INTRODUCTION:

Formulation development and optimization ongoing process in the design, manufacture and marketing of any therapeutic agent. Depending on the design and delivery goals of a particular dosage form, this process of formulation development and optimization may require a significant amount of time as well as financial investment. Formulation optimization may require altering formulation composition, manufacturing, equipment and batch sizes. In the past when these types of changes are applied to a formulation, bioavailability studies would also have to be performed in many instances to ensure that the ‘new’ formulation displayed statistically similar in vivo behavior as the old formulation. This requirement delayed the marketing of the new formulation and added time and cost to the process of formulation optimization.

Recently a ‘Biopharmaceutical classification system’ was proposed by USFDA in 1996 to minimize the need for additional bioavailability studies as a part of the formulation design and was based on scientifically sound research. It provide a science based guidance on solubility and permeability drug issue, which are indicator of predictive IVIVC (in vivo iv vitro correlation) allows dissolution testing for subsequent formulation changes which takes places as a function of product optimization

without the need for additional bioavailability/ bioequivalence studies.

The purpose of this report is to provide a regulatory perspective of valid IVIVC in product development and optimization. It is a document in support of an oral extended release(ER) drug product for submission in a New Drug Application (NDA), Abbreviated New Drug Application (ANDA) or Antibiotic Drug Application.(ADA) and also as a surrogate for in vivo bioequivalence during the initial approval process or because of certain pre or post approval changes. (eg. Formulation, equipment, process and manufacturing site changes) .

IVIVC BASICS AND DEFINITIONS:

IVIVC simply means a mathematical model that can describe the relationship between in vitro and in vivo properties of a drug product, so that in vivo properties can be predicted from its in vitro behavior.

According to FDA, “IVIVC is a predictive mathematical model describing relationship between in vitro properties of dosage form and relevant in vivo response. Generally the in vitro property is rate or extent of drug dissolution or release while in vivo response is the plasma drug concentration or amount absorbed^1’2.”

The United States Pharmacopoeia (USP) also defines IVIVC as “the establishment of a relationship between a biological property, or a parameter derived from a biological property produced from a dosage form, and physicochemical property of the same dosage form”.³

Categories of in Vitro/In Vivo Correlation:

Five categories of correlation found in FDA guidelines. Each level denotes its ability to predict in vivo response of dosage form from its in vitro property. Higher the level better is the correlation¹.

1. Level A correlation.

2. Level B correlation.

3. Level C correlation.

4. Multiple level C correlation.

5. Level D correlation.

FIGURE-1

1. Level A correlation:

It represents the relationship between in vitro dissolution and in vivo in put rate (in vivo absorption of drug from dosage form)^1.A hypothetical level A model showing relationship between fraction absorbed and fraction dissolved, is shown in Figure 1

For developing correlation between two parameters one variable should be common between them. Here data available is in vitro dissolution profile and in vivo plasma drug concentration profile. As shown in Figure, no direct comparison is possible¹. To have comparison between these two data, data transformation is required As shown in figure4, data transformation makes the comparison possible.

The in vitro properties like percent drug dissolved or fraction of drug dissolved can be used while in vivo properties like percent drug absorbed or fraction of drug absorbed can be used respectively. Level A IVIVC is considered as predictive model for relationship between the entire in vitro release time course and entire in vivo response time course⁴.

2. Level B correlation:

In this level of correlation Figure No. 2, the mean in vitro dissolution time (MDT in vitro) is compared with either the mean in vivo residence time (MRT in vivo) or mean in vivo dissolution time (MDT in vivo) derived by using principle of statistical moment analysis.¹

Even though it utilizes all in vitro and in vivo data, it is not considered as point-to-point correlation, since number of in vivo curves can produce similar residence time value. Hence this correlation becomes least useful for regulatory purposes.¹

When in vitro curve and in vivo curve are super-imposable the relationship is called as 1:1 relationship. But if scaling factor is required to make curve super-imposable the relationship is called as point-to-point relationship⁵.

