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[Federal Register: April 8, 2004 (Volume 69, Number 68) [Rules a!d Regulatio!

s ["age #8$2$%#8$6$ From t&e Federal Register '!li!e (ia )"' A**ess [+ais,a**ess,gpo,go( [-'./-:0r08ap04%#4 [["age #8$2$ %%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%% "art /V

-epartme!t o0 1ealt& a!d 1uma! 2er(i*es

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Food a!d -rug Admi!istratio!

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2# .FR "arts 206, 230, 4#4, 600, a!d 60#

Supplements and Other Changes to an Approved Application; Final Rule

Guidance for Industry on Changes to an Approved NDA or ANDA; Availa ility; Notice [["age #8$28 %%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%% -5"AR675N6 'F 15A861 AN- 197AN 25RV/.52 Food a!d -rug Admi!istratio! 2# .FR "arts 206, 230, 4#4, 600, a!d 60#

[-o*:et No, #999N%0#94 R/N 09#0%A;6# 2uppleme!ts a!d 't&er .&a!ges to a! Appro(ed Appli*atio! A)5N.<: Food a!d -rug Admi!istratio!, 112, A.6/'N: Fi!al rule, %%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%% 2977AR<: 6&e Food a!d -rug Admi!istratio! (F-A) is ame!di!g its regulatio!s o! suppleme!ts a!d ot&er *&a!ges to a! appro(ed appli*atio! to impleme!t t&e ma!u0a*turi!g *&a!ges pro(isio! o0 t&e Food a!d -rug Admi!istratio! 7oder!i=atio! A*t o0 #99$ (t&e 7oder!i=atio! A*t), 6&e 0i!al rule re>uires ma!u0a*turers to assess t&e e00e*ts o0 ma!u0a*turi!g *&a!ges o! t&e ide!tit?, stre!gt&, >ualit?, purit?, a!d pote!*? o0 a drug or biologi*al produ*t as t&ose 0a*tors relate to t&e sa0et? or e00e*ti(e!ess o0 t&e produ*t, 6&e 0i!al rule sets 0ort& re>uireme!ts 0or *&a!ges re>uiri!g suppleme!t submissio! a!d appro(al be0ore t&e distributio! o0 t&e produ*t made usi!g t&e *&a!ge, *&a!ges re>uiri!g suppleme!t submissio! at least 40 da?s prior to t&e distributio! o0 t&e produ*t, *&a!ges re>uiri!g suppleme!t submissio! at t&e time o0 distributio!, a!d *&a!ges to be des*ribed i! a! a!!ual report, -A652: 6&is rule is e00e*ti(e @u!e 22, 2004, F'R F9R615R /NF'R7A6/'N .'N6A.6: -a(id @, .ummi!gs, .e!ter 0or -rug 5(aluatio! a!d Resear*& (1F-%43$), Food a!d -rug Admi!istratio!, 3600 Fis&ers 8a!e, Ro*:(ille, 7- 2083$, 40#%444%3#8$, or Robert A, <etter, .e!ter 0or ;iologi*s 5(aluatio! a!d Resear*& (1F7%#0), Food a!d -rug Admi!istratio!, #40# Ro*:(ille "i:e, Ro*:(ille, 7- 20832, 40#%82$%04$4, 29""8575N6AR< /NF'R7A6/'N: /, ;a*:grou!d 2e*tio! ##6 o0 t&e 7oder!i=atio! A*t ("ubli* 8a+ #03%##3) ame!ded t&e Federal Food, -rug, a!d .osmeti* A*t (t&e a*t) b? addi!g se*tio! 306A (2# 9,2,., 436a), 6&at se*tio! des*ribes re>uireme!ts a!d pro*edures 0or ma:i!g a!d reporti!g ma!u0a*turi!g *&a!ges to appro(ed !e+ drug a!d abbre(iated !e+ drug appli*atio!s, to !e+ a!d abbre(iated a!imal drug appli*atio!s, a!d to li*e!se appli*atio!s 0or biologi*al produ*ts u!der se*tio! 43# o0 t&e "ubli* 1ealt& 2er(i*e ("12) A*t (t&e "12 a*t), 2e*tio! 306A o0 t&e a*t re(ises *urre!t pro*edures 0or appro(i!g ma!u0a*turi!g *&a!ges, 7aAor ma!u0a*turi!g *&a!ges, as de0i!ed i! se*tio! 306A o0 t&e a*t, are o0 a t?pe determi!ed b? t&e 2e*retar? o0 1ealt& a!d 1uma! 2er(i*es (t&e 2e*retar?) to &a(e a substa!tial pote!tial to ad(ersel? a00e*t t&e ide!tit?, stre!gt&, >ualit?, purit?, a!d pote!*? as t&e? ma? relate to t&e sa0et? a!d e00e*ti(e!ess o0 a drug, 2u*& *&a!ges re>uire prior appro(al o0 a suppleme!tal appli*atio!, 2e*tio! 306A o0 t&e a*t also states t&at t&e 2e*retar? ma? re>uire submissio! o0 a suppleme!tal appli*atio! 0or drugs made +it& ma!u0a*turi!g *&a!ges t&at are !ot maAor a!d ma?

establis& *ategories o0 ma!u0a*turi!g *&a!ges 0or +&i*& a suppleme!tal appli*atio! is re>uired, /! su*& a *ase, t&e appli*a!t ma? begi! distributio! o0 a drug 40 da?s a0ter F-A &as re*ei(ed a suppleme!tal appli*atio! u!less t&e age!*? !oti0ies t&e appli*a!t +it&i! t&e 40%da? period t&at prior appro(al o0 t&e appli*atio! is re>uired, 9!der t&e statute, F-A ma? also desig!ate a *ategor? o0 ma!u0a*turi!g *&a!ges t&at permit t&e appli*a!t to begi! distributi!g a drug made +it& su*& *&a!ges upo! re*eipt b? t&e age!*? o0 a suppleme!tal appli*atio! 0or t&e *&a!ge, Fi!all?, F-A ma? also aut&ori=e appli*a!ts to distribute drugs ma!u0a*tured +it& a *&a!ge +it&out submitti!g a suppleme!tal appli*atio!, 6&e la+ pro(ides t&at F-A ma? establis& *ategories o0 ma!u0a*turi!g *&a!ges t&at ma? be made +it&out submitti!g a suppleme!tal appli*atio!, A, -e(elopme!t o0 t&e Regulatio! /! t&e Federal Register o0 @u!e 28, #999 (64 FR 44608), F-A publis&ed a proposed rule to impleme!t se*tio! 306A o0 t&e a*t 0or &uma! !e+ drug appli*atio!s (N-As) a!d abbre(iated !e+ drug appli*atio!s (AN-As), as +ell as 0or li*e!sed biologi*al produ*ts (t&e @u!e #999 proposal), /! t&at same issue o0 t&e Federal Register (64 FR 44660), F-A a!!ou!*ed t&e a(ailabilit? o0 a dra0t guida!*e 0or i!dustr? e!titled BB.&a!ges to a! Appro(ed N-A or AN-A,CC 6&is guida!*e +as i!te!ded to assist appli*a!ts i! determi!i!g &o+ t&e? s&ould report *&a!ges to a! appro(ed N-A or AN-A u!der se*tio! 306A o0 t&e a*t as +ell as u!der t&e proposed re(isio!s to t&e &uma! drug regulatio!s pertai!i!g to suppleme!ts a!d ot&er *&a!ges to a! appro(ed appli*atio!, /! t&e Federal Register o0 No(ember 24, #999 (64 FR 63$#6), F-A a!!ou!*ed t&e a(ailabilit? o0 a guida!*e to assist appli*a!ts i! determi!i!g &o+ t&e? s&ould report *&a!ges to a! appro(ed N-A or AN-A u!der se*tio! 306A o0 t&e a*t, pe!di!g 0i!ali=atio! o0 t&e @u!e #999 proposal, F-A &as re(ised t&e guida!*e to *o!0orm to t&is 0i!al rule a!d is a!!ou!*i!g t&e a(ailabilit? o0 t&e guida!*e else+&ere i! t&is issue o0 t&e Federal Register, ;, A Ris:%;ased Approa*& 6&e publi*atio! o0 t&is 0i!al rule is a! importa!t step i! t&e pro*ess o0 adopti!g a ris:%based approa*& to t&e regulatio! o0 p&arma*euti*als, /! t&e #990s, F-A spo!sored resear*& at t&e 9!i(ersit? o0 7ar?la!d a!d ot&er u!i(ersities o! t&e t?pes o0 *&emistr? a!d ma!u0a*turi!g *&a!ges to immediate release solid oral drug produ*ts t&at *ould a00e*t drug per0orma!*e (i,e,, ide!tit?, stre!gt&, >ualit?, purit?, a!d pote!*?) a!d, t&ere0ore, sa0et? a!d e00e*ti(e!ess, 9si!g t&at resear*&, F-ACs .e!ter 0or -rug 5(aluatio! a!d Resear*& (.-5R) bega! to de(elop a ris:%based approa*& to t&e impleme!tatio! o0 ma!u0a*turi!g *&a!ges, 6&e approa*& pro(ided 0or a *o!ti!ued &ig& le(el o0 s*ruti!? b? F-A o0 *&a!ges t&at +ere most li:el? to a00e*t t&e per0orma!*e o0 a drug a!d de*reased s*ruti!? o0 *&a!ges t&at +ere !ot li:el? to a00e*t t&e per0orma!*e o0 a drug, 6&e ris:%based approa*& +as 0irst eDplai!ed i! a series o0 guida!*e do*ume!ts (t&e 2*ale%up a!d "ostappro(al .&a!ges (29"A.) guida!*es) t&at redu*ed t&e regulator? burde! o0 obtai!i!g F-A aut&ori=atio! to ma:e *ertai! *&a!ges, 6&e +or: *o!ti!ued i! regulatio!s issued b? t&e .e!ter 0or ;iologi*s 5(aluatio! a!d Resear*& (.;5R) i! #99$ (2# .FR 60#,#2), /! No(ember #99$, t&is ris:%based approa*& +as *odi0ied i! se*tio! ##6 o0 t&e 7oder!i=atio! A*t,

6&is 0i!al rule impleme!ts se*tio! ##6 o0 t&e 7oder!i=atio! A*t b? i!*orporati!g t&e statutor? sta!dards 0or *&ara*teri=i!g proposed *&a!ges as &a(i!g substa!tial, moderate, or mi!imal pote!tial to ad(ersel? a00e*t t&e ide!tit?, stre!gt&, >ualit?, purit?, a!d pote!*? o0 a drug as t&e? ma? relate to its sa0et? a!d e00e*ti(e!ess a!d determi!i!g submissio! re>uireme!ts based o! t&e pote!tial ris:s asso*iated +it& t&e *&a!ges, For *&a!ges +it& a substa!tial pote!tial to a00e*t t&e desig!ated *&ara*teristi*s o0 a drug, F-A must re(ie+ a!d appro(e a suppleme!t t&at *o!tai!s i!0ormatio! s&o+i!g t&at t&e proposed *&a!ge +ill !ot ad(ersel? a00e*t t&e drugCs *&ara*teristi*s (i,e,, i!0ormatio! de(eloped b? t&e &older o0 t&e appli*atio! to (alidate t&e e00e*t o0 t&e proposed *&a!ge) be0ore distributio! o0 t&e produ*t made usi!g t&e *&a!ge, [["age #8$29 /t +as a!ti*ipated +&e! se*tio! ##6 o0 t&e 7oder!i=atio! A*t +as +ritte! t&at t&e s*ie!*e o0 ma!u0a*turi!g +ould e(ol(e o(er time a!d a00e*t +&et&er *&a!ges +ould be *o!sidered maAor or !o!maAor, 6o a**ommodate 0uture te*&!ologi*al ad(a!*eme!ts, se*tio! ##6 o0 t&e 7oder!i=atio! A*t a!d t&is 0i!al impleme!ti!g regulatio! bot& pro(ide t&at F-A ma?, b? regulatio! or guida!*e, *&a!ge t&e desig!atio! o0 a parti*ular *ategor? o0 *&a!ge 0rom maAor to !o!maAor or (i*e (ersa, 6&is *o!*ept o0 a! e(ol(i!g ris:%based approa*& to ma!u0a*turi!g *&a!ges also is *o!siste!t +it& t&e age!*?Cs )ood 7a!u0a*turi!g "ra*ti*es /!itiati(e (BB"&arma*euti*al *)7"s 0or t&e 2#st .e!tur?,CC &ttp:EE0r+ebgate,a**ess,gpo,go(E*gi%bi!Elea(i!g,*giF 0romGlea(i!gFR,&tmlHlogGli!:logHtoG&ttp:EE+++,0da,go(E*derEgmpEi!deD,&tm ), 6&e goals o0 t&at i!itiati(e, lau!*&ed i! August 2002, i!*lude: I;98856 5!suri!g t&at state%o0%t&e%art p&arma*euti*al s*ie!*e is utili=ed i! t&e regulator? re(ie+ a!d i!spe*tio! poli*iesJ I;98856 5!*ouragi!g t&e adoptio! o0 !e+ te*&!ologi*al ad(a!*es i! &ig& >ualit? a!d e00i*ie!t ma!u0a*turi!g b? t&e p&arma*euti*al i!dustr?J I;98856 Assessi!g t&e appli*able *urre!t good ma!u0a*turi!g pra*ti*e (.)7") re>uireme!ts relati(e to t&e best >ualit? ma!ageme!t pra*ti*esJ I;98856 2tre!gt&e!i!g publi* &ealt& prote*tio! b? impleme!ti!g ris:%based approa*&es t&at 0o*us bot& i!dustr? a!d F-A atte!tio! o! *riti*al areas 0or impro(i!g produ*t sa0et? a!d >ualit?J a!d I;98856 5!&a!*i!g t&e *o!siste!*? a!d *oordi!atio! o0 F-ACs drug >ualit? o(ersig&t a*ti(ities, 2pe*i0i*all?, o!e o0 t&e e00orts o0 t&e .)7" i!itiati(e is to 0a*ilitate *o!ti!uous impro(eme!t a!d i!!o(atio! i! ma!u0a*turi!g b? allo+i!g ma!u0a*turers to ma:e *ertai! t?pes o0 *&a!ges i! t&eir pro*esses +it&out prior F-A appro(al, 6&is rule, i! :eepi!g +it& t&at i!itiati(e, pro(ides 0or a me*&a!ism o0 *o!ti!uous impro(eme!t t&roug& t&e guida!*e pro*ess (2# .FR #0,##3) t&at ma? pro(ide 0or less burde!some do*ume!tatio! o0 *ertai! *&a!ges as ma!u0a*turi!g pro*esses a!d p&arma*euti*al s*ie!*e de(elop, //, 1ig&lig&ts o0 Re(isio!s to t&e "roposed Rule A, -e0i!itio!s

F-A &as re(ised t&e proposed de0i!itio! o0 BBspe*i0i*atio!CC b? *&a!gi!g t&e p&rase BBot&er *ompo!e!ts i!*ludi!g *o!tai!er *losure s?stems a!d i!%pro*ess materialsCC to BB*ompo!e!ts, i!%pro*ess materials, *o!tai!er *losure s?stems, a!d ot&er materials used i! t&e produ*tio! o0 a drug substa!*e or drug produ*t,CC F-A made t&is *&a!ge 0or *o!siste!*? +it& ot&er regulatio!s, F-A proposed a de0i!itio! 0or t&e term BB(alidate t&e e00e*ts o0 t&e *&a!ge,CC /! t&e 0i!al rule, t&e age!*? &as *&a!ged t&e +ord BB(alidateCC to BBassessCC a!d pro(ides a de0i!itio! 0or t&e term BBassess t&e e00e*ts o0 t&e *&a!ge,CC ;, .&a!ges to a! Appro(ed Appli*atio! 6&e proposal re>uired t&at t&e &older o0 a! appro(ed appli*atio! (alidate t&e e00e*ts o0 ma!u0a*turi!g *&a!ges o! t&e ide!tit?, stre!gt&, >ualit?, purit?, a!d pote!*? o0 t&e drug as t&ese 0a*tors ma? relate to t&e sa0et? or e00e*ti(e!ess o0 t&e drug, F-A &as re(ised t&is pro(isio! to re>uire t&at t&e &older o0 a! appro(ed appli*atio! assess t&e e00e*ts o0 ma!u0a*turi!g *&a!ges, F-A &as deleted t&e p&rase BBo! t&e ide!tit?, stre!gt&, >ualit?, purit?, a!d pote!*? o0 t&e drug produ*t as t&ese 0a*tors ma? relate to t&e sa0et? or e00e*ti(e!ess o0 t&e drug produ*tCC be*ause t&is i!0ormatio! is alread? i!*luded i! t&e de0i!itio! o0 t&e term BBassess t&e e00e*ts o0 t&e *&a!ge,CC "re(iousl?, 2e*, 4#4,$0(*) (2# .FR 4#4,$0(*)) stated t&at t&e appli*a!t +&o submits a *&a!ges%bei!g%e00e*ted suppleme!t to F-A must promptl? re(ise all promotio!al labeli!g a!d ad(ertisi!g to ma:e it *o!siste!t +it& a!? *&a!ge i! t&e labeli!g, 6&e proposal retai!ed t&is pro(isio! a!d F-A stated i! t&e preamble t&at t&e re>uireme!t +ould appl? e>uall? to all labeli!g *&a!ges, F-A &as re(ised t&is pro(isio! to limit t&e re>uireme!t to t&ose labeli!g *&a!ges submitted i! suppleme!tal appli*atio!s a!d !ot to t&ose i! a!!ual reports, 6&e proposal re>uired t&e appli*a!t to i!*lude i! a *o(er letter a list o0 all *&a!ges *o!tai!ed i! t&e suppleme!t or a!!ual report, F-A &as *lari0ied t&at t&e re>uireme!t to i!*lude t&e list o0 *&a!ges i! a *o(er letter applies o!l? to *&a!ges *o!tai!ed i! a suppleme!tJ t&e i!0ormatio! is alread? submitted i! a! a!!ual report, ., .&a!ges Re>uiri!g 2uppleme!t 2ubmissio! a!d Appro(al "rior to -istributio! o0 t&e "rodu*t 7ade 9si!g t&e .&a!ge (7aAor .&a!ges) F-A &as limited t&e re>uireme!t to i!*lude o!l? t&ose *&a!ges to a drug produ*t *o!tai!er *losure s?stem t&at i!(ol(e *&a!ges i! t&e t?pe or *ompositio! o0 a pa*:agi!g *ompo!e!t, F-A i!te!ds to pro(ide additio!al guida!*e o! *o!tai!er *losure s?stems *&a!ges t&at +ill be *o!sidered moderate *&a!ges or *&a!ges t&at *a! be reported i! a! a!!ual report, F-A proposed to re>uire t&at a re0ere!*e list o0 rele(a!t sta!dard operati!g pro*edures (2'"s) be *o!tai!ed i! all suppleme!ts submitted u!der t&is se*tio!, F-A &as re(ised t&is pro(isio! to spe*i0? t&at a re0ere!*e list o0 rele(a!t 2'"s must be submitted 0or *&a!ges to a !atural produ*t, a re*ombi!a!t deoD?ribo!u*lei* a*id (-NA)%deri(ed protei!Epol?peptide produ*t, or a *ompleD or *o!Augate o0 a drug substa!*e +it& a mo!o*lo!al a!tibod?, a!d 0or *&a!ges to t&e sterili=atio! pro*ess a!d test met&odologies related to sterili=atio! pro*ess (alidatio!, -, .&a!ges Re>uiri!g 2uppleme!t 2ubmissio! at 8east 40 -a?s "rior to

-istributio! o0 t&e -rug "rodu*t 7ade 9si!g t&e .&a!ge (7oderate .&a!ges) F-A &as re(ised t&e @u!e #999 proposal to *lari0? t&at t&e re>uireme!t to submit #2 *opies o0 0i!is&ed produ*t labeli!g applies to suppleme!ts 0or *&a!ges t&at ma? be impleme!ted 40 da?s a0ter F-A re*ei(es t&e suppleme!t, F-A &as *lari0ied t&at t&e *&a!ges i! t&e *o!tai!er *losure s?stem submitted i! suppleme!ts u!der t&ese moderate *&a!ges pro(isio!s do !ot i!*lude t&e *&a!ges des*ribed u!der t&e pro(isio!s re>uiri!g prior appro(al or t&e *&a!ges submitted i! a! a!!ual report, F-A &as re(ised t&e *&a!ges solel? a00e*ti!g a !atural protei! produ*t, a re*ombi!a!t -NA%deri(ed protei!Epol?peptide produ*t, or a *ompleD or *o!Augate o0 a drug +it& a mo!o*lo!al a!tibod? to spe*i0? t&e use o0 BBdi00ere!t e>uipme!tCC i!stead o0 BB!e+ or di00ere!t e>uipme!tCC 0or *&a!ges i! produ*tio! s*ale, a!d e>uipme!t o0 BBa di00ere!t desig!CC i!stead o0 BBsimilar but !ot ide!ti*al desig! a!d operati!g pri!*ipleCC 0or t&e repla*eme!t o0 e>uipme!t, F-A is also addi!g to t&e moderate *&a!ges pro(isio!s a *&a!ge i! t&e relaDatio! o0 a! a**epta!*e *riterio! or deletio! o0 a test to *ompl? +it& a! o00i*ial *ompe!dium t&at is *o!siste!t +it& F-A statutor? a!d regulator? re>uireme!ts, F-A is !ot re>uiri!g t&at a prior appro(al suppleme!t be submitted 0or t&is t?pe o0 *&a!ge be*ause t&e *&a!ge &as bee! re(ie+ed b? t&e 9!ited 2tates "&arma*opeia (92"), a!d F-A a!d t&e publi* &a(e &ad a! opportu!it? to re(ie+, i! ge!eral, t&e *&a!ge t&roug& t&e 92" pro*ess, 1o+e(er, be*ause F-A +ill !ot &a(e re(ie+ed su*& a *&a!ge i! t&e *o!teDt o0 ea*& i!di(idual appli*atio! a00e*ted b? t&e *&a!ge, a *&a!ges%bei!g%e00e*ted%i!%40%da?s suppleme!t +ill still be re>uired, F-A &as re(ised t&e proposal to *lari0? t&at t&e appli*a!t ma? !ot [["age #8$40 distribute t&e drug produ*t u!til t&e suppleme!t 0or a *&a!ge u!der t&is pro(isio! &as bee! ame!ded to pro(ide missi!g i!0ormatio! t&at &as bee! re>uested b? F-A, 5, .&a!ges 6&at 7a? ;e /mpleme!ted K&e! F-A Re*ei(es a 2uppleme!t (7oderate .&a!ges) F-A &as *lari0ied t&at labeli!g *&a!ges t&at !ormall? re>uire a prior appro(al suppleme!t ma?, at t&e age!*?Cs re>uest, be impleme!ted +&e! F-A re*ei(es a suppleme!t, F, .&a!ges 6o ;e -es*ribed i! t&e NeDt A!!ual Report F-A &as re(ised t&e @u!e #999 proposal to state t&at a!? *&a!ge made to *ompl? +it& a! o00i*ial *ompe!dium t&at is *o!siste!t +it& F-A statutor? a!d regulator? re>uireme!ts ma? be submitted i! t&e !eDt a!!ual report, eD*ept a *&a!ge i!(ol(i!g t&e relaDatio! o0 a! a**epta!*e *riterio! or deletio! o0 a test to *ompl? +it& a! o00i*ial *ompe!dium, F-A &as re(ised t&e @u!e #999 proposal to *lari0? t&at t&e maAorit? o0 *&a!ges *o!*er!i!g repla*eme!t o0 e>uipme!t +it& e>uipme!t o0 t&e same desig! a!d operati!g pri!*iples ma? be submitted i! a! a!!ual report, 1o+e(er, t&ere are *ertai! e>uipme!t *&a!ges ide!ti0ied i! t&is rule t&at re>uire submissio! i! a *&a!ges%bei!g%e00e*ted%i!%40%da?s

suppleme!t or a *&a!ges%bei!g%e00e*ted suppleme!t, F-A &as re(ised t&e @u!e #999 proposal to *lari0? t&at *ertai! *&a!ges made to t&e *o!tai!er *losure s?stems 0or sterile drug produ*ts ma? be submitted i! a!!ual reports, as ma? *ertai! *&a!ges 0or !o!sterile drug produ*t *o!tai!er *losure s?stems, 6&e *&a!ges are t&ose based o! a s&o+i!g o0 e>ui(ale!*? u!der a! appro(ed or o00i*ial *ompe!dium proto*ol, F-A &as re(ised t&e @u!e #999 proposal to *lari0? t&at a! eDte!sio! o0 a! eDpiratio! dati!g period t&at *a! be reported i! a! a!!ual report *a! be based o! produ*tio! bat*&es i!stead o0 0ull produ*tio! bat*&es, F-A *o!siders a produ*tio! bat*& to be o!e made at produ*tio! s*ale usi!g produ*tio! e>uipme!t i! a produ*tio! 0a*ilit? as spe*i0ied i! t&e appli*atio!, "rodu*tio! s*ale does !ot !e*essaril? mea! t&e largest bat*& si=e produ*ed, but a bat*& o0 a si=e or +it&i! a bat*& si=e ra!ge t&at &as bee! appro(ed i! t&e appli*atio!, F-A &as deleted t&e re>uireme!t t&at a! a!!ual report *o!tai! a list o0 all produ*ts i!(ol(ed i! t&e *&a!ges, F-A &as also *lari0ied t&at a! a!!ual report must i!*lude t&e date ea*& *&a!ge +as impleme!ted i!stead o0 t&e date ea*& *&a!ge +as made, F-A *o!siders BBt&e date ea*& *&a!ge +as impleme!tedCC to be t&e date t&at t&e *o!ditio! establis&ed i! t&e appro(ed appli*atio! is *&a!ged, !ot +&e! t&e produ*t made +it& t&e *&a!ge is distributed, F-A &as also re(ised t&e @u!e #999 proposal to *lari0? +&e! (alidatio! proto*ols a!d 2'"s must be i!*luded i! a! a!!ual report submissio!, ), 't&er /!0ormatio! F-A &as re(ised t&e @u!e #999 proposal to *lari0? t&at a proto*ol must be submitted as a prior appro(al suppleme!t i0 t&e proto*ol +as !ot alread? i!*luded i! a! appro(ed appli*atio! or +&e! *&a!gi!g a! appro(ed proto*ol, /! t&e @u!e #999 proposal, F-A used t&e terms BBdrug,CC BBdrug produ*t,CC BBdrug substa!*e,CC a!d BBprodu*t,CC 6&e age!*? &as sta!dardi=ed t&e termi!olog? t&roug&out t&e 0i!al rule a!d used t&e terms BBdrug produ*t,CC BBdrug substa!*e,CC a!dEor BBprodu*tCC as appropriate, /! additio!, t&e age!*? &as made mi!or edits to t&e 0i!al rule i! respo!se to 0ormer "reside!t .li!to!Cs @u!e #, #998, memo o! plai! la!guage i! )o(er!me!t +riti!g, ///, Respo!ses to .omme!ts o! t&e @u!e #999 "roposal F-A re*ei(ed *omme!ts o! most aspe*ts o0 t&e @u!e #999 proposal 0rom more t&a! 40 p&arma*euti*al *ompa!ies, p&arma*euti*al i!dustr? asso*iatio!s, a!d ot&er i!terested perso!s, 6&e *omme!ts a!d t&e age!*?Cs respo!ses 0ollo+, A, )e!eral .omme!ts (.omme!t #) 7a!? *omme!ts said t&e @u!e #999 proposal does !ot meet t&e i!te!t o0 .o!gress +&e! establis&i!g se*tio! 306A o0 t&e a*t, 6&e *omme!ts said t&at .o!gress eDpe*ted t&e 0ollo+i!g: (#) 2ig!i0i*a!t *&a!ges i! F-ACs past pra*ti*es o! ma!u0a*turi!g *&a!gesJ (2) substa!tial impro(eme!t i! t&e ma!ageme!t o0 te*&!i*al suppleme!ts 0or ma!u0a*turi!g *&a!gesJ (4) regulator? relie0 +it&out *ompromisi!g >ualit?, sa0et?, or e00i*a*? o0 drugsJ (4) appropriate a*tio! o! t&e mar:eti!g o0 regulated produ*ts i! a ma!!er t&at does !ot u!dul? impede i!!o(atio! or produ*t a(ailabilit?J (3) redu*tio! i! reporti!g a!d regulator? re>uireme!tsJ a!d (6) a small !umber o0 maAor ma!u0a*turi!g

*&a!ges t&at re>uire prior appro(al, but t&at most *&a!ges +ould re>uire a less burde!some mea!s o0 reporti!g t&a! &as bee! re>uired i! t&e past, 2e(eral *omme!ts said t&e @u!e #999 proposal ge!erates !e+ re>uireme!ts 0or ma:i!g regulator? submissio!s, adds !e+ *ategories 0or ma:i!g t&ose submissio!s, a!d i!*reases t&e do*ume!tatio! burde! o! i!dustr?, '!e *omme!t also !oted t&at t&e 29"A. guida!*esL#L +ould !ot 0ul0ill t&e .o!gressio!al i!te!t be*ause t&e? +ere publis&ed be0ore t&e 7oder!i=atio! A*t, %%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%% %%%% L#L As eDplai!ed i! t&e @u!e #999 proposal, F-A de(eloped t&e 29"A. guida!*es to ease preappro(al re>uireme!ts b? *ategori=i!g *ertai! ma!u0a*turi!g *&a!ges a**ordi!g to +&et&er t&e? &ad a mi!or, moderate, or maAor pote!tial to a00e*t produ*t >ualit? a!d per0orma!*e, %%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%% %%%% F-A belie(es t&at t&ese regulatio!s are *o!siste!t +it& t&e i!te!t o0 .o!gress a!d t&at t&e regulator? re>uireme!ts a!d reporti!g *ategories are *o!siste!t +it& se*tio! 306A o0 t&e a*t, 2e*tio! 306A o0 t&e a*t pro(ides F-A +it& *o!siderable 0leDibilit? to determi!e t&e i!0ormatio! a!d 0ili!g me*&a!ism re>uired 0or t&e age!*? to assess t&e e00e*t o0 ma!u0a*turi!g *&a!ges i! t&e sa0et? a!d e00e*ti(e!ess o0 t&e produ*t, 6&ere is a *orrespo!di!g !eed to retai! su*& 0leDibilit? i! t&e proposed regulatio!s impleme!ti!g se*tio! 306A o0 t&e a*t to e!sure t&at t&e least burde!some mea!s 0or reporti!g *&a!ges are a(ailable, F-A belie(es t&at su*& 0leDibilit? +ill allo+ it to be respo!si(e to i!*reasi!g :!o+ledge o0 a!d eDperie!*e +it& *ertai! t?pes o0 *&a!ges a!d &elp e!sure t&e e00i*a*? a!d sa0et? o0 t&e produ*ts i!(ol(ed, For eDample, a *&a!ge t&at ma? *urre!tl? be *o!sidered to &a(e a substa!tial pote!tial to &a(e a! ad(erse e00e*t o! t&e sa0et? or e00e*ti(e!ess o0 t&e produ*t ma?, at a later date, based o! !e+ i!0ormatio! or ad(a!*es i! te*&!olog?, be determi!ed to &a(e a lesser pote!tial to &a(e su*& a! ad(erse e00e*t, .o!(ersel?, a *&a!ge origi!all? *o!sidered to &a(e a mi!imal or moderate pote!tial to &a(e a! ad(erse e00e*t o! t&e sa0et? or e00e*ti(e!ess o0 t&e produ*t ma? later, as a result o0 !e+ i!0ormatio!, be 0ou!d to &a(e a! i!*reased, substa!tial pote!tial to ad(ersel? e00e*t t&e produ*t, 6&e age!*? belie(es it *a! more readil? respo!d to :!o+ledge gai!ed 0rom ma!u0a*turi!g eDperie!*e, 0urt&er resear*& a!d data *olle*tio!, a!d ad(a!*es i! te*&!olog? b? issui!g regulatio!s t&at set out broad, ge!eral *ategories o0 ma!u0a*turi!g *&a!ges a!d b? usi!g guida!*e do*ume!ts to pro(ide F-ACs *urre!t t&i!:i!g o! t&e spe*i0i* *&a!ges t&at 0all i!to t&ose ge!eral *ategories, 6&e regulatio!s pro(ide 0or a !e+ approa*& to regulati!g postappro(al ma!u0a*turi!g *&a!ges, 6&e approa*& is based o! t&e pote!tial 0or a *&a!ge to ad(ersel? a00e*t t&e ide!tit?, stre!gt&, >ualit?, purit?, or pote!*? o0 drug produ*ts as t&ese 0a*tors relate to t&e sa0et? a!d e00e*ti(e!ess o0 t&e produ*t, 6&e [["age #8$4# regulatio!s a!d *ompa!io! guida!*e BB.&a!ges to a! Appro(ed N-A or AN-ACC +ill pro(ide sig!i0i*a!t regulator? relie0 b? allo+i!g postappro(al ma!u0a*turi!g *&a!ges to be impleme!ted more rapidl?,

+&ile still e!suri!g t&e ide!tit?, stre!gt&, >ualit?, purit?, a!d pote!*? o0 drug produ*ts, 6&e regulatio! redu*es t&e o(erall !umber o0 suppleme!ts re>uiri!g F-A appro(al prior to produ*t distributio!, /! additio!, ma!? *&a!ges t&at are *urre!tl? reported i! suppleme!ts +ould be reported i! a!!ual reports, 6&e regulatio! +ill !ot i!*rease t&e !umber o0 a!!ual reports but +ill allo+ appli*a!ts to i!*lude i! a! a!!ual report i!0ormatio! *urre!tl? re>uired to be reported to t&e age!*? i! a suppleme!tal appli*atio!, 6&e !umber o0 ma!u0a*turi!g *&a!ges *urre!tl? reported i! suppleme!ts t&at +ill be reported i! a!!ual reports is approDimatel? #,284, For eDample, u!der t&e pre(ious regulatio!s, all ma!u0a*turi!g site *&a!ges 0or drug produ*ts re>uired prior appro(al, No+ o!l? a 0e+ t?pes o0 drug produ*t ma!u0a*turi!g site *&a!ges must be submitted i! a prior appro(al suppleme!t, 6&e maAorit? *a! be submitted i! a *&a!ges%bei!g% e00e*ted%i!%40%da?s suppleme!t or i! a! a!!ual report, 7oreo(er, F-A 0urt&er redu*ed ma!? reporti!g re>uireme!ts 0rom t&e le(els re*omme!ded i! pre(ious F-A guida!*es, For eDample, t&e 29"A. guida!*es re*omme!ded !oti0i*atio! i! a! a!!ual report +&e! mo(i!g produ*tio! operatio!s bet+ee! buildi!gs at t&e same ma!u0a*turi!g site, No+, ge!erall? !o !oti0i*atio! is re>uired 0or su*& *&a!ges a00e*ti!g drug produ*ts t&at +ere *o(ered u!der t&e 0ollo+i!g 29"A. guida!*es: (#) BB/mmediate% Release 2olid 'ral -osage Forms: 2*ale%9p a!d "ost%Appro(al .&a!ges: .&emistr?, 7a!u0a*turi!g a!d .o!trols, /! Vitro -issolutio! 6esti!g, a!d /! Vi(o ;ioe>ui(ale!*e -o*ume!tatio!CC (29"A.%/R)J (2) BB7odi0ied Release 2olid 'ral -osage Forms: 2*ale%9p a!d "ost%Appro(al .&a!ges: .&emistr?, 7a!u0a*turi!g a!d .o!trols, /! Vitro -issolutio! 6esti!g, a!d /! Vi(o ;ioe>ui(ale!*e -o*ume!tatio!CC (29"A.%7R)J a!d (4) BBNo!sterile 2emisolid -osage Forms: 2*ale%9p a!d "ost%Appro(al .&a!ges: .&emistr?, 7a!u0a*turi!g a!d .o!trols, /! Vitro Release 6esti!g, a!d /! Vi(o ;ioe>ui(ale!*eCC (29"A.%22), F-A belie(es t&at t&e approa*& to postappro(al *&a!ges embodied i! t&e 29"A. guida!*es is *o!siste!t +it& se*tio! 306A o0 t&e a*t, 1o+e(er, *ertai! aspe*ts o0 t&ese do*ume!ts !eed to be updated to be *o!siste!t +it& spe*i0i* re>uireme!ts i!*luded i! t&e a*t, For eDample, t&e !e+ reporti!g *ategor? 0or *&a!ges%bei!g%e00e*ted%i!%40%da?s suppleme!ts !eeds to be i!*orporated, F-A i!te!ds to update t&ese guida!*es i! t&e !ear 0uture, (.omme!t 2) 2e(eral *omme!ts said t&at F-A s&ould adopt a BBde*isio! treeCC or BB:e? >uestio!sCC approa*& i! impleme!ti!g se*tio! 306A o0 t&e a*t, 6&e *omme!ts *o!te!d t&at t&is approa*& +ould allo+ a !e+ approa*& to ma!u0a*turi!g *&a!ges t&at bases t&e regulator? reporti!g re>uireme!ts o! t&e results o0 s*ie!ti0i* *ompariso! o0 pre% a!d post%*&a!ge material rat&er t&a! allo+i!g t&e reporti!g *ategor? to be determi!ed b? t&e pote!tial 0or a *&a!ge to &a(e a! ad(erse e00e*t, 6&e de*isio! tree +ould 0o*us o! a!s+eri!g t&e :e? >uestio!s rat&er t&a! eD&austi(e *ategori=atio! o0 pote!tial t?pes o0 *&a!ges, '!e *omme!t pro(ided eDamples o0 de*isio! trees 0or *o!sideratio!, F-A agrees t&at de*isio! trees are a (iable approa*& to postappro(al ma!u0a*turi!g *&a!ges, 1o+e(er, a de*isio! tree must *o!sider t&e pote!tial 0or a *&a!ge to &a(e a! ad(erse e00e*t to be *o!siste!t +it& se*tio! 306A o0 t&e a*t, 6&e a*t bases t&e reporti!g *ategor? 0or a *&a!ge o! t&e pote!tial 0or t&at *&a!ge to &a(e a! ad(erse e00e*t, !ot o! t&e out*ome o0 assessme!t studies, /! some *ases, based o! t&e pote!tial 0or a! ad(erse e00e*t, t&e a*t +ould re>uire F-A to re(ie+ a *&a!ge prior to distributio! o0 t&e drug produ*t +it& t&e *&a!ge, e(e! i0 t&e appli*a!t *o!*ludes t&at its

studies a!d data demo!strate t&at t&e *&a!ge &as !o sig!i0i*a!t ad(erse e00e*t, F-A must e(aluate +&et&er t&e studies per0ormed b? t&e appli*a!t +ere su00i*ie!t to assess t&e e00e*t o0 t&e *&a!ge a!d +&et&er t&e data support t&e appli*a!tCs *laim t&at t&e *&a!ge &as !ot ad(ersel? a00e*ted t&e ide!tit?, stre!gt&, >ualit?, purit?, a!d pote!*? o0 t&e drug produ*t as t&e? ma? relate to t&e sa0et? or e00e*ti(e!ess o0 a drug produ*t, For eDample, a! appli*a!t ma? de*ide to de(elop a! i! (i(oEi! (itro *orrelatio! (/V/V.) 0or a! eDte!ded release oral dosage 0orm (see .-5RCs guida!*e e!titled BB5Dte!ded Release 'ral -osage Forms: -e(elopme!t, 5(aluatio!, a!d Appli*atio! o0 /! (itroE/! (i(o .orrelatio!sCC (2eptember #99$)), /0 a! /V/V. is establis&ed, t&e dissolutio! test +ill be used b? t&e appli*a!t as a surrogate 0or i! (i(o bioe>ui(ale!*e +&e! it is !e*essar? to do*ume!t bioe>ui(ale!*e 0or postappro(al *&a!ges, 5stablis&i!g a! /V/V. &as a sig!i0i*a!t pote!tial to a00e*t t&e ide!tit?, stre!gt&, >ualit?, purit?, a!d pote!*? o0 t&e drug produ*t as t&e? ma? relate to sa0et? a!d e00e*ti(e!ess o0 t&e drug produ*t, a!d re>uires a prior appro(al suppleme!t, 6&e appli*a!t, based o! its e(aluatio! o0 t&e data, ma? belie(e t&at a! /V/V. &as bee! establis&ed but t&e age!*?, a0ter e(aluatio! o0 t&e appli*a!tCs data, ma? !ot *o!*ur, /0 t&e appli*a!t de*ided t&at a prior appro(al suppleme!t +as !ot !e*essar? based o! its *o!*lusio!s t&at a! /V/V. &as bee! establis&ed a!d impleme!ted t&e *&a!ge +it&out +aiti!g 0or t&e age!*?Cs *o!*urre!*e, a drug produ*t t&at is !ot bioe>ui(ale!t *ould be distributed to t&e publi*, F-A regulates a +ide ra!ge o0 produ*ts, a!d a de*isio! tree s&ould address t&e 0a*t t&at t&e pote!tial 0or ad(erse e00e*t +ill (ar? depe!di!g o! 0a*tors su*& as t&e dosage 0orm a!d route o0 admi!istratio!, For eDample, i! ge!eral, pa*:agi!g *&a!ges t&at i!(ol(e pare!teral drug produ*ts are (ie+ed b? F-A to &a(e a &ig&er pote!tial to &a(e a! ad(erse e00e*t o! t&e >ualit? o0 t&e drug produ*t as it relates to t&e sa0et? a!d e00i*a*? o0 t&e drug produ*t t&a! a pa*:agi!g *&a!ge 0or a solid oral dosage 0orm produ*t, 8ea*&ables 0rom t&e pa*:agi!g i!to pare!teral drug produ*ts are more li:el? to o**ur t&a! 0or a solid oral dosage 0orm, a!d i0 lea*&i!g o**urs, t&ere is a &ig&er pote!tial 0or ad(erse rea*tio!s be*ause o0 t&e route o0 admi!istratio!, A sa0et? determi!atio! b? F-A must be made be0ore t&e *&a!ge is impleme!ted, A! appli*a!t +is&i!g to rel? o! a de*isio! tree *a! submit t&e de*isio! tree usi!g a! appropriate me*&a!ism, su*& as submissio! o0 a *omparabilit? proto*ol *o!tai!i!g a de*isio! tree, a!d F-A +ill e(aluate t&e de*isio! tree 0or *o!siste!*? +it& se*tio! 306A o0 t&e a*t, (.omme!t 4) A!ot&er *omme!t said t&at t&e proposal *o!sisted o0 &eig&te!ed reporti!g re>uireme!ts 0or *&a!ges i! pa*:agi!g materials 0or sterile li>uid dosage 0orms, "re(iousl?, u!der 2e*, 4#4,$0(b), *&a!ges i! pa*:agi!g 0or sterile li>uid dosage 0orms routi!el? re>uired prior appro(al b? F-A be0ore t&e? *ould be impleme!ted, 6&e 0i!al rule, at 2e*, 4#4,$0(b)(2)(iii), still emp&asi=es t&e importa!*e, 0rom t&e sa0et? perspe*ti(e, o0 e!suri!g t&e sterilit? o0 drug produ*ts b? re>uiri!g t&at *&a!ges t&at ma? a00e*t drug produ*t sterilit? assura!*e be reported i! a prior appro(al suppleme!t, 1o+e(er, t&e guida!*e BB.&a!ges to a! Appro(ed N-A or AN-A,CC a!!ou!*ed else+&ere i! t&is issue o0 t&e Federal Register, i!*ludes *ertai! *&a!ges i! t&e pa*:agi!g o0 t&ese produ*ts t&at *a! be impleme!ted b? mea!s ot&er t&a! prior appro(al suppleme!ts, 6&is a*tio! &as redu*ed, rat&er t&a! &eig&te!ed, t&e regulator? [["age #8$42

burde! relati!g to t&e pa*:agi!g o0 sterile li>uid dosage 0orms, F-A &as i!*luded t&ese *&a!ges i! t&e guida!*e be*ause, as stated i! t&e proposal, t&e age!*? belie(es it *a! more readil? respo!d to :!o+ledge gai!ed 0rom ma!u0a*turi!g eDperie!*e, 0urt&er resear*& a!d data *olle*tio!, a!d ad(a!*es i! te*&!olog? b? issui!g regulatio!s t&at set out broad, ge!eral *ategories o0 ma!u0a*turi!g *&a!ges a!d b? usi!g guida!*e do*ume!ts to pro(ide F-ACs *urre!t t&i!:i!g o! t&e spe*i0i* *&a!ges t&at 0all i!to t&ose ge!eral *ategories (64 FR 44608 at 446#0), 2e*tio! 306A o0 t&e a*t eDpli*itl? pro(ides F-A t&e aut&orit? to use guida!*e do*ume!ts to determi!e t&e t?pe o0 *&a!ges t&at do or do !ot &a(e a substa!tial pote!tial to ad(ersel? a00e*t t&e sa0et? or e00e*ti(e!ess o0 t&e drug produ*t, As dis*ussed pre(iousl? i! t&is do*ume!t, t&e use o0 guida!*e do*ume!ts +ill allo+ F-A to more easil? a!d >ui*:l? modi0? a!d update importa!t i!0ormatio!, )uida!*e do*ume!ts +ill be de(eloped a**ordi!g to t&e pro*edures set out i! F-ACs good guida!*e pra*ti*es (see t&e Federal Register o0 2eptember #9, 2000 (63 FR 36468), a!d 2# .FR #0,##3), (.omme!t 4) A!ot&er *omme!t re>uested t&at F-A spe*i0i*all? address i! t&e 0i!al rule a!dEor guida!*e or i! separate guida!*e &o+ a *&a!ge i! t&e de(i*e aspe*t o0 a drug%de(i*e *ombi!atio! produ*t is to be reported i! appli*atio!s, 6&e *omme!t said t&at +&e! establis&i!g rules 0or reporti!g *&a!ges i! pa*:agi!g a!d pa*:agi!g *ompo!e!ts, F-A s&ould !ot simpl? appl? t&e rules 0or *&a!ges to drugs a!d biologi*s to t&e de(i*e%li:e aspe*ts o0 *ombi!atio! produ*ts, Rat&er, t&e *omme!t said, F-A s&ould *o!sider &o+ t&e e>ui(ale!t *&a!ge is ma!aged 0or t&e a!alogous medi*al de(i*e a!d appl? t&at approa*&, .-5R a!d .;5R +or: *ooperati(el? +it& t&e .e!ter 0or -e(i*es a!d Radiologi*al 1ealt& (.-R1) i! t&e re(ie+ o0 drug%de(i*e *ombi!atio!s, -etermi!atio!s as to +&i*& regulatio!s appl? to a gi(e! *ombi!atio! produ*t are produ*t a!d appli*atio! spe*i0i*, 2po!sors o0 *ombi!atio! produ*ts s&ould *o!sult +it& t&e .e!ter t&at pro(ided t&e appro(al o0 t&eir appli*atio! a!d +it& t&e '00i*e o0 .ombi!atio! "rodu*ts to determi!e +&at re>uireme!ts are appli*able to t&e *&a!ges t&e? +is& to ma:e to t&eir produ*t, (.omme!t 3) 2e(eral *omme!ts said t&at t&e proposal put a! o(er+&elmi!g emp&asis o! postappro(al *&a!ges 0or drug produ*ts a!d little o! drug substa!*es, 6&e *omme!ts ide!ti0ied t&e 0ollo+i!g *o!*er!s: (#) 6&e proposal is +ritte! e!tirel? 0rom t&e perspe*ti(e o0 N-A a!d AN-A appli*a!ts a!d i!*ludes !ot&i!g 0or -rug 7aster File (-7F) &oldersJ (2) a reporti!g *lassi0i*atio! s?stem depe!di!g o! t&e pote!tial o0 a *&a!ge to &a(e a! impa*t ma? usuall? +or: i! t&e drug produ*t area but is less apt to +or: 0or t&e drug substa!*e, +&ere t&e a*tual *&a!ge ma? o!l? be gauged b? t&e data obtai!ed +&e! t&e *&a!ge is madeJ a!d (4) t&e pro*esses used i! drug produ*t a!d drug substa!*e ma!u0a*turi!g di00er greatl?, ma:i!g it di00i*ult to determi!e &o+ t&e *&a!ges outli!ed 0or drug produ*ts appl? to drug substa!*es, 2e(eral *omme!ts said t&at a separate do*ume!t addressi!g *&a!ges relati!g to drug substa!*es s&ould be prepared, 6&e regulatio!s emp&asi=e *&a!ges i! drug produ*ts a!d are +ritte! 0or N-A a!d AN-A appli*a!ts be*ause t&e regulatio!s des*ribe t&e pro*edures 0or !oti0?i!g F-A about *&a!ges i! *o!ditio!s establis&ed i! a! appro(ed drug produ*t appli*atio!, .&a!ges i! a drug substa!*e are o!l? o!e o0 ma!? t?pes o0 *&a!ges t&at ma? o**ur i! a drug produ*t appli*atio!, F-A &as pro(ided spe*i0i* re*omme!datio!s o! drug substa!*e *&a!ges i! t&e guida!*e e!titled BB.&a!ges to a! Appro(ed N-A or AN-A,CC /! t&e Federal Register o0 Februar? #6, 200# (66 FR #0699),

t&e age!*? a!!ou!*ed a guida!*e t&at 0o*uses spe*i0i*all? o! postappro(al ma!u0a*turi!g *&a!ges 0or *ertai! drug substa!*es e!titled BB;A."A. /: /!termediates i! -rug 2ubsta!*e 2?!t&esis, ;ul: A*ti(es "ostappro(al .&a!ges: .&emistr?, 7a!u0a*turi!g, a!d .o!trols -o*ume!tatio!CC (t&e ;A."A. / guida!*e), F-A belie(es t&at t&e ;A."A. / guida!*e addresses t&e *o!*er!s eDpressed i! t&e *omme!ts, (.omme!t 6) 2e(eral *omme!ts reiterated *omme!ts pre(iousl? pro(ided to t&e age!*? o! t&e guida!*es e!titled BB;A."A. /CC a!d BB.&a!ges to a! Appro(ed N-A or AN-A,CC a!d as:ed F-A to *o!sider t&ese *omme!ts i! 0i!ali=i!g t&e proposed regulatio!, F-A &as *o!sidered a!d addressed t&ese resubmitted *omme!ts i! t&is do*ume!t to t&e eDte!t t&at t&e? +ere appli*able to t&e proposed regulatio!, (.omme!t $) A!ot&er *omme!t said t&at F-A s&ould pro(ide 0or realisti* a!d +or:able 0ili!g me*&a!isms a!d re>uireme!ts +it& regard to *&a!ges i! t&e ma!u0a*turi!g o0 drug substa!*es +&ere t&e i!0ormatio! is i!*luded i! -7Fs, 6&e regulatio!s a!d *ompa!io! guida!*e e!titled BB.&a!ges to a! Appro(ed N-A or AN-ACC pro(ide re*omme!datio!s o! reporti!g *&a!ges i! t&e *o!ditio!s establis&ed i! a! appro(ed appli*atio!, i!*ludi!g *&a!ges i! drug substa!*e *o(ered b? -7Fs, /ssues relati!g to -7Fs a!d &o+ t&ese are used i! t&e appli*atio! re(ie+ pro*ess are outside t&e s*ope o0 t&is rulema:i!g, (.omme!t 8) '!e *omme!t stated t&at t&e rule s&ould *learl? address &o+ *&a!ges i! t&e ma!u0a*ture o0 p&arma*euti*al pa*:agi!g a!d p&arma*euti*al pa*:agi!g *ompo!e!ts are to be &a!dled, 6&e *omme!t said t&at t&e *urre!t regulatio! a!d t&e proposal a!d guida!*e address t&is issue i!*ompletel?, a!d 0re>ue!tl? pa*:agi!g a!d pa*:agi!g *ompo!e!t ma!u0a*turers are le0t to tr? to i!terpret t&e regulatio! as it applies to pa*:agi!g, F-A &as *lari0ied t&e re>uireme!ts 0or pa*:agi!g *ompo!e!ts i! t&e 0i!al regulatio!s as a result o0 t&e publi* *omme!ts a!d &as i!*luded i!0ormatio! o! t&is topi* i! t&e guida!*e BB.&a!ges to a! Appro(ed N-A or AN-A,CC (.omme!t 9) 2e(eral *omme!ts said t&at t&e use o0 broad a!d (ague terms (e,g,, a!? *&a!ge, ma? impa*t) s&ould be mi!imi=ed, 6&e *omme!ts said t&at su*& terms le!d t&emsel(es to di00ere!t i!terpretatio!s, are li:el? to *ause *o!0usio! a!d i!*o!siste!t appli*atio!, a!d are li:el? to result i! more burde!some reporti!g re>uireme!ts 0or *&a!ges t&at +ould be more appropriatel? *ategori=ed as moderate a!dEor mi!or *&a!ges, '!e *omme!t said t&at F-A s&ould re(ise t&ese terms, a!d suggested addi!g t&e modi0ier BBsig!i0i*a!tCC or BBsig!i0i*a!tl?CC i! se(eral i!sta!*es to s&arpe! t&e i!te!ded mea!i!g, 6&e *omme!t said t&at si!*e t&e term BBsig!i0i*a!tCC is itsel0 u!de0i!ed, it suggests t&at, i! t&is *o!teDt, BBsig!i0i*a!tCC mea!s BBli:el? to ad(ersel? a00e*t t&e ide!tit?, stre!gt&, >ualit?, purit? or pote!*? o0 t&e related produ*t,CC F-A agrees t&at t&e use o0 broad a!d (ague terms s&ould be mi!imi=ed a!d &as *lari0ied t&e regulatio!, as appropriate, i! respo!se to *omme!ts re*ei(ed o! t&e use o0 su*& terms as BBa!? *&a!geCC a!d BBma? impa*t,CC a!d t&ose *omme!ts suggesti!g addi!g t&e term BBsig!i0i*a!t,CC (.omme!t #0) '!e *omme!t as:ed +&et&er t&e 0i!al regulatio!s +ill *o!tai! re0ere!*es to appropriate guida!*e do*ume!ts, 6&e 0i!al regulatio!s do !ot re0ere!*e spe*i0i* guida!*e do*ume!ts, F-A *o!ti!ues to update a!d de(elop guida!*es to address parti*ular regulator? a!d s*ie!ti0i* issues, a!d a!? re0ere!*es i!*luded i! a

regulatio! ma? >ui*:l? be*ome outdated, )uida!*es t&at pro(ide F-ACs *urre!t t&i!:i!g o! spe*i0i* topi*s *a! be lo*ated o! t&e /!ter!et at &ttp:EE0r+ebgate,a**ess,gpo,go(E*gi%bi!Elea(i!g,*giF 0romGlea(i!gFR,&tmlHlogGli!:logHtoG&ttp:EE+++,0da,go(E*derE [["age #8$44 guida!*eEi!deD,&tm a!d &ttp:EE0r+ebgate,a**ess,gpo,go(E*gi% bi!Elea(i!g,*giF 0romGlea(i!gFR,&tmlHlogGli!:logHtoG&ttp:EE+++,0da,go(E*berEguideli!es,& tm, (.omme!t ##) '!e *omme!t said t&at alt&oug& t&e proposal applies o!l? to &uma! drugs a!d biologi*s, t&e .e!ter 0or Veteri!ar? 7edi*i!e (.V7) ma? be prepari!g a similar proposal a!d ma? be *ompelled to appl? most i0 !ot all o0 t&e pri!*iples des*ribed i! t&e proposed rule, 6&e *omme!t said t&at t&e a!imal drug i!dustr? is (er? pleased +it& t&e su**ess0ul #996 .V7 i!itiati(e, BBAlter!ate Admi!istrati(e "ro*ess 0or t&e /mpleme!tatio! a!d 2ubmissio! o0 2uppleme!tal .&emistr?, 7a!u0a*turi!g a!d .o!trol .&a!ges (AA"),CC 6&e *omme!t said t&at its support o0 t&e 7oder!i=atio! A*t +as gi(e! based o! t&e legal i!terpretatio! t&at t&e 7oder!i=atio! A*t did !ot pre*lude t&e *o!ti!uatio! o0 t&e AA" program, 6&e *omme!t said t&at t&e AA" program su**i!*tl? pro(ides a pro*ess 0or determi!i!g mi!or suppleme!tal *&emistr?, ma!u0a*turi!g, a!d *o!trol *&a!ges t&at are reported o! a bie!!ial basis, 6&e *omme!t *o!ti!ues to stro!gl? support t&e *o!*epts embodied i! t&e AA" a!d is *o!*er!ed t&at impleme!tatio! o0 t&e proposed rule +ould be more burde!some, o! bot& F-A a!d i!dustr?, t&a! t&e AA", 6&e *omme!t said t&at .V7 a!d A!imal 1ealt& /!stitute (A1/) member *ompa!ies &a(e &ad 4 ?ears o0 su**ess0ul impleme!tatio! o0 t&is program a!d belie(e t&at t&e proposed rule, i0 applied to a!imal drugs, +ould be a maAor step ba*:+ards, .omme!ts relati!g to t&e AA" are outside t&e s*ope o0 t&is rulema:i!g a!d s&ould be dire*ted to t&e proposed rule 0or (eteri!ar? drug produ*ts e!titled BB2uppleme!ts a!d 't&er .&a!ges to Appro(ed Ne+ A!imal -rug Appli*atio!sCC (publis&ed i! t&e Federal Register o0 '*tober #, #999 (64 FR 3428#)) (t&e '*tober #999 proposal), ;, -e0i!itio!s F-A proposed to ame!d t&e de0i!itio!s se*tio!s o0 t&e regulatio!s o! appli*atio!s 0or F-A appro(al to mar:et a !e+ drug (2e*, 4#4,4 (2# .FR 4#4,4)) a!d a biologi*al produ*t (2e*, 600,4 (2# .FR 600,4)) b? addi!g de0i!itio!s 0or BBspe*i0i*atio!CC a!d BB(alidate t&e e00e*ts o0 t&e *&a!ge,CC "roposed 2e*, 2e*, 4#4,4(b) a!d 600,4(&&) de0i!ed BBspe*i0i*atio!CC as t&e >ualit? sta!dard (i,e,, tests, a!al?ti*al pro*edures, a!d a**epta!*e *riteria) pro(ided i! a! appro(ed appli*atio! to *o!0irm t&e >ualit? o0 drug substa!*es, drug produ*ts, i!termediates, ra+ materials, reage!ts, a!d ot&er *ompo!e!ts i!*ludi!g *o!tai!er *losure s?stems, a!d i!%pro*ess materials, 6&e term BBa**epta!*e *riteriaCC re0ers to !umeri*al limits, ra!ges, or ot&er *riteria 0or t&e tests des*ribed, F-A &as re(ised t&e proposed de0i!itio! o0 spe*i0i*atio! to ma:e t&e use o0 t&e term BB*ompo!e!tCC *o!siste!t +it& t&e de0i!itio! o0 BB*ompo!e!tCC at 2e*, 2#0,4 (2# .FR 2#0,4), F-A &as re(ised t&e de0i!itio! as 0ollo+s:

