stability Testing of Natural Products_2003

DR. HARISH KAKRANI, PURVI PUR VI KAKRANI KAKRANI

STABILITY y

y

y

Stability can be defin defined as the exten extent to whic which the drug produc product reta retains its its original original properties properties & characteri acterisstics tics durin during its its stora torage period. period. Expiry date is a date after whic which the potency potency of of the activitie activitiess woul ls. ould be lost or reduc reduced to sub-poten ub-potent leve evels. ssar y to y to ensure nsure the produc Stability testing is necessar product is y throughout qual y throughout of acc of accept eptaable qual qualit it y throughout qualit it y throughout its its entire stora torage period period

Dr. Ha Hari rissh Kak Kakrran ani, i, Purvi Kak Kakrran anii

2

SIGNIFICANCE OF STABILITY TESTING y

Chemical hemical degra degradation tion may l ay lead to under-medication due to

lowerin owering of the conc nceentra tration tion of drug in in dosa dosage ge form.

Patien tient has has to rec receive the right & stand andard qual qualit it y y drug. drug. Durin During decomposition of drug substance or drug product may l ay lead to toxic product Say i ay in case case of p-a p-amin mino sali salicyli cylic acid, acid, it is is con verted to p-a p-amin mino phen phenol (toxic) (toxic).. y

y

y

y

In poly poly herbal herbal formula formulatio tions ns,, degra degradation tion of any of any o on e constitue nstituen nt may may llead to its its decreased concentration in blood. y

The patien tient has has to rec receive a uniform dos dose of drug throughout

shel helf l f life. y y

Determina Determinatio tion n of shelf life of a of a produc product. Determina Determinatio tion n of degra degradation tion produc product and and the poss possibi ibillit y it y degradation pathway . Dr. Ha Hari rissh Kak Kakrran ani, i, Purvi Kak Kakrran anii

3

TYPES OF STABILITY T y pe of Stability

Condition Maintained throughout the shelf life of drug product

Chemic hemical

Each active active in ingredien gredient reta retains its its chemical hemical integrit y tegrit y and and labe labelled potency potency withi within n the spec pecified limit

Ph ysi ysical

The original original Ph ysi ysical properties propertie s includi ncludin ng appea ppearance ance

palat alatabil bilit y it y , un uniformit y iformit y , diss disso olution ution and and suspen pendabil bilit y it y Microbiol robiological ogical

Res Resistance ance to mic microbial robial growth is is reta retained accordi accordin ng to spec pecified requiremen requirement.

Thera herapeutic peutic

Thera herapeutic peutic effec effect rema remains unc nch hanged anged

Toxic oxicological ogical

No sign ignifican ificantt inc incre reas asee in in toxic toxicit y o y occ ccur urss


4

FACTORS AFFECTING AFFECTI NG STABIL STABILITY ITY OF O F HERBAL HE RBAL FORMULATIONS Factor actorss affec ffectin ting stabil bilit y of y of formula formulatio tion n

Ph ysi ysical

Chemical hemical

Loss Loss of vola volati tille constitue nstituen nts; Loss Loss of wa water; ter; Abs Absorption orption of wa water; ter; Cr yst ystal growth; growth; Color change anges; s; Poly Poly morphic morphic change angess

Ester Ester H y drolys drolysiis, Amide h y h y drolys drolysiis, Oxida Oxidation tion, Isomerisa omerisatio tion n, Poly Po ly merisa merisatio tion n, Deca Decarbox rbox yla ylatio tion n


5

PHYSICAL PHYSI CAL DEGRA DEGRADA DATIO TION N Loss of volatile constit constituents:

1.

Many c Many constitue nstituen nts are vo re vola lati tille at ambie mbien nt tempera temperature turess Due to this this, the y the y m may be ay be lost from pha pharmac rmaceuti eutical cal prepa preparations tions.. Exampl mple: Di Dill ll water, camphor camphor wa water. 2. Loss of water water: E v apora poration tion of wa water from liquid, semi-s emi-solid formula formulatio tions ns & o/w emuls emulsio ions ns crack ackiing of thes these sys system temss. Loss Loss of wa water from aqueous queous solution ution cr ys ysttall alliz izaatio tion n of of ssolute 3. Absorption of water/ Moisture: Higher humidit y humidit y m may l ay lead to mois moisture absorption orption gen generally erally obs observed with solid pha pharmac rmaceuti euticals cals.. his absorbed mois moisture may may p partic rticipa ipate in in drug degra degradatio tion n This its itself as f as a reac reacttant ant leadin ding to h y drolys drolysiis, h y dra dration tion, isomeriza omerization tion or other biomol biomolecular lar chemical hemical reac reactio tions ns.. y y y

y

y

y

y


6

PHYSICAL DEGRADATION y

Remediess for stabi Remedie billiz izaatio tion n against nst mois moisture absorption orption: y

y

Use of mois moisture proof proof packagi ackagin ng, dess dessiicant cants are are often often used to el elimina iminate te mois moisture in in packagi ackagin ng. Mois oisture proof proof fi f ilm coatin tings.

4. Crystal growth: ommon in sy rups rups Common Fluctua tuations tions in the ambien mbient tempera temperature i.e. in in day & ay & night cr yst ystal growth occ occur urss. Usually thi ally thiss probl problem occ ccur urss when when the vehicl vehiclee bec becomes omes super upersa satur turaated with solute prec precipita ipitation tion of s of solute occ ccur urss seedin eeding occ occur urss cr yst ystal growth. Remediess: Remedie Sel Select suita uitable stor toraage conditio ditions ns.. Inc ncre reas asee the produ producct vi visc sco osit it y y , so tha that diffus diffusio ion n of s of solute towa towards rds cr yst ystal seed Inc ncorpor orporaation tion of s of surf ace ace ac active tive age gen nts. y y

y

y

y

y

y


7

PHYSICAL DEGRADATION 5. Color changes:

Indica dicative tive of c of chemical hemical or photoc photochemical hemical change angess. Remediess for stabil Remedie biliza ization tion against nst photodegra photodegradation tion:

y

y

y

y

Use of photoprotec photoprotective ive fil films Fil Film coatin tings on the formula formulatio tions ns,, say ca say cap psules.

6. Polymorphic changes: y

y

Many s Many subs ubstance ances exis exist in in two or more poly poly meric meric forms forms . Upon Upon stora torage in the dr y dr y sstate or in in suspens pensio ion n interter-ccon ver verssio ion n of thes these forms forms alter alteraations tions in solubil ubilt y .


8

CHEMICAL DEGRADATION HYDROLYSIS:

1. y

Considered nsidered to be maj major or cau cause of deteriora deterioration tion of drugs drugs, es esp.

y

in aqueous queous solutions utions Defin Defined as the reac reactio tion n of a of a compoun ompound with wa water. 2 forms forms of h y drolys drolysiis:

y y

y

y y

y

y

ccur urss when when the salt salts of weak weak acid acidss (e.g. Ionic hydrolysis: Occ potass potassium ium acet acetaate) te) & bas basees (e.g. codien odiene phospha phate) te) interac teractt with wa water to give alkali alkaline & acidi acidicc solutions utions res respec pectively tively ncludess cle clea v age of drug mol molecule. It is is Molecular hydrolysis: Include muc much slower slower proc process & an irrevers irreversibl ible too. H y drolys drolysiis may be ay be of 3 t y pes pes: Ester Ester h y drolys drolysiis Amide h y h y drolys drolysiis Rin Ri ng alter alteraation tion Dr. Ha Hari rissh Kak Kakrran ani, i, Purvi Kak Kakrran anii

9

CHEMICAL DEGRADATION a) Ester hydrolysis: Prev ale alent in f att y y ac acid idss. In vol vol ves ves rupture of a of a cov ale alent bon bond between between C- atom & Oatom. A lkali lkaline h y drolys drolysiis of an of an ester: Irreversible & quantitative beca becau use the res resultant ant acid acid is is at onc ncee neutral eutralized. ized. A cid h y drolys drolysiis of an of an ester: Reversible proc process; may be ay be esse ssentially tially ccompl ompleted in in either direc direction tion b y an y an exc excess of wa water or alcoho alcoholl. Remediess: Remedie

y y

y

y

y y

y

y

y

Lowerin Lowering buffer conc nceentra tration tion Partial rtial or compl omplete replac replaceme emen nt of wa water with non-aqueous queous sol ven vent, say prop yl prop yleene glyco lycol. Addin Adding compl omplexin exing agen gent, say ca say caffie ffien ne. B y formu y formula lati tin ng in in form of dr y dr y powder. powder. Dr. Ha Hari rissh Kak Kakrran ani, i, Purvi Kak Kakrran anii

