Supplement and Changes to an Approved Applicationr

8/13/2019 Supplement and Changes to an Approved Applicationr

1/87

[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 [+aisa**essgpogo

[-'./-:r08ap04%#4

[["age #8$2$

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"art /V

-epartme!t o 1ealt& a!d 1uma! eri*es

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Food a!d -rug Admi!istratio!

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2# .FR "arts 206, 230, #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;

Availaility; Notice

[["age #8$28

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-5"AR75N 'F 15A1 AN- 17AN 5RV/.5

Food a!d -rug Admi!istratio!

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


2/87

[-o*et No #999N%0#9

R/N 09#0%A;6#

uppleme!ts a!d 't&er .&a!ges to a! Approed Appli*atio!

A5N.


3/87

establis& *ategories o ma!ua*turi!g *&a!ges or +&i*& a suppleme!tal

appli*atio! is re>uired /! su*& a *ase, t&e appli*a!t ma? begi!

distributio! o a drug 0 da?s ater F-A &as re*eied a suppleme!tal

appli*atio! u!less t&e age!*? !otiies t&e appli*a!t +it&i! t&e 0%da?

period t&at prior approal o t&e appli*atio! is re>uired !der t&e

statute, F-A ma? also desig!ate a *ategor? o ma!ua*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!*? o a suppleme!tal appli*atio! or

t&e *&a!ge Fi!all?, F-A ma? also aut&ori=e appli*a!ts to distribute

drugs ma!ua*tured +it& a *&a!ge +it&out submitti!g a suppleme!tal

appli*atio! &e la+ proides t&at F-A ma? establis& *ategories o

ma!ua*turi!g *&a!ges t&at ma? be made +it&out submitti!g a

suppleme!tal appli*atio!

A -eelopme!t o t&e Regulatio!

/! t&e Federal Register o @u!e 28, #999 (64 FR 4608), F-A

publis&ed a proposed rule to impleme!t se*tio! 306A o t&e a*t or

&uma! !e+ drug appli*atio!s (N-As) a!d abbreiated !e+ drug

appli*atio!s (AN-As), as +ell as or li*e!sed biologi*al produ*ts (t&e

@u!e #999 proposal) /! t&at same issue o t&e Federal Register (64 FR4660), F-A a!!ou!*ed t&e aailabilit? o a drat guida!*e or i!dustr?

e!titled BB.&a!ges to a! Approed N-A or AN-ACC &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! approed N-A or AN-A u!der se*tio! 306A o t&e a*t as

+ell as u!der t&e proposed reisio!s to t&e &uma! drug regulatio!s

pertai!i!g to suppleme!ts a!d ot&er *&a!ges to a! approed appli*atio!

/! t&e Federal Register o Noember 2, #999 (64 FR 63$#6), F-A

a!!ou!*ed t&e aailabilit? o a guida!*e to assist appli*a!ts i!

determi!i!g &o+ t&e? s&ould report *&a!ges to a! approed N-A or AN-A

u!der se*tio! 306A o t&e a*t, pe!di!g i!ali=atio! o t&e @u!e #999

proposal F-A &as reised t&e guida!*e to *o!orm to t&is i!al rule

a!d is a!!ou!*i!g t&e aailabilit? o t&e guida!*e else+&ere i! t&is

issue o t&e Federal Register

; A Ris%;ased Approa*&

&e publi*atio! o t&is i!al rule is a! importa!t step i! t&e

pro*ess o adopti!g a ris%based approa*& to t&e regulatio! o

p&arma*euti*als /! t&e #990s, F-A spo!sored resear*& at t&e !iersit?

o 7ar?la!d a!d ot&er u!iersities o! t&e t?pes o *&emistr? a!d

ma!ua*turi!g *&a!ges to immediate release solid oral drug produ*ts

t&at *ould ae*t drug perorma!*e (ie, ide!tit?, stre!gt&, >ualit?,

purit?, a!d pote!*?) a!d, t&ereore, saet? a!d ee*tie!ess si!g

t&at resear*&, F-ACs .e!ter or -rug 5aluatio! a!d Resear*& (.-5R)

bega! to deelop a ris%based approa*& to t&e impleme!tatio! o

ma!ua*turi!g *&a!ges &e approa*& proided or a *o!ti!ued &ig& leel

o s*ruti!? b? F-A o *&a!ges t&at +ere most liel? to ae*t t&eperorma!*e o a drug a!d de*reased s*ruti!? o *&a!ges t&at +ere !ot

liel? to ae*t t&e perorma!*e o a drug

&e ris%based approa*& +as irst eDplai!ed i! a series o guida!*e

do*ume!ts (t&e *ale%up a!d "ostapproal .&a!ges ("A.) guida!*es)

t&at redu*ed t&e regulator? burde! o obtai!i!g F-A aut&ori=atio! to

mae *ertai! *&a!ges &e +or *o!ti!ued i! regulatio!s issued b? t&e

.e!ter or ;iologi*s 5aluatio! a!d Resear*& (.;5R) i! #99$ (2# .FR

60##2) /! Noember #99$, t&is ris%based approa*& +as *odiied i!

se*tio! ##6 o t&e 7oder!i=atio! A*t


4/87

&is i!al rule impleme!ts se*tio! ##6 o t&e 7oder!i=atio! A*t b?

i!*orporati!g t&e statutor? sta!dards or *&ara*teri=i!g proposed

*&a!ges as &ai!g substa!tial, moderate, or mi!imal pote!tial to

adersel? ae*t t&e ide!tit?, stre!gt&, >ualit?, purit?, a!d pote!*?

o a drug as t&e? ma? relate to its saet? a!d ee*tie!ess a!d

determi!i!g submissio! re>uireme!ts based o! t&e pote!tial riss

asso*iated +it& t&e *&a!ges For *&a!ges +it& a substa!tial pote!tial

to ae*t t&e desig!ated *&ara*teristi*s o a drug, F-A must reie+ a!d

approe a suppleme!t t&at *o!tai!s i!ormatio! s&o+i!g t&at t&e

proposed *&a!ge +ill !ot adersel? ae*t t&e drugCs *&ara*teristi*s

(ie, i!ormatio! deeloped b? t&e &older o t&e appli*atio! to

alidate t&e ee*t o t&e proposed *&a!ge) beore distributio! o t&e

produ*t made usi!g t&e *&a!ge

[["age #8$29

/t +as a!ti*ipated +&e! se*tio! ##6 o t&e 7oder!i=atio! A*t +as

+ritte! t&at t&e s*ie!*e o ma!ua*turi!g +ould eole oer time a!d

ae*t +&et&er *&a!ges +ould be *o!sidered maor or !o!maor o

a**ommodate uture te*&!ologi*al ada!*eme!ts, se*tio! ##6 o t&e

7oder!i=atio! A*t a!d t&is i!al impleme!ti!g regulatio! bot& proidet&at F-A ma?, b? regulatio! or guida!*e, *&a!ge t&e desig!atio! o a

parti*ular *ategor? o *&a!ge rom maor to !o!maor or i*e ersa

&is *o!*ept o a! eoli!g ris%based approa*& to ma!ua*turi!g

*&a!ges also is *o!siste!t +it& t&e age!*?Cs ood 7a!ua*turi!g

"ra*ti*es /!itiatie (BB"&arma*euti*al *7"s or t&e 2#st .e!tur?,CC

&ttp:EEr+ebgatea**essgpogoE*gi%bi!Eleai!g*gi

romGleai!gFR&tmlHlogGli!logHtoG&ttp:EE+++dagoE*derEgmpEi!deD&tm

) &e goals o t&at i!itiatie, lau!*&ed

i! August 2002, i!*lude:

I;5 5!suri!g t&at state%o%t&e%art p&arma*euti*al

s*ie!*e is utili=ed i! t&e regulator? reie+ a!d i!spe*tio! poli*iesJ

I;5 5!*ouragi!g t&e adoptio! o !e+ te*&!ologi*al

ada!*es i! &ig& >ualit? a!d ei*ie!t ma!ua*turi!g b? t&e

p&arma*euti*al i!dustr?J

I;5 Assessi!g t&e appli*able *urre!t good

ma!ua*turi!g pra*ti*e (.7") re>uireme!ts relatie to t&e best >ualit?

ma!ageme!t pra*ti*esJ

I;5 tre!gt&e!i!g publi* &ealt& prote*tio! b?

impleme!ti!g ris%based approa*&es t&at o*us bot& i!dustr? a!d F-A

atte!tio! o! *riti*al areas or improi!g produ*t saet? a!d >ualit?J

a!d

I;5 5!&a!*i!g t&e *o!siste!*? a!d *oordi!atio! o

F-ACs drug >ualit? oersig&t a*tiities

pe*ii*all?, o!e o t&e eorts o t&e .7" i!itiatie is to

a*ilitate *o!ti!uous improeme!t a!d i!!oatio! i! ma!ua*turi!g b?

allo+i!g ma!ua*turers to mae *ertai! t?pes o *&a!ges i! t&eirpro*esses +it&out prior F-A approal &is rule, i! eepi!g +it& t&at

i!itiatie, proides or a me*&a!ism o *o!ti!uous improeme!t t&roug&

t&e guida!*e pro*ess (2# .FR #0##3) t&at ma? proide or less

burde!some do*ume!tatio! o *ertai! *&a!ges as ma!ua*turi!g pro*esses

a!d p&arma*euti*al s*ie!*e deelop

// 1ig&lig&ts o Reisio!s to t&e "roposed Rule

A -ei!itio!s
http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/cder/gmp/index.htmhttp://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/cder/gmp/index.htmhttp://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/cder/gmp/index.htmhttp://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/cder/gmp/index.htm


5/87

F-A &as reised t&e proposed dei!itio! o BBspe*ii*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! o a drug substa!*e or drug produ*tCC F-A made t&is *&a!ge

or *o!siste!*? +it& ot&er regulatio!s F-A proposed a dei!itio! or

t&e term BBalidate t&e ee*ts o t&e *&a!geCC /! t&e i!al rule, t&e

age!*? &as *&a!ged t&e +ord BBalidateCC to BBassessCC a!d proides a

dei!itio! or t&e term BBassess t&e ee*ts o t&e *&a!geCC

; .&a!ges to a! Approed Appli*atio!

&e proposal re>uired t&at t&e &older o a! approed appli*atio!

alidate t&e ee*ts o ma!ua*turi!g *&a!ges o! t&e ide!tit?,

stre!gt&, >ualit?, purit?, a!d pote!*? o t&e drug as t&ese a*tors ma?

relate to t&e saet? or ee*tie!ess o t&e drug F-A &as reised t&is

proisio! to re>uire t&at t&e &older o a! approed appli*atio! assess

t&e ee*ts o ma!ua*turi!g *&a!ges F-A &as deleted t&e p&rase BBo!

t&e ide!tit?, stre!gt&, >ualit?, purit?, a!d pote!*? o t&e drug

produ*t as t&ese a*tors ma? relate to t&e saet? or ee*tie!ess ot&e drug produ*tCC be*ause t&is i!ormatio! is alread? i!*luded i! t&e

dei!itio! o t&e term BBassess t&e ee*ts o t&e *&a!geCC

"reiousl?, e* #4$0(*) (2# .FR #4$0(*)) stated t&at t&e

appli*a!t +&o submits a *&a!ges%bei!g%ee*ted suppleme!t to F-A must

promptl? reise all promotio!al labeli!g a!d adertisi!g to mae it

*o!siste!t +it& a!? *&a!ge i! t&e labeli!g &e proposal retai!ed t&is

proisio! 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 reised t&is proisio!

