STABILITY TESTING Photostability - IAGIM

1 International Journal of Generic DrugsInternational Journal273of Generic DrugsISSN 0793 694X US/Canada ISSN 0793 7784 EuroISSN 0793 7822 Pacific RimSTABILITY TESTINGP hotostabilityin New Drug Products ..evaluating Photostability is foremost for new chemical entities only - notin generic drugs, provided the container-closure protection is the 'INTRODUCTIONn June 1998 the FDA issued forcomment, a lengthy 110 page draftguidance titled ' STABILITY TESTING ofDrug Substance and DrugProducts' The STABILITY guidanceinterweaves the requirements of NDAsand ANDAs for both drug substanceand drug product and borrows heavilyfrom the European Guidelinesdo not readily affectGeneric DevelopmentThe New Draft Guidance to industry isextremely comprehensive and isintended to replace the ageing 1987guidelines, thus harmonising therequirements for US.

2 EU and JapanThey contain detailedrecommendations on all currentaspects of STABILITY TESTING , Photostability , including reducedtesting procedures via the use ofbracketing and matrixing Part III article deals with theproposed guidance namely aspectsaffecting the Photostability stabilitytesting in New Drug ApplicationsPhotostability Draft Guidelines do notreadily affect generic developmentproviding that the packagingconfiguration and protection againstlight is equal or better than thereference and one of the twostandardized caution phrases'PROTECT FROM LIGHT' appears onthe package ICH Harmonized TripartiteGuideline on STABILITY TESTING ofNew Drug Substances andProducts (hereafter referred to as)

3 Theparent guidance) notes that lighttesting should be an integral part ofstress ICH Q1B guidance Photo- STABILITY TESTING of New DrugSubstances and Products primarilyaddresses the generation ofphotostability information for newmolecular entities and associated drugproducts and the use of the data indetermining whether precautionarymeasures in manufacturing, labeling,or packaging are needed to mitigateexposure to Developersshould at leastbe aware of theDraft PhotostabilityGuidelinesQ1B does not specifically addressother Photostability studies that maybe needed to support, for example,the Photostability of a product underin-use conditions or the photostabilityof analytical Journal of Generic DrugsInternational Journal274of Generic DrugsISSN 0793 694X US/Canada ISSN 0793 7784 EuroISSN 0793 7822 Pacific RimBecause data are generated on adirectly exposed drug substance aloneand/or in simple solutions and drugproducts when studies are conductedas described in the Q1B guidance.

4 Knowledge of photostabilitycharacteristics may be useful indetermining when additional studiesmay be needed or in providingjustification for not performingadditional Developersshould check thereference drug'slabelling and literaturefor photo-instabilityFor example, if a product has beendetermined to photodegrade upondirect exposure but is adequatelyprotected by packaging, an in-usestudy may be needed to support theuse of the product ( , a parenteraldrug that is infused over a period oftime).The test conditions for in-use studieswill vary depending on the productand use but should depend on andrelate to the directions for use of theparticular studies are usuallyconducted only in conjunction with thefirst approval of a new some circumstances, Photostability studies should berepeated if certain post-approval orsupplemental changes, such aschanges in formulation or packaging,are made to the product, or if a newdosage form is these studies should berepeated depends on thephotostability characteristicsdetermined at the time of initial filingand the type of changes example.

5 If initial studiesdemonstrate that an active moiety in asimple solution degrades uponexposure to light and the tablet drugproduct is stable, a subsequent filingrequesting approval of a liquid dosageform may warrant additional studies tocharacterize the photostabilitycharacteristics of the new stress testingis part ofthe stress testingin ANY STABILITY indicatingassay developmentPhotostability studies need not beconducted for products that duplicatea commercially available listed drugproduct provided that the packaging(immediate container/closure andmarket pack) and labeling storagestatements regarding light duplicatethose of the reference listed deviations in packaging or labelingstatements are made, additionalstudies may be decision as to whether additionalstudies should be conducted will bemade on a case-by-case basis by theagencies chemistry review intrinsic photostabilitycharacteristics of new drugsubstances and products should beevaluated to demonstrate that, asappropriate, light exposure does notresult in unacceptable , Photostability TESTING iscarried out on a single batch ofmaterial selected as described in thesection Selection of Batches.