2pe*i0i*atio! mea!s t&e >ualit? sta!dard (i,e,, tests, a!al?ti*al pro*edures, a!d a**epta!*e *riteria) pro(ided i! a! appro(ed appli*atio! to *o!0irm t&e >ualit? o0 drug substa!*es, drug produ*ts, i!termediates, ra+ materials, reage!ts, *ompo!e!ts, i!% pro*ess materials, *o!tai!er *losure s?stems, a!d ot&er materials used i! t&e produ*tio! o0 a drug substa!*e or drug produ*t, For t&e purpose o0 t&is de0i!itio!, a**epta!*e *riteria mea!s !umeri*al limits, ra!ges, or ot&er *riteria 0or t&e tests des*ribed, F-A &as made t&e same *&a!ges to proposed 2e*, 600,4(&&) (!e+ 2e*, 600,4(AA)) a!d *lari0ied t&e de0i!itio! o0 spe*i0i*atio! 0or biologi*al produ*ts b? repla*i!g t&e p&rase BBdrug substa!*es, drug produ*tsCC +it& BBprodu*ts,CC 6&e term BBprodu*tsCC is de0i!ed i! 2e*, 600,4(g), (.omme!t #2) 2e(eral *omme!ts stated t&at BBi!termediates, ra+ materials, reage!ts, a!d ot&er *ompo!e!ts i!*ludi!g *o!tai!er *losure s?stems, a!d i!%pro*ess materialsCC s&ould be deleted 0rom t&e de0i!itio! o0 spe*i0i*atio!, a!d *&a!ges 0or t&ese materials s&ould be &a!dled separatel? 0rom t&e 0i!al rule a!d 0i!al guida!*e, 6&e *omme!ts said t&at t&e de0i!itio! is !ot *o!siste!t +it& t&e /!ter!atio!al .o!0ere!*e o! 1armo!isatio! (/.1) guida!*e o! spe*i0i*atio!s e!titled BB6est "ro*edures a!d A**epta!*e .riteria 0or Ne+ -rug 2ubsta!*es a!d Ne+ -rug "rodu*ts: .&emi*al 2ubsta!*esCC (/.1 M6A), +&i*& i!*ludes o!l? drug substa!*e a!d drug produ*t, 6&e *omme!ts said t&at to i!*lude items be?o!d t&e drug substa!*e a!d drug produ*t represe!ts a le(el o0 *ompleDit? t&at +ould be better dealt +it& i! guida!*es t&at *a! ade>uatel? e(aluate t&e sig!i0i*a!*e o0 *&a!ges to spe*i0i* items, F-A de*li!es to re(ise t&e de0i!itio! as re>uested, 2e*tio! 303 o0 t&e a*t (2# 9,2,., 433) re>uires t&at a 0ull des*riptio! o0 t&e met&ods used i!, a!d t&e 0a*ilities a!d *o!trols used 0or, t&e ma!u0a*ture, pro*essi!g, a!d pa*:i!g o0 a drug be pro(ided i! a! appli*atio!, 6&e regulatio!s at 2e*, 4#4,30(d)(#) (2# .FR 4#4,30(d)(#)) re>uire t&at a! appli*atio! i!*lude spe*i0i*atio!s as are !e*essar? to e!sure t&e ide!tit?, stre!gt&, >ualit?, purit?, a!d pote!*? o0 t&e drug substa!*e a!d drug produ*t, 7oreo(er, t&e regulatio! at 2e*, 4#4,30(d)(#)(ii)(a) spe*i0i*all? re>uires t&at spe*i0i*atio!s be pro(ided 0or ea*& *ompo!e!t, /t ide!ti0ies spe*i0i*atio!s 0or *o!tai!er *losures s?stems as a! eDample o0 a spe*i0i*atio! !eeded to e!sure t&e ide!tit?, stre!gt&, >ualit?, purit?, a!d pote!*? o0 t&e drug produ*t, For biologi*s, a! appli*a!t must submit a 0ull des*riptio! o0 ma!u0a*turi!g met&ods (2e*, 60#,2 (2# .FR 60#,2)), /!termediates, ra+ materials, reage!ts, *o!tai!er *losure s?stems, i!%pro*ess materials a!d ot&er materials t&at are used i! t&e ma!u0a*ture o0 drug substa!*es, drug produ*ts, a!d biologi*s are *o!sidered part o0 t&e ma!u0a*turi!g met&od a!d *a! &a(e a dire*t e00e*t o! t&e ide!tit?, stre!gt&, >ualit?, purit?, a!d pote!*? o0 t&e drug substa!*e, drug produ*t, or biologi*, K&ile t&e eDte!t o0 a spe*i0i*atio! (e,g,, !umber or t?pe o0 tests, stri*t!ess o0 a**epta!*e *riteria) 0or t&ese materials ma? (ar? depe!di!g o! t&eir use i! a gi(e! ma!u0a*turi!g pro*ess, F-A &as re>uired spe*i0i*atio!s 0or t&ese materials to be i!*luded i! appli*atio!s as part o0 t&e des*riptio! o0 t&e ma!u0a*turi!g met&od a!d +ill *o!ti!ue to do so, 6&e /.1 M6A guida!*e a!d t&e /.1 guida!*e o! spe*i0i*atio!s e!titled BB6est "ro*edures a!d A**epta!*e .riteria 0or ;iote*&!olog?E ;iologi*al "rodu*tsCC (/.1 M6;) are limited i! s*ope, For eDample, /.1 M6A spe*i0i*all? eD*ludes 0erme!tatio! produ*ts, /!terpreti!g t&e limitatio!s o0 t&e /.1 guida!*es to mea! t&at spe*i0i*atio!s are !ot re>uired 0or 0erme!tatio! produ*ts or ot&er materials outside t&e s*ope

o0 /.1 M6A or /.1 M6; +ould be i!*orre*t, F-A re>uires spe*i0i*atio!s 0or i!termediates, ra+ materials, reage!ts, *o!tai!er *losure s?stems, i!%pro*ess materials, a!d ot&er materials used i! t&e ma!u0a*turi!g pro*ess to be i!*luded i! t&e appli*atio! a!d, t&ere0ore, &as i!*luded t&ese materials i! t&e de0i!itio! o0 spe*i0i*atio!, A!? *&a!ges i! a spe*i0i*atio!, eD*ept editorial, must be reported to F-A a!d appli*a!ts !eed guida!*e o! &o+ to impleme!t t&ese *&a!ges, F-A de*li!es de0erri!g re*omme!datio!s o! t&ese *&a!ges to a later guida!*e a!d &as pro(ided guida!*e o! t&e re*omme!ded reporti!g *ategories 0or *&a!ges i! spe*i0i*atio!s i! F-ACs guida!*es e!titled BB.&a!ges to a! Appro(ed N-A or AN-ACC a!d BB.&a!ges to a! Appro(ed Appli*atio! 0or 2pe*i0ied ;iote*&!olog? a!d 2pe*i0ied 2?!t&eti* ;iologi*al "rodu*tsCC (@ul? #99$), (.omme!t #4) '!e *omme!t said t&at t&e term BBspe*i0i*atio!s a!d test pro*eduresCC +as used i! part 4#4 (2# .FR part 4#4) i! t&e past, but t&e proposal repla*ed t&is +it& t&e term BBspe*i0i*atio!,CC +&i*& is i!te!ded to mea! bot& tests a!d spe*i0i*atio!s, 6&e *omme!t said t&at usi!g o!e +ord to represe!t se(eral t&i!gs is *o!0usi!g [["age #8$44 a!d re*omme!ded retai!i!g t&e pre(ious termi!olog?, F-A de*li!es to re(ise t&e use o0 t&e term BBspe*i0i*atio!CC as re>uested, /! t&e past, BBspe*i0i*atio!CC as used i! part 4#4 mea!t !umeri*al limits, ra!ges, or ot&er *riteria 0or a test, /! de(elopi!g t&e /.1 M6A a!d /.1 M6; guida!*es, F-A agreed to de0i!e spe*i0i*atio! di00ere!tl?, A spe*i0i*atio!, as de0i!ed i! /.1 M6A a!d /.1 M6;, i!*ludes tests, a!al?ti*al pro*edures, a!d a**epta!*e *riteria, F-A &as used t&e /.1 M6A a!d /.1 M6; termi!olog? i! t&is rule to promote *o!siste!*? +it& t&e /.1 do*ume!ts, (.omme!t #4) '!e *omme!t ide!ti0ied (arious t?pes o0 spe*i0i*atio! *&a!ges a!d re*omme!ded &o+ t&ese s&ould be *ategori=ed a!d reported, F-A de*li!es to eDpa!d t&e dis*ussio! o0 spe*i0i*atio! *&a!ges i! t&e regulatio!, As stated i! t&e @u!e #999 proposal, t&e age!*? belie(es it *a! more readil? respo!d to :!o+ledge gai!ed 0rom ma!u0a*turi!g eDperie!*e, 0urt&er resear*& a!d data *olle*tio!, a!d ad(a!*es i! te*&!olog? b? issui!g regulatio!s t&at set out broad, ge!eral *ategories o0 ma!u0a*turi!g *&a!ges a!d b? usi!g guida!*e do*ume!ts to pro(ide F-ACs *urre!t t&i!:i!g o! t&e spe*i0i* *&a!ges t&at 0all i!to t&ose ge!eral *ategories (64 FR 44608 at 446#0), F-A &as pro(ided re*omme!datio!s o! spe*i0i* *&a!ges i! spe*i0i*atio!s i! F-ACs guida!*es e!titled BB.&a!ges to a! Appro(ed N-A or AN-ACC a!d BB.&a!ges to a! Appro(ed Appli*atio! 0or 2pe*i0ied ;iote*&!olog? a!d 2pe*i0ied 2?!t&eti* ;iologi*al "rodu*ts,CC "roposed 2e*, 2e*, 4#4,4(b) a!d 600,4(ii) de0i!ed BB(alidate t&e e00e*ts o0 t&e *&a!geCC as a! assessme!t o0 t&e e00e*t o0 a ma!u0a*turi!g *&a!ge o! t&e ide!tit?, stre!gt&, >ualit?, purit?, or pote!*? o0 a drug as t&ese 0a*tors relate to t&e sa0et? or e00e*ti(e!ess o0 t&e drug, (.omme!t #3) 7a!? *omme!ts re*omme!ded t&at F-A repla*e t&e terms (alidate or (alidatio! +it& assess or assessme!t, 2e(eral *omme!ts stated t&at alt&oug& F-A used t&e terms *o!siste!tl? +it& .o!gressCs use o0 t&e terms i! se*tio! 306A o0 t&e a*t, t&e? belie(e t&at t&e term BB(alidateCC is li:el? to *ause *o!0usio! be*ause t&is term &as lo!g bee! asso*iated +it& a!d &as spe*i0i* mea!i!g u!der F-ACs .)7" regulatio!, F-A agrees a!d &as re(ised t&e de0i!itio! as re>uested b? repla*i!g

BB(alidateCC +it& BBassess,CC /! additio!, as a result o0 *omme!ts re>uesti!g t&at t&e use o0 t&e terms drug, drug produ*t, drug substa!*e, a!d produ*t be sta!dardi=ed, F-A &as *lari0ied t&e de0i!itio! i! 2e*, 4#4,4(b) b? repla*i!g t&e term BBdrugCC +it& BBdrug produ*t,CC F-A &as *lari0ied t&e de0i!itio! i! proposed 2e*, 600,4(ii) (!e+ 2e*, 600,4(::)) b? repla*i!g t&e term BBdrugCC +it& BBprodu*t,CC 6&e terms drug produ*t a!d produ*ts are de0i!ed at 2e*, 2e*, 4#4,4(b) a!d 600,4(g), respe*ti(el?, F-A, o! its o+! i!itiati(e, &as also re(ised t&e p&rase BBpurit?, or pote!*?CC to BBpurit?, a!d pote!*?CC a!d t&e p&rase BBas t&ese 0a*tors relateCC to BBas t&ese 0a*tors ma? relateCC to be *o!siste!t +it& se*tio! 306A(b) o0 t&e a*t, a!d t&e p&rase BBto assess t&e e00e*tCC to BBto e(aluate t&e e00e*tsCC 0or *larit?, F-A !otes t&at +&ile t&e e00e*t o0 a ma!u0a*turi!g *&a!ge o! t&e ide!tit?, stre!gt&, >ualit?, purit? a!d pote!*? o0 a drug or biologi*al produ*t is to be assessed, t&is assessme!t *ould i!(ol(e testi!g o0 materials dire*tl? a00e*ted b? a *&a!ge (e,g,, drug substa!*e) i! additio! to or i!stead o0 drug or biologi*al produ*t testi!g, (.omme!t #6) 2e(eral *omme!ts re*omme!ded t&at u!ambiguous de0i!itio!s o0 substa!tial, moderate, a!d mi!imal pote!tial 0or ad(erse e00e*ts be added to t&e regulatio!, a!d o!e *omme!t re*omme!ded t&at eDamples be added 0or *lari0i*atio!, '!e *omme!t as:ed t&at a de0i!itio! o0 !atural produ*t be added, F-A de*li!es to re(ise t&e regulatio! as re>uested, 6&e regulatio!s appl? to ma!? t?pes o0 *&a!ges 0or a broad spe*trum o0 produ*ts, 6&e mea!i!g o0 substa!tial, moderate, a!d mi!imal pote!tial 0or ad(erse e00e*ts is most easil? illustrated t&roug& t&e use o0 eDamples, F-A &as de*ided to use guida!*e do*ume!ts to pro(ide spe*i0i* eDamples o0 *&a!ges t&at are *o!sidered to &a(e substa!tial, moderate, a!d mi!imal pote!tial to &a(e ad(erse e00e*t rat&er t&a! e!umerate t&em i! t&e regulatio!, F-A &as pro(ided ma!? eDamples o0 t?pes o0 *&a!ges i! F-ACs guida!*es e!titled BB.&a!ges to a! Appro(ed N-A or AN-ACC a!d BB.&a!ges to a! Appro(ed Appli*atio! 0or 2pe*i0ied ;iote*&!olog? a!d 2pe*i0ied 2?!t&eti* ;iologi*al "rodu*ts,CC /! additio!, F-A &as pro(ided a! eDpla!atio! o0 t&e term BB!atural produ*tsCC i! t&e guida!*e o! BB.&a!ges to a! Appro(ed N-A or AN-A,CC (.omme!t #$) .o!*er!i!g t&e regulatio!s o! t&e *o!te!t a!d 0ormat o0 a! appli*atio! i! 2e*, 4#4,30, o!e *omme!t !oted t&at 2e*, 4#4,30(d)(#)(i) a!d (d)(i)(ii) i!*ludes t&e 0ollo+i!g stateme!t 0or drug substa!*e a!d drug produ*t: BBRe0ere!*e to t&e *urre!t editio! o0 t&e 92"ENF [Natio!al Formular? ma? satis0? t&e rele(a!t re>uireme!ts i! t&e paragrap&,CC 6&e *omme!t said it appeared t&at t&is stateme!t +as bei!g deleted a!d *o!te!ded t&at it s&ould be retai!ed i! t&e regulatio!s, F-A is *lari0?i!g t&at t&is se!te!*e &as !ot bee! deleted 0rom 2e*, 4#4,30(d)(#)(i) or (d)(#)(ii), As stated i! t&e @u!e #999 proposal, F-A is re(isi!g t&e 0irst t+o se!te!*es o0 t&ese paragrap&s, ., .&a!ges to a! Appro(ed Appli*atio! "roposed 2e*, 4#4,$0(a)(#) set 0ort& ge!eral re>uireme!ts u!der +&i*& a! appli*a!t must !oti0? F-A about ea*& *&a!ge i! ea*& *o!ditio! establis&ed i! a! appro(ed appli*atio! be?o!d t&e (ariatio!s alread? pro(ided 0or i! t&e appli*atio!, 6&e !oti*e is re>uired to des*ribe t&e *&a!ge 0ull?, -epe!di!g o! t&e t?pe o0 *&a!ge, t&e appli*a!t must !oti0? F-A about t&e *&a!ge i! a suppleme!t u!der 2e*, 4#4,$0(b) or (*) or b? i!*lusio! o0 t&e i!0ormatio! i! a! a!!ual report u!der 2e*,

4#4,$0(d), (.omme!t #8) '!e *omme!t said t&at t&e stateme!ts BBa! appli*a!t must !oti0? F-A about ea*& *&a!ge i! ea*& *o!ditio! establis&ed i! a! appro(ed appli*atio! be?o!d t&e (ariatio!s alread? pro(ided 0or i! t&e appli*atio!CC a!d t&at BBt&e !oti*e is re>uired to des*ribe t&e *&a!ge 0ull?CC s&ould be *lari0ied be*ause it *ould be o(erl? burde!some 0rom t&e sta!dpoi!t t&at some *&a!ges, 0or eDample, *&a!ges made to bat*& re*ords submitted as part o0 t&e appli*atio!, ma? !ot re>uire reporti!g u!der 2e*, 4#4,$0, F-A de*li!es to re(ise t&e regulatio! as re>uested a!d !otes t&at t&e age!*? does !ot eDpe*t to be i!0ormed about !o!substa!ti(e editorial *&a!ges i! i!0ormatio! i!*luded i! a! appli*atio!, No!substa!ti(e editorial *&a!ges i!*lude su*& *&a!ges as *orre*tio!s o0 spelli!g or t?pograp&i*al errors or re0ormatti!g o0 do*ume!ts (e,g,, bat*& re*ords, spe*i0i*atio! s&eets), "roposed 2e*, 2e*, 4#4,$0(a)(2) a!d 60#,#2(a)(2) (2# .FR 60#,#2(a)(2)) re>uired t&e &older o0 a! appro(ed appli*atio! to (alidate t&e e00e*ts o0 ma!u0a*turi!g *&a!ges o! t&e ide!tit?, stre!gt&, >ualit?, purit?, or pote!*? o0 a drug as t&ese 0a*tors ma? relate to t&e sa0et? or e00e*ti(e!ess o0 t&e drug be0ore distributi!g a drug made +it& a ma!u0a*turi!g *&a!ge, (.omme!t #9) A 0e+ *omme!ts said t&at t&e proposal +ould i!*rease t&e reporti!g burde! despite t&e spe*i0i* pro(isio! i! t&e 7oder!i=atio! A*t 0or &a(i!g assessme!t data at t&e time o0 submissio! o0 ma!u0a*turi!g *&a!ge suppleme!ts, 6&e *omme!t said t&at t&e 7oder!i=atio! A*t spe*i0ies t&at a drug made +it& a ma!u0a*turi!g *&a!ge ma? be distributed o!l? a0ter *ompleti!g studies t&at assess t&e e00e*ts o0 t&e *&a!ge, 6&e *omme!t said [["age #8$43 t&at t&e legislati(e i!te!t o0 t&e 7oder!i=atio! A*t is t&at i0 appropriate studies *ompari!g pre% a!d post*&a!ge material are per0ormed a!d !o e(ide!*e o0 a! ad(erse e00e*t is 0ou!d, t&e! a redu*ed reporti!g *ategor? 0or t&e e(aluated *&a!ges is appropriate, 6&e *omme!t reaso!ed t&at a gi(e! proposed ma!u0a*turi!g *&a!ge *a! i!deed &a(e substa!tial pote!tial 0or ad(erse e00e*ts at its i!*eptio! be*ause little mig&t be :!o+! about t&e impa*ts o0 t&e *&a!ge, 1o+e(er, b? t&e time a*tual material &as bee! made +it& t&e *&a!ge a!d assessme!t studies &a(e bee! su**ess0ull? *ompleted, most or all o0 t&e pote!tial impa*ts o0 t&e *&a!ge &a(e bee! elimi!ated, 6&e *omme!t said t&at t&e assessme!t i!0ormatio! s&ould permit a redu*ed reporti!g re>uireme!t, F-A disagrees +it& t&ese *omme!ts, 2e*tio! 306A(*)(2) o0 t&e a*t states t&at a maAor ma!u0a*turi!g *&a!ge is BBa *&a!ge t&at is determi!ed b? t&e 2e*retar? to &a(e substa!tial pote!tial to ad(ersel? a00e*t t&e ide!tit?, stre!gt&, >ualit?, purit?, or pote!*? o0 t&e drug as t&e? ma? relate to t&e sa0et? or e00e*ti(e!ess o0 a drugCC (emp&asis added), 6&e a*t bases t&e reporti!g *ategor? 0or a *&a!ge o! t&e pote!tial 0or t&at *&a!ge to &a(e a! ad(erse e00e*t, !ot o! t&e out*ome o0 t&e assessme!t studies, 6&e *omme!t implies t&at t&e o!l? *&a!ges t&at +ould be reported i! a prior appro(al suppleme!t are t&ose +&ere t&e appli*a!tCs studies to assess t&e e00e*ts o0 t&e *&a!ge demo!strate t&at t&ere is i! 0a*t a! ad(erse e00e*t o! t&e ide!tit?, stre!gt&, >ualit?, purit?, or pote!*? o0 t&e drug as t&e? ma? relate to t&e sa0et? or e00e*ti(e!ess o0 a drug produ*t, F-A does !ot belie(e t&at t&is +as t&e i!te!t o0 .o!gress, 2ome ma!u0a*turi!g *&a!ges &a(e a! ad(erse e00e*t o! t&e ide!tit?, stre!gt&, >ualit?, purit?, or pote!*?

o0 t&e drug produ*t, /! ma!? *ases, t&e appli*a!t *&ooses !ot to impleme!t t&ese ma!u0a*turi!g *&a!ges, but sometimes t&e appli*a!t +is&es to do so, /0 a! assessme!t i!di*ates t&at a *&a!ge &as ad(ersel? a00e*ted t&e ide!tit?, stre!gt&, >ualit?, purit?, or pote!*? o0 t&e drug produ*t, t&e *&a!ge must be submitted i! a prior appro(al suppleme!t, regardless o0 t&e re*omme!ded reporti!g *ategor? 0or t&e *&a!ge, For eDample, a pro*ess *&a!ge re*omme!ded 0or a *&a!ges%bei!g% e00e*ted%i!%40%da?s suppleme!t *ould *ause t&e 0ormatio! o0 a !e+ degrada!t t&at re>uires >uali0i*atio! a!dEor ide!ti0i*atio!, 6&e appli*a!t ma? belie(e t&at t&ere are !o sa0et? *o!*er!s relati!g to t&e !e+ degrada!t, 5(e! so, t&e appli*a!t must submit t&is *&a!ge i! a prior appro(al suppleme!t +it& appropriate i!0ormatio! to support t&e *o!ti!ued sa0et? a!d e00e*ti(e!ess o0 t&e produ*t, -uri!g t&e re(ie+ o0 t&e prior appro(al suppleme!t, F-A +ill assess t&e impa*t o0 a!? ad(erse e00e*t o! t&e drug produ*t as t&is *&a!ge ma? relate to t&e sa0et? or e00e*ti(e!ess o0 t&e drug produ*t, F-A also re*ei(ed *omme!ts re>uesti!g t&at t&e term BBassessCC be used i!stead o0 BB(alidate,CC F-A &as made t&is *&a!ge i! 2e*, 2e*, 4#4,$0(a)(2) a!d 60#,#2(a)(2), +&ere appropriate, /! 2e*, 4#4,$0(a)(2), F-A, o! its o+! i!itiati(e, &as deleted t&e p&rase BBo! t&e ide!tit?, stre!gt&, >ualit?, purit?, a!d pote!*? o0 t&e drug produ*t as t&ese 0a*tors ma? relate to t&e sa0et? or e00e*ti(e!ess o0 t&e drug produ*tCC be*ause BBassess t&e e00e*ts o0 t&e *&a!ge,CC as de0i!ed i! 2e*, 4#4,4(b), i!*ludes t&is p&rase, "roposed 2e*, 2e*, 4#4,$0(a)(4) a!d 60#,#2(a)(4) stated t&at !ot+it&sta!di!g t&e suppleme!t submissio! re>uireme!ts, a! appli*a!t must ma:e a ma!u0a*turi!g *&a!ge i! a**orda!*e +it& a regulatio! or guida!*e t&at pro(ides 0or a less burde!some !oti0i*atio! o0 t&e *&a!ge, (.omme!t 20) 2e(eral *omme!ts !oted t&at t&e? +ere pleased t&at t&e pro(isio! t&at a *&a!ge *a! be made BBi! a**orda!*e +it& a regulatio! or guida!*e t&at pro(ides 0or a less burde!some !oti0i*atio! o0 t&e *&a!geCC +as proposed be*ause it permits less burde!some reporti!g me*&a!isms 0or *&a!ges, F-A a*:!o+ledges t&ese *omme!ts a!d &as retai!ed t&is pro(isio! i! t&e 0i!al rule, "roposed 2e*, 2e*, 4#4,$0(a)(4) a!d 60#,#2(a)(4) stated t&at t&e appli*a!t must promptl? re(ise all promotio!al labeli!g a!d ad(ertisi!g to ma:e it *o!siste!t +it& a!? labeli!g *&a!ge impleme!ted i! a**orda!*e +it& t&is se*tio!, (.omme!t 2#) 2e(eral *omme!ts said t&at t&e pre(ious pro(isio!s i! 2e*, 4#4,$0 limited t&e re>uireme!t to promptl? re(ise all promotio!al labeli!g a!d ad(ertisi!g to t&ose *&a!ges t&at +ere to be 0iled i! a *&a!ges%bei!g%e00e*ted suppleme!t, a!d t&at t&is re>uireme!t is !ot !e*essar? 0or t&e t?pe o0 labeli!g *&a!ges t&at +ould be 0iled i! a! a!!ual report, 6&e *omme!ts suggested t&at t&is re>uireme!t be limited to t&ose labeli!g *&a!ges t&at +ould be 0iled i! suppleme!tal appli*atio!s, 6&e age!*? agrees +it& t&e *omme!ts a!d &as re(ised 2e*, 4#4,$0(a)(4) to re>uire appli*a!ts to re(ise promotio!al labeli!g a!d ad(ertisi!g to ma:e it *o!siste!t +it& labeli!g *&a!ges impleme!ted i! a**orda!*e +it& 2e*, 4#4,$0(b) a!d (*), /! additio!, 2e*, 60#,#2(a)(4) re>uires appli*a!ts to re(ise promotio!al labeli!g a!d ad(ertisi!g to ma:e it *o!siste!t +it& labeli!g *&a!ges impleme!ted i! a**orda!*e +it& 2e*, 60#,#2(0)(#) a!d (0)(2), "roposed 2e*, 4#4,$0(a)(3) stated t&at, eD*ept 0or a suppleme!t pro(idi!g 0or a *&a!ge i! t&e labeli!g, t&e appli*a!t must i!*lude i!

ea*& suppleme!tal appli*atio! pro(idi!g 0or a *&a!ge u!der paragrap& (b) or (*) a stateme!t *erti0?i!g t&at a 0ield *op? o0 t&e suppleme!t &as bee! pro(ided to t&e appli*a!tCs &ome F-A distri*t o00i*e, (.omme!t 22) A 0e+ *omme!ts re>uested t&at F-A *lari0? +&et&er t&e 0ield *op? t&at is to be se!t to t&e appli*a!tCs BB&ome F-A distri*t o00i*eCC s&ould be t&e F-A o00i*e +&ere t&e *&a!ge is bei!g made or t&e F-A o00i*e i! t&e distri*t o0 t&e *ompa!?Cs *orporate &ead>uarters 0rom +&ere t&e submissio! do*ume!ts are se!t, 6&e *omme!ts also said t&at i0 t&e 0ield *op? s&ould be se!t to t&e o00i*e +&ere t&e *&a!ge is bei!g made, F-A s&ould *lari0? +&at F-A o00i*e(s) ser(e 0or *&a!ges made i!ter!atio!all?, 6&e *omme!t said t&at t&e *lari0i*atio! +ill &elp to e!sure t&at t&e appropriate do*ume!ts get to t&e *orre*t F-A distri*t o00i*e, 7aili!g i!0ormatio! 0or 0ield *opies is pro(ided i! 2e*, 4#4,440(a)(4), .urre!tl?, F-A re*omme!ds t&at t&e BBappli*a!tCs &ome F-A distri*t o00i*eCC re0erred to i! 2e*, 4#4,440(a)(4) be t&e distri*t o00i*e +&ere t&e appli*a!tCs &ead>uarters is lo*ated, F-A &as *lari0ied t&is pro(isio! b? *ross%re0ere!*i!g 2e*, 4#4,440(a)(4), 2e*tio! 4#4,440(a)(4) also pro(ides maili!g i!0ormatio! 0or i!ter!atio!al appli*a!ts, F-A, o! its o+! i!itiati(e, &as also *lari0ied t&e pro(isio! b? addi!g BBame!dme!ts to suppleme!ts,CC A 0ield *op? o0 a! ame!dme!t to a suppleme!t, +&i*& is submitted b? a! appli*a!t to i!*orporate additio!al or *orre*ted i!0ormatio! i!to t&eir origi!al suppleme!t, is *urre!tl? re>uired u!der 2e*, 4#4,440(a)(4), "roposed 2e*, 2e*, 4#4,$0(a)(6) a!d 60#,#2(a)(3) added a re>uireme!t t&at a list o0 all *&a!ges *o!tai!ed i! t&e suppleme!t or a!!ual report must be i!*luded i! t&e *o(er letter 0or t&e suppleme!t or a!!ual report, (.omme!t 24) 7a!? *omme!ts agreed t&at a list o0 *&a!ges s&ould be i!*luded i! t&e *o(er letter 0or a suppleme!t, 1o+e(er, t&e *omme!ts disagreed t&at a list o0 all *&a!ges *o!tai!ed i! t&e a!!ual report s&ould be i!*luded i! a *o(er letter, 6&e *omme!ts said t&at i!*ludi!g a list i! a *o(er letter to a! a!!ual report is o(erburde!some be*ause *o(er letters are !ot re>uired 0or a!!ual reports, o!l? a Form F-A 2232, a!d a list o0 *&a!ges is alread? pro(ided [["age #8$46 i! a se*tio! o0 a! a!!ual report, 2e(eral *omme!ts said t&at a! appli*a!t s&ould &a(e t&e optio! o0 pro(idi!g t&e list i! a lo*atio! ot&er t&a! t&e *o(er letter, su*& as at t&e begi!!i!g o0 t&e suppleme!t, F-A agrees +it& t&e re>uests to permit t&e list o0 *&a!ges to be pro(ided i! t&e summar? se*tio! o0 t&e a!!ual report a!d &as re(ised 2e*, 2e*, 4#4,$0(a)(6) a!d 60#,#2(a)(3) to re>uire *&a!ges to be listed i! t&e *o(er letter o!l? 0or suppleme!tal appli*atio!s, A! a!!ual report is re>uired to *o!tai! a brie0 summar? o0 sig!i0i*a!t !e+ i!0ormatio! 0rom t&e pre(ious ?ear t&at mig&t a00e*t t&e sa0et?, e00e*ti(e!ess, or labeli!g o0 t&e drug produ*t (2e*, 4#4,8#(b)(2)(i)), F-ACs guida!*e 0or i!dustr? e!titled BBFormat a!d .o!te!t 0or t&e .7. 2e*tio! o0 a! A!!ual ReportCC (2eptember #994) states, regardi!g t&e summar? o0 !e+ i!0ormatio!, t&at t&e 0irm s&ould i!*lude i! t&e a!!ual report BBa brie0 summar? o0 all *&a!ges made to t&e appli*atio! duri!g t&e reporti!g period i!*ludi!g *&a!ges made i! a**orda!*e +it& appro(ed suppleme!ts u!der 2# .FR 4#4,$0(b) a!d N N N suppleme!ts u!der 2# .FR 4#4,$0(*)N N N,CC 2uppleme!ts are !ot re>uired to &a(e a summar? se*tio! (2e*, 4#4,30(*)),

F-A is re>uiri!g t&at a list o0 *&a!ges be pro(ided i! bot& suppleme!tal appli*atio!s a!d a!!ual reports, F-A proposed t&is re>uireme!t as a mea!s to more e00i*ie!tl? lo*ate a!d ide!ti0? *&a!ges i! +&at are o0te! do*ume!ts o0 substa!tial le!gt&, 6&e list +ill also allo+ F-A to >ui*:l? assess +&et&er t&e appropriate reporti!g *ategor? +as used, 6o a*&ie(e t&ese obAe*ti(es, it is esse!tial t&at t&e list be i! a *o!siste!t lo*atio! 0or ea*& t?pe o0 submissio!, (.omme!t 24) 2e(eral *omme!ts +ere *o!*er!ed t&at t&e list o0 *&a!ges, i0 i!*luded i! a *o(er letter, +ould !ot be *o!sidered *o!0ide!tial i!0ormatio!, 6&e sta!dards 0or dis*losi!g spe*i0i* i!0ormatio! 0rom a *o(er letter or appli*atio! do !ot di00er depe!di!g o! +&ere t&is i!0ormatio! is pro(ided, /!0ormatio! t&at is eDempted 0rom dis*losure (e,g,, trade se*ret or *o!0ide!tial *ommer*ial i!0ormatio!) is !ot dis*losed +&et&er it is i! a *o(er letter or a! appli*atio! (see also 2e*, 2e*, 4#4,440 a!d 60#,3# (2# .FR 60#,3#)), (.omme!t 23) '!e *omme!t re>uested t&at t&e p&rase BBlist o0 all *&a!gesCC be re(ised to BBa brie0 summar? o0 maAor *&a!ges,CC F-A de*li!es to re(ise t&e regulatio! as suggested, 5a*& *&a!ge, i!*ludi!g moderate a!d mi!or *&a!ges, s&ould be listed, F-A !otes t&at t&e des*riptio! o0 t&e listed *&a!ge s&ould be i! su00i*ie!t detail to allo+ t&e age!*? to >ui*:l? determi!e +&et&er t&e appropriate reporti!g *ategor? 0or t&e *&a!ge &as bee! used, For eDample, des*ribi!g a *&a!ge as BBa *&a!ge i! t&e drug produ*t spe*i0i*atio!CC does !ot pro(ide su00i*ie!t detail, A des*riptio! su*& as BBdeletio! o0 t&e 0riabilit? test a!d asso*iated a**epta!*e *riteria a!d a!al?ti*al pro*edure 0rom t&e drug produ*t spe*i0i*atio!CC +ould allo+ F-A to >ui*:l? assess +&et&er t&e appropriate reporti!g *ategor? +as used, 6&e detailed i!0ormatio! about ea*& *&a!ge a!d t&e i!0ormatio! de(eloped to assess t&e e00e*ts o0 t&e *&a!ge +ould be pro(ided i! t&e suppleme!t or else+&ere i! t&e a!!ual report, (.omme!t 26) 2e(eral *omme!ts suggested *&a!ges i! Form F-A 2232 t&at a**ompa!ies a! a!!ual report, F-A de*li!es to re(ise Form F-A 2232 be*ause it is !ot +it&i! t&e s*ope o0 t&is regulatio!, -, .&a!ges Re>uiri!g 2uppleme!t 2ubmissio! a!d Appro(al "rior to -istributio! o0 t&e "rodu*t 7ade 9si!g t&e .&a!ge (7aAor .&a!ges) "roposed 2e*, 4#4,$0(b)(#) re>uired t&at a suppleme!t re>uiri!g prior appro(al must be submitted 0or a!? *&a!ge i! t&e produ*t, produ*tio! pro*ess, >ualit? *o!trols, e>uipme!t, or 0a*ilities t&at &as a substa!tial pote!tial to &a(e a! ad(erse e00e*t o! t&e ide!tit?, stre!gt&, >ualit?, purit?, or pote!*? o0 t&e produ*t as t&ese 0a*tors ma? relate to t&e sa0et? or e00e*ti(e!ess o0 t&e produ*t, (.omme!t 2$) 7a!? *omme!ts as:ed +&et&er a prior appro(al suppleme!t +ould be re>uired e(e! i0 t&e appli*a!t &as demo!strated t&at t&e *&a!ge &as !o sig!i0i*a!t ad(erse a00e*t, 2e*tio! 306A(*)(2) o0 t&e a*t states t&at a maAor ma!u0a*turi!g *&a!ge is BBa *&a!ge t&at is determi!ed b? t&e 2e*retar? to &a(e substa!tial pote!tial to ad(ersel? a00e*t t&e ide!tit?, stre!gt&, >ualit?, purit?, or pote!*? o0 t&e drug as t&e? ma? relate to t&e sa0et? or e00e*ti(e!ess o0 a drug,CC 6&e a*t bases t&e reporti!g *ategor? 0or a *&a!ge o! t&e pote!tial 0or t&at *&a!ge to &a(e a! ad(erse e00e*t, !ot o! t&e out*ome o0 t&e assessme!t studies, F-A +ould eDpe*t a prior appro(al suppleme!t to be submitted 0or a *&a!ge t&at &as substa!tial pote!tial to ad(ersel? a00e*t t&e ide!tit?, stre!gt&,

>ualit?, purit?, or pote!*? o0 a drug produ*t e(e! i0 t&e appli*a!t *o!*ludes t&at t&eir studies a!d data demo!strate t&at t&e *&a!ge &as !o ad(erse e00e*t, "rior to distributio! o0 t&e drug produ*t made +it& t&e *&a!ge, F-A must e(aluate +&et&er t&e studies per0ormed b? t&e appli*a!t +ere su00i*ie!t to assess t&e e00e*t o0 t&e *&a!ge a!d t&at t&e data support t&e appli*a!tCs *laim t&at t&e *&a!ge &as !ot ad(ersel? a00e*ted t&e ide!tit?, stre!gt&, >ualit?, purit?, or pote!*? o0 t&e drug produ*t as t&e? ma? relate to t&e sa0et? or e00e*ti(e!ess o0 a drug produ*t, (.omme!t 28) '!e *omme!t said t&at se*tio! 306A o0 t&e a*t ide!ti0ies maAor *&a!ges as 0ormulatio!, spe*i0i*atio!, or t&ose re>uiri!g studies i! a**orda!*e +it& part 420 (2# .FR part 420) to demo!strate t&e e>ui(ale!*e o0 t&e drug produ*t to t&e drug produ*t as ma!u0a*tured +it&out t&e *&a!ge or to t&e re0ere!*e listed drug, 6&e *omme!t said t&at F-A &as proposed prior appro(al suppleme!ts 0or *&a!ges t&at are *learl? outside o0 t&ese t&ree maAor *&a!ge *ategories, A!ot&er *omme!t said it appears t&at F-A &as o(erutili=ed se*tio! 306A(*)(2)(.) o0 t&e a*t, F-A disagrees t&at it &as o(erutili=ed t&is part o0 t&e a*t, /! additio! to t&e t&ree maAor *&a!ges ide!ti0ied pre(iousl? i! t&is do*ume!t, se*tio! 306A(*)(2)(.) o0 t&e a*t states t&at a maAor *&a!ge BBis a!ot&er t?pe o0 *&a!ge determi!ed b? t&e 2e*retar? b? regulatio! or guida!*e to &a(e a substa!tial pote!tial to ad(ersel? a00e*t t&e sa0et? or e00e*ti(e!ess o0 t&e drug,CC /! pre(ious regulatio!s, ma!? ma!u0a*turi!g *&a!ges re>uired prior appro(al suppleme!ts, F-A &as used t&is pro(isio! o0 t&e a*t to ide!ti0? a limited !umber o0 *&a!ges t&at it *o!siders to &a(e a substa!tial pote!tial to ad(ersel? a00e*t t&e ide!tit?, stre!gt&, >ualit?, purit?, or pote!*? o0 t&e drug as t&e? ma? relate to t&e sa0et? or e00e*ti(e!ess o0 a drug, 6&e regulatio! redu*es t&e o(erall !umber o0 suppleme!ts re>uiri!g F-A appro(al prior to produ*t distributio!, /! additio!, ma!? *&a!ges t&at are *urre!tl? reported i! suppleme!ts +ill be able to be reported i! a!!ual reports, 6&e regulatio! +ill !ot i!*rease t&e !umber o0 a!!ual reports but +ill allo+ appli*a!ts to i!*lude i! a! a!!ual report i!0ormatio! *urre!tl? re>uired to be reported to t&e age!*? i! a suppleme!tal appli*atio!, 7oreo(er, F-A 0urt&er redu*ed ma!? reporti!g re>uireme!ts 0rom t&e le(els re*omme!ded i! pre(ious F-A guida!*es, "roposed 2e*, 4#4,$0(b)(2)(i) pro(ided t&at, eD*ept as pro(ided i! 2e*, 4#4,$0(*) a!d (d), prior appro(al is re>uired 0or *&a!ges i! t&e >ualitati(e or >ua!titati(e 0ormulatio! o0 t&e drug, i!*ludi!g i!a*ti(e i!gredie!ts, or i! t&e spe*i0i*atio!s pro(ided i! t&e appro(ed appli*atio!, (.omme!t 29) A 0e+ *omme!ts re*omme!ded t&at proposed [["age #8$4$ 2e*, 4#4,$0(b)(2)(i) be re(ised to better re0le*t se*tio! 306A(*)(2)(A) o0 t&e a*t +&i*& allo+s eD*eptio!s to t&e re>uireme!t to obtai! prior appro(al be0ore *&a!gi!g t&e >ualitati(e or >ua!titati(e 0ormulatio! o0 t&e drug, '!e *omme!t re*omme!ded t&e pro(isio! be re(ised to state: BB5D*ept as pro(ided i! paragrap&s (*) a!d (d) o0 t&is se*tio! or eDempted b? regulatio! or guida!*e N N N,CC F-A de*li!es to re(ise t&e regulatio! as re>uested, 2e*tio! 306A(*)(2)(A) o0 t&e a*t states t&at a prior appro(al suppleme!t is re>uired +&e! a *&a!ge BBis made i! t&e >ualitati(e or >ua!titati(e 0ormulatio! o0 t&e drug i!(ol(ed or t&e spe*i0i*atio!s i! t&e appro(ed appli*atio! or li*e!se N N N (u!less eDempted b? t&e 2e*retar? b?

regulatio! or guida!*e N N N),CC "roposed 2e*, 4#4,$0 is *o!siste!t +it& t&e pro(isio!s o0 t&e a*t, 5Demptio!s b? regulatio! are pro(ided i! 2e*, 4#4,$0(*) or (d), 6&is la!guage is alread? i!*luded i! 2e*, 4#4,$0(b)(2)(i), /! additio!, F-A ma? use guida!*e do*ume!ts to pro(ide 0or a less burde!some !oti0i*atio! o0 a spe*i0i* *&a!ge, 6&is eDemptio! is i!*luded i! 2e*, 4#4,$0(a)(4) a!d applies to 2e*, 4#4,$0(b)(2)(i) as +ell as t&e ot&er *&a!ges listed i! 2e*, 4#4,$0, (.omme!t 40) 2e(eral *omme!ts !oted t&at t&e 29"A. guida!*es allo+ed 0or some *&a!ges i! >ualitati(e or >ua!titati(e 0ormulatio! o0 t&e drug produ*t to be 0iled i! *&a!ges%bei!g%e00e*ted suppleme!ts or a!!ual reports, '!e *omme!t said t&at t&e regulatio!s s&ould 0ollo+ t&e sta!dards i! t&e 29"A. guida!*es, F-A &as !ot i!*orporated t&e >ualitati(e a!d >ua!titati(e 0ormulatio! *&a!ge i!0ormatio! 0rom t&e 29"A. guida!*es i! t&e regulatio! be*ause, as stated i! t&e proposal, t&e age!*?Cs approa*& is to issue regulatio!s t&at set out broad, ge!eral *ategories o0 ma!u0a*turi!g *&a!ges a!d use guida!*e do*ume!ts to pro(ide F-ACs *urre!t t&i!:i!g o! t&e spe*i0i* *&a!ges i!*luded i! t&ose *ategories, (.omme!t 4#) 2e(eral *omme!ts said t&at *&a!ges i! spe*i0i*atio! to *ompl? +it& a! o00i*ial *ompe!dium s&ould !ot re>uire prior appro(al suppleme!ts, F-A is !ot re>uiri!g prior appro(al suppleme!ts 0or spe*i0i*atio! *&a!ges made to *ompl? +it& a! o00i*ial *ompe!dium, A *omplete dis*ussio! o0 t&is issue is pro(ided u!der se*tio! ///,F o0 t&is do*ume!t, BB.&a!ges 6o ;e -es*ribed i! t&e NeDt A!!ual Report,CC i! respo!se to *omme!ts o! 2e*, 4#4,$0(d)(2)(i), (.omme!t 42) '!e *omme!t re*omme!ded t&e proposed la!guage be re(ised to limit spe*i0i*atio! *&a!ges to t&ose 0or drug substa!*e or drug produ*t, F-A *o!siders a spe*i0i*atio! to be a >ualit? sta!dard (i,e,, tests, a!al?ti*al pro*edures, a!d a**epta!*e *riteria) pro(ided i! a! appro(ed appli*atio! to *o!0irm t&e >ualit? o0 drug substa!*es, drug produ*ts, i!termediates, ra+ materials, reage!ts, *ompo!e!ts, i!% pro*ess materials, *o!tai!er *losure s?stems, or ot&er materials used i! t&e produ*tio! o0 a drug substa!*e or drug produ*t, 6&ere0ore, F-A de*li!es to re(ise t&e proposal as suggested, "roposed 2e*, 4#4,$0(b)(2)(ii) re>uired prior appro(al 0or *&a!ges re>uiri!g *ompletio! o0 studies i! a**orda!*e +it& part 420 to demo!strate t&e e>ui(ale!*e o0 t&e drug to t&e drug as ma!u0a*tured +it&out t&e *&a!ge or to t&e re0ere!*e listed drug, (.omme!t 44) '!e *omme!t said t&at re0ere!*e to part 420 suggests t&at bioe>ui(ale!*e must be addressed 0or BBa *&a!ge i! t&e ma!u0a*turi!g pro*ess N N N,CC 6&e *omme!t said t&at t&is +ill lead to sig!i0i*a!t i!terpretatio! issues, 6&e *omme!t said t&at a sele*ti(e subset o0 maAor ma!u0a*turi!g *&a!ges t&at trul? &a(e BBsubsta!tial pote!tialCC s&ould be spe*i0ied &ere, A!ot&er *omme!t said t&at +&e! t&e produ*t is a true solutio!, *&a!ges to t&e ma!u0a*turi!g pro*ess (!ot 0ormulatio!) are &ig&l? u!li:el? to *&a!ge t&e 0ormulatio! a!d additio!al *li!i*al (bioe>ui(ale!*e) studies s&ould !ot al+a?s be re>uired, F-A de*li!es to re(ise t&e proposal based o! t&ese *omme!ts, 6&e re>uireme!ts 0or +&e! a stud? is !eeded to demo!strate t&e e>ui(ale!*e o0 a drug produ*t made +it& t&e proposed *&a!ge to a drug produ*t made +it&out t&e *&a!ge or to t&e re0ere!*e listed drug are pro(ided i! part 420, "art 4#4 is !ot i!te!ded to suppleme!t, supersede, or *lari0? t&ese re>uireme!ts, 2e*tio! 4#4,$0(b)(2)(ii) spe*i0ies o!l? t&at i0 su*& a stud? is re>uired u!der part 420 to support a postappro(al