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

&e proposal re>uired t&e appli*a!t to i!*lude i! a *oer letter a

list o all *&a!ges *o!tai!ed i! t&e suppleme!t or a!!ual report F-A

&as *lariied t&at t&e re>uireme!t to i!*lude t&e list o *&a!ges i! a

*oer letter applies o!l? to *&a!ges *o!tai!ed i! a suppleme!tJ t&e

i!ormatio! is alread? submitted i! a! a!!ual report

. .&a!ges Re>uiri!g uppleme!t ubmissio! a!d Approal "rior to

-istributio! o t&e "rodu*t 7ade si!g t&e .&a!ge (7aor .&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!ole *&a!ges i! t&e t?pe

or *ompositio! o a pa*agi!g *ompo!e!t F-A i!te!ds to proide

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 reere!*e list o relea!t sta!dard

operati!g pro*edures ('"s) be *o!tai!ed i! all suppleme!ts submittedu!der t&is se*tio! F-A &as reised t&is proisio! to spe*i? t&at a

reere!*e list o relea!t '"s must be submitted or *&a!ges to a

!atural produ*t, a re*ombi!a!t deoD?ribo!u*lei* a*id (-NA)%deried

protei!Epol?peptide produ*t, or a *ompleD or *o!ugate o a drug

substa!*e +it& a mo!o*lo!al a!tibod?, a!d or *&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 uppleme!t ubmissio! at east 0 -a?s "rior to


6/87

-istributio! o t&e -rug "rodu*t 7ade si!g t&e .&a!ge (7oderate

.&a!ges)

F-A &as reised t&e @u!e #999 proposal to *lari? t&at t&e

re>uireme!t to submit #2 *opies o i!is&ed produ*t labeli!g applies to

suppleme!ts or *&a!ges t&at ma? be impleme!ted 0 da?s ater F-A

re*eies t&e suppleme!t

F-A &as *lariied 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 proisio!s do !ot

i!*lude t&e *&a!ges des*ribed u!der t&e proisio!s re>uiri!g prior

approal or t&e *&a!ges submitted i! a! a!!ual report

F-A &as reised t&e *&a!ges solel? ae*ti!g a !atural protei!

produ*t, a re*ombi!a!t -NA%deried protei!Epol?peptide produ*t, or a

*ompleD or *o!ugate o a drug +it& a mo!o*lo!al a!tibod? to spe*i?

t&e use o BBdiere!t e>uipme!tCC i!stead o BB!e+ or diere!t

e>uipme!tCC or *&a!ges i! produ*tio! s*ale, a!d e>uipme!t o BBa

diere!t desig!CC i!stead o BBsimilar but !ot ide!ti*al desig! a!d

operati!g pri!*ipleCC or t&e repla*eme!t o e>uipme!t

F-A is also addi!g to t&e moderate *&a!ges proisio!s a *&a!ge i!

t&e relaDatio! o a! a**epta!*e *riterio! or deletio! o a test to

*ompl? +it& a! oi*ial *ompe!dium t&at is *o!siste!t +it& F-Astatutor? a!d regulator? re>uireme!ts F-A is !ot re>uiri!g t&at a

prior approal suppleme!t be submitted or t&is t?pe o *&a!ge be*ause

t&e *&a!ge &as bee! reie+ed b? t&e !ited tates "&arma*opeia ("),

a!d F-A a!d t&e publi* &ae &ad a! opportu!it? to reie+, i! ge!eral,

t&e *&a!ge t&roug& t&e " pro*ess 1o+eer, be*ause F-A +ill !ot &ae

reie+ed su*& a *&a!ge i! t&e *o!teDt o ea*& i!diidual appli*atio!

ae*ted b? t&e *&a!ge, a *&a!ges%bei!g%ee*ted%i!%0%da?s suppleme!t

+ill still be re>uired

F-A &as reised t&e proposal to *lari? t&at t&e appli*a!t ma? !ot

[["age #8$0

distribute t&e drug produ*t u!til t&e suppleme!t or a *&a!ge u!der

t&is proisio! &as bee! ame!ded to proide missi!g i!ormatio! t&at &as

bee! re>uested b? F-A

5 .&a!ges &at 7a? ;e /mpleme!ted K&e! F-A Re*eies a uppleme!t

(7oderate .&a!ges)

F-A &as *lariied t&at labeli!g *&a!ges t&at !ormall? re>uire a

prior approal suppleme!t ma?, at t&e age!*?Cs re>uest, be impleme!ted

+&e! F-A re*eies a suppleme!t

F .&a!ges o ;e -es*ribed i! t&e NeDt A!!ual Report

F-A &as reised t&e @u!e #999 proposal to state t&at a!? *&a!ge

made to *ompl? +it& a! oi*ial *ompe!dium t&at is *o!siste!t +it& F-Astatutor? a!d regulator? re>uireme!ts ma? be submitted i! t&e !eDt

a!!ual report, eD*ept a *&a!ge i!oli!g t&e relaDatio! o a!

a**epta!*e *riterio! or deletio! o a test to *ompl? +it& a! oi*ial

*ompe!dium

F-A &as reised t&e @u!e #999 proposal to *lari? t&at t&e maorit?

o *&a!ges *o!*er!i!g repla*eme!t o e>uipme!t +it& e>uipme!t o t&e

same desig! a!d operati!g pri!*iples ma? be submitted i! a! a!!ual

report 1o+eer, t&ere are *ertai! e>uipme!t *&a!ges ide!tiied i! t&is

rule t&at re>uire submissio! i! a *&a!ges%bei!g%ee*ted%i!%0%da?s


7/87

suppleme!t or a *&a!ges%bei!g%ee*ted suppleme!t

F-A &as reised t&e @u!e #999 proposal to *lari? t&at *ertai!

*&a!ges made to t&e *o!tai!er *losure s?stems or sterile drug produ*ts

ma? be submitted i! a!!ual reports, as ma? *ertai! *&a!ges or

!o!sterile drug produ*t *o!tai!er *losure s?stems &e *&a!ges are

t&ose based o! a s&o+i!g o e>uiale!*? u!der a! approed or oi*ial

*ompe!dium proto*ol

F-A &as reised t&e @u!e #999 proposal to *lari? t&at a! eDte!sio!

o 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 o ull 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! a*ilit? as spe*iied 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*& o a si=e or +it&i! a bat*& si=e ra!ge

t&at &as bee! approed i! t&e appli*atio!

F-A &as deleted t&e re>uireme!t t&at a! a!!ual report *o!tai! a

list o all produ*ts i!oled i! t&e *&a!ges F-A &as also *lariied

t&at a! a!!ual report must i!*lude t&e date ea*& *&a!ge +as impleme!ted

i!stead o 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 approed appli*atio! is *&a!ged, !ot +&e! t&e produ*t made +it&t&e *&a!ge is distributed F-A &as also reised t&e @u!e #999 proposal

to *lari? +&e! alidatio! proto*ols a!d '"s must be i!*luded i! a!

a!!ual report submissio!

't&er /!ormatio!

F-A &as reised t&e @u!e #999 proposal to *lari? t&at a proto*ol

must be submitted as a prior approal suppleme!t i t&e proto*ol +as

!ot alread? i!*luded i! a! approed appli*atio! or +&e! *&a!gi!g a!

approed 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*tCC &e

age!*? &as sta!dardi=ed t&e termi!olog? t&roug&out t&e i!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

i!al rule i! respo!se to ormer "reside!t .li!to!Cs @u!e #, #998, memo

o! plai! la!guage i! oer!me!t +riti!g

/// Respo!ses to .omme!ts o! t&e @u!e #999 "roposal

F-A re*eied *omme!ts o! most aspe*ts o t&e @u!e #999 proposal

rom more t&a! 0 p&arma*euti*al *ompa!ies, p&arma*euti*al i!dustr?

asso*iatio!s, a!d ot&er i!terested perso!s &e *omme!ts a!d t&e

age!*?Cs respo!ses ollo+

A e!eral .omme!ts

(.omme!t #) 7a!? *omme!ts said t&e @u!e #999 proposal does !ot meett&e i!te!t o .o!gress +&e! establis&i!g se*tio! 306A o t&e a*t &e

*omme!ts said t&at .o!gress eDpe*ted t&e ollo+i!g: (#) ig!ii*a!t

*&a!ges i! F-ACs past pra*ti*es o! ma!ua*turi!g *&a!gesJ (2)

substa!tial improeme!t i! t&e ma!ageme!t o te*&!i*al suppleme!ts or

ma!ua*turi!g *&a!gesJ () regulator? relie +it&out *ompromisi!g

>ualit?, saet?, or ei*a*? o drugsJ (4) appropriate a*tio! o! t&e

mareti!g o regulated produ*ts i! a ma!!er t&at does !ot u!dul? impede

i!!oatio! or produ*t aailabilit?J (3) redu*tio! i! reporti!g a!d

regulator? re>uireme!tsJ a!d (6) a small !umber o maor ma!ua*turi!g


8/87

*&a!ges t&at re>uire prior approal, but t&at most *&a!ges +ould

re>uire a less burde!some mea!s o reporti!g t&a! &as bee! re>uired i!

t&e past eeral *omme!ts said t&e @u!e #999 proposal ge!erates !e+

re>uireme!ts or mai!g regulator? submissio!s, adds !e+ *ategories or

mai!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 "A. guida!*esL#L +ould !ot

ulill t&e .o!gressio!al i!te!t be*ause t&e? +ere publis&ed beore t&e

7oder!i=atio! A*t

%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%

%%%%

L#L As eDplai!ed i! t&e @u!e #999 proposal, F-A deeloped t&e

"A. guida!*es to ease preapproal re>uireme!ts b? *ategori=i!g

*ertai! ma!ua*turi!g *&a!ges a**ordi!g to +&et&er t&e? &ad a mi!or,

moderate, or maor pote!tial to ae*t produ*t >ualit? a!d

perorma!*e

%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%

%%%%

F-A beliees t&at t&ese regulatio!s are *o!siste!t +it& t&e i!te!t

o .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 o t&e a*t e*tio! 306A o

t&e a*t proides F-A +it& *o!siderable leDibilit? to determi!e t&e

i!ormatio! a!d ili!g me*&a!ism re>uired or t&e age!*? to assess t&e

ee*t o ma!ua*turi!g *&a!ges i! t&e saet? a!d ee*tie!ess o t&e

produ*t &ere is a *orrespo!di!g !eed to retai! su*& leDibilit? i!

t&e proposed regulatio!s impleme!ti!g se*tio! 306A o t&e a*t to e!sure

t&at t&e least burde!some mea!s or reporti!g *&a!ges are aailable

F-A beliees t&at su*& leDibilit? +ill allo+ it to be respo!sie to

i!*reasi!g !o+ledge o a!d eDperie!*e +it& *ertai! t?pes o *&a!ges

a!d &elp e!sure t&e ei*a*? a!d saet? o t&e produ*ts i!oled For

eDample, a *&a!ge t&at ma? *urre!tl? be *o!sidered to &ae a

substa!tial pote!tial to &ae a! aderse ee*t o! t&e saet? or

ee*tie!ess o t&e produ*t ma?, at a later date, based o! !e+

i!ormatio! or ada!*es i! te*&!olog?, be determi!ed to &ae a lesser

pote!tial to &ae su*& a! aderse ee*t .o!ersel?, a *&a!ge

origi!all? *o!sidered to &ae a mi!imal or moderate pote!tial to &ae

a! aderse ee*t o! t&e saet? or ee*tie!ess o t&e produ*t ma?

