1-6_Establishing_impurity_specifications.ppt

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Establishing Impurity Specifications, 19 January 20111 |

Establishing ImpuritySpecifications

Antony Fake h!

"#$ %e&icines re'ualification rogramme


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Abbre(iations

API Active Pharmaceutical Ingredient

FPP Finished Pharmaceutical Product

LOD Loss on DryingPDE Permitted daily exposure

TDI Total daily intake

TT Threshold o! Toxological oncern


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Impurities

Impurities are un"anted chemicals present in the API orFPP arising !rom normal manu!acture#

They are not chemicals accidently or maliciously

introduced#

Impurities have no therapeutic value and are potentially

harm!ul# There!ore they need to $e controlled#


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Impurities )2*

%uestion&

I! a manu!acturer controls impurity content in accordance

"ith a pharmacopoeial monograph can "e accept the

speci!ications'


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Impurity )+*

%uestion&

I! a manu!acturer controls impurity content in accordance

"ith a pharmacopoeial monograph can "e accept the

speci!ications'

(n!ortunately no) monographs are developed $ased upon

ho" the API "as prepared historically#

A particular manu!acturer*s manu!acturing method may leadto unexpected impurities) due to a di!!erent route o!

synthesis) di!!erent reagents) etc#


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$(er(ie

+etting an impurity limit

,# -hat are the potential impurities'

.# -hat impurities actually occur'

/# -hen to speci!y impurities#

0# +etting limits !or impurities#


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-hat are the potential impurities'


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"hat are the potential impurities-

The !irst step in setting impurity speci!ications is toconsider "hat potential impurities might $e present)

$ased upon all availa$le in!ormation#

This step is o!ten poorly per!ormed $y applicants#

There is a tendency to skip this step in discussions and

1ust adopt pharmacopoeial speci!ications i! a monograph

exists#


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API +2

3eaction

intermediate

Final API

FPP

Potential Impurities

"hat are the potential impurities- )2*


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API +2

3eaction

intermediate

Final API

FPP


3esidue o! the API +2

3esidue o! the intermediate



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API +2

3eaction

intermediate

Final API

FPP

+2

impuritiesPotential Impurities

3esidue o! the +2


Impurities in the +2



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API +2

3eaction

intermediate

Final API

FPP

3eagents

+olvents

atalysts

+olvents

+2


3esidue o! the +2



3eagents

+olvents

atalysts

3eagents+olvents

atalysts



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API +2

3eaction

intermediate

Final API

FPP

3eagents

+olvents

atalysts

+olvents

4y5products

4y5products

+2


3esidue o! the +2



3eagents

+olvents

atalysts

3eaction $y5products

3eagents+olvents

atalysts



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API +2

3eaction

intermediate

Final API

FPP

3eagents

+olvents

atalysts

+olvents

Degradation

4y5products

4y5products

+2

impurities

3eagents+olvents

atalysts



3esidue o! the +2



3eagents+olvents

atalysts


Degradation products


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API +2

3eaction

intermediate

Final API

FPP

3eagents

+olvents

atalysts

+olvents

Degradation

4y5products

4y5products

+2

impurities

Excipient5API

interactions

3eagents+olvents

atalysts



3esidue o! the +2


Impurities in the +2 3eagents

+olvents

atalysts


Degradation products

Excipient5API interactions


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API +2

3eaction

intermediate

Final API

FPP

3eagents

+olvents

atalysts

+olvents'

Degradation

4y5products

4y5products

+2

impurities

ontainer5API

interactions

Excipient5API

interactions

3eagents+olvents

atalysts



3esidue o! the +2



3eagents

+olvents

atalysts


Degradation productsExcipient5API interactions

ontainer closure interactions


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"hat are the potential impurities- )+*

It is essential to have a detailed kno"ledge o! thepreparation o! the API and the controls place upon the

API starting materials) reaction intermediates) reagents

and solvents#

It is essential to kno" ho" the API degrades#

+imilarly) the manner o! preparation o! the FPP is

important# Are there solvents involved) heat) "ater etc'


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"hat are the potential impurities- ).*

2ost o! the potential impurities arise during thepreparation o! the API and its su$se6uent degradation#

The !ocus o! FPP impurities is usually limited to

degradation products) or occasionally API5Excipient andAPI5API interactions 7isonia8id9ri!ampicin:#

Typically FPP impurity speci!ications only control !or API

degradation products#

onse6uently) there is a large !ocus on the control o!

impurities in the API#


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"hat are the potential impurities- )/*

Impurities introduced during manu!acture

API degradation products

API reaction $y5products

Determining most o! the potential impurities does notre6uire a great deal o! chemistry kno"ledge# Impurities

can $e divided into&


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"hat are the potential impurities- )*