10

CHEMICAL DEGRADATION b) Amide hydrolysis : H y droly droly tic tic cl cleea v age of an of an amide res results in forma formation tion of an of an acid acid & an amin mine. c) Ring alteration alteration: A h y droly droly tic tic reac reactio tion n can proc proceed as a res result of rin ring cleea v age with subs cl ubsequen equent attack ttack b y H y H+ or OH- io ion n. droly tic tic reac reactio tion n was reported to proc proceed b y ri y rin ng The h y droly open opening for an amin mine attack ttack b y w y water or OHion io n to give a carbi carbin nolami lamin ne in intermedia termediate dec decompos omposition ition to formal formaldeh deh y de de & 4-a 4-amin mino-6 chloro- mben benzen zene dis disulfona fonamide. mide. y

y

y


11

CHEMICAL CHEMI CAL DEGRADA DEGRADATION TION 2. OXIDA TION:

Inst nstabil bilit y it y iin number of formula formulatio tions ns is due to oxida oxidation tion of active active in ingredien gredient when when expo expossed to atmo tmosspheri phericc ox y gen gen. Media ediated b y b y free free ra radicals dicals or b y mo y mollecular lar ox y gen gen. Oxidaatio Oxid tion n is:

y

y

y

y

y

Remov al al of an of an electropos tropositive atom, ra radical dical or electron tron Addition Addition of el electron tronega egative atom or ra radical dical

Predic Prediction tion of s of susc sceptibi eptibillit y of y of the compoun ompound to oxida oxidation tion from a stand andard oxida oxidation tion- reduction tion poten potential tial:

y

y

y

y

y

Eh = E0 + o.o592 n log [oxidized form]/ [reduc [reduced form] Where Eh= reduc reduction tion poten potential tial E0= stand andard reduc reduction tion poten potential tial n= number of io ions ns trans transferred ferred per ion ion. Dr. Ha Hari rissh Kak Kakrran ani, i, Purvi Kak Kakrran anii

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CHEMICAL DEGRADATION y

Auto-oxidatio Auto-oxida tion n is free ra radical dical chain reac reactio tion n whic which proc proceeds eeds quite slow slowly ly u under the in inf luenc uencee of mol molecular lar ox y gen gen Free ra radicals dicals are produc produced b y re y reac actio tions ns in vol vol vin ving hemoly hemoly tic tic bon bond fiss fissio ion n of a of a cov ale alent bon bond. Mai Mainly o nly occ ccur urss in oi oils ls & f ats containing unsatur nsaturaated linkage nkagess. Only s nly small amoun mount of ox y gen gen is needed j eeded ju ust to in initia itiate the reac reactio tion n. y

y y

R ancidit ancidit y y iis a term coverin overing many many tt y pical pical off- f la la vors vors formed b y a y auto oxida oxidation tion of unsa unsatur turaated f att y ac y acid idss pres present in in oi oill or f at. 3. ISOMERISA TION: Isomeri omerisa satio tion n: Con vers versio ion n of an of an active active drug in into a less active active or inac inactive tive is isomer ha ha vin ving same same struc tructural tural formula formula but differin differing in in stereoc tereochemical hemical co configura figuration tion. y

y


13


y

In stereoi tereoissomeri omerissm, the atoms toms maki aking up the is isomers omers are joi join ned up in in the same same order, but still till manage anage to ha ha ve a differen different spatial tial arran rrangeme gemen nt. Optical Optical isomeris omerism is one form of s of stereois tereoisomeris omerism molecules tha that differ three-dimens three-dimensio ionally nally b b y Optical isomers are mol the plac placeme emen nt of s of subs ubstituen tituents arou aroun nd on one or more atoms toms in a mol molecule. give n their name name beca becau use the y the y were were firs first Optical isomers were given able to be dis distin tinguis guished b y how y how the y the y rot rotaated plan plane-po e-pola larized rized light. Optical Optical isomerisa omerisatio tion n can be further divided in into: R acemiz acemizaatio tion n: This his in vol vol ves ves con vers versio ion n of an of an optically optically ac active tive form of a of a drug in into its its enantiomorph. nantiomorph. y

y

y

y

y

The proc process contin tinues ues until til equal equal conc nceenttra ttration tion of 2 optically optically ac active tive

from is is obta obtained. Dr. Ha Hari rissh Kak Kakrran ani, i, Purvi Kak Kakrran anii

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Epimeri satio n: a compoun pimerisa tion ompound ha vin ving more than than 1 asy mmetric carbon n atom in mmetric carbo in the mol molecule. y

y

Exampl mple: epimerisa epimerisatio tion n frequen frequently fou ly foun nd in in carboh carboh y dra drates tes, more spec pecifically ifically ssucros rose.

satio n: Loss y is due to Geometrical isomeri Geometrical omerisa tion Loss of ac of activit tivit y i differenc differencee in potency potency exhibited exhibited b y b y -- cis & -trans -trans isomers omers of s of some organ organiic compoun ompounds y

Exampl mple: A ctive form of vita vitamin min A mol molecule has has all trans trans configura figuration tion.

POLYMERIZA TION:

4. y

y

In vol vol ves ves combina ombinatio tion n of 2 or more iden identical tical mol molecules to form a muc much larger larger & compl omplex mol molecule This his is a major ajor cau cause of degra degradation tion of an of anti tisseptic eptic from aldeh aldeh y de. de. Dr. Ha Hari rissh Kak Kakrran ani, i, Purvi Kak Kakrran anii

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CHEMICAL DEGRADATION 5. DECARBOXYLA TION: y

y

y

Loss Loss of CO2 Mai Mainly o nly occ ccur urss when when paren renteral teral solutions utions of s of sodium bica bicarbo rbona nate te autocla utocla ved. Remed y : CO2 is is passed assed in into the solution ution for 1 min minute.

6. ABSORPTION OF CO2: y

Most frequen frequent occ ccurre urrenc ncee than than the deca decarbox rbox ylatio ylation n.


16

ICH GUIDELINES FOR STABILITY STUDIES International Conference Conference on Harmonisation


17

INTRODUCTION y

y

y

Patien tient taki aking a pha pharmac rmaceuti eutical cal produc product expec expects the produc product to be safe safe and and efficac efficaciou iouss. Phaarmac Ph rmaceuti eutical cal regula regulator tor y y aagenc gencie iess worl world wide deman demand d tha that the produc product rema remains its its iden identit y tit y , qual qualit it y y , purit y purit y an and d potency potency for for the time the produc product is is commerc ommercially a ally a v ailab lable.

V arious rious stabil bilit y guide y guidellines desc describi ribin ng the t y t y pes pes of s of studies tudies &t y &t y pes pes of da data needed are: y y y y y y y y y

Food and and Drug Admin Administra tration tion (FDA ) Interna ternatio tional nal Conferenc ferencee on Harmon rmoniza ization tion (ICH) European uropean Unio ion n Guidel Guidelines (EU) Jap Japane anese Guidel Guidelines (MHW ) Worl World Heal Health th Organ Organiz izaation tion (WHO) (WHO) Guidel Guidelines Gul Gulf Central tral Committee (GCC)  For Gul Gulf Coun ountries tries A sso ssociation tion of South East East A sian Nations tions (ASE (ASE AN AN)) Easter Eastern n Mediterran editerraneean Region Region etc etc. Thera herapeutic peutic Good Admin Administra tration tion (TGA )  For Austral traliia Dr. Ha Hari rissh Kak Kakrran ani, i, Purvi Kak Kakrran anii

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INTRODUCTION y

ly ICH guidel accepted Curren urrently I guidelines are mos most commonly ommonly acc epted y tesstin whic which provides provides informa formation tion on stabil bilit y te ting within within n(EU), Jap Japan, an, and and Un the areas reas of E of European uropean unio ion United Sta States tes.