later, as a result o !e+ i!ormatio!, be ou!d to &ae a! i!*reased,

substa!tial pote!tial to adersel? ee*t t&e produ*t

&e age!*? beliees it *a! more readil? respo!d to !o+ledge gai!ed

rom ma!ua*turi!g eDperie!*e, urt&er resear*& a!d data *olle*tio!,

a!d ada!*es i! te*&!olog? b? issui!g regulatio!s t&at set out broad,

ge!eral *ategories o ma!ua*turi!g *&a!ges a!d b? usi!g guida!*e

do*ume!ts to proide F-ACs *urre!t t&i!i!g o! t&e spe*ii* *&a!ges

t&at all i!to t&ose ge!eral *ategories &e regulatio!s proide or a

!e+ approa*& to regulati!g postapproal ma!ua*turi!g *&a!ges &e

approa*& is based o! t&e pote!tial or a *&a!ge to adersel? ae*t t&eide!tit?, stre!gt&, >ualit?, purit?, or pote!*? o drug produ*ts as

t&ese a*tors relate to t&e saet? a!d ee*tie!ess o t&e produ*t

&e

[["age #8$#

regulatio!s a!d *ompa!io! guida!*e BB.&a!ges to a! Approed N-A or

AN-ACC +ill proide sig!ii*a!t regulator? relie b? allo+i!g

postapproal ma!ua*turi!g *&a!ges to be impleme!ted more rapidl?,


9/87

+&ile still e!suri!g t&e ide!tit?, stre!gt&, >ualit?, purit?, a!d

pote!*? o drug produ*ts

&e regulatio! redu*es t&e oerall !umber o suppleme!ts re>uiri!g

F-A approal 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 &e regulatio! +ill !ot i!*rease t&e !umber o a!!ual reports

but +ill allo+ appli*a!ts to i!*lude i! a! a!!ual report i!ormatio!

*urre!tl? re>uired to be reported to t&e age!*? i! a suppleme!tal

appli*atio! &e !umber o ma!ua*turi!g *&a!ges *urre!tl? reported i!

suppleme!ts t&at +ill be reported i! a!!ual reports is approDimatel?

#,28

For eDample, u!der t&e preious regulatio!s, all ma!ua*turi!g site

*&a!ges or drug produ*ts re>uired prior approal No+ o!l? a e+ t?pes

o drug produ*t ma!ua*turi!g site *&a!ges must be submitted i! a prior

approal suppleme!t &e maorit? *a! be submitted i! a *&a!ges%bei!g%

ee*ted%i!%0%da?s suppleme!t or i! a! a!!ual report 7oreoer, F-A

urt&er redu*ed ma!? reporti!g re>uireme!ts rom t&e leels re*omme!ded

i! preious F-A guida!*es For eDample, t&e "A. guida!*es re*omme!ded

!otii*atio! i! a! a!!ual report +&e! moi!g produ*tio! operatio!s

bet+ee! buildi!gs at t&e same ma!ua*turi!g site No+, ge!erall? !o

!otii*atio! is re>uired or su*& *&a!ges ae*ti!g drug produ*ts t&at+ere *oered u!der t&e ollo+i!g "A. guida!*es: (#) BB/mmediate%

Release olid 'ral -osage Forms: *ale%p a!d "ost%Approal .&a!ges:

.&emistr?, 7a!ua*turi!g a!d .o!trols, /! Vitro -issolutio! esti!g,

a!d /! Vio ;ioe>uiale!*e -o*ume!tatio!CC ("A.%/R)J (2) BB7odiied

Release olid 'ral -osage Forms: *ale%p a!d "ost%Approal .&a!ges:

.&emistr?, 7a!ua*turi!g a!d .o!trols, /! Vitro -issolutio! esti!g,

a!d /! Vio ;ioe>uiale!*e -o*ume!tatio!CC ("A.%7R)J a!d ()

BBNo!sterile emisolid -osage Forms: *ale%p a!d "ost%Approal

.&a!ges: .&emistr?, 7a!ua*turi!g a!d .o!trols, /! Vitro Release

esti!g, a!d /! Vio ;ioe>uiale!*eCC ("A.%)

F-A beliees t&at t&e approa*& to postapproal *&a!ges embodied i!

t&e "A. guida!*es is *o!siste!t +it& se*tio! 306A o t&e a*t

1o+eer, *ertai! aspe*ts o t&ese do*ume!ts !eed to be updated to be

*o!siste!t +it& spe*ii* re>uireme!ts i!*luded i! t&e a*t For eDample,

t&e !e+ reporti!g *ategor? or *&a!ges%bei!g%ee*ted%i!%0%da?s

suppleme!ts !eeds to be i!*orporated F-A i!te!ds to update t&ese

guida!*es i! t&e !ear uture

(.omme!t 2) eeral *omme!ts said t&at F-A s&ould adopt a

BBde*isio! treeCC or BBe? >uestio!sCC approa*& i! impleme!ti!g se*tio!

306A o t&e a*t &e *omme!ts *o!te!d t&at t&is approa*& +ould allo+ a

!e+ approa*& to ma!ua*turi!g *&a!ges t&at bases t&e regulator?

reporti!g re>uireme!ts o! t&e results o s*ie!tii* *ompariso! o 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 or a *&a!ge to &ae a! aderse ee*t

&e de*isio! tree +ould o*us o! a!s+eri!g t&e e? >uestio!s rat&er

t&a! eD&austie *ategori=atio! o pote!tial t?pes o *&a!ges '!e

*omme!t proided eDamples o de*isio! trees or *o!sideratio! F-A agrees t&at de*isio! trees are a iable approa*& to

postapproal ma!ua*turi!g *&a!ges 1o+eer, a de*isio! tree must

*o!sider t&e pote!tial or a *&a!ge to &ae a! aderse ee*t to be

*o!siste!t +it& se*tio! 306A o t&e a*t &e a*t bases t&e reporti!g

*ategor? or a *&a!ge o! t&e pote!tial or t&at *&a!ge to &ae a!

aderse ee*t, !ot o! t&e out*ome o assessme!t studies /! some

*ases, based o! t&e pote!tial or a! aderse ee*t, t&e a*t +ould

re>uire F-A to reie+ a *&a!ge prior to distributio! o t&e drug

produ*t +it& t&e *&a!ge, ee! i t&e appli*a!t *o!*ludes t&at its


10/87

studies a!d data demo!strate t&at t&e *&a!ge &as !o sig!ii*a!t aderse

ee*t F-A must ealuate +&et&er t&e studies perormed b? t&e

appli*a!t +ere sui*ie!t to assess t&e ee*t o 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

adersel? ae*ted t&e ide!tit?, stre!gt&, >ualit?, purit?, a!d pote!*?

o t&e drug produ*t as t&e? ma? relate to t&e saet? or ee*tie!ess

o a drug produ*t For eDample, a! appli*a!t ma? de*ide to deelop a!

i! ioEi! itro *orrelatio! (/V/V.) or a! eDte!ded release oral

dosage orm (see .-5RCs guida!*e e!titled BB5Dte!ded Release 'ral

-osage Forms: -eelopme!t, 5aluatio!, a!d Appli*atio! o /! itroE/!

io .orrelatio!sCC (eptember #99$)) / a! /V/V. is establis&ed, t&e

dissolutio! test +ill be used b? t&e appli*a!t as a surrogate or i!

io bioe>uiale!*e +&e! it is !e*essar? to do*ume!t bioe>uiale!*e or

postapproal *&a!ges 5stablis&i!g a! /V/V. &as a sig!ii*a!t pote!tial

to ae*t t&e ide!tit?, stre!gt&, >ualit?, purit?, a!d pote!*? o t&e

drug produ*t as t&e? ma? relate to saet? a!d ee*tie!ess o t&e drug

produ*t, a!d re>uires a prior approal suppleme!t &e appli*a!t, based

o! its ealuatio! o t&e data, ma? beliee t&at a! /V/V. &as bee!

establis&ed but t&e age!*?, ater ealuatio! o t&e appli*a!tCs data,

ma? !ot *o!*ur / t&e appli*a!t de*ided t&at a prior approal

suppleme!t +as !ot !e*essar? based o! its *o!*lusio!s t&at a! /V/V. &asbee! establis&ed a!d impleme!ted t&e *&a!ge +it&out +aiti!g or t&e

age!*?Cs *o!*urre!*e, a drug produ*t t&at is !ot bioe>uiale!t *ould be

distributed to t&e publi*

F-A regulates a +ide ra!ge o produ*ts, a!d a de*isio! tree s&ould

address t&e a*t t&at t&e pote!tial or aderse ee*t +ill ar?

depe!di!g o! a*tors su*& as t&e dosage orm a!d route o

admi!istratio! For eDample, i! ge!eral, pa*agi!g *&a!ges t&at i!ole

pare!teral drug produ*ts are ie+ed b? F-A to &ae a &ig&er pote!tial

to &ae a! aderse ee*t o! t&e >ualit? o t&e drug produ*t as it

relates to t&e saet? a!d ei*a*? o t&e drug produ*t t&a! a pa*agi!g

*&a!ge or a solid oral dosage orm produ*t ea*&ables rom t&e

pa*agi!g i!to pare!teral drug produ*ts are more liel? to o**ur t&a!

or a solid oral dosage orm, a!d i lea*&i!g o**urs, t&ere is a &ig&er

pote!tial or aderse rea*tio!s be*ause o t&e route o admi!istratio!

A saet? determi!atio! b? F-A must be made beore 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! o

a *omparabilit? proto*ol *o!tai!i!g a de*isio! tree, a!d F-A +ill

ealuate t&e de*isio! tree or *o!siste!*? +it& se*tio! 306A o t&e

a*t

(.omme!t ) A!ot&er *omme!t said t&at t&e proposal *o!sisted o

&eig&te!ed reporti!g re>uireme!ts or *&a!ges i! pa*agi!g materials

or sterile li>uid dosage orms

"reiousl?, u!der e* #4$0(b), *&a!ges i! pa*agi!g or sterile

li>uid dosage orms routi!el? re>uired prior approal b? F-A beore

t&e? *ould be impleme!ted &e i!al rule, at e* #4$0(b)(2)(iii),

still emp&asi=es t&e importa!*e, rom t&e saet? perspe*tie, oe!suri!g t&e sterilit? o drug produ*ts b? re>uiri!g t&at *&a!ges t&at

ma? ae*t drug produ*t sterilit? assura!*e be reported i! a prior

approal suppleme!t 1o+eer, t&e guida!*e BB.&a!ges to a! Approed N-A

or AN-A,CC a!!ou!*ed else+&ere i! t&is issue o t&e Federal Register,

i!*ludes *ertai! *&a!ges i! t&e pa*agi!g o t&ese produ*ts t&at *a! be

impleme!ted b? mea!s ot&er t&a! prior approal suppleme!ts &is a*tio!