*&a!ge, t&e postappro(al *&a!ge must be submitted usi!g a prior appro(al suppleme!t, .&a!ges t&at re>uire a stud? u!der part 420 are *o!sidered maAor *&a!ges t&at &a(e a sig!i0i*a!t pote!tial to a00e*t t&e ide!tit?, stre!gt&, >ualit?, purit?, or pote!*? o0 t&e produ*t as it relates to t&e sa0et? or e00e*ti(e!ess o0 a produ*t, a!d F-A +ould !eed to re(ie+ su*& studies be0ore a produ*t made +it& t&e *&a!ge is pla*ed i!to distributio!, "roposed 2e*, 4#4,$0(b)(2)(iii) re>uired prior appro(al 0or *&a!ges t&at ma? a00e*t produ*t sterilit? assura!*e, su*& as *&a!ges i! produ*t or *ompo!e!t sterili=atio! met&od(s) or a! additio!, deletio!, or substitutio! o0 steps i! a! asepti* pro*essi!g operatio!, (.omme!t 44) 7a!? *omme!ts stated t&at t&e proposed la!guage +as too broad a!d s&ould be modi0ied to state BB*&a!ges t&at ma? sig!i0i*a!tl? a00e*t produ*t sterilit? assura!*eCC or BB*&a!ges t&at sig!i0i*a!tl? a00e*t produ*t sterilit? assura!*eCC, '!e *omme!t said t&at t&e term BBma? a00e*tCC is !ot appropriate be*ause a!? *&a!ge ma? a00e*t o!e or more attributes o0 a sterile drug, 2terilit? o0 drug produ*ts or drug substa!*es is a 0u!dame!tal a!d esse!tial >ualit? attribute o0 t&ese drugs a!d is a *riti*al aspe*t o0 t&e sa0et? assessme!t, 6&e ma!u0a*ture o0 a sterile drug is a! eDa*ti!g, di00i*ult, a!d &ig&l? *o!trolled series o0 pro*esses, espe*iall? i! t&e *ase o0 asepti*all? pro*essed drugs, 6&e *o!*ept o0 sig!i0i*a!*e or BBsig!i0i*a!tl? a00e*tCC implies t&at a measureme!t o0 a! attribute, su*& as sterilit?, *a! be made, 1o+e(er, !o test is se!siti(e e!oug& to dete*t u!a**eptable sterilit? assura!*e le(els (i,e,, t&e probabilit? o0 a !o!sterile u!it), For eDample, a bat*& o0 drug produ*t tested usi!g t&e sta!dard drug produ*t sterilit? test des*ribed i! t&e 92"ENF +ill 0ail t&e sterilit? test o!l? +&e! at least #4 per*e!t o0 t&e bat*& is *o!tami!ated (93 per*e!t *o!0ide!*e le(el), 6&is sterilit? assura!*e le(el is u!a**eptable, 6&e probabilit? o0 !o!sterile u!its 0or termi!all? sterili=ed a!d asepti*all? pro*essed drugs is !ormall? eDpe*ted b? F-A to be less t&a! 0,000# per*e!t a!d 0,# per*e!t, respe*ti(el?, F-A e!sures t&e sa0et? o0 sterile drugs b? assessi!g t&e e00i*a*? o0 a gi(e! sterili=atio! pro*ess 0or a spe*i0i* drug a!d b? e!suri!g t&at t&e 0a*ilities produ*i!g sterile drugs *ompl? +it& .)7"s, 6&e assessme!t o0 t&e e00i*a*? o0 a sterili=atio! pro*ess i!*ludes re(ie+ o0 multiple proto*ols a!d s*ie!ti0i* eDperime!ts desig!ed to demo!strate t&at t&e sterili=atio! pro*ess a!d asso*iated *o!trol pro*edures *a! reprodu*ibl? deli(er a sterile produ*t, 6&e data deri(ed 0rom t&e eDperime!ts a!d *o!trol pro*edures allo+ *ertai! *o!*lusio!s to be dra+! about t&e probabilit? o0 !o!sterile u!its, A properl? (alidated sterili=atio! pro*ess +ill pro(ide t&e sterilit? assura!*e le(el re>uired b? F-A to e!sure t&e sa0et? o0 sterile drugs, ;e*ause o0 t&e la*: o0 ade>uate test pro*edures 0or assessi!g sterilit? a!d t&e *ompleDit? i! e(aluati!g t&e pro*ess (alidatio! a!d *o!trols i!0ormatio! to determi!e t&e le(el o0 sterilit? assura!*e t&at a gi(e! pro*ess pro(ides 0or a spe*i0i* drug, F-A &as used t&e term BBma? a00e*tCC a!d de*li!es to re(ise t&e proposal as suggested, [["age #8$48 (.omme!t 43) 7a!? *omme!ts stated t&at t&e proposed la!guage s&ould be *lari0ied to state BB*&a!ges t&at ma? ad(ersel? a00e*t produ*t sterilit? assura!*e N N NCC or BB*&a!ges t&at ma? redu*e (or de*rease) produ*t sterilit? assura!*e N N NCC, Ne+ 2e*, 4#4,$0(b)(#) alread? ide!ti0ies t&at t&e *&a!ges t&at s&ould be submitted i! prior appro(al suppleme!ts are t&ose t&at &a(e a

substa!tial pote!tial to &a(e a! BBad(erse e00e*t,CC F-A de*li!es to re(ise proposed 2e*, 4#4,$0(b)(2)(iii) as re>uested be*ause t&e additio! o0 t&e term BBad(ersel?CC is redu!da!t, F-A emp&asi=es t&at t&e assessme!t o0 +&et&er a *&a!ge ma? ad(ersel? a00e*t sterilit? assura!*e is a *ompleD a!d multidime!sio!al a!al?sis, For eDample, a *&a!ge to a more stri!ge!t termi!al sterili=atio! pro*ess, +&ile i! t&eor? pro(idi!g a lo+er probabilit? o0 !o!sterile u!its, ma? damage t&e *o!tai!er *losure s?stem so t&at sterilit? o0 i!di(idual u!its *ould !ot be mai!tai!ed, (.omme!t 46) 2e(eral *omme!ts said t&at t&e proposed la!guage is too restri*ti(e be*ause it i!di*ates t&at all *&a!ges to sterile produ*ts s&ould be submitted i! prior appro(al suppleme!ts, 6&e *omme!ts said t&at t&is *o!tradi*ts +&at is i! t&e guida!*e e!titled BB.&a!ges to a! Appro(ed N-A or AN-A,CC +&i*& ide!ti0ies some *&a!ges t&at do !ot &a(e to be 0iled i! prior appro(al suppleme!ts, '!e *omme!t ide!ti0ied spe*i0i* eDamples o0 ma!u0a*turi!g *&a!ges 0or sterile produ*ts a!d said t&at t&ese s&ould !ot be *o!sidered maAor *&a!ges, F-A *o!siders *&a!ges t&at ma? a00e*t t&e sterilit? assura!*e le(el o0 a drug to &a(e sig!i0i*a!t pote!tial to a00e*t t&e sa0et? o0 t&e drug, 6&ere0ore, F-A &as ide!ti0ied t&is *&a!ge as o!e t&at re>uires prior appro(al, As stated i! t&e @u!e #999 proposal, t&is rulema:i!g sets out broad, ge!eral *ategories o0 ma!u0a*turi!g *&a!ges, a!d t&e age!*? uses guida!*e do*ume!ts to pro(ide F-ACs *urre!t t&i!:i!g o! t&e spe*i0i* *&a!ges i!*luded i! t&ose *ategories, 9!der 2e*, 4#4,$0(a)(4), a! appli*a!t must !oti0? F-A o0 a ma!u0a*turi!g *&a!ge i! a**orda!*e +it& eit&er a regulatio! or a guida!*e t&at addresses t&e same issues as t&e regulatio! but t&at pro(ides 0or a less burde!some !oti0i*atio! o0 t&e *&a!ge t&a! t&e regulatio! (0or eDample, b? submissio! o0 a suppleme!t t&at does !ot re>uire appro(al prior to distributio! o0 t&e produ*t), For eDample, i! t&e guida!*e e!titled BB.&a!ges to a! Appro(ed N-A or AN-A,CC F-A &as ide!ti0ied less burde!some reporti!g *ategories 0or *ertai! *&a!ges t&at it belie(es &a(e less pote!tial to a00e*t sterilit? assura!*e a!d *o!se>ue!tl? t&e sa0et? o0 t&e drug, (.omme!t 4$) A 0e+ *omme!ts said t&at t&is pro(isio! i!*reases t&e regulator? burde! +it& respe*t to sterile produ*ts, 6&e *omme!ts said t&at o!l? 0u!dame!tal *&a!ges to sterile pro*essi!g re>uire prior appro(al, F-A disagrees +it& t&is *omme!t, 9!der t&e pre(ious regulatio!s at 2e*, 4#4,$0, ma!u0a*turi!g site, pro*essi!g, a!d pa*:agi!g *&a!ges 0or sterile drugs almost al+a?s re>uired a prior appro(al suppleme!t (pre(ious 2e*, 4#4,$0(b)(#)(i(), (b)(#)((), (b)(2)(i(), (b)(2)((), a!d (b)(2)((i)), 9!der 2e*, 4#4,$0(*) a!d (d), *ertai! *&a!ges related to sterile drugs ma? be submitted i! *&a!ges%bei!g%e00e*ted suppleme!ts or a!!ual reports (0or eDample, 2e*, 4#4,$0(d)(2)(i) a!d (iii)), /! t&e guida!*e e!titled BB.&a!ges to a! Appro(ed N-A or AN-A,CC F-A &as ide!ti0ied ma!? *&a!ges related to sterile drugs t&at ma? !o+ be submitted i! *&a!ges%bei!g%e00e*ted suppleme!ts or a!!ual reports, "roposed 2e*, 4#4,$0(b)(2)(i() re>uired prior appro(al 0or *&a!ges i! t&e s?!t&esis or ma!u0a*ture o0 t&e drug substa!*e t&at ma? a00e*t t&e impurit? pro0ile a!dEor t&e p&?si*al, *&emi*al, or biologi*al properties o0 t&e drug substa!*e, (.omme!t 48) '!e *omme!t said t&at t&e proposal s&ould be re(ised to state BB.&a!ges i! t&e route o0 s?!t&esis or N N N,CC .&a!ges su*& as a! additio!al re*r?stalli=atio! step (usi!g t&e same sol(e!ts, a!d so 0ort&) s&ould be *o!sidered 0or *&a!ges%bei!g%e00e*ted status, F-A de*li!es to re(ise t&e proposal as suggested, .&a!ges i! t&e

s?!t&esis, i!*ludi!g t&e route o0 s?!t&esis, ma? &a(e a! e00e*t o! t&e impurit? pro0ile a!dEor t&e p&?si*al, *&emi*al, or biologi*al properties o0 t&e drug substa!*e, For eDample, a *&a!ge i! a sol(e!t used i! t&e *r?stalli=atio! step ma? a00e*t t&e impurit? pro0ile a!d p&?si*al properties o0 t&e drug substa!*e e(e! t&oug& t&is *&a!ge +ould !ot be *o!sidered a *&a!ge i! t&e BBroute o0 s?!t&esis,CC (.omme!t 49) 2e(eral *omme!ts stated t&at t&e proposed la!guage s&ould be *lari0ied to state BB*&a!ges t&at ma? ad(ersel? a00e*t t&e impurit? pro0ile N N NCC be*ause *&a!ges t&at impro(e t&e >ualit? o0 t&e drug substa!*e s&ould !ot re>uire a prior appro(al suppleme!t, Ne+ 2e*, 4#4,$0(b)(#) states t&at t&e *&a!ges t&at s&ould be submitted i! prior appro(al suppleme!ts are t&ose t&at &a(e a substa!tial pote!tial to &a(e a! BBad(erse e00e*t,CC F-A de*li!es to re(ise t&e pro(isio! as re>uested be*ause t&e additio! o0 t&e term BBad(ersel?CC is redu!da!t, (.omme!t 40) '!e *omme!t suggested t&at F-A *&a!ge BBma? a00e*t t&e impurit? pro0ile o0 t&e drug produ*tCC to BBare li:el? to a00e*t t&e impurit? pro0ile o0 t&e drug produ*t,CC 6&e *omme!t said t&at ma!? 0a*tors *ould a00e*t t&e impurit? pro0ile, a!d t&is stri!ge!t reporti!g re>uireme!t s&ould be reser(ed 0or 0a*tors t&at are li:el? to produ*e a *&a!ge, F-A belie(es t&e p&rase BBma? a00e*tCC is appropriate be*ause t&e de*isio! o! +&et&er a *&a!ge s&ould be *o!sidered a maAor, moderate, or mi!or *&a!ge is based o! t&e pote!tial 0or t&e *&a!ge to ad(ersel? a00e*t t&e ide!tit?, stre!gt&, >ualit?, purit?, or pote!*? o0 t&e drug as t&e? ma? relate to t&e sa0et? or e00e*ti(e!ess o0 a drug produ*t, F-A *o!siders a *&a!ge t&at BBma? a00e*t t&e impurit? pro0ile a!dEor t&e p&?si*al, *&emi*al, or biologi*al properties o0 t&e drug substa!*eCC to be a *&a!ge t&at &as a substa!tial pote!tial to result i! a! ad(erse e00e*t a!d de*li!es to delete BBma?,CC (.omme!t 4#) '!e *omme!t said t&at i!serti!g t&e *lause BBbe?o!d t&ose studied i! t&e pre%*li!i*al studies a!d re>uiri!g a *&a!ge i! t&e appro(ed spe*i0i*atio!sCC a0ter impurit? pro0ile +ould add *larit?, 6&e *omme!t said t&at a**ordi!g to t&e /.1 guida!*e e!titled BB/mpurities i! Ne+ -rug 2ubsta!*esCC (/.1 M4A), impurities belo+ a *ertai! t&res&old +ould !ot !e*essaril? re>uire registratio!, 6&e pro*ess o0 >uali0?i!g impurities a!d determi!i!g i0 a post*&a!ge impurit? pro0ile 0or a drug substa!*e is e>ui(ale!t or better t&a! t&e impurit? pro0ile o0 t&e pre*&a!ge material is a *ompleD issue, F-A does !ot belie(e it is possible to *lari0? t&e regulatio!s to ade>uatel? address t&e ma!? di00ere!t t?pes o0 &uma! drugs it regulates, For eDample, !ot all drug appro(als re>uire pre*li!i*al studies, F-A de*li!es to re(ise t&e proposal as suggested, F-A publis&ed t&e ;A."A. / guida!*e to pro(ide re*omme!datio!s o! &o+ to e(aluate *&a!ges i! impurit? pro0iles, (.omme!t 42) 2e(eral *omme!ts said t&at t&e proposed regulatio!s +ere !ot *o!siste!t +it& t&e ;A."A. / guida!*e, 2e(eral *omme!ts said t&at t&e proposal +as mu*& more restri*ti(e t&a! +&at +as i!*luded i! t&e ;A."A. / guida!*e, '!e *omme!t said t&at *&a!ges i! drug substa!*e s?!t&esis route, +&i*& o**ur prior to t&e 0ormatio! o0 :e? i!termediates, s&ould !ot be regarded as maAor *&a!ges, si!*e t&e pote!tial to impa*t t&e >ualit?, stre!gt&, ide!tit?, a!d purit? o0 t&e 0i!al produ*t is lo+, [["age #8$49 F-A de*li!es to re(ise t&e regulatio!s as re>uested, 6&e ;A."A. /

guida!*e is a! eDample o0 a guida!*e t&at permits *ertai! spe*i0i* *&a!ges t&at 0all u!der t&e ge!eral *ategor? o0 a *&a!ge t&at BBma? a00e*t t&e impurit? pro0ile a!dEor t&e p&?si*al, *&emi*al, or biologi*al properties o0 t&e drug substa!*eCC to be reported usi!g a less burde!some met&od o0 !oti0i*atio!, 9!der 2e*, 4#4,$0(a)(4), a! appli*a!t must !oti0? F-A o0 a ma!u0a*turi!g *&a!ge i! a**orda!*e +it& eit&er a regulatio! or a guida!*e t&at addresses t&e same issues as t&e regulatio! but t&at pro(ides 0or a less burde!some !oti0i*atio! o0 t&e *&a!ge t&a! t&e regulatio! (0or eDample, b? submissio! o0 a suppleme!t t&at does !ot re>uire appro(al prior to distributio! o0 t&e produ*t), "roposed 2e*, 4#4,$0(b)(2)(() re>uired prior appro(al 0or *&a!ges i! labeli!g, eD*ept t&ose des*ribed i! 2e*, 4#4,$0(*)(6)(iii), (d)(2)(iD), or (d)(2)(D), '! its o+! i!itiati(e, F-A &as re(ised 2e*, 4#4,$0(b)(2)(() to add: BB/0 appli*able, a!? *&a!ge to a 7edi*atio! )uide re>uired u!der part 208 o0 t&is *&apter, eD*ept 0or *&a!ges i! t&e i!0ormatio! spe*i0ied i! 2e*, 208,20(b)(8)(iii) a!d (b)(8)(i() o0 t&is *&apter,CC 6&is pro(isio!, +&i*& +as pre(iousl? i! 2e*, 4#4,$0(b)(4)(ii), +as i!ad(erte!tl? omitted 0rom t&e proposed rule, (.omme!t 44) 7a!? *omme!ts said t&at F-A s&ould *lari0? BBlabeli!gCC to i!di*ate BBdrug produ*t labeli!gCC be*ause drug substa!*e labeli!g *&a!ges !eed !ot be submitted, F-A de*li!es to re(ise t&e regulatio!s as re>uested, 6&e term BBlabeli!gCC i! 2e*, 4#4,$0 is *o!siste!t +it& BBlabeli!gCC as used i! part 20# (2# .FR part 20#), "art 20# applies to t&e labeli!g o0 drugs a!dEor drug produ*ts, "roposed 2e*, 4#4,$0(b)(2)((i) re>uired prior appro(al 0or *&a!ges i! a *o!tai!er *losure s?stem t&at *o!trols drug deli(er? or t&at ma? a00e*t t&e impurit? pro0ile o0 t&e drug produ*t, (.omme!t 44) 2e(eral *omme!ts re>uested t&at t&e proposed la!guage be *lari0ied to state BB*&a!ges t&at ma? ad(ersel? a00e*t t&e impurit? pro0ile N N NCC or BB*&a!ges t&at ad(ersel? a00e*t t&e impurit? pro0ile NNN,CC F-A de*li!es to re(ise t&e pro(isio! be*ause t&e additio! o0 t&e term BBad(ersel?CC is redu!da!t, Ne+ 2e*, 4#4,$0(b)(#) alread? states t&at t&e *&a!ges t&at s&ould be 0iled i! prior appro(al suppleme!ts are t&ose t&at &a(e a substa!tial pote!tial to &a(e a! BBad(erse e00e*t,CC F-A belie(es t&e p&rase BBma? a00e*tCC is appropriate be*ause t&e de*isio! o! +&et&er a *&a!ge s&ould be *o!sidered a maAor, moderate, or mi!or *&a!ge is based o! t&e pote!tial 0or t&e *&a!ge to ad(ersel? a00e*t t&e ide!tit?, stre!gt&, >ualit?, purit?, or pote!*? o0 t&e drug as t&e? ma? relate to t&e sa0et? or e00e*ti(e!ess o0 a drug produ*t, F-A *o!siders a *&a!ge t&at BBma? a00e*t t&e impurit? pro0ile o0 t&e drug produ*tCC to be a *&a!ge t&at &as a substa!tial pote!tial to result i! a! ad(erse e00e*t a!d de*li!es to delete BBma?,CC (.omme!t 43) '!e *omme!t re>uested *lari0i*atio! o0 +&at is mea!t b? BB*o!trols drug deli(er?,CC su*& as >ua!tit? dispe!sed, ma*&i!e *alibratio!, a!d (olume o0 0ill, For some drug produ*ts, t&e *o!tai!er *losure s?stem itsel0, rat&er t&a! a perso!, regulates t&e amou!t o0 drug produ*t t&at is admi!istered to a patie!t, 6&ese *o!tai!er *losure s?stems are *o!sidered to BB*o!trol drug deli(er?,CC For eDample, a patie!t t&at uses a metered dose i!&alatio! produ*t as i!stru*ted *a!!ot *o!trol t&e amou!t o0 drug produ*t t&e *o!tai!er *losure s?stem deli(ers or (eri0? t&at t&e appropriate amou!t &as bee! admi!istered, K&ere a drug produ*t *o!tai!er *losure s?stem *o!trols drug deli(er?, F-A re>uires i!0ormatio! to be submitted to support t&at t&e *o!tai!er *losure

s?stem *a! a**uratel? a!d repeatedl? deli(er t&e re>uired amou!t o0 drug produ*t, 6&e desig! a!d operatio! o0 t&ese *o!tai!er *losure s?stems is *riti*al to e!sure t&at t&e patie!t re*ei(es t&e *orre*t dose, A drug produ*t ma? !ot be sa0e or e00e*ti(e i0 a patie!t re*ei(es too mu*& or too little o0 t&e drug produ*t, .&a!ges i! t&ese s?stems are *o!sidered to &a(e a substa!tial pote!tial to ad(ersel? a00e*t t&e ide!tit?, stre!gt&, >ualit?, purit?, or pote!*? o0 t&e drug as t&e? ma? relate to t&e sa0et? or e00e*ti(e!ess o0 a drug produ*t, .o!tai!er *losure s?stems 0or drug produ*ts +&ere a perso! *o!trols t&e amou!t o0 drug produ*t admi!istered a!dEor +&i*& allo+ 0or (eri0i*atio! t&at t&e appropriate amou!t &as bee! admi!istered (e,g,, !umber o0 tablets, milliliters o0 li>uid) are !ot *o!sidered *o!tai!er *losure s?stems t&at BB*o!trol drug deli(er?,CC (.omme!t 46) A!ot&er *omme!t as:ed +&et&er t&is se*tio! spe*i0i*all? re0ers to t&e 0i!al pa*:aged produ*t o!l?, .&a!ges i! BBa *o!tai!er *losure s?stem t&at *o!trols drug deli(er?CC applies o!l? to t&e mar:eted drug produ*t *o!tai!er *losure s?stem, a!d t&e la!guage &as bee! re(ised i! t&e 0i!al rule to *lari0? t&is, .&a!ges t&at BBma? a00e*t t&e impurit? pro0ile o0 t&e drug produ*tCC applies to a!? t?pe o0 *o!tai!er *losure s?stem, (.omme!t 4$) '!e *omme!t !oted a! appare!t *o!0li*t bet+ee! 2e*, 4#4,$0(b)(2)((i), +&i*& sa?s t&at a BB*&a!ge i! a *o!tai!er *losure s?stem t&at N N N ma? a00e*t t&e impurit? pro0ile o0 t&e drug produ*tCC s&ould be submitted i! a prior appro(al suppleme!t a!d 2e*, 4#4,$0(*)(2)(i), +&i*& sa?s t&at BBa *&a!ge i! t&e *o!tai!er *losure s?stem t&at does !ot a00e*t t&e >ualit? o0 t&e 0i!al drug produ*tCC s&ould be submitted i! a *&a!ges%bei!g%e00e*ted%i!%40%da?s suppleme!t, 6&e *omme!t said t&at t&is +ould allo+ 0or i!*o!siste!t a!d o(erl? *o!ser(ati(e i!terpretatio!s o0 +&at mig&t 0all i!to t&is latter *ategor?, F-A agrees t&at *lari0i*atio! o0 t&e +ordi!g i! t&ese t+o pro(isio!s o0 t&e regulatio!s is !eeded, F-A &as parti*ular *o!*er!s about *&a!ges i! t&e t?pe (e,g,, glass to &ig& de!sit? pol?et&?le!e (1-"5), 1-"5 to pol?(i!?l *&loride, (ial to s?ri!ge) or *ompositio! (e,g,, o!e 1-"5 resi! to a!ot&er 1-"5 resi!) o0 pa*:agi!g *ompo!e!ts be*ause t&ese *&a!ges ma? a00e*t t&e impurit? pro0ile o0 t&e drug produ*t, 6&ese *o!*er!s are *ompou!ded b? t&e 0a*t t&at, i! most *ases, t&e pa*:agi!g *ompo!e!t ma!u0a*turer *o!siders t&e ma!u0a*turi!g pro*ess *o!0ide!tial i!0ormatio! a!d dis*loses it o!l? to F-A, 6&ere0ore, a! appli*a!t does !ot &a(e :!o+ledge o0 all pote!tial impurities t&at a di00ere!t t?pe or *ompositio! o0 a pa*:agi!g *ompo!e!t ma? i!trodu*e i!to a produ*t, -epe!di!g o! t&e dosage 0orm a00e*ted a!d its route o0 admi!istratio!, F-A ma? &a(e to e(aluate t&e sa0et? o0 *&a!ges i! t&e t?pe or *ompositio! o0 a pa*:agi!g *ompo!e!t, ;e*ause o0 t&e sa0et? *o!*er!s relati!g to !e+ impurities 0rom a pa*:agi!g *ompo!e!t +it& t&is t?pe o0 *&a!ge, F-A *o!siders su*& *&a!ges to &a(e a substa!tial pote!tial to ad(ersel? a00e*t t&e ide!tit?, stre!gt&, >ualit?, purit?, or pote!*? o0 t&e drug as t&e? ma? relate to t&e sa0et? or e00e*ti(e!ess o0 a drug produ*t, F-A &as re(ised 2e*, 4#4,$0(b)(2)((i) to limit t&e re>uireme!t to situatio!s i!(ol(i!g *&a!ges i! t&e t?pe or *ompositio! o0 a pa*:agi!g *ompo!e!t, F-A *o!siders a deletio! or additio! o0 a pa*:agi!g *ompo!e!t to 0all +it&i! t&e mea!i!g o0 a *&a!ge i! t&e t?pe o0 pa*:agi!g *ompo!e!t, F-A ma?, t&roug& regulatio!s or guida!*e, ide!ti0? *ertai! dosage 0orms a!dEor routes o0 admi!istratio! +&ere t&ere is a lo+er pote!tial 0or ad(erse e00e*t a!d allo+ *&a!ges i! t?pe or *ompositio! o0 a pa*:agi!g *ompo!e!t i! t&ese situatio!s to be reported i! *&a!ges%bei!g%e00e*ted

suppleme!ts or a!!ual reports, For *o!siste!*? +it& t&e proposal, F-A &as re(ised 2e*, 4#4,30(d)(#)(ii)(a) to [["age #8$40 *&a!ge BB*o!tai!ers a!d *losure s?stemsCC to BB*o!tai!er *losure s?stems,CC "roposed 2e*, 4#4,$0(b)(2)((ii) re>uired prior appro(al 0or *&a!ges solel? a00e*ti!g a !atural produ*t, a re*ombi!a!t -NA%deri(ed protei!Epol?peptide produ*t, or a *ompleD or *o!Augate o0 a drug +it& a mo!o*lo!al a!tibod? 0or t&e 0ollo+i!g: (#) .&a!ges i! t&e (irus or ad(e!titious age!t remo(al or i!a*ti(atio! met&od(s)J (2) *&a!ges i! t&e sour*e material or *ell li!eJ a!d (4) establis&me!t o0 a !e+ master *ell ba!: or seed, (.omme!t 48) 2e(eral *omme!ts re>uested t&at F-A delete t&e re0ere!*e to BB!atural produ*ts,CC +&ile ot&ers re>uested t&at F-A pro(ide a de0i!itio! 0or !atural produ*ts, A 0e+ *omme!ts as:ed +&et&er 0erme!tatio!%based produ*ts are *o!sidered !atural produ*ts, F-A de*li!es to delete !atural produ*ts 0rom t&is pro(isio!, 6&e *&a!ges ide!ti0ied i! t&is pro(isio! are *o!sidered to be maAor *&a!ges a!d appl? e>uall? to a !atural produ*t, a re*ombi!a!t -NA%deri(ed protei!Epol?peptide, or a *ompleD or *o!Augate o0 a drug substa!*e +it& a mo!o*lo!al a!tibod?, F-A &as pro(ided a de0i!itio! o0 !atural produ*t i! t&e guida!*e e!titled BB.&a!ges to a! Appro(ed N-A or AN-ACC but de*li!es to pro(ide t&e de0i!itio! i! t&e regulatio! be*ause ad(a!*eme!ts i! te*&!olog? ma? re>uire t&at t&e de0i!itio! be re(ised, F-A &as de0i!ed !atural produ*t i! t&e guida!*e to mea! BBmaterials (e,g,, drug substa!*e, eD*ipie!ts) t&at are deri(ed 0rom pla!ts, a!imals, or mi*roorga!isms, 6&e spe*i0i* re*omme!datio!s 0or !atural produ*ts are !ot appli*able to i!orga!i* *ompou!ds (e,g,, salts, mi!erals),CC Ferme!tatio! based produ*ts are *o!sidered !atural produ*ts, (.omme!t 49) A 0e+ *omme!ts said t&at t&is pro(isio! i!*reases t&e regulator? burde! +it& respe*t to !atural produ*ts, '!e *omme!t said t&at t&ere +as !o !eed to disti!guis& a !atural produ*t, a re*ombi!a!t -NA%deri(ed protei!Epol?peptide, or a *ompleD or *o!Augate o0 a drug substa!*e +it& a mo!o*lo!al a!tibod? 0rom ot&er produ*ts, F-A disagrees +it& t&ese *omme!ts, 9!der t&e pre(ious regulatio!s at 2e*, 4#4,$0, ma!? ma!u0a*turi!g pro*ess *&a!ges 0or drug substa!*es a!d drug produ*ts, i!*ludi!g t&ose 0or a !atural produ*t, a re*ombi!a!t -NA%deri(ed protei!Epol?peptide, or a *ompleD or *o!Augate o0 a drug substa!*e +it& a mo!o*lo!al a!tibod?, re>uired a prior appro(al suppleme!t (pre(ious 2e*, 4#4,$0(b)(#)(i() a!d (b)(2)(()), F-A &as redu*ed t&e reporti!g *ategor? 0or ma!? ma!u0a*turi!g pro*ess *&a!ges relati!g to t&ese produ*ts b? allo+i!g t&em to be reported i! *&a!ges% bei!g%e00e*ted suppleme!ts or a!!ual reports, 1o+e(er, t&e t&ree *&a!ges spe*i0ied i! t&is pro(isio!, +&i*& are u!i>ue to t&ese spe*i0i* t?pes o0 drugs, are *o!sidered to &a(e a substa!tial pote!tial to ad(ersel? a00e*t t&e ide!tit?, stre!gt&, >ualit?, purit?, or pote!*? o0 t&e drug produ*t as t&e? ma? relate to t&e sa0et? or e00e*ti(e!ess o0 a drug produ*t, Virus or ad(e!titious age!t remo(al or i!a*ti(atio! pro*esses are t&e mea!s b? +&i*& F-A e!sures t&at ad(e!titious age!ts su*& as por*i!e paro(irus, i0 prese!t, are remo(ed, Failure to remo(e su*& ad(e!titious age!ts &as a sig!i0i*a!t pote!tial to ad(ersel? a00e*t publi* sa0et?, .&a!ges i! sour*e material or *ell li!e a!d establis&me!t o0 a !e+ master *ell ba!: or seed &a(e a substa!tial

pote!tial to a00e*t t&e >ualit? o0 a drug substa!*e, For eDample, a *&a!ge i! sour*e material (e,g,, spe*ies, geograp&i* regio! o0 &ar(esti!g) *ould result i! di00ere!t impurities or *o!tami!a!ts (e,g,, pesti*ides) t&a! +ere pre(iousl? see! or a *&a!ge i! pote!*?, "roposed 2e*, 4#4,$0(b)(4) stated t&at t&e appli*a!t must obtai! appro(al o0 a suppleme!t 0rom F-A be0ore distributi!g a produ*t usi!g a *&a!ge a!d spe*i0ied t&e i!0ormatio! to be i!*luded i! t&e suppleme!t, (.omme!t 30) A 0e+ *omme!ts re>uested addi!g BBas appropriateCC as 0ollo+s: BB5D*ept 0or submissio!s u!der paragrap& (e) o0 t&is se*tio!, t&e 0ollo+i!g s&all be *o!tai!ed i! t&e suppleme!t, as appropriate,CC 6&e *omme!ts said t&at !ot all listed material is rele(a!t 0or e(er? submissio!, F-A de*li!es to re(ise t&e pro(isio! as re>uested, F-A eDpe*ts t&at t&e i!0ormatio! spe*i0ied i! 2e*, 4#4,$0(b)(4)(i) t&roug& (b)(4)(() +ill be !eeded 0or almost all suppleme!tal appli*atio!s, F-A belie(es t&at t&e additio! o0 BBas appropriateCC ma? i!*orre*tl? gi(e t&e impressio! t&at t&is i!0ormatio! is !ot routi!el? !eeded a!d +ould result i! suppleme!tal appli*atio!s bei!g submitted +it& i!su00i*ie!t i!0ormatio!, F-A ma? spe*i0? i! a guida!*e t&at i!0ormatio! re>uired i! 2e*, 4#4,$0(b)(4)(i) t&roug& (b)(4)(() is !ot !eeded 0or a parti*ular *&a!ge, 1o+e(er, i! t&e abse!*e o0 su*& a re*omme!datio!, F-A +ould eDpe*t 2e*, 4#4,$0(b)(4)(i) t&roug& (b)(4)(() to be addressed i! ea*& suppleme!tal appli*atio!, 6&e i!0ormatio! i! 2e*, 4#4,$0(b)(4)((i) a!d (b)(4)((ii) is !eeded o!l? i! *ertai! situatio!s, a!d t&is is *learl? i!di*ated, "roposed 2e*, 4#4,$0(b)(4)((i) stated t&at 0or a !atural produ*t, a re*ombi!a!t -NA%deri(ed protei!Epol?peptide produ*t, or a *ompleD or *o!Augate o0 a drug +it& a mo!o*lo!al a!tibod?, rele(a!t (alidatio! proto*ols must be pro(ided i! additio! to t&e re>uireme!ts i! 2e*, 4#4,$0(b)(4)(i() a!d (b)(4)((), (.omme!t 3#) '!e *omme!t said t&at t&e re>uireme!t t&at rele(a!t (alidatio! proto*ols be pro(ided is o(erl? restri*ti(e a!d burde!some, 6&e *omme!t suggested t&at t&is stateme!t be rep&rased to state BB(alidatio! proto*ols ma? be re>uested b? t&e F-A,CC A!ot&er *omme!t re*omme!ded t&at t&is se*tio! be deleted be*ause t&ere is !o !eed 0or di00ere!t re>uireme!ts 0or t&ese produ*ts, 6&e *omme!t said t&at t&is i!0ormatio! (rele(a!t (alidatio! proto*ols) is a(ailable 0or re(ie+ o!site, 6&e *omme!t said t&at i0 F-A disagrees a!d 0eels t&at spe*ial re>uireme!ts are +arra!ted, t&e *omme!t re*omme!ded t&ese spe*i0i* details be more appropriatel? *aptured i! t&e guida!*e i!stead, 9!less ot&er+ise spe*i0ied b? F-A, (alidatio! proto*ols a!d data !eed !ot be 0iled i! t&e appli*atio!, For most produ*ts, F-A does !ot re>uire t&e submissio! o0 (alidatio! proto*ols a!d data, 1o+e(er, 0or a !atural produ*t, a re*ombi!a!t -NA%deri(ed protei!Epol?peptide, or a *ompleD or *o!Augate o0 a drug substa!*e +it& a mo!o*lo!al a!tibod?, F-A does re>uire t&e submissio! o0 (alidatio! proto*ols 0or *ertai! *riti*al ma!u0a*turi!g pro*esses u!i>ue to t&ese drug substa!*es a!d drug produ*ts, For eDample, F-A +ould eDpe*t t&e (alidatio! proto*ol 0or t&e (irus or ad(e!titious age!t remo(al or i!a*ti(atio! pro*ess to be submitted i! a! appli*atio!, F-A *urre!tl? re>uires t&is t?pe o0 i!0ormatio! to be submitted i! a! appli*atio! a!d belie(es it is !e*essar?J t&ere0ore, F-A de*li!es to re(ise t&e regulatio! as suggested, "roposed 2e*, 4#4,$0(b)(4)((ii) stated t&at 0or sterili=atio! pro*ess a!d test met&odologies, rele(a!t (alidatio! proto*ols must be pro(ided i! additio! to t&e re>uireme!ts i! 2e*, 4#4,$0(b)(4)(i() a!d (b)(4)((),

(.omme!t 32) '!e *omme!t said t&at t&e i!*lusio! o0 (alidatio! proto*ols 0or sterili=atio! assura!*e is !e+, 6&e *omme!t also said t&at submitti!g all (alidatio! data is di00ere!t 0rom data summaries pre(iousl? re>uested a!d pro(ided 0or mi*robiologi*al *o!sults, F-A disagrees +it& t&is *omme!t, 6&e i!0ormatio! o! sterilit? assura!*e F-A eDpe*ts a! appli*a!t to pro(ide i! a! appli*atio! a!d t&e 0ormat o0 t&e data are des*ribed i! t&e guida!*e [["age #8$4# e!titled BB2ubmissio! o0 -o*ume!tatio! o0 2terili=atio! "ro*ess Validatio! i! Appli*atio!s 0or 1uma! a!d Veteri!ar? -rug "rodu*ts,CC 6&e pro(isio!s o0 2e*, 4#4,$0(b)(4)((ii) are *o!siste!t +it& *urre!t F-A poli*?, (.omme!t 34) '!e *omme!t said t&at *lari0i*atio! is !eeded t&at t&e test met&odologies a!d (alidatio! proto*ols re0erred to i! t&is se*tio! are 0or t&e sterili=atio! pro*ess o!l?, F-A agrees a!d &as repla*ed BBtest met&odologiesCC +it& BBtest met&odologies related to sterili=atio! pro*ess (alidatio!CC i! !e+ 2e*, 4#4,$0(b)(4)((ii), "roposed 2e*, 4#4,$0(b)(4)((iii) stated t&at a re0ere!*e list o0 rele(a!t 2'"s, +&e! appli*able, must be *o!tai!ed i! t&e suppleme!t, (.omme!t 34) 7a!? *omme!ts re*omme!ded t&at re0ere!*e to 2'"s be deleted, 2e(eral o0 t&ese *omme!ts said t&at it +as u!*lear +&at (alue a re0ere!*e list o0 2'"s pro(ides i! t&e di(isio! re(ie+ pro*ess a!d t&at 2'"s are ge!erall? *o!sidered a .)7" issue, '!e *omme!t said t&at re0ere!*e to appropriate 2'"s is *urre!tl? re>uired o!l? as it pertai!s to sterili=atio! pro*esses a!d biologi* produ*ts, 6&e *omme!t also *o!te!ded t&at i!*lusio! o0 a re0ere!*e list o0 2'"s i! t&e submissio! 0or a!? t?pe o0 *&a!ge is !ot !e*essar?, 2e(eral *omme!ts said t&at BB+&e! appli*ableCC +as too (ague a!d o!e *omme!t re*omme!ded t&at t&e pro(isio! be re(ised to state BBA re0ere!*e list o0 rele(a!t sta!dard operati!g pro*edures (2'"s) 0or asepti* pro*essi!g operatio!s,CC A! appli*a!t is re>uired to submit a BB0ull des*riptio! o0 *o!trols used 0or t&e ma!u0a*ture, pro*essi!g, a!d pa*:i!g o0 a drugCC (se*tio! 303 o0 t&e a*t), 6&is i!0ormatio! ma? be submitted i! di00ere!t 0orms, i!*ludi!g 2'"s, /! most *ases, 2'"s do !ot i!*lude i!0ormatio! rele(a!t to t&e N-A or AN-A re(ie+, but rat&er i!0ormatio! rele(a!t to determi!i!g a! appli*a!tCs *omplia!*e +it& .)7"s, 1o+e(er, i! t&e *ase o0 a !atural produ*t, a re*ombi!a!t -NA%deri(ed protei!Epol?peptide, a *ompleD or *o!Augate o0 a drug substa!*e +it& a mo!o*lo!al a!tibod?, or a sterili=atio! pro*ess, i!0ormatio! *o!tai!ed i! 2'"s is o0te! rele(a!t to t&e re(ie+ o0 *ertai! aspe*ts o0 a! appli*atio!, F-A &as deleted proposed 2e*, 4#4,$0(b)(4)((iii) a!d re(ised 2e*, 4#4,$0(b)(4)((i) a!d (b)(4)((ii) to limit t&e !eed 0or i!0ormatio! o! 2'"s i! t&ese situatio!s, 6&e age!*? *lari0ies t&at i!0ormatio! regardi!g 2'"s is !eeded i! some *ases, F-A +is&es to emp&asi=e t&at +&ile t&e i!0ormatio! is !eeded 0or t&e appli*atio! re(ie+, it is !ot al+a?s !e*essar? to submit t&e a*tual 2'" as lo!g as t&e re>uired i!0ormatio! is pro(ided i! su00i*ie!t detail as part o0 t&e appli*atio!, '! its o+! i!itiati(e, F-A &as re(ised 2e*, 4#4,$0(b)(4)(i() b? repla*i!g t&e p&rase BBe(aluate t&e e00e*t o0 t&e *&a!ge N N N ((alidati!g t&e e00e*ts o0 t&e *&a!ge)CC +it& BBassess t&e e00e*ts o0 t&e *&a!geCC be*ause t&e term is de0i!ed at 2e*, 4#4,4(b), /! t&e i!trodu*tor? teDt o0 2e*, 4#4,$0(b)(4), F-A repla*ed t&e p&rase BBt&e 0ollo+i!g s&allCC +it& BBt&e 0ollo+i!g i!0ormatio! mustCC to add

*larit?, "roposed 2e*, 2e*, 4#4,$0(b)(4) a!d 60#,#2(b)(4) pro(ided t&at a! appli*a!t ma? re>uest a! eDpedited re(ie+ o0 a suppleme!t i0 a dela? i! ma:i!g t&e *&a!ge +ould impose a! eDtraordi!ar? &ards&ip or 0or publi* &ealt& reaso!s, (.omme!t 33) '!e *omme!t said t&at a *omplete de0i!itio! o0 eDpedited re(ie+ 0rom F-ACs BB7a!ual o0 "oli*ies a!d "ro*eduresCC (7A""s) s&ould be i!*orporated i! t&e regulatio!, '!e *omme!t said F-A s&ould *o!sider addi!g ma!dator? (e!dor%imposed *&a!ges (+it&out su00i*ie!t rea*tio! time) to t&e list o0 BB!ot reaso!abl? 0oresee!CC e(e!ts, F-A &as publis&ed t+o 7A""s o! eDpedited re(ie+%%7A"" 3420,# e!titled BBRe>uests 0or 5Dpedited Re(ie+ o0 2uppleme!ts to Appro(ed AN-As a!d AA-AsCC a!d 7A"" 34#0,4 e!titled BBRe>uests 0or 5Dpedited Re(ie+ o0 N-A .&emistr? 2uppleme!ts,CC 6&ese 7A""s *o!tai! *riteria t&at F-A uses i! gra!ti!g eDpedited re(ie+ based o! publi* &ealt& !eed, eDtraordi!ar? &ards&ip o! t&e appli*a!t, or age!*? !eed, F-A de*li!es to add t&is detailed i!0ormatio! o! i!ter!al F-A pro*edures to t&e regulatio! but e!*ourages appli*a!ts to re(ie+ t&ese 7A""s to see &o+ F-A +ould assess a re>uest 0or a! eDpedited re(ie+, 6&e 7A""s alread? i!*lude BBabrupt dis*o!ti!uatio! o0 suppl? o0 a*ti(e i!gredie!t, pa*:agi!g material, or *o!tai!er *losureCC as a! eDample o0 a! eDtraordi!ar? &ards&ip t&at +as !ot reaso!abl? 0oresee!, A! appli*a!t is re>uired to submit su00i*ie!t do*ume!tatio! to support a !eed 0or a! eDpedited re(ie+, /! t&e *ase o0 a! abrupt dis*o!ti!uatio! o0 suppl?, F-A +ill re>uire i!0ormatio! to support t&at t&e dis*o!ti!uatio! +as abrupt su*& as +&e! t&e supplier i!0ormed t&e appli*a!t o0 t&e dis*o!ti!uatio! o0 suppl?, t&e amou!t o0 supplies a(ailable i!%&ouse a!d 0rom t&e supplier, a!d t&e date t&e supplies are eDpe*ted to ru! out, F-A emp&asi=es t&at i!ade>uate pla!!i!g o! t&e part o0 a! appli*a!t is !ot a reaso! 0or F-A to eDpedite t&e re(ie+ o0 a suppleme!t based o! eDtraordi!ar? &ards&ip, (.omme!t 36) A 0e+ *omme!ts re>uested t&at F-A pro(ide 0eedba*: to t&e spo!sor o! a**epta!*e or re0usal o0 a! BBeDpedited re(ie+CC re>uest +it&i! 40 da?s, F-ACs 7A""s 3240,# a!d 34#0,4 des*ribe pro*edures 0or pro*essi!g eDpedited re(ie+ re>uests, All re>uests 0or eDpedited re(ie+ are re(ie+ed promptl?, usuall? +it&i! 40 da?s o0 re*eipt, /0 t&e re(ie+ di(isio! de!ies t&e re>uest, t&e appli*a!t +ill be *o!ta*ted, F-A de*li!es to spe*i0? t&at it +ill *o!ta*t appli*a!ts to ad(ise t&em t&at t&eir eDpedited re(ie+ re>uest &as bee! gra!ted or t&at t&e de*isio! +ill be made +it&i! 40 da?s, 1o+e(er, appli*a!ts *a! *o!ta*t t&e re(ie+ di(isio! at a!? time about t&e status o0 t&eir re>uest, 5, .&a!ges Re>uiri!g 2uppleme!t 2ubmissio! at 8east 40 -a?s "rior to -istributio! o0 t&e -rug "rodu*t 7ade 9si!g t&e .&a!ge (7oderate .&a!ges) "roposed 2e*, 4#4,$0(*)(#) re>uired t&at a suppleme!t be submitted 0or a!? *&a!ge i! t&e produ*t, produ*tio! pro*ess, >ualit? *o!trols, e>uipme!t, or 0a*ilities t&at &as a moderate pote!tial to &a(e a! ad(erse e00e*t o! t&e ide!tit?, stre!gt&, >ualit?, purit?, or pote!*? o0 t&e produ*t as t&ese 0a*tors ma? relate to t&e sa0et? or e00e*ti(e!ess o0 t&e produ*t, /0 t&e *&a!ge *o!*er!s labeli!g, #2 *opies o0 t&e 0i!al pri!ted labeli!g must be i!*luded, (.omme!t 3$) '!e *omme!t said t&at i! t&e preamble to t&e 0i!al rule, F-A s&ould 0urt&er *lari0? t&e *riteria to be used to disti!guis&

bet+ee! *&a!ges%bei!g%e00e*ted suppleme!ts t&at *a! be impleme!ted immediatel? a!d t&ose +&ere distributio! *a!!ot o**ur u!til 40 da?s a0ter F-A re*ei(es t&e suppleme!t, 6&e de*isio! b? F-A as to +&et&er a moderate *&a!ge s&ould be *lassi0ied as o!e t&at *a! be impleme!ted b? a! appli*a!t +&e! F-A re*ei(es a suppleme!t or o!e re>uiri!g suppleme!t submissio! at least 40 da?s prior to distributio! o0 t&e drug produ*t made usi!g t&e *&a!ge depe!ds o! ma!? 0a*tors, 2ome o0 t&ese 0a*tors i!*lude t&e !eed 0or F-A to (eri0? *omplia!*e status, dosage 0orm, route o0 admi!istratio!, or +&et&er, based o! F-ACs eDperie!*e, a parti*ular t?pe o0 *&a!ge is usuall? *omplete a!d pro(ides t&e proper i!0ormatio!, /t is !ot possible to pro(ide a ge!eral list o0 0a*tors *o!sidered be*ause di00ere!t 0a*tors are *o!sidered b? F-A 0or ea*& t?pe o0 *&a!ge, (.omme!t 38) A 0e+ *omme!ts re>uested *&a!ges i! t&e 0ormat o0 t&is se*tio!, '!e *omme!t said t&at suppleme!ts 0or *&a!ges bei!g e00e*ted i! 40 da?s as +ell as *&a!ges bei!g [["age #8$42 e00e*ted immediatel? are de0i!ed as BBmoderate *&a!ges,CC 6&e *omme!t as:ed +&et&er t&ere *a! be di00ere!t (erbiage 0or t&ese t+o *ategories to allo+ di00ere!tiatio!, A!ot&er *omme!t suggested t&at t&e t+o t?pes o0 *&a!ges%bei!g%e00e*ted suppleme!ts s&ould be separated i!to di00ere!t paragrap&s u!der t&is se*tio!, F-A de*li!es to re(ise t&e regulatio!s as re>uested, F-A belie(es t&at t&e 0ormat a!d terms are ade>uate a!d +ill !ot be u!*lear +&e! i!di(iduals be*ome more 0amiliar +it& t&e regulatio!s a!d t&e guida!*e, (.omme!t 39) '!e *omme!t said it re*og!i=es t&at t&e suppleme!ts 0or *&a!ges bei!g e00e*ted i! 40 da?s is a statutor? *lassi0i*atio!, 6&e *omme!t said t&at, u!0ortu!atel?, t&e pro(isio! does !ot pro(ide material ad(a!tage o(er a *&a!ges%bei!g%e00e*ted suppleme!t 0or eit&er t&e age!*? or t&e i!dustr?, espe*iall? 0or !e+ *&emi*al e!tities (N.5s), 6&e *omme!t said t&at, i!stead, t&e pro(isio! adds a 40%da? +ait period t&at does !ot *urre!tl? eDist 0or N.5s, 6&e *omme!t said t&at, 0rom F-ACs poi!t o0 (ie+, t&e re(ie+er +ill be spe!di!g t+i*e t&e amou!t o0 time o! t&e same appli*atio!, 0irst 0or a! admi!istrati(e re(ie+ 0or t&e *omplete!ess o0 t&e i!0ormatio! a!d later to a*tuall? re(ie+ t&e appli*atio!, 6&e *omme!t said t&at 0rom i!dustr?Cs poi!t o0 (ie+, t&e 40%da? +ait period does !ot !e*essaril? pro(ide i!*reased assura!*e o0 a! appro(al a*tio!, 6&e *omme!t suggested t&at a!? *&a!ge t&at *a! be t&e subAe*t o0 a *&a!ges%bei!g%e00e*ted%i!%40%da?s suppleme!t *ould Aust as easil? be re*lassi0ied as a *&a!ges%bei!g% e00e*ted suppleme!t, 6&e *omme!t said t&at t&is +ould sa(e time 0or bot& F-A a!d i!dustr?, F-A de*li!es to re(ise t&e regulatio! as re>uested, 6&e *&a!ges% bei!g%e00e*ted%i!%40%da?s pro(isio! allo+s *ertai! *&a!ges pre(iousl? re>uiri!g prior appro(al to be impleme!ted rapidl?, t&us redu*i!g t&e per*e!tage o0 suppleme!ts re>uiri!g prior appro(al, F-A re*og!i=es t&at t&e publi* &ealt& *a! be ade>uatel? prote*ted +it&out re>uiri!g appro(al o0 *ertai! ma!u0a*turi!g *&a!ges prior to distributio! o0 t&e produ*t made +it& t&e *&a!ge, F-A *o!ti!ues to belie(e t&at it is importa!t t&at su*& *&a!ges be do*ume!ted a!d (alidated so t&ere is a me*&a!ism 0or assessi!g t&e *o!se>ue!*es o0 t&e *&a!ges a!d t&at t&e age!*? appro(e su*& *&a!ges, Read? a**ess to i!0ormatio! regardi!g su*& *&a!ges t&roug& submissio! o0 a suppleme!t 40 da?s be0ore distributio! o0 t&e produ*t +ould prote*t agai!st t&e distributio! o0 u!sa0e or i!e00e*ti(e produ*ts +&ile speedi!g t&e a(ailabilit? o0 impro(ed