6 In theparent some circumstances, thesestudies should be repeated if certainvariations and changes are made toInternational Journal of Generic DrugsInternational Journal275of Generic DrugsISSN 0793 694X US/Canada ISSN 0793 7784 EuroISSN 0793 7822 Pacific Rimthe product ( , formulation,packaging).Whether these studies should berepeated depends on the photo- STABILITY characteristics determined atthe time of initial filing and the type ofvariation and / or change made. [ICHQ1B] Stages forLight Stress TESTING exist::Exposed Active materialDrug Product - outside packDrug Product - in Primary PackDrug Product - Final Marketing PackA systematic approach to photo- STABILITY TESTING is recommendedcovering, as appropriate, studies suchas: (See flow chart attached.)

7 Nn Tests on the drug substance;nn Tests on the exposed drug productoutside of the immediate pack; and ifnecessary,nn Tests on the drug product in theimmediate pack; and if necessary,nn Tests on the drug product in themarketing pack (with secondary cartonand label - where required). [ICH Q1B]The extent of drug product testingshould be established by assessingwhether or not acceptable change hasoccurred at the end of the lightexposure TESTING as described in theDecision Flow Chart forPhotostability TESTING of DrugProducts. Acceptable change ischange within limits justified by theapplicant. [ICH Q1B]The formal labeling requirements forphotolabile drug substances and drugproducts are established by national /regional requirements.

8 [ICH Q1B]LIGHT SOURCESThe light sources described belowmay be used for Photostability applicant should either maintainan appropriate control of temperatureto minimize the effect of localizedtemperature changes or include a darkcontrol in the same environmentunless otherwise both options 1 and 2, apharmaceutical manufacturer /applicant can rely on the spectraldistribution specification of the lightsource manufacturer. [ICH Q1B]Standard Light Sourcesfor light chambersare set with controlledexposure temperaturesOption 1 Any light source that is designed toproduce an output similar to the D65 /ID65 emission standard such as anartificial daylight fluorescent lampcombining visible and ultraviolet (UV)outputs, xenon, or metal halide is the internationally recognizedstandard for outdoor daylight asdefined in ISO 10977 (1993).

9 ID65 is the equivalent indoor indirectdaylight a light source emitting significantradiation below 320 nanometers (nm),an appropriate filter(s) may be fitted toeliminate such radiation. [ICHQ1B]Option 2 For option 2 the same sample shouldbe exposed to both the cool whitefluorescent and near ultraviolet A cool white fluorescent lampdesigned to produce an output similarto that specified in ISO10977 (1993);and;nn A near UV fluorescent lamp havinga spectral distribution from 320 nm to400 nm with a maximum energyInternational Journal of Generic DrugsInternational Journal276of Generic DrugsISSN 0793 694X US/Canada ISSN 0793 7784 EuroISSN 0793 7822 Pacific Rimemission between 350 nm and 370nm; a significant proportion of UVshould be in both bands of 320 to 360nm and 360 to 400 nm.

10 [ICH Q1B]PROCEDURE [ICH Q1B]For confirmatory studies, samplesshould be exposed to light providingan overall illumination of not less million lux hours and an integratednear ultraviolet energy of not less than200 watt hours/square meter to allowdirect comparisons to be madebetween the drug substance and may be exposed side-by-side with a validated chemicalactinometric system to ensure thespecified light exposure is obtained, orfor the appropriate duration of timewhen conditions have been monitoredusing calibrated example of an actinometricprocedure is protected samples ( , wrapped inaluminum foil) are used as darkcontrols to evaluate the contribution ofthermally induced change to the totalobserved change, these should beplaced alongside the authenticsample.