&as redu*ed, rat&er t&a! &eig&te!ed, t&e regulator?

[["age #8$2


11/87

burde! relati!g to t&e pa*agi!g o sterile li>uid dosage orms 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!*? beliees it *a! more readil? respo!d to !o+ledge

gai!ed rom ma!ua*turi!g eDperie!*e, urt&er resear*& a!d data

*olle*tio!, a!d ada!*es i! te*&!olog? b? issui!g regulatio!s t&at set

out broad, ge!eral *ategories o ma!ua*turi!g *&a!ges a!d b? usi!g

guida!*e do*ume!ts to proide F-ACs *urre!t t&i!i!g o! t&e spe*ii*

*&a!ges t&at all i!to t&ose ge!eral *ategories (64 FR 4608 at 46#0)

e*tio! 306A o t&e a*t eDpli*itl? proides F-A t&e aut&orit? to use

guida!*e do*ume!ts to determi!e t&e t?pe o *&a!ges t&at do or do !ot

&ae a substa!tial pote!tial to adersel? ae*t t&e saet? or

ee*tie!ess o t&e drug produ*t As dis*ussed preiousl? i! t&is

do*ume!t, t&e use o guida!*e do*ume!ts +ill allo+ F-A to more easil?

a!d >ui*l? modi? a!d update importa!t i!ormatio! uida!*e do*ume!ts

+ill be deeloped a**ordi!g to t&e pro*edures set out i! F-ACs good

guida!*e pra*ti*es (see t&e Federal Register o eptember #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*ii*all? address

i! t&e i!al rule a!dEor guida!*e or i! separate guida!*e &o+ a *&a!ge

i! t&e dei*e aspe*t o a drug%dei*e *ombi!atio! produ*t is to bereported i! appli*atio!s &e *omme!t said t&at +&e! establis&i!g rules

or 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 or *&a!ges to drugs a!d biologi*s to t&e

dei*e%lie aspe*ts o *ombi!atio! produ*ts Rat&er, t&e *omme!t said,

F-A s&ould *o!sider &o+ t&e e>uiale!t *&a!ge is ma!aged or t&e

a!alogous medi*al dei*e a!d appl? t&at approa*&

.-5R a!d .;5R +or *ooperatiel? +it& t&e .e!ter or -ei*es a!d

Radiologi*al 1ealt& (.-R1) i! t&e reie+ o drug%dei*e *ombi!atio!s

-etermi!atio!s as to +&i*& regulatio!s appl? to a gie! *ombi!atio!

produ*t are produ*t a!d appli*atio! spe*ii* po!sors o *ombi!atio!

produ*ts s&ould *o!sult +it& t&e .e!ter t&at proided t&e approal o

t&eir appli*atio! a!d +it& t&e 'i*e o .ombi!atio! "rodu*ts to

determi!e +&at re>uireme!ts are appli*able to t&e *&a!ges t&e? +is& to

mae to t&eir produ*t

(.omme!t 3) eeral *omme!ts said t&at t&e proposal put a!

oer+&elmi!g emp&asis o! postapproal *&a!ges or drug produ*ts a!d

little o! drug substa!*es &e *omme!ts ide!tiied t&e ollo+i!g

*o!*er!s: (#) &e proposal is +ritte! e!tirel? rom t&e perspe*tie o

N-A a!d AN-A appli*a!ts a!d i!*ludes !ot&i!g or -rug 7aster File (-7F)

&oldersJ (2) a reporti!g *lassii*atio! s?stem depe!di!g o! t&e

pote!tial o a *&a!ge to &ae a! impa*t ma? usuall? +or i! t&e drug

produ*t area but is less apt to +or or 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 () t&e pro*esses used i! drug produ*t a!d drug substa!*e

ma!ua*turi!g dier greatl?, mai!g it dii*ult to determi!e &o+ t&e

*&a!ges outli!ed or drug produ*ts appl? to drug substa!*es eeral

*omme!ts said t&at a separate do*ume!t addressi!g *&a!ges relati!g todrug substa!*es s&ould be prepared

&e regulatio!s emp&asi=e *&a!ges i! drug produ*ts a!d are +ritte!

or N-A a!d AN-A appli*a!ts be*ause t&e regulatio!s des*ribe t&e

pro*edures or !oti?i!g F-A about *&a!ges i! *o!ditio!s establis&ed i!

a! approed drug produ*t appli*atio! .&a!ges i! a drug substa!*e are

o!l? o!e o ma!? t?pes o *&a!ges t&at ma? o**ur i! a drug produ*t

appli*atio! F-A &as proided spe*ii* re*omme!datio!s o! drug

substa!*e *&a!ges i! t&e guida!*e e!titled BB.&a!ges to a! Approed N-A

or AN-ACC /! t&e Federal Register o Februar? #6, 200# (66 FR #0699),


12/87

t&e age!*? a!!ou!*ed a guida!*e t&at o*uses spe*ii*all? o!

postapproal ma!ua*turi!g *&a!ges or *ertai! drug substa!*es e!titled

BB;A."A. /: /!termediates i! -rug ubsta!*e ?!t&esis, ;ul A*ties

"ostapproal .&a!ges: .&emistr?, 7a!ua*turi!g, a!d .o!trols

-o*ume!tatio!CC (t&e ;A."A. / guida!*e) F-A beliees t&at t&e ;A."A. /

guida!*e addresses t&e *o!*er!s eDpressed i! t&e *omme!ts

(.omme!t 6) eeral *omme!ts reiterated *omme!ts preiousl?

proided to t&e age!*? o! t&e guida!*es e!titled BB;A."A. /CC a!d

BB.&a!ges to a! Approed N-A or AN-A,CC a!d ased F-A to *o!sider t&ese

*omme!ts i! i!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 proide or

realisti* a!d +orable ili!g me*&a!isms a!d re>uireme!ts +it& regard

to *&a!ges i! t&e ma!ua*turi!g o drug substa!*es +&ere t&e

i!ormatio! is i!*luded i! -7Fs

&e regulatio!s a!d *ompa!io! guida!*e e!titled BB.&a!ges to a!

Approed N-A or AN-ACC proide re*omme!datio!s o! reporti!g *&a!ges i!

t&e *o!ditio!s establis&ed i! a! approed appli*atio!, i!*ludi!g

*&a!ges i! drug substa!*e *oered b? -7Fs /ssues relati!g to -7Fs a!d&o+ t&ese are used i! t&e appli*atio! reie+ pro*ess are outside t&e

s*ope o t&is rulemai!g

(.omme!t 8) '!e *omme!t stated t&at t&e rule s&ould *learl? address

&o+ *&a!ges i! t&e ma!ua*ture o p&arma*euti*al pa*agi!g a!d

p&arma*euti*al pa*agi!g *ompo!e!ts are to be &a!dled &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 re>ue!tl? pa*agi!g a!d pa*agi!g *ompo!e!t

ma!ua*turers are let to tr? to i!terpret t&e regulatio! as it applies

to pa*agi!g

F-A &as *lariied t&e re>uireme!ts or pa*agi!g *ompo!e!ts i! t&e

i!al regulatio!s as a result o t&e publi* *omme!ts a!d &as i!*luded

i!ormatio! o! t&is topi* i! t&e guida!*e BB.&a!ges to a! Approed N-A

or AN-ACC

(.omme!t 9) eeral *omme!ts said t&at t&e use o broad a!d ague

terms (eg, a!? *&a!ge, ma? impa*t) s&ould be mi!imi=ed &e *omme!ts

said t&at su*& terms le!d t&emseles to diere!t i!terpretatio!s, are

liel? to *ause *o!usio! a!d i!*o!siste!t appli*atio!, a!d are liel?

to result i! more burde!some reporti!g re>uireme!ts or *&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 reise t&ese terms, a!d

suggested addi!g t&e modiier BBsig!ii*a!tCC or BBsig!ii*a!tl?CC i!

seeral i!sta!*es to s&arpe! t&e i!te!ded mea!i!g &e *omme!t said

t&at si!*e t&e term BBsig!ii*a!tCC is itsel u!dei!ed, it suggests

t&at, i! t&is *o!teDt, BBsig!ii*a!tCC mea!s BBliel? to adersel?

ae*t t&e ide!tit?, stre!gt&, >ualit?, purit? or pote!*? o t&e

related produ*tCC

F-A agrees t&at t&e use o broad a!d ague terms s&ould bemi!imi=ed a!d &as *lariied t&e regulatio!, as appropriate, i! respo!se

to *omme!ts re*eied o! t&e use o 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!ii*a!tCC

(.omme!t #0) '!e *omme!t ased +&et&er t&e i!al regulatio!s +ill

*o!tai! reere!*es to appropriate guida!*e do*ume!ts

&e i!al regulatio!s do !ot reere!*e spe*ii* guida!*e do*ume!ts

F-A *o!ti!ues to update a!d deelop guida!*es to address parti*ular

regulator? a!d s*ie!tii* issues, a!d a!? reere!*es i!*luded i! a


13/87

regulatio! ma? >ui*l? be*ome outdated uida!*es t&at proide F-ACs

*urre!t t&i!i!g o! spe*ii* topi*s *a! be lo*ated o! t&e /!ter!et at

&ttp:EEr+ebgatea**essgpogoE*gi%bi!Eleai!g*gi

romGleai!gFR&tmlHlogGli!logHtoG&ttp:EE+++dagoE*derE

[["age #8$

guida!*eEi!deD&tm a!d &ttp:EEr+ebgatea**essgpogoE*gi%

bi!Eleai!g*gi

romGleai!gFR&tmlHlogGli!logHtoG&ttp:EE+++dagoE*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 or Veteri!ar? 7edi*i!e

(.V7) ma? be prepari!g a similar proposal a!d ma? be *ompelled to appl?

most i !ot all o t&e pri!*iples des*ribed i! t&e proposed rule &e

*omme!t said t&at t&e a!imal drug i!dustr? is er? pleased +it& t&e

su**essul #996 .V7 i!itiatie, BBAlter!ate Admi!istratie "ro*ess or

t&e /mpleme!tatio! a!d ubmissio! o uppleme!tal .&emistr?,

7a!ua*turi!g a!d .o!trol .&a!ges (AA")CC &e *omme!t said t&at itssupport o t&e 7oder!i=atio! A*t +as gie! 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! o t&e AA" program &e *omme!t said t&at t&e AA" program

su**i!*tl? proides a pro*ess or determi!i!g mi!or suppleme!tal

*&emistr?, ma!ua*turi!g, a!d *o!trol *&a!ges t&at are reported o! a

bie!!ial basis &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! o t&e

proposed rule +ould be more burde!some, o! bot& F-A a!d i!dustr?, t&a!

t&e AA" &e *omme!t said t&at .V7 a!d A!imal 1ealt& /!stitute (A1/)

member *ompa!ies &ae &ad ?ears o su**essul impleme!tatio! o t&is

program a!d beliee t&at t&e proposed rule, i applied to a!imal drugs,

+ould be a maor step ba*+ards

.omme!ts relati!g to t&e AA" are outside t&e s*ope o t&is

rulemai!g a!d s&ould be dire*ted to t&e proposed rule or eteri!ar?

drug produ*ts e!titled BBuppleme!ts a!d 't&er .&a!ges to Approed Ne+

A!imal -rug Appli*atio!sCC (publis&ed i! t&e Federal Register o

'*tober #, #999 (64 FR 328#)) (t&e '*tober #999 proposal)

