) and should be, considered~ for other tests such as water content.” should be revised to read: --. Presentation of results from all bat-&es.,for a particular test in tabular and/or graphical‘format is ‘ often helpful in justifying-the acceptance criteria. Collated batch analyses data are not G&ranted for all * tests. However, collated data should be provided’ for assay, impurities (e.g., degradation products, residual solvents), active uniformity, and the uniformity of either the’ actlve-release or the a&&elease-rate and the reporting ofcollated data should be cqnsidered for other “4 ^_ such l__*. tests , ,_., as~,water content:. , .,.. : L ‘ ” t’ ! .: :’ . Page “40” Lines “1415 - $422,” “Justification for the proposed drug product specification should’ provided. / be The justification should be based on relevant development data “~@2j,“%andards ;I‘ an official compendium, batch analyses (P.S.4)) characterization of.impurities (P.5.5), stability studies (P.8), discussion. in, thissection shouSd“ui$y data and toxicology data, and any other relevant data: The ‘ information that are located in other seczions;of t-he,“Vapplication,either by reference or’in summary. Data from the clinical efficacy and safety, lAoAvailability, bioeqmvalence, and primary stability batches and, when available and relevant, development and process validation batches shouI~ be ‘ considered in justifying the specification. If multiple manufacturing sites are planned;.it can be v&able to consider data from these sites in establishing the tests‘ and acceptance criteria. This is particularly true ‘ when there is limited~ i,mtialSe~perience with the manufacture of the drug product at any particular site. Jus&cation‘ for ‘ in-process test that is used in lieu $a finished product test should be included in an P.S.4.” should be revised ~w.^~.~l~l.“^. ,“, L > to read: ,___ ._$a ,I ” ,* “,. “, _, i^ _” ,>lil>>. “.< * * I i.,. Justification for the proposed drug product specification should be provided. The jukifkation should i be based on x ., I .,.;,,‘ ._ I ., ,, ! .,_ {a, , .I, ,a ..(,, _, ,/,; ;,_... l Relevant development data (P.2), 0 The distributional properties in the dosage‘units in each batch required to ensure that each batch: a) meets the property the applicable CGM requirements ‘ and Ir) will, if tested, befound to consist ofarticles.hav& that every article in the batch will,’ with a high degree if “certainty, ‘ meet the applicable standards. in an official compendium .I_ y,,,. . l Batch analyses (P.5.4) that demonstrate the,uni&rmity of the batch with respect to its’ critical distributional
quality properties,
l l l l


. _(” !


This reviewer concurs with the corntyer&$~ / ,: /’

proposed changes.





Characterization of impurities (P. 5 S), Stability studies (P:8), Toxicology data, and Any other relevant data.



I j,

The discussion in this section. sho,uld unify dita and’information that are located in other sections of the application, either by reference or in summary. Data from the clinical efficacy and safety, an$’ ieiGiy st-bifiti ‘gacbK.s “$nd, “ -”‘ v&en available and relevant, bioavailability, bioeqmv&nce, development and process validation batches should, be, considered., .in,-4, . // justifying the specification. If _.1“\_a . ‘ multiple manufacturing sites‘are planned’ .it’ can be “valuable toI, ij/ ,_~,e_,‘data “L.. Xese sites in , /‘ consider -‘_. from l true when there is ,limited initial establishing the tests and acceptance criteria.,’ Thisis’ pXcularly experience with the manufacture of the drug product at any particular‘ site. Justification, including the
.I ?,. j. . _ ., # c. If! ; /I , h,,.e,.>I’“.’ i ” .“L..zw ,.,, ,bjl,. ,,‘ “i .a.. ‘ “^” >+.4;‘ , I, I. : I ~~





rationale that +arly” establish& that thk projo& su&itutjon “cam&es with ail’ of ih;L &$1&k ~Cd;iip‘ j , _. ; requirements set forth in.’2i‘ Cl%??r, for ~~.‘ ;t;~~~~~~~~~~~~~~~s~ test’ that is to be used r-n lieu of a finished product test should be included in P.3.%. ‘ 1

: ..

This reviewer finds the commenter’ s proposal to be a distinct improvement I, ./ ‘ ,.-, 3 ::. . .. ,. over the existing text. In addjtion,’ the’ proposed text should assist the appl&nts in’ assuring that their justifications are truly scientifzic$,l.ly sound and based on the results data from the testjng of sufficient numbers of ba~~~h-reb~es~~~~‘ ati;e~samp:jes. ‘ If the applicants fojlow the guidance, the’ the‘ ri ~revi’ of their applications eti should be speeded by the lessened. “data’ gathering” a’ ~collation” tiorkload on nd _ Is ,,;., ; _;I‘ ,_‘ _” ‘I IAr, -I. ..,:,, the PAI inspectorate. ’_ , !‘ I ..
30 Page “41” ! .I Lines “1456 -, 1459,” “In these or ‘ similar ‘ cjrcumstanc~es, .an @p&ant ,, , /
protocol for a test, which would provide for the test to be dropped agreed number of production batches have met, certain, @ter{a.” Shl>~rd~~b;:~revise’ ;i,t.~S,ead: $, -:’ _ ,..; ~ , could propose a sunset test from the speci&$iori after an