19

ICH y

The inter natio nal confere ncee of harmo niz n of terna tional ferenc rmon izaatio tion

y

nt for regis n of pha aceuti cal technical requireme tec requiremen registr traatio tion pharm rmac eutical for human human use (ICH) is a unique pro j pro jeect tha that brin brings y authorities an, and and together the regula regulator tor y a uthorities of E of Europe, Ja urope, Jap pan, cal indus USA an USA and d experts experts from the pha pharmac rmaceuti eutical dustr y tr y iin scie ntific and tec aspeccts of three regions regions to disc discu uss sc ien tific and technical aspe produc product regis registra tration tion. The objectives of s of such harmon rmoniza ization tion is: y

y

y

A more ec economical omical use of human human,, anim animal al,, and and ma material terial res resourc ources. The elimina iminatio tion n of unn unneecessar ssar y de y delay lay iin the gl global obal devel developmen opment and and a v ailabi labillit y it y of of n new medic medicines. Mai Maintaining safegu safeguaards rds on Qual Qualit it y , safet safet y an y and d efficacy efficacy an and d regula regulator tor y y ob oblliga igations tions to protec protect publ public heal health th Dr. Ha Hari rissh Kak Kakrran ani, i, Purvi Kak Kakrran anii

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TITLES UNDER ICH GUIDELINES PARAMETER Sta Stabil bilit y it y

S UB SECTIONS

SUB-SECTION TITLE

Q 1A (R2) (R2)

Sta Stabil bilit y it y te tesstin ting in in New drugs drugs & produc products

Q 1B

Photo- stabil bilit y te y tesstin ting

Q 1C

Sta Stabil bilit y it y te tesstin ting: New dosa dosage ge forms forms

Q 1D

Bracketi acketin ng & Matrixi Matrixin ng Des Designs igns for stabil bilit y it y Testin ting of Drug Subs Substance ances & Drug Produc Products

Q 1E 1E

E v alu aluation tion of Sta Stabil bilit y d y data

Q 1F

Stabil bilit y it y D Data Package ackage for Regis Registra tration tion in Clima imatic tic zon zones   & V V

A naly naly tical tical v alid alidaation tion

Q 2A

Definitions itions & termin terminolog y og y

Q 2B

Methodol ethodolog y og y

Impurities Impuritie s

Q 3A

Impurit y te y tesstin ting in in New drug

Q 3B

Impurities in dosa dosage ge forms forms: Adden Addendum to the guidel guideline on impurities impuritie s in New drug Subs Substance ances

Q 3C

Impurities Impuritie s: Res Residual idual sol ven vents


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Q1A (R2): ST STABILITY ABILITY TESTING T ESTING NEW DRUG

AND PRODUCT y

Basic Concepts For Stability Testing :y

There are two pa parts rts : For Active Substance 1. y

y

y

y

y

y

y

y

y

Stress Stress Testin ting Sel Selection tion of Ba Batches hes Container Closure S ystem ystem Spec Specifica ificatio tion n Testin ting Frequency Frequency Stora Storage Conditions ditions Sta Stabil bilit y Commitmen ommitment E v alu aluation tion Sta Statemen tements/La /Labell belliing Dr. Ha Hari rissh Kak Kakrran ani, i, Purvi Kak Kakrran anii

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(R2): STABILI STABILITY TY TESTING NEW Q1A (R2): DRUG AND PRODUCT roduct: 2. For pharmaceutical prod y y y y y y y y y y

Sel Selection tion of Ba Batches hes ystem Container Closure S ystem Spec Specifica ifi catio tion n ting Frequency Frequency Testin Stora Storage Conditions ditions Sta Stabil bilit y it y Commitmen ommitment E v alu aluation tion Sta Statemen tements/La /Labell belliing In-us -use stabil bilit y it y V aria riations tions y

On-goin -going Sta Stabil bilit y Studie y Studiess Dr. Ha Hari rissh Kak Kakrran ani, i, Purvi Kak Kakrran anii

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I. STABILIT STABILITY Y TESTING FOR ACTIVE SUBSTANCE 1.1 GENERAL: y

y

For active active subs ubstance ances not desc described ribed in in an offic official pha pharmac rmacopoei opoeial al mon monogra ograph, stabil bilit y s y studies tudies are required. For ac active tive sub ubsstanc ancees de desc scribed ribed in in an offi officcial ph phaarm rmac acopoei opoeial al mon monogra ograph, whic which covers overs the degra degradation tion produc products and and for whic which suita uitable limits imits ha ve been been set but a re-tes re-test period is is not defin defined, two options options are accept acceptaable: y

y

manuf uf acturer acturer confirms firms tha that the ac active tive sub ubsstanc ancee comp ompllie iess with The man the pha pharm rmac acopoei opoeial al mo mon nogr ograaph immedia immediately tely prior prior to the manuf anuf acture acture of the pha pharmac rmaceuti eutical cal produc product. In In this this case case no stabil bilit y it y studies tudies on the active active subs ubstance ance are required manuf uf acturer acturer establishe hess a re-te re-tesst period based ased on on the res results of The man long term tes testin ting stabil bilit y it y sstudies tudies conduc ducted on on the active active subs ubstance. ance. Dr. Ha Hari rissh Kak Kakrran ani, i, Purvi Kak Kakrran anii

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I. STABILIT STABILITY Y TESTING FOR ACTIVE SUBSTANCE 1.2 Stress Testing: active subs ance can hel Stress Stress tes testin ting of the active ubstance help iden identif y ly degraadatio n produ the likely degr tion produccts, whic which can in turn turn n path ayss and and the hel help establish the degr degraadatio tion thw way nsiic stabi y of intri trins billit y of the mol molecule. active subs ance the foll ng approac For an active ubstance followi owin pproache hess may be used: y

y

y

y

No data are required on on the degra degradation tion produc products, if an if an active active subs ubstance ance is is desc described ribed in in an offic official pha pharmac rmacopoei opoeial al mon monogra ograph. For active active subs ubstance ances not desc described ribed in in an offic official pha pharmac rmacopoei opoeial al mon monogra ograph, there are two options options: Dr. Ha Hari rissh Kak Kakrran ani, i, Purvi Kak Kakrran anii

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I. STABILIT STABILITY Y TESTING FOR ACTIVE SUBSTANCE y

y

y

When When a v ailab lable, it is is accept acceptaable to provide the rel relev ant ant da data publ published in the litera iterature to support the propos propo sed degra degradation tion pathways; thways; When When no da data are a v ailab lable in in the sc scie ien ntific tific litera iterature, incl includi udin ng offic official pha pharmac rmacopoei opoeias as,, stress tress tes testin ting shoul hould be performed.

ly to be carried carried out on Stress Stress tes testin ting is is likely to on a single batch active subs ance. of the active ubstance. y

y y

y

It shoul hould incl include ude the effec effect of temper of temperaature turess (in (in 10°C inc ncreme remen nts (e.g., 50°C, 60°C, etc etc.) above tha that for acce accelera erated tes testin ting), humidit y humidit y (e.g., (e.g., 75% RH or grea greater) ter) where appropria ppropriate, oxid oxidaatio tion n and and photo photolys lysiis on the active active subs ubstance. ance. Photosstabi Photo billit y y te tessti tin ng shoul hould be an integral tegral part of s of stress tress tes testin ting. Dr. Ha Hari rissh Kak Kakrran ani, i, Purvi Kak Kakrran anii

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I. STABILIT STABILITY Y TESTING FOR ACTIVE SUBSTANCE 1. 3 Selection of Batches Data from formal formal stabil bilit y s y studies tudies provided on on at least ast 3 primaar y prim y b batche hess of the active active subs ubstance. ance. primar y b y batches hes shoul hould be man manuf uf actured actured to a min minimum The prima of pi of pillot scal scalee. Pillot ba Pi batches hes manuf anuf actured actured b y the y the same same syntheti syntheticc route and and method of manuf anuf acture acture tha that simu imula late tess the final final pro proccess to be used for produc production tion batches hes. y

y

y

1.4 Container Closure System The stabil bilit y s y studies tudies shoul hould be conduc ducted on on the active active subs ubstance ance packaged ackaged in in a container cl clo osure system system tha that is is the same same as or simu imula late tess the packa packagi gin ng propos proposed for stor toraage and and dis distribution tribution. Dr. Ha Hari rissh Kak Kakrran ani, i, Purvi Kak Kakrran anii 27 y

I. STABILIT STABILITY Y TESTING FOR ACTIVE SUBSTANCE 1.5 Specification y

Sta Stabil bilit y it y sstudies tudies shoul hould y

y

Shoul Should cover, as appropria ppropriate, the ph ysi ysical, cal, chemical hemical,, biol biological ogical,, and and mic microbiol robiological ogical attributes ttributes. Include nclude tes testin ting of thos those attributes ttributes of the active active subs ubstance ance tha that Are susc sceptib eptiblle to change ange durin during stora torage and and Are likely to ly to inf luenc uencee qual qualit it y y , safet safet y , and/or and/or efficacy efficacy y

y


28

I. STABILIT STABILITY Y TESTING FOR ACTIVE SUBSTANCE 1.6 Testing Frequency For active active subs ubstance ances with a propos proposed re-tes re-test period of a of at least ast 12 mon months ths, the frequency frequency of of tes testin ting at the long term stora torage condition dition shoul hould normally ormally be be y

y

y

y

E ver y ver y three three mon months ths over the firs first y ear, E ver y ver y ssix mon months ths over the second y ear, and and A nnu nnually there ally thereaafter through the propos proposed re-tes re-test period.