; -ei!itio!s

F-A proposed to ame!d t&e dei!itio!s se*tio!s o t&e regulatio!s

o! appli*atio!s or F-A approal to maret a !e+ drug (e* #4 (2#

.FR #4)) a!d a biologi*al produ*t (e* 600 (2# .FR 600)) b?

addi!g dei!itio!s or BBspe*ii*atio!CC a!d BBalidate t&e ee*ts o

t&e *&a!geCC "roposed e* e* #4(b) a!d 600(&&) dei!ed

BBspe*ii*atio!CC as t&e >ualit? sta!dard (ie, tests, a!al?ti*al

pro*edures, a!d a**epta!*e *riteria) proided i! a! approedappli*atio! to *o!irm t&e >ualit? o 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 &e term

BBa**epta!*e *riteriaCC reers to !umeri*al limits, ra!ges, or ot&er

*riteria or t&e tests des*ribed

F-A &as reised t&e proposed dei!itio! o spe*ii*atio! to mae

t&e use o t&e term BB*ompo!e!tCC *o!siste!t +it& t&e dei!itio! o

BB*ompo!e!tCC at e* 2#0 (2# .FR 2#0) F-A &as reised t&e

dei!itio! as ollo+s:
http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/cder/http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/cder/http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/cber/guidelines.htmhttp://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/cber/guidelines.htmhttp://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/cber/guidelines.htmhttp://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/cber/guidelines.htmhttp://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/cder/http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/cder/http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/cber/guidelines.htmhttp://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/cber/guidelines.htmhttp://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/cber/guidelines.htm


14/87

pe*ii*atio! mea!s t&e >ualit? sta!dard (ie, tests,

a!al?ti*al pro*edures, a!d a**epta!*e *riteria) proided i! a!

approed appli*atio! to *o!irm t&e >ualit? o 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! o a drug substa!*e or drug produ*t For t&e

purpose o t&is dei!itio!, a**epta!*e *riteria mea!s !umeri*al

limits, ra!ges, or ot&er *riteria or t&e tests des*ribed

F-A &as made t&e same *&a!ges to proposed e* 600(&&) (!e+

e* 600()) a!d *lariied t&e dei!itio! o spe*ii*atio! or

biologi*al produ*ts b? repla*i!g t&e p&rase BBdrug substa!*es, drug

produ*tsCC +it& BBprodu*tsCC &e term BBprodu*tsCC is dei!ed i! e*

600(g)

(.omme!t #2) eeral *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 rom t&e

dei!itio! o spe*ii*atio!, a!d *&a!ges or t&ese materials s&ould be

&a!dled separatel? rom t&e i!al rule a!d i!al guida!*e &e *omme!ts

said t&at t&e dei!itio! is !ot *o!siste!t +it& t&e /!ter!atio!al

.o!ere!*e o! 1armo!isatio! (/.1) guida!*e o! spe*ii*atio!s e!titled

BBest "ro*edures a!d A**epta!*e .riteria or Ne+ -rug ubsta!*es a!dNe+ -rug "rodu*ts: .&emi*al ubsta!*esCC (/.1 M6A), +&i*& i!*ludes o!l?

drug substa!*e a!d drug produ*t &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 leel o

*ompleDit? t&at +ould be better dealt +it& i! guida!*es t&at *a!

ade>uatel? ealuate t&e sig!ii*a!*e o *&a!ges to spe*ii* items

F-A de*li!es to reise t&e dei!itio! as re>uested e*tio! 303 o

t&e a*t (2# . 33) re>uires t&at a ull des*riptio! o t&e met&ods

used i!, a!d t&e a*ilities a!d *o!trols used or, t&e ma!ua*ture,

pro*essi!g, a!d pa*i!g o a drug be proided i! a! appli*atio! &e

regulatio!s at e* #430(d)(#) (2# .FR #430(d)(#)) re>uire t&at a!

appli*atio! i!*lude spe*ii*atio!s as are !e*essar? to e!sure t&e

ide!tit?, stre!gt&, >ualit?, purit?, a!d pote!*? o t&e drug substa!*e

a!d drug produ*t 7oreoer, t&e regulatio! at e* #430(d)(#)(ii)(a)

spe*ii*all? re>uires t&at spe*ii*atio!s be proided or ea*&

*ompo!e!t /t ide!tiies spe*ii*atio!s or *o!tai!er *losures s?stems

as a! eDample o a spe*ii*atio! !eeded to e!sure t&e ide!tit?,

stre!gt&, >ualit?, purit?, a!d pote!*? o t&e drug produ*t For

biologi*s, a! appli*a!t must submit a ull des*riptio! o ma!ua*turi!g

met&ods (e* 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!ua*ture o drug substa!*es, drug

produ*ts, a!d biologi*s are *o!sidered part o t&e ma!ua*turi!g met&od

a!d *a! &ae a dire*t ee*t o! t&e ide!tit?, stre!gt&, >ualit?,

purit?, a!d pote!*? o t&e drug substa!*e, drug produ*t, or biologi*

K&ile t&e eDte!t o a spe*ii*atio! (eg, !umber or t?pe o tests,

stri*t!ess o a**epta!*e *riteria) or t&ese materials ma? ar?

depe!di!g o! t&eir use i! a gie! ma!ua*turi!g pro*ess, F-A &asre>uired spe*ii*atio!s or t&ese materials to be i!*luded i!

appli*atio!s as part o t&e des*riptio! o t&e ma!ua*turi!g met&od a!d

+ill *o!ti!ue to do so

&e /.1 M6A guida!*e a!d t&e /.1 guida!*e o! spe*ii*atio!s

e!titled BBest "ro*edures a!d A**epta!*e .riteria or ;iote*&!olog?E

;iologi*al "rodu*tsCC (/.1 M6;) are limited i! s*ope For eDample, /.1

M6A spe*ii*all? eD*ludes erme!tatio! produ*ts /!terpreti!g t&e

limitatio!s o t&e /.1 guida!*es to mea! t&at spe*ii*atio!s are !ot

re>uired or erme!tatio! produ*ts or ot&er materials outside t&e s*ope


15/87

o /.1 M6A or /.1 M6; +ould be i!*orre*t

F-A re>uires spe*ii*atio!s or 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!ua*turi!g pro*ess to be i!*luded i! t&e

appli*atio! a!d, t&ereore, &as i!*luded t&ese materials i! t&e

dei!itio! o spe*ii*atio! A!? *&a!ges i! a spe*ii*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 deerri!g re*omme!datio!s o!

t&ese *&a!ges to a later guida!*e a!d &as proided guida!*e o! t&e

re*omme!ded reporti!g *ategories or *&a!ges i! spe*ii*atio!s i! F-ACs

guida!*es e!titled BB.&a!ges to a! Approed N-A or AN-ACC a!d BB.&a!ges

to a! Approed Appli*atio! or pe*iied ;iote*&!olog? a!d pe*iied

?!t&eti* ;iologi*al "rodu*tsCC (@ul? #99$)

(.omme!t #) '!e *omme!t said t&at t&e term BBspe*ii*atio!s a!d

test pro*eduresCC +as used i! part #4 (2# .FR part #4) i! t&e past,

but t&e proposal repla*ed t&is +it& t&e term BBspe*ii*atio!,CC +&i*&

is i!te!ded to mea! bot& tests a!d spe*ii*atio!s &e *omme!t said

t&at usi!g o!e +ord to represe!t seeral t&i!gs is *o!usi!g

[["age #8$4

a!d re*omme!ded retai!i!g t&e preious termi!olog?

F-A de*li!es to reise t&e use o t&e term BBspe*ii*atio!CC as

re>uested /! t&e past, BBspe*ii*atio!CC as used i! part #4 mea!t

!umeri*al limits, ra!ges, or ot&er *riteria or a test /! deelopi!g

t&e /.1 M6A a!d /.1 M6; guida!*es, F-A agreed to dei!e spe*ii*atio!

diere!tl? A spe*ii*atio!, as dei!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!tiied arious t?pes o spe*ii*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! o spe*ii*atio! *&a!ges i!

t&e regulatio! As stated i! t&e @u!e #999 proposal, t&e age!*?

beliees it *a! more readil? respo!d to !o+ledge gai!ed rom

ma!ua*turi!g eDperie!*e, urt&er resear*& a!d data *olle*tio!, a!d

ada!*es i! te*&!olog? b? issui!g regulatio!s t&at set out broad,

ge!eral *ategories o ma!ua*turi!g *&a!ges a!d b? usi!g guida!*e

do*ume!ts to proide F-ACs *urre!t t&i!i!g o! t&e spe*ii* *&a!ges

t&at all i!to t&ose ge!eral *ategories (64 FR 4608 at 46#0) F-A &as

proided re*omme!datio!s o! spe*ii* *&a!ges i! spe*ii*atio!s i! F-ACs



?!t&eti* ;iologi*al "rodu*tsCC

"roposed e* e* #4(b) a!d 600(ii) dei!ed BBalidate t&e

ee*ts o t&e *&a!geCC as a! assessme!t o t&e ee*t o a

ma!ua*turi!g *&a!ge o! t&e ide!tit?, stre!gt&, >ualit?, purit?, or

pote!*? o a drug as t&ese a*tors relate to t&e saet? oree*tie!ess o 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 eeral *omme!ts

stated t&at alt&oug& F-A used t&e terms *o!siste!tl? +it& .o!gressCs

use o t&e terms i! se*tio! 306A o t&e a*t, t&e? beliee t&at t&e term

BBalidateCC is liel? to *ause *o!usio! be*ause t&is term &as lo!g

bee! asso*iated +it& a!d &as spe*ii* mea!i!g u!der F-ACs .7"

regulatio!

F-A agrees a!d &as reised t&e dei!itio! as re>uested b? repla*i!g


16/87

BBalidateCC +it& BBassessCC /! additio!, as a result o *omme!ts

re>uesti!g t&at t&e use o t&e terms drug, drug produ*t, drug

substa!*e, a!d produ*t be sta!dardi=ed, F-A &as *lariied t&e

dei!itio! i! e* #4(b) b? repla*i!g t&e term BBdrugCC +it& BBdrug

produ*tCC F-A &as *lariied t&e dei!itio! i! proposed e* 600(ii)

(!e+ e* 600()) b? repla*i!g t&e term BBdrugCC +it& BBprodu*tCC

&e terms drug produ*t a!d produ*ts are dei!ed at e* e* #4(b)

a!d 600(g), respe*tiel? F-A, o! its o+! i!itiatie, &as also

reised t&e p&rase BBpurit?, or pote!*?CC to BBpurit?, a!d pote!*?CC

a!d t&e p&rase BBas t&ese a*tors relateCC to BBas t&ese a*tors ma?

relateCC to be *o!siste!t +it& se*tio! 306A(b) o t&e a*t, a!d t&e

p&rase BBto assess t&e ee*tCC to BBto ealuate t&e ee*tsCC or

*larit? F-A !otes t&at +&ile t&e ee*t o a ma!ua*turi!g *&a!ge o!

t&e ide!tit?, stre!gt&, >ualit?, purit? a!d pote!*? o a drug or

biologi*al produ*t is to be assessed, t&is assessme!t *ould i!ole

testi!g o materials dire*tl? ae*ted b? a *&a!ge (eg, drug

substa!*e) i! additio! to or i!stead o drug or biologi*al produ*t

testi!g

(.omme!t #6) eeral *omme!ts re*omme!ded t&at u!ambiguous

dei!itio!s o substa!tial, moderate, a!d mi!imal pote!tial or aderse

ee*ts be added to t&e regulatio!, a!d o!e *omme!t re*omme!ded t&ateDamples be added or *larii*atio! '!e *omme!t ased t&at a

dei!itio! o !atural produ*t be added

F-A de*li!es to reise t&e regulatio! as re>uested &e regulatio!s

appl? to ma!? t?pes o *&a!ges or a broad spe*trum o produ*ts &e

mea!i!g o substa!tial, moderate, a!d mi!imal pote!tial or aderse

ee*ts is most easil? illustrated t&roug& t&e use o eDamples F-A &as

de*ided to use guida!*e do*ume!ts to proide spe*ii* eDamples o

*&a!ges t&at are *o!sidered to &ae substa!tial, moderate, a!d mi!imal

pote!tial to &ae aderse ee*t rat&er t&a! e!umerate t&em i! t&e

regulatio! F-A &as proided ma!? eDamples o t?pes o *&a!ges i! F-ACs



?!t&eti* ;iologi*al "rodu*tsCC /! additio!, F-A &as proided a!

eDpla!atio! o t&e term BB!atural produ*tsCC i! t&e guida!*e o!

