FOUR LEVELS OF IVIVC AND THEIR EFFECTIVE IMPLEMENTATION TO DEVELOP QUALITY DRUGS

Dr. Bhaswat S. ChakrabortySr. VP & Chair, R&D Core Committee

Cadila Pharmaceuticals Ltd.Former Senior Clinical Reviewer, TPD (Canadian FDA)

Presented at the IVIVC & BABE SUMMIT 2015Holiday Inn, Mumbai, Nov. 23, 2015

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CONTENT GUIDELINES LEVEL A

Correlation of the entire in vitro and in-vivo profiles pertaining to regulatory relevance

LEVEL B The principles of statistical moment analysis

LEVEL C One or more PK parameters correlated with amount of drug

dissolved at several time point of dissolution profile LEVEL D

Semi quantitative; rank order correlation Case study

Conclusion 2

UNDERSTANDING CORRELATION Correlation:

Strength of associative relationship between two variables Broad class of statistical relationships involving dependence

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4Four sets of data with the same correlation of 0.816

DEFINITION OF IVIVC IVIVC is the predictive, mathematical models

relating an in-vitro property such as dissolution and an in-vivo response, e.g., amount of drug absorbed, thus allowing an evaluation of the QC specifications, change in process, site, formulation and application for a biowaiver etc. –US FDA

Establishment of a rational relationship between a biological property, or a parameter derived from a biological property produced by a dosage form, and a physicochemical property or characteristic of the same dosage form. – USP

5Valid in-vitro and in-vivo methods valid IVIVC

BIOPHARMACEUTICS CLASSIFICATION SYSTEM (BCS) & IVIVC EXPECTATIONS

Amidon et al. (1995), Pharm Res, 12, 413-420

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SYSTEMIC DRUG ABSORPTION: CARBAMAZEPINE CR 15N STABLE ISOTOPE STUDY

Wilding et al. Br J Clin Pharmac (1991), 32, 573-579

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CUMULATIVE IN-VIVO ABSORPTION OF CBZ FROM THE OROS SYSTEM IN INDIVIDUAL SUBJECTS COMPARED WITH CUMULATIVE IN VITRO RELEASE

Wilding et al. Br J Clin Pharmac (1991), 32, 573-579

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BCS Class PK Data IVIVR

API –Physicochemi-cal Properties

Scale factor

Dosage Form Properties

BioreleventDissolution

Computer Modeling Using Convolution including Transporters, PK Models, and PK Parameters, API properties or Drug Release Data

IVIVC

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GENERAL APPROACH TO DEVELOP IVIVC

Wang et al (2009) Diss Tech, 8, 6-12

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IVIVC CORRELATION LEVELS1. Level A: highest level; point to point relationship

between in-vitro dissolution rate and in-vivo input rate of the drug from the dosage form

2. Level B: uses statistical moments; MDTvitro of the product is compared to either MRT or MDTvivo

3. Level C: one dissolution time point (t50%, t90%..) is compared to one mean PK parameter (AUC, tmax or Cmax)

4. Multiple Level C: relates one or several PK parameters (AUC, Cmax ..) to the amount of drug dissolved in-vitro at several time points

5. Level D: is a rank order and qualitative analysis. 10

LEVEL A: POINT TO POINT CORRELATION % Drug absorbed calculated by means of model

dependent techniques such as Wagner-Nelson or Loo-Riegelman or by model-independent deconvolution

These techniques utilize all of the dissolution and plasma level data

Purpose of Level A corr. is to define a direct relationship such that measurement of in-vitro dissolution rate is a surrogate for in-vivo performance change in manufacturing site, method of manufacture, raw

material supplies, minor formulation modification, product strength using the same formulation can be justified

excellent quality control procedure since it is predictive of the dosage form’s in-vivo performance

Of highest regulatory value 11

Sakore S.and Chakraborty B. (2011). J Bioequiv Availab, S3: 1-12.

LEVEL B: UTILIZING STATISTICAL MOVEMENT As mentioned above, it uses statistical

moments; MDTvitro of the product is compared to either MRT or MDTvivo

Level B correlation uses entire in-vitro & in-vivo data, yet it is not a point-to-point corr., since number of different in-vivo curves will produce similar MRT values

A level B correlation does not uniquely reflect the actual in-vivo plasma level curves

Alone is not enough to justify SUPAC, biowaiver etc. 12

Sakore S.and Chakraborty B. (2011). J Bioequiv Availab, S3: 1-12.

LEVEL C: ONE DISSOLUTION PT. TO ONE PK PARAMETER Level C relates one dissolution time point (t50%,

t90%, etc.) to one mean PK param. e.g., AUC, tmax or Cmax

This is a weak level of correlation as only partial relationship between absorption and dissolution

Does not reflect the complete shape plasma-conc. time curve, defining performance of a drug in-vivo

In the early stages of formulation development Level C correlations can be useful when pilot formulations are being selected

Biowaiver is generally not possible 13

Sakore S.and Chakraborty B. (2011). J Bioequiv Availab, S3: 1-12.

MULTIPLE LEVEL C Relationship between Cmax, AUC, or any PK

parameters and amount of drug dissolved at several time points of dissolution profile

It may be used to justify a biowaivers provided that the correlation has been established over the entire dissolution profile with one or more PK parameters

Multiple Level C correlation should be based on at least three dissolution time points covering the early, middle, and late stages of the dissolution profile

Level A is sometimes likely when multiple level C is achieved at each time point at the same parameter

thus effect on the in-vivo performance of any change in dissolution can be assessed

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Sakore S.and Chakraborty B. (2011). J Bioequiv Availab, S3: 1-12.