1.7 Storage Conditions The stora torage conditions ditions and and the lengths gths of s of studies tudies cho hossen shoul hould be suffic ufficien ient to cover stora torage, shipmen hipment, and and subs ubsequen equent use with due rega regard to the cl clim imaatic tic zon zone(s) e(s) in whic which the active active subs ubstance ance is is inten tended to be stored. y


29

I. STABILIT STABILITY Y TESTING FOR ACTIVE SUBSTANCE The long-term tes testin ting Shoul Should cover a min minimum of 12 1 2 mon months ths dura duration tion on at least ast three prima primar y b y batches hes at the time of s of submiss ubmissio ion n and and Shoul Should be contin tinued for a period of time suffic ufficien ient to cover the propos proposed re-tes re-test period. 1.7.1 General Case: y

y

y

Term

Duration

Testing condition

Lon Long term

12 mon months ths

Intermedia termediate

6 mon months ths

30°C± 2°C/65% /65% RH RH ± 5% RH RH

A cce ccelera erated

6 months ths

40°C± 2°C/75% /75% RH RH ± 5% RH

25°C ± 2°C/60% /60% RH ± 5% RH RH or 30°C ± 2°C/65%RH /65%RH ± 5% RH


30

I. STABILIT STABILITY Y TESTING FOR ACTIVE SUBSTANCE y

If s sign ignifican ifi cantt change ange occ occur urss at any time any time durin during six mon months ths tes testin ting at the acce accelera erated stora torage condition dition, additional dditional tes testin ting at the in intermedia termediate stora torage condition dition shoul hould be conduc ducted and and ev alu aluated against nst sign ignifican ifi cantt change ange criteria riteria.

1.7.2 Active substances intended i ntended for storage in a

refrigerator Term

Duration

Testing conditions

Lon Long term

12 mon months ths

5°C ± 3°C


6 mon months ths

25°C ± 2°C/60% /60% RH ± 5% RH RH or 30°C ± 2°C/65% /65% RH RH ± 5% RH RH


31

I. STABILI STABILITY TY TESTING FOR ACTIVE ACTI VE SUBSTANCE y

ange occ ccur and six mon If s If sign ignifican ificantt change urss between between three and months ths accelera tes testin ting at the acce erated stora torage condition dition: y

The propos proposed re-tes re-test period shoul hould be bas based ed on on the real real

time da data a v ailab lable at the long term stora torage condition dition. y

ange occ ccur If s If sign ignifican ificantt change urss within within the firs first three mon months ths accelera tes testin ting at the acce erated stora torage condition dition: y

A disc di scu ussio ssion n shoul hould be provided to address ddress the effec effect of short term exc excurs ursio ions ns outs outside the labe labell stora torage condition dition, e.g. durin during shippin hipping or han hand dling.


32

I. STABILIT STABILITY Y TESTING FOR ACTIVE SUBSTANCE 1.7. 3 Active substances intended i ntended for storage in a

freezer Term

Duration

Testing Conditions

Lon Long term

12 mon months ths

- 20°C ± 5°C

y

In the absenc ncee of an of an acce accelera erated stora torage condition dition for active active subs ubstance ances inten tended to be stored in in a freezer, tes testin ting on on a single ba batch at an elev ated tempera temperature (e.g. 5°C ± 3°C or 25°C ± 2°C or 30°C ± 2°C) for an appropria ppropriate time period shoul hould be conduc ducted to address ddress the effec effect of s of short term exc excurs ursio ions ns outs outside the propos proposed labe labell stora torage condition dition


33

I. STABILIT STABILITY Y TESTING FOR ACTIVE SUBSTANCE 1.8 E valuation: E v alu aluatin ting the stabil bilit y it y iinforma formation tion (incl (includi udin ng, as appropria ppropriate, res results of the ph ysi ysical, cal, chemical hemical,, biol biological ogical,, and and mic microbiol robiological ogical tes tests), s), a re-te re-tesst period is is established appl pplicab cable to all future ba batches hes of the active active subs ubstance ance manuf anuf actured actured un under simila imilarr circ ircums umstance ances. riaabi billit y y of of in individual dividual batches hes affec ffects the The degree of v ari confidenc fidencee tha that a future produc production tion batch will will rema remain within within spec pecifica ifi catio tion n throughout the assig assign ned re-tes re-test period. y

y


34

I. STABILIT STABILITY Y TESTING FOR ACTIVE SUBSTANCE 1.9 Statements/Labelling: A sstora A torage statemen tement shoul hould be es established for the labe labelling bas based ed on on the stabil bilit y it y ev ev alu aluation tion of the active active subs ubstance. ance. Where appl pplicab cable, spec pecific ifi c instru nstrucctions tions shoul hould be provided, y

y

y

Exampl mple: Partic rticular larly for ly for active active subs ubstance ances tha that cannot cannot tol tolera erate freezin freezing, terms terms such as ambien mbient conditions ditions or room tempera temperature mus must be a voided.


35

II. ST STABILIT ABILITY Y TESTING FOR PHARMACEUTICAL PHAR MACEUTICAL SUBST SUBSTANCE ANCE 2.1 General: y

The des y studies design ign of the formal formal stabil bilit y s tudies for the cal produc pha pharmac rmaceuti eutical product shoul hould be bas based ed on: Knowl owledge of the th e beha beha vior and and properties properties of the active active subs ubstance ance From stabil bilit y s y studies tudies on the active active subs ubstance ance From pre-for pre-formu mula latio tion n studies tudies. y

y

y


36

II. ST STABILIT ABILITY Y TESTING FOR PHARMACEUTICAL PHARMACEUT ICAL SUBST SUBSTANCE ANCE 2.2 Selection of Batches y

y

y

y

y studies astt Data from stabil bilit y s tudies shoul hould be provided on on at leas y b cal produc three prima primar y batche hess of the pha pharmac rmaceuti eutical product. y batches same formula n The prima primar y b hes shoul hould be of the same formulatio tion and and packaged ackaged in same container cl clo system as in the same osure system propos proposed for ma marketin eting. T wo of the three ba ast pi scalee b atches hes shoul hould be at least pillot scal and the third on aller, if j batches hes and one can be smaller, if ju ustified. cal produc Where poss po ssib iblle, ba batches hes of the pha pharmac rmaceuti eutical product shoul actured b y hould be man manuf uf actured b y u using differen different batches hes of the active active subs ance. ubstance. Dr. Ha Hari rissh Kak Kakrran ani, i, Purvi Kak Kakrran anii

37

II. ST STABILIT ABILITY Y TESTING FOR PHARMACEUTICAL PHARMACEUT ICAL SUBST SUBSTANCE ANCE 2. 3 Container Closure System y

Conduc ducted on on the dosa dosage ge form packa packaged ged in in the container

closure system clo system propos proposed for ma marketin eting. 2.4 Specification y

y

ysical, cal, chemical Shoul Should cover, as appropria ppropriate, the ph ysi hemical,, and mi biol biological ogical,, and microbiol robiological ogical attributes ttributes, pres preserv ative conten antioxidan ant, antimiccrobial and tent (e.g. antioxid t, antimi robial pres preserv ative) tive), and nalit y tessts (e.g. for a dos system func functio tional it y te dose del deliver y iver y sys tem)). naly tical alidaated. A naly tical proc procedures edures shoul hould be fully fully v v alid Dr. Ha Hari rissh Kak Kakrran ani, i, Purvi Kak Kakrran anii

38

II. ST STABILIT ABILITY Y TESTING FOR PHARMACEUTICAL PHARMACEUT ICAL SUBST SUBSTANCE ANCE 2.5 Testing Frequency For produc products with a propos proposed shel helf l f life of a of at least ast 12 mon months ths, the frequency frequency of of tes testin ting at the long term stora torage condition dition shoul hould normally ormally be be y

y

y

y

y

E ver y ver y three three mon months ths over the firs first y ear, E ver y ver y ssix mon months ths over the second y ear, and and A nnu nnually there ally thereaafter through the propos proposed shel helf l f life.