BB.&a!ges to a! Approed N-A or AN-ACC

(.omme!t #$) .o!*er!i!g t&e regulatio!s o! t&e *o!te!t a!d ormat

o a! appli*atio! i! e* #430, o!e *omme!t !oted t&at e*

#430(d)(#)(i) a!d (d)(i)(ii) i!*ludes t&e ollo+i!g stateme!t or

drug substa!*e a!d drug produ*t: BBReere!*e to t&e *urre!t editio! o

t&e "ENF [Natio!al Formular? ma? satis? t&e relea!t re>uireme!ts

i! t&e paragrap&CC &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 *lari?i!g t&at t&is se!te!*e &as !ot bee! deleted rom

e* #430(d)(#)(i) or (d)(#)(ii) As stated i! t&e @u!e #999

proposal, F-A is reisi!g t&e irst t+o se!te!*es o t&ese paragrap&s

. .&a!ges to a! Approed Appli*atio!

"roposed e* #4$0(a)(#) set ort& ge!eral re>uireme!ts u!der

+&i*& a! appli*a!t must !oti? F-A about ea*& *&a!ge i! ea*& *o!ditio!

establis&ed i! a! approed appli*atio! be?o!d t&e ariatio!s alread?

proided or i! t&e appli*atio! &e !oti*e is re>uired to des*ribe t&e

*&a!ge ull? -epe!di!g o! t&e t?pe o *&a!ge, t&e appli*a!t must

!oti? F-A about t&e *&a!ge i! a suppleme!t u!der e* #4$0(b) or

(*) or b? i!*lusio! o t&e i!ormatio! i! a! a!!ual report u!der e*


17/87

#4$0(d)

(.omme!t #8) '!e *omme!t said t&at t&e stateme!ts BBa! appli*a!t

must !oti? F-A about ea*& *&a!ge i! ea*& *o!ditio! establis&ed i! a!

approed appli*atio! be?o!d t&e ariatio!s alread? proided or i! t&e

appli*atio!CC a!d t&at BBt&e !oti*e is re>uired to des*ribe t&e *&a!ge

ull?CC s&ould be *lariied be*ause it *ould be oerl? burde!some rom

t&e sta!dpoi!t t&at some *&a!ges, or eDample, *&a!ges made to bat*&

re*ords submitted as part o t&e appli*atio!, ma? !ot re>uire reporti!g

u!der e* #4$0

F-A de*li!es to reise t&e regulatio! as re>uested a!d !otes t&at

t&e age!*? does !ot eDpe*t to be i!ormed about !o!substa!tie

editorial *&a!ges i! i!ormatio! i!*luded i! a! appli*atio!

No!substa!tie editorial *&a!ges i!*lude su*& *&a!ges as *orre*tio!s o

spelli!g or t?pograp&i*al errors or reormatti!g o do*ume!ts (eg,

bat*& re*ords, spe*ii*atio! s&eets)

"roposed e* e* #4$0(a)(2) a!d 60##2(a)(2) (2# .FR

60##2(a)(2)) re>uired t&e &older o a! approed appli*atio! to

alidate t&e ee*ts o ma!ua*turi!g *&a!ges o! t&e ide!tit?,

stre!gt&, >ualit?, purit?, or pote!*? o a drug as t&ese a*tors ma?

relate to t&e saet? or ee*tie!ess o t&e drug beore distributi!g a

drug made +it& a ma!ua*turi!g *&a!ge (.omme!t #9) A e+ *omme!ts said t&at t&e proposal +ould i!*rease

t&e reporti!g burde! despite t&e spe*ii* proisio! i! t&e

7oder!i=atio! A*t or &ai!g assessme!t data at t&e time o submissio!

o ma!ua*turi!g *&a!ge suppleme!ts &e *omme!t said t&at t&e

7oder!i=atio! A*t spe*iies t&at a drug made +it& a ma!ua*turi!g

*&a!ge ma? be distributed o!l? ater *ompleti!g studies t&at assess t&e

ee*ts o t&e *&a!ge &e *omme!t said

[["age #8$3

t&at t&e legislatie i!te!t o t&e 7oder!i=atio! A*t is t&at i

appropriate studies *ompari!g pre% a!d post*&a!ge material are

perormed a!d !o eide!*e o a! aderse ee*t is ou!d, t&e! a redu*ed

reporti!g *ategor? or t&e ealuated *&a!ges is appropriate &e

*omme!t reaso!ed t&at a gie! proposed ma!ua*turi!g *&a!ge *a! i!deed

&ae substa!tial pote!tial or aderse ee*ts at its i!*eptio! be*ause

little mig&t be !o+! about t&e impa*ts o t&e *&a!ge 1o+eer, b? t&e

time a*tual material &as bee! made +it& t&e *&a!ge a!d assessme!t

studies &ae bee! su**essull? *ompleted, most or all o t&e pote!tial

impa*ts o t&e *&a!ge &ae bee! elimi!ated &e *omme!t said t&at t&e

assessme!t i!ormatio! s&ould permit a redu*ed reporti!g re>uireme!t

F-A disagrees +it& t&ese *omme!ts e*tio! 306A(*)(2) o t&e a*t

states t&at a maor ma!ua*turi!g *&a!ge is BBa *&a!ge t&at is

determi!ed b? t&e e*retar? to &ae substa!tial pote!tial to adersel?

ae*t t&e ide!tit?, stre!gt&, >ualit?, purit?, or pote!*? o t&e drug

as t&e? ma? relate to t&e saet? or ee*tie!ess o a drugCC (emp&asis

added) &e a*t bases t&e reporti!g *ategor? or a *&a!ge o! t&epote!tial or t&at *&a!ge to &ae a! aderse ee*t, !ot o! t&e out*ome

o t&e assessme!t studies &e *omme!t implies t&at t&e o!l? *&a!ges

t&at +ould be reported i! a prior approal suppleme!t are t&ose +&ere

t&e appli*a!tCs studies to assess t&e ee*ts o t&e *&a!ge demo!strate

t&at t&ere is i! a*t a! aderse ee*t o! t&e ide!tit?, stre!gt&,

>ualit?, purit?, or pote!*? o t&e drug as t&e? ma? relate to t&e

saet? or ee*tie!ess o a drug produ*t F-A does !ot beliee t&at

t&is +as t&e i!te!t o .o!gress ome ma!ua*turi!g *&a!ges &ae a!

aderse ee*t o! t&e ide!tit?, stre!gt&, >ualit?, purit?, or pote!*?


18/87

o t&e drug produ*t /! ma!? *ases, t&e appli*a!t *&ooses !ot to

impleme!t t&ese ma!ua*turi!g *&a!ges, but sometimes t&e appli*a!t

+is&es to do so / a! assessme!t i!di*ates t&at a *&a!ge &as adersel?

ae*ted t&e ide!tit?, stre!gt&, >ualit?, purit?, or pote!*? o t&e

drug produ*t, t&e *&a!ge must be submitted i! a prior approal

suppleme!t, regardless o t&e re*omme!ded reporti!g *ategor? or t&e

*&a!ge For eDample, a pro*ess *&a!ge re*omme!ded or a *&a!ges%bei!g%

ee*ted%i!%0%da?s suppleme!t *ould *ause t&e ormatio! o a !e+

degrada!t t&at re>uires >ualii*atio! a!dEor ide!tii*atio! &e

appli*a!t ma? beliee t&at t&ere are !o saet? *o!*er!s relati!g to t&e

!e+ degrada!t 5e! so, t&e appli*a!t must submit t&is *&a!ge i! a

prior approal suppleme!t +it& appropriate i!ormatio! to support t&e

*o!ti!ued saet? a!d ee*tie!ess o t&e produ*t -uri!g t&e reie+ o

t&e prior approal suppleme!t, F-A +ill assess t&e impa*t o a!?

aderse ee*t o! t&e drug produ*t as t&is *&a!ge ma? relate to t&e

saet? or ee*tie!ess o t&e drug produ*t

F-A also re*eied *omme!ts re>uesti!g t&at t&e term BBassessCC be

used i!stead o BBalidateCC F-A &as made t&is *&a!ge i! e* e*

#4$0(a)(2) a!d 60##2(a)(2), +&ere appropriate /! e*

#4$0(a)(2), F-A, o! its o+! i!itiatie, &as deleted t&e p&rase BBo!

t&e ide!tit?, stre!gt&, >ualit?, purit?, a!d pote!*? o t&e drugprodu*t as t&ese a*tors ma? relate to t&e saet? or ee*tie!ess o

t&e drug produ*tCC be*ause BBassess t&e ee*ts o t&e *&a!ge,CC as

dei!ed i! e* #4(b), i!*ludes t&is p&rase

"roposed e* e* #4$0(a)() a!d 60##2(a)() stated t&at

!ot+it&sta!di!g t&e suppleme!t submissio! re>uireme!ts, a! appli*a!t

must mae a ma!ua*turi!g *&a!ge i! a**orda!*e +it& a regulatio! or

guida!*e t&at proides or a less burde!some !otii*atio! o t&e

*&a!ge

(.omme!t 20) eeral *omme!ts !oted t&at t&e? +ere pleased t&at t&e

proisio! t&at a *&a!ge *a! be made BBi! a**orda!*e +it& a regulatio!

or guida!*e t&at proides or a less burde!some !otii*atio! o t&e

*&a!geCC +as proposed be*ause it permits less burde!some reporti!g

me*&a!isms or *&a!ges

F-A a*!o+ledges t&ese *omme!ts a!d &as retai!ed t&is proisio! i!

t&e i!al rule

"roposed e* e* #4$0(a)(4) a!d 60##2(a)(4) stated t&at t&e

appli*a!t must promptl? reise all promotio!al labeli!g a!d adertisi!g

to mae it *o!siste!t +it& a!? labeli!g *&a!ge impleme!ted i!

a**orda!*e +it& t&is se*tio!