produ*ts, 6&e pro(isio! is i!te!ded to be!e0it t&e publi* &ealt& be*ause it permits F-A to stop or dela? a produ*t 0rom bei!g distributed to t&e publi* +&e! t&e produ*t is made +it& a maAor *&a!ge (i,e,, o!e +it& a substa!tial pote!tial to &a(e a! ad(erse e00e*t o! t&e ide!tit?, stre!gt&, >ualit?, purit?, or pote!*? o0 t&e produ*t as t&ese 0a*tors ma? relate to t&e sa0et? or e00e*ti(e!ess o0 t&e produ*t) t&at is improperl? *ategori=ed as a moderate *&a!ge, 6&e pro(isio! also permits t&e age!*? to a*t +&e! i!0ormatio! !e*essar? to demo!strate t&at t&e *&a!ge &as !ot ad(ersel? a00e*ted produ*t >ualit? is !ot pro(ided, (.omme!t 60) 2e(eral *omme!ts re*omme!ded i!serti!g BBo!l?CC i! t&e last se!te!*e to read: BB/0 t&e *&a!ge *o!*er!s o!l? labeli!g, i!*lude #2 *opies o0 0i!al pri!ted label,CC '!e *omme!t said t&at t&ere are *&a!ges t&at &a(e mi!or impa*ts o! labeli!g (0or eDample, sig!ature *&a!ges) t&at, i0 impleme!ted as stated, +ould result i! a! i!*reased regulator? burde! to pro(ide 0i!is&ed produ*t labeli!g prior to *&a!ge impleme!tatio!, F-A de*li!es to re(ise t&e regulatio! as re>uested be*ause *&a!ges% bei!g%e00e*ted suppleme!ts (+it&i! 40 da?s a!d immediatel?) t&at i!*lude bot& ma!u0a*turi!g *&a!ges a!d labeli!g *&a!ges must also i!*lude #2 *opies o0 t&e 0i!al pri!ted labeli!g, i0 appropriate, 1o+e(er, F-A &as *lari0ied t&at t&e o!l? labeli!g *&a!ges t&at re>uire submissio! o0 #2 *opies o0 0i!is&ed produ*t labeli!g at t&e time o0 suppleme!t submissio! are t&ose *lassi0ied as a moderate *&a!ge, .&a!ges%bei!g%e00e*ted ma!u0a*turi!g suppleme!ts t&at result i! labeli!g *&a!ges t&at are *lassi0ied as mi!or u!der 2e*, 4#4,$0(d) do !ot &a(e to i!*lude *opies o0 0i!al pri!ted labeli!g, 6&e 0i!al pri!ted labeli!g 0or t&ese mi!or labeli!g *&a!ges *a! be submitted i! t&e !eDt a!!ual report i! a**orda!*e +it& 2e*, 4#4,8#(b)(2)(iii), F-A &as *lari0ied 2e*, 4#4,$0(*)(#) to eDplai! +&e! 0i!al pri!ted labeli!g must be submitted b? re(isi!g t&e last se!te!*e to read BB/0 t&e suppleme!t pro(ides 0or a labeli!g *&a!ge u!der paragrap& (*)(6)(iii) o0 t&is se*tio!, #2 *opies o0 t&e 0i!al pri!ted labeli!g must be i!*luded,CC (.omme!t 6#) '!e *omme!t said t&at F-A s&ould delete t&e re>uireme!t to pro(ide #2 *opies o0 t&e 0i!al pri!ted labeli!g +it& a *&a!ges%bei!g%e00e*ted labeli!g suppleme!t, 6&e *omme!t said t&at alt&oug& t&e spe*i0ied *&a!ges ma? be submitted i! a *&a!ges%bei!g% e00e*ted suppleme!t, at times t&e? ma? !ot be impleme!ted u!til a0ter t&e submissio!, 6&e *omme!t said t&at to pri!t 0i!al labeli!g spe*i0i*all? 0or t&e *&a!ges%bei!g%e00e*ted suppleme!t is u!!e*essaril? eDpe!si(e a!d *ompli*ates t&e !ormal labeli!g pri!ti!g pro*ess, 6&e *omme!t said t&at a! alter!ati(e +ould be to submit a t?ped *op? o0 t&e labeli!g a!d submit t&e 0i!al pri!ted labeli!g i! t&e a!!ual report, F-A de*li!es to re(ise t&e regulatio! as re>uested, 7oderate labeli!g *&a!ges, +&i*& are t&ose t&at &a(e a moderate pote!tial to &a(e a! ad(erse e00e*t o! t&e ide!tit?, stre!gt&, >ualit?, purit?, or pote!*? o0 t&e produ*t as t&ese 0a*tors ma? relate to t&e sa0et? or e00e*ti(e!ess o0 t&e produ*t, *a! be impleme!ted immediatel? +it&out F-ACs prior appro(al, /! F-ACs eDperie!*e, errors t&at o**urred +&e! dra0t labeli!g +as *o!(erted to 0i!al pri!ted labeli!g &a(e made t&e 0i!al pri!ted labeli!g u!a**eptable, Also, F-A re(ie+s !ot o!l? t&e *o!te!t o0 labeli!g 0or a**ura*? but also t&e 0ormat (e,g,, la?out, si=e o0 pri!t) 0or *larit?, A t?ped *op? o0 t&e labeli!g does !ot al+a?s a**uratel? re0le*t t&e 0ormat o0 t&e 0i!al pri!ted labeli!g, 6&e labeli!g s&ould be a(ailable 0or re(ie+ at t&e time o0 submissio! +&et&er or !ot t&e appli*a!t i!te!ds to impleme!t t&e *&a!ge

immediatel? upo! F-A re*eipt o0 t&e suppleme!t, (.omme!t 62) '!e *omme!t stated t&at *urre!t 2e*, 4#4,$0(*)(4) permits a di00ere!t 0a*ilit? to be used 0or t&e produ*tio! o0 t&e drug substa!*e u!der *ertai! *o!ditio!s, 6&e *omme!t said t&at t&e proposal does !ot i!*lude t&is pro(isio!, a!d t&at F-A i!te!ds to pro(ide re*omme!datio!s *o!*er!i!g t&is i! *ertai! guida!*e do*ume!ts, 6&e *omme!t said t&at t&is pro(isio! o0 *urre!t 2e*, 4#4,$0 s&ould be retai!ed i! t&e re(ised regulatio! be*ause t&e i!dustr? is 0amiliar +it& t&e pro(isio! a!d &as used it 0or ?ears, F-A de*li!es to re(ise t&e proposal as re>uested, As stated i! t&e proposal, t&e age!*?Cs approa*& is to issue regulatio!s t&at set out broad, ge!eral *ategories o0 ma!u0a*turi!g *&a!ges a!d use guida!*e do*ume!ts to pro(ide F-ACs *urre!t t&i!:i!g o! t&e spe*i0i* *&a!ges i!*luded i! t&ose *ategories, F-A &as pro(ided re*omme!datio!s o! *&a!ges i! ma!u0a*turi!g sites i! F-ACs guida!*e e!titled BB.&a!ges to a! Appro(ed N-A or AN-A,CC "roposed 2e*, 4#4,$0(*)(2)(i) stated t&at *&a!ges re>uiri!g suppleme!t submissio! at least 40 da?s prior to distributio! o0 t&e drug produ*t made usi!g t&e *&a!ge (moderate *&a!ges) i!*ludes t&e 0ollo+i!g *&a!ge: A *&a!ge i! t&e *o!tai!er *losure s?stem t&at does !ot a00e*t t&e >ualit? o0 t&e 0i!al drug produ*t, [["age #8$44 (.omme!t 64) 7a!? *omme!ts re*omme!ded t&at t&e re>uireme!t s&ould be *&a!ged to i!*lude BBsig!i0i*a!t *&a!geCC a!dEor BBad(ersel? a00e*t,CC so t&at t&e regulatio! +ould read: BBA sig!i0i*a!t *&a!ge i! t&e *o!tai!er *losure s?stem t&at does !ot ad(ersel? a00e*t t&e >ualit? o0 t&e 0i!al drug produ*t,CC F-A de*li!es to re(ise t&e pro(isio! as re>uested, Ne+ 2e*, 4#4,$0(*)(#) alread? states t&at t&e *&a!ges t&at s&ould be 0iled i! *&a!ges%bei!g%e00e*ted suppleme!ts are t&ose t&at &a(e a moderate pote!tial to &a(e a! BBad(erse e00e*t,CC Addi!g t&e +ord BBad(ersel?CC to t&is pro(isio! is redu!da!t, Addi!g t&e term BBsig!i0i*a!tCC is also i!appropriate be*ause a!? *&a!ge, +&et&er big or small, s&ould !ot ad(ersel? a00e*t t&e >ualit? o0 t&e 0i!al drug produ*t, 2ome ma!u0a*turi!g *&a!ges &a(e a! ad(erse e00e*t o! t&e ide!tit?, stre!gt&, >ualit?, purit?, or pote!*? o0 t&e drug produ*t, /! ma!? *ases, t&e appli*a!t *&ooses !ot to impleme!t t&ese ma!u0a*turi!g *&a!ges, but sometimes t&e appli*a!t +is&es to do so, /0 a! assessme!t i!di*ates t&at a *&a!ge &as ad(ersel? a00e*ted t&e ide!tit?, stre!gt&, >ualit?, purit?, or pote!*? o0 t&e drug produ*t, t&e *&a!ge s&ould be submitted i! a prior appro(al suppleme!t, regardless o0 t&e re*omme!ded reporti!g *ategor? 0or t&e *&a!ge, For eDample, a pro*ess *&a!ge re*omme!ded 0or a *&a!ges%bei!g%e00e*ted%i!%40%da?s suppleme!t *ould *ause t&e 0ormatio! o0 a !e+ degrada!t t&at re>uires >uali0i*atio! a!dEor ide!ti0i*atio!, 6&e appli*a!t ma? belie(e t&at t&ere are !o sa0et? *o!*er!s relati!g to t&e !e+ degrada!t, 5(e! so, t&e appli*a!t s&ould submit t&is *&a!ge i! a prior appro(al suppleme!t +it& appropriate i!0ormatio! to support t&e *o!ti!ued sa0et? a!d e00e*ti(e!ess o0 t&e produ*t, -uri!g t&e re(ie+ o0 t&e prior appro(al suppleme!t, F-A +ill assess t&e impa*t o0 a!? ad(erse e00e*t o! t&e drug produ*t as t&is *&a!ge ma? relate to t&e sa0et? or e00e*ti(e!ess o0 t&e drug produ*t, (.omme!t 64) '!e *omme!t !oted a! appare!t *o!0li*t bet+ee! proposed 2e*, 4#4,$0(b)(2)((i), +&i*& stated t&at a BB*&a!ge i! a *o!tai!er *losure s?stem t&at N N N ma? a00e*t t&e impurit? pro0ile o0 t&e drug produ*tCC s&ould be 0iled i! a prior appro(al suppleme!t, a!d

proposed 2e*, 4#4,$0(*)(2)(i), +&i*& stated t&at BBa *&a!ge i! t&e *o!tai!er *losure s?stem t&at does !ot a00e*t t&e >ualit? o0 t&e 0i!al drug produ*tCC s&ould be 0iled i! a *&a!ges%bei!g%e00e*ted%i!%40%da?s suppleme!t, 6&e *omme!t said t&at t&is +ould allo+ 0or i!*o!siste!t a!d o(erl? *o!ser(ati(e i!terpretatio!s o0 +&at mig&t 0all u!der 2e*, 4#4,$0(b)(2)((i), F-A agrees a!d &as *lari0ied t&e +ordi!g i! t&ese t+o pro(isio!s, .&a!ges to proposed 2e*, 4#4,$0(b)(2)((i) +ere dis*ussed pre(iousl? u!der se*tio! ///,. o0 t&is do*ume!t, For *o!siste!*?, 2e*, 4#4,$0(*)(2)(i) +as re(ised to eD*lude *&a!ges t&at +ould be i!*luded u!der 2e*, 4#4,$0(b) a!d (d), F-A emp&asi=es t&at t&e *o!tai!er *losure s?stem a!d pa*:agi!g *ompo!e!t *&a!ges ide!ti0ied i! 2e*, 4#4,$0(b) must be 0iled i! a prior appro(al suppleme!t e(e! i0 a! appli*a!t *o!*ludes t&at t&e >ualit? o0 t&e drug produ*t &as !ot bee! ad(ersel? a00e*ted, 6&e pro(isio! &as also bee! re(ised to sta!dardi=e termi!olog?, as re>uested, b? *&a!gi!g BB0i!al drug produ*tCC to BBdrug produ*t,CC "roposed 2e*, 4#4,$0(*)(2)(ii) stated t&at *&a!ges re>uiri!g suppleme!t submissio! at least 40 da?s prior to distributio! o0 t&e drug produ*t made usi!g t&e *&a!ge (moderate *&a!ges) i!*luded t&e 0ollo+i!g *&a!ge: .&a!ges solel? a00e*ti!g a !atural protei! produ*t, a re*ombi!a!t -NA%deri(ed protei!Epol?peptide produ*t or a *ompleD or *o!Augate o0 a drug +it& a mo!o*lo!al a!tibod?, i!*ludi!g t&e 0ollo+i!g: (#) A! i!*rease or de*rease i! produ*tio! s*ale duri!g 0i!is&i!g steps t&at i!(ol(es !e+ or di00ere!t e>uipme!tJ a!d (2) repla*eme!t o0 e>uipme!t +it& t&at o0 similar, but !ot ide!ti*al, desig! a!d operati!g pri!*iple t&at does !ot a00e*t t&e pro*ess met&odolog? or pro*ess operati!g parameters, (.omme!t 63) 2e(eral *omme!ts said t&at &a(i!g spe*ial re>uireme!ts 0or t&is *ategor? o0 produ*ts represe!ts additio!al regulator? reporti!g re>uireme!ts be?o!d *urre!t pra*ti*e, A 0e+ *omme!ts re*omme!ded t&at t&is se*tio! be deleted, '!e *omme!t said t&at t&ese produ*ts s&ould !ot be regulated di00ere!tl? t&a! t&e traditio!al produ*ts, 6&e *omme!t said t&at i0 F-A disagrees a!d 0eels t&at t&is re>uireme!t is +arra!ted, t&e spe*i0i* details be *aptured i! t&e guida!*e i!stead, F-A de*li!es to re(ise t&e regulatio! as re>uested, 6&ere are spe*i0i* issues a!d *o!*er!s relati!g to t&e produ*tio! o0 protei!s t&at are !ot routi!el? asso*iated +it& ot&er *lasses o0 drugsJ t&ere0ore, F-A &as spe*i0ied *ertai! re>uireme!ts 0or protei!s, "rotei!s are sus*eptible to de!aturatio!, -e!aturatio! *a! be *aused b? *&a!ges i! s&eer 0or*e as a result o0 s*ale a!dEor e>uipme!t *&a!ges, Also, protei!s di00ere!tiall? adsorb to sur0a*es, 6&e ide!tit?, stre!gt&, >ualit?, purit?, or pote!*? o0 t&e produ*t *ould be a00e*ted b? *&a!ges i! s*ale or e>uipme!t be*ause o0 t&ese *&ara*teristi*s, (.omme!t 66) A 0e+ *omme!ts re>uested t&at F-A *lari0? +&et&er t&is se*tio! applies to drug produ*ts or drug substa!*e, F-A agrees a!d &as *lari0ied t&e proposed la!guage, +&i*& is i!te!ded to appl? to bot& drug substa!*e a!d drug produ*t, (.omme!t 6$) A 0e+ *omme!ts re*omme!ded t&at F-A delete re0ere!*e to BB!atural protei! produ*ts,CC 6&e *omme!ts also re>uested *lari0i*atio! as to +&et&er t&e de0i!itio! !atural produ*ts i!*ludes 0erme!tatio! produ*ts, F-A de*li!es to re(ise t&e regulatio! as re>uested, /ssues about s*ale a!d e>uipme!t a!d *o!*er!s asso*iated +it& protei!s are t&e same +&et&er t&e protei! is deri(ed 0rom a !atural sour*e or b? ot&er mea!s, su*& as -NA te*&!olog?, 6&e de0i!itio! o0 !atural produ*ts +as

dis*ussed i! *omme!t !umber 48 o0 t&is do*ume!t, Natural protei!s are a subset o0 !atural produ*ts, (.omme!t 68) '!e *omme!t said t&at t&is se*tio! applies to bot& a! i!*rease a!d de*rease i! bat*& si=e i!(ol(i!g !e+ e>uipme!t, 6&e *omme!t as:ed +&et&er !e+ e>uipme!t i!*ludes repla*eme!t e>uipme!t, F-A agrees a!d &as *lari0ied t&e proposed la!guage, 6&e p&rase BB!e+ or di00ere!t e>uipme!tCC &as bee! repla*ed b? t&e p&rase BBdi00ere!t e>uipme!t,CC -i00ere!t e>uipme!t *a! i!*lude !e+ models, *&a!ges i! *apa*it?, *o!stru*tio! materials (e,g,, glass%li!ed ta!:s to stai!less steel), e>uipme!t desig!, a!dEor e>uipme!t operati!g pri!*iples, /0 a s*ale *&a!ge i!(ol(es repla*i!g e>uipme!t +it& e>uipme!t t&at is ide!ti*al i! all *riti*al aspe*ts (e,g,, same model a!d *apa*it?, same *o!stru*tio! materials), t&is is a t?pe o0 *&a!ge t&at *ould be reported i! a! a!!ual report, For t&e same reaso!s, F-A is re(isi!g 2e*, 60#,#2(*)(2)(ii) to delete t&e +ord BB!e+,CC (.omme!t 69) A 0e+ *omme!ts re>uested *lari0i*atio! o0 BB0i!is&i!g steps,CC F-A de*li!es to re(ise t&e regulatio!s to pro(ide *lari0i*atio! o0 t&e term BB0i!is&i!g steps,CC /! ge!eral, 0i!is&i!g steps are *o!sidered t&ose steps i! t&e ma!u0a*turi!g pro*ess +&ere t&e stabilit?, or t&e propert? a!d per0orma!*e, o0 a protei! produ*t is less li:el? to be a00e*ted b? *&a!ges i! s*ale or e>uipme!t, 6&e steps i! a ma!u0a*turi!g pro*ess t&at +ould be *o!sidered 0i!is&i!g steps depe!d o! t&e ma!u0a*turi!g pro*ess a!d t&e spe*i0i* protei! bei!g ma!u0a*tured, A parti*ular ma!u0a*turi!g step ma? be [["age #8$44 *o!sidered a 0i!is&i!g step 0or o!e produ*t but !ot 0or a!ot&er, A! appli*a!t is e!*ouraged to dis*uss +it& F-A +&i*& steps +ould be *o!sidered 0i!is&i!g steps 0or a parti*ular produ*t a!d pro*ess, 6&is dis*ussio! s&ould o**ur as earl? i! t&e pro*ess as possible, i!*ludi!g duri!g i!(estigatio!al !e+ drug (/N-) meeti!gs, (.omme!t $0) A 0e+ *omme!ts re>uested *lari0i*atio! o0 t&e di00ere!*e bet+ee! e>uipme!t t&at is BBsimilar but !ot ide!ti*al,CC proposed as a *&a!ges%bei!g%e00e*ted%i!%40%da?s suppleme!t, a!d t&e 29"A. termi!olog? o0 e>uipme!t o0 t&e BBsame desig! a!d operati!g pri!*iple,CC +&i*& is alread? de0i!ed i! t&e 29"A. guida!*es a!d t&e @u!e #999 proposal as a! a!!ual report *&a!ge, 6&e *omme!t said t&at t&e di00ere!*e is !ot readil? appare!t a!d ma? lead to (ar?i!g i!terpretatio!s o0 regulator? submissio! re>uireme!ts, 6&e *omme!ts said t&at 0or e>uipme!t *&a!ges t&at are o0 di00ere!t operati!g pri!*iple a!d desig!, F-A s&ould *o!sider t&e maAor *&a!ge *ategor?, a!d 0or e>uipme!t *&a!ges t&at are o0 t&e same operati!g pri!*iple but di00ere!t desig!, F-A s&ould *o!sider t&e moderate *&a!ge *ategor?, F-A agrees a!d &as *lari0ied t&e re>uireme!t b? repla*i!g t&e p&rase BBo0 similar, but !ot ide!ti*al, desig! a!d operati!g pri!*iple t&atCC +it& t&e p&rase BBt&at o0 a di00ere!t desig! t&at,CC 5>uipme!t o0 a di00ere!t desig! ma? or ma? !ot &a(e a di00ere!t operati!g pri!*iple, (.omme!t $#) '!e *omme!t suggested i!serti!g t&e +ord BBad(ersel?CC be0ore BBa00e*tCC to read: BBRepla*eme!t o0 e>uipme!t +it& t&at o0 similar, but !ot ide!ti*al, desig! a!d operati!g pri!*iple t&at does !ot ad(ersel? a00e*t t&e pro*ess met&odolog? or pro*ess operati!g parameters,CC 6&e *omme!t said t&at repla*eme!t o0 e>uipme!t t&at does !ot ad(ersel? a00e*t t&e pro*ess met&odolog? or operati!g parameters a!dEor positi(el? a00e*ts pro*ess met&odolog? or operati!g parameters

s&ould be reported as a mi!or *&a!ge, F-A de*li!es to re(ise t&e pro(isio! as re>uested, Ne+ 2e*, 4#4,$0(*)(#) alread? states t&at t&e *&a!ges t&at s&ould be 0iled i! *&a!ges%bei!g%e00e*ted suppleme!ts are t&ose t&at &a(e a moderate pote!tial to &a(e a! BBad(erse e00e*t,CC Addi!g t&e +ord BBad(ersel?CC to t&is pro(isio! is redu!da!t, "roposed 2e*, 4#4,$0(*)(4) stated t&at pe!di!g appro(al o0 t&e suppleme!t b? F-A, eD*ept as pro(ided i! paragrap& (*)(6), distributio! o0 t&e produ*t made usi!g t&e *&a!ge ma? begi! !ot less t&a! 40 da?s a0ter re*eipt o0 t&e suppleme!t b? F-A, 6&e i!0ormatio! listed i! 2e*, 4#4,$0(b)(4)(i) t&roug& (b)(4)((iii) must be *o!tai!ed i! t&e suppleme!t, (.omme!t $2) '!e *omme!t said t&at t&e last se!te!*e i! 2e*, 4#4,$0(*)(4) s&ould be re(ised to read: BB6&e i!0ormatio! listed i! paragrap&s (b)(4)(i) t&roug& (b)(4)((ii) N N NCC be*ause *urre!tl? .)7" (alidatio! i!0ormatio!, i!*ludi!g a re0ere!*e to appropriate 2'"s, is re>uired to be submitted i! appli*atio!s o!l? as it pertai!s to sterili=atio! pro*esses, F-A &as re(ised 2e*, 4#4,$0(*)(4) to ma:e it *o!siste!t +it& t&e *&a!ges made i! 2e*, 4#4,$0(b)(4) to address t&e *o!*er!s raised b? t&e *omme!t (see dis*ussio! i! *omme!t !umbers 30 t&roug& 34 i! se*tio! ///,. o0 t&is do*ume!t) a!d also to *lari0? t&e term BBprodu*t,CC (.omme!t $4) '!e *omme!t said t&at a time li!e a!d dispute resolutio! pro*ess !eeds to be de0i!ed b? regulatio! or guida!*e i! *ase o0 disputes regardi!g t&e t?pe o0 i!0ormatio! !eeded to support a *&a!ge, F-A does !ot belie(e it is !e*essar? to re(ise proposed 2e*, 4#4,$0 to address t&is issue, A*tio!s b? re(ie+ers or ot&er .e!ter o00i*ials ma? be appealed t&roug& t&e appeals me*&a!ism alread? i! pla*e i! ea*& .e!ter to t&e .e!ter -ire*tor a!d, ultimatel?, to t&e .ommissio!er o0 Food a!d -rugs, -ispute resolutio! pro*edures are detailed i! 2# .FR #0,$3 a!d 2# .FR 4#2,48, a!d 2e*, 2e*, 4#4,#04 a!d 60#,#2(&), F-A &as also pro(ided additio!al i!0ormatio! i! guida!*e do*ume!ts, /! t&e Federal Register o0 7ar*& $, 2000 (63 FR #20#9), F-A issued a guida!*e e!titled BBFormal -ispute Resolutio!J Appeals Abo(e t&e -i(isio! 8e(el,CC 6&e guida!*e des*ribes t&e me*&a!ism 0or resolutio! o0 pro*edural (i!*ludi!g admi!istrati(e) a!d s*ie!ti0i* disputes i! .-5R a!d .;5R, "roposed 2e*, 4#4,$0(*)(3) stated t&at t&e appli*a!t must !ot distribute t&e produ*t made usi!g t&e *&a!ge i0, +it&i! 40 da?s 0ollo+i!g F-ACs re*eipt o0 t&e suppleme!t, F-A i!0orms t&e appli*a!t t&at eit&er: (#) 6&e *&a!ge re>uires appro(al prior to distributio! o0 t&e produ*t i! a**orda!*e +it& paragrap& (b)J or (2) a!? o0 t&e i!0ormatio! re>uired u!der 2e*, 4#4,$0(*)(4) is missi!g, 6&e appli*a!t must !ot distribute t&e produ*t made usi!g t&e *&a!ge u!til F-A determi!es t&at *omplia!*e is a*&ie(ed, (.omme!t $4) '!e *omme!t said t&at i0 F-A determi!es +it&i! 40 da?s o0 re*eipt o0 t&e suppleme!t t&at t&e *&a!ge is properl? submitted but t&e re>uired i!0ormatio! is i!*omplete, t&e appli*a!t +ould be re>uired to suppl? t&e missi!g i!0ormatio! a!d +ait u!til F-A determi!es t&at t&e suppleme!t is i! *omplia!*e be0ore distributi!g t&e produ*t, 6&e *omme!t *o!te!ded t&at as lo!g as t&e 0irm submits t&e data re>uested b? F-A, it s&ould be able to go to mar:et a!d !ot +ait u!til F-A determi!es t&at t&e suppleme!t is BBi! *omplia!*e,CC +&i*& *ould ta:e mo!t&s si!*e F-A is !ot !o+ bou!d b? t&e 40%da? re>uireme!t, F-A agrees a!d &as *lari0ied t&e re>uireme!t based o! t&is *omme!t, F-A &as re(ised 2e*, 4#4,$0(*)(3) to pro(ide t&at, i! t&e *ase o0

missi!g i!0ormatio!, t&e appli*a!t must !ot distribute t&e drug produ*t u!til t&e suppleme!t &as bee! ame!ded to pro(ide t&e missi!g i!0ormatio!, (.omme!t $3) '!e *omme!t as:ed, +&e! additio!al i!0ormatio! is pro(ided, +&et&er F-ACs determi!atio! o0 *omplia!*e +it& t&e re>uireme!ts o0 t&is se*tio! is e>ui(ale!t to a! appro(al o0 t&e suppleme!t, F-A &as re(ised t&is se*tio!, a!d t&is *omme!t is !o lo!ger appli*able, 1o+e(er, F-A *lari0ies t&at it se!ds a 0ormal letter to a! appli*a!t stati!g t&at a parti*ular suppleme!t is appro(ed a!d t&at !o ot&er *ommu!i*atio! 0rom F-A s&ould be *o!strued as a! appro(al, "roposed 2e*, 4#4,$0(*)($) stated t&at i0 t&e age!*? disappro(es t&e suppleme!tal appli*atio!, it ma? order t&e ma!u0a*turer to *ease distributio! o0 t&e drug produ*ts made +it& t&e ma!u0a*turi!g *&a!ge, (.omme!t $6) A 0e+ *omme!ts re*omme!ded t&at F-A repla*e t&is re>uireme!t +it& t&e 0ollo+i!g: BB/0 F-A later determi!es t&at t&e suppleme!tal appli*atio! is !ot immediatel? appro(able, t&e age!*? +ill +or: +it& t&e appli*a!t to resol(e all issues a!d to assure t&e *o!ti!ued a(ailabilit? o0 t&e drug,CC A!ot&er *omme!t re*omme!ded t&at t&is re>uireme!t be limited to o!l? t&ose *ases +&ere a! ad(erse e00e*t o! sa0et? or e00i*a*? *a! be demo!strated, '!e *omme!t said t&at alt&oug& t&is is t&e la!guage *o!tai!ed i! se*tio! 306A(d)(4)(;)(iii) o0 t&e a*t, it is a re(ersal o0 lo!g%time F-A poli*? o0 allo+i!g 0irms to respo!d to de0i*ie!*ies a!d get t&e suppleme!t appro(ed +it&out i!ter0eri!g +it& distributio!, 6&e *omme!t said t&at F-A s&ould *o!ti!ue its lo!g%sta!di!g poli*?, F-A de*li!es to re(ise t&e pro(isio! as re>uested, 6&e regulatio! is *o!siste!t +it& se*tio! 306A(d)(4)(;)(iii) o0 t&e a*t, 6&ere ma? be some i!sta!*es +&ere F-A determi!es, a0ter t&e drug produ*t made usi!g t&e *&a!ge &as bee! distributed, t&at t&e i!0ormatio! submitted i! t&e suppleme!t 0ails to ade>uatel? demo!strate t&e *o!ti!ued sa0et? a!d [["age #8$43 e00e*ti(e!ess o0 t&e drug produ*t, /! su*& *ases, F-A +ill ma:e all possible e00orts to resol(e problems +it& t&e appli*a!t *o!*er!i!g t&e suppleme!t submissio! +it&out re>uiri!g t&e remo(al o0 t&e drug produ*t 0rom t&e mar:etpla*e, /! *ases +&ere F-A determi!es t&at t&ere ma? be a da!ger to publi* &ealt& due to *o!ti!ued mar:eti!g o0 t&e drug produ*t or +&e! F-A determi!es t&at t&e issues ma? !ot ot&er+ise be resol(ed, t&e age!*? ma? re>uire t&at t&e appli*a!t *ease distributio! o0 t&e drug produ*t made usi!g t&e *&a!ge or t&at t&e produ*t be remo(ed 0rom distributio! pe!di!g resolutio! o0 t&e issues related to t&e *&a!ge, (.omme!t $$) '!e *omme!t said t&at i0 F-A disappro(es a *&a!ges% bei!g%e00e*ted%i!%40%da?s suppleme!t, t&e spo!sor s&ould be !oti0ied +it&i! 40 da?s o0 t&is submissio! as stated i! 2e*, 4#4,$0(*)(3)(ii), F-A de*li!es to re(ise t&e regulatio! based o! t&is *omme!t, F-A i!te!ds duri!g t&e 40%da? period to 0o*us its re(ie+ o! determi!i!g +&et&er t&e appli*a!t reported t&e *&a!ge usi!g t&e appropriate me*&a!ism a!d, i0 so, +&et&er a!? o0 t&e re>uired i!0ormatio! is missi!g, F-A i!te!ds to per0orm t&e substa!ti(e re(ie+ o0 t&e submissio! as eDpeditiousl? as possible, but t&is is u!li:el? to o**ur +it&i! 40 da?s o0 re*eipt o0 t&e suppleme!t, F, .&a!ges For K&i*& -istributio! o0 t&e -rug "rodu*t /!(ol(ed 7a? .omme!*e K&e! F-A Re*ei(es a 2uppleme!t (7oderate .&a!ges)

"roposed 2e*, 4#4,$0(*)(6) stated t&at F-A ma? desig!ate a *ategor? o0 *&a!ges 0or +&i*& t&e &older o0 a! appro(ed appli*atio! ma:i!g su*& a *&a!ge ma? begi! distributio! o0 t&e drug upo! re*eipt b? F-A o0 a suppleme!tal appli*atio! 0or t&e *&a!ge, 6&ese *&a!ges i!*lude, u!der 2e*, 4#4,$0(*)(6)(i), a! additio! to a spe*i0i*atio! or *&a!ges i! t&e met&ods or *o!trols to pro(ide i!*reased assura!*e t&at t&e drug +ill &a(e t&e *&ara*teristi*s o0 ide!tit?, stre!gt&, >ualit?, purit?, or pote!*? t&at it purports or is represe!ted to possess, (.omme!t $8) 2e(eral *omme!ts re*omme!ded t&at a! additio! to a spe*i0i*atio! or *&a!ge i! t&e met&ods or *o!trols to pro(ide i!*reased assura!*e t&at t&e drug +ill &a(e t&e *&ara*teristi*s o0 ide!tit?, stre!gt&, >ualit?, purit?, or pote!*? t&at it purports or is represe!ted to possess s&ould be *o!sidered to &a(e a mi!imal pote!tial to &a(e a! ad(erse e00e*t a!d s&ould be allo+ed to be 0iled i! t&e a!!ual report, F-A de*li!es to re(ise t&e regulatio! as re>uested, F-A &as ide!ti0ied *ertai! spe*i0i* *&a!ges t&at pro(ide i!*reased assura!*e t&at ma? be submitted i! a! a!!ual report, su*& as t&e tig&te!i!g o0 a! a**epta!*e *riterio!, 1o+e(er, t&is is a ge!eral pro(isio! a!d t&e assessme!t o0 +&et&er or !ot a *&a!ge pro(ides BBi!*reased assura!*eCC is subAe*ti(e a!d must be supported b? studies a!d data, as appropriate, F-A must &a(e t&e opportu!it? to *o!*ur +it& a! appli*a!tCs assessme!t t&at a *&a!ge pro(ides BBi!*reased assura!*eCC i! a timel? ma!!er, Reporti!g o0 su*& *&a!ges i! a! a!!ual report +ould !ot a00ord F-A t&is opportu!it? be*ause a *&a!ge ma? be i! e00e*t 0or up to a ?ear be0ore F-A +ould &a(e t&e opportu!it? to re(ie+ t&e *&a!ge, .&a!ges t&at do !ot !e*essaril? pro(ide i!*reased assura!*e ma? be a t?pe o0 *&a!ge t&at must be submitted i! a *&a!ges%bei!g%e00e*ted% i!%40%da?s suppleme!t or a suppleme!t t&at re>uires appro(al prior to distributio! o0 t&e produ*t made usi!g t&e *&a!ge, (.omme!t $9) '!e *omme!t re*omme!ded t&at F-A *&a!ge BBadditio! to a spe*i0i*atio! or *&a!ges i! t&e met&ods or *o!trolsCC to BBadditio! to a spe*i0i*atio! or *&a!ges i! t&e tests, a!al?ti*al pro*edures, or a**epta!*e *riteria,CC F-A de*li!es to re(ise t&e regulatio! as re>uested, 6&e p&rase BBmet&ods or *o!trolsCC is !ot used b? F-A to mea! tests, a!al?ti*al pro*edures, or a**epta!*e *riteria, 7et&ods a!d *o!trols relate to t&e ma!u0a*turi!g pro*ess, "roposed 2e*, 4#4,$0(*)(6)(ii) i!*luded t&e 0ollo+i!g *ategor?: A *&a!ge i! t&e si=e a!dEor s&ape o0 a *o!tai!er 0or a !o!sterile drug produ*t, eD*ept 0or solid dosage 0orms, +it&out a *&a!ge i! t&e labeled amou!t o0 produ*t or 0rom o!e *o!tai!er *losure s?stem to a!ot&er, (.omme!t 80) A 0e+ *omme!ts re*omme!ded addi!g BBa sterile drug produ*t, or a sterile drug substa!*eCC to read BBN N N *o!tai!er 0or a !o!sterile drug produ*t, eD*ept 0or solid dosage 0orms, a sterile drug produ*t, or a sterile drug substa!*e +it&out a *&a!ge,CC 6&e *omme!ts said t&at *&a!ges i! t&e si=e a!d s&ape o0 *o!tai!ers 0or sterile drug substa!*es or sterile drug produ*ts &a(e o!l? moderate pote!tial impa*t, 6&e *omme!ts said t&at t&is is espe*iall? true +&e! t&e !ature o0 t&e si=eEs&ape *&a!ges are (er? mi!or, as is o0te! t&e *ase +&e! suppliers ma:e mi!ute adAustme!ts i! t&eir pa*:agi!g *ompo!e!ts, F-A de*li!es to re(ise t&e regulatio! as re>uested, As dis*ussed i! t&e *omme!ts 0or 2e*, 4#4,$0(b)(2)(iii) i! se*tio! ///,. o0 t&is do*ume!t, sterilit? o0 drug produ*ts or drug substa!*es is a 0u!dame!tal a!d esse!tial >ualit? attribute o0 t&ese drugs a!d is a *riti*al aspe*t o0 t&e sa0et? assessme!t, .&a!ges i! t&e *o!tai!er *losure s?stem, e(e! i0 mi!imal, ma? a00e*t t&e sterilit? assura!*e o0

t&e drug produ*t a!d are a maAor *&a!ge, For sterile drug substa!*es, t&e e00e*t o0 *&a!ges i! t&e si=e a!dEor s&ape o0 t&e *o!tai!er *losure s?stem is *o!sidered b? F-A to be o0 lo+er ris: be*ause o0 t&e di00ere!*es i! pro*edures 0or sterili=i!g drug substa!*es a!d drug produ*ts, but t&e ris: is still &ig&er t&a! 0or !o!sterile produ*ts, 6&ere0ore, F-A de*li!es to spe*i0? i! t&e regulatio!s t&at t&ese *&a!ges *a! be submitted i! a *&a!ges%bei!g%e00e*ted suppleme!t, Additio!al i!0ormatio! o! *&a!gi!g *o!tai!er *losure s?stems 0or sterile drug substa!*es or drug produ*ts is i!*luded i! t&e guida!*e BB.&a!ges to a! Appro(ed N-A or AN-A,CC (.omme!t 8#) 2e(eral *omme!ts pertai!ed to t&e p&rase BB+it&out a *&a!ge i! t&e labeled amou!t o0 produ*t,CC 6&e *omme!ts said t&at proportio!al *&a!ges (i,e,, ratio o0 t&e amou!t o0 drug produ*t to si=e o0 *o!tai!er) are !ot eDpe*ted to ad(ersel? a00e*t t&e drug produ*t, a!d o!e o0 t&ese *omme!ts re*omme!ded t&at F-A s&ould add BBa!d a *&a!ge i! t&e labeled amou!t o0 produ*t as lo!g as t&e si=e o0 t&e *o!tai!erE*losure s?stem is *&a!ged proportio!all?,CC 't&er *omme!ts said t&at a *orrespo!di!g *&a!ge i! 0ill >ua!tit?, alo!g +it& a *&a!ge i! *o!tai!er si=e, is eDpe*ted a!d readil? a**eptable a!d t&at it is illogi*al to assume t&at a *&a!ge i! t&e amou!t o0 produ*t +ould prese!t a!? greater ris: t&a! a *&a!ge i! *o!tai!er si=e, F-A de*li!es to re(ise t&e regulatio! as re>uested or +it& similar la!guage i!*luded i! 2e*, 4#4,$0(d)(2)(i(), 6&e p&rase BBlabeled amou!t o0 produ*tCC re0ers to t&e total >ua!tit? o0 drug produ*t (e,g,, milliliters, grams), F-A &as i!*luded t&e p&rase BB+it&out a *&a!ge i! t&e labeled amou!t o0 produ*tCC be*ause o0 t&e age!*?Cs *o!*er! about t&e proli0eratio! o0 u!it%o0%use *o!tai!ers t&at ma? i!(ite t&e misuse o0 drug produ*ts, A u!it%o0%use *o!tai!er is o!e t&at *o!tai!s a spe*i0i* >ua!tit? o0 a drug produ*t a!d t&at is i!te!ded to be dispe!sed to t&e patie!t +it&out 0urt&er modi0i*atio! eD*ept 0or t&e additio! o0 appropriate labeli!g, Alt&oug& 0e+ i! !umber, some drug produ*ts ma? *ause li0e%t&reate!i!g side e00e*ts, su*& as perma!e!t li(er damage, i0 used 0or lo!ger periods o0 time t&a! re*omme!ded i! t&e labeli!g, 2imilarl?, *ertai! drugs must be used 0or a spe*i0i* le!gt& o0 time (e,g,, a!tibioti*s) or t&e treatme!t ma? be i!e00e*ti(e, 9!it%o0% [["age #8$46 use *o!tai!ers t&at *o!tai! a >ua!tit? o0 drug produ*t t&at i!(ite u!deruse or o(eruse o0 t&e produ*t as re*omme!ded i! t&e labeli!g ma? be a publi* &ealt& ris:, F-A *o!siders *&a!ges i! t&e labeled amou!t o0 a !o!sterile drug produ*t i! a u!it%o0%use *o!tai!er to &a(e a moderate pote!tial to ad(ersel? a00e*t t&e sa0et? a!d e00i*a*? o0 t&e drug produ*t a!d eDpe*ts t&at t&ese *&a!ges +ould !ormall? be submitted i! a *&a!ges%bei!g%e00e*ted%i!%40%da?s suppleme!t u!der 2e*, 4#4,$0(*)(2)(i), 6&is +ould gi(e F-A a! opportu!it? to raise a *o!*er! about a pa*:age prese!tatio! prior to distributio! o0 t&e produ*t, F-ACs *o!*er! is less +&e! t&e BBlabeled amou!t o0 produ*tCC is *&a!ged i! multiple%u!it *o!tai!ers 0or !o!sterile drug produ*ts, F-A *o!siders t&is *&a!ge to &a(e t&e same le(el o0 ris: as a *&a!ge i! t&e si=e a!dEor s&ape o0 t&e *o!tai!er, A multiple%u!it *o!tai!er is a *o!tai!er t&at permits +it&dra+al o0 su**essi(e portio!s o0 t&e *o!te!ts +it&out *&a!gi!g t&e stre!gt&, >ualit?, or purit? o0 t&e remai!i!g portio!, 6&is t?pe o0 *o!tai!er is !ot 0or dire*t distributio! to patie!ts, but is used b? &ealt& *are pra*titio!ers +&o dispe!se t&e drug i! smaller amou!ts i! a**orda!*e +it& a p&?si*ia!Cs

i!stru*tio!s, K&ile F-A de*li!es to re(ise t&e regulatio!s to spe*i0? t&e disti!*tio! bet+ee! u!it%o0%use a!d multiple%use *o!tai!ers be*ause o0 t&e *ompleDit? o0 t&e issue, F-A +ill address t&is issue +&e! re(isi!g t&e guida!*es BB.&a!ges to a! Appro(ed N-A or AN-ACC a!d BB.&a!ges to a! Appro(ed Appli*atio! 0or 2pe*i0ied ;iote*&!olog? a!d 2pe*i0ied 2?!t&eti* ;iologi*al "rodu*ts,CC "roposed 2e*, 4#4,$0(*)(6)(iii)(.) i!*luded as a moderate *&a!ge a *&a!ge i! t&e labeli!g to add or stre!gt&e! a! i!stru*tio! about dosage a!d admi!istratio! t&at is i!te!ded to i!*rease t&e sa0e use o0 t&e produ*t, (.omme!t 82) '!e *omme!t said t&at F-A s&ould repla*e t&e +ords BBa!d admi!istratio!CC i! 2e*, 4#4,$0(*)(6)(iii)(.) +it& t&e +ords BBadmi!istratio! a!d storage,CC F-A de*li!es to re(ise t&e regulatio! as re>uested, 6&e additio! or stre!gt&e!i!g o0 a storage stateme!t *ould re0le*t a *&a!ge i! t&e eDpe*ted *&ara*teristi*s or >ualit? o0 a drug produ*t a!d +ould be a maAor *&a!ge, Also, o!e o0 F-ACs obAe*ti(es is to &a(e t&e same drug produ*ts stored similarl? to a(oid *o!0usio! i! t&e mar:etpla*e, F-A +ould !eed to re(ie+ t&e proposed *&a!ge prior to impleme!tatio! to determi!e i0: (#) 6&e *&a!ge is appropriate, (2) a!? *&a!ges i! produ*t >ualit? *ausi!g t&e labeli!g *&a!ge sig!i0i*a!tl? impa*t t&e sa0et? or e00e*ti(e!ess o0 t&e drug, a!d (4) t&ere are ot&er issues t&at !eed to be addressed eit&er o! a! i!di(idual *ompa!? basis or globall?, "roposed 2e*, 4#4,$0(*)(6)(iii)(5) i!*luded as a moderate *&a!ge a!? ot&er *&a!ge spe*i0i*all? re>uested b? F-A, (.omme!t 84) '!e *omme!t said t&at a!? *&a!ges made to t&e labeli!g t&at are spe*i0i*all? re>uired b? t&e F-A s&ould be reportable i! t&e a!!ual report, F-A de*li!es to re(ise t&e @u!e #999 proposal as re>uested but &as re(ised 2e*, 4#4,$0(*)(6)(iii)(5) to pro(ide *lari0i*atio!, As stated i! t&e @u!e #999 proposal, F-A proposed addi!g t&is se*tio! to allo+ labeli!g *&a!ges t&at !ormall? re>uire prior appro(al to be submitted i! a *&a!ges%bei!g%e00e*ted suppleme!t +&e! F-A spe*i0i*all? re>uests t&e *&a!ge, F-A &as *lari0ied 2e*, 4#4,$0(*)(6)(iii)(5) as 0ollo+s: BBA!? labeli!g *&a!ge !ormall? re>uiri!g a suppleme!t submissio! a!d appro(al prior to distributio! o0 t&e drug produ*t t&at F-A spe*i0i*all? re>uests be submitted u!der t&is pro(isio!,CC F-A &as also *lari0ied 2e*, 60#,#2(0)(2)(i)(5) as 0ollo+s: BBA!? labeli!g *&a!ge !ormall? re>uiri!g a suppleme!t submissio! a!d appro(al prior to distributio! o0 t&e produ*t t&at F-A spe*i0i*all? re>uests be submitted u!der t&is pro(isio!,CC ), .&a!ges 6o ;e -es*ribed i! t&e NeDt A!!ual Report (7i!or .&a!ges) "roposed 2e*, 4#4,$0(d)(#) re>uired t&at *&a!ges i! t&e produ*t, produ*tio! pro*ess, >ualit? *o!trols, e>uipme!t, or 0a*ilities t&at &a(e a mi!imal pote!tial to &a(e a! ad(erse e00e*t o! t&e ide!tit?, stre!gt&, >ualit?, purit?, or pote!*? o0 t&e produ*t as t&ese 0a*tors ma? relate to t&e sa0et? or e00e*ti(e!ess o0 t&e produ*t must be do*ume!ted b? t&e appli*a!t i! t&e !eDt a!!ual report i! a**orda!*e +it& 2e*, 4#4,8#(b)(2), "roposed 2e*, 4#4,$0(d)(2)(i) re>uired t&e 0ollo+i!g *&a!ge to be do*ume!ted i! t&e !eDt a!!ual report: A!? *&a!ge made to *ompl? +it& a! o00i*ial *ompe!dium t&at is *o!siste!t +it& F-A re>uireme!ts a!d pro(ides i!*reased assura!*e t&at t&e drug +ill &a(e t&e *&ara*teristi*s o0 ide!tit?, stre!gt&, >ualit?, purit?, or pote!*? t&at it purports or is represe!ted to possess,