At the acce accelera erated stora torage condition dition, a min minimum of three time poin points, incl includi udin ng the in initial itial and and final final time poin points (e.g. 0, 3, and and 6 mon months) ths) from a 6-mon 6-month stud y i y is rec recommen ommended. Dr. Ha Hari rissh Kak Kakrran ani, i, Purvi Kak Kakrran anii

39

II. ST STABILIT ABILITY Y TESTING FOR PHARMACEUTICAL PHARMACEUT ICAL SUBST SUBSTANCE ANCE y

When When tes testin ting at the in intermedia termediate stora torage condition dition is called called for as a res ange at the result of s of sign ignifican ificantt change acce accelera erated stora torage condition dition, a min minimum of four four time ng the in and final poin points, incl includi udin initial itial and final time poin points (e.g. y is 0, 6, 9, 12 mon months) ths) from a 12-mon 12-month stud y i rec recommen ommended.


40

II. ST STABILIT ABILITY Y TESTING FOR PHARMACEUTICAL PHARMACEUT ICAL SUBST SUBSTANCE ANCE 2.6 Storage: y

In gen general eral,, a pha pharmac rmaceuti eutical cal produc product shoul hould be ev alu aluated under stora torage conditions ditions (with appropria ppropriate tol toleranc erancees) tha that tes test: y y y

y

Its Its thermal thermal stabil bilit y it y If a If appl pplicab cable, its its sensitivit nsitivit y to y to mois moisture or poten potential tial for sol ven vent loss Photos Photostabil bilit y it y te tesstin ting conduc ducted on on at least ast one prima primar y b y batch of the pha pharmac rmaceuti eutical cal produc product.

Sta Stabil bilit y s y studies tudies conduc ducted on on one ba batch of the pha pharmac rmaceuti eutical cal produc product for up to three mon months ths at 50°C/ambien mbient humidit y humidit y m may be useful eful to iden identif y the y the formula formulatio tion n and and packa packagi gin ng ma material terial adequa dequate for extremely extremely hot hot and and dr y c y conditions ditions.. Dr. Ha Hari rissh Kak Kakrran ani, i, Purvi Kak Kakrran anii

41

II. ST STABILIT ABILITY Y TESTING FOR PHARMACEUTICAL PHARMACEUT ICAL SUBST SUBSTANCE ANCE y

The stora and the lengths torage conditions ditions and gths of s of studies tudies cho hossen

shoul and hould be suffic ufficien ient to cover stora torage, ge, shipmen hipment, and subs clim ubsequen equent use with due rega regard to the cl imaatic tic zon zone(s) e(s) in whic which the produc product is inten tended to be ma marketed. 2.6.1 General case Term

Duration Testing condition

Long ter

12

ont s

Inter ediate

ont s

cceelera cc erated

ont s

25°C 2°C/ 30°C 2°C/ 5 30°C 2°C/ 5 0°C

2°C/75


5 5

or

5 5 42

II. ST STABILIT ABILITY Y TESTING FOR PHARMACEUTICAL PHARMACEUT ICAL SUBST SUBSTANCE ANCE 2.6.2 Pharmaceutical prod roducts packaged in impermeable containers: y

y studies Sta Stabil bilit y s tudies for produc products stored in in impermea impermeable containers any y ccontro lled ers can be condu duccted un under an troll ed or ambie nt humidit y n. mbien humidit y cconditio dition y

Reas Reaso on bein being, Sens Sensitivit itivit y y to to mois moisture or poten potential tial for sol ven vent loss is not a conc ncer ern n for pha pharmac rmaceuti eutical cal produc products packaged ackaged in in impermea impermeable containers ers tha that provide a perman permaneent ba barrier to passa passage ge of mois moisture or sol ven vent.


43

II. ST STABILIT ABILITY Y TESTING FOR PHARMACEUTICAL PHARMACEUT ICAL SUBST SUBSTANCE ANCE 2.6. 3 Pharmaceutical prod roducts packaged in semipermeable containers y

y

ased ackaged in Aqueous-b Aqueous -bas ed produc products packaged in semi-permea emi-permeable containers aluated for poten al water loss ss,, in ers shoul hould be ev alu potenti tial addition ysical, cal, chemical and ddition to ph ysi hemical,, biol biological ogical,, and mic microbiol robiological ogical stabil bilit y . and Other compa omparable approac pproache hess can be devel developed and ased produc reported for non-aqueous queous, sol ven vent-b t-based products. Dr. Ha Hari rissh Kak Kakrran ani, i, Purvi Kak Kakrran anii

44

II. ST STABILIT ABILITY Y TESTING FOR PHARMACEUTICAL PHARMACEUT ICAL SUBST SUBSTANCE ANCE Term

Duration Testing condition

Lon Long term

12 mon months ths 25°C ± 2°C/40% /40% RH ± 5% RH RH or 30°C ± 2°C/35% RH ± 5% RH

Intermedia termediate

6 mon months ths 30°C ± 2°C/35% RH ± 5% RH


than 25% RH 6 months ths 40°C ± 2°C/not more than

y

y

A 5% loss in water from its A 5% its initial itial v alue alue is is considered nsidered a sig ign nifi ifican cantt chan ange ge for a produc product packaged ackaged in in a semi-permea emi-permeable container after an equiv ale alent of three mon months ths stora torage at 40°C/NM /NMT 25% RH. However, for small containers ers (1 ml ml or less) or unit-dos it-dose produc products, a water loss of 5% or more after an equiv ale alent of three mon months ths stora torage at 40°C/NM /NMT 25% RH may may be be appropria ppropriate. Dr. Ha Hari rissh Kak Kakrran ani, i, Purvi Kak Kakrran anii

45

II. ST STABILIT ABILITY Y TESTING FOR PHARMACEUTICAL PHARMACEUT ICAL SUBST SUBSTANCE ANCE nifi cantt chan ange aceuti cal In gen general eral,, sig ign ifican ge for a ph phaarm rmac eutical producct is defin produ defined as: y

y y

y y

A 5% change ange in assay from assay from its its initial itial v alue alue;; or f ailure to meet the accept acceptanc ancee criteria riteria for potency potency whe when n using biol biological ogical or immun immunological ogical proc procedures; edures; A ny degr ny degraadation tion produc product exc exceedin eeding its its accept acceptanc ancee criterion; riterion; Failure to meet the accept acceptanc ancee criteria riteria for appea ppearance, ance, ph ysi ysical attributes ttributes, and and func functio tional nalit it y te y tesst conditions; ditions; and, and, as appropria ppropriate for the dosa dosage ge form: Failure to meet the accept acceptanc ancee criterion riterion for pH; pH; or Failure to meet the accept acceptanc ancee criteria riteria for diss disso olution ution for 12 dosa dosage ge units its. Dr. Ha Hari rissh Kak Kakrran ani, i, Purvi Kak Kakrran anii

46

II. ST STABILIT ABILITY Y TESTING FOR PHARMACEUTICAL PHARMACEUT ICAL SUBST SUBSTANCE ANCE 2.6.4 Pharmaceutical prod roducts intended intended for storage storage in

a refrigerator Term

Duration

Testing conditions

Lon Long term

12 mon months ths

5°C ± 3°C


6 mon months ths

y

25°C ± 2°C/60% /60% RH ± 5% RH RH or 30°C ± 2°C/65% /65% RH RH ± 5% RH RH

ange occ ccur and six If s If sign ignifican ificantt change urss between between three and accelera mon months ths tes testin ting at the acce erated stora torage condition dition, the propos proposed shel helf l f life shoul hould be bas based ed on the real real time da data a v ailab lable from the long term stora torage condition dition. Dr. Ha Hari rissh Kak Kakrran ani, i, Purvi Kak Kakrran anii