(.omme!t 2#) eeral *omme!ts said t&at t&e preious proisio!s i!

e* #4$0 limited t&e re>uireme!t to promptl? reise all promotio!al

labeli!g a!d adertisi!g to t&ose *&a!ges t&at +ere to be iled i! a

*&a!ges%bei!g%ee*ted suppleme!t, a!d t&at t&is re>uireme!t is !ot

!e*essar? or t&e t?pe o labeli!g *&a!ges t&at +ould be iled i! a!

a!!ual report &e *omme!ts suggested t&at t&is re>uireme!t be limited

to t&ose labeli!g *&a!ges t&at +ould be iled i! suppleme!tal

appli*atio!s &e age!*? agrees +it& t&e *omme!ts a!d &as reised e*

#4$0(a)(4) to re>uire appli*a!ts to reise promotio!al labeli!g a!d

adertisi!g to mae it *o!siste!t +it& labeli!g *&a!ges impleme!ted i!

a**orda!*e +it& e* #4$0(b) a!d (*) /! additio!, e*

60##2(a)(4) re>uires appli*a!ts to reise promotio!al labeli!g a!d

adertisi!g to mae it *o!siste!t +it& labeli!g *&a!ges impleme!ted i!

a**orda!*e +it& e* 60##2()(#) a!d ()(2)

"roposed e* #4$0(a)(3) stated t&at, eD*ept or a suppleme!t

proidi!g or a *&a!ge i! t&e labeli!g, t&e appli*a!t must i!*lude i!


19/87

ea*& suppleme!tal appli*atio! proidi!g or a *&a!ge u!der paragrap&

(b) or (*) a stateme!t *erti?i!g t&at a ield *op? o t&e suppleme!t

&as bee! proided to t&e appli*a!tCs &ome F-A distri*t oi*e

(.omme!t 22) A e+ *omme!ts re>uested t&at F-A *lari? +&et&er t&e

ield *op? t&at is to be se!t to t&e appli*a!tCs BB&ome F-A distri*t

oi*eCC s&ould be t&e F-A oi*e +&ere t&e *&a!ge is bei!g made or t&e

F-A oi*e i! t&e distri*t o t&e *ompa!?Cs *orporate &ead>uarters rom

+&ere t&e submissio! do*ume!ts are se!t &e *omme!ts also said t&at i

t&e ield *op? s&ould be se!t to t&e oi*e +&ere t&e *&a!ge is bei!g

made, F-A s&ould *lari? +&at F-A oi*e(s) sere or *&a!ges made

i!ter!atio!all? &e *omme!t said t&at t&e *larii*atio! +ill &elp to

e!sure t&at t&e appropriate do*ume!ts get to t&e *orre*t F-A distri*t

oi*e

7aili!g i!ormatio! or ield *opies is proided i! e*

#4440(a)(4) .urre!tl?, F-A re*omme!ds t&at t&e BBappli*a!tCs &ome

F-A distri*t oi*eCC reerred to i! e* #4440(a)(4) be t&e

distri*t oi*e +&ere t&e appli*a!tCs &ead>uarters is lo*ated F-A &as

*lariied t&is proisio! b? *ross%reere!*i!g e* #4440(a)(4)

e*tio! #4440(a)(4) also proides maili!g i!ormatio! or

i!ter!atio!al appli*a!ts F-A, o! its o+! i!itiatie, &as also

*lariied t&e proisio! b? addi!g BBame!dme!ts to suppleme!tsCC Aield *op? o 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!ormatio! i!to t&eir

origi!al suppleme!t, is *urre!tl? re>uired u!der e* #4440(a)(4)

"roposed e* e* #4$0(a)(6) a!d 60##2(a)(3) added a

re>uireme!t t&at a list o all *&a!ges *o!tai!ed i! t&e suppleme!t or

a!!ual report must be i!*luded i! t&e *oer letter or t&e suppleme!t

or a!!ual report

(.omme!t 2) 7a!? *omme!ts agreed t&at a list o *&a!ges s&ould be

i!*luded i! t&e *oer letter or a suppleme!t 1o+eer, t&e *omme!ts

disagreed t&at a list o all *&a!ges *o!tai!ed i! t&e a!!ual report

s&ould be i!*luded i! a *oer letter &e *omme!ts said t&at i!*ludi!g

a list i! a *oer letter to a! a!!ual report is oerburde!some be*ause

*oer letters are !ot re>uired or a!!ual reports, o!l? a Form F-A

2232, a!d a list o *&a!ges is alread? proided

[["age #8$6

i! a se*tio! o a! a!!ual report eeral *omme!ts said t&at a!

appli*a!t s&ould &ae t&e optio! o proidi!g t&e list i! a lo*atio!

ot&er t&a! t&e *oer letter, su*& as at t&e begi!!i!g o t&e

suppleme!t

F-A agrees +it& t&e re>uests to permit t&e list o *&a!ges to be

proided i! t&e summar? se*tio! o t&e a!!ual report a!d &as reised

e* e* #4$0(a)(6) a!d 60##2(a)(3) to re>uire *&a!ges to be

listed i! t&e *oer letter o!l? or suppleme!tal appli*atio!s

A! a!!ual report is re>uired to *o!tai! a brie summar? o

sig!ii*a!t !e+ i!ormatio! rom t&e preious ?ear t&at mig&t ae*tt&e saet?, ee*tie!ess, or labeli!g o t&e drug produ*t (e*

#48#(b)(2)(i)) F-ACs guida!*e or i!dustr? e!titled BBFormat a!d

.o!te!t or t&e .7. e*tio! o a! A!!ual ReportCC (eptember #994)

states, regardi!g t&e summar? o !e+ i!ormatio!, t&at t&e irm s&ould

i!*lude i! t&e a!!ual report BBa brie summar? o 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& approed suppleme!ts u!der 2# .FR #4$0(b) a!d

suppleme!ts u!der 2# .FR #4$0(*) CC uppleme!ts are !ot re>uired

to &ae a summar? se*tio! (e* #430(*))


20/87

F-A is re>uiri!g t&at a list o *&a!ges be proided 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 ei*ie!tl? lo*ate a!d ide!ti? *&a!ges

i! +&at are ote! do*ume!ts o substa!tial le!gt& &e list +ill also

allo+ F-A to >ui*l? assess +&et&er t&e appropriate reporti!g *ategor?

+as used o a*&iee t&ese obe*ties, it is esse!tial t&at t&e list be

i! a *o!siste!t lo*atio! or ea*& t?pe o submissio!

(.omme!t 24) eeral *omme!ts +ere *o!*er!ed t&at t&e list o

*&a!ges, i i!*luded i! a *oer letter, +ould !ot be *o!sidered

*o!ide!tial i!ormatio!

&e sta!dards or dis*losi!g spe*ii* i!ormatio! rom a *oer

letter or appli*atio! do !ot dier depe!di!g o! +&ere t&is i!ormatio!

is proided /!ormatio! t&at is eDempted rom dis*losure (eg, trade

se*ret or *o!ide!tial *ommer*ial i!ormatio!) is !ot dis*losed +&et&er

it is i! a *oer letter or a! appli*atio! (see also e* e* #440

a!d 60#3# (2# .FR 60#3#))

(.omme!t 23) '!e *omme!t re>uested t&at t&e p&rase BBlist o all

*&a!gesCC be reised to BBa brie summar? o maor *&a!gesCC

F-A de*li!es to reise 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! o t&e listed *&a!ge s&ould be i! sui*ie!t detail toallo+ t&e age!*? to >ui*l? determi!e +&et&er t&e appropriate reporti!g

*ategor? or 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*ii*atio!CC does !ot proide

sui*ie!t detail A des*riptio! su*& as BBdeletio! o t&e riabilit?

test a!d asso*iated a**epta!*e *riteria a!d a!al?ti*al pro*edure rom

t&e drug produ*t spe*ii*atio!CC +ould allo+ F-A to >ui*l? assess

+&et&er t&e appropriate reporti!g *ategor? +as used &e detailed

i!ormatio! about ea*& *&a!ge a!d t&e i!ormatio! deeloped to assess

t&e ee*ts o t&e *&a!ge +ould be proided i! t&e suppleme!t or

else+&ere i! t&e a!!ual report

(.omme!t 26) eeral *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 reise Form F-A 2232 be*ause it is !ot +it&i! t&e

s*ope o t&is regulatio!

- .&a!ges Re>uiri!g uppleme!t ubmissio! a!d Approal "rior to

-istributio! o t&e "rodu*t 7ade si!g t&e .&a!ge (7aor .&a!ges)

"roposed e* #4$0(b)(#) re>uired t&at a suppleme!t re>uiri!g

prior approal must be submitted or a!? *&a!ge i! t&e produ*t,

produ*tio! pro*ess, >ualit? *o!trols, e>uipme!t, or a*ilities t&at &as

a substa!tial pote!tial to &ae a! aderse ee*t o! t&e ide!tit?,

stre!gt&, >ualit?, purit?, or pote!*? o t&e produ*t as t&ese a*tors

ma? relate to t&e saet? or ee*tie!ess o t&e produ*t

(.omme!t 2$) 7a!? *omme!ts ased +&et&er a prior approal

suppleme!t +ould be re>uired ee! i t&e appli*a!t &as demo!strated

t&at t&e *&a!ge &as !o sig!ii*a!t aderse ae*t e*tio! 306A(*)(2) o t&e a*t states t&at a maor ma!ua*turi!g

*&a!ge is BBa *&a!ge t&at is determi!ed b? t&e e*retar? to &ae

substa!tial pote!tial to adersel? ae*t t&e ide!tit?, stre!gt&,

>ualit?, purit?, or pote!*? o t&e drug as t&e? ma? relate to t&e

saet? or ee*tie!ess o a drugCC &e a*t bases t&e reporti!g

*ategor? or a *&a!ge o! t&e pote!tial or t&at *&a!ge to &ae a!

aderse ee*t, !ot o! t&e out*ome o t&e assessme!t studies F-A +ould

eDpe*t a prior approal suppleme!t to be submitted or a *&a!ge t&at

&as substa!tial pote!tial to adersel? ae*t t&e ide!tit?, stre!gt&,


21/87

>ualit?, purit?, or pote!*? o a drug produ*t ee! i 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 aderse ee*t "rior to distributio! o t&e drug produ*t made +it&

t&e *&a!ge, F-A must ealuate +&et&er t&e studies perormed b? t&e

appli*a!t +ere sui*ie!t to assess t&e ee*t o 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

adersel? ae*ted t&e ide!tit?, stre!gt&, >ualit?, purit?, or pote!*?

o t&e drug produ*t as t&e? ma? relate to t&e saet? or ee*tie!ess

o a drug produ*t

(.omme!t 28) '!e *omme!t said t&at se*tio! 306A o t&e a*t

ide!tiies maor *&a!ges as ormulatio!, spe*ii*atio!, or t&ose

re>uiri!g studies i! a**orda!*e +it& part 20 (2# .FR part 20) to

demo!strate t&e e>uiale!*e o t&e drug produ*t to t&e drug produ*t as

ma!ua*tured +it&out t&e *&a!ge or to t&e reere!*e listed drug &e

*omme!t said t&at F-A &as proposed prior approal suppleme!ts or

*&a!ges t&at are *learl? outside o t&ese t&ree maor *&a!ge

*ategories A!ot&er *omme!t said it appears t&at F-A &as oerutili=ed

se*tio! 306A(*)(2)(.) o t&e a*t

F-A disagrees t&at it &as oerutili=ed t&is part o t&e a*t /!

additio! to t&e t&ree maor *&a!ges ide!tiied preiousl? i! t&is

do*ume!t, se*tio! 306A(*)(2)(.) o t&e a*t states t&at a maor *&a!geBBis a!ot&er t?pe o *&a!ge determi!ed b? t&e e*retar? b? regulatio!

or guida!*e to &ae a substa!tial pote!tial to adersel? ae*t t&e

saet? or ee*tie!ess o t&e drugCC /! preious regulatio!s, ma!?

ma!ua*turi!g *&a!ges re>uired prior approal suppleme!ts F-A &as used

t&is proisio! o t&e a*t to ide!ti? a limited !umber o *&a!ges t&at

it *o!siders to &ae a substa!tial pote!tial to adersel? ae*t t&e

ide!tit?, stre!gt&, >ualit?, purit?, or pote!*? o t&e drug as t&e? ma?

relate to t&e saet? or ee*tie!ess o a drug &e regulatio! redu*es

t&e oerall !umber o suppleme!ts re>uiri!g F-A approal 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

&e regulatio! +ill !ot i!*rease t&e !umber o a!!ual reports but +ill

allo+ appli*a!ts to i!*lude i! a! a!!ual report i!ormatio! *urre!tl?

re>uired to be reported to t&e age!*? i! a suppleme!tal appli*atio!