-hat impurities are introduced during manu!acture'

These can $e determined !rom the detailed

manu!acturing process description#

They are the solvents) reagents) catalysts) residue

starting material) reaction intermediates used in

manu!acture#


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-hat are the possi$le degradation impurities'

These can $e determined !rom the results o! stress

studies#

+igni!icant degradation products should $e identi!ied and

treated as potential impurities#


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-hat are the possi$le reaction $y5products'

;ere some chemistry kno"ledge "ould $e help!ul#

Advice&

Look !or areas o! !unctionality) particularly 5O) 5


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At 5O $onds oxidation) reduction) cleavage) additionand elimination can readily occur#


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Additions to dou$le $onds "ithin the molecule mayoccur unintentionally) and even i! intentional are not

,==> speci!ic#


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+tereochemical impurities can arise#


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ertain chemical structures ?alert structures? are considered to $e genoto3ic#


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"hat are the potential impurities- )1+*

@enotoxins must $e considered care!ully due to theirtoxicity at even very lo" levels#

The most common situation that arises is the use o! the

reagents methylsulphonic acid or toluene sulphonic acid#

In the presence o! alcohols like methanol or ethanol they

can !orm sulphonate esters# These esters are genotoxic#

3emem$er) i! the impurity and the API share the samealert structure then the impurity does not need to $e

controlled as a genotoxin#


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-hat impurities actually occur'


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"hat impurities actually occur-

AI S%

+tep ,

+tep /

Final AI

+tep .

hance

hance o! an impurity occurring

+tep impurity is introduced

Enantiomers


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"hat impurities actually occur- )2*

Investigation o! $atch analysis and long5term sta$ility data is re6uired#

Impurities present at levels greater than the I; reporting threshold

should $e reported $y the manu!acturer#

Potential impurities can $e excluded $y either testing the !inal API or

FPP) or a relevant proceeding molecule#

+ome pharmacopoeial impurities may not $e present i! a di!!erent

manner o! preparation)7 reagents) synthesis: is used#

For degradants) look to long5term sta$ility data# The presence o! animpurity under accelerated conditions does not mean it "ill appear

under long5term conditions


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"hat impurities actually occur- )+*

Analytical methods

I! you are looking !or an impurity using a test method that

can not detect the impurity then you are "asting your

time# Demonstrated speci!icity and appropriateLOD9LO%s are important) especially !or genotoxins#

It is important !or the manu!acturer to detail the methods

used# This is o!ten not clear in su$mitted dossiers i!

di!!erent test methods have $een used at di!!erent times#


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-hen to speci!y impurities#


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"hen to specify impurities

The I; divides impurities into

Organic impurities 7process5 and drug5related:

3esidual solvents

Inorganic impurities


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"hen to specify impurities )2*

Organic impurities

Any impurity routinely o$served in $atch data or long5term

sta$ility trials should $e controlled $y the impurity

speci!ications#

Impurities o$served $elo" the I; identi!ication threshold

need not $e individually speci!ied in the speci!ications#

They can $e controlled under the limit !or any unspeci!ied

impurity#

Impurities a$ove the I; identi!ication threshold need to $e

identi!ied and individually speci!ied in the speci!ications#


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"hen to specify impurities )+*

3egardless o! the related su$stance re6uirements o! an applica$lepharmacopoeial monograph) a test !or any unspeci!ied impurity and

total impurities should $e included#

%a3imum &aily &ose I&entification 4hreshol& 5 4he loer of6

7 of AI 4!I

AI . g =#,=> ,#= mg

B . g =#=C> 5

F , mg ,#=> C ug

, mg ,= mg =#C> .= ug

B ,= mg . g =#.> . mg

B . g =#,=> 5


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"hen to specify impurities ).*

@enotoxins

I! a genotoxin is !ormed or is likely to $e !ormed during manu!acture or

storage then a limit !or this impurity should $e included in speci!ications#

I! $atch data 7 pilot or / production: demonstrate that levels o! the

impurity are at or $elo" /=> o! the allo"a$le limit then non5routine

testing may $e adopted# It should still $e specifie

For instance) i! methylsulphonic acid and methanol "ere used in the

last step) $ut methane methylsulphonate "as not detected then it

may $e appropriate to test once annually#

i! methylsulphonic acid and methanol "ere used in the !irst o! threesteps) $ut methane methylsulphonate "as not detected then it may

$e appropriate to speci!y the test is to $e applied "hen there is a

change in manu!acture#


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"hen to specify impurities )/*