F-A re*ei(ed #8 *omme!ts o! t&is pro(isio!, Fi0tee! *omme!ts re>uested t&at F-A *&a!ge t&is re>uireme!t to read BBA!? *&a!ge to *ompl? +it& a! o00i*ial *ompe!diumJCC t+o *omme!ts re>uested t&at F-A *&a!ge t&is re>uireme!t to read BBA!? *&a!ge made to *ompl? +it& a! o00i*ial *ompe!dium t&at is *o!siste!t +it& F-A re>uireme!tsJCC a!d o!e *omme!t did !ot pro(ide a suggested re(isio!, F-A de*li!es to re(ise t&e pro(isio! as re>uested i! t&e *omme!ts but &as re(ised t&e pro(isio! to pro(ide 0urt&er *lari0i*atio!, 6&e basis 0or t&is de*isio! is dis*ussed belo+, 6&e maAorit? o0 t&e *omme!ts pertai!ed to drugs regulated u!der, a!d t&e statutor? re>uireme!ts regardi!g o00i*ial *ompe!dia i!*luded i!, t&e a*t, 6&ere0ore, F-A &as respo!ded to t&e *omme!ts 0rom t&is perspe*ti(e, F-A &as made *orrespo!di!g *&a!ges to 2e*, 60#,#2(*) a!d (d) 0or biologi*s regulated u!der se*tio! 43# o0 t&e "12 A*t, (.omme!t 84) 7a!? *omme!ts said t&at t&e proposal to re>uire suppleme!tal appli*atio!s 0or some *&a!ges t&at are made to *ompl? +it& a! o00i*ial *ompe!dium 0ails to re*og!i=e t&e legal status o0 t&e 92"E NF u!der t&e a*t a!d u!dermi!es t&e aut&orit? o0 t&e 92"ENF as o00i*ial *ompe!dia a!d sour*es o0 sta!dards, '!e *omme!t stated t&at i0 a drug produ*t meets *ompe!dial re>uireme!ts, it is *o!sidered u!adulterated u!der t&e a*t, A!ot&er *omme!t stated t&at t&e 92" is t&e respo!sible *ompe!dial bod? 0or regulator? spe*i0i*atio!s, 9!der se*tio! 30#(b) o0 t&e a*t (2# 9,2,., 43#(b)), a drug t&at is re*og!i=ed i! a! o00i*ial *ompe!dium ma? be *o!sidered adulterated i0 its stre!gt& di00ers 0rom, or its >ualit? or purit? 0all belo+, t&e sta!dards set i! t&e *ompe!dium, -etermi!atio!s o0 adulteratio! u!der t&is pro(isio! o0 t&e a*t must be made i! a**orda!*e +it& t&e a!al?ti*al pro*edures set i! t&e *ompe!dium, K&e! t&ere is !o a!al?ti*al pro*edure pres*ribed i! t&e *ompe!dium or t&e tests pres*ribed i! t&e *ompe!dium are i!su00i*ie!t, t&e age!*? *a! 0ollo+ t&e pro*ess outli!ed i! t&e statute a!d issue a regulatio! to pro(ide a! appropriate a!al?ti*al pro*edure, As stated i! t&e a*t, !o drug de0i!ed i! a! o00i*ial *ompe!dium +ill be *o!sidered adulterated u!der se*tio! 30#(b) o0 t&e a*t be*ause its stre!gt& di00ers 0rom, or its >ualit? or purit? 0all belo+, t&e sta!dards set i! t&e *ompe!dium i0 t&e di00ere!*es 0rom t&e sta!dard are stated i! its label, 9!der se*tio! 302(g) o0 t&e a*t (2# 9,2,., 432), a drug t&at is re*og!i=ed i! a! o00i*ial *ompe!dium ma? be *o!sidered misbra!ded i0 t&e drug is !ot pa*:aged a!d labeled as pres*ribed i! t&e *ompe!dium, 6&e age!*? is a+are o0 t&e legal status o0 t&e 92"ENF u!der t&e a*t as a sta!dard 0or determi!i!g +&et&er a drug ma? be *o!sidered adulterated or misbra!ded, A *ompe!dial produ*t t&at 0ails to *ompl? +it& 92"ENF sta!dards [["age #8$4$ ma? be *o!sidered to be adulterated or misbra!ded u!der t&e a*t, 1o+e(er, a *ompe!dial produ*t *a! still be *o!sidered adulterated or misbra!ded u!der ot&er pro(isio!s o0 se*tio!s 30# or 302 o0 t&e a*t, e(e! i0 it *omplies +it& 92"ENF sta!dards, K&ile t&e sta!dards i! t&e 92"ENF are legall? e!0or*eable sta!dards 0or determi!i!g +&et&er a produ*t is *o!sidered adulterated u!der se*tio! 30# o0 t&e a*t, t&ese sta!dards are !ot *o!sidered t&e *omplete regulator? spe*i0i*atio!, 6&e age!*? is respo!sible 0or establis&i!g regulator? spe*i0i*atio!s as part o0 t&e appro(al o0 a! appli*atio!, 9!der se*tio!s 303(b) a!d 303(A) o0 t&e a*t (2# 9,2,., 433(b) a!d 433(A)) , a! appli*atio! must i!*lude a 0ull des*riptio! o0 t&e met&ods

used i! a!d t&e 0a*ilities a!d *o!trols used 0or, t&e ma!u0a*ture, pro*essi!g, a!d pa*:i!g o0 t&e drug, /0 t&e spe*i0i*atio!s i!*luded i! t&e des*riptio! are *o!sidered i!ade>uate to e!sure a!d preser(e t&e ide!tit?, stre!gt&, >ualit?, purit?, or pote!*? o0 t&e drug, t&e age!*? +ill re0use to appro(e t&e appli*atio!, 2ta!dards establis&ed b? a! o00i*ial *ompe!dium ma? be i!ade>uate 0or t&e purposes o0 appro(i!g a! appli*atio! u!der se*tio! 303 o0 t&e a*t, 6&e 92" a*:!o+ledges t&at: K&ile o!e o0 t&e primar? obAe*ti(es o0 t&e "&arma*opeia is to assure t&e user o0 o00i*ial arti*les o0 t&eir ide!tit?, stre!gt&, >ualit?, a!d purit?, it is ma!i0estl? impossible to i!*lude i! ea*& mo!ograp& a test 0or e(er? impurit?, *o!tami!a!t, or adultera!t t&at mig&t be prese!t, i!*ludi!g mi*robial *o!tami!atio!, 6&ese ma? arise 0rom a *&a!ge i! t&e sour*es o0 t&e material or 0rom a *&a!ge i! t&e pro*essi!g, or ma? be i!trodu*ed 0rom eDtra!eous sour*es, 6ests suitable 0or dete*ti!g su*& o**urre!*es, t&eir prese!*e o0 +&i*& is i!*o!siste!t +it& appli*able good ma!u0a*turi!g pra*ti*e or good p&arma*euti*al pra*ti*e, s&ould be emplo?ed i! additio! to t&e tests pro(ided i! t&e i!di(idual mo!ograp&, (92" 23, )e!eral Noti*es, page $), 2imilarl?, +&ile t&e labeli!g re>uireme!ts i! t&e 92"ENF are legall? e!0or*eable sta!dards 0or determi!i!g +&et&er a produ*t is misbra!ded u!der se*tio! 302 o0 t&e a*t, use o0 t&ese sta!dards alo!e does !ot e!sure *omplia!*e +it& t&e a*t, 6&e 92" states BBarti*les i! t&is "&arma*opeia are subAe*t to *omplia!*e +it& su*& labeli!g re>uireme!ts as ma? be promulgated b? go(er!me!tal bodies i! additio! to t&e "&arma*opeial re>uireme!ts set 0ort& 0or t&e arti*les,CC (92" 23, )e!eral Noti*es, page #2), Not all *ompe!dial sta!dards or *&a!ges i! eDisti!g *ompe!dial sta!dards are: (#) Ade>uate to e!sure a!d preser(e t&e ide!tit?, stre!gt&, >ualit?, purit?, or pote!*? o0 t&e drug or (2) *o!siste!t +it& ot&er re>uireme!ts o0 t&e a*t, For eDample, a deletio! o0 a! impurit? test ma? result i! a! i!ade>uate sta!dard 0or e!suri!g t&e purit? o0 t&e drug, 6&ere0ore, t&e age!*? does !ot belie(e t&at all *&a!ges made to *ompl? +it& a! o00i*ial *ompe!dium are o0 a t?pe t&at s&ould be reported i! a! a!!ual report, (.omme!t 83) 7a!? *omme!ts stated t&at t&e p&rases BB+&i*& are *o!siste!t +it& F-A re>uireme!tsCC a!d BBpro(ides i!*reased assura!*e t&at t&e drug +ill &a(e t&e *&ara*teristi*s o0 ide!tit?, stre!gt&, >ualit?, purit?, or pote!*? t&at it purports or is represe!ted to possessCC are u!*lear, 2e(eral *omme!ts stated t&at BB*o!siste!t +it& F-A re>uireme!tsCC allo+s 0or i!di(idual re(ie+ i!terpretatio!s, 2e(eral *omme!ts said t&at deleti!g or +ide!i!g a spe*i0i*atio! due to a *&a!ge i! t&e 92" s&ould be allo+ed i! a! a!!ual report, F-A *o!*urs t&at t&e pro(isio!s regardi!g *&a!ges to *ompl? +it& a! o00i*ial *ompe!dium s&ould be *lari0ied, 2eparate dis*ussio!s o0 labeli!g, a!al?ti*al pro*edures, a!d a**epta!*e *riteria a!d test *&a!ges 0ollo+, alo!g +it& a dis*ussio! o0 t&e p&rase BB*o!siste!t +it& F-A re>uireme!ts,CC 8abeli!g: 9!der se*tio! 302(g) o0 t&e a*t, a drug re*og!i=ed i! a! o00i*ial *ompe!dium ma? be *o!sidered misbra!ded i0 t&e drug is !ot pa*:aged a!d labeled as pres*ribed i! t&e *ompe!dium, 6&e met&od o0 pa*:i!g ma? be modi0ied +it& t&e *o!se!t o0 t&e age!*?, '!e *omme!t stated t&at t&ere +ould be *o!0usio! i! t&e mar:etpla*e i0 *ompe!dial labeli!g *&a!ges +ere !ot i!stituted u!i0orml?, 6&e age!*? *o!*urs t&at all labeli!g *&a!ges made to *ompl? +it& a! o00i*ial *ompe!dium t&at are *o!siste!t +it& F-A re>uireme!ts s&ould be reported i! a! a!!ual report, 6&ese *&a!ges &a(e mi!imal pote!tial to &a(e a! ad(erse e00e*t

o! t&e ide!tit?, stre!gt&, >ualit?, purit?, or pote!*? o0 t&e produ*t as t&ese 0a*tors ma? relate to t&e sa0et? a!d e00e*ti(e!ess o0 t&e produ*t, .o!siste!t labeli!g promotes t&e sa0e use o0 produ*ts a!d redu*es *o!0usio! i! t&e mar:etpla*e, A!al?ti*al pro*edures: For *ompe!dial drugs, t&e determi!atio! o0 +&et&er t&e drug is adulterated u!der se*tio! 30#(b) o0 t&e a*t must be made i! a**orda!*e +it& t&e a!al?ti*al pro*edures set i! t&e *ompe!dium eD*ept +&e! !o a!al?ti*al pro*edure is pres*ribed i! t&e *ompe!dium or t&e tests pres*ribed i! t&e o00i*ial *ompe!dium are i!su00i*ie!t, /! t&ese situatio!s, t&e age!*? *a! 0ollo+ t&e pro*ess outli!ed i! t&e statute a!d issue a regulatio! to pro(ide a! appropriate a!al?ti*al pro*edure, ;e*ause o0 t&e legal status o0 *ompe!dial a!al?ti*al pro*edures i! t&e a*t a!d ot&er re>uireme!ts relati!g to a!al?ti*al pro*edures i! t&e statute, t&e age!*? *o!*urs t&at *&a!ges i! a!al?ti*al pro*edures to *ompl? +it& a! o00i*ial *ompe!dium ma? be 0iled i! a! a!!ual report, eD*ept 0or *&a!ges to *ompl? +it& a! o00i*ial *ompe!dium t&at result i! t&e deletio! o0 a test or t&e relaDatio! o0 a! a**epta!*e *riterio!, 6&e age!*? +is&es to emp&asi=e t&at u!der F-ACs .)7"s, t&e suitabilit? o0 all a!al?ti*al pro*edures, i!*ludi!g *ompe!dial pro*edures, must be (eri0ied u!der a*tual *o!ditio!s o0 use, For eDample, a! assa? a!al?ti*al pro*edure +&ere degradatio! produ*ts, impurities, or eD*ipie!ts i!ter0ere +it& t&e a!al?sis is !ot *o!sidered a! a**eptable a!al?ti*al pro*edure, 6&e use o0 u!a**eptable a!al?ti*al pro*edures, e(e! i0 spe*i0ied i! a! o00i*ial *ompe!dium, *a! be *o!sidered a (iolatio! o0 t&e a*t, 6&e age!*? also +is&es to emp&asi=e t&at a *&a!ge 0rom a! appro(ed a!al?ti*al pro*edure t&at is *apable o0 >ua!ti0?i!g impurities to a *ompe!dial a!al?ti*al pro*edure t&at *a!!ot >ua!ti0? impurities is i! esse!*e a deletio! o0 a! impurities test, 6&is *&a!ge o0 pro*edure s&ould !ot be reported i! a! a!!ual report, but s&ould be reported as a!? ot&er re>uest 0or deletio! o0 a! appro(ed test, 6ests a!d a**epta!*e *riteria: 9!der se*tio!s 303(b) a!d 303(A) o0 t&e a*t, a! appli*atio! must i!*lude a 0ull des*riptio! o0 t&e met&ods used i! a!d t&e 0a*ilities a!d *o!trols used 0or, t&e ma!u0a*ture, pro*essi!g, a!d pa*:i!g o0 t&e drug, /0 t&e spe*i0i*atio!s i!*luded i! t&e des*riptio! are *o!sidered i!ade>uate to e!sure a!d preser(e t&e ide!tit?, stre!gt&, >ualit?, purit?, or pote!*? o0 t&e drug, t&e age!*? +ill re0use to appro(e t&e appli*atio!, As pre(iousl? dis*ussed i! t&is do*ume!t, t&e sta!dards establis&ed b? a! o00i*ial *ompe!dium ma? be i!ade>uate 0or appro(i!g a! appli*atio! u!der se*tio! 303 o0 t&e a*t, As part o0 t&e detailed appli*atio! re(ie+ pro*ess a!d i! a**orda!*e +it& se*tio! 303 o0 t&e a*t, F-A re>uires t&at t&e appli*atio! i!*lude tests a!d a**epta!*e *riteria t&at t&e age!*? belie(es are !e*essar? to e!sure a!d preser(e t&e ide!tit?, stre!gt&, >ualit?, purit?, a!d pote!*? o0 t&e produ*t, 6&e spe*i0i*atio!s i!*luded i! t&e appli*atio! are legall? bi!di!g upo! t&e appli*a!t, a!d a produ*t t&at 0ails to *ompl? +it& t&e spe*i0i*atio!s i!*luded i! t&e appli*atio! *a! be *o!sidered a! u!appro(ed drug u!der se*tio! 303 o0 t&e a*t, .ompe!dial sta!dards are o0te! [["age #8$48 used i! e(aluati!g t&e spe*i0i*atio!s proposed i! t&e appli*atio!, 1o+e(er, *ompe!dial sta!dards must o0te! be suppleme!ted +it& additio!al tests, su*& as a spe*i0i* test 0or impurities, to e!sure t&e ide!tit?, stre!gt&, >ualit?, purit?, a!d pote!*? o0 t&e drug, Also, t&e tests a!d a**epta!*e *riteria i! a! appli*atio! are o0te! appro(ed

+it&out be!e0it o0 a *ompe!dial sta!dard 0or a drug be*ause !o *ompe!dial sta!dard &as bee! establis&ed, 2ituatio!s *ould arise +&ere, 0or eDample, F-A re>uires tests a!d a**epta!*e *riteria 0or spe*i0i* impurities as part o0 appro(al o0 a! appli*atio!, 6&ese impurities are !ot spe*i0ied i! a! eDisti!g mo!ograp& or are !ot i!*luded i! a mo!ograp& publis&ed subse>ue!t to t&e appro(al o0 t&e drug, /0 F-A allo+ed all *&a!ges to *ompl? +it& a! o00i*ial *ompe!dium to be i!*luded i! a! a!!ual report, t&e appli*a!t *ould i!terpret t&is pro(isio! as allo+i!g t&em to delete t&e tests +&i*& +ere re>uired as a *o!ditio! o0 appro(i!g t&e appli*atio!, A *&a!ge to relaD a! a**epta!*e *riterio! or delete a test is *o!sidered a maAor *&a!ge, 6&e age!*? !eeds to re(ie+ a re>uest 0or t&is t?pe o0 *&a!ge i! t&e *o!teDt o0 a parti*ular N-A or AN-A to determi!e i0 t&e *&a!ge +ill ad(ersel? a00e*t t&e ide!tit?, stre!gt&, >ualit?, purit?, or pote!*? o0 t&e produ*t, .&a!ges su*& as t&ese, +&e! re>uested solel? at t&e i!itiati(e o0 t&e appli*a!t, must be 0iled i! a prior appro(al suppleme!t, Reporti!g t&ese *&a!ges i! a! a!!ual report is !ot appropriate, 1o+e(er, +&e! a *&a!ge to relaD a! a**epta!*e *riterio! or delete a test is made to *ompl? +it& a *&a!ge to a! o00i*ial *ompe!dium, t&e *&a!ge is *o!sidered to &a(e a moderate pote!tial to &a(e a! ad(erse e00e*t o! t&e ide!tit?, stre!gt&, >ualit?, purit?, or pote!*? o0 t&e produ*t as t&ese 0a*tors ma? relate to t&e sa0et? a!d e00e*ti(e!ess o0 t&e produ*t, 6&e *&a!ge is *o!sidered moderate be*ause: (#) 6&e *&a!ge &as bee! re(ie+ed b? a! i!depe!de!t group t&at &as t&e goal o0 promoti!g publi* &ealt& a!d (2) t&e age!*? &as &ad t&e opportu!it? t&roug& t&e 92" pro*ess o0 re(ie+i!g t&e proposed *&a!ge i! ge!eral, but !ot !e*essaril? i! t&e *o!teDt o0 ea*& i!di(idual appli*atio! a00e*ted b? t&e *&a!ge, ;ased o! t&ese 0a*tors, t&e age!*? +ill re>uire a *&a!ges%bei!g%e00e*ted%i!%40%da?s suppleme!t 0or a *&a!ge to relaD a! a**epta!*e *riterio! or delete a test to *ompl? +it& a *&a!ge to a! o00i*ial *ompe!dium, A *&a!ge made to *ompl? +it& a! o00i*ial *ompe!dium t&at results i! a tig&te!i!g o0 a! appro(ed a**epta!*e *riterio! or a! additio! o0 a test is *o!sidered a mi!or *&a!ge a!d ma? be 0iled i! a! a!!ual report, (.omme!t 86) F-A proposed t&at *&a!ges to *ompl? +it& a! o00i*ial *ompe!dium *ould be reported i! a! a!!ual report o!l? i0 t&e? +ere *o!siste!t +it& F-A re>uireme!ts, 2e(eral *omme!ts stated t&at BB*o!siste!t +it& F-A re>uireme!tsCC allo+s 0or i!di(idual re(ie+ i!terpretatio!s, F-A de*li!es to delete t&is p&rasi!g but +is&es to *lari0? t&at t&e term re>uireme!ts mea!s t&e re>uireme!ts o0 t&e a*t or t&e appli*able pro(isio!s i! t&e .ode o0 Federal Regulatio!s (.FR), A! a!!ual report or *&a!ges%bei!g%e00e*ted%i!%40%da?s suppleme!t s&ould !ot be used to impleme!t a *&a!ge to *ompl? +it& a! o00i*ial *ompe!dium +&e! t&at *&a!ge is !ot *o!siste!t +it& ot&er F-A statutor? or regulator? re>uireme!ts, A! eDample o0 t&is is a *&a!ge to a *ompe!dial a!al?ti*al pro*edure, +&e! a di00ere!t a!al?ti*al pro*edure is spe*i0ied i! t&e regulatio!s (e,g,, 2# .FR part 6#0) be*ause t&e use o0 t&e *ompe!dial a!al?ti*al pro*edure is !ot *o!siste!t +it& F-A regulatio!s, A!ot&er eDample o0 t&is is a *&a!ge to a *ompe!dial a!al?ti*al pro*edure t&at is pro(e! !ot to be suitable u!der a*tual *o!ditio!s o0 use be*ause t&e use o0 su*& a! a!al?ti*al pro*edure, e(e! i0 spe*i0ied i! a! o00i*ial *ompe!dium, is !ot *o!siste!t +it& .)7"s (2# .FR 2##,#94), /0 situatio!s li:e t&is o**ur, appli*a!ts s&ould *o!ta*t t&e age!*?, i!0orm t&em o0 t&e situatio!, a!d re>uest ad(i*e, For t&e reaso! dis*ussed pre(iousl? i! t&is do*ume!t, t&e age!*? is addi!g 2e*, 2e*, 4#4,$0(*)(2)(iii) a!d 60#,#2(*)(2)(i() to re>uire a

*&a!ges%bei!g%e00e*ted%i!%40%da?s suppleme!t 0or a relaDatio! o0 a! a**epta!*e *riterio! or deletio! o0 a test to *ompl? +it& a! o00i*ial *ompe!dium t&at is *o!siste!t +it& F-A statutor? a!d regulator? re>uireme!ts, 6&e age!*? is re(isi!g 2e*, 4#4,$0(d)(2)(i) as 0ollo+s: BBA!? *&a!ge made to *ompl? +it& a! o00i*ial *ompe!dium, eD*ept a *&a!ge des*ribed i! paragrap& (*)(2)(iii) o0 t&is se*tio!, t&at is *o!siste!t +it& F-A statutor? a!d regulator? re>uireme!ts,CC 6&e age!*? is also re(isi!g 2e*, 60#,#2(d)(2)(i) as 0ollo+s: BBA!? *&a!ge made to *ompl? +it& a! o00i*ial *ompe!dium, eD*ept a *&a!ge des*ribed i! paragrap& (*)(2)(i() o0 t&is se*tio!, t&at is *o!siste!t +it& F-A statutor? a!d regulator? re>uireme!ts,CC (.omme!t 8$) 2e(eral *omme!ts stated t&at a drug must *ompl? +it& t&e *ompe!dial >ualit? sta!dards or it ma? be *o!sidered adulterated or misbra!ded, 6&e *omme!ts +e!t o! to sa? t&at +&e! t&e 92" ma:es a *&a!ge a!d a *ompa!? *a!!ot *ompl? u!til F-A appro(es t&e *&a!ge, t&e mar:eted drug i! t&e i!ter(e!i!g period te*&!i*all? ma? be misbra!ded or adulterated i0 it 0ails to meet t&e *&a!ged *ompe!dial re>uireme!ts, 6&e age!*? +is&es to *lari0? as part o0 t&is 0i!al rule t&e *ir*umsta!*es u!der +&i*& a suppleme!tal appli*atio! must be submitted 0or *&a!ges to *ompl? +it& a! o00i*ial *ompe!dium, A suppleme!tal appli*atio! must be submitted o!l? +&e! t&e *&a!ge i!(ol(es a relaDatio! o0 a! a**epta!*e *riterio! or deletio! o0 a test, 6&e sta!dards 0or t&e drug +ill di00er 0rom t&e sta!dards pres*ribed i! t&e o00i*ial *ompe!dium u!til t&e age!*? appro(es t&e *&a!ge, 1o+e(er, u!der t&ese *ir*umsta!*es, t&e drug as mar:eted +ill &a(e tig&ter spe*i0i*atio!s or more testi!g +ill be per0ormed t&a! &as bee! spe*i0ied i! t&e o00i*ial *ompe!dium, 6&ere0ore, t&e drug +ill !ot 0all belo+ t&e sta!dards set i! t&e o00i*ial *ompe!dium a!d +ould !ot be *o!sidered adulterated u!der se*tio! 30#(b) o0 t&e a*t, (.omme!t 88) '!e *omme!t said t&at t&e proposed la!guage implies t&at t&ere ma? be separate a!dEor di00ere!t re>uireme!ts to 0ul0ill 92" a!d F-A *riteria, 't&er *omme!ts said t&at t&e same produ*t, 0rom di00ere!t appli*a!ts, s&ould be &eld to t&e same sta!dards, As dis*ussed pre(iousl? i! t&is do*ume!t, +&ile t&e spe*i0i*atio!s i! a! o00i*ial *ompe!dium are legall? e!0or*eable sta!dards u!der se*tio! 302(b) o0 t&e a*t 0or determi!i!g +&et&er a produ*t is *o!sidered adulterated, t&ese sta!dards ma? !ot be su00i*ie!t to e!sure a!d preser(e t&e ide!tit?, stre!gt&, >ualit?, purit?, a!d pote!*? o0 t&e drug as re>uired u!der se*tio! 303 o0 t&e a*t 0or appro(al to mar:et a drug, )e!erall?, F-A uses *ompe!dial sta!dards i! e(aluati!g t&e spe*i0i*atio!s proposed i! a! appli*atio!, 1o+e(er, *ompe!dial sta!dards must o0te! be suppleme!ted +it& additio!al tests to e!sure t&e ide!tit?, stre!gt&, >ualit?, purit?, or pote!*? o0 t&e drug, 2imilarl?, +&ile t&e labeli!g re>uireme!ts i! 92"ENF are legall? e!0or*eable sta!dards 0or determi!i!g +&et&er a produ*t is misbra!ded u!der se*tio! 302(g) o0 t&e a*t, use o0 t&ese sta!dards alo!e does !ot e!sure *omplia!*e +it& t&e a*t, 6&e statutor? re>uireme!ts regardi!g *ompe!dial sta!dards as +ell as ot&er statutor? re>uireme!ts must be *o!sidered to e!sure *omplia!*e +it& t&e a*t, 6&e re>uireme!ts u!der se*tio!s 30#(b) a!d 302(g) o0 t&e a*t 0or determi!i!g +&et&er a produ*t is adulterated or misbra!ded a!d o0 [["age #8$49 se*tio! 303 o0 t&e a*t 0or appro(i!g a! appli*atio! are applied *o!siste!tl? to all produ*ts, 9!der se*tio!s 303(b) a!d 303(A) o0 t&e a*t, t&e spe*i0i*atio!s i!*luded i! t&e appli*atio! must be *o!sidered

ade>uate to e!sure a!d preser(e t&e ide!tit?, stre!gt&, >ualit?, purit?, a!d pote!*? o0 t&e drug or else t&e age!*? must re0use to appro(e t&e appli*atio!, 1o+e(er, t&is does !ot mea! t&at t&e spe*i0i*atio!s appro(ed i! di00ere!t appli*atio!s 0or t&e same drug are ide!ti*al, For eDample, di00ere!t a!al?ti*al pro*edures ma? be appro(ed as lo!g as t&e a!al?ti*al pro*edures are appropriate a!d (alid, A!ot&er eDample is t&at +&ere sol(e!ts are used, t&e age!*? routi!el? a!d *o!siste!tl? re>uests tests a!d a**epta!*e *riteria 0or residual sol(e!ts, 1o+e(er, be*ause di00ere!t ma!u0a*turers use di00ere!t sol(e!ts, t&e tests a!d a**epta!*e *riteria +ill (ar? depe!di!g o! t&e sol(e!ts used, /! all *ases, t&e appro(ed spe*i0i*atio!s +ill &a(e bee! determi!ed b? t&e age!*? to be ade>uate to e!sure a!d preser(e t&e ide!tit?, stre!gt&, >ualit?, purit?, a!d pote!*? o0 t&e drug, (.omme!t 89) 7a!? *omme!ts stated t&at F-A is i!(ol(ed i! t&e 92" re(isio! pro*ess a!d s&ould use t&is pro*ess to resol(e a!? di00ere!*es bet+ee! *ompe!dial re>uireme!ts a!d F-A re>uireme!ts a!d e!sure t&at *ompe!dial *&a!ges do !ot *ompromise sa0et? a!d e00i*a*?, '!*e t&is is a**omplis&ed, all *&a!ges to *ompl? +it& a *ompe!dial *&a!ge s&ould be submitted i! a! a!!ual report, 6&e 92" pro*ess 0or de(elopi!g or *&a!gi!g a mo!ograp&, ge!eral !oti*e, or ge!eral *&apter is a! ope! pro*ess, A!?o!e +&o is i!terested i! a parti*ular issue &as t&e opportu!it? to *omme!t, F-A parti*ipates i! ma!? 92" a*ti(ities, i!*ludi!g Aoi!t *ommittees a!d publi* 0orums, a!d &as desig!ated perso!s t&roug&out t&e age!*? to a*t as liaiso!s to t&e 92", F-A re*og!i=es t&at publi* sta!dards su*& as t&ose i!stituted b? t&e 92" are be!e0i*ial, 1o+e(er, t&e 92" is a !o!go(er!me!tal orga!i=atio! t&at +or:s i!depe!de!tl? 0rom F-A, a!d F-A &as !o aut&orit? to stop 92" 0rom impleme!ti!g a !e+ or re(ised sta!dard, F-A must e!sure t&e ide!tit?, stre!gt&, >ualit?, purit?, a!d pote!*? o0 drugs b? re>uiri!g appropriate spe*i0i*atio!s, .ompe!dial sta!dards are !ot al+a?s su00i*ie!t to pro(ide t&is assura!*e, 7oreo(er, *ertai! *&a!ges i! a publi* sta!dard, su*& as deletio! o0 a test or relaDatio! o0 a! a**epta!*e *riterio!, *a!!ot al+a?s be *o!sidered a! impro(eme!t i! t&e sta!dard, !or is it al+a?s *lear t&at t&e *&a!ge +ill !ot lesse! t&e assura!*e o0 t&e ide!tit?, stre!gt&, >ualit?, purit?, or pote!*? o0 t&e produ*ts a00e*ted b? t&e *&a!ge, A0ter re(ie+ o0 a *&a!ge su*& as t&ese i! t&e *o!teDt o0 a spe*i0i* N-A or AN-A, F-A ma? *o!0irm t&at t&e *&a!ge does !ot ad(ersel? a00e*t t&e drug, 1o+e(er, allo+i!g su*& a *&a!ge to be do*ume!ted i! a! a!!ual report +ould !ot pro(ide t&e opportu!it? 0or t&e age!*? to assess t&e e00e*t o0 t&e *&a!ge i! a timel? ma!!er, F-A *o!siders t&e pro(isio!s i! t&e 0i!al rule !e*essar? to e!sure t&e sa0et? a!d e00e*ti(e!ess o0 drugs, (.omme!t 90) 2e(eral *omme!ts said t&at t&e proposed pro(isio! regardi!g *&a!ges to *ompl? +it& a! o00i*ial *ompe!dium +as i!*o!siste!t +it& t&e i!te!t o0 t&e 7oder!i=atio! A*t, F-A disagrees +it& t&ese *omme!ts, 2e*tio! 306A o0 t&e a*t re>uires a *&a!ge i! t&e spe*i0i*atio!s i! t&e appro(ed appli*atio! to be submitted i! a suppleme!tal appli*atio! a!d appro(ed b? t&e age!*? prior to t&e appli*a!t distributi!g t&e produ*t a00e*ted b? t&e *&a!ge (se*tio! 306A(*)(2)(A) o0 t&e a*t), 6&e a*t does !ot disti!guis& bet+ee! *&a!ges i! *ompe!dial a!d !o!*ompe!dial spe*i0i*atio!s, 6&e a*t allo+s t&e 2e*retar? to eDempt b? regulatio! or guida!*e t&e re>uireme!t t&at *&a!ges i! spe*i0i*atio!s ma? be submitted i! prior appro(al suppleme!ts, 1o+e(er, t&e a*t also re>uires t&e age!*? to establis& t&e reporti!g *ategor? 0or a *&a!ge based o! t&e pote!tial 0or t&e *&a!ge to ad(ersel? a00e*t t&e ide!tit?, stre!gt&, >ualit?,

purit?, a!d pote!*? o0 t&e drug as t&e? ma? relate to t&e sa0et? a!d e00e*ti(e!ess o0 t&e drug, 6&e age!*? belie(es t&e pro(isio!s i! t&e 0i!al rule regardi!g *&a!ges to *ompl? +it& *&a!ges i! a! o00i*ial *ompe!dium are *o!siste!t +it& t&e i!te!t o0 t&e 7oder!i=atio! A*t, (.omme!t 9#) '!e *omme!t also said t&at t&e proposal +as !ot *o!siste!t +it& t&e i!itiati(es u!der t&e Natio!al "art!ers&ip 0or Rei!(e!ti!g )o(er!me!t (R5)'), t&e Natio!al 6e*&!olog? 6ra!s0er a!d Ad(a!*eme!t A*t (t&e N66AA) o0 #993 a!d t&e "aper+or: Redu*tio! A*t o0 #993 (t&e "RA), F-A disagrees +it& t&is *omme!t, 6&e *omme!t states t&at o!e o0 F-ACs goals u!der R5)' is a more e00i*ie!t drug de(elopme!t pro*ess a!d re(ie+ pro*ess t&at +ill lo+er t&e de(elopme!t *osts a!d redu*e b? a! a(erage o0 # ?ear t&e time re>uired to bri!g importa!t !e+ drugs to t&e Ameri*a! people, 6&is R5)' goal relates to i!itiati(es 0or drugs prior to appro(al b? F-A a!d is !ot perti!e!t to t&is rule, 1o+e(er, o!e R5)' i!itiati(e +as to redu*e t&e !umber o0 ma!u0a*turi!g *&a!ges t&at re>uire age!*? preappro(al 0or biologi*al produ*ts a!d F-A re(ised its regulatio!s to a*&ie(e t&is goal (see t&e Federal Register o0 @a!uar? 29, #996 (6# FR 2$49), a!d @ul? 24, #99$ (62 FR 49890)), F-A supports t&e R5)' obAe*ti(e to tra!s0orm F-A i!to a *ustomer%orie!ted, results% dri(e! orga!i=atio! a!d belie(es t&at t&e 0i!al rule, +&i*& redu*es regulator? burde! +it& respe*t to postappro(al *&a!ges 0or bot& biologi*al produ*ts a!d &uma! drugs, a*&ie(es t&is obAe*ti(e, 6&e Natio!al 6e*&!olog? 6ra!s0er A*t o0 #993 (N66AA) ("ubli* 8a+ #04%##4, #3 9,2,., 4$0# (#996)) e!*ourages t&e use o0 (olu!tar? *o!se!sus sta!dards b? Federal age!*ies as a mea!s to *arr? out poli*? obAe*ti(es a!d puts i!to la+ t&e poli*ies o0 '7; .ir*ular A%##9 (see t&e Federal Register o0 Februar? #9, #998 (64 FR 8346)), 6&e sta!dards set b? 92"ENF are !ot (olu!tar? sta!dards be*ause t&e sta!dards are re*og!i=ed i! se*tio!s 30# a!d 302 o0 t&e a*t 0or t&e purposes o0 determi!i!g i0 a *ompe!dial drug is adulterated or misbra!ded, 6&ere0ore, t&e N66AA is !ot perti!e!t, F-A is aut&ori=ed to *ooperate +it& asso*iatio!s a!d s*ie!ti0i* so*ieties i! t&e re(isio! o0 t&e 92" (2# 9,2,., 4$$), F-A is a *ommitted parti*ipa!t i! t&is e!dea(or a!d i! de(elopi!g ot&er (olu!tar? a!d !o!(olu!tar? *o!se!sus sta!dards, 6&e purposes o0 t&e "RA (44 9,2,., 430#%4320) i!*lude mi!imi=i!g paper+or: 0or busi!ess resulti!g i! *olle*tio! o0 i!0ormatio! 0or t&e go(er!me!t, e!suri!g t&e greatest publi* be!e0it 0rom t&e i!0ormatio! *olle*ted, a!d mi!imi=i!g t&e *ost to t&e go(er!me!t o0 t&e *olle*tio! o0 i!0ormatio!, 2e*tio! 306A(b) o0 t&e a*t states t&at a drug made +it& a ma!u0a*turi!g *&a!ge (+&et&er a maAor ma!u0a*turi!g *&a!ge or ot&er+ise) ma? be distributed o!l? i0, be0ore distributio! o0 t&e drug as so made, t&e &older i!(ol(ed (alidates t&e e00e*t o0 t&e *&a!ge o! t&e ide!tit?, stre!gt&, >ualit?, purit?, a!d pote!*? o0 t&e drug as t&ese 0a*tors ma? relate to t&e sa0et? a!d e00e*ti(e!ess o0 t&e drug, 7oreo(er, ea*& suppleme!tal appli*atio! or a!!ual report must *o!tai! su*& i!0ormatio! as t&e 2e*retar? determi!es to be appropriate a!d i!*lude t&e i!0ormatio! de(eloped b? t&e appli*a!t to (alidate t&e e00e*ts o0 t&e *&a!ge (se*tio!s 306A(*)(#), (d)(2)(A), a!d (d)(4)(A) o0 t&e a*t), 6&e i!0ormatio! t&at +ill be submitted to support a *&a!ge is i!depe!de!t o0 t&e reporti!g *ategor? 0or t&e *&a!ge, F-A +ill re>uire t&e same t?pe o0 i!0ormatio! to be submitted to support a *&a!ge i! a *ompe!dial spe*i0i*atio! regardless o0 +&et&er t&e *&a!ge is reported i! a suppleme!tal appli*atio! or a!!ual [["age #8$30

report, 6&ere is !o additio!al paper+or: burde! based solel? o! t&e desig!atio! o0 a reporti!g *ategor? 0or a parti*ular *&a!ge, (.omme!t 92) 7a!? *omme!ts said t&at re>uiri!g *ompe!dial *&a!ges to be reported i! a!?t&i!g ot&er t&a! a! a!!ual report +as a! i!*rease i! regulator? burde! o(er +&at &as bee! do!e i! t&e past, 2e(eral *omme!ts said t&at t&ere &as bee! !o publi* dis*ussio! about a!? *o!*er!s +it& t&e pre(ious poli*? to allo+ *&a!ges to *ompl? +it& *ompe!dial *&a!ges to be 0iled i! a! a!!ual report, F-A re*og!i=es t&at t&ere &as bee! *o!0usio! about t&e pro(isio! i! pre(ious 2e*, 4#4,$0(d)(#) t&at allo+ed a!? *&a!ge made to *ompl? +it& a! o00i*ial *ompe!dium to be reported i! a! a!!ual report, /! t&e Federal Register o0 @u!e 4, #986 (3# FR 204#0), F-A publis&ed a proposed rule to *lari0? a!d limit t&e t?pes o0 *ompe!dial *&a!ges t&at *ould be made i! a! a!!ual report, F-A +as prepari!g to issue a 0i!al rule regardi!g t&is proposal +&e! .o!gress i!itiated dis*ussio!s about postappro(al ma!u0a*turi!g *&a!ges, F-A dela?ed publis&i!g t&e 0i!al rule a!d i!*orporated re(isio!s regardi!g reporti!g o0 *&a!ges to *ompl? +it& a! o00i*ial *ompe!dium i!to its proposed rule impleme!ti!g se*tio! 306A o0 t&e a*t, 6&e pro(isio!s i! t&e 0i!al rule 0or *&a!ges made to *ompl? +it& a! o00i*ial *ompe!dium mig&t be (ie+ed b? some as a! i!*rease i! burde! o(er &o+ F-A &as bee! i!terpreti!g t&is regulatio! i! t&e past, 1o+e(er, F-A belie(es t&at t&e pro(isio!s are !e*essar? a!d *o!siste!t +it& t&e re>uireme!ts o0 se*tio! 306A o0 t&e a*t to establis& a reporti!g *ategor? 0or a *&a!ge based o! t&e pote!tial 0or t&e *&a!ge to ad(ersel? a00e*t t&e ide!tit?, stre!gt&, >ualit?, purit?, or pote!*? o0 t&e drug produ*t as t&e? ma? relate to t&e sa0et? a!d e00e*ti(e!ess o0 t&e drug produ*t, As eDplai!ed pre(iousl?, t&e i!0ormatio! t&at +ill be submitted to support a *&a!ge is i!depe!de!t o0 t&e reporti!g *ategor? 0or t&e *&a!ge, F-A +ill re>uire t&e same t?pe o0 i!0ormatio! to be submitted to support a *&a!ge i! a *ompe!dial spe*i0i*atio! regardless o0 +&et&er t&e *&a!ge is reported i! a suppleme!tal appli*atio! or a!!ual report, 6&ere is !o additio!al paper+or: burde! based solel? o! t&e desig!atio! o0 a reporti!g *ategor? 0or a parti*ular *&a!ge, (.omme!t 94) '!e *omme!t stated t&at *&a!ges made to *ompl? +it& *&a!ges i! a! o00i*ial *ompe!dium s&ould !ot &a(e to i!*lude all t&e i!0ormatio! !eeded 0or !o!*ompe!dial produ*ts, 6&e *omme!t +e!t o! to sa? t&at a 0ull des*riptio! o0 t&e test met&ods a!d limits s&ould !ot be !e*essar? a!d t&at t&e *ompa!? s&ould !ot &a(e to submit data demo!strati!g t&e suitabilit? o0 a *ompe!dial *&a!ge 0or t&e drug produ*t i0 t&e *ompe!dial *&a!ge is 0or a test met&od *&a!ge or ot&er *&a!ge !ot spe*i0i*all? a00e*ti!g t&e >ualit? or t&e morp&olog? o0 t&e material i! >uestio!, As pre(iousl? dis*ussed i! t&is do*ume!t, u!der se*tio! 306A o0 t&e a*t, ea*& suppleme!tal appli*atio! or a!!ual report must *o!tai! t&e i!0ormatio! t&at t&e age!*? &as determi!ed to be appropriate a!d must i!*lude t&e i!0ormatio! de(eloped b? t&e appli*a!t to (alidate t&e e00e*ts o0 t&e *&a!ge, )uida!*e o! t&e i!0ormatio! t&at s&ould be submitted to support *ompe!dial a!d !o!*ompe!dial a!al?ti*al pro*edures is a(ailable 0rom F-A, 9!der proposed 2e*, 4#4,$0(d)(2)(ii), t&e 0ollo+i!g *&a!ge +as to be do*ume!ted i! t&e !eDt a!!ual report: 6&e deletio! or redu*tio! o0 a! i!gredie!t i!te!ded to a00e*t o!l? t&e *olor o0 t&e produ*t, (.omme!t 94) '!e *omme!t re*omme!ded *&a!gi!g t&e re>uireme!t to read BBt&e deletio!, redu*tio! or repla*eme!t +it& a *olor pre(iousl? used i! ot&er .-5RE.;5R appro(ed produ*ts,CC F-A de*li!es to re(ise t&e regulatio! as re>uested, F-A belie(es

t&at a!? re*omme!datio!s it ma? ma:e *o!*er!i!g !oti0i*atio! i! a! a!!ual report o0 *&a!ges i!(ol(i!g repla*eme!t o0 *olors are best &a!dled i! guida!*e do*ume!ts so t&at t&e issues a!d *o!ditio!s asso*iated +it& su*& *&a!ges *a! be 0ull? eDplai!ed, (.omme!t 93) '!e *omme!t said t&at *&a!ges i! 0ormulatio!, regardless o0 t&e i!te!ded purpose o0 t&e i!gredie!t, are more appropriatel? addressed i! terms o0 per*e!t *&a!ge allo+ed at ea*& le(el as deli!eated i! t&e 29"A. guida!*es, F-A agrees t&at t&e issues relati!g to *&a!ges i! *ompo!e!ts a!d *ompositio! 0or spe*i0i* dosage 0orm drug produ*ts are better &a!dled i! guida!*e do*ume!ts, +&ere t&e? *a! be dis*ussed i! detail, rat&er t&a! i! t&e regulatio!s, F-A i!*luded t&is spe*i0i* pro(isio! i! t&e proposed regulatio!s be*ause t&is a!!ual report *&a!ge, +it& mi!or editi!g *&a!ges, &as bee! i! t&e regulatio! si!*e #983, 9!der proposed 2e*, 4#4,$0(d)(2)(iii), t&e 0ollo+i!g *&a!ge +as to be do*ume!ted i! t&e !eDt a!!ual report: Repla*eme!t o0 e>uipme!t +it& t&at o0 t&e same desig! a!d operati!g pri!*iples eD*ept 0or e>uipme!t used +it& a !atural protei! produ*t, a re*ombi!a!t -NA%deri(ed protei!E pol?peptide produ*t, or a *ompleD or *o!Augate o0 a drug +it& a mo!o*lo!al a!tibod?, (.omme!t 96) 2e(eral *omme!ts suggested t&at F-A delete all +ords a0ter BBpri!*iplesCC to read: BBRepla*eme!t o0 e>uipme!t +it& t&at o0 t&e same desig! a!d operati!g pri!*iples,CC '!e *omme!t said t&at it is reaso!able to report i! a! a!!ual report repla*eme!t +it& e>uipme!t o0 t&e same desig! a!d operati!g pri!*iples 0or t&ese (i,e,, protei!) produ*ts, F-A de*li!es to re(ise t&e regulatio! as re>uested but &as re(ised it to pro(ide *larit?, As dis*ussed i! se*tio! ///,- o0 t&is do*ume!t i! respo!se to *omme!ts o! BB.&a!ges Re>uiri!g 2uppleme!t 2ubmissio! at 8east 40 -a?s "rior to -istributio! o0 t&e -rug "rodu*t 7ade 9si!g t&e .&a!ge (7oderate .&a!ge),CC *&a!ges to ide!ti*al e>uipme!t used i! t&e produ*tio! o0 protei!s *ould be reported i! a! a!!ual report, 1o+e(er, a *&a!ge to e>uipme!t o0 t&e same desig! a!d operati!g pri!*iple, but !ot ide!ti*al e>uipme!t (e,g,, *apa*it?), is !ot *o!sidered a mi!or *&a!ge 0or protei! produ*ts, F-A &as re(ised 2e*, 4#4,$0(d)(2)(iii) as 0ollo+s: BBRepla*eme!t o0 e>uipme!t +it& t&at o0 t&e same desig! a!d operati!g pri!*iples eD*ept t&ose e>uipme!t *&a!ges des*ribed i! paragrap& (*) o0 t&is se*tio!,CC (.omme!t 9$) '!e *omme!t said t&e repla*eme!t o0 e>uipme!t o0 t&e same desig! a!d operati!g pri!*iples s&ould !ot &a(e to be reported, 6&e *omme!t said t&at 0or *o!siste!*? +it& t&e eDisti!g 29"A. guida!*es, o!l? a 29"A. sub*lass (i,e,, desig!) *&a!ge s&ould be reported, F-A de*li!es to re(ise t&e regulatio! as re>uested, F-ACs re>uireme!t to report *&a!ges i! e>uipme!t o0 t&e same desig! a!d operati!g pri!*iple i! a! a!!ual report is *o!siste!t +it& t&e eDisti!g 29"A. guida!*es, /! t&e 0uture, F-A ma? issue guida!*e lesse!i!g t&e reporti!g re>uireme!ts i! t&is area 0or spe*i0i* *ases, 1o+e(er, be*ause o0 t&e di(ersit? o0 drug produ*ts a!d ma!u0a*turi!g pro*esses regulated, F-A is u!able at t&is time to lo+er t&e re>uireme!ts as suggested i! t&e *omme!ts, 9!der proposed 2e*, 2e*, 4#4,$0(d)(2)(i() a!d 60#,#2(d)(2)((), t&e 0ollo+i!g *&a!ge +as to be do*ume!ted i! t&e !eDt a!!ual report: A *&a!ge i! t&e si=e a!dEor s&ape o0 a *o!tai!er *o!tai!i!g t&e same !umber o0 dosage u!its 0or a !o!sterile solid dosage 0orm, +it&out a *&a!ge 0rom o!e *o!tai!er *losure s?stem to a!ot&er,

(.omme!t 98) 2e(eral *omme!ts said t&at F-A s&ould delete BB*o!tai!i!g t&e same !umber o0 dosage u!its,CC 6&e *omme!ts said t&at proportio!al *&a!ges (i,e,, ratio o0 t&e amou!t o0 drug [["age #8$3# produ*t to si=e o0 *o!tai!er) are !ot eDpe*ted to ad(ersel? a00e*t t&e drug produ*t, t&at a *orrespo!di!g *&a!ge i! 0ill >ua!tit?, alo!g +it& a *&a!ge i! *o!tai!er si=e, is eDpe*ted a!d readil? a**eptable, a!d t&at it is illogi*al to assume t&at a *&a!ge i! t&e amou!t o0 produ*t +ould prese!t a!? greater ris: t&a! a *&a!ge i! *o!tai!er si=e, F-A de*li!es to re(ise t&e regulatio! as re>uested, As dis*ussed i! t&e respo!se to *omme!t 8# o0 t&is do*ume!t, F-A is *o!*er!ed about t&e proli0eratio! o0 u!it%o0%use *o!tai!ers t&at ma? i!(ite t&e misuse o0 drug produ*ts, 9!der proposed 2e*, 2e*, 4#4,$0(d)(2)(() a!d 60#,#2(d)(2)(i(), t&e 0ollo+i!g *&a!ge +as to be do*ume!ted i! t&e !eDt a!!ual report: A *&a!ge +it&i! t&e *o!tai!er *losure s?stem 0or a !o!sterile drug produ*t, based upo! a s&o+i!g o0 e>ui(ale!*? to t&e appro(ed s?stem u!der a proto*ol appro(ed i! t&e appli*atio! or publis&ed i! a! o00i*ial *ompe!dium, (.omme!t 99) '!e *omme!t said t&at t&e proposal, +it&out 0urt&er eDpla!atio!, alters t&e reporti!g *ategor? appli*able to *&a!ges +it&i! t&e *o!tai!erE*losure s?stem 0or sterile li>uid drugs t&at are made based o! a s&o+i!g o0 e>ui(ale!*? to t&e appro(ed s?stem u!der a proto*ol appro(ed i! t&e appli*atio! or publis&ed i! a! o00i*ial *ompe!dium (0or eDample, t&e 92"), 6&e *omme!t said t&at u!der *urre!t 2e*, 4#4,$0(d)(6), t&ese *&a!ges are des*ribed i! t&e a!!ual report a!d do !ot re>uire F-A prior appro(al, 6&e *omme!t said t&at F-A &as !ot pro(ided a!? ratio!ale 0or its proposal to re>uire a suppleme!t to be 0iled i! *o!!e*tio! +it& a!? *&a!ge +it&i! a pa*:agi!g material 0or a sterile li>uid drug, e(e! i! situatio!s i! +&i*& t&e *&a!ge is based o! a s&o+i!g o0 e>ui(ale!*? to t&e appro(ed s?stem u!der a proto*ol appro(ed i! t&e appli*atio! or publis&ed i! a! o00i*ial *ompe!dium, a!d re*omme!ded t&at BB!o!sterileCC be deleted, 6&e *omme!t said t&at i! t&e same +a?, it +ould be u!dul? burde!some to re>uire F-A prior appro(al 0or a *&a!ge +it&i! a *o!tai!erE*losure s?stem 0or a material based o! a determi!atio! o0 e>ui(ale!*? made i! a**orda!*e +it& a 92" mo!ograp& t&at is spe*i0i*all? desig!ed 0or t&at purpose, 6&e *omme!t said, 0or eDample, t&e 92" *&apter 0or BB"ol?et&?le!e 6erep&t&alate ("56) ;ottles a!d "ol?et&?le!e 6erep&t&alate ) ("56)) ;ottlesCC pro(ides sta!dards a!d tests to *&ara*teri=e "56 a!d "56) bottles BBt&at are i!ter*&a!geabl? suitable 0or pa*:agi!g li>uid oral dosage 0ormsCC (92" 23, )e!eral .&apter I66# (2002 ed,)), 6&e *omme!t said t&at F-A is pro(ided +it& t&e opportu!it? to re(ie+ a!d *omme!t o! 92" mo!ograp&s be0ore t&e? are publis&ed i! 0i!al 0ormJ t&us, t&e re>uireme!t 0or a! additio!al F-A prior re(ie+ o0 a *&a!ge made i! a**orda!*e +it& 92" mo!ograp& is u!!e*essar?, F-A de*li!es to re(ise t&e regulatio! as re>uested, All *o!tai!er *losure s?stems *&a!ges must be supported +it& data to demo!strate t&at (arious *&ara*teristi*s o0 t&e drug produ*t a!dEor *o!tai!er *losure s?stem are u!*&a!ged or e>ui(ale!t (e,g,, p&?si*al, *&emi*al), For a sterile drug produ*t, &o+e(er, data must also be pro(ided to support t&at t&e sterilit? assura!*e le(el a!d t&e mai!te!a!*e o0 sterilit? 0or t&e produ*t &as !ot bee! a00e*ted, 2terilit? o0 drug produ*ts is a 0u!dame!tal a!d esse!tial >ualit? attribute o0 t&ese drugs a!d is a *riti*al aspe*t o0 t&e sa0et? assessme!t, F-A +ould *o!sider a!

assessme!t o0 t&e e00e*ts o0 a *&a!ge i! a *o!tai!er *losure s?stem 0or a sterile produ*t to be i!ade>uate i0 it did !ot i!*lude tests a!d data relati!g to sterilit? assura!*e a!d mai!te!a!*e o0 sterilit?, F-A *o!siders *&a!ges i! t&e *o!tai!er *losure s?stem 0or sterile drug produ*ts to be *&a!ges t&at ma? a00e*t t&e sterilit? assura!*e a!dEor mai!te!a!*e o0 sterilit? o0 a drug a!d, t&ere0ore, ma? &a(e sig!i0i*a!t pote!tial to a00e*t t&e sa0et? o0 t&e drug, 6&ere0ore, F-A &as ide!ti0ied t&is *&a!ge as o!e t&at re>uires prior appro(al (see *omme!t 44 o0 t&is do*ume!t), As stated i! t&e @u!e #999 proposal, t&is rulema:i!g sets out broad, ge!eral *ategories o0 ma!u0a*turi!g *&a!ges, a!d t&e age!*? uses guida!*e do*ume!ts to pro(ide F-ACs *urre!t t&i!:i!g o! t&e spe*i0i* *&a!ges i!*luded i! t&ose *ategories, 6&roug& guida!*e, F-A ma? ide!ti0? *ertai! *o!tai!er *losure s?stem *&a!ges 0or sterile drug produ*ts t&at *a! be reported ot&er t&a! b? submissio! o0 a prior appro(al suppleme!t, Furt&ermore, a! appli*a!t *ould submit a *omparabilit? proto*ol t&at +ould allo+ it to impleme!t postappro(al *&a!ges i! sterile *o!tai!er *losure s?stems +it&out a prior appro(al suppleme!t, F-A !otes t&at, as o0 2002, !o o00i*ial *ompe!dia &as 0i!ali=ed a! e>ui(ale!*? proto*ol 0or *o!tai!er *losure s?stems 0or sterile drug produ*ts, /0 su*& a proto*ol is publis&ed i! t&e 0uture, F-A +ill *o!sider ide!ti0?i!g i! a guida!*e a reporti!g *ategor? ot&er t&a! a prior appro(al suppleme!t 0or t&e *ompe!dial proto*ol i0 t&e proto*ol ade>uatel? addresses t&e appropriate s*ie!ti0i* issues, F-A spe*i0i*all? +is&es to address t&e *omme!tCs impli*atio! t&at *&a!ges made u!der t&e 92" mo!ograp& 0or BB"ol?et&?le!e 6erep&t&alate ;ottles a!d "ol?et&?le!e 6erep&t&alate ) ;ottlesCC *ould be submitted i! a! a!!ual report u!der t&is pro(isio!, As +it& a!? *&a!ge a!d as re>uired b? t&e a*t, t&e appli*a!t must assess t&e e00e*ts o0 t&e *&a!ge o! t&e ide!tit?, stre!gt&, >ualit?, purit?, a!d pote!*? o0 t&e drug produ*t as t&ese 0a*tors ma? relate to t&e sa0et? a!d e00e*ti(e!ess o0 t&e produ*t, 7oreo(er, 92" I66# states t&at BBt&e suitabilit? o0 a spe*i0i* "56 or "56) bottle 0or use i! t&e dispe!si!g o0 a parti*ular p&arma*euti*al li>uid oral dosage 0orm must be establis&ed b? appropriate testi!g,CC 6esti!g solel? b? t&e sta!dards set i! t&is ge!eral *&apter +ould !ot usuall? be *o!sidered b? F-A to be su00i*ie!t to assess t&e e00e*ts o0 t&e *&a!ge be*ause t&e i!tera*tio! bet+ee! a spe*i0i* drug produ*t a!d spe*i0i* *o!tai!er a!d *losure s?stem s&ould be assessed, 9!der proposed 2e*, 2e*, 4#4,$0(d)(2)((i) a!d 60#,#2(d)(2)(iii), t&e 0ollo+i!g *&a!ge +as to be do*ume!ted i! t&e !eDt a!!ual report: A! eDte!sio! o0 a! eDpiratio! dati!g period based upo! 0ull s&el0 li0e data o! 0ull produ*tio! bat*&es obtai!ed 0rom a proto*ol appro(ed i! t&e appli*atio!, (.omme!t #00) 7a!? *omme!ts re*omme!ded *&a!ges relati!g to t&e p&rase BB0ull produ*tio! bat*&es,CC A 0e+ *omme!ts re*omme!ded deleti!g t&e p&rase be*ause t&is re>uireme!t +ould u!!e*essaril? i!*rease regulator? burde!, is u!!e*essaril? restri*ti(e, a!dEor be*ause appli*a!ts s&ould be allo+ed to use eit&er pilot or produ*tio! bat*&es to eDte!d a! eDpiratio! date, '!e *omme!t 0urt&er said t&at pilot bat*&es *a! be used to support t&e sa0et? a!d e00i*a*? o0 t&e produ*t a!d 0or appro(al o0 a! N-A eDpiratio! dateJ t&ere0ore, pilot bat*&es s&ould be allo+ed to support a! eDte!sio! o0 a! eDpiratio! dati!g period, A!ot&er *omme!t re*omme!ded t&at BB0ullCC be repla*ed b? BBprodu*tio!%s*ale,CC 6&e *omme!t said t&at t&e +ord BB0ullCC ma? *ause *o!0usio!, +&ere bat*& s*ale 0or a produ*t ma? be (aried, 6&e *omme!t said t&at BB0ullCC *ould be i!terpreted as t&at o!l? t&e largest si=e

bat*& o0 a! appro(ed bat*& si=e ra!ge *ould be used to support a! eDte!sio! o0 a! eDpiratio! dati!g period, '!e *omme!t said t&at it s&ould be *lari0ied t&at t&e bat*& !eed !ot &a(e bee! sold, '!e *omme!t said t&at produ*tio! lots s&ould be de0i!ed i! t&e BBde0i!itio!sCC se*tio! to i!*lude (alidatio!Es*ale%up bat*&es ma!u0a*tured b? t&e represe!tati(e produ*tio! pro*ess +it&i! a te!%0old bat*& si=e 0or *o!siste!*? +it& 29"A.E;A."A., [["age #8$32 F-A &as re(ised 2e*, 2e*, 4#4,$0(d)(2)((i) a!d 60#,#2(d)(2)(iii) b? repla*i!g t&e term BB0ull produ*tio! bat*&CC +it& BBprodu*tio! bat*&,CC F-A de*li!es to i!*lude a de0i!itio! o0 produ*tio! bat*& i! t&e regulatio!s, A de0i!itio! is i!*luded i! t&e /.1 guida!*e e!titled BB2tabilit? 6esti!g o0 Ne+ -rug 2ubsta!*es a!d -rug "rodu*ts,CC F-A *o!siders a produ*tio! bat*& to be o!e made at produ*tio! s*ale usi!g produ*tio! e>uipme!t i! a produ*tio! 0a*ilit? as spe*i0ied i! t&e appli*atio!, "rodu*tio! s*ale does !ot !e*essaril? mea! t&e largest bat*& si=e produ*ed, but a bat*& o0 a si=e or +it&i! a bat*& si=e ra!ge t&at &as bee! appro(ed i! t&e appli*atio!, 6&e bat*& !eed !ot &a(e bee! sold, but s&ould be o!e t&at is eligible to be sold (e,g,, must pass its spe*i0i*atio!), /! *ertai! *ases, F-A allo+s data 0rom pilot bat*&es to be used to support appro(al o0 a! appli*atio!, 6&is is *o!siste!t +it& F-ACs e00orts to redu*e t&e time it ta:es to bri!g !e+ drugs to mar:et, '0te! t&ere are *&a!ges +&e! mo(i!g 0rom a pilot ma!u0a*turi!g pro*ess to a produ*tio! pro*ess, Alt&oug& t&ese are usuall? mi!or i! !ature a!d !ot eDpe*ted to a00e*t t&e stabilit? o0 t&e produ*t, t&e de0i!iti(e data to support a! eDpiratio! date s&ould be based o! produ*tio! bat*&esJ t&ere0ore, F-A de*li!es to re(ise t&e regulatio! to i!*lude pilot bat*&es, F-A +ould eDpe*t re>uests 0or a! eDte!sio! o0 a! eDpiratio! dati!g period based o! data 0rom pilot bat*&es to be submitted i! a prior appro(al suppleme!t, 9!der proposed 2e*, 2e*, 4#4,$0(d)(2)((ii) a!d 60#,#2(d)(2)((ii), t&e 0ollo+i!g *&a!ge is do*ume!ted i! t&e !eDt a!!ual report: BB6&e additio!, deletio!, or re(isio! o0 a! alter!ate a!al?ti*al pro*edure t&at pro(ides t&e same or i!*reased assura!*e o0 t&e ide!tit?, stre!gt&, >ualit?, purit?, or pote!*? o0 t&e material bei!g tested as t&e a!al?ti*al pro*edure des*ribed i! t&e appro(ed appli*atio!,CC F-A, o! its o+! i!itiati(e, is *lari0?i!g t&ese se*tio!s as 0ollo+s: BB6&e additio! or re(isio! o0 a! alter!ati(e a!al?ti*al pro*edure t&at pro(ides t&e same or i!*reased assura!*e o0 t&e ide!tit?, stre!gt&, >ualit?, purit?, or pote!*? o0 t&e material bei!g tested as t&e a!al?ti*al pro*edure des*ribed i! t&e appro(ed appli*atio!, or deletio! o0 a! alter!ati(e a!al?ti*al pro*edure,CC 9!der proposed 2e*, 4#4,$0(d)(2)((iii), t&e 0ollo+i!g *&a!ge is to be do*ume!ted i! t&e !eDt a!!ual report: 6&e additio! b? embossi!g, debossi!g, or e!gra(i!g o0 a *ode impri!t to a solid oral dosage 0orm drug produ*t ot&er t&a! a modi0ied release dosage 0orm, or a mi!or *&a!ge i! a! eDisti!g *ode impri!t, (.omme!t #0#) A 0e+ *omme!ts re>uested t&at F-A re(ise t&is pro(isio! to allo+ t&e additio! o0 a! i!: impri!t, '!e *omme!t 0urt&er said t&at u!der part 206 (2# .FR part 206) (/mpri!ti!g o0 2olid 'ral -osage Form -rug "rodu*ts For 1uma! 9se), +&i*& &as bee! i! e00e*t 0or o(er 3 ?ears, all solid dosage 0orms are re>uired to &a(e impri!ts a!d t&at t&e re>uireme!t to impri!t i!*ludes a! i!: *ode impri!t, A!ot&er *omme!t said it is !ot *lear +&et&er t&e pro(isio! i!*ludes i!: pri!ti!g, a!d a *ross%re0ere!*e to part 206 ma? also be &elp0ul, '!e