LEVEL D: RANK ORDER & QUALITATIVE It is not a formal correlation but it is a semi

quantitative (qualitative analysis) and rank order correlation

Not considered useful for regulatory purpose but can be serves as an aid in the development of a formulation or processing procedure

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Sakore S.and Chakraborty B. (2011). J Bioequiv Availab, S3: 1-12.

Level A – point-point; first deconvolution to get in-vivo %drug absorbed, then compare with %dissolved

Level B – Statistical moments; MRT or MDT in-vivo vs. MDT in vitro

Level C – single point; PK parameter vs. %dissolved

Level A

Level B

Level ALevel C

Malinowski and Marroum, Encyclopedia of Contr. Drug Deliv.

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OVERALL IVIVC DEVELOPMENT FOR MR FORMULATIONS

For Market

Retig et al. Diss Tech, Feb. 2008, 6-8

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CASE STUDY TO DEVELOP A LEVEL A CORRELATION

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THE PRODUCT A new type of prolonged release Hydrocodone

formulation based on Egalet® technology Three tablet GMP batches (A to C) developed, all

containing 20mg of Hydrocodone as tartrate salt. They differed solely by the mass of the final tablet,

corresponding to different diameters and lengths of the tablet (6, 7.5 or 9 mm, respectively) and adjusted by an increase of excipients’ mass

An IR tablet of 10 mg of Hydrocodone in combination with 325 mg of Paracetamol was also included in the clinical study as a reference and in order to perform deconvolution

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Hemmingsen PH et al.(2011). Pharmaceutics,3:73-87

DISSOLUTION STUDIES Pharmacopoeial media: phosphate buffer pH 6.8; USP

Apparatus 2 paddle method (Vankel VK7025 coupled to a Varian Cary 50 UV-visible spectrophotometer); dissolution vol: 1,000 mL; paddle speed: 50 rpm: temp.: 37 °C.

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Hemmingsen PH et al.(2011). Pharmaceutics,3:73-87

IN-VIVO BIOAVAILABILITY STUDIES 4-arm, single dose, randomized cross-over study comparing

three test tablets to the reference Plasma samples (0 - 42 hr) were measured by a validated

HPLC-MS method Cmax, Tmax & AUC were calculated, bioequivalence parameters

under consideration were Cmax and AUC Tmax was not analyzed as prolonged release formulation is involved

Absorption kinetics were calculated using a deconvolution technique using the IR reference tablet as response function Deconvolution allows isolating the input (« absorption ») function

as a function of the observed concentration for the studied tablet and for the IR reference tablet

This input function reflected the in-vivo release observed after administration of the PR test tablets

Simulations of the curves from the theoretic input were performed using convolution 21

Hemmingsen PH et al.(2011). Pharmaceutics,3:73-87

IN-VIVO BIOAVAILABILITY STUDIES

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Hemmingsen PH et al.(2011). Pharmaceutics,3:73-87

IN-VIVO RELEASE & ABSORPTION OF 3 TABLETS

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Hemmingsen PH et al.(2011). Pharmaceutics,3:73-87

IVIVC The clinical study was designed to support a level A

correlation In a linear correlation, the in-vitro dissolution and in-vivo

input curves may be directly super-imposable or may be made to be super-imposable by the use of a scaling factor e.g., if the dissolution is faster than the in vivo input rate then the

two curves are not super-imposable in this case a time scaling may be applied on the in vitro data for

each %absorbed, the corresponding time in-vitro using a Levy’s plot

Model predictability was estimated internally by comparison of prediction errors on Cmax & AUC derived from mean observed and predicted in vivo data obtained by convolution

Regulatory guidelines state prediction errors for Cmax and AUC should not exceed 10 % as a mean and none greater than 15%

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DISSOLUTION VS. IN-VIVO ABSORPTION

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TIME SCALING: LEVY’S PLOT

Hemmingsen PH et al.(2011).

Pharmaceutics,3:73-87

IVIVC OF ALL FORMULATIONS USING A COMMON NON-LINEAR TIME SCALE

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Hemmingsen PH et al.(2011). Pharmaceutics,3:73-87

PREDICTABILITY BASED ON AUC AND CMAX

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Based on IVIVC & in vitro data, input kinetics were back calculated and then, based on this input function, a convolution was performed to simulate the in vivo plasma concentration curveThe predictability was good and in accordance with the FDA recommendation (5) with a mean error of −0.32% and −6.63% on Cmax and AUCinf, respectively, no case being greater than +10%

Hemmingsen PH et al.(2011). Pharmaceutics,3:73-87

CALCULATION OF DISSOLUTION LIMITSOne application of IVIVC is to predict bioavailability and to set dissolution limits. The residual error from ANOVA for Cmax and AUC and modelized absorption to a multi zero order absorption and a few more steps dissolution limits for bioequivalence.

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IN-VIVO PREDICTION OF FORMULATION B TO ENSURE BIOEQUIVALENCEBased on the dissolution limits and on the modelization of the absorption, the in-vivo curves were simulated in three conditions corresponding to the modelized absorption

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Hemmingsen PH et al.(2011). Pharmaceutics,3:73-87

CONCLUSIONS Biorelevant and reliable dissolution profiles can predict the in-

vivo absorption of drugs from CR formulations Batches with similar dissolution will be BE and dissimilar

dissolution will be non-BE Level A (point-to-point) is most useful for regulatory

purposes; multiple level C is also acceptable for regulatory purposes

At least 3 lots (desirable, fast and slow) must be established with IVIVC and proper reference

Time scaling and modeling of in-vitro & in-vivo parameters must be accurate and validated

Predictability should be high IVIVC is useful in

QbD, SUPAC and biowaivers…30

Thank You Very MuchAcknowledge: Raji Nair

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