47

II. ST STABILIT ABILITY Y TESTING FOR PHARMACEUTICAL PHARMACEUT ICAL SUBST SUBSTANCE ANCE 2.6.5 Pharmaceutical products intended for storage in a

freezer

y

y

Term

Duration

Testing Conditions

Lon Long term

12 mon months ths

- 20°C ± 5°C

For pha pharmac rmaceuti eutical cal produc products inten tended for stora torage in a freezer, the shel helf l f life shoul hould be bas based ed on on the real real time da data obta obtained at the long term stora torage condition dition. In the absenc ncee of an of an acce accelera erated stora torage condition dition, tes testin ting on on a single batch at an elev ated tempera temperature (e.g., 5°C ± 3°C or 25°C ± 2°C or 30°C ± 2°C) for an appropria ppropriate time period conduc ducted to address ddress the effec effect of s of short term exc excurs ursio ions ns outs outside the propos proposed labe labell stora torage condition dition. Dr. Ha Hari rissh Kak Kakrran ani, i, Purvi Kak Kakrran anii

48

II. ST STABILIT ABILITY Y TESTING FOR PHARMACEUTICAL PHARMACEUT ICAL SUBST SUBSTANCE ANCE 2.7 E valuation y

y is If analys If analysiis shows hows tha that the ba batch-to-ba h-to-batch v aria riabil bilit y i small, all, it is antageous is adv ant geous to combin ombine the da data into one overall overall estima timate. y

This his can be don done b y fir y firsst apply pply ing appropria ppropriate statis tistical tical

tes tests. y

nappropriaate to combin If it is is inappropri ombine data from several everal batches hes, the overall overall shel helf l f life shoul hould be bas based ed on the min minimum acceptanc ancee time a batch can be expec expected to rema remain within within accept criteria riteria. Dr. Ha Hari rissh Kak Kakrran ani, i, Purvi Kak Kakrran anii

49

II. ST STABILITY ABILITY TESTING TESTING FOR PHARMACEUTICAL SUBSTANCE 2.8 Statements/Labelling y

ng statemen cable: The foll followi owin tements shoul hould be us used if a if appl pplicab Testing condition where the stability of Recommended the pharmaceutical product has been labelling

shown

condition

For coun ountries tries in Clima imatic tic Zo Zon nes I and and II: 25°C/60% RH (l (long term) term) 30°C/65% RH (in (intermedia termediate) te) 40°C/75% RH (acc (acceelera erated) ted)

Store bel below 30C

for coun ountries tries in Clima imatic tic Zo Zon nes III and and IVA : Store & trans transport port 30°C/65% RH (l (long term) term) bel below 30C 40°C/75% RH (acc (acceelera erated) ted) Dr. Ha Hari rissh Kak Kakrran ani, i, Purvi Kak Kakrran anii

50

II. ST STABILITY ABILITY TESTING TESTING FOR PHARMACEUTICAL SUBSTANCE 2.9 In-use stability y tesstin The purpos purpose of in-us -use stabil bilit y te ting is is to establish  cable  the period of time durin where appl pplicab during whic which a mul multi-dos ti-dose produc product can be used whils whilstt reta retaining accept acceptaable qual y onc ncee the container is open and the qualit it y o opened and firs first dos dose is removed. ast pil scale batches A min minimum of two ba batches hes, at least pilot scale hes, shoul jected to the tes hould be sub je test. y

y

y

y

At least ast one of the ba batches hes shoul hould be cho hossen tow towards rds the end of its its shel helf l f life.

lable, one batch shoul If s If such res results are not a v ailab hould be be y studies tes tested at the final final poin point of the submitted stabil bilit y s tudies. Dr. Ha Hari rissh Kak Kakrran ani, i, Purvi Kak Kakrran anii

51

II. ST STABILITY ABILITY TESTING TESTING FOR PHARMACEUTICAL SUBSTANCE 2.10 Variations Onc ncee the pha pharmac rmaceuti eutical cal produc product has has been been regis registered, additional dditional stabil bilit y s y studies tudies are required when whenever maj major or v aria riations tions are ma made like the foll followi owin ng: ange in the man manuf uf acturi acturin ng proc process; 1. Change ange in the compos omposition ition of the pha pharmac rmaceuti eutical cal 2. Change produc product; 3. Change ange of the th e immedia immediate packagi ackagin ng. y


52

II. ST STABILITY ABILITY TESTING TESTING FOR PHARMACEUTICAL SUBSTANCE 2.11 On-going Stability Studies y

y

al, the stabil y of the pha cal After approv al, bilit y of pharmac rmaceuti eutical accordin ng to a contin produc product shoul hould be mon monitored accordi tinuous uous appropria ppropriate progra programme tha that will will permit the detec detection tion of any any sstabil y issue. ssue. bilit y i y prograamme is The purpos purpose of the on on-goin -going stabil bilit y progr is: y

To mo monitor the produc product over its its shel helf l f life and and

y

determine tha that the produc product rema remains, ns, and and can be expec expected To determin to rema remain, within within spec pecifica ifi catio tions ns under the labe labell lled ed stora torage conditions ditions..


53

II. ST STABILITY ABILITY TESTING TESTING FOR PHARMACEUTICAL SUBSTANCE y

The protoc protocol for an on-goin -going stabil bilit y progr y prograamme shoul hould

exten extend to the en end of the shel helf l f life period the foll followi owin ng parameters meters: y

y

y y y y y y

Number of batch(es) h(es) per stren trength and and differen different ba batch sizes izes, if appl pplicab cable; Rel Relev ant ant ph ysi ysical, cal, chemical hemical,, mic microbiol robiological ogical and and biol biological ogical tes test methods; methods; A ccept cceptanc ancee criteria; riteria; Referenc Referencee to tes test methods; methods; Desc Descriptio ription n of the container clo closure system( system(s); s); Testin ting in interv als als (time poin points); Desc Descriptio ription n of the conditions ditions of s of stora torage Other appl pplicab cable parameters meters spec pecific ific to the pha pharmac rmaceuti eutical cal produc product. Dr. Ha Hari rissh Kak Kakrran ani, i, Purvi Kak Kakrran anii

54

TYPES OF STABILI STABILITY TY STUDIES STUDIES y y y y y y

ccelera y stud y A cce erated stabil bilit y s y stud y Intermedia termediate stabil bilit y s y stud y Lon Long term (real (real time) time) stabil bilit y s y stud y Stress Stress tes testin ting / Short term stabil bilit y s Forc orced degra degradation tion tes testin ting & cycling stabil y stud y Thermal hermal cycli bilit y s


55

TYPES OF STABILITY STABILITY STUDIES- ST STABILITY ABILITY PROFILES y

y

Accelerated stability study Storage condition

Testing condition

Controll trolled ed room tempera temperature: 20-250C

400C and and 75% RH for 6 mon mo nths ths

Refrigera Refrigerated condition dition: 2-80C

250C and and 60% RH for 6 mon mo nths ths

Freezer condition dition: -20 to -100C

50C for 6 mon months ths

Intermediate stability study Storage condition

Testing condition

Controll trolled ed room tempera temperature 20-250C

300C and and 60% RH for 6 mon months ths

Refrigera Refrigerated condition dition 2-80C


Freezer condition dition -20 to -100C



56

TYPES OF ST STABILITY STUDIES- ST STABILITY ABILITY PROFILES y

y

Long term (real time) stability stabilit y study: Storage condition

Testing condition






-200C for 12 mon months ths

Stress testing / short term stability st udy Storage condition

Testing condition


600C and and 75% 75% RH for for 2 days days


400C and and 75% 75% RH for 2 days days


250C and and 60% RH RH for for 2 days days


57

WHO GUIDELINES ON STABILITY OF PHARMACEUTICAL PRODUCTS


58

WHO GUIDELINES GUID ELINES ON STABILITY STABILITY

STUDIES ccelera y tesstin A cce erated stabil bilit y te ting on two ba batches hes shoul hould be be conduc ducted, on one of whic which mu must be either commerc ommercial batch scale batch. or a pil pilotot-scale

y

y

y

al time stabil y tesstin Initially itially re real bilit y te ting shoul hould be conduc ducted on on two ba batches hes for the expec expected shel helf l f life of the produc product, one of whic which shoul hould be commerc ommercial batch. y

y

A pil pilot ba batch shoul hould not be smaller aller than than one eighth of the commerc ommercial batch.