*omme!t re>uested t&at +ordi!g s&ould be added to allo+ 0or i!: pri!ti!g o! modi0ied dosage 0orms, as t&is s&ould !ot impa*t drug release, F-A de*li!es to re(ise t&e regulatio! as re>uested a!d is *lari0?i!g t&at i!:s are !ot i!*luded i! t&is pro(isio!, F-A belie(es t&at a!? re*omme!datio!s o! &o+ to report t&e additio! o0 i!:s is best &a!dled i! guida!*e do*ume!ts so t&at t&e issues a!d *o!ditio!s asso*iated +it& su*& *&a!ges *a! be 0ull? eDplai!ed, For eDample, F-A +ould eDpe*t t&at a!? *olors used i! a! i!: impri!t +ould &a(e a! a**eptable status u!der F-A regulatio! (e,g,, 2# .FR parts $4 a!d $4), (.omme!t #02) '!e *omme!t said t&at F-A s&ould delete t&e +ord BBmi!orCC 0rom t&e p&rase BBmi!or *&a!geCC i! t&e *ode impri!t pro(isio! (proposed 2e*, 4#4,$0(d)(2)((iii)), F-A de*li!es to re(ise t&e pro(isio! as re>uested, 6&e term BBmi!orCC &as bee! i!*luded i! t&is part o0 t&e regulatio! si!*e #983, ;ased o! F-ACs eDperie!*e, t&is +ordi!g &as !ot bee! 0ou!d to be u!*lear, !or &as it resulted i! i!*o!siste!t impleme!tatio! o0 su*& *&a!ges, 9!der proposed 2e*, 4#4,$0(d)(2)(D), t&e 0ollo+i!g *&a!ge +as to be do*ume!ted i! t&e !eDt a!!ual report: A! editorial or similar mi!or *&a!ge i! labeli!g, (.omme!t #04) A 0e+ *omme!ts re>uested t&at F-A pro(ide i! t&e regulatio!s spe*i0i* eDamples o0 editorial or similar mi!or *&a!ges i! labeli!g, F-A de*li!es to pro(ide spe*i0i* eDamples i! t&e regulatio!s, As stated i! t&e @u!e #999 proposal, t&e age!*?Cs approa*& is to issue regulatio!s t&at set out broad, ge!eral *ategories o0 ma!u0a*turi!g *&a!ges a!d use guida!*e do*ume!ts to pro(ide F-ACs *urre!t t&i!:i!g o! t&e spe*i0i* *&a!ges i!*luded i! t&ose *ategories, F-A &as pro(ided re*omme!datio!s o! a!d eDamples o0 spe*i0i* *&a!ges i! spe*i0i*atio!s i! F-ACs guida!*es e!titled BB.&a!ges to a! Appro(ed N-A or AN-ACC a!d BB.&a!ges to a! Appro(ed Appli*atio! 0or 2pe*i0ied ;iote*&!olog? a!d 2pe*i0ied 2?!t&eti* ;iologi*al "rodu*ts,CC "roposed 2e*, 4#4,$0(d)(4)(i) a!d (d)(4)(ii) re>uired t&at, 0or *&a!ges des*ribed i! t&e a!!ual report, t&e appli*a!t must submit a list o0 all produ*ts i!(ol(ed, a stateme!t b? t&e &older o0 t&e appro(ed appli*atio! t&at t&e e00e*ts o0 t&e *&a!ge &a(e bee! (alidated, a!d a 0ull des*riptio! o0 t&e ma!u0a*turi!g a!d *o!trols *&a!ges, i!*ludi!g t&e ma!u0a*turi!g site(s) or area(s) i!(ol(ed, (.omme!t #04) 7a!? *omme!ts re*omme!ded t&at t&e term BB(alidatedCC be repla*ed +it& BBassessedCC or BBassessed, as appropriateCC, 6&e *omme!tsC reaso!i!g +as similar to t&at dis*ussed pre(iousl? i! similar *omme!ts 0or 2e*, 4#4,4(b) u!der se*tio! ///,A o0 t&is do*ume!t e!titled BB-e0i!itio!s,CC F-A &as repla*ed t&e term BB(alidatedCC +it& BBassessed,CC 1o+e(er, F-A de*li!es to add t&e term BBas appropriate,CC 2e*tio! 306A o0 t&e a*t re>uires a! appli*a!t to assess t&e e00e*ts o0 ea*& *&a!ge, F-A belie(es t&at t&e additio! o0 BBas appropriateCC ma? i!*orre*tl? gi(e t&e impressio! t&at t&is i!0ormatio! is !ot routi!el? !eeded a!d +ould result i! *&a!ges bei!g submitted +it& i!su00i*ie!t i!0ormatio!, (.omme!t #03) .o!*er!i!g t&e p&rase BBa list o0 all produ*ts i!(ol(ed,CC o!e *omme!t as:ed +&et&er t&e same *&a!ges, proposed 0or multiple produ*ts, &a(e to be i!*luded i! t&is list, a!d +&et&er F-A +a!ts to be !oti0ied as to all o0 t&e produ*ts t&at are a00e*ted i! all a!!ual reports, 6&e *omme!t as:ed 0or *lari0i*atio!, F-A &as deleted t&e p&rase BBa list o0 all produ*ts i!(ol(ed,CC F-A does !ot eDpe*t t&e listi!g o0 *ross re0ere!*es to drug produ*ts

appro(ed i! ot&er appli*atio!s, F-A does eDpe*t t&e *&a!ges to be des*ribed 0ull? (2e*, 4#4,$0(d)(4)(ii)), /0 t&ere are multiple produ*ts i! a! appli*atio! (e,g,, stre!gt&s), F-A +ould eDpe*t t&e des*riptio! to ide!ti0? +&i*& produ*ts i! t&e appli*atio! are a00e*ted b? t&e *&a!ge, (.omme!t #06) '!e *omme!t said i!*ludi!g a stateme!t t&at a *&a!ge &as bee! (alidated or assessed prese!ts u!due additio!al burde! to t&e appli*a!t, 6&e *omme!t said t&at assessme!t is guara!teed i! t&e 0ili!g (ia pro(isio! o0 rele(a!t supporti(e data a!d t&at restati!g t&is 0a*t o0 *omplia!*e +it& regulator? re>uireme!ts is redu!da!t, F-A disagrees t&at t&e re>uireme!t to i!*lude t&is stateme!t is a! u!due [["age #8$34 additio!al burde! a!d de*li!es to re(ise t&e regulatio! as re>uested, (.omme!t #0$) A 0e+ *omme!ts said t&at spe*i0?i!g details o0 eDa*t BBareas i!(ol(edCC is i!appropriate, si!*e t&is i!0ormatio! is !ot t?pi*all? part o0 t&e N-A 0ili!g, but is subAe*t to 0ield i!spe*tio!, 6&e *omme!t said it s&ould !ot be pro(ided i! t&e a!!ual report, F-A disagrees t&at t&is i!0ormatio! is o!l? !e*essar? 0or 0ield i!spe*tio!s a!d de*li!es to ma:e t&e re(isio!, 6&is i!0ormatio! ma? !ot be esse!tial i! all *ases, 1o+e(er, it is !e*essar? 0or ma!? ma!u0a*turi!g site *&a!ges, For eDample, F-A re>uires t&e spe*i0i* 0illi!g li!eEroom 0or sterile produ*ts to be ide!ti0ied i! t&e appli*atio!, "roposed 2e*, 4#4,$0(d)(4)(iii) re>uired t&at, 0or *&a!ges des*ribed i! t&e a!!ual report, t&e appli*a!t must submit t&e date ea*& *&a!ge +as made, a *ross%re0ere!*e to rele(a!t (alidatio! proto*ols a!dEor 2'"s, a!d rele(a!t data 0rom studies a!d tests per0ormed to e(aluate t&e e00e*t o0 t&e *&a!ge o! t&e ide!tit?, stre!gt&, >ualit?, purit?, or pote!*? o0 t&e produ*t as t&ese 0a*tors ma? relate to t&e sa0et? or e00e*ti(e!ess o0 t&e produ*t ((alidatio!), (.omme!t #08) '!e *omme!t re*omme!ded t&at 2e*, 4#4,$0(d)(4)(iii) be deleted e!tirel? be*ause it represe!ts additio!al reporti!g re>uireme!ts t&at are !ot *o!siste!t +it& t&e a*t, F-A de*li!es to delete 2e*, 4#4,$0(d)(4)(iii), 2e*tio! 306A(d)(2)(A) o0 t&e a*t re>uires t&at a! a!!ual report *o!tai! su*& i!0ormatio! as F-A determi!es to be appropriate a!d t&e i!0ormatio! de(eloped to assess t&e e00e*ts o0 t&e *&a!ge, F-A is spe*i0?i!g t&e t?pe o0 i!0ormatio! it eDpe*ts to be i!*luded i! a! a!!ual report, a!d t&is a*tio! is *o!siste!t +it& t&e a*t, (.omme!t #09) A 0e+ *omme!ts re*omme!ded t&at F-A s&ould delete t&e p&rase BBt&e date ea*& *&a!ge +as made,CC 6&e *omme!ts i!*luded t&e 0ollo+i!g reaso!s 0or t&is re*omme!datio!: (#) 2pe*i0?i!g a! eDa*t impleme!tatio! date +ould prese!t a! u!due burde! o! bot& ma!u0a*turi!g a!d regulator? a00airs perso!!el, (2) t&e additio! o0 t&is i!0ormatio! to eDisti!g pra*ti*e +ould result i! i!*reased regulator? burde!, (4) t&e re>uireme!t is ambiguous as to +&et&er t&e date is to be t&e date t&e produ*t +as made +it& t&e *&a!ge or some ot&er date su*& as t&e date t&e produ*t made +it& t&e *&a!ge +as put i!to mar:et distributio!, a!d (4) t&e data represe!t i!0ormatio! best suited 0or a 0ield i!spe*tio!, 2ome *omme!ts stated t&at t&e 0a*t t&at a! appli*a!t &as reported a *&a!ge i! a! a!!ual report *o(eri!g a spe*i0ied time period s&ould be su00i*ie!t 0or age!*? re(ie+, F-A de*li!es to re(ise t&e regulatio! as re>uested, 6&e date +&e! a *&a!ge is impleme!ted is importa!t to ide!ti0? t&e produ*tio! bat*&es

t&at ma? be a00e*ted b? t&e *&a!ge, 6&is is importa!t 0or (arious reaso!s, i!*ludi!g allo+i!g re(ie+ers to *ompare data 0rom di00ere!t bat*&es prepared at di00ere!t times to determi!e i0 a *&a!ge &as a00e*ted produ*t >ualit?, F-A &as re>uired t&e date o0 impleme!tatio! 0or *&a!ges reported i! a!!ual reports si!*e #983 u!der 2e*, 4#4,8#(b)(2)(i()(b) a!d does !ot belie(e t&at t&is pro(isio! *a! be *o!strued as a! u!due or additio!al burde! or t&e sole pur(ie+ o0 a 0ield i!spe*tio!, 6o mai!tai! *o!siste!*? +it& 2e*, 4#4,8#(b)(2)(i()(b), F-A &as re(ised t&e p&rase to read: BB6&e date ea*& *&a!ge +as impleme!ted,CC F-A *o!siders BBt&e date ea*& *&a!ge +as impleme!tedCC to be t&e date t&at t&e *o!ditio! establis&ed i! t&e appro(ed appli*atio! is *&a!ged, !ot +&e! t&e produ*t made +it& t&e *&a!ge is distributed, (.omme!t ##0) 7a!? *omme!ts said t&at t&e p&rase BBa *ross% re0ere!*e to rele(a!t (alidatio! proto*ols a!dEor 2'"CsCC s&ould be deleted, 6&e *omme!ts i!*luded t&e 0ollo+i!g reaso!s 0or t&is re*omme!datio!: (#) 6&e additio! o0 t&is i!0ormatio! to eDisti!g pra*ti*e +ould result i! i!*reased regulator? burde!, (2) t&e re>uireme!t is ambiguous as (alidatio! proto*ols a!dEor 2'"s are !eeded o!l? i! *ertai! situatio!s, a!d (4) t&e data represe!t i!0ormatio! best suited 0or a 0ield i!spe*tio!, F-A &as re(ised t&is pro(isio! to *lari0? +&e! a *ross%re0ere!*e to (alidatio! proto*ols a!d 2'"Cs are !eeded, As dis*ussed earlier i! t&is do*ume!t i! respo!se to similar *omme!ts o! 2e*, 4#4,$0(b)(4), (alidatio! proto*ols a!d data !eed !ot be submitted i! t&e appli*atio!, u!less ot&er+ise spe*i0ied b? F-A, but s&ould be retai!ed at t&e 0a*ilit? a!d be a(ailable 0or re(ie+ b? F-A at t&e age!*?Cs dis*retio!, For most produ*ts, F-A does !ot re>uire t&e submissio! o0 (alidatio! proto*ols a!d data, 1o+e(er, 0or a !atural produ*t, a re*ombi!a!t -NA% deri(ed protei!Epol?peptide, a *ompleD or *o!Augate o0 a drug substa!*e +it& a mo!o*lo!al a!tibod?, or sterili=atio! pro*ess, F-A does re>uire t&e submissio! o0 (alidatio! proto*ols 0or *ertai! *riti*al ma!u0a*turi!g pro*esses u!i>ue to t&ese drug substa!*es a!d drug produ*ts, /! additio!, a! appli*a!t is re>uired to submit a BB0ull des*riptio! o0 *o!trols used 0or, t&e ma!u0a*ture, pro*essi!g, a!d pa*:i!g o0 a drugCC (se*tio! 303 o0 t&e a*t), 6&is i!0ormatio! ma? be submitted i! di00ere!t 0orms, i!*ludi!g 2'"s, /! most *ases, 2'"s do !ot i!*lude i!0ormatio! rele(a!t to t&e N-A or AN-A re(ie+, but rat&er i!0ormatio! rele(a!t to determi!i!g a! appli*a!tCs *omplia!*e +it& .)7"s, 1o+e(er, i! t&e *ase o0 a !atural produ*t, a re*ombi!a!t -NA% deri(ed protei!Epol?peptide, a *ompleD or *o!Augate o0 a drug substa!*e +it& a mo!o*lo!al a!tibod?, or a sterili=atio! pro*ess, i!0ormatio! *o!tai!ed i! 2'"s is o0te! rele(a!t to t&e re(ie+ o0 *ertai! aspe*ts o0 a! appli*atio!, (.omme!t ###) A 0e+ *omme!ts re*omme!ded t&at t&e term BB(alidatio!CC be deleted, F-A also re*ei(ed *omme!ts re>uesti!g t&at t&e use o0 t&e terms drug, drug produ*t, drug substa!*e, a!d produ*t be sta!dardi=ed, F-A, o! its o+! i!itiati(e, &as di(ided proposed 2e*, 4#4,$0(d)(4)(iii) i!to t&ree paragrap&s to pro(ide *larit?, F-A &as *lari0ied t&e i!0ormatio! origi!all? proposed i! 2e*, 4#4,$0(d)(4)(iii) b? ma:i!g *&a!ges *o!siste!t +it& 2e*, 4#4,$0(b)(4)((i) a!d (b)(4)((ii) a!d deleti!g t&e term BB(alidatio!,CC '! its o+! i!itiati(e, F-A is repla*i!g t&e stateme!t BBe(aluate t&e e00e*t o0 t&e *&a!ge o! t&e ide!tit?, stre!gt&, >ualit?, purit?, or pote!*? o0 t&e produ*t as t&ese 0a*tors ma? relate to t&e sa0et? or e00e*ti(e!ess o0 t&e produ*t ((alidatio!)CC +it& BBassess t&e e00e*ts

o0 t&e *&a!geCC be*ause t&is p&rase is de0i!ed i! 2e*, 1, "roto*ols

4#4,4(b),

"roposed 2e*, 4#4,$0(e) stated t&at a! appli*a!t ma? submit o!e or more proto*ols des*ribi!g t&e spe*i0i* tests a!d (alidatio! studies a!d a**eptable limits to be a*&ie(ed to demo!strate t&e la*: o0 ad(erse e00e*t 0or spe*i0ied t?pes o0 ma!u0a*turi!g *&a!ges o! t&e ide!tit?, stre!gt&, >ualit?, purit?, or pote!*? o0 t&e drug as t&ese 0a*tors ma? relate to t&e sa0et? or e00e*ti(e!ess o0 t&e drug, 2u*& proto*ols, or *&a!ges to a proto*ol, +ould be submitted as a suppleme!t re>uiri!g appro(al 0rom F-A prior to distributio! o0 a drug produ*ed +it& t&e ma!u0a*turi!g *&a!ge, 6&e suppleme!t, i0 appro(ed, ma? subse>ue!tl? Austi0? a redu*ed reporti!g *ategor? be*ause o0 t&e redu*ed ris: o0 a! ad(erse e00e*t, (.omme!t ##2) 7a!? *omme!ts re*omme!ded t&at proto*ols be submitted i! *&a!ges%bei!g%e00e*ted suppleme!ts, 6&e reaso!s 0or t&is re*omme!datio! i!*luded: (#) 6&e eDpe*ted bre(it? o0 t&e re(ie+ o0 t&e proto*ol, (2) t&e proposed *&a!ge *ould be impleme!ted a!d appro(ed i! t&e time it ta:es 0or appro(al a!d eDe*utio! o0 t&e proto*ol, a!d (4) t&e abilit? to impleme!t a proto*ol 0aster +ould bri!g [["age #8$34 mu*& !eeded regulator? relie0, '!e *omme!t said t&at ma!dator? limits o! proto*ol re(ie+ times s&ould be establis&ed, ot&er+ise t&ere ma? be less o0 a! i!*e!ti(e 0or appli*a!ts to adopt t&is pro*edure, A!ot&er *omme!t said t&at re>uiri!g prior appro(al 0or t&ese proto*ols ma? be *o!strued as a! i!*rease i! regulator? burde!, F-A de*li!es to re(ise t&e regulatio! as re>uested, 6&e time it ta:es F-A to re(ie+ i!0ormatio! is !ot a 0a*tor i! determi!i!g &o+ t&e *&a!ge s&ould be submitted, 1o+e(er, F-A does eDpe*t t&at it +ill ta:e a substa!tial amou!t o0 time to re(ie+ su*& a proto*ol, /t is eDpe*ted t&at appli*a!ts +ill use proto*ols to Austi0? a redu*ed reporti!g *ategor? 0or a parti*ular *&a!ge, For eDample, appli*a!ts ma? re>uest t&at t&e? be allo+ed to impleme!t a maAor *&a!ge +it&out prior appro(al b? F-A, 6&ese proto*ols +ill i! e00e*t redu*e regulator? o(ersig&t o0 t&e spe*i0ied *&a!ges, a!d F-A *o!siders t&is redu*ed o(ersig&t to &a(e a substa!tial pote!tial to &a(e a! ad(erse e00e*t o! t&e ide!tit?, stre!gt&, >ualit?, purit?, or pote!*? o0 t&e drug produ*t as t&ese 0a*tors ma? relate to t&e sa0et? or e00e*ti(e!ess o0 t&e drug produ*t, 6&ere0ore, t&ese proto*ol submissio!s are *lassi0ied as maAor *&a!ges, K&et&er or !ot a proposed *&a!ge *ould be impleme!ted a!d appro(ed i! t&e time it ta:es 0or appro(al a!d eDe*utio! o0 t&e proto*ol +ould be a 0a*tor i! a! appli*a!tCs de*isio! to submit a proto*ol, 1o+e(er, i!*reased e00i*ie!*? *ould be a*&ie(ed o(erall be*ause a proto*ol *a! be used repeatedl? 0or *&a!ges +it&i! t&e s*ope o0 t&e proto*ol, Also, 0e+er or !o de0i*ie!*ies are eDpe*ted +it& a *&a!ge impleme!ted usi!g a proto*ol, i0 properl? eDe*uted, t&a! +it& a *&a!ge 0or +&i*& t&e spe*i0i* tests, studies, a!d a**epta!*e *riterio! +ere !ot dis*ussed +it& t&e age!*? prior to t&e submissio! o0 t&e i!0ormatio!, F-A *o!ti!uall? stri(es to redu*e re(ie+ times, i!*ludi!g t&e time it ta:es to appro(e ma!u0a*turi!g *&a!ges, /! additio!, t&is rule redu*es t&e o(erall regulator? burde! b? allo+i!g ma!? *&a!ges to be impleme!ted +it&out prior appro(al b? F-A, As pre(iousl? dis*ussed i! t&is do*ume!t, F-A *o!siders a proto*ol submissio! to be a maAor *&a!ge, 6&ere0ore, F-A de*li!es to allo+ t&ese *&a!ges to be submitted

i! a *&a!ges%bei!g%e00e*ted suppleme!t to e00e*t 0aster impleme!tatio!, F-A also de*li!es to establis& ma!dator? limits o! proto*ol re(ie+ times, 6&e timi!g o0 a re(ie+ o0 a suppleme!t 0or a proto*ol +ill be i! a**orda!*e +it& *urre!t pra*ti*e 0or re(ie+i!g suppleme!ts re>uiri!g F-A appro(al prior to impleme!tatio!, F-A does !ot agree t&at re>uiri!g prior appro(al 0or t&ese proto*ols is a! i!*rease i! regulator? burde!, K&ere pre(iousl? allo+ed b? regulatio!s, t&ese *&a!ges +ere spe*i0ied as re>uiri!g prior appro(al, a!d t&is rule Aust eDte!ds t&at optio! o0 submitti!g proto*ols 0or all &uma! drugs, F-A emp&asi=es t&at t&e submissio! o0 a proto*ol is (olu!tar?, a!d i0 a! appli*a!t de*ides t&at submissio! o0 a proto*ol is !ot be!e0i*ial, t&e appli*a!t *a! ma:e *&a!ges to a! appro(ed appli*atio! b? ot&er mea!s spe*i0ied i! t&e regulatio!s, (.omme!t ##4) '!e *omme!t said it +ould li:e to operate +it& t&e u!dersta!di!g t&at i0 a rele(a!t proto*ol is subse>ue!tl? publis&ed i! a! o00i*ial *ompe!dium or F-A do*ume!t, t&e less burde!some proto*ol ma? be applied, F-A is u!able to address t&is >uestio! i! a ge!eral ma!!er be*ause o0 t&e *ompleDit? o0 t&e issues a!d t&e !e+!ess o0 *omparabilit? proto*ols 0or &uma! drugs, A *omparabilit? proto*ol is a! appli*a!t a!d drug produ*t spe*i0i* do*ume!t, K&et&er a *omparabilit? proto*ol *ould be superseded +ould depe!d o! t&e produ*t a!d *&a!ges *o(ered b? a *omparabilit? proto*ol, (.omme!t ##4) F-A re*ei(ed ma!? *omme!ts re>uesti!g spe*i0i* guida!*e o! de(elopi!g proto*ols, A 0e+ *omme!ts re*omme!ded t&at F-A issue a guida!*e do*ume!t t&at i!*ludes spe*i0i* eDamples o0 *omparabilit? proto*ols t&at are appro(able, A!ot&er *omme!t said t&at t&e *omparabilit? proto*ol guida!*e s&ould *o!tai! a su00i*ie!t le(el o0 detail o! testi!g re>uireme!ts, '!e *omme!t said it +ould +el*ome F-ACs i!(ol(eme!t i! dra0ti!g BB*ommo!CC *omparabilit? proto*ols, so t&at *o!siste!t re>uireme!ts are imposed o! all spo!sors, 6&e *omme!t said t&at, alter!ati(el?, F-A guida!*e o! *omparabilit? proto*ol 0ormat a!d *o!te!t +ould be &elp0ul, /! t&e Federal Register o0 Februar? 23, 2004 (68 FR 8$$2), F-A publis&ed a dra0t guida!*e o! *omparabilit? proto*ols, F-A +is&es to ad(ise appli*a!ts t&at +&ile i! *ertai! *ases F-A ma? be able to pro(ide spe*i0i* eDamples o0 a**eptable proto*ols or BB*ommo!CC *omparabilit? proto*ols, it is li:el? t&at t&ese +ill be limited be*ause a *omparabilit? proto*ol is a! appli*a!t% a!d drug produ*t% spe*i0i* do*ume!t, Appli*a!ts +ill, i! most *ases, be respo!sible 0or de(elopi!g t&eir o+! proto*ols, (.omme!t ##3) '!e *omme!t said t&at, i! a ma!!er similar to t&e pro*edure de(eloped 0or dissemi!ati!g bioe>ui(ale!*e guida!*e i!0ormatio!, *omparabilit? proto*ols t&at &a(e bee! re(ie+ed a!d appro(ed b? t&e age!*? s&ould be made a(ailable u!der t&e Freedom o0 /!0ormatio! A*t, 6&e *omme!t said t&at t&is pra*ti*e +ill &elp promote &armo!i=atio! +it&i! t&e age!*? +it& respe*t to postappro(al *&a!ge a!d ma? pro(ide i!terested parties +it& guida!*e o! t&e age!*?Cs ge!eral submissio! re>uireme!ts, A0ter F-A issues a! appro(al letter, data a!d i!0ormatio! i! a! appli*atio! +ill be eligible 0or publi* dis*losure to t&e eDte!t permitted b? t&e appli*able statutes a!d age!*? regulatio!s (see, 0or eDample, t&e Freedom o0 /!0ormatio! A*t (3 9,2,., 332), t&e 6rade 2e*rets A*t (#8 9,2,., #903), 2# .FR part 20, a!d 2e*, 2e*, 4#4,440 a!d 60#,3#), (.omme!t ##6) '!e *omme!t re*omme!ded t&at F-A e!*ourage t&e use o0 pa*:agi!g e>ui(ale!*? proto*ols to redu*e regulator? reporti!g burde!s,

eDpedite appro(al o0 ma!u0a*turi!g *&a!ges, a!d simpli0? reporti!g *oordi!atio! 0or pa*:agi!g ma!u0a*turers, 6&e *omme!t !oted t&at submissio! o0 t&ese proto*ols +as sometimes dis*ouraged b? F-A i! t&e past, 6&e *omme!t also suggested t&at su*& proto*ols ma? be submitted +it&i! 6?pe /// drug master 0iles (-7Fs) to eDpedite t&e impleme!tatio! o0 ma!u0a*turi!g *&a!ges at t&e pa*:agi!g a!d pa*:agi!g *ompo!e!t ma!u0a*turer le(el, "roto*ols, i!*ludi!g pa*:agi!g e>ui(ale!*? proto*ols, ma? be submitted 0or F-A *o!sideratio!, 9!der *ertai! *ir*umsta!*es, su*& as *&a!ges a00e*ti!g a large !umber o0 appli*atio!s, F-A ma? re(ie+ a proto*ol submitted to a 6?pe /// -7F t&at +ill be used to support *&a!ges a00e*ti!g drug produ*t appli*atio!s, /!0ormatio! i! a -7F is !ot appro(ed or disappro(edJ t&ere0ore, a!? proto*ol submitted to a -7F *a!!ot be appro(ed (2e*, 4#4,420), Admi!istrati(e issues relati!g to re(ie+ o0 proto*ols i! a -7F prese!t some u!i>ue *&alle!ges, a!d a -7F &older s&ould *oordi!ate +it& t&e age!*? prior to submitti!g su*& a proto*ol, (.omme!t ##$) '!e *omme!t re>uested t&at t&e +ords BB(alidatio! studiesCC be *lari0ied, 6&e *omme!t as:ed +&et&er t&is mea!s BBassessme!t studiesCC to assess t&e impa*t o0 t&e *&a!ge, or does it re0er to .)7" (alidatio! studies, 6&e *omme!t said t&at i0 it re0ers to .)7" (alidatio! studies, it s&ould o!l? be appli*able 0or sterilit? (alidatio!, A 0e+ *omme!ts re>uested t&at t&e pro(isio! be *lari0ied to state t&at a proto*ol *a! be submitted i! a! origi!al appli*atio!, [["age #8$33 F-A &as *lari0ied t&e pro(isio! b? deleti!g t&e +ord BB(alidatio!CC a!d i!di*ati!g t&at a proto*ol ma? be submitted i! a! origi!al appli*atio!, Various t?pes o0 studies, i!*ludi!g (alidatio! studies, ma? be !eeded i! a proto*ol, A *omparabilit? proto*ol *a! be submitted i! a! origi!al appli*atio! or a0ter appro(al o0 t&e appli*atio! i! a suppleme!t re>uiri!g appro(al 0rom F-A prior to distributio! o0 a drug produ*t produ*ed +it& t&e ma!u0a*turi!g *&a!ge, '! its o+! i!itiati(e F-A &as re(ised 2e*, 4#4,$0(e) b? repla*i!g t&e p&rase BBa**epta!*e limitsCC +it& BBa**epta!*e *riteriaCC to promote *o!siste!*? i! t&e termi!olog? used i! t&e de0i!itio! o0 spe*i0i*atio! a!d t&e p&rase BBpurit?, or pote!*?CC +it& BBpurit?, a!d pote!*?CC 0or *o!siste!*? +it& se*tio! 306A o0 t&e a*t, /, /mpleme!tatio! o0 t&e Fi!al Rule a!d )uida!*e (.omme!t ##8) 2e(eral *omme!ts urged F-A to +it&dra+ t&e @u!e #999 proposal a!d guida!*e a!d de(elop !e+ do*ume!ts a!d permit a! opportu!it? 0or *omme!t, 6&e *omme!ts e!*ouraged F-A to +or: i! *ollaboratio! +it& t&e i!dustr? a!d t&e publi* i! *ra0ti!g impro(ed (ersio!s o0 t&ese do*ume!ts, 6&e *omme!ts *o!te!ded t&at t&e @u!e #999 proposal a!d guida!*e 0ail to reali=e t&e i!te!t o0 .o!gress to relie(e regulator? burde!J t&at a substa!tial !umber o0 i!di(idual issues i! t&e @u!e #999 proposed rule a!d guida!*e re>uire re(isio!J t&at t&ere +as a la*: o0 i!dustr? a!d publi* i!(ol(eme!t i! dra0ti!g t&e do*ume!tsJ a!d, too s&ort a time period +as gi(e! 0or *omme!ts a!d subse>ue!t re(isio!s, F-A de*li!es to +it&dra+ t&e @u!e #999 proposal a!d guida!*e, F-ACs pro*edures 0or rulema:i!g are go(er!ed b? t&e Admi!istrati(e "ro*edure A*t (3 9,2,., 334) a!d set 0ort& i! F-A regulatio!s at 2# .FR #0,40 a!d #0,80, )uida!*es are de(eloped i! a**orda!*e +it& t&e pro*edures set

out i! F-ACs good guida!*e pra*ti*es regulatio! (see t&e Federal Register o0 2eptember #9, 2000 (63 FR 36468), a!d 2# .FR #0,##3), As dis*ussed pre(iousl? i! t&is do*ume!t, t&e use o0 guida!*e do*ume!ts +ill allo+ F-A to more easil? a!d >ui*:l? modi0? a!d update importa!t i!0ormatio!, 7oreo(er, se*tio! 306A o0 t&e a*t eDpli*itl? pro(ides F-A t&e aut&orit? to use guida!*e do*ume!ts to determi!e t&e t?pe o0 *&a!ges t&at do or do !ot &a(e a substa!tial pote!tial to ad(ersel? a00e*t t&e sa0et? or e00e*ti(e!ess o0 t&e drug produ*t, /! t&e @u!e #999 proposal, F-A proposed to impleme!t se*tio! 306A o0 t&e a*t 0or &uma! N-As a!d AN-As a!d 0or li*e!sed biologi*al produ*ts, /! t&at same issue o0 t&e Federal Register, F-A a!!ou!*ed t&e a(ailabilit? o0 a dra0t guida!*e 0or i!dustr? e!titled BB.&a!ges to a! Appro(ed N-A or AN-ACC to assist appli*a!ts i! determi!i!g &o+ t&e? s&ould report *&a!ges to a! appro(ed N-A or AN-A u!der se*tio! 306A o0 t&e a*t a!d u!der t&e proposed re(isio!s to t&e &uma! drug regulatio!s pertai!i!g to suppleme!ts a!d ot&er *&a!ges to a! appro(ed appli*atio!, F-A allo+ed 0or publi* parti*ipatio! i! t&e de(elopme!t o0 t&e regulatio! a!d guida!*e *o!siste!t +it& F-A regulatio!s a!d poli*? a!d to t&e eDte!t pra*ti*able, 6&e time period to pro(ide publi* *omme!t +as *o!siste!t +it& F-ACs regulatio!s a!d statutor? re>uireme!ts, F-A also &eld a publi* meeti!g o! August #9, #999, to &ear *omme!ts o! t&e guida!*e a!d t&e proposed rule, /! t&e Federal Register o0 No(ember 24, #999 (64 FR 63$#6), F-A a!!ou!*ed t&e a(ailabilit? o0 a 0i!al guida!*e to assist appli*a!ts i! determi!i!g &o+ t&e? s&ould report *&a!ges to a! appro(ed N-A or AN-A u!der se*tio! 306A o0 t&e a*t (t&e No(ember #999 guida!*e), F-A &as *are0ull? *o!sidered t&e publi* *omme!ts a!d &as re(ised t&e regulatio! a!d t&e guida!*e as appropriate, F-A belie(es t&at t&e 0i!al regulatio! a!d guida!*e pro(ide 0or sig!i0i*a!t redu*tio! i! regulator? burde! a!d t&ere0ore 0ul0ill t&e i!te!t o0 .o!gress, (.omme!t ##9) '!e *omme!t re*omme!ded t&at F-A publis& t&e 0i!al rule as soo! as possible to mi!imi=e *o!0usio! duri!g t&e tra!sitio! period +&e! se*tio! 306A o0 t&e a*t +ill go(er! *&a!ges, F-A &as *are0ull? *o!sidered t&e publi* *omme!ts submitted o! t&e @u!e #999 proposal a!d &as issued a 0i!al rule as eDpeditiousl? as possible, (.omme!t #20) '!e *omme!t stated t&at t&e 0i!al rule s&ould be impleme!ted t&roug& a BBp&asi!g i!CC o0 t&e regulatio! i! order to edu*ate i!dustr? a!d age!*? re(ie+ers, 6&e *omme!t stated t&at t&e 0i!al promulgatio! a!d impleme!tatio! o0 t&e proposed rule s&ould be u!derta:e! i! *o!Au!*tio! +it& a! i!dustr?%+ide edu*atio!al e00ort, 6&e *omme!t said t&at due to t&e *ost a!d broad s*ope o0 t&e proposal, semi!ars or publi* +or:s&ops o! t&e 0i!al rule +ould be o0 (alue a!d +ould allo+ 0or additio!al i!put 0rom all a00e*ted parties, 6&e *omme!t stated t&at t&e impa*t o0 t&e proposed rule +ill a00e*t regulator? pra*ti*es a!d eDpe*tatio!s o0 ma!u0a*turers, a!d b? *arr?i!g out semi!ars, F-A *ould publi*i=e a!d prepare all *o!*er!ed 0or t&e !e+ re>uireme!ts, 6&e *omme!t also stated t&at t&e publi* semi!ars +ould ser(e to *lari0? regulator? eDpe*tatio!s a!d i!terpretatio!s, F-A does !ot belie(e t&at p&asi!g%i! t&e regulatio! is !e*essar? be*ause se*tio! 306A &as bee! i! e00e*t si!*e No(ember 20, #999, but does i!te!d to dis*uss t&e re(ised regulatio! a!d 0i!al guida!*e i! publi* 0orums, F-A &as alread? &eld publi* 0orums, su*& as t&e Ameri*a! Asso*iatio! o0 "&arma*euti*al 2*ie!tists (AA"2)EF-A Kor:s&op o! 2treamli!i!g t&e .7. Regulator? "ro*ess 0or N-As a!d AN-As (@u!e ##%#4, 2002) to obtai! 0eedba*: o! postappro(al *&a!ges, F-A +ill *o!sider t&e i!0ormatio! obtai!ed 0rom t&is +or:s&op i! a!? 0uture updates o0 t&e

guida!*e, F-A does !ot eDpe*t its re(ie+ers to e!*ou!ter ma!? di00i*ulties i! t&e impleme!tatio! o0 t&is regulatio! as F-A re(ie+ers &a(e bee! +or:i!g +it& se*tio! 306A o0 t&e a*t si!*e it be*ame e00e*ti(e, (.omme!t #2#) A!ot&er *omme!t said t&at F-A s&ould issue a +ritte! eDpla!atio! or &old a publi* meeti!g to dis*uss t&e impa*t o0 allo+i!g t&e *urre!t statute to eDpire +it&out a !e+ rule bei!g 0ormall? appro(ed, 6&e *omme!t said t&at F-A s&ould !ot allo+ t&e proposal to be impleme!ted +it&out ade>uate publi* *omme!t a!d re(ie+ simpl? be*ause t&e statute ma? eDpire, 6&e statute &as !ot eDpired, a!d F-A assumes t&at t&e *omme!t re0ers to t&e eDpiratio! o0 2e*, 4#4,$0, .o!gress ma!dated t&at se*tio! 306A o0 t&e a*t BBta:es e00e*t upo! t&e e00e*ti(e date o0 regulatio!s promulgated b? t&e 2e*retar? o0 1ealt& a!d 1uma! 2er(i*es to impleme!t su*& ame!dme!t, or upo! t&e eDpiratio! o0 t&e 24%mo!t& period begi!!i!g o! t&e date o0 t&e e!a*tme!t o0 t&is A*t, +&i*&e(er o**urs 0irstCC (se*tio! ##6(b) o0 t&e 7oder!i=atio! A*t), 2i!*e No(ember 20, #999, F-ACs regulatio! o0 N-A a!d AN-A postappro(al *&a!ges &as bee! based o! se*tio! 306A o0 t&e a*t, 6&e guida!*e e!titled BB.&a!ges to a! Appro(ed N-A or AN-ACC &as represe!ted F-ACs *urre!t t&i!:i!g o! &o+ to appl? t&e re>uireme!ts o0 se*tio! 306A o0 t&e a*t, F-A &as allo+ed 0or publi* parti*ipatio! *o!siste!t +it& appli*able regulatio!s a!d statutes, (.omme!t #22) '!e *omme!t re>uested t&at F-A *o!sider BBgra!d0at&eri!gCC *&a!ges alread? i! progress b? i!dustr? based upo! alread? appro(ed 29"A. guida!*es, 6&e *omme!t said t&at its abilit? to *o!ti!ue to suppl? produ*t to t&e mar:etpla*e *a! be ad(ersel? a00e*ted b? !o+ &a(i!g [["age #8$36 to rede0i!e t&e reporti!g re>uireme!ts a!d eDte!d t&e time to impleme!tatio!, F-A de*li!es to pro(ide 0or gra!d0at&eri!g o0 *&a!ges alread? i! progress, F-A does !ot belie(e t&at t&is is !e*essar?, F-A *are0ull? *o!sidered t&e eDisti!g 29"A. guida!*es +&e! de(elopi!g t&e regulatio!s a!d t&e guida!*e BB.&a!ges to a! Appro(ed N-A or AN-ACC a!d does !ot belie(e t&at t&ere +ill be situatio!s +&ere impleme!tatio! time +ill be sig!i0i*a!tl? eDte!ded, 6&ere ma? be a limited !umber o0 *ases +&ere impleme!tatio! ma? be dela?ed 0or 40 da?s be*ause o0 t&e !e+ reporti!g *ategor? spe*i0ied i! se*tio! 306A o0 t&e a*t BB2uppleme!t%%*&a!ges bei!g e00e*ted i! 40 da?s,CC but F-A does !ot belie(e t&is is a! u!due &ards&ip, (.omme!t #24) A *omme!t !oted t&at a !umber o0 rele(a!t guida!*e do*ume!ts re>uired to support t&e proposed regulatio!s are !ot ?et impleme!ted (e,g,, stabilit?), !or is t&e guida!*e BB.&a!ges to a! Appro(ed N-A or AN-A,CC 6&e *omme!t re*omme!ded t&at a 0i!ite period be establis&ed i! +&i*& t&ese guida!*e do*ume!ts be *ompleted a!d issued, A 0e+ *omme!ts re*omme!ded t&at all a00e*ted guida!*e do*ume!ts, su*& as t&e 29"A. guida!*es, be re(ised eDpeditiousl? to mi!imi=e *o!0usio! regardi!g *o!0li*ti!g i!0ormatio!, '!e *omme!t re*omme!ded related guida!*es be re(ie+ed +it&i! 60 da?s a0ter issua!*e o0 t&e 0i!al rule, /! t&e Federal Register o0 No(ember 24, #999, F-A a!!ou!*ed t&e a(ailabilit? o0 a 0i!al (ersio! o0 t&e guida!*e 0or i!dustr? e!titled BB.&a!ges to a! Appro(ed N-A or AN-A,CC 6&is guida!*e &as bee! re(ised to *o!0orm to t&is 0i!al rule re(isi!g 2e*, 4#4,$0, F-A *o!ti!ues to update a!d de(elop guida!*es to address parti*ular regulator? a!d

s*ie!ti0i* issues, F-A publis&es t&ese guida!*es as eDpeditiousl? as possible gi(e! its resour*es a!d priorities, /0 guida!*e 0or eit&er re*omme!ded 0ili!g *ategories a!dEor i!0ormatio! t&at s&ould be submitted to support a parti*ular postappro(al ma!u0a*turi!g *&a!ge is !ot a(ailable, t&e appropriate F-A sta00 *a! be *o!sulted 0or ad(i*e, (.omme!t #24) '!e *omme!t re>uested t&at duri!g t&e tra!sitio! period, F-A permit i!dustr? to use t&e guida!*e do*ume!t t&at pro(ides t&e least burde!some regulator? re>uireme!t a!d t&e lo+est reporti!g *ategor?, 2e*tio! 306A o0 t&e a*t a!d t&e 0i!al regulatio!s pro(ide 0or a !e+ approa*& to establis&i!g t&e reporti!g *ategor? 0or postappro(al *&a!ges a!d 0or a! additio!al reporti!g *ategor?, 6o a**ommodate t&ese *&a!ges, F-A &as stated t&at to t&e eDte!t t&e re*omme!datio!s o! reporti!g *ategories i! t&e guida!*e BB.&a!ges to a! Appro(ed N-A or AN-ACC are 0ou!d to be i!*o!siste!t +it& guida!*e publis&ed be0ore t&e BB.&a!ges to a! Appro(ed N-A or AN-ACC guida!*e +as 0i!ali=ed, t&e re*omme!ded reporti!g *ategories i! t&e pre(iousl? publis&ed guida!*es are superseded, (.omme!t #23) '!e *omme!t !oted t&at t&e preamble to t&e @u!e #999 proposal stated t&at to t&e eDte!t t&at t&e re*omme!datio!s o! reporti!g *ategories i! t&e dra0t guida!*e, +&e! 0i!ali=ed, are i!*o!siste!t +it& pre(iousl? publis&ed guida!*e, su*& as t&e 29"A. guida!*es, t&e re*omme!ded reporti!g *ategories i! su*& prior guida!*e +ill be superseded b? t&is !e+ guida!*e upo! its publi*atio! i! 0i!al 0orm, 6&e *omme!t said t&at .-5R i!te!ds to update t&e pre(iousl? publis&ed guida!*es su*& as 29"A., to ma:e t&em *o!siste!t +it& t&is !e+ guida!*e, 6&e *omme!t said it +&oll? supports t&e *reatio! a!d use o0 guida!*e do*ume!ts a!d, i! t&is parti*ular i!sta!*e, re*omme!ds t&at t&e 29"A. pro(isio!s relati!g to *&a!ges i! t&e >ualitati(e or >ua!titati(e 0ormulatio! o0 t&e drug be retai!ed, 6&e *omme!t said t&at a!? re(isio!s to *urre!t guida!*e do*ume!ts s&ould !ot result i! more burde!some re>uireme!ts, 6&e re*omme!datio!s i! t&e 29"A. guida!*es regardi!g >ualitati(e a!d >ua!titati(e 0ormulatio! *&a!ges *a! still be used, F-A i!te!ds to re(ise *urre!t do*ume!ts as appropriate, @, .omme!ts 2pe*i0i* to ;iologi*al "rodu*ts (.omme!t #26) A 0e+ *omme!ts dis*ussed t&e !eed 0or F-A to issue guida!*e 0or t&e blood ba!:i!g i!dustr? 0or *&a!ges to a! appro(ed appli*atio!, 6&e *omme!ts spe*i0i*all? re>uested *lari0i*atio! o! t&e submissio! o0 i!0ormatio! pertai!i!g to a!!ual reports, *omparabilit? proto*ols, *&a!ges i! t&e site o0 testi!g 0rom o!e 0a*ilit? to a!ot&er, a!d e>uipme!t upgrades e(e! +&e! a *&a!ge is due to e>uipme!t upgrades t&at &a(e alread? re*ei(ed 30#(:) *leara!*e, /! additio!, t&e *omme!ts said t&at F-A !eeded to *o!sider t&e least burde!some me*&a!ism 0or submitti!g t&e (arious *&a!ges, F-A agrees t&at guida!*e 0or t&e blood ba!:i!g i!dustr? is !eeded i! t&is area, a!d i! t&e Federal Register o0 August $, 200# (66 FR 4#24$), F-A issued t&e guida!*e BB)uida!*e 0or /!dustr?: .&a!ges to a! Appro(ed Appli*atio!: ;iologi*al "rodu*ts: 1uma! ;lood a!d ;lood .ompo!e!ts /!te!ded 0or 6ra!s0usio! or 0or Furt&er 7a!u0a*ture,CC 6&e guida!*e is i!te!ded to assist ma!u0a*turers o0 K&ole ;lood, ;lood .ompo!e!ts, 2our*e "lasma, a!d 2our*e 8eu:o*?tes i! determi!i!g +&i*& reporti!g me*&a!ism is appropriate 0or a *&a!ge to a! appro(ed li*e!se appli*atio!, 9!der ea*& se*tio! o0 t&e guida!*e, F-A pro(ides *ategories o0 *&a!ges to be reported u!der 2e*, 60#,#2, A list o0

