In-Vitro-In-Vivo Correlation Definitions and …

1 International Journal of Generic Drugs e-* International Journal of Generic Drugs e-* 0793 758X US/ CanadaISSN 0793 7776 Euro ISSN 0793 7849 Pacific RimIn- vitro -In- vivo Correlation DefinitionsandRegulatory GuidanceNattee Sirisuth and Natalie D. Eddington1,2*1 Pharmacokinetics Biopharmaceutics Laboratory2 Department of Pharmaceutical Sciences Schoolof Pharmacy, University of Maryland atBaltimore 100 Penn Street, AHB Baltimore, MD21201-6808 (410) (Fax) 706-6710 (410) 706-6580 purpose of this report is to presentdefinitions of the various levels of invitro in vivo correlations (IVIVCs)

2 And toprovide a regulatory perspective on itsutility in product development importance of a representativedissolution testing method thataccurately describes the in vivo releaserate is discussed in the context ofdeveloping a predictive role of the dissolution testingmethod in IVIVC development andvalidation is to serve as a surrogatemeasure of the rate and extent of addition, the BiopharmaceuticalClassification System provides ascience-based guidance on solubilityand permeability drug issues, which areindicators of predictive valid IVIVC will allow for dissolutiontesting for subsequent formulationchanges which take place as a functionof product optimization without the needfor additional bioavailability /bioequivalency development andoptimization is an ongoing process inthe design.

3 Manufacturer and marketingof any therapeutic on the design and deliverygoals of a particular dosage form, thisprocess of formulation development andoptimization may require a significantamount of time as well as optimization may requirealtering formulation composition,manufacturing, equipment and batchsizes. In the past when these types ofchanges are applied to a formulation,bioavailability studies would also haveto be performed in many instances toensure that the new formulationdisplayed statistically similar in-vivobehavior as the old course this requirement delayed themarketing of the new formulation andadded time and cost to the process offormulation a regulatory guidance wasdeveloped to minimize the need foradditional bioavailability studies as partof the formulation guidance referred to as the.

4 InVitro/In vivo Correlation Guidance wasdeveloped by the Food and DrugAdministration and was based onscientifically sound research.(1) International Journal of Generic Drugs e-* International Journal of Generic Drugs e-* 0793 758X US/ CanadaISSN 0793 7776 Euro ISSN 0793 7849 Pacific RimIt states that the main objective ofdeveloping and evaluating an IVIVC isto enable the dissolution test to serve asa surrogate for in vivo bioavailabilitystudies (Figure 1).This may reduce the number ofbioequivalence studies required forapproval as well as during scale-up andpost-approval changes.

5 (2) definition of In vitro -In-VivoCorrelationsAn In- vitro in- vivo Correlation (IVIVC)has been defined by the Food and DrugAdministration (FDA) as a predictivemathematical model describing therelationship between an in- vitro propertyof a dosage form and an in-vivoresponse .1 Generally, the in- vitro property is therate or extent of drug dissolution orrelease while the in- vivo response is theplasma drug concentration or amount ofdrug United States Pharmacopoeia(USP) also defines IVIVC as theestablishment of a relationship betweena biological property, or a parameterderived from a biological propertyproduced from a dosage form, and aphysicochemical property of the samedosage form.

6 (3)Typically, the parameter derived fromthe biological property is AUC or Cmax,while the physicochemical property isthe in vitro dissolution linear relationship with slope of unity,if possible, is preferred, as thedissolution profile is a representative ofthe absorption profile.(1,3)Figure 2 presents a linear correlationbetween Cmax and the percentdissolved in 15 minutes for animmediate release dosage , IVIVCs are basicallymathematical relationships, non-linearcorrelations may also be plays an important role in productdevelopment in that it:- first, serves as a surrogate of in vivoand assists in supporting biowaivers; second, supports and / or validatesthe use of dissolution methods andspecifications.

7 And Thirdly, assists in quality controlduring manufacturing and selectingappropriate formulations (1,4).The first and main role of establishingIVIVC is to use dissolution test as asurrogate for human benefit of this is to minimize thenumber of bioequivalence studiesperformed during the initial approvalprocess and during the scaling-up andpost-approval changes (1).Additional advantages of an IVIVC is toassist in validating or setting dissolutionspecifications. This is because theIVIVC includes in- vivo relevance to in- vitro dissolution specification.

8 In otherwords, dissolution specifications are setbased on the performance of thebiobatch general dissolution time pointspecification is 10% deviation from themean dissolution profile obtained fromthe biobatch (1).Bioequivalency between formulationswould be expected if the formulation(s)fall within the upper and lower limits ofthe specification setting basedon an IVIVC can also be used as aquality control for product , this quality control maysometimes be more rigorous than theusual control standard since it dependson the product use of IVIVC, however, is limited toa certain drug product.

9 It can be usedonly on that particular International Journal of Generic Drugs e-* International Journal of Generic Drugs e-* 0793 758X US/ CanadaISSN 0793 7776 Euro ISSN 0793 7849 Pacific RimThe IVIVC cannot be used across theproducts, especially drug product withdifferent release mechanisms (1,5).This premise has been recentlyinvestigated in our laboratory. In thiswork, two major types of oral extendedrelease dosage forms were compared: coated pellets filled in a gelatincapsule and a hydrophilic matrix tablet formulation wasmanufactured under separateinvestigations using fluid active compound, metoprololtartrate, was blended with the releaserate-controlling polymer (hydroxypropylmethylcellulose) and with otherexcipients, such as a filler (lactose anddicalcium phosphate), a binder(hydroxypropylmethylcellulose) and alubricant (magnesium stearate).

10 The granules were then compressedinto a tablet. A Correlation developedwith the hydroxypropyl methylcellulosesystem and was applied to predictingthe in vivo behavior of the multi-particulate gelatin IVIVC was predictive of the extentof absorption. Prediction errorsassociated with AUC were found to beless than 10 , the IVIVC was unable toaccurately estimate the rate of drugabsorption, Cmax. Prediction errorswere found to be greater than 20 %.These results support the contentionthat IVIVCs are product specific. IVIVCis usually developed when drugdissolution is a rate-limiting step for thein vivo absorption and consequently thebioavailability of an oral solid dosageform depends on two main processes.