One batch can be a pil pilot scale scale ba batch.

y tesstin Sta Stabil bilit y te ting shoul hould be conduc ducted on on the dosa dosage ge form ackaged in clo system propos packaged in the container cl osure system proposed for marketin eting Dr. Ha Hari rissh Kak Kakrran ani, i, Purvi Kak Kakrran anii

59

WHO GUIDELINES GUIDEL INES ON STABILITY STABILITY

STUDIES y

Sta Stabil bilit y s y studies tudies shoul hould incl include ude tes testin ting of thos those attributes ttributes of the pha pharmac rmaceuti eutical cal produc product th that are susc sceptib eptiblle to change ange durin during stora torage and and are likely to ly to inf luenc uencee qual qualit it y , safet safet y , and and efficacy efficacy . y

y

y

The tes testin ting shoul hould cover, as appropria ppropriate, the ph ys ph ysiical, cal, chemical hemical,,

biol biological ogical and and mic microbiol robiological ogical attributes ttributes, pres preserv ative conten tent (e.g. antioxid antioxidan ant, t, antimi antimiccrobial robial pres preserv ative) tive). A naly naly tical tical proc procedures edures shoul hould be fully fully v v alid alidaated and and stabil bilit y it y indica dicati tin ng

If s If sign ignifican ifi cantt change ange occ ccur urss between between 3 and and 6 mon months ths tes testin ting at the acce accelera erated stora torage condition dition, the propos proposed shel helf-l f-life shoul hould be bas based ed on the real real-time -time da data a v ailab lable from the longterm stora torage condition dition. Dr. Ha Hari rissh Kak Kakrran ani, i, Purvi Kak Kakrran anii

60

GUID ELINES ON STABILITY STABILITY WHO GUIDELINES STUDIES y

y

y

y studies Sta Stabil bilit y s tudies for produc products stored in in impermea impermeable containers any ccontroll ers can be conduc ducted un under any trolled ed or ambien mbient humidit y humidit y ccondition dition. ange occ ccur If n If no sign ignifican ificantt change urss durin during 6 mon month's th's acce accelera and real y tesstin erated and real time stabil bilit y te ting, the produc product will will allowed to plac nal shel be allowed placee in the ma market with a provis provisio ional helflife of up to 24 mon months ths. y tesstin However, However, real real time stabil bilit y te ting shoul hould be contin tinued up to the propos proposed shel helf-l f-life.


61

WHO GUIDELINES GUIDEL INES ON STABILITY STABILITY

STUDIES y

y

ncee the pha cal produc Onc pharmac rmaceuti eutical product has been been regis registered, additional y studies dditional stabil bilit y s tudies are required when whe never ay affec y of the active active v aria riations tions tha that may a ffect the stabil bilit y of cal subs ance or pha cal produc pha pharmac rmaceuti eutical ubstance pharmac rmaceuti eutical product are ajor v aria made, such as major riations tions like the foll follow owiing: y

ange in the man manuf uf acturi acturin ng proc process. ss. Change

y

Change ange in the compos omposition ition of the pha pharmac rmaceuti eutical cal produc product.

y

Change ange of the t he immedia immediate packagi ackagin ng.

The ongoin y prograamme shoul going stabil bilit y progr hould be desc described ribed in in

a written and re written protoc protocol, and results formal formalized ized as a report. Dr. Ha Hari rissh Kak Kakrran ani, i, Purvi Kak Kakrran anii

62

GUID ELINES ON STABILITY STABILITY WHO GUIDELINES STUDIES y

y tesstin Condition dition for real real time stabil bilit y te ting: 30°C ± 2°C/65% RH ±5% RH; RH; condition dition for acce accelera erated stabil bilit y it y te tesstin ting: 40°C ± 2°C/75% /75% RH ± 5% RH RH.. y


63

STABILITY TESTING OF HERBAL DRUGS Dr. Ha Hari rissh Kak Kakrran ani, i, Purvi Kak Kakrran anii

64

INDICATIV INDICA TIVE E SUBST SUBSTANCE ANCE FOR STABI ST ABILIT LITY Y TEST TEST y y

y

Indicative Indicative substance can be termed as biom biomaarker er.. y in the plan Biomarker is a chemical hemical entit y i plantt material terial tha that ay or may n ay not be chemically ned and and serves may or hemically defi defin erves as a characteri acterisstic lant. tic fin fingerprin gerprint of tha that plant. y of in ance: Uti Utilit y of indica dicative tive subs ubstance y

y

A ctive subs ubstance ances are necessar ssar y to y to be ev alu aluated for the shel helf l f life of the formula formulatio tion n. So if the active active constitue nstituen nt is is unknow nknown n, us use of in indica dicative tive subs ubstance ance to ev alu aluate the stabil bilit y l y limits imits.


65

INDICATIV INDICA TIVE E SUBST SUBSTANCE ANCE FOR STABI ST ABILIT LITY Y TEST TEST y

actorss considered nsidered in ances: Factor in selection tion of in indica dicative tive subs ubstance y

Multipl tiplicit y it y of of cconstitue nstituen nts, their qual qualit itaative & quan quantit titaative differenc differencees through the growin growing period & numerous umerous other inf luenc uencees. So the mos most labi labille compoun ompound mus must be cho hossen as indica dicative tive subs ubstance ance. Each Each t y pe pe of prepa preparation tion requires requires its its own own t y pe pe of in indica dicative tive subs ubstance, ance, as its its labi labillit y it y differ differss grea greatly u ly under v arious rious en viron vironmen mental conditions ditions.. y

y

y

A h y grosc groscopi opicc subs ubstance ance woul would not be a suita uitable ma marker for a dr y dr y prep prepaaration tion Dr. Ha Hari rissh Kak Kakrran ani, i, Purvi Kak Kakrran anii

66

INDICATIV INDICA TIVE E SUBST SUBSTANCE ANCE FOR STABI ST ABILIT LITY Y TEST TEST y

Simila Similarrly i ly in case case of s of subs ubstance ances sensitive nsitive to oxida oxidation tion or light, ev alu aluation tion don done in in foll followi owin ng ways ways: y y

y

For any al any alter teraations tions in the formula formulatio tion n durin during stora torage, ev alu aluation tion don done b y : y

y

y

Organ Organo oleptic eptic: Taste, aste, smell mell & appea ppearance. ance. Chemical hemical & ph ysi ysical. cal.

Determina Determinatio tion n of dens densit it y , refrac refractive tive in index, alcoho alcoholl conten tent, in in case cases of l of liquid formula formulatio tions ns TLC compa omparis rison of fres fresh ma material terial with tha that on compl ompletion etion of manuf anuf acture. acture.

Care shoul hould be tak takeen not to in interpret ever y ever y llittl ittle alter alteraation tion

as a serious erious inst nstabil bilit y it y Dr. Ha Hari rissh Kak Kakrran ani, i, Purvi Kak Kakrran anii

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STABILIZATION & STABILITY y

y

cal prepa nsists of Stabilization of a of a pha pharmac rmaceuti eutical preparation tion consi antee its y or stabil meas measure uress tha that gua guarantee its keepin eeping qual qualit it y or bilit y . METHODS OF ST ABILIZA TION OF SOLIDS:

Drying:

1.