(arious *&a!ges t&at 0alls u!der ea*& *ategor? is also pro(ided, 6&e lists are !ot i!te!ded to be all%i!*lusi(e, 6&e guida!*e des*ribes t&e 0ormat 0or t&e a!!ual report a!d 0urt&er eDplai!s t&e *omparabilit? proto*ol, 6&e guida!*e also addresses 0a*ilit? a!d e>uipme!t *&a!ges, 6&e 3#0(:) *leara!*e o0 a de(i*e to be used i! a blood ba!: setti!g pro(ides assura!*e t&at t&e de(i*e is substa!tiall? e>ui(ale!t to a legall? mar:eted de(i*e 0or +&i*& premar:et appro(al +as !ot re>uired, For e>uipme!t upgrades related to a 3#0(:) de(i*e, t&e *leara!*e o0 t&e de(i*e does !ot address impleme!tatio! o0 t&e de(i*e i! a spe*i0i* blood ba!: setti!g !or does it address t&e pro*edures used b? t&e establis&me!t, t&e >uali0i*atio! a!d trai!i!g o0 sta00 operati!g t&e e>uipme!t, o!site (alidatio! o0 pro*esses, a!d o!goi!g pro*ess *o!trol a!d >ualit? *o!trol, 6&e *ategor? 0or +&i*& a *&a!ge is to be reported depe!ds o! t&e impa*t o0 t&e *&a!ge upo! t&e spe*i0i* biologi*al produ*t, (.omme!t #2$) '!e *omme!t as:ed +&at a!al?sis F-A &as per0ormed to determi!e +&at t?pes o0 *&a!ges s&ould be re(ie+ed b? t&e age!*?, For eDample, i! t&e Federal Register o0 August 4, #994 (38 FR 4#448), F-A, i! addi!g re>uireme!ts to t&e labeli!g .)7" regulatio!s, pro(ided a! a!al?sis t&at labeli!g errors a**ou!ted 0or a! i!ordi!ate !umber o0 re*alls, F-A t&e! issued regulatio!s to address t&is problem, 6&e *omme!t said, &o+e(er, t&at labeli!g *&a!ges are !ot addressed i! .;5RCs guida!*e o! *&a!ge *o!trol a!d &istori*all? &a(e !ot bee! emp&asi=ed duri!g re(ie+ o0 suppleme!ts a!d ot&er *&a!ges to a! appro(ed appli*atio!, 6&e *omme!t as:ed i0 .;5R &as do!e a!? s?stemati*, met&odi*al, +ritte! re(ie+ o0 +ar!i!g letters, re(o*atio!s, suspe!sio!s, re*alls, i!Au!*tio!s, 484%items, a!d so 0ort&, so t&at re(ie+ o0 suppleme!ts is 0o*used o! problems t&at F-A :!o+s are li:el? to result i! publi* &ealt& *o!*er!s, regulator?, or legal a*tio!, "rior to t&e @a!uar? 29, #996 (6# FR 2$49), proposed re(isio! o0 2e*, 60#,#2, F-A per0ormed a! i!0ormal retrospe*ti(e re(ie+ o0 suppleme!ts, /t [["age #8$3$ +as t&e i!te!t o0 t&at re(ie+ to 0o*us t&e re(ie+ o0 ma!u0a*turi!g *&a!ges o! t&ose +it& t&e greatest pote!tial 0or ad(erse e00e*t o! t&e produ*ts, 8abeli!g *&a!ges, alt&oug& !ot ge!erall? tra*:ed as suppleme!ts at t&at time, +ere also *o!sidered i! t&e re(ie+, F-A does !ot agree +it& t&e *omme!t t&at labeli!g *&a!ges &a(e !ot bee! emp&asi=ed duri!g re(ie+ o0 suppleme!ts, 9!til t&e publi*atio! o0 t&e @ul? 24, #99$ 0i!al rule (62 FR 49890) (t&e @ul? #99$ 0i!al rule) t&at re(ised 2e*, 60#,#2, all labeli!g *&a!ges re>uired appro(al prior to impleme!tatio!, 6&e @ul? #99$ 0i!al rule allo+ed *ertai! mi!or editorial *&a!ges to be part o0 a! a!!ual report, 't&er *&a!ges i!te!ded to e!&a!*e t&e sa0et? o0 use o0 t&e produ*t *ould be reported as a *&a!ges%bei!g%e00e*ted suppleme!t, 2ubsta!ti(e *&a!ges to labeli!g still re>uire appro(al prior to impleme!tatio!, (.omme!t #28) '!e *omme!t said t&at i! t&e @ul? #99$ 0i!al rule, F-A &as asserted t&at re(isio! o0 t&e *&a!ge%reporti!g regulatio!s +ill redu*e t&e burde! o0 reporti!g *&a!ges to t&e age!*?, 6&e *omme!t as:ed +&et&er t&is is s?!o!?mous +it& redu*i!g t&e !umber o0 reports o0 *&a!ges to t&e age!*?, /0 !ot, t&e *omme!t as:ed +&at is mea!t b? BBredu*i!g t&e burde!:CC 0or eDample, redu*tio! o0 t&e amou!t o0 time bet+ee! submissio! a!d appro(al, or redu*tio! o0 t&e amou!t o0 data submitted, 6&e *omme!t as:ed +&et&er F-A &as a*tuall? a!al?=ed t&e !umber o0 suppleme!ts submitted si!*e t&e origi!al *&a!ges to t&e

reporti!g re>uireme!ts, a!d +&et&er t&e !umber o0 suppleme!ts &as bee! redu*ed, 6&e *omme!t as:ed +&et&er t&e a!al?sis i!*ludes suppleme!ts due to labeli!g *&a!ges, 6&e *omme!t !oted t&at F-A allo+ed 0or t&e submissio! o0 BB*omparabilit? proto*ols,CC 6&e *omme!t said t&at o!*e a *omparabilit? proto*ol is re(ie+ed a!d appro(ed, t&e *&a!ge still must be reported, albeit a preappro(al suppleme!t ma? be redu*ed to a *&a!ges%bei!g%e00e*ted suppleme!t, a!d so 0ort&, 0or ea*& *ategor? o0 *&a!ge, 6&e *omme!t as:ed +&et&er F-A &as *o!sidered t&ese t?pes o0 submissio!s i! determi!i!g i0 t&e !umber o0 submissio!s &as bee! redu*ed a!d i0 t&e total re(ie+ time 0or a *&a!ge &as bee! redu*ed, Fe+er reports +as o!l? part o0 t&e redu*tio! o0 reporti!g burde! me!tio!ed i! t&e @ul? #99$ 0i!al rule, 6&e re(isio! o0 2e*, 60#,#2 +as also i!te!ded to allo+ 0or more rapid impleme!tatio! o0 *ertai! ma!u0a*turi!g *&a!ges a!d to de*rease t&e amou!t o0 i!0ormatio! re>uired 0or t&ose *&a!ges *o!tai!ed i! a! a!!ual report, K&ile t&e *omparabilit? proto*ol +as i!*luded i! t&e assessme!t, +it&out eDperie!*e it +as di00i*ult to determi!e +&et&er it +ould a*tuall? result i! de*reased reporti!g or i!*reased e00i*ie!*?, 6&ere is still i!su00i*ie!t eDperie!*e +it& t&ese suppleme!ts to ma:e a *lear determi!atio! o! t&at poi!t, No 0ormal *ompariso! &as bee! made o0 !umbers o0 suppleme!ts re*ei(ed i! .;5R be0ore a!d a0ter t&e re(isio! o0 2e*, 60#,#2, 7ultiple *&a!ges to regulator? approa*&es ma:e a dire*t *ompariso! (er? di00i*ult, 8abeli!g *&a!ges, +&ile re>uiri!g appro(al, +ere !ot tra*:ed as suppleme!ts prior to t&e re(isio!, .o!se>ue!tl?, !umbers o0 labeli!g *&a!ges are !ot readil? a(ailable t&roug& a! automated data s?stem, 6&e *&a!ge to t&e ;iologi*s 8i*e!se Appli*atio! 0rom t&e "rodu*t 8i*e!se Appli*atio!E5stablis&me!t 8i*e!se Appli*atio! approa*& also &as &ad a! e00e*t o! t&e !umber o0 submissio!s to .;5R, Furt&er, as t&e *omme!t poi!ts out, t&ere are !o+ more appli*a!ts submitti!g suppleme!ts o! more produ*ts, 5(e! i0 a *ompariso! o0 suppleme!t submissio! !umbers +ere do!e, t&e results +ould be di00i*ult to e(aluate, (.omme!t #29) '!e *omme!t said t&at t&e @u!e #999 proposal ma? perpetuate some eDisti!g *o!0usio! about t&e appli*abilit? o0 t&e regulatio!s set 0ort& i! part 600 (2# .FR part 600), .urre!t part 600 does !ot i!*lude t&e term drugJ &o+e(er, i! t&e de0i!itio!s se*tio! o0 proposed 2e*, 600,4(&&) a!d (ii), as +ell as i! se(eral ot&er pla*es i! t&e @u!e #999 proposal, t&e term BBdrugCC is used rat&er t&a! biologi*al produ*t, 6&e *omme!t re>uested t&at F-A re(ise t&e @u!e #999 proposal to *lari0? t&ose se*tio!s t&at appl? eD*lusi(el? to biologi*al produ*ts, a!d t&ose t&at appl? to bot& drugs a!d biologi*al produ*ts, F-A agrees +it& t&e *omme!t, F-A is *lari0?i!g t&e de0i!itio!s i! proposed 2e*, 600,4(&&) a!d (ii) (!e+ 2e*, 600,4(AA) a!d (::)) b? repla*i!g t&e terms BBdrug substa!*e(s)CC a!d BBdrug produ*t(s)CC +it& BBprodu*t(s),CC 6&e term BBprodu*tsCC is de0i!ed i! 2e*, 600,4(g), For !e+ drugs, t&e terms BBdrug substa!*e(s)CC or BBdrug produ*t(s)CC are !o+ used *o!siste!tl? t&roug&out part 4#4 i! t&is rule, (.omme!t #40) '!e *omme!t said t&at 2e*, 60#,#2(d)(4)(iii) +ould re>uire blood establis&me!ts to submit a stateme!t t&at t&e e00e*ts o0 t&e *&a!ge &a(e bee! (alidated, 6&e *omme!t said t&at t&is is a! additio!al, alt&oug& mi!or, i!*rease i! t&e do*ume!tatio! a!d reporti!g burde! 0or t&e blood i!dustr?, ;e*ause blood establis&me!ts are alread? re>uired to :eep (alidatio! do*ume!tatio! o! 0ile, a!d blood establis&me!ts are i!spe*ted o! a regular basis, t&e *omme!t re>uested t&at t&e re>uireme!t to submit su*& a stateme!t be deleted 0or blood establis&me!ts, F-A disagrees +it& t&e *omme!t t&at blood establis&me!ts s&ould be

eDempt 0rom t&e re>uireme!ts o0 2e*, 60#,#2(d)(4)(iii), 6&ese establis&me!ts are alread? re>uired to report t&e items listed i! 2e*, 60#,#2(d)(4)(i) a!d (d)(4)(ii), Addi!g a stateme!t t&at t&e e00e*ts o0 t&e *&a!ge &a(e bee! assessed does !ot add burde! be?o!d t&e eDisti!g re>uireme!t a!d pro(ides (aluable i!0ormatio! to t&e age!*? *o!*er!i!g t&e establis&me!tCs *&a!ge *o!trols, (.omme!t #4#) '!e *omme!t said t&at t&e @u!e #999 proposal +ould re>uire t&at a suppleme!t or a!!ual report i!*lude i! t&e *o(er letter a list o0 all *&a!ges *o!tai!ed i! t&e suppleme!t or a!!ual report, 6&e *omme!t said t&at t&is !e+ re>uireme!t +ill i!*rease t&e reporti!g burde! 0or blood establis&me!ts, 6&e *omme!t said t&at .;5R &as stated t&at Form F-A 436& is a *o(er letter, 6&e *omme!t as:ed +&? t&e! must blood establis&me!ts 0ill out t&is additio!al !e+ BB*o(er letter,CC 6&e *omme!t also said t&at to re>uire blood establis&me!ts to reiterate all o0 t&e *&a!ges t&at t&e? &a(e *ompiled a!d reported i! t&eir a!!ual reports i! a *o(er letter a**ompa!?i!g t&at a!!ual report is dupli*atio! o0 e00ort, 6&e *omme!t said t&at t&e a!!ual report itsel0 is a! i!*rease i! t&e reporti!g burde! o0 blood establis&me!ts a!d +as !ot re>uired be0ore t&e impleme!tatio! o0 t&e 0orm +it& its i!te!ded paper+or: redu*tio! a!d regulator? e00i*ie!*? goals, 6&e *omme!t re>uested t&at multiple *o(er letters a!d t&e re>uireme!t to reiterate all o0 t&e *&a!ges *o!tai!ed i! t&e report be deleted, F-A agrees i! part +it& t&e *omme!t, "roposed 2e*, 60#,#2(a)(3) &as bee! re(ised to remo(e t&e re0ere!*e to a *o(er letter 0or a!!ual reports, 6&e !eed 0or a list o0 t&e *&a!ges *o!tai!ed i! t&e suppleme!t results 0rom t&e pra*ti*e o0 i!*ludi!g more t&a! a si!gle *&a!ge i! a suppleme!t, 6&is list is !e*essar? to e!sure t&at all *&a!ges are properl? ide!ti0ied a!d addressed i! a timel? ma!!er, 6&e *omme!t misi!terprets stateme!ts b? .;5R o! t&e !ature a!d use o0 Form F-A 436&, F-A &as eDplai!ed t&at Form F-A 436& is esse!tiall? a *o(er s&eet t&at pro(ides F-A +it& i!0ormatio! !e*essar? 0or t&e ide!ti0i*atio! a!d admi!istrati(e pro*essi!g o0 a submissio!, /t does !ot pro(ide detailed i!0ormatio! o! t&e *o!te!t o0 a submissio!, su*& as t&e !umber o0 *&a!ges t&at mig&t be [["age #8$38 *o(ered, 6&is !e*essar? i!0ormatio! ma? be *o!(e?ed most easil? i! a simple *o(er letter t&at is pro(ided +it& t&e suppleme!tal appli*atio!, /t is !ot F-ACs i!te!t t&at i!0ormatio! i! t&e *ompleted Form F-A 436& be dupli*ated i! a *o(er letter, (.omme!t #42) '!e *omme!t said F-A re>uires t&at a 0ield *op? o0 a suppleme!t (eD*ept 0or labeli!g) be pro(ided to a! appli*a!tCs lo*al F-A o00i*e, As t&e 0ield i!spe*tio! 0or*e is !o+ routi!el? i!(ol(ed i! t&e i!spe*tio! o0 biologi*s, t&e *omme!t as:ed +&et&er F-A &as *o!sidered ma:i!g t&is a re>uireme!t +it& regard to .;5R suppleme!ts, F-A disagrees +it& t&e *omme!t, F-A &as *o!sidered eDte!di!g t&e 0ield *op? re>uireme!t to .;5R suppleme!ts, 6&e 0ield i!spe*tio! 0or*e is i!(ol(ed i! t&e i!spe*tio! o0 biologi*al produ*ts t&roug& t&e 6eam ;iologi*s /!itiati(e, 9!der t&is program, a *adre o0 i!spe*tors &as bee! dra+! 0rom 0ield o00i*es t&roug&out F-A, .o!se>ue!tl?, it is u!li:el? t&at t&e perso!!el parti*ipati!g i! a gi(e! i!spe*tio! +ould be assig!ed to t&at appli*a!tCs &ome F-A o00i*e, F-A does !ot belie(e t&at eDte!di!g t&e 0ield *op? re>uireme!t to .;5R suppleme!ts &as su00i*ie!t be!e0it to t&e age!*? to Austi0? t&e additio!al paper+or: re>uireme!ts, (.omme!t #44) '!e *omme!t said t&at t&e proposal to allo+ a!

appli*a!t to re>uest a! eDpedited re(ie+ o0 a suppleme!t i0 a dela? i! ma:i!g t&e *&a!ge +ould impose a! eDtraordi!ar? &ards&ip or 0or publi* &ealt& reaso!s s&ould be reser(ed 0or ma!u0a*turi!g *&a!ges made !e*essar? b? *atastrop&i* e(e!ts (0or eDample, 0ire), 6&ese re>uests s&ould be limited to e(e!ts t&at *ould !ot be reaso!abl? 0oresee! a!d 0or +&i*& t&e appli*a!t *ould !ot pla!, 6&e poli*? o0 .;5R a!d .-5R &as bee! t&at appli*a!ts re>uesti!g eDpedited re(ie+ be*ause o0 *atastrop&i* e(e!ts s&ould do so o!l? +&e! t&e e(e!t *ould !ot be reaso!abl? 0oresee!, Re>uests 0or eDpedited re(ie+ +ill be e(aluated o! a *ase%b?%*ase basis a!d it s&ould be u!derstood t&at !ot all re>uests +ill be gra!ted, (.omme!t #44) '!e *omme!t !oted t&at t&e proposal states t&at i0 F-A disappro(es a suppleme!tal appli*atio!, F-A ma? order t&e ma!u0a*turer to *ease distributio! o0 t&e drug produ*ts made usi!g t&e ma!u0a*turi!g *&a!ge, 6&e *omme!t said t&at ma!? blood establis&me!ts +ill !ot e(e! attempt to use t&is pro(isio! be*ause o0 t&e possibilit? o0 a re*all bei!g re>uired b? F-A i0 t&e ma!u0a*turer &as misAudged t&e *ategori=atio! o0 t&e suppleme!t, 6&e *omme!t said t&at t&is u!*ertai!t? &as alread? resulted i! blood establis&me!ts pursui!g a! u!!e*essaril? *o!ser(ati(e approa*& to reporti!g *ertai! t?pes o0 *&a!ges a!d, *o!se>ue!tl?, impleme!ti!g !e+ te*&!ologies slo+er t&a! !e*essar?, 6&e *omme!t said t&at to &elp blood establis&me!ts impleme!t pro*ess impro(eme!ts more e00i*ie!tl?, t&e proposal s&ould be re(ised to i!*lude eDamples o0 *ir*umsta!*es u!der +&i*& a *ease distributio! a!d subse>ue!t re*all +ould li:el? be ordered a!d t&ose u!der +&i*& it +ould !ot, F-A disagrees +it& t&e *omme!t about t&e blood i!dustr?Cs 0ailure to use t&e pro(isio!, 6&e reaso! 0or t&e 40%da? dela? asso*iated +it& t&e *&a!ges%bei!g%e00e*ted%i!%40%da?s suppleme!t is to allo+ t&e age!*? to !oti0? t&e appli*a!t be0ore t&e produ*t is distributed t&at t&e? &a(e sele*ted t&e +ro!g *ategor? 0or t&e suppleme!t, /! t&e *ase +&ere t&e *ategor? is *orre*tl? *&ose! but t&e suppleme!t *a!!ot be appro(ed, t&e age!*? +ill +or: +it& t&e appli*a!t to mi!imi=e t&e impa*t o0 t&at de*isio!, As dis*ussed pre(iousl? i! t&is do*ume!t, .;5R &as publis&ed a guida!*e 0or t&e ;lood /!dustr? t&at *lari0ies +&at *ategories *&a!ges s&ould 0all i!to a!d +&at i!0ormatio! s&ould be submitted to de*rease t&e possibilit? o0 a! error t&at mig&t result i! a re*all, As pre(iousl? me!tio!ed i! t&is do*ume!t, t&e a(ailabilit? o0 t&e guida!*e +as a!!ou!*ed i! t&e Federal Register o0 August $, 200# (66 FR 4#24$), (.omme!t #43) '!e *omme!t !oted t&at t&e @u!e #999 proposal states t&at additio!s, deletio!s, or re(isio!s to alter!ati(e a!al?ti*al pro*edures (t&at pro(ide t&e same or i!*reased assura!*e o0 t&e ide!ti*al stre!gt&, >ualit?, purit?, or pote!*? o0 t&e material bei!g tested as t&e a!al?ti*al pro*edure des*ribed i! t&e appro(ed appli*atio!) be i!*luded i! t&e a!!ual report, 6&e *omme!t said t&at blood establis&me!ts *urre!tl? are permitted to use 2e*, 640,#20 to obtai! appro(al 0or alter!ate pro*edures, 6&e *omme!t said t&at si!*e F-A +ill alread? be a+are o0 t&is *&a!ge o! t&e date t&e? &a(e gra!ted t&e appro(al, su*& *&a!ge s&ould !ot !eed to be i!*luded i! blood i!dustr? a!!ual reports, 6&e *omme!t said t&at i! :eepi!g +it& t&e paper+or: redu*tio! pri!*iples o0 t&e 7oder!i=atio! A*t, t&is se*tio! s&ould be re(ised so reporti!g o0 *&a!ges alread? appro(ed u!der 2e*, 640,#20 re>uests is !ot re>uired i! a! a!!ual report, 6&e *omme!t &as misi!terpreted t&e *o!*ept o0 a! BBalter!ati(eCC a!al?ti*al pro*edure (o!e pro*edure t&at *a! be substituted 0or a!ot&er) +it& t&e *o!*ept o0 a! alter!ati(e or a! eD*eptio! to a re>uireme!t i! t&e regulatio!s t&at t&e appli*a!t (ie+s as pro(idi!g

e>ui(ale!t sa0et? or e00i*a*?, /! t&e *ase o0 t&e latter, t&e appli*a!t must re>uest appro(al u!der 2e*, 640,#20 be0ore impleme!ti!g ot&er+ise t&e? +ill be i! (iolatio! o0 t&e regulator? re>uireme!t, A! alter!ati(e or eD*eptio! appro(ed u!der 2e*, 640,#20 does !ot &a(e to be i!*luded i! a! a!!ual report, (.omme!t #46) '!e *omme!t *o!*er!ed proposed 2e*, 60#,#2(0)(2)(i)(5) +&i*& pro(ides t&at labeli!g *&a!ges t&at !ormall? re>uire a prior appro(al suppleme!t be submitted i! a *&a!ges bei!g e00e*ted suppleme!t +&e! F-A spe*i0i*all? re>uests t&e *&a!ge, 6&e *omme!t said t&at i!dustr?%+ide labeli!g *&a!ges s&ould be *ategori=ed as a! a!!ual report 0or blood establis&me!ts si!*e u!i0orm labeli!g re>uireme!ts alread? eDist, a!d t&e blood establis&me!t +ould simpl? be reporti!g t&at t&e? &a(e adopted t&e *&a!ge, /! additio!, F-A alread? permits reporti!g o0 *&a!ges to pro*edures i!itiated at t&e re>uest o0 F-A to be reported i! a! a!!ual report, 6&e *omme!t re>uested t&at 0or blood establis&me!ts, F-A re>uire t&at i!dustr?%+ide labeli!g *&a!ges be reported to F-A i! a! a!!ual report, F-A agrees i! part +it& t&e *omme!t, 7a!? i!dustr?%+ide labeli!g *&a!ges are i!itiated b? t&e age!*? t&roug& guida!*e, /0 labeli!g *&a!ges i!*lude spe*i0i* la!guage *o!siste!t +it& F-A re*omme!datio!s, *&a!ges to t&at spe*i0i* labeli!g ma? be reported i! t&e a!!ual report, For eDample, a maAorit? o0 t&e blood i!dustr? uses t&e Ameri*a! Asso*iatio! o0 ;lood ;a!:s *ir*ular o0 i!0ormatio! t&at F-A re(ie+s a!d re*og!i=es as a**eptable be0ore it is pri!ted 0or use b? t&e blood i!dustr?, /! t&is *ase, F-A does !ot !eed to re(ie+ i!di(idual submissio!s, 1o+e(er, i0 a! establis&me!t uses a! i!di(iduall? prepared *ir*ular, F-A +ould +a!t a!? *&a!ge to be submitted to F-A, at a mi!imum, at t&e time t&e *&a!ge is e00e*ted be*ause o0 t&e impa*t t&e *&a!ge ma? &a(e o! t&e sa0e a!d e00e*ti(e use o0 a produ*t, )e!erall?, guida!*e o! re*omme!ded *&a!ges to labeli!g +ill i!*lude i!0ormatio! o! &o+ to report t&e *&a!ge, /V, .o!0ormi!g Ame!dme!ts 6&e regulatio!s o! suppleme!ts a!d *&a!ges to a! appro(ed appli*atio! or li*e!se are *ited t&roug&out F-ACs regulatio!s, ;e*ause F-A is re(isi!g t&ese regulatio!s, t&e age!*? is ta:i!g t&is opportu!it? to ma:e *o!0ormi!g ame!dme!ts to 2# .FR parts 3, 206, 230, 4#4, 600, a!d 60# to re0le*t t&is 0i!al rule, 6&ese *o!0ormi!g ame!dme!ts +ill e!sure t&e a**ura*? a!d *o!siste!*? o0 t&e regulatio!s, [["age #8$39 V, A!al?sis o0 /mpa*ts F-A &as eDami!ed t&e impa*ts o0 t&e 0i!al rule u!der 5De*uti(e 'rder #2866 a!d t&e Regulator? FleDibilit? A*t (3 9,2,., 60#%6#2), a!d t&e 9!0u!ded 7a!dates Re0orm A*t o0 #993 ("ubli* 8a+ #04%4), 5De*uti(e 'rder #2866 dire*ts age!*ies to assess all *osts a!d be!e0its o0 a(ailable regulator? alter!ati(es a!d, +&e! regulatio! is !e*essar?, to sele*t regulator? approa*&es t&at maDimi=e !et be!e0its (i!*ludi!g pote!tial e*o!omi*, e!(iro!me!tal, publi* &ealt& a!d sa0et?, a!d ot&er ad(a!tagesJ distributi(e impa*tsJ a!d e>uit?), 5De*uti(e 'rder #2866 *lassi0ies a rule as sig!i0i*a!t i0 it meets a!? o!e o0 a !umber o0 spe*i0ied *o!ditio!s, i!*ludi!g &a(i!g a! a!!ual e00e*t o! t&e e*o!om? o0 O#00 millio! or ad(ersel? a00e*ti!g i! a material +a? a se*tor o0 t&e e*o!om?, *ompetitio!, or Aobs, 9!der t&e Regulator? FleDibilit?

A*t, i0 a rule &as a sig!i0i*a!t e*o!omi* impa*t o! a substa!tial !umber o0 small e!tities, a! age!*? must a!al?=e regulator? optio!s t&at +ould mi!imi=e a!? sig!i0i*a!t impa*t o0 t&e rule o! small e!tities, 2e*tio! 202 o0 t&e 9!0u!ded 7a!dates Re0orm A*t re>uires t&at age!*ies prepare a +ritte! assessme!t o0 a!ti*ipated *osts a!d be!e0its be0ore proposi!g a!? rule t&at ma? result i! a! eDpe!diture b? 2tate, lo*al, a!d tribal go(er!me!ts, i! t&e aggregate, or b? t&e pri(ate se*tor o0 O#00 millio! i! a!? o!e ?ear (adAusted a!!uall? 0or i!0latio!), 6&e age!*? belie(es t&at t&is rule is *o!siste!t +it& t&e regulator? p&ilosop&? a!d pri!*iples ide!ti0ied i! 5De*uti(e 'rder #2866 a!d i! t&ese t+o statutes, As s&o+! i! t&e 0ollo+i!g paragrap&s, t&e rule +ill !ot be sig!i0i*a!t as de0i!ed b? t&e 5De*uti(e order a!d t&e 9!0u!ded 7a!dates Re0orm A*t, a!d t&e age!*? *erti0ies t&at t&e rule +ill !ot &a(e a sig!i0i*a!t e*o!omi* impa*t o! a substa!tial !umber o0 small e!tities, 6&e purpose o0 t&e rule is to impleme!t se*tio! 306A o0 t&e a*t a!d to redu*e t&e !umber o0 ma!u0a*turi!g *&a!ges subAe*t to suppleme!ts re>uiri!g F-A appro(al prior to produ*t distributio!, 6&e rule a00e*ts all drug ma!u0a*turers t&at submit ma!u0a*turi!g suppleme!ts a!d +ill result i! a substa!tial redu*tio! i! burde!s to appli*a!ts ma:i!g ma!u0a*turi!g *&a!ges subAe*t to t&e regulatio!, 6&e rule permits earlier impleme!tatio! o0 t&e *&a!ges a!d >ui*:er mar:eti!g o0 produ*ts impro(ed b? ma!u0a*turi!g or labeli!g modi0i*atio!s, Faster impleme!tatio! *a! result i! mar:ed gai!s i! produ*tio! e00i*ie!*?, For eDample, a report b? t&e 5aster! Resear*& )roup, /!*, (5R)), a! F-A *o!tra*tor, o! t&e e00e*ts o0 t&e 29"A.%/R 0ou!d t&at redu*i!g t&e !umber o0 *&a!ges t&at re>uire preappro(al gi(es *ompa!ies greater *o!trol o(er t&eir produ*tio! resour*es, +&i*& *ould lead to sig!i0i*a!t !et sa(i!gs to i!dustr? (5R), "&arma*euti*al /!dustr? .ost 2a(i!gs 6&roug& 9se o0 t&e 2*ale%9p a!d "ost%Appro(al )uida!*e 0or /mmediate Release 2olid 'ral -osage Forms (29"A.%/R), @a!uar? $, #998, .o!tra*t No, 224%94%840#), 5R) estimated t&at *ompa!ies ma? alread? &a(e sa(ed O$# millio! i! #99$ due to t&e age!*?Cs impleme!tatio! o0 more 0leDible reporti!g pro*edures 0or *&emistr?, ma!u0a*turi!g, a!d *o!trol *&a!ges, 6&is rule +ould lead to additio!al sa(i!gs be*ause it eDpa!ds t&ese *&a!ges to ot&er drug produ*ts to impro(e produ*t labeli!g a!d ma!u0a*turi!g met&ods, ;e*ause t&e rule +ill be!e0it ma!u0a*turers regardless o0 si=e a!d impose !o additio!al *osts, t&e age!*? *erti0ies t&at t&is rule +ill !ot &a(e a sig!i0i*a!t ad(erse e*o!omi* impa*t o! a substa!tial !umber o0 small e!tities, V/, "aper+or: Redu*tio! A*t o0 #993 6&is 0i!al rule *o!tai!s *olle*tio!s o0 i!0ormatio! t&at are subAe*t to re(ie+ b? '7; u!der t&e "RA (44 9,2,., 430#%4320), BB.olle*tio! o0 i!0ormatio!CC i!*ludes a!? re>uest or re>uireme!t t&at perso!s obtai!, mai!tai!, retai!, or report i!0ormatio! to t&e age!*?, or dis*lose i!0ormatio! to a t&ird part? or to t&e publi* (44 9,2,., 4302(4) a!d 3 .FR #420,4(*)), 6&e title, des*riptio!, a!d respo!de!t des*riptio! o0 t&e i!0ormatio! *olle*tio! are s&o+! u!der t&is se*tio! o0 t&e do*ume!t +it& a! estimate o0 t&e a!!ual reporti!g burde!, /!*luded i! t&e estimate is t&e time 0or re(ie+i!g i!stru*tio!s, gat&eri!g a!d mai!tai!i!g t&e data !eeded, a!d *ompleti!g a!d re(ie+i!g t&e *olle*tio! o0 i!0ormatio!, 6itle: 2uppleme!ts a!d 't&er .&a!ges to a! Appro(ed Appli*atio!,

-es*riptio!: 6&e 0i!al rule sets 0ort& re>uireme!ts 0or ma!u0a*turi!g *&a!ges re>uiri!g suppleme!t submissio! a!d F-A appro(al prior to t&e distributio! o0 t&e produ*t made usi!g t&e *&a!ge, *&a!ges re>uiri!g suppleme!t submissio! at least 40 da?s prior to t&e distributio! o0 t&e produ*t, *&a!ges re>uiri!g suppleme!t submissio! at t&e time o0 distributio!, a!d *&a!ges to be des*ribed i! a! a!!ual report, 6&e regulatio! redu*es t&e rate o0 i!*rease i! t&e !umber o0 ma!u0a*turi!g *&a!ges subAe*t to suppleme!ts a!d t&e o(erall !umber o0 suppleme!ts re>uiri!g F-A appro(al prior to produ*t distributio!, 7a!? *&a!ges t&at are *urre!tl? reported i! suppleme!ts +ill be able to be reported i! a!!ual reports, 2uppleme!t submissio!s *o!tai! more burde!some reporti!g re>uireme!ts t&a! a submissio! t&roug& a! a!!ual report, 6&e regulatio! +ill !ot i!*rease t&e !umber o0 a!!ual reports but +ill allo+ appli*a!ts to i!*lude i! a! a!!ual report i!0ormatio! *urre!tl? re>uired to be reported to t&e age!*? i! a suppleme!tal appli*atio!, 6&e !umber o0 ma!u0a*turi!g *&a!ges *urre!tl? reported i! suppleme!ts t&at +ill be reported i! a!!ual reports is approDimatel? #,284, 2e*tio!s 4#4,$0(a)(2) a!d 60#,#2(a)(2) re>uire, ge!erall?, t&at t&e &older o0 a! appro(ed appli*atio! must assess t&e e00e*ts o0 a ma!u0a*turi!g *&a!ge be0ore distributi!g a drug produ*t made +it& t&e *&a!ge, 6&is se*tio! impleme!ts se*tio! 306A(a)(#) a!d 306A(b) o0 t&e a*t, +&i*& re>uire t&e &older o0 a! appro(ed appli*atio! to (alidate t&e e00e*ts o0 a ma!u0a*turi!g *&a!ge o! t&e ide!tit?, stre!gt&, >ualit?, purit?, or pote!*? o0 t&e drug as t&ese 0a*tors ma? relate to t&e sa0et? or e00e*ti(e!ess o0 t&e drug be0ore distributi!g a drug made +it& t&e *&a!ge, 9!der se*tio! 306A(d)(4)(A) o0 t&e a*t, i!0ormatio! de(eloped b? t&e appli*a!t to (alidate t&e e00e*ts o0 t&e *&a!ge regardi!g ide!tit?, stre!gt&, >ualit?, purit?, a!d pote!*? is re>uired to be submitted to F-A as part o0 t&e suppleme!t or a!!ual report, 6&us, estimates 0or (alidatio! re>uireme!ts are i!*luded i! t&e estimates 0or suppleme!ts a!d a!!ual reportsJ !o separate estimates are pro(ided 0or 2e*, 2e*, 4#4,$0(a)(2) a!d 60#,#2(a)(2) i! table # o0 t&is do*ume!t, Furt&ermore, !o estimates are re>uired 0or t&e guida!*e e!titled BB.&a!ges to a! Appro(ed N-A or AN-A,CC be*ause it does !ot pro(ide re*omme!datio!s o! t&e spe*i0i* i!0ormatio! t&at s&ould be de(eloped b? t&e appli*a!t to (alidate t&e e00e*t o0 t&e *&a!ge o! t&e ide!tit?, stre!gt& (e,g,, assa?, *o!te!t u!i0ormit?), >ualit? (e,g,, p&?si*al, *&emi*al, a!d biologi*al properties), purit? (e,g,, impurities a!d degradatio! produ*ts), or pote!*? (e,g,, biologi*al a*ti(it?, bioa(ailabilit?, bioe>ui(ale!*e) o0 a produ*t as t&e? ma? relate to t&e sa0et? or e00e*ti(e!ess o0 t&e produ*t, 2e*tio!s 4#4,$0(a)(4) a!d 60#,#2(a)(4) re>uire, ge!erall?, t&at t&e appli*a!t must promptl? re(ise all promotio!al labeli!g a!d ad(ertisi!g to ma:e it *o!siste!t +it& a!? labeli!g *&a!ges impleme!ted, 6&e tra!smittal to F-A o0 ad(ertiseme!ts a!d promotio!al labeli!g 0or drugs a!d biologi*s is a**ompa!ied b? Form F-A 2234 a!d regulated b? 2e*, 2e*, 4#4,8#(b)(4)(i) a!d 60#,#2(0)(4), 6&is i!0ormatio! *olle*tio! [["age #8$60 is appro(ed b? '7; u!til '*tober 4#, 2004, u!der '7; *o!trol !umber 09#0%04$6, 6&ere0ore, t&e burde! 0or t&is re>uireme!t is !ot estimated i! table # o0 t&is do*ume!t, 2e*tio! 4#4,$0(a)(3) re>uires t&e appli*a!t to i!*lude i! ea*& suppleme!t (eD*ept 0or a suppleme!t pro(idi!g 0or a *&a!ge i! t&e

labeli!g) a!d ame!dme!t to ea*& suppleme!t a stateme!t *erti0?i!g t&at a 0ield *op? &as bee! pro(ided i! a**orda!*e +it& 2e*, 4#4,440(a)(4), 6&e i!0ormatio! *olle*tio! 0or submitti!g a 0ield *op? u!der 2e*, 4#4,440(a)(4) is appro(ed b? '7; u!til 7ar*& 4#, 2003, u!der '7; *o!trol !umber 09#0%000#, ;ased o! data *o!*er!i!g t&e !umber o0 suppleme!ts a!d ame!dme!ts to suppleme!ts *urre!tl? re*ei(ed b? t&e age!*?, F-A estimates t&at approDimatel? 8,336 *erti0i*atio!s +ill be submitted a!!uall? as re>uired b? 2e*, 4#4,$0(a)(3), F-A estimates t&at approDimatel? 394 appli*a!ts +ill submit t&ese *erti0i*atio!s, F-A estimates t&at preparatio! o0 a stateme!t *erti0?i!g t&e 0ield *op? +ill ta:e appli*a!ts a! a(erage o0 3 mi!utes, 2e*tio!s 4#4,$0(a)(6) a!d 60#,#2(a)(3) re>uire t&e appli*a!t to i!*lude a list o0 all *&a!ges *o!tai!ed i! t&e suppleme!t or a!!ual reportJ 0or suppleme!ts, t&is list must be pro(ided i! t&e *o(er letter, 6&e i!0ormatio! *olle*tio! 0or submitti!g a! a!!ual report u!der 2e*, 4#4,8#(b)(2) is appro(ed b? '7; u!til 7ar*& 4#, 2003, u!der '7; *o!trol !umber 09#0%000#, ;ased o! data *o!*er!i!g t&e !umber o0 suppleme!ts *urre!tl? re*ei(ed b? t&e age!*?, F-A estimates t&at approDimatel? 4,984 lists o0 all *&a!ges i! t&e suppleme!t +ill be submitted a!!uall? as re>uired b? 2e*, 4#4,$0(a)(6), F-A estimates t&at approDimatel? 394 appli*a!ts +ill submit t&ese lists, ;e*ause t&e i!0ormatio! re>uired +ould be ge!erated i! prepari!g t&e suppleme!t, t&e age!*? estimates t&at, u!der 2e*, 4#4,$0(a)(6), it +ill ta:e approDimatel? # &our to i!*lude a list o0 *&a!ges i! a *o(er letter 0or a suppleme!t, F-A estimates t&at approDimatel? 2,984 lists o0 all *&a!ges i! t&e suppleme!t or a!!ual report +ill be submitted a!!uall? as re>uired b? 2e*, 60#,#2(a)(3), F-A estimates t&at approDimatel? #90 appli*a!ts +ill submit t&ese lists, ;e*ause t&e i!0ormatio! re>uired +ould be ge!erated i! prepari!g t&e suppleme!t or a!!ual report, t&e age!*? estimates t&at, u!der 2e*, 60#,#2(a)(3), it +ill ta:e approDimatel? # &our to i!*lude a list o0 *&a!ges 0or a suppleme!t or a! a!!ual report, 2e*tio! 4#4,$0(b) a!d *urre!t 2e*, 60#,#2(b) set 0ort& re>uireme!ts 0or *&a!ges re>uiri!g suppleme!t submissio! a!d appro(al prior to distributio! o0 t&e produ*t made usi!g t&e *&a!ge (maAor *&a!ges), 2e*tio! 4#4,$0(b)(#) a!d *urre!t 2e*, 60#,#2(b)(#) pro(ide, ge!erall?, t&at a suppleme!t must be submitted 0or a!? *&a!ge i! t&e drug substa!*e, drug produ*t, produ*tio! pro*ess, >ualit? *o!trols, e>uipme!t, or 0a*ilities t&at &as a substa!tial pote!tial to &a(e a! ad(erse e00e*t o! t&e ide!tit?, stre!gt&, >ualit?, purit?, or pote!*? o0 t&e drug produ*t as t&ese 0a*tors ma? relate to t&e sa0et? or e00e*ti(e!ess o0 t&e drug produ*t, 2e*tio! 4#4,$0(b)(4) a!d *urre!t 2e*, 60#,#2(b)(4) spe*i0? t&e i!0ormatio! t&at must be *o!tai!ed i! t&e suppleme!t, ;ased o! data *o!*er!i!g t&e !umber o0 suppleme!ts *urre!tl? re*ei(ed b? t&e age!*?, F-A estimates t&at approDimatel? #,$44 suppleme!ts +ill be submitted a!!uall? u!der 2e*, 4#4,$0(b)(#) a!d (b)(4), F-A estimates t&at approDimatel? 394 appli*a!ts +ill submit su*& suppleme!ts, a!d t&at it +ill ta:e approDimatel? #30 &ours to prepare a!d submit to F-A ea*& suppleme!t, F-A estimates t&at approDimatel? 904 suppleme!ts +ill be submitted a!!uall? u!der 2e*, 60#,#2(b)(#) a!d (b)(4), F-A estimates t&at approDimatel? #90 appli*a!ts +ill submit su*& suppleme!ts, a!d t&at it +ill ta:e approDimatel? #30 &ours to prepare a!d submit to F-A ea*& suppleme!t, 9!der 2e*, 2e*, 4#4,$0(b)(4) a!d 60#,#2(b)(4), a! appli*a!t ma? as: F-A to eDpedite its re(ie+ o0 a suppleme!t 0or publi* &ealt& reaso!s or i0 a dela? i! ma:i!g t&e *&a!ge des*ribed i! it +ould impose

a! eDtraordi!ar? &ards&ip o! t&e appli*a!t, 2u*& a suppleme!t a!d its maili!g *o(er s&ould be mar:ed: BB"rior Appro(al 2uppleme!t%5Dpedited Re(ie+ Re>uested,CC 6&e burde! 0or a! appli*a!tCs re>uest 0or a! eDpedited re(ie+ o0 a suppleme!t b? mar:i!g t&e maili!g *o(er is mi!imal a!d is i!*luded i! t&e burde! &our estimates 0or submitti!g a suppleme!t u!der 2e*, 4#4,$0(b)(#) a!d (b)(4) a!d 2e*, 60#,#2(b)(#) a!d (b)(4), 2e*tio! 4#4,$0(*) a!d *urre!t 2e*, 60#,#2(*) set 0ort& re>uireme!ts 0or *&a!ges re>uiri!g suppleme!t submissio! at least 40 da?s prior to distributio! o0 t&e produ*t made usi!g t&e *&a!ge (moderate *&a!ges), 2e*tio! 4#4,$0(*)(#) a!d *urre!t 2e*, 60#,#2(*)(#) re>uire, ge!erall?, t&at a suppleme!t must be submitted 0or a!? *&a!ge i! t&e drug substa!*e, drug produ*t, produ*tio! pro*ess, >ualit? *o!trols, e>uipme!t, or 0a*ilities t&at &as a moderate pote!tial to &a(e a! ad(erse e00e*t o! t&e ide!tit?, stre!gt&, >ualit?, purit?, or pote!*? o0 t&e drug produ*t as t&ese 0a*tors ma? relate to t&e sa0et? or e00e*ti(e!ess o0 t&e drug produ*t, 9!der 2e*, 4#4,$0(*)(4) a!d *urre!t 2e*, 60#,#2(*)(#), t&e suppleme!t must gi(e a 0ull eDpla!atio! o0 t&e basis 0or t&e *&a!ge a!d ide!ti0? t&e date o! +&i*& t&e *&a!ge is to be made, 6&e suppleme!t must be labeled BB2uppleme!t%%.&a!ges ;ei!g 500e*ted i! 40 -a?s,CC 9!der 2e*, 4#4,$0(*)(4) a!d *urre!t 2e*, 60#,#2(*)(4), t&e i!0ormatio! listed pre(iousl? 0or 2e*, 4#4,$0(b)(4) a!d *urre!t 2e*, 60#,#2(b)(4) must be *o!tai!ed i! t&e suppleme!t, ;ased o! data *o!*er!i!g t&e !umber o0 suppleme!ts *urre!tl? re*ei(ed b? t&e age!*?, F-A estimates t&at approDimatel? 2,$34 suppleme!ts +ill be submitted a!!uall? u!der 2e*, 4#4,$0(*)(#), (*)(4), a!d (*)(4), F-A estimates t&at approDimatel? 394 appli*a!ts +ill submit su*& suppleme!ts, a!d t&at it +ill ta:e approDimatel? 93 &ours to prepare a!d submit to F-A ea*& suppleme!t, F-A estimates t&at approDimatel? 233 suppleme!ts +ill be submitted a!!uall? u!der 2e*, 60#,#2(*)(#) a!d (*)(4), F-A estimates t&at approDimatel? 98 appli*a!ts +ill submit su*& suppleme!ts, a!d t&at it +ill ta:e approDimatel? 93 &ours to prepare a!d submit to F-A ea*& suppleme!t, 9!der 2e*, 4#4,$0(*)(6) a!d *urre!t 2e*, 60#,#2(*)(3), F-A ma? desig!ate a *ategor? o0 *&a!ges 0or t&e purpose o0 pro(idi!g t&at, i! t&e *ase o0 a *&a!ge i! su*& *ategor?, t&e &older o0 a! appro(ed appli*atio! ma? *omme!*e distributio! o0 t&e drug produ*t upo! re*eipt b? t&e age!*? o0 a suppleme!t 0or t&e *&a!ge, 6&e suppleme!t must be labeled BB2uppleme!t%%.&a!ges ;ei!g 500e*ted,CC /0 t&e suppleme!t pro(ides 0or a labeli!g *&a!ge, #2 *opies o0 t&e 0i!al pri!ted labeli!g must be i!*luded, ;ased o! data *o!*er!i!g t&e !umber o0 suppleme!ts *urre!tl? re*ei(ed b? t&e age!*?, F-A estimates t&at approDimatel? 486 suppleme!ts +ill be submitted a!!uall? u!der 2e*, 4#4,$0(*)(6), F-A estimates t&at approDimatel? 486 appli*a!ts +ill submit su*& suppleme!ts, a!d t&at it +ill ta:e approDimatel? 93 &ours to prepare a!d submit to F-A ea*& suppleme!t, F-A estimates t&at approDimatel? 4$ suppleme!ts +ill be submitted a!!uall? u!der 2e*, 60#,#2(*)(3), F-A estimates t&at approDimatel? 44 appli*a!ts +ill submit su*& suppleme!ts, a!d t&at it +ill ta:e approDimatel? 93 &ours to prepare a!d submit to F-A ea*& suppleme!t, 2e*tio! 4#4,$0(d) a!d *urre!t 2e*, 60#,#2(d) set 0ort& re>uireme!ts 0or *&a!ges to be des*ribed i! a! a!!ual report (mi!or *&a!ges), 2e*tio! 4#4,$0(d)(#) a!d *urre!t 2e*, 60#,#2(d)(#) [["age #8$6#

pro(ide, ge!erall?, t&at *&a!ges i! t&e drug substa!*e, drug produ*t, produ*tio! pro*ess, >ualit? *o!trols, e>uipme!t, or 0a*ilities t&at &a(e a mi!imal pote!tial to &a(e a! ad(erse e00e*t o! t&e ide!tit?, stre!gt&, >ualit?, purit?, or pote!*? o0 t&e drug produ*t as t&ese 0a*tors ma? relate to t&e sa0et? or e00e*ti(e!ess o0 t&e drug produ*t must be do*ume!ted i! t&e !eDt a!!ual report, 2e*tio! 4#4,$0(d)(4) a!d *urre!t 2e*, 60#,#2(d)(4) (i!*ludi!g proposed 2e*, 60#,#2(d)(4)(iii)) list t&e i!0ormatio! t&at must be i!*luded i! t&e a!!ual report 0or des*ribi!g *&a!ges u!der t&is se*tio!, ;ased o! data *o!*er!i!g t&e !umber o0 suppleme!ts a!d a!!ual reports *urre!tl? re*ei(ed b? t&e age!*?, F-A estimates t&at approDimatel? 6,929 a!!ual reports +ill i!*lude do*ume!tatio! o0 *ertai! ma!u0a*turi!g *&a!ges as re>uired u!der 2e*, 4#4,$0(d)(#) a!d (d)(4), F-A estimates t&at approDimatel? $04 appli*a!ts +ill submit su*& i!0ormatio!, a!d t&at it +ill ta:e approDimatel? 43 &ours to prepare a!d submit to F-A t&e i!0ormatio! 0or ea*& a!!ual report, F-A estimates t&at approDimatel? 22$ a!!ual reports +ill i!*lude do*ume!tatio! o0 *ertai! ma!u0a*turi!g *&a!ges as re>uired u!der *urre!t 2e*, 60#,#2(d)(#) a!d (d)(4), F-A estimates t&at approDimatel? #66 appli*a!ts +ill submit su*& i!0ormatio!, a!d t&at it ta:es approDimatel? 43 &ours to prepare a!d submit to F-A t&e i!0ormatio! 0or ea*& a!!ual report, 2e*tio! 4#4,$0(e) a!d *urre!t 2e*, 60#,#2(e) state, ge!erall?, t&at a! appli*a!t ma? submit o!e or more proto*ols des*ribi!g t&e spe*i0i* tests a!d studies a!d a**epta!*e *riteria to be a*&ie(ed to demo!strate t&e la*: o0 ad(erse e00e*t 0or spe*i0ied t?pes o0 ma!u0a*turi!g *&a!ges o! t&e ide!tit?, stre!gt&, >ualit?, purit?, a!d pote!*? o0 t&e drug produ*t as t&ese 0a*tors ma? relate to t&e sa0et? or e00e*ti(e!ess o0 t&e drug produ*t, A!? su*& proto*ols, i0 !ot i!*luded i! t&e appro(ed appli*atio!, or *&a!ges to a! appro(ed proto*ol, must be submitted as a suppleme!t re>uiri!g appro(al 0rom F-A prior to distributio! o0 a drug produ*t produ*ed +it& t&e ma!u0a*turi!g *&a!ge, 6&e suppleme!t, i0 appro(ed, ma? subse>ue!tl? Austi0? a redu*ed reporti!g *ategor? 0or t&e parti*ular *&a!ge be*ause t&e use o0 t&e proto*ol 0or t&at t?pe o0 *&a!ge redu*es t&e pote!tial ris: o0 a! ad(erse e00e*t, ;ased o! data *o!*er!i!g t&e !umber o0 suppleme!ts *urre!tl? re*ei(ed b? t&e age!*?, F-A estimates t&at approDimatel? 30 proto*ols +ill be submitted a!!uall? u!der 2e*, 4#4,$0(e), F-A estimates t&at approDimatel? 30 appli*a!ts +ill submit su*& proto*ols, a!d t&at it +ill ta:e approDimatel? 200 &ours to prepare a!d submit to F-A ea*& proto*ol, F-A estimates t&at approDimatel? 20 proto*ols +ill be submitted a!!uall? u!der 2e*, 60#,#2(e), F-A estimates t&at approDimatel? #4 appli*a!ts +ill submit su*& proto*ols, a!d t&at it +ill ta:e approDimatel? 200 &ours to prepare a!d submit to F-A ea*& proto*ol, .urre!t 2e*, 60#,#2(0) sets 0ort& t&e re>uireme!ts 0or suppleme!t submissio! 0or labeli!g *&a!ges 0or biologi*al produ*ts, .urre!t 2e*, 60#,#2(0)(2)(i)(A) t&roug& (0)(2)(i)(-) spe*i0? t&ose labeli!g *&a!ges 0or +&i*& a! appli*a!t must submit a suppleme!t to F-A at t&e time t&e *&a!ge is made, 2e*tio! 60#,#2(0)(2)(i)(5) adds to t&ese t?pes o0 *&a!ges BBa!? labeli!g *&a!ge !ormall? re>uiri!g a suppleme!t submissio! a!d appro(al prior to distributio! o0 t&e produ*t t&at F-A spe*i0i*all? re>uests be submitted u!der t&is pro(isio!,CC ;ased o! data *o!*er!i!g t&e !umber o0 suppleme!ts *urre!tl? re*ei(ed b? t&e age!*?, F-A estimates t&at approDimatel? #2 labeli!g suppleme!ts +ill be submitted a!!uall? u!der *urre!t 2e*, 60#,#2(0)(#), F-A estimates

t&at approDimatel? #2 appli*a!ts +ill submit t&ese suppleme!ts, a!d t&at it +ill ta:e approDimatel? 40 &ours to prepare a!d submit to F-A ea*& suppleme!t, F-A estimates t&at approDimatel? #0 labeli!g suppleme!ts +ill be submitted a!!uall? u!der *urre!t 2e*, 60#,#2(0)(2), i!*ludi!g t&ose t&at +ill be submitted u!der !e+ 2e*, 60#,#2(0)(2)(i)(5), F-A estimates t&at approDimatel? #0 appli*a!ts +ill submit t&ese suppleme!ts, a!d t&at it +ill ta:e approDimatel? 20 &ours to prepare a!d submit to F-A ea*& suppleme!t, F-A estimates t&at approDimatel? #00 a!!ual reports 0or labeli!g *&a!ges +ill be submitted u!der *urre!t 2e*, 60#,#2(0)(4), F-A estimates t&at approDimatel? $0 appli*a!ts +ill submit t&ese reports, a!d t&at it +ill ta:e approDimatel? #0 &ours to prepare a!d submit to F-A ea*& report, F-A estimates t&at approDimatel? #,493 labeli!g suppleme!ts +ill be submitted a!!uall? u!der *urre!t 2e*, 60#,#2(0)(4), F-A estimates t&at approDimatel? 6# appli*a!ts +ill submit t&ese suppleme!ts, a!d t&at it +ill ta:e approDimatel? #0 &ours to prepare a!d submit to F-A ea*& suppleme!t, 2e*tio! 4#4,$0(0) states t&at a! appli*a!t must *ompl? +it& t&e pate!t i!0ormatio! re>uireme!ts u!der se*tio! 303(*)(2) o0 t&e a*t, 2e*tio! 4#4,$0(g) states t&at a! appli*a!t must i!*lude a!? appli*able eD*lusi(it? i!0ormatio! +it& a suppleme!t as re>uired u!der 2e*, 4#4,30(A), "ate!t a!d eD*lusi(it? i!0ormatio! *olle*tio! re>uireme!ts are appro(ed b? '7; u!til 7ar*& 4#, 2003, u!der '7; *o!trol !umber 09#0%000#, 6&ere0ore, t&is re>uireme!t is !ot estimated i! table # o0 t&is do*ume!t, .omme!ts Re*ei(ed o! F-ACs "roposed /!0ormatio! .olle*tio! ;urde! 5stimates: .o!*er!i!g t&e a**ura*? o0 F-ACs estimate o0 t&e burde! o0 t&e proposed *olle*tio! o0 i!0ormatio!, i!*ludi!g t&e (alidit? o0 t&e met&odolog? a!d assumptio!s used, o!e *omme!t said t&at F-A &as u!derestimated t&e i!0ormatio! *olle*tio! burde!, 6&e *omme!t suggested t&e 0ollo+i!g re(ised estimates: For 2e*, 4#4,$0(b)(#) a!d (b)(4), t&e *omme!t estimated #60 &ours per respo!seJ 0or 2e*, 4#4,$0(*)(#), (*)(4), a!d (*)(4), 80 &ours per respo!seJ 0or 2e*, 4#4,$0(*)(6), 80 &ours per respo!seJ 0or 2e*, 4#4,$0(d)(#) a!d (d)(4), 23 &ours per respo!seJ 0or 2e*, 4#4,$0(e), 240 &ours per respo!se, 6&e *omme!t assumed t&at t&e !umber o0 &ours estimated re0ers to t&e !umber o0 &ours re>uired b? regulator? a00airs perso!!el to *olle*t, assemble, a!d prepare data re>uired 0or a submissio!, 't&er related a*ti(ities, su*& as ma!u0a*turi!g (alidatio! lots a!d *o!du*ti!g stabilit? studies, are !ot part o0 t&e estimates, si!*e t&e? are ma!u0a*turi!g a*ti(ities t&at +ould be *o!du*ted, as appropriate, regardless o0 t&e reporti!g re>uireme!ts, 6&e *omme!t said its estimates are based o! a! a(erage time re>uired 0or submissio!s, a!d t&e a*tual time re>uired 0or a parti*ular submissio! *a! (ar?, based o! t&e *ompleDit? o0 t&e submitted *&a!ge, 6&e *omme!t said t&at alt&oug& t&e proposal +ould *&a!ge t&e reporti!g le(el o0 *&a!ges, t&e asso*iated BBpaper+or:CC 0or t&ese *&a!ges is !ot sig!i0i*a!tl? redu*ed a!d i! some *ases is i!*reased, .o!*er!i!g t&e proposed re>uireme!t i! 2e*, 4#4,$0(e) t&at a! appli*a!t ma? submit o!e or more proto*ols, t&e *omme!t !oted t&at t&ese proto*ols must be submitted as a suppleme!t re>uiri!g appro(al 0rom F-A prior to distributio! o0 a drug produ*ed +it& t&e ma!u0a*turi!g *&a!ge, 6&e *omme!t said t&at, based o! its eDperie!*e, t&e estimate o0 20 &ours 0or t&ese proto*ol submissio!s is sig!i0i*a!tl? u!derestimated a!d t&at 240 &ours is a more reaso!able estimate, 6&e *omme!t said t&at t&ese proto*ols are, i! e00e*t,

suppleme!ts re>uiri!g prior appro(al a!d, t&ere0ore, +ould re>uire t&e same !umber o0 &ours to prepare as a prior appro(al suppleme!t u!der 2e*, 4#4,$0(b)(#) a!d (b)(4), Additio!all?, o!*e t&e data 0or t&e *&a!ge &as bee! ge!erated, t&e *&a!ge re>uires a! additio!al submissio! i! order to impleme!t t&e *&a!ge, Assumi!g t&e data ge!erated *ould be submitted [["age #8$62 u!der 2e*, 4#4,$0(*), t&e !umber o0 &ours to submit *&a!ges u!der proposed 2e*, 4#4,$0(e) +ould be a *ombi!atio! o0 t&e !umber o0 &ours re>uired to submit a *&a!ge u!der 2e*, 4#4,$0(b) a!d (*), A!ot&er *omme!t said t&at t&e estimated time i! t&e proposal to *olle*t t&e re>uested i!0ormatio! 0or ea*& t?pe o0 suppleme!t is lo+, 6&e *omme!t said t&at F-A u!derestimated t&e time to prepare t&e do*ume!ts addressed i! t&e proposal a!d t&at F-A s&ould ta:e greater *are i! e(aluati!g t&e !e*essar? steps re>uired i! prepari!g a suppleme!t or report, !ot Aust t&e do*ume!t preparatio!, For prior appro(ed suppleme!ts u!der 2e*, 4#4,$0(b), t&e *omme!t said t&at t&e estimate o0 80 &ours is lo+ a!d s&ould be i!*reased b? at least #0 &ours, 6&e o!l? time sa(i!g t&at *a! be gai!ed u!der t&is re>uireme!t is +&e! a 0irm *a! submit multiple suppleme!ts 0or t&e same *&a!ge (site *&a!ge), +&i*& is a! u!*ommo! o**urre!*eJ smaller 0irms submit o!e suppleme!t at a time, For *&a!ges%bei!g%e00e*ted suppleme!ts u!der 2e*, 4#4,$0(*), t&e *omme!t said t&at 30 &ours 0or t&ese t?pes o0 suppleme!ts is lo+, 6&e *omme!t as:ed +&at is t&e di00ere!*e bet+ee! t&is t?pe o0 suppleme!t a!d prior appro(al suppleme!ts ot&er t&a! t&e 0ili!g me*&a!ism, For a!!ual reports u!der 2e*, 4#4,$0(d), t&e *omme!t said t&at #0 &ours is lo+ a!d t&at t&e data t&at go i!to su*& a report is *olle*ted o(er t&e e!tire ?ear be0ore t&e report ma? be put toget&er, 6&e *omme!t said t&at a! a(erage o0 20 &ours is more reaso!able, .o!*er!i!g proto*ols u!der 2e*, 4#4,$0(e), t&e *omme!t said t&at 20 &ours to prepare a suitabilit? proto*ol is a large u!derestimate, a!d t&at 0irms +ill spe!d a large amou!t o0 time to determi!e Aust +&i*& tests a!d spe*i0i*atio!s to i!*lude i! t&e proto*ol, i! additio! to prepari!g t&e proto*ol itsel0, 6&e *omme!t also said t&at t&e a!al?sis a!d reporti!g o0 t&e results o0 t&e *ompleted proto*ols +as !ot i!*luded i! t&e estimate, F-A &as *o!sidered t&e abo(e *omme!ts as +ell as ot&er i!0ormatio! it &as re*ei(ed a!d &as re(ised t&e proposed i!0ormatio! *olle*tio! burde! estimates, 6&e estimate 0or BB&ours per respo!seCC 0or 2e*, 2e*, 4#4,$0(b)(#) a!d (b)(4) a!d 60#,#2(b)(#) a!d (b)(4) &as bee! i!*reased 0rom 80 &ours to #30 &oursJ t&e estimate 0or 2e*, 2e*, 4#4,$0(*)(#), (*)(4), a!d (*)(4) a!d 60#,#2(*)(#) a!d (*)(4) &as bee! i!*reased 0rom 30 &ours to 93 &oursJ t&e estimate 0or 2e*, 2e*, 4#4,$0(*)(6) a!d 60#,#2(*)(3) &as bee! i!*reased 0rom 30 &ours to 93 &oursJ t&e estimate 0or 2e*, 2e*, 4#4,$0(d)(#) a!d (d)(4) a!d 60#,#2(d)(#) a!d (d)(4) &as bee! i!*reased 0rom #0 &ours to 43 &oursJ a!d t&e estimate 0or 2e*, 2e*, 4#4,$0(e) a!d 60#,#2(e) &as bee! i!*reased 0rom 20 &ours to 200 &ours, -es*riptio! o0 Respo!de!ts: ;usi!ess or ot&er 0or%pro0it orga!i=atio!s, 6able #,%%5stimated A!!ual Reporti!g ;urde!L#L %%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%% %%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%