3esidual solvents

The a$sence o! speci!ic test should $e demonstrated on at

least / production $atches or pilot scale $atches#

8se& in last step rior to the last step

lass I +peci!y +peci!y i! detected

lass II +peci!y +peci!y i! B,=> o! the I;%/ limit 7option I:

lass III # ontrol$y Loss on Drying test permissi$le#


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"hen to specify impurities )*

2etals either used in the last step or not consistentlyremoved !rom previous steps#

B /=> o! applica$le limit /=> o! applica$le limit

lass I +peci!y


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+etting limits !or impurities


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Setting limits for impurities

The limits must $e 6uali!ied as sa!e#

The limits should realistically re!lect $atch and sta$ility

data#


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Setting limits for impurities )2*

Organic ImpuritiesAn organic impurity a$ove the applica$le I; 6uali!ication thresholdneeds to $e 6uali!ied#

%a3imum &aily &ose :ualification 4hreshol& 5 4he loer of6

7 of AI 4!IAI .g =#,C> ,#= mg

B .g =#=C> 5

F ,= mg ,#=> C= ug

,= mg 5 ,== mg =#C> .== ug

B ,== mg 5 . g =#.> / mg

B . g =#,C> 5


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Setting limits for impurities )+*

Through toxicological trials#

4y comparison to a limit speci!ied in the Ph#Int#) Ph#Eur#) or (+P !or

a specificimpurity# It could even $e in a monograph !or another

su$stance# A statement in a monograph o! ?any other impurity ? can not $e used as 1usti!ication !or an impurity limit) as it is not

speci!ic#

4y comparison to levels !ound in an innovator or pre6uali!ied FPP#

4y comparison to a limit previously approved in a pre6uali!ied FPP#

This is a last resort#

I! the impurity limit is greater than the I; 6uali!ication threshold then it

should $e 6uali!ied&


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Setting limits for impurities ).*

The limit !or any unspeci!ied impurity should $e at the I;identi!ication threshold#

The limit !or total impurity content should re!lect $atch data#

These concepts are applica$le to synthetic APIs) $ut could $e usedon a case $y case $asis !or semi5synthetic APIs#


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Setting limits for impurities )/*

@enotoxins& E2EA9;2P9%-P9.C,/009.==

Are considered unsa!e at any level#

A limit !or a genotoxin "ith an understood toxicity can $e calculated

$ased upon the kno"n PDE#

A limit !or a genotoxin "ithout su!!icient toxicity in!ormation must

determine $ased upon a TT o! ,#Cug9day#

2ax limit TT9maximum dose#

Levels a$ove this limit need to 1usti!ied toxicologically#

Limits !or genotoxins like a!latoxins)


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Setting limits for impurities )*

3esidual solvents

I; limits apply %/730:

lass I solvents +ee ta$le ,) %/730:

lass III solvents C=== ppm is accepta$le "ithout !urther

1usti!ication might $e controlled $y LOD 7=#C>:

lass III solvent limits a$ove C=== ppm are permissi$le) $ut it "ould

tend to indicate poor manu!acturing control#


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lass II solvents . methods !or calculating limits

Option , Ta$le o! %/730: 5 prede!ined limits#

Good for APIs and FPPs

Option . A limit $ased upon the calculated total

exposure to the solvent in the FPP#


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For instance& Acetonitrile

The option , limit is 0,= ppm $ased on a PDE o! 0#, mg9day#

The option . limit allo"s potentially a limit higher than 0,= ppm#

Option . permits up to 0#, mg o! acetonitrile in the FPP#

The limit o! 0,= ppm may $e exceeded in the API provided the totalamount o! residual acetonitirile in the FPP does not exceed 0#, mg#


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This can lead to API manu!acturers 1usti!ying limits like this&

Acetonitrile 7PDE 0#, mg9day: in 8idovudine 7/== mg per day:

(sing the I; !ormula&

2ax limit ,=== x 0#,9=#/

,/)= ppm 7seems a little excessive:#


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4(T

"provided that it has been demonstrated that the residual solvent has

been reduced to the practical minimum. The limits should be realistic

in relation to analytical precision, manufacturing capability,

reasonable variation in the manufacturing process, and the limits should

reflect contemporary manufacturing standards." I!#$%&'

4asically) "e might accept ,=== ppm 7i#e# B0,= ppm: i! supported $y

$atch data) $ut not .= times this value#

Also) option . applies to the total amount o! solvent in the FPP# I! theamount o! solvent in the API is excessive it may cause pro$lems !or the

setting FPP limits#


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2etal residues& E2EA5;2P5+-P50005.===


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Either adopt the stated concentration 7ppm: limits 7dose ,= g:) or

+et a limit !or each metal such that the content o! all metals o! a

particular su$class) $ased on maximum dose) do not exceed the

recommended PDE# 2etal contamination !rom all sources in theFPP must $e considered#


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