Ph ysi ysical, cal, chemical hemical or mic microbial robial contamina minatio tions ns take ake plac placee more eas easiily i ly in liquid prepa preparations tions,, es esp. in aqueous queous medium, than than in dr y dr y produ produccts

y

y

y

So dr y dr y ing of prepa preparations tions & es esp. keepin eeping such prepa preparations tions dr y i y is the simpl implest & bes best method of protec protection tion

Res Residual idual mois moisture conten tent in in the dried extrac extractts is limited to a maximum of 5%; 5%; as extrac extractts are dried more than than this this limit, the y the y re reaadily dily aattrac ttractt wa water from surroun urroundin ding atmos tmosphere.Dr. Ha Hari rissh Kak Kakrran ani, i, Purvi Kak Kakrran anii 68


R ate at whic which the extrac extractts absorbs orbs mois moisture depen depends on ace are its its spe peccifi ificc surf ace reaa. This his means means tha that spray pray dried dried & freeze dried extrac extr actts are nsitive than more sensitive than roll roller er or oven oven dried on ones. This act kept in his f act in min mind whil while grin grindin ding extrac extractts: y

y

y

y

Not don done in in rooms rooms where there is is high atmo tmosspheri phericc humidit y humidit y . A lso lso there shoul hould be no noti oticceable down down w waard temperaature differenc temper differencee from the air in the room to the material terial bein being mill milled, ed, as otherwis otherwise water v apor will will condens densee on the cold extrac extract. t. Dr. Ha Hari rissh Kak Kakrran ani, i, Purvi Kak Kakrran anii

69


y

y

y

cannot be stored over a dr y Large quan quantitie titiess of extrac extractts cannot dr y ing agen large gent, as uneconomically omically la rge quan quantitie titiess of the dr y dr y ing agen gent will will be required to ens e nsure ure an adequa dequate absorption orption cap capacit acit y . ysiical chan ange ccur Ph ys gess rarely rely o occ ur at all under the above men mention tioned conditions ditions.. Chemi cal chan ange ns,, hemical gess, such as enz y matic tic reac reactio tions slow ly wh h y drolys drolysiis, oxida oxidations tions , proc proceed extremely extremely sl owly wheen stora lace protec torage in a coo ooll place protected from light, as well as adequa anteed. dequate dr y dr y ing, are gua guaranteed. Entr En y of y the choic tr y of ox y gen gen mus must be res restric tricted b y the hoice of suita acking ma uitable packi materials terials.. Dr. Ha Hari rissh Kak Kakrran ani, i, Purvi Kak Kakrran anii

70


y

y of pack Impermea Impermeabil bilit y of packiing ma material terial to ox y gen gen shoul hould be check acking ma syntheticc (plas c) hecked ed if this this packi material terial is a syntheti (plasti tic) subs ance. ubstance. cases: In extreme case y

y

y

y

Materi Material al mus must be v acuum acuum pack packed ed Seal Sealed ed un under an inert gas gas..

Microbial alteraations cation n of the robial alter tions,, i.e. gen generally erally mu mulltipl tiplicatio acteriaa pres bacteri present in the produc product, is depen dependen dent on res residual idual mois moisture conten tent in the produc product. METHODS OF ST ABILIZA TION OF LIQUID PR EPARA TIONS: y

A lterna ternative tive proc processe sses proc proceed more ra rapidly pidly iin liquid ph y topha topharmac rmaceuti eutical cal prepa preparations tions than than in dr y dr y o ones. Dr. Ha Hari rissh Kak Kakrran ani, i, Purvi Kak Kakrran anii

71


followi owin ng alter alteraations tions are rela relative tively ly eeasy to asy to rec recogn ognize: The foll Ph ysi ysical alter alteraations tions such as forma formation tion of s of sedimen ediments, color change angess, etc etc. A ltera terations tions due to mic microbial robial growth, rec recogn ogniza izable b y the y the forma formation tion of pell pelliicle cle of moul mould, cloudi cloudin ness or a sedimen ediment whic which can be easi asily di ly dissturbed. Chemical hemical alter alteraations tions,, when when thes these can be detec detected organ organo oleptically eptically b y s y smell mell,, tas taste te or appea ppearance. ance. hemical alter alteraations tions such as h y droly droly tic tic dec decompos omposition ition, Chemical racemiz acemizaation tion, oxida oxidation tion, etc etc., detec detected with diffic difficult y i.e. y i.e. with analy tical tical appa pparatus tus & agen gents. y

y

y

y

y

Preven Prevention tion of mic microbial robial growth in in liquid formula formulatio tions ns b y dieth ylp ylp y roca rocarbo rbon nic ester prohibited, as this this subs ubstance ance may may poss possib ibly ly form form car carcinogen ogenic urethan urethanees with free amin mino acid acidss or amin mines in the subs ubstra trate. Dr. Ha Hari rissh Kak Kakrran ani, i, Purvi Kak Kakrran anii

72

PARAMETERS FOR EVALUATION OF STABILITY y y y y y y y y

y

Appea Appearance ance, Colour, Odour, Taste aste Particl rticlee size, Fl Flowa owabil bilit y , Vi Visc sco osit y it y , Clarit larit y , pH Moi oissture conten tent Sedimen Sedimentation tion, Fl Flocc ccu ulatio lation n Emuls mulsio ion n breaka breakage ge Fria Friabil bilit y it y , Ha Hardn rdness Extrac xtractive tive V alue aluess ( in in selected sol ven vents) Vo V olati latille ma matter conten tents, Free f att y ac y acid idss/ acidit acidit y y , Peroxide v alue aluess Microbial robial parameters meters y y y

y

Total otal via viable coun ount (TPC)

Y east ast and and moul mould coun ount ( YMC) Coi oill form coun ount and and other pa pathogens thogens

Spec Specific ifi c parameters meters appl pplicab cable to formula formulatio tion n / dosa dosage ge form Dr. Ha Hari rissh Kak Kakrran ani, i, Purvi Kak Kakrran anii

73

VALIDATION OF ANALYTICAL PROCEDURES y

nsidered in alidaation V arious rious parameters meters considered in v alid tion of analy of analy tical tical proc procedures edures can be expla explaiined through foll foll.. parameters meters: Purit y of y of rea reagen gents, referenc referencee subs ubstance ances, sol ven vents, etc etc. Rea Reagen gents, referenc referencee subs ubstance ance & sol ven vents are required for iden identit y te y tesstin ting & later later quan quantit titaative analysi analysis. Their purit y purit y mus must be spec pecified or gua guaranteed anteed b y 2 y 2 in indepen dependen dent analysi analysis methods methods e.g. GC-MS & NM NMR. VALIDA TION PARA ME METERS: y

y

1.

Identity testing: In order to be certa ertain in, for for exa exampl mple, TLC, th and corres that a certa ertain band orrespon ponds to a defin defined ance, the dis ances migra referenc referencee subs ubstance, distance migrated on on chroma y are compa hromatogra tograph y a ompared with eac each h other. Dr. Ha Hari rissh Kak Kakrran ani, i, Purvi Kak Kakrran anii

74

VALIDATION OF ANALYTICAL PROCEDURES A cchroma hromatogra tographic phic method can only 2. Specificity : A active subs ance spec determin determine an active ubstance pecifically ifically if if the chroma system selectively active hromatogra tographic phic system tively ssepa eparates tes the active subs ance from impurities ubstance impurities, degra degradation tion produc products & exc excipien ipients. asis of any analy tical of any analy tical method is is a 3. Linearity : The basi nal rela nship nceentra func functio tional relatio tions hip between between the conc tration tion of a of a subs ance & the meas alue. Ideally ubstance measured ured v alue. Ideally there there shoul hould be a linear calibr calibraation asses through the tion curve whic which passe origin origin whe when tes tested gra graphically phically . nsitivit y de y desc scribe y of an an ribess the abil bilit y of 4. Sensitivity : The sensitivit analysi analysis method to reac angess in the subs ances reactt to change ubstance nceentra (e.g. conc tration) tion).. Dr. Ha Hari rissh Kak Kakrran ani, i, Purvi Kak Kakrran anii

75

VALIDATION OF ANALYTICAL PROCEDURES n of an precisio ion of an analy tical tical method is is 5. Precision: The prec y the coeffic given given b y the oefficien ient of v aria riation tion of the method. This his y of aa determina n is a meas measure ure of the repea repeatibil tibilit y of determinatio tion nstrucctions method for fo r whi whicch exac exactt methodol methodological ogical instru tions are a v ailab lable. 6. Trueness: The truen analysis is determin trueness of an of an analysi determined b y systemaatic the system tic errors errors in vol vol ved. ved. The truen trueness can be y the agreemen analysis defin defined b y the greement of the meas measured ured analysi alue with the ac al v alue alue. v alue actu tual


76

stability Testing of Natural Products_2003

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