FIGURE-2

All data with every point from both in vitro and in vivo curve is utilized for development of correlation, therefore it becomes more meaningful than any other type of correlation and very useful from regulatory perspective¹. It is the highest level of correlation and most preferred to achieve, since this allows biowaiver for changes in manufacturing site, raw material suppliers, and minor changes in formulation^1,5.

3. Level C correlation Fig-3:

It is a single point correlation that is established in between one dissolution parameter like t_50%and one of the pharmacokinetic parameters like t_ax,c_max or AUC . It does not reflect the complete shape of plasma drug concentration time curve, which is the critical factor that defines the performance of drug product¹. Level B and C IVIVCs have been developed for several purposes in formulation development, for example, for selecting the appropriate excipients and optimizing manufacturing processes, for quality control purposes, and for characterizing the release patterns of a newly formulated immediate release (IR) and modified release (MR) products relative to the reference^6-15

Development of Level A Correlation:

As level A correlation is most meaningful and useful, only Level A correlation development and evaluation will be discussed in detail. Schematic diagram of development of level A correlation is shown in Figure4 At least three formulations should be developed with different release rates that is slow, medium and fast release rate (at least differ by ±10%) so that comparable difference between in vivo property (t_max,c_max or AUC) of these formulation is possible¹.

In vitro data should be obtained from optimized in vitro dissolution study, generally by using official dissolution apparatus. In case unofficial apparatus is used, it should be permitted by CDER office before study ¹.

Optimization of dissolution testing should be done to get best in vivo simulations and higher possible correlation. Once dissolution testing method is developed, same method should be used for all the formulations. The dissolution testing should be performed on 12 individual dosage forms from each lot and mean values should be considered¹.

To obtain in vivo data, bioavailability (BA) study in sufficient number of healthy volunteers (6-12) should be performed. The crossover study design is generally preferred; if not possible parallel study design is also acceptable. The drug product should be administered in fasting state, however if intolerable it can be administered in fed state and the effect of food should be considered²⁰.

The data so obtained in in vitro and in vivo studies after data transformation should be processed to develop mathematical model that describe relationship between them. The time scaling factor (if required) for superimposition of curves should not be different for different release rates.¹ Generally two methods are used for development of correlations.

1) Two stage deconvolution approach: It involve estimation of in vivo absorption profile from plasma drug concentration time profile using Wagner Nelson or Looe-Riegelman method^16,17, subsequently the relationship with in vitro data is evaluated.

2) One Stage Convolution Approach: It computes the in vivo absorption and simultaneously models the in vitro – in vivo data.

Two stage methods allows for systematic model development while one stage method obviates the need for administration of an intravenous, oral solution or IR bolus dose¹⁸. .

IVIVC Models:

IVIVC models can be developed by defining the correlation(s) between in vitro dissolution as in vivo input rate .A successful IVIVC model can be developed if in vitro dissolution is the rate-limiting step in the sequence of events leading to appearance of the drug in the systemic circulation following oral or other routes of administration. Thus, the dissolution test can be utilized as a surrogate for bioequivalence studies (involving human subjects) if the developed IVIVC is predictive of in vivo performance of the product. For orally administered drugs, IVIVC is expected for highly permeable drugs, or drugs under dissolution rate-limiting conditions, which is supported by the Biopharmaceutical Classification System (BCS).^21,22 For extended-release formulations following oral administration, modified BCS containing the three classes (high aqueous solubility, low aqueous solubility, and variable solubility) is proposed.²³

IVIVC Model Development:
Development of an IVIVC consists of model development and model validation. A number of methods are available to probe the in vitro-in vivo relationships. Among the earliest methods are the two-stage deconvolution methods that involve estimation of the in vivo absorption profile from the concentration-time data using the Wagner-Nelson or Loo-Riegelman methods (Stage 1).^16,17 Subsequent to the estimation of the in vivo absorption profile, the relationship with in vitro dissolution is evaluated (Stage 2). More recently, one-stage convolution-based approaches for IVIVC have been investigated.¹⁰ The one-stage convolution methods compute the in vivo absorption and simultaneously model the in vitro-