, ,.“, ,__ ”” /__ x___. / -i*i,tin.r i ),,_ _I ,__ .x

In these or stiilar circumstances, an applicant could propose a s&&t te3 ‘ protocol for a test, which would provide for the test to be dropped from the specification after’ an &reed number of production batches have met certain criteria provided th‘ ap&icablk‘ C~XlP~&&tions e do ‘ explici;tly re&zire the test in Lot‘ _,,^.__*” . ,,, /_ ,. (_ question to be conducted on each.batch.33

This reviewer concurs with the commenter’ s, suggested proviso. ’ In addition, this reviewer” would, like to rem ind.”,, ‘ 2*,“:;“.. ,‘ % that, tihere the, , reader :.A::‘ ,\” .“:r.;I,? W .,., ~,‘ ~anufacfurers’ ~~,~~e,<~~~~~~~~~”~cts are well controlle*d and ,A \_I’wart-a-nted, those ‘ _ routinely produce drug‘ product lots w’ ithin’ lim its tighter than those required for CGMP compliance should strongly consider using ‘ the well-defined ‘ :inspection plans set forth in IS0 that, if properly applied; ‘ perm it some reduction in’ the number that ar,e required for a -valid test even in cases where f$e. ‘ inputs (components and inprocess materials) a-re:not .‘ rigorously _ controllecl‘ r’ i’ ‘ .s .’ . ,.‘ , .,J,
31 Page “41” Footnote “33 f n “33 A proposal
approval 33 in a prior approval




submitted i -,I,,-‘ l,ii-;. post

to drop a test, based on historical data, can also:be supplement.” should be revised to, read: &ar~ace&cals

Provided the test is not-required by the CGMPforfinished

each batch, a proposal to drop a test, base*d onh&torGal&ta~ in a prior approval supplement.

> . I‘j, ‘ -,*,*,_ .I ,/ , ,,, f? 1> can also be submrtted post approval

* (21 6FR 211) to de conducted on

This reviewer co,rii&rs.,l~&jth 1p:i’“::* commenter’ ,“,IY( proposed the ;.a,j:I* #<pg*pr s revjsion, but .‘ 6 ~ a,*.,C” ) 1S:L:-.? suggests that a sponsor consi’ der the.,PQIT alternatrve (tiith ‘ valid stages) or, if the test is. not di#ectly or indirectly. required by CGMP and is tr’ iy u’ superfluous, that test should not be filed in the application. : .. > \ ,,~ ,i ,, ,,.
32 Page “58” Lines “2J20 -.21,22,”
After the definition of “&cyptaxick criteria: Numerical knits, ranges, or other suitable measures for acceptance of results,of &ra$ica~ procedures (ICH’ g6Aj. In these or similar circumstances, an applicant ‘ could propose a suns& ieZ f&o’ col for a’test,’ ‘ Which Gould provide for the test to be dropped from t&specification after an agreed number of production ” ,; i ,., j *v I I -, :. ‘ -- r . ’ . 8 ,*-I.. ,_ ::. ;,. _ , a I. ,c , ., ._” I ,;ml~ I_ x > r,, ,,1: I ‘”.”_$L... ,,*! a,,/,1>#.,.” \J..‘ , ..,.”_: /” .~: A; f,.‘ ~ ..“.L”. ..*.;*.. _I_ : ^ &.;..;.,;4 ., l,._. 2,8 : ‘ ~ ,



:I” ., ;.. sh&d l%rev&d’ 2: ” ,bat&es ha;ve met certain I_ILl‘ ,,,A’“ y,&lpQ&&,- ‘ -~~~.~~,,~~‘ &inse&‘ 1” criteria. ”:‘ *~z$“/ a *‘+&& &,”‘ :_ &<.$.$‘ *:yt;, T ‘ the defin%ion i::i, the-draft ,. * ys “ ^X~~~~~~~ 1 p;: l”-gj;$$.b;w” 1’““““:” c :” .” :<z i.: :“z”* :-. ..,.“A / _ *,,,,,,:“-J-~. ,icc, 4‘ Active Pharmaceutlc$%gre~ut,(API~ as follows: -,


Active Pharmqceuti@l ‘ Itigredienf (API): The cbmpdnent cont&ni@ the drug substance or.eq((yq ingredient (21 ‘ CFR 21$3(b)(7)) th’ is kvailhbie fir ir&&o~ into ’ & the formulation of a b&h of drug$roduct, or, &e Agency ‘ September‘ i f99(.dej%iti~n,
Active Pharmaceutical Itigredi& (API): ’“any substance that is represented for use in a drug and that, when used in the manu.Facturing;’@ro<e&i& or packaging of a’ drug, becomes an for active ingredient or a fhished ddsage”fGfm $f”tf;e ~d&$*(S6p‘ t&6er TO, ip%;l~“&d*nce Industry Manufacture, Processing or Holding of Active ‘ Pharrnaceuka~ &r&en&,‘ bIS%~~~fO~ fiRAFT, ‘ . /, pgs 2 - 3, at D. 3). ‘ ‘ I~,

Although the commer3er~pr~p&d *‘ ckfinitiot%,~this r&k&x t&6 $hk’ ‘ hs t/-x$ the first is the defitjitib.6 that jt$:$@-kjy shbuld add fsthe Glos$ary as”follbws:’ Activ‘ Pharmaqutica! Ingredieht:‘ dokponent e The’ containing”the’ ~activ ingredient (as defined in 21 CFR 21?(3)(b)(7) or drug sub&@ (as

defined in d-is guiddnce)~that is, ~j$l$$Gp
into the formulation

the ?cz?y!tifw3?r;

1 * .


of,a batch r>f d.rug prbducf. ; ><%

.k ),






.’ .”