7oreoer, F-A urt&er redu*ed ma!? reporti!g re>uireme!ts rom t&e

leels re*omme!ded i! preious F-A guida!*es

"roposed e* #4$0(b)(2)(i) proided t&at, eD*ept as proided i!

e* #4$0(*) a!d (d), prior approal is re>uired or *&a!ges i! t&e

>ualitatie or >ua!titatie ormulatio! o t&e drug, i!*ludi!g i!a*tie

i!gredie!ts, or i! t&e spe*ii*atio!s proided i! t&e approed

appli*atio!

(.omme!t 29) A e+ *omme!ts re*omme!ded t&at proposed

[["age #8$$

e* #4$0(b)(2)(i) be reised to better rele*t se*tio!

306A(*)(2)(A) o t&e a*t +&i*& allo+s eD*eptio!s to t&e re>uireme!t toobtai! prior approal beore *&a!gi!g t&e >ualitatie or >ua!titatie

ormulatio! o t&e drug '!e *omme!t re*omme!ded t&e proisio! be

reised to state: BB5D*ept as proided i! paragrap&s (*) a!d (d) o

t&is se*tio! or eDempted b? regulatio! or guida!*e CC

F-A de*li!es to reise t&e regulatio! as re>uested e*tio!

306A(*)(2)(A) o t&e a*t states t&at a prior approal suppleme!t is

re>uired +&e! a *&a!ge BBis made i! t&e >ualitatie or >ua!titatie

ormulatio! o t&e drug i!oled or t&e spe*ii*atio!s i! t&e approed

appli*atio! or li*e!se (u!less eDempted b? t&e e*retar? b?


22/87

regulatio! or guida!*e )CC "roposed e* #4$0 is *o!siste!t

+it& t&e proisio!s o t&e a*t 5Demptio!s b? regulatio! are proided

i! e* #4$0(*) or (d) &is la!guage is alread? i!*luded i! e*

#4$0(b)(2)(i) /! additio!, F-A ma? use guida!*e do*ume!ts to proide

or a less burde!some !otii*atio! o a spe*ii* *&a!ge &is eDemptio!

is i!*luded i! e* #4$0(a)() a!d applies to e* #4$0(b)(2)(i)

as +ell as t&e ot&er *&a!ges listed i! e* #4$0

(.omme!t 0) eeral *omme!ts !oted t&at t&e "A. guida!*es

allo+ed or some *&a!ges i! >ualitatie or >ua!titatie ormulatio! o

t&e drug produ*t to be iled i! *&a!ges%bei!g%ee*ted suppleme!ts or

a!!ual reports '!e *omme!t said t&at t&e regulatio!s s&ould ollo+ t&e

sta!dards i! t&e "A. guida!*es

F-A &as !ot i!*orporated t&e >ualitatie a!d >ua!titatie

ormulatio! *&a!ge i!ormatio! rom t&e "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 o

ma!ua*turi!g *&a!ges a!d use guida!*e do*ume!ts to proide F-ACs

*urre!t t&i!i!g o! t&e spe*ii* *&a!ges i!*luded i! t&ose *ategories

(.omme!t #) eeral *omme!ts said t&at *&a!ges i! spe*ii*atio! to

*ompl? +it& a! oi*ial *ompe!dium s&ould !ot re>uire prior approal

suppleme!ts F-A is !ot re>uiri!g prior approal suppleme!ts or spe*ii*atio!

*&a!ges made to *ompl? +it& a! oi*ial *ompe!dium A *omplete

dis*ussio! o t&is issue is proided u!der se*tio! ///F o t&is

do*ume!t, BB.&a!ges o ;e -es*ribed i! t&e NeDt A!!ual Report,CC i!

respo!se to *omme!ts o! e* #4$0(d)(2)(i)

(.omme!t 2) '!e *omme!t re*omme!ded t&e proposed la!guage be

reised to limit spe*ii*atio! *&a!ges to t&ose or drug substa!*e or

drug produ*t

F-A *o!siders a spe*ii*atio! to be a >ualit? sta!dard (ie,

tests, a!al?ti*al pro*edures, a!d a**epta!*e *riteria) proided i! a!

approed appli*atio! to *o!irm t&e >ualit? o 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! o a drug substa!*e or drug produ*t &ereore, F-A

de*li!es to reise t&e proposal as suggested

"roposed e* #4$0(b)(2)(ii) re>uired prior approal or *&a!ges

re>uiri!g *ompletio! o studies i! a**orda!*e +it& part 20 to

demo!strate t&e e>uiale!*e o t&e drug to t&e drug as ma!ua*tured

+it&out t&e *&a!ge or to t&e reere!*e listed drug

(.omme!t ) '!e *omme!t said t&at reere!*e to part 20 suggests

t&at bioe>uiale!*e must be addressed or BBa *&a!ge i! t&e

ma!ua*turi!g pro*ess CC &e *omme!t said t&at t&is +ill lead to

sig!ii*a!t i!terpretatio! issues &e *omme!t said t&at a sele*tie

subset o maor ma!ua*turi!g *&a!ges t&at trul? &ae BBsubsta!tial

pote!tialCC s&ould be spe*iied &ere A!ot&er *omme!t said t&at +&e!

t&e produ*t is a true solutio!, *&a!ges to t&e ma!ua*turi!g pro*ess

(!ot ormulatio!) are &ig&l? u!liel? to *&a!ge t&e ormulatio! a!dadditio!al *li!i*al (bioe>uiale!*e) studies s&ould !ot al+a?s be

re>uired

F-A de*li!es to reise t&e proposal based o! t&ese *omme!ts &e

re>uireme!ts or +&e! a stud? is !eeded to demo!strate t&e e>uiale!*e

o 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 reere!*e listed drug are proided i! part

20 "art #4 is !ot i!te!ded to suppleme!t, supersede, or *lari?

t&ese re>uireme!ts e*tio! #4$0(b)(2)(ii) spe*iies o!l? t&at i

su*& a stud? is re>uired u!der part 20 to support a postapproal


23/87


24/87

substa!tial pote!tial to &ae a! BBaderse ee*tCC F-A de*li!es to

reise proposed e* #4$0(b)(2)(iii) as re>uested be*ause t&e

additio! o t&e term BBadersel?CC is redu!da!t F-A emp&asi=es t&at

t&e assessme!t o +&et&er a *&a!ge ma? adersel? ae*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? proidi!g a lo+er probabilit? o !o!sterile u!its, ma? damage

t&e *o!tai!er *losure s?stem so t&at sterilit? o i!diidual u!its

*ould !ot be mai!tai!ed

(.omme!t 6) eeral *omme!ts said t&at t&e proposed la!guage is

too restri*tie be*ause it i!di*ates t&at all *&a!ges to sterile

produ*ts s&ould be submitted i! prior approal suppleme!ts &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! Approed N-A or AN-A,CC +&i*& ide!tiies some *&a!ges

t&at do !ot &ae to be iled i! prior approal suppleme!ts '!e *omme!t

ide!tiied spe*ii* eDamples o ma!ua*turi!g *&a!ges or sterile

produ*ts a!d said t&at t&ese s&ould !ot be *o!sidered maor *&a!ges

F-A *o!siders *&a!ges t&at ma? ae*t t&e sterilit? assura!*e leel

o a drug to &ae sig!ii*a!t pote!tial to ae*t t&e saet? o t&e

drug &ereore, F-A &as ide!tiied t&is *&a!ge as o!e t&at re>uires

prior approal As stated i! t&e @u!e #999 proposal, t&is rulemai!gsets out broad, ge!eral *ategories o ma!ua*turi!g *&a!ges, a!d t&e

age!*? uses guida!*e do*ume!ts to proide F-ACs *urre!t t&i!i!g o! t&e

spe*ii* *&a!ges i!*luded i! t&ose *ategories !der e*

#4$0(a)(), a! appli*a!t must !oti? F-A o a ma!ua*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 proides or a less burde!some

!otii*atio! o t&e *&a!ge t&a! t&e regulatio! (or eDample, b?

submissio! o a suppleme!t t&at does !ot re>uire approal prior to

distributio! o t&e produ*t) For eDample, i! t&e guida!*e e!titled

BB.&a!ges to a! Approed N-A or AN-A,CC F-A &as ide!tiied less

burde!some reporti!g *ategories or *ertai! *&a!ges t&at it beliees

&ae less pote!tial to ae*t sterilit? assura!*e a!d *o!se>ue!tl? t&e

saet? o t&e drug

(.omme!t $) A e+ *omme!ts said t&at t&is proisio! i!*reases t&e

regulator? burde! +it& respe*t to sterile produ*ts &e *omme!ts said

t&at o!l? u!dame!tal *&a!ges to sterile pro*essi!g re>uire prior

approal

F-A disagrees +it& t&is *omme!t !der t&e preious regulatio!s at

e* #4$0, ma!ua*turi!g site, pro*essi!g, a!d pa*agi!g *&a!ges or

sterile drugs almost al+a?s re>uired a prior approal suppleme!t

(preious e* #4$0(b)(#)(i), (b)(#)(), (b)(2)(i), (b)(2)(), a!d

(b)(2)(i)) !der e* #4$0(*) a!d (d), *ertai! *&a!ges related to

sterile drugs ma? be submitted i! *&a!ges%bei!g%ee*ted suppleme!ts or

a!!ual reports (or eDample, e* #4$0(d)(2)(i) a!d (iii)) /! t&e

guida!*e e!titled BB.&a!ges to a! Approed N-A or AN-A,CC F-A &as

ide!tiied ma!? *&a!ges related to sterile drugs t&at ma? !o+ be

submitted i! *&a!ges%bei!g%ee*ted suppleme!ts or a!!ual reports "roposed e* #4$0(b)(2)(i) re>uired prior approal or *&a!ges

i! t&e s?!t&esis or ma!ua*ture o t&e drug substa!*e t&at ma? ae

Supplement and Changes to an Approved Applicationr

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