No, o0 Respo!ses per 6otal A!!ual 1ours 6otal 2# .FR 2e*tio! per 1ours No, o0 Respo!de!ts

Respo!de!t Respo!ses Respo!se %%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%% %%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%% 4#4,$0(a)(3) 394 #4 8,336 3 $#4 mi!utes %%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%% %%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%% 4#4,$0(a)(6) 394 8 4,984 # 4,984 %%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%% %%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%% 4#4,$0(b)(#), (b)(4) 394 4 #,$44 #30 26#,600 %%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%% %%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%% 4#4,$0(*)(#), (*)(4), (*)(4) 394 3 2,$34 93 26#,640 %%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%% %%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%% 4#4,$0(*)(6) 486 # 486 93 46,#$0 %%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%% %%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%% 4#4,$0(d)(#), (d)(4) $04 #0 6,929 43 242,3#3 %%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%% %%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%% 4#4,$0(e) 30 # 30 200 #0,000 %%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%% %%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%% 60#,#2(a)(3) #90 #6 2,984 # 2,984 %%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%% %%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%% 60#,#2(b)(#), (b)(4) #90 3 904 #30 #43,430 %%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%% %%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%% 60#,#2(*)(#), (*)(4) 98 4 233 93 24,223 %%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%% %%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%% 60#,#2(*)(3) 44 # 4$ 93 4,463 %%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%% %%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%

60#,#2(d)(#), (d)(4) #66 # 22$ 43 $,943 %%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%% %%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%% 60#,#2(e) #4 # 20 200 4,000 %%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%% %%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%% 60#,#2(0)(#) #2 # #2 40 480 %%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%% %%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%% 60#,#2(0)(2) #0 # #0 20 200 %%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%% %%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%% 60#,#2(0)(4) $0 # #00 #0 #,000 %%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%% %%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%% 60#,#2(0)(4) 6# 23 #,493 #0 #4,930 %%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%% %%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%% 6otal #,024,4# 0 %%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%% %%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%% L#L 6&ere are !o *apital *osts or operati!g a!d mai!te!a!*e *osts asso*iated +it& t&is *olle*tio! o0 i!0ormatio!, 6&e i!0ormatio! *olle*tio! pro(isio!s i! t&is 0i!al rule &a(e bee! appro(ed u!der '7; *o!trol !umber 09#0%0348, 6&is appro(al eDpires August 4#, 2003, A! age!*? ma? !ot *o!du*t or spo!sor, a!d a perso! is !ot re>uired to respo!d to, a *olle*tio! o0 i!0ormatio! u!less it displa?s a *urre!tl? (alid '7; *o!trol !umber, [["age #8$64 V//, 5!(iro!me!tal /mpa*t 6&e age!*? &as determi!ed u!der 2# .FR 23,40(&) t&at t&is a*tio! is o0 a t?pe t&at does !ot i!di(iduall? or *umulati(el? &a(e a sig!i0i*a!t e00e*t o! t&e &uma! e!(iro!me!t, 6&ere0ore, !eit&er a! e!(iro!me!tal assessme!t !or a! e!(iro!me!tal impa*t stateme!t is re>uired, V///, Federalism F-A &as a!al?=ed t&is 0i!al rule i! a**orda!*e +it& t&e pri!*iples set 0ort& i! 5De*uti(e 'rder #4#42, F-A &as determi!ed t&at t&e rule does !ot *o!tai! poli*ies t&at &a(e substa!tial dire*t e00e*ts o! t&e 2tates, o! t&e relatio!s&ip bet+ee! t&e Natio!al )o(er!me!t a!d t&e 2tates, or o! t&e distributio! o0 po+er a!d respo!sibilities amo!g t&e (arious le(els o0 go(er!me!t, A**ordi!gl?, t&e age!*? &as *o!*luded

t&at t&e rule does !ot *o!tai! poli*ies t&at &a(e 0ederalism impli*atio!s as de0i!ed i! t&e order, a!d, *o!se>ue!tl?, a 0ederalism summar? impa*t stateme!t is !ot re>uired, 8ist o0 2ubAe*ts 2# .FR "arts 206 a!d 230 -rugs, 2# .FR "art 4#4 Admi!istrati(e pra*ti*e a!d pro*edure, .o!0ide!tial busi!ess i!0ormatio!, -rugs, Reporti!g a!d re*ord:eepi!g re>uireme!ts, 2# .FR "art 600 ;iologi*s, Reporti!g a!d re*ord:eepi!g re>uireme!ts, 2# .FR "art 60# Admi!istrati(e pra*ti*e a!d pro*edure, ;iologi*s, .o!0ide!tial busi!ess i!0ormatio!, 0 6&ere0ore, u!der t&e Federal Food, -rug, a!d .osmeti* A*t a!d u!der aut&orit? delegated to t&e .ommissio!er o0 Food a!d -rugs, 2# .FR parts 206, 230, 4#4, 600, a!d 60# are ame!ded as 0ollo+s: "AR6 206%%/7"R/N6/N) 'F 2'8/- 'RA8 -'2A)5 F'R7 -R9) "R'-9.62 F'R 197AN 925 0 #%4, 6&e aut&orit? *itatio! 0or 2# .FR part 206 *o!ti!ues to read as 0ollo+s: 262, 2e*, Aut&orit?: 2# 9,2,., 42#, 44#, 43#, 432, 433, 4$#J 42 9,2,.,

206,#0

[Ame!ded

0 4, 2e*tio! 206,#0 .ode impri!t re>uired is ame!ded i! t&e 0irst se!te!*e o0 paragrap& (b) b? remo(i!g t&e p&rase BB2e*, 4#4,$0(b)(2)(Di) or (b)(2)(Dii)CC a!d b? addi!g i! its pla*e t&e p&rase BB2e*, 4#4,$0(b)CC, "AR6 230%%2"5./A8 R5M9/R575N62 F'R 2"5./F/. 197AN -R9)2 0 3, 6&e aut&orit? *itatio! 0or 2# .FR part 230 *o!ti!ues to read as 0ollo+s: Aut&orit?: 2# 9,2,., 42#, 446, 442, 432, 434, 433, 46#(a), 462(a) a!d (*), 4$#, 4$3(b),

2e*,

230,230

[Ame!ded

0 6, 2e*tio! 230,230 1eDa*&lorop&e!e, as a *ompo!e!t o0 drug a!d *osmeti* produ*ts is ame!ded i! t&e last se!te!*e o0 paragrap& (*)(4)(ii) b? remo(i!g t&e p&rase BB2e*, 4#4,$0(*)(2)CC a!d b? addi!g i! its pla*e t&e p&rase BB2e*, 4#4,$0(*)(6)(iii)CC, "AR6 4#4%%A""8/.A6/'N2 F'R F-A A""R'VA8 6' 7ARP56 A N5K -R9) 0 $, 6&e aut&orit? *itatio! 0or 2# .FR part 4#4 *o!ti!ues to read as 0ollo+s: Aut&orit?: 2# 9,2,., 42#, 44#, 43#, 432, 434, 433, 433a, 436, 436a, 436b, 436*, 4$#, 4$4, 4$9e, 0 8, 2e*tio! 4#4,4 is ame!ded i! paragrap& (b) b? alp&abeti*all? addi!g t&e de0i!itio!s 0or BBAssess t&e e00e*ts o0 t&e *&a!geCC a!d BB2pe*i0i*atio!CC to read as 0ollo+s: 2e*, 4#4,4 -e0i!itio!s,

N N N N N (b) N N N Assess t&e e00e*ts o0 t&e *&a!ge mea!s to e(aluate t&e e00e*ts o0 a ma!u0a*turi!g *&a!ge o! t&e ide!tit?, stre!gt&, >ualit?, purit?, a!d pote!*? o0 a drug produ*t as t&ese 0a*tors ma? relate to t&e sa0et? or e00e*ti(e!ess o0 t&e drug produ*t, N N N N N 2pe*i0i*atio! mea!s t&e >ualit? sta!dard (i,e,, tests, a!al?ti*al pro*edures, a!d a**epta!*e *riteria) pro(ided i! a! appro(ed appli*atio! to *o!0irm t&e >ualit? o0 drug substa!*es, drug produ*ts, i!termediates, ra+ materials, reage!ts, *ompo!e!ts, i!%pro*ess materials, *o!tai!er *losure s?stems, a!d ot&er materials used i! t&e produ*tio! o0 a drug substa!*e or drug produ*t, For t&e purpose o0 t&is de0i!itio!, a**epta!*e *riteriamea!s !umeri*al limits, ra!ges, or ot&er *riteria 0or t&e tests des*ribed, N N N N N 0 9, 2e*tio! 4#4,30 is ame!ded: 0 a, /! paragrap& (d)(#)(ii)(b) b? remo(i!g t&e p&rase BBspe*i0i*atio!s a!d test pro*eduresCC a!d b? addi!g i! its pla*e t&e +ord BBspe*i0i*atio!CCJ 0 b, /! paragrap& (d)(#)(() b? remo(i!g t&e p&rase BB5D*ept 0or a 0oreig! appli*a!t, t&eCC a!d b? addi!g i! its pla*e t&e +ord BB6&eCCJ 0 *, /! paragrap& (d)(4)(i) b? addi!g t&e +ord BBpro*eduresCC a0ter t&e +ord BBa!al?ti*alCCJ 0 d, /! paragrap& (d)(4)(ii) b? remo(i!g t&e p&rases BBspe*i0i*atio!s or

a!al?ti*al met&odsCC a!d BBspe*i0i*atio! or a!al?ti*al met&odsCC ea*& time t&e? appear a!d b? addi!g i! t&eir pla*es t&e p&rase BBtests, a!al?ti*al pro*edures, a!d a**epta!*e *riteriaCCJ 0 e, /! paragrap& (d)(4)(i() b? remo(i!g t&e +ord BBmet&odsCC a!d b? addi!g i! its pla*e t&e +ord BBpro*eduresCCJ 0 0, /! t&e last se!te!*e o0 paragrap& (e)(#) i!trodu*tor? teDt a!d i! t&e 0irst se!te!*e o0 paragrap& (e)(2)(i) b? remo(i!g t&e +ord BBmet&odsCC ea*& time it appears a!d b? addi!g i! its pla*e t&e +ord BBpro*eduresCCJ a!d 0 g, ;? re(isi!g t&e 0irst t+o se!te!*es o0 paragrap&s (d)(#)(i) a!d (d)(#)(ii)(a) to read as 0ollo+s: 2e*, 4#4,30 .o!te!t a!d 0ormat o0 a! appli*atio!,

N N N N N (d) N N N (#) N N N (i) -rug substa!*e, A 0ull des*riptio! o0 t&e drug substa!*e i!*ludi!g its p&?si*al a!d *&emi*al *&ara*teristi*s a!d stabilit?J t&e !ame a!d address o0 its ma!u0a*turerJ t&e met&od o0 s?!t&esis (or isolatio!) a!d puri0i*atio! o0 t&e drug substa!*eJ t&e pro*ess *o!trols used duri!g ma!u0a*ture a!d pa*:agi!gJ a!d t&e spe*i0i*atio!s !e*essar? to e!sure t&e ide!tit?, stre!gt&, >ualit?, a!d purit? o0 t&e drug substa!*e a!d t&e bioa(ailabilit? o0 t&e drug produ*ts made 0rom t&e substa!*e, i!*ludi!g, 0or eDample, tests, a!al?ti*al pro*edures, a!d a**epta!*e *riteria relati!g to stabilit?, sterilit?, parti*le si=e, a!d *r?stalli!e 0orm, 6&e appli*atio! ma? pro(ide additio!all? 0or t&e use o0 alter!ati(es to meet a!? o0 t&ese re>uireme!ts, i!*ludi!g alter!ati(e sour*es, pro*ess *o!trols, a!d a!al?ti*al pro*edures,N N N (ii)(a) -rug produ*t, A list o0 all *ompo!e!ts used i! t&e ma!u0a*ture o0 t&e drug produ*t (regardless o0 +&et&er t&e? appear i! t&e drug produ*t) a!d a stateme!t o0 t&e *ompositio! o0 t&e drug produ*tJ t&e spe*i0i*atio!s 0or ea*& *ompo!e!tJ t&e !ame a!d address o0 ea*& ma!u0a*turer o0 t&e drug produ*tJ a des*riptio! o0 t&e ma!u0a*turi!g a!d pa*:agi!g pro*edures a!d i!%pro*ess *o!trols 0or t&e drug produ*tJ t&e spe*i0i*atio!s !e*essar? to e!sure t&e ide!tit?, stre!gt&, >ualit?, purit?, pote!*?, a!d bioa(ailabilit? o0 t&e drug produ*t, i!*ludi!g, 0or eDample, tests, a!al?ti*al pro*edures, a!d a**epta!*e *riteria relati!g to sterilit?, dissolutio! rate, *o!tai!er *losure s?stemsJ a!d stabilit? data +it& proposed eDpiratio! [["age #8$64 dati!g, 6&e appli*atio! ma? pro(ide additio!all? 0or t&e use o0 alter!ati(es to meet a!? o0 t&ese re>uireme!ts, i!*ludi!g alter!ati(e *ompo!e!ts, ma!u0a*turi!g a!d pa*:agi!g pro*edures, i!%pro*ess *o!trols, a!d a!al?ti*al pro*edures, N N N N N N N N 2e*, 0 4#4,60 [Ame!ded

#0, 2e*tio! 4#4,60 Ame!dme!ts to a! u!appro(ed appli*atio! is ame!ded i! paragrap& (*) b? remo(i!g t&e p&rase BB, ot&er t&a! a 0oreig! appli*a!t,CC, 0 ##, 2e*tio! 4#4,$0 is re(ised to read as 0ollo+s: 2e*, 4#4,$0 2uppleme!ts a!d ot&er *&a!ges to a! appro(ed appli*atio!,

(a) .&a!ges to a! appro(ed appli*atio!, (#) 6&e appli*a!t !oti0? F-A about ea*& *&a!ge i! ea*& *o!ditio! establis&ed i! a! appro(ed appli*atio! be?o!d t&e (ariatio!s alread? pro(ided 0or i! t&e appli*atio!, 6&e !oti*e is re>uired to des*ribe t&e *&a!ge 0ull?, -epe!di!g o! t&e t?pe o0 *&a!ge, t&e appli*a!t must !oti0? F-A about it i! a suppleme!t u!der paragrap& (b) or (*) o0 t&is se*tio! or b? i!*lusio! o0 t&e i!0ormatio! i! t&e a!!ual report to t&e appli*atio! u!der paragrap& (d) o0 t&is se*tio!, (2) 6&e &older o0 a! appro(ed appli*atio! u!der se*tio! 303 o0 t&e a*t must assess t&e e00e*ts o0 t&e *&a!ge be0ore distributi!g a drug produ*t made +it& a ma!u0a*turi!g *&a!ge, (4) Not+it&sta!di!g t&e re>uireme!ts o0 paragrap&s (b) a!d (*) o0 t&is se*tio!, a! appli*a!t must ma:e a *&a!ge pro(ided 0or i! t&ose paragrap&s i! a**orda!*e +it& a regulatio! or guida!*e t&at pro(ides 0or a less burde!some !oti0i*atio! o0 t&e *&a!ge (0or eDample, b? submissio! o0 a suppleme!t t&at does !ot re>uire appro(al prior to distributio! o0 t&e produ*t or i! a! a!!ual report), (4) 6&e appli*a!t must promptl? re(ise all promotio!al labeli!g a!d ad(ertisi!g to ma:e it *o!siste!t +it& a!? labeli!g *&a!ge impleme!ted i! a**orda!*e +it& paragrap&s (b) a!d (*) o0 t&is se*tio!, (3) 5D*ept 0or a suppleme!t pro(idi!g 0or a *&a!ge i! t&e labeli!g, t&e appli*a!t must i!*lude i! ea*& suppleme!t a!d ame!dme!t to a suppleme!t pro(idi!g 0or a *&a!ge u!der paragrap& (b) or (*) o0 t&is se*tio! a stateme!t *erti0?i!g t&at a 0ield *op? &as bee! pro(ided i! a**orda!*e +it& 2e*, 4#4,440(a)(4), (6) A suppleme!t or a!!ual report must i!*lude a list o0 all *&a!ges *o!tai!ed i! t&e suppleme!t or a!!ual report, For suppleme!ts, t&is list must be pro(ided i! t&e *o(er letter, (b) .&a!ges re>uiri!g suppleme!t submissio! a!d appro(al prior to distributio! o0 t&e produ*t made usi!g t&e *&a!ge (maAor *&a!ges), (#) A suppleme!t must be submitted 0or a!? *&a!ge i! t&e drug substa!*e, drug produ*t, produ*tio! pro*ess, >ualit? *o!trols, e>uipme!t, or 0a*ilities t&at &as a substa!tial pote!tial to &a(e a! ad(erse e00e*t o! t&e ide!tit?, stre!gt&, >ualit?, purit?, or pote!*? o0 t&e drug produ*t as t&ese 0a*tors ma? relate to t&e sa0et? or e00e*ti(e!ess o0 t&e drug produ*t, (2) 6&ese *&a!ges i!*lude, but are !ot limited to: (i) 5D*ept t&ose des*ribed i! paragrap&s (*) a!d (d) o0 t&is se*tio!, *&a!ges i! t&e >ualitati(e or >ua!titati(e 0ormulatio! o0 t&e drug produ*t, i!*ludi!g i!a*ti(e i!gredie!ts, or i! t&e spe*i0i*atio!s pro(ided i! t&e appro(ed appli*atio!J (ii) .&a!ges re>uiri!g *ompletio! o0 studies i! a**orda!*e +it& part 420 o0 t&is *&apter to demo!strate t&e e>ui(ale!*e o0 t&e drug produ*t to t&e drug produ*t as ma!u0a*tured +it&out t&e *&a!ge or to t&e re0ere!*e listed drugJ (iii) .&a!ges t&at ma? a00e*t drug substa!*e or drug produ*t sterilit? assura!*e, su*& as *&a!ges i! drug substa!*e, drug produ*t,

or *ompo!e!t sterili=atio! met&od(s) or a! additio!, deletio!, or substitutio! o0 steps i! a! asepti* pro*essi!g operatio!J (i() .&a!ges i! t&e s?!t&esis or ma!u0a*ture o0 t&e drug substa!*e t&at ma? a00e*t t&e impurit? pro0ile a!dEor t&e p&?si*al, *&emi*al, or biologi*al properties o0 t&e drug substa!*eJ (() 6&e 0ollo+i!g labeli!g *&a!ges: (A) .&a!ges i! labeli!g, eD*ept t&ose des*ribed i! paragrap&s (*)(6)(iii), (d)(2)(iD), or (d)(2)(D) o0 t&is se*tio!J (;) /0 appli*able, a!? *&a!ge to a 7edi*atio! )uide re>uired u!der part 208 o0 t&is *&apter, eD*ept 0or *&a!ges i! t&e i!0ormatio! spe*i0ied i! 2e*, 208,20(b)(8)(iii) a!d (b)(8)(i() o0 t&is *&apter, ((i) .&a!ges i! a drug produ*t *o!tai!er *losure s?stem t&at *o!trols t&e drug produ*t deli(ered to a patie!t or *&a!ges i! t&e t?pe (e,g,, glass to &ig& de!sit? pol?et&?le!e (1-"5), 1-"5 to pol?(i!?l *&loride, (ial to s?ri!ge) or *ompositio! (e,g,, o!e 1-"5 resi! to a!ot&er 1-"5 resi!) o0 a pa*:agi!g *ompo!e!t t&at ma? a00e*t t&e impurit? pro0ile o0 t&e drug produ*t, ((ii) .&a!ges solel? a00e*ti!g a !atural produ*t, a re*ombi!a!t -NA%deri(ed protei!Epol?peptide, or a *ompleD or *o!Augate o0 a drug substa!*e +it& a mo!o*lo!al a!tibod? 0or t&e 0ollo+i!g: (A) .&a!ges i! t&e (irus or ad(e!titious age!t remo(al or i!a*ti(atio! met&od(s)J (;) .&a!ges i! t&e sour*e material or *ell li!eJ a!d (.) 5stablis&me!t o0 a !e+ master *ell ba!: or seed, ((iii) .&a!ges to a drug produ*t u!der a! appli*atio! t&at is subAe*t to a (alidit? assessme!t be*ause o0 sig!i0i*a!t >uestio!s regardi!g t&e i!tegrit? o0 t&e data supporti!g t&at appli*atio!, (4) 6&e appli*a!t must obtai! appro(al o0 a suppleme!t 0rom F-A prior to distributio! o0 a drug produ*t made usi!g a *&a!ge u!der paragrap& (b) o0 t&is se*tio!, 5D*ept 0or submissio!s u!der paragrap& (e) o0 t&is se*tio!, t&e 0ollo+i!g i!0ormatio! must be *o!tai!ed i! t&e suppleme!t: (i) A detailed des*riptio! o0 t&e proposed *&a!geJ (ii) 6&e drug produ*t(s) i!(ol(edJ (iii) 6&e ma!u0a*turi!g site(s) or area(s) a00e*tedJ (i() A des*riptio! o0 t&e met&ods used a!d studies per0ormed to assess t&e e00e*ts o0 t&e *&a!geJ (() 6&e data deri(ed 0rom su*& studiesJ ((i) For a !atural produ*t, a re*ombi!a!t -NA%deri(ed protei!E pol?peptide, or a *ompleD or *o!Augate o0 a drug substa!*e +it& a mo!o*lo!al a!tibod?, rele(a!t (alidatio! proto*ols a!d a list o0 rele(a!t sta!dard operati!g pro*edures must be pro(ided i! additio! to t&e re>uireme!ts i! paragrap&s (b)(4)(i() a!d (b)(4)(() o0 t&is se*tio!J a!d ((ii) For sterili=atio! pro*ess a!d test met&odologies related to sterili=atio! pro*ess (alidatio!, rele(a!t (alidatio! proto*ols a!d a list o0 rele(a!t sta!dard operati!g pro*edures must be pro(ided i! additio! to t&e re>uireme!ts i! paragrap&s (b)(4)(i() a!d (b)(4)(() o0 t&is se*tio!, (4) A! appli*a!t ma? as: F-A to eDpedite its re(ie+ o0 a suppleme!t 0or publi* &ealt& reaso!s or i0 a dela? i! ma:i!g t&e *&a!ge des*ribed i! it +ould impose a! eDtraordi!ar? &ards&ip o! t&e appli*a!t, 2u*& a suppleme!t a!d its maili!g *o(er s&ould be plai!l? mar:ed: BB"rior Appro(al 2uppleme!t%5Dpedited Re(ie+ Re>uested,CC (*) .&a!ges re>uiri!g suppleme!t submissio! at least 40 da?s prior to distributio! o0 t&e drug produ*t made usi!g t&e *&a!ge (moderate *&a!ges), (#) A suppleme!t must be submitted 0or a!? *&a!ge i! t&e drug

substa!*e, drug produ*t, produ*tio! pro*ess, >ualit? *o!trols, e>uipme!t, or 0a*ilities t&at &as a moderate pote!tial to &a(e a! ad(erse e00e*t o! t&e ide!tit?, stre!gt&, [["age #8$63 >ualit?, purit?, or pote!*? o0 t&e drug produ*t as t&ese 0a*tors ma? relate to t&e sa0et? or e00e*ti(e!ess o0 t&e drug produ*t, /0 t&e suppleme!t pro(ides 0or a labeli!g *&a!ge u!der paragrap& (*)(6)(iii) o0 t&is se*tio!, #2 *opies o0 t&e 0i!al pri!ted labeli!g must be i!*luded, (2) 6&ese *&a!ges i!*lude, but are !ot limited to: (i) A *&a!ge i! t&e *o!tai!er *losure s?stem t&at does !ot a00e*t t&e >ualit? o0 t&e drug produ*t, eD*ept t&ose des*ribed i! paragrap&s (b) a!d (d) o0 t&is se*tio!J a!d (ii) .&a!ges solel? a00e*ti!g a !atural protei!, a re*ombi!a!t -NA% deri(ed protei!Epol?peptide or a *ompleD or *o!Augate o0 a drug substa!*e +it& a mo!o*lo!al a!tibod?, i!*ludi!g: (A) A! i!*rease or de*rease i! produ*tio! s*ale duri!g 0i!is&i!g steps t&at i!(ol(es di00ere!t e>uipme!tJ a!d (;) Repla*eme!t o0 e>uipme!t +it& t&at o0 a di00ere!t desig! t&at does !ot a00e*t t&e pro*ess met&odolog? or pro*ess operati!g parameters, (iii) RelaDatio! o0 a! a**epta!*e *riterio! or deletio! o0 a test to *ompl? +it& a! o00i*ial *ompe!dium t&at is *o!siste!t +it& F-A statutor? a!d regulator? re>uireme!ts, (4) A suppleme!t submitted u!der paragrap& (*)(#) o0 t&is se*tio! is re>uired to gi(e a 0ull eDpla!atio! o0 t&e basis 0or t&e *&a!ge a!d ide!ti0? t&e date o! +&i*& t&e *&a!ge is to be made, 6&e suppleme!t must be labeled BB2uppleme!t%%.&a!ges ;ei!g 500e*ted i! 40 -a?sCC or, i0 appli*able u!der paragrap& (*)(6) o0 t&is se*tio!, BB2uppleme!t%% .&a!ges ;ei!g 500e*ted,CC (4) "e!di!g appro(al o0 t&e suppleme!t b? F-A, eD*ept as pro(ided i! paragrap& (*)(6) o0 t&is se*tio!, distributio! o0 t&e drug produ*t made usi!g t&e *&a!ge ma? begi! !ot less t&a! 40 da?s a0ter re*eipt o0 t&e suppleme!t b? F-A, 6&e i!0ormatio! listed i! paragrap&s (b)(4)(i) t&roug& (b)(4)((ii) o0 t&is se*tio! must be *o!tai!ed i! t&e suppleme!t, (3) 6&e appli*a!t must !ot distribute t&e drug produ*t made usi!g t&e *&a!ge i0 +it&i! 40 da?s 0ollo+i!g F-ACs re*eipt o0 t&e suppleme!t, F-A i!0orms t&e appli*a!t t&at eit&er: (i) 6&e *&a!ge re>uires appro(al prior to distributio! o0 t&e drug produ*t i! a**orda!*e +it& paragrap& (b) o0 t&is se*tio!J or (ii) A!? o0 t&e i!0ormatio! re>uired u!der paragrap& (*)(4) o0 t&is se*tio! is missi!gJ t&e appli*a!t must !ot distribute t&e drug produ*t made usi!g t&e *&a!ge u!til t&e suppleme!t &as bee! ame!ded to pro(ide t&e missi!g i!0ormatio!, (6) 6&e age!*? ma? desig!ate a *ategor? o0 *&a!ges 0or t&e purpose o0 pro(idi!g t&at, i! t&e *ase o0 a *&a!ge i! su*& *ategor?, t&e &older o0 a! appro(ed appli*atio! ma? *omme!*e distributio! o0 t&e drug produ*t i!(ol(ed upo! re*eipt b? t&e age!*? o0 a suppleme!t 0or t&e *&a!ge, 6&ese *&a!ges i!*lude, but are !ot limited to: (i) Additio! to a spe*i0i*atio! or *&a!ges i! t&e met&ods or *o!trols to pro(ide i!*reased assura!*e t&at t&e drug substa!*e or drug produ*t +ill &a(e t&e *&ara*teristi*s o0 ide!tit?, stre!gt&, >ualit?, purit?, or pote!*? t&at it purports or is represe!ted to possessJ (ii) A *&a!ge i! t&e si=e a!dEor s&ape o0 a *o!tai!er 0or a

!o!sterile drug produ*t, eD*ept 0or solid dosage 0orms, +it&out a *&a!ge i! t&e labeled amou!t o0 drug produ*t or 0rom o!e *o!tai!er *losure s?stem to a!ot&erJ (iii) .&a!ges i! t&e labeli!g to a**omplis& a!? o0 t&e 0ollo+i!g: (A) 6o add or stre!gt&e! a *o!trai!di*atio!, +ar!i!g, pre*autio!, or ad(erse rea*tio!J (;) 6o add or stre!gt&e! a stateme!t about drug abuse, depe!de!*e, ps?*&ologi*al e00e*t, or o(erdosageJ (.) 6o add or stre!gt&e! a! i!stru*tio! about dosage a!d admi!istratio! t&at is i!te!ded to i!*rease t&e sa0e use o0 t&e drug produ*tJ (-) 6o delete 0alse, misleadi!g, or u!supported i!di*atio!s 0or use or *laims 0or e00e*ti(e!essJ or (5) A!? labeli!g *&a!ge !ormall? re>uiri!g a suppleme!t submissio! a!d appro(al prior to distributio! o0 t&e drug produ*t t&at F-A spe*i0i*all? re>uests be submitted u!der t&is pro(isio!, ($) /0 t&e age!*? disappro(es t&e suppleme!tal appli*atio!, it ma? order t&e ma!u0a*turer to *ease distributio! o0 t&e drug produ*t(s) made +it& t&e ma!u0a*turi!g *&a!ge, (d) .&a!ges to be des*ribed i! a! a!!ual report (mi!or *&a!ges), (#) .&a!ges i! t&e drug substa!*e, drug produ*t, produ*tio! pro*ess, >ualit? *o!trols, e>uipme!t, or 0a*ilities t&at &a(e a mi!imal pote!tial to &a(e a! ad(erse e00e*t o! t&e ide!tit?, stre!gt&, >ualit?, purit?, or pote!*? o0 t&e drug produ*t as t&ese 0a*tors ma? relate to t&e sa0et? or e00e*ti(e!ess o0 t&e drug produ*t must be do*ume!ted b? t&e appli*a!t i! t&e !eDt a!!ual report i! a**orda!*e +it& 2e*, 4#4,8#(b)(2), (2) 6&ese *&a!ges i!*lude, but are !ot limited to: (i) A!? *&a!ge made to *ompl? +it& a *&a!ge to a! o00i*ial *ompe!dium, eD*ept a *&a!ge des*ribed i! paragrap& (*)(2)(iii) o0 t&is se*tio!, t&at is *o!siste!t +it& F-A statutor? a!d regulator? re>uireme!ts, (ii) 6&e deletio! or redu*tio! o0 a! i!gredie!t i!te!ded to a00e*t o!l? t&e *olor o0 t&e drug produ*tJ (iii) Repla*eme!t o0 e>uipme!t +it& t&at o0 t&e same desig! a!d operati!g pri!*iples eD*ept t&ose e>uipme!t *&a!ges des*ribed i! paragrap& (*) o0 t&is se*tio!J (i() A *&a!ge i! t&e si=e a!dEor s&ape o0 a *o!tai!er *o!tai!i!g t&e same !umber o0 dosage u!its 0or a !o!sterile solid dosage 0orm drug produ*t, +it&out a *&a!ge 0rom o!e *o!tai!er *losure s?stem to a!ot&erJ (() A *&a!ge +it&i! t&e *o!tai!er *losure s?stem 0or a !o!sterile drug produ*t, based upo! a s&o+i!g o0 e>ui(ale!*? to t&e appro(ed s?stem u!der a proto*ol appro(ed i! t&e appli*atio! or publis&ed i! a! o00i*ial *ompe!diumJ ((i) A! eDte!sio! o0 a! eDpiratio! dati!g period based upo! 0ull s&el0 li0e data o! produ*tio! bat*&es obtai!ed 0rom a proto*ol appro(ed i! t&e appli*atio!J ((ii) 6&e additio! or re(isio! o0 a! alter!ati(e a!al?ti*al pro*edure t&at pro(ides t&e same or i!*reased assura!*e o0 t&e ide!tit?, stre!gt&, >ualit?, purit?, or pote!*? o0 t&e material bei!g tested as t&e a!al?ti*al pro*edure des*ribed i! t&e appro(ed appli*atio!, or deletio! o0 a! alter!ati(e a!al?ti*al pro*edureJ ((iii) 6&e additio! b? embossi!g, debossi!g, or e!gra(i!g o0 a *ode impri!t to a solid oral dosage 0orm drug produ*t ot&er t&a! a modi0ied release dosage 0orm, or a mi!or *&a!ge i! a! eDisti!g *ode impri!tJ (iD) A *&a!ge i! t&e labeli!g *o!*er!i!g t&e des*riptio! o0 t&e drug produ*t or i! t&e i!0ormatio! about &o+ t&e drug produ*t is

supplied, t&at does !ot i!(ol(e a *&a!ge i! t&e dosage stre!gt& or dosage 0ormJ a!d (D) A! editorial or similar mi!or *&a!ge i! labeli!g, (4) For *&a!ges u!der t&is *ategor?, t&e appli*a!t is re>uired to submit i! t&e a!!ual report: (i) A stateme!t b? t&e &older o0 t&e appro(ed appli*atio! t&at t&e e00e*ts o0 t&e *&a!ge &a(e bee! assessedJ (ii) A 0ull des*riptio! o0 t&e ma!u0a*turi!g a!d *o!trols *&a!ges, i!*ludi!g t&e ma!u0a*turi!g site(s) or area(s) i!(ol(edJ (iii) 6&e date ea*& *&a!ge +as impleme!tedJ (i() -ata 0rom studies a!d tests per0ormed to assess t&e e00e*ts o0 t&e *&a!geJ a!d, (() For a !atural produ*t, re*ombi!a!t -NA%deri(ed protei!E pol?peptide, *ompleD or *o!Augate o0 a drug substa!*e +it& a mo!o*lo!al a!tibod?, sterili=atio! pro*ess or test met&odolog? [["age #8$66 related to sterili=atio! pro*ess (alidatio!, a *ross%re0ere!*e to rele(a!t (alidatio! proto*ols a!dEor sta!dard operati!g pro*edures, (e) "roto*ols, A! appli*a!t ma? submit o!e or more proto*ols des*ribi!g t&e spe*i0i* tests a!d studies a!d a**epta!*e *riteria to be a*&ie(ed to demo!strate t&e la*: o0 ad(erse e00e*t 0or spe*i0ied t?pes o0 ma!u0a*turi!g *&a!ges o! t&e ide!tit?, stre!gt&, >ualit?, purit?, a!d pote!*? o0 t&e drug produ*t as t&ese 0a*tors ma? relate to t&e sa0et? or e00e*ti(e!ess o0 t&e drug produ*t, A!? su*& proto*ols, i0 !ot i!*luded i! t&e appro(ed appli*atio!, or *&a!ges to a! appro(ed proto*ol, must be submitted as a suppleme!t re>uiri!g appro(al 0rom F-A prior to distributio! o0 a drug produ*t produ*ed +it& t&e ma!u0a*turi!g *&a!ge, 6&e suppleme!t, i0 appro(ed, ma? subse>ue!tl? Austi0? a redu*ed reporti!g *ategor? 0or t&e parti*ular *&a!ge be*ause t&e use o0 t&e proto*ol 0or t&at t?pe o0 *&a!ge redu*es t&e pote!tial ris: o0 a! ad(erse e00e*t, (0) "ate!t i!0ormatio!, 6&e appli*a!t must *ompl? +it& t&e pate!t i!0ormatio! re>uireme!ts u!der se*tio! 303(*)(2) o0 t&e a*t, (g) .laimed eD*lusi(it?, /0 a! appli*a!t *laims eD*lusi(it? u!der 2e*, 4#4,#08 upo! appro(al o0 a suppleme!t 0or *&a!ge to its pre(iousl? appro(ed drug produ*t, t&e appli*a!t must i!*lude +it& its suppleme!t t&e i!0ormatio! re>uired u!der 2e*, 4#4,30(A), 2e*, 4#4,8# [Ame!ded

0 #2, 2e*tio! 4#4,8# 't&er postmar:eti!g reports is ame!ded i! paragrap& (b)(#)(ii) b? remo(i!g t&e +ord BBspe*i0i*atio!sCC a!d b? addi!g i! its pla*e t&e +ord BBspe*i0i*atio!CC, 2e*, 4#4,94 [Ame!ded

0 #4, 2e*tio! 4#4,94 .o!te!t a!d 0ormat o0 a! abbre(iated appli*atio! is ame!ded i! t&e se*o!d se!te!*e o0 paragrap& (d)(2) b? remo(i!g t&e +ord BBmet&odsCC ea*& time it appears a!d b? addi!g i! its pla*e t&e +ord BBpro*eduresCC,

2e*,

4#4,4#0

[Ame!ded

0 #4, 2e*tio! 4#4,4#0 /mports a!d eDports o0 !e+ drugs is ame!ded i! paragrap& (b)(2) b? remo(i!g t&e +ord BBspe*i0i*atio!sCC a!d b? addi!g i! its pla*e t&e +ord BBspe*i0i*atio!CC, 2e*, 4#4,440 [Ame!ded

0 #3, 2e*tio! 4#4,440 A(ailabilit? 0or publi* dis*losure o0 data a!d i!0ormatio! i! a! appli*atio! or abbre(iated appli*atio! is ame!ded i! paragrap& (e)(6) b? remo(i!g t&e +ord BBmet&odCC bot& times it appears a!d b? addi!g i! its pla*e t&e +ord BBpro*edureCC, "AR6 600%%;/'8')/.A8 "R'-9.62: )5N5RA8 0 #6, 6&e aut&orit? *itatio! 0or 2# .FR part 600 *o!ti!ues to read as 0ollo+s: Aut&orit?: 2# 9,2,., 42#, 43#, 432, 434, 433, 460, 460i, 4$#, 4$4J 42 9,2,., 2#6, 262, 264, 264a, 264, 400aa%23, 0 #$, 2e*tio! 600,4 is ame!ded b? addi!g paragrap&s (AA) a!d (::) to read as 0ollo+s: 2e*, 600,4 -e0i!itio!s,

N N N N N (AA) Assess t&e e00e*ts o0 t&e *&a!ge, as used i! 2e*, 60#,#2 o0 t&is *&apter, mea!s to e(aluate t&e e00e*ts o0 a ma!u0a*turi!g *&a!ge o! t&e ide!tit?, stre!gt&, >ualit?, purit?, a!d pote!*? o0 a produ*t as t&ese 0a*tors ma? relate to t&e sa0et? or e00e*ti(e!ess o0 t&e produ*t, (::) 2pe*i0i*atio!, as used i! 2e*, 60#,#2 o0 t&is *&apter, mea!s t&e >ualit? sta!dard (i,e,, tests, a!al?ti*al pro*edures, a!d a**epta!*e *riteria) pro(ided i! a! appro(ed appli*atio! to *o!0irm t&e >ualit? o0 produ*ts, i!termediates, ra+ materials, reage!ts, *ompo!e!ts, i!%pro*ess materials, *o!tai!er *losure s?stems, a!d ot&er materials used i! t&e produ*tio! o0 a produ*t, For t&e purpose o0 t&is de0i!itio!, a**epta!*e *riteria mea!s !umeri*al limits, ra!ges, or ot&er *riteria 0or t&e tests des*ribed, "AR6 60#%%8/.5N2/N) 0 #8, 6&e aut&orit? *itatio! 0or 2# .FR part 60# *o!ti!ues to read as 0ollo+s: Aut&orit?: #3 9,2,., #43#%#36#J 2# 9,2,., 42#, 43#, 432, 434, 433, 436b, 460, 460*%4600, 460&%460A, 4$#, 4$4, 4$9e, 48#J 42 9,2,., 2#6, 24#, 262, 264, 264J se* #22, "ub, 8, #03%##3, ### 2tat, 2422 (2# 9,2,., 433 !ote),

0 #9, 2e*tio! 60#,#2 is ame!ded b? re(isi!g paragrap&s (a), (b)(2)(i), (*)(2)(ii), (d)(2)(i) t&roug& (d)(2)((), a!d (d)(2)((ii)J b? addi!g paragrap&s (b)(4), (*)(2)(i(), (*)(6), (d)(4)(iii), a!d (0)(2)(i)(5)J a!d b? remo(i!g a!d reser(i!g paragrap& (*)(2)(i) to read as 0ollo+s: 2e*, 60#,#2 .&a!ges to a! appro(ed appli*atio!,

(a) )e!eral, (#) As pro(ided b? t&is se*tio!, a! appli*a!t must i!0orm t&e Food a!d -rug Admi!istratio! (F-A) about ea*& *&a!ge i! t&e produ*t, produ*tio! pro*ess, >ualit? *o!trols, e>uipme!t, 0a*ilities, respo!sible perso!!el, or labeli!g establis&ed i! t&e appro(ed li*e!se appli*atio!(s), (2) ;e0ore distributi!g a produ*t made usi!g a *&a!ge, a! appli*a!t must assess t&e e00e*ts o0 t&e *&a!ge a!d demo!strate t&roug& appropriate (alidatio! a!dEor ot&er *li!i*al a!dEor !o!*li!i*al laborator? studies t&e la*: o0 ad(erse e00e*t o0 t&e *&a!ge o! t&e ide!tit?, stre!gt&, >ualit?, purit?, or pote!*? o0 t&e produ*t as t&e? ma? relate to t&e sa0et? or e00e*ti(e!ess o0 t&e produ*t, (4) Not+it&sta!di!g t&e re>uireme!ts o0 paragrap&s (b), (*), a!d (0) o0 t&is se*tio!, a! appli*a!t must ma:e a *&a!ge pro(ided 0or i! t&ose paragrap&s i! a**orda!*e +it& a regulatio! or guida!*e t&at pro(ides 0or a less burde!some !oti0i*atio! o0 t&e *&a!ge (0or eDample, b? submissio! o0 a suppleme!t t&at does !ot re>uire appro(al prior to distributio! o0 t&e produ*t or i! a! a!!ual report), (4) 6&e appli*a!t must promptl? re(ise all promotio!al labeli!g a!d ad(ertisi!g to ma:e it *o!siste!t +it& a!? labeli!g *&a!ge impleme!ted i! a**orda!*e +it& paragrap&s (0)(#) a!d (0)(2) o0 t&is se*tio!, (3) A suppleme!t or a!!ual report must i!*lude a list o0 all *&a!ges *o!tai!ed i! t&e suppleme!t or a!!ual report, For suppleme!ts, t&is list must be pro(ided i! t&e *o(er letter, (b) N N N (2) N N N (i) 5D*ept as pro(ided i! paragrap&s (*) a!d (d) o0 t&is se*tio!, *&a!ges i! t&e >ualitati(e or >ua!titati(e 0ormulatio!, i!*ludi!g i!a*ti(e i!gredie!ts, or i! t&e spe*i0i*atio!s pro(ided i! t&e appro(ed appli*atio!J N N N N N (4) A! appli*a!t ma? as: F-A to eDpedite its re(ie+ o0 a suppleme!t 0or publi* &ealt& reaso!s or i0 a dela? i! ma:i!g t&e *&a!ge des*ribed i! it +ould impose a! eDtraordi!ar? &ards&ip o! t&e appli*a!t, 2u*& a suppleme!t a!d its maili!g *o(er s&ould be plai!l? mar:ed: BB"rior Appro(al 2uppleme!t%5Dpedited Re(ie+ Re>uested, (*) N N N (2) N N N (i) [Reser(ed (ii) A! i!*rease or de*rease i! produ*tio! s*ale duri!g 0i!is&i!g steps t&at i!(ol(es di00ere!t e>uipme!tJ a!d N N N N N (i() RelaDatio! o0 a! a**epta!*e *riterio! or deletio! o0 a test to *ompl? +it& a! o00i*ial *ompe!dium t&at is *o!siste!t +it& F-A statutor? a!d regulator? re>uireme!ts, N N N N N (6) /0 t&e age!*? disappro(es t&e suppleme!tal appli*atio!, it ma? order t&e ma!u0a*turer to *ease distributio! o0

[["age #8$6$ t&e produ*ts made +it& t&e ma!u0a*turi!g *&a!ge, (d) N N N (2) N N N (i) A!? *&a!ge made to *ompl? +it& a *&a!ge to a! o00i*ial *ompe!dium, eD*ept a *&a!ge des*ribed i! paragrap& (*)(2)(i() o0 t&is se*tio!, t&at is *o!siste!t +it& F-A statutor? a!d regulator? re>uireme!ts, (ii) 6&e deletio! or redu*tio! o0 a! i!gredie!t i!te!ded o!l? to a00e*t t&e *olor o0 t&e produ*t, eD*ept t&at a *&a!ge i!te!ded o!l? to a00e*t ;lood )roupi!g Reage!ts re>uires suppleme!t submissio! a!d appro(al prior to distributio! o0 t&e produ*t made usi!g t&e *&a!ge i! a**orda!*e +it& t&e re>uireme!ts set 0ort& i! paragrap& (b) o0 t&is se*tio!J (iii) A! eDte!sio! o0 a! eDpiratio! dati!g period based upo! 0ull s&el0 li0e data o! produ*tio! bat*&es obtai!ed 0rom a proto*ol appro(ed i! t&e appli*atio!J (i() A *&a!ge +it&i! t&e *o!tai!er *losure s?stem 0or a !o!sterile produ*t, based upo! a s&o+i!g o0 e>ui(ale!*? to t&e appro(ed s?stem u!der a proto*ol appro(ed i! t&e appli*atio! or publis&ed i! a! o00i*ial *ompe!diumJ (() A *&a!ge i! t&e si=e a!dEor s&ape o0 a *o!tai!er *o!tai!i!g t&e same !umber o0 dosage u!its 0or a !o!sterile solid dosage 0orm produ*t, +it&out a *&a!ge 0rom o!e *o!tai!er *losure s?stem to a!ot&erJ N N N N N ((ii) 6&e additio! or re(isio! o0 a! alter!ati(e a!al?ti*al pro*edure t&at pro(ides t&e same or i!*reased assura!*e o0 t&e ide!tit?, stre!gt&, >ualit?, purit?, or pote!*? o0 t&e material bei!g tested as t&e a!al?ti*al pro*edure des*ribed i! t&e appro(ed appli*atio!, or deletio! o0 a! alter!ati(e a!al?ti*al pro*edure, (4) N N N (iii) A stateme!t b? t&e &older o0 t&e appro(ed appli*atio! or li*e!se t&at t&e e00e*ts o0 t&e *&a!ge &a(e bee! assessed, N N N N N (0) N N N (2) N N N (i) N N N (5) A!? labeli!g *&a!ge !ormall? re>uiri!g a suppleme!t submissio! a!d appro(al prior to distributio! o0 t&e produ*t t&at F-A spe*i0i*all? re>uests be submitted u!der t&is pro(isio!, -ated: 7ar*& 24, 2004, @e00re? 2&ure!, Assista!t .ommissio!er 0or "oli*?, [FR -o*, 04%$342 Filed 4%$%04J 8:43 am ;/88/N) .'-5 4#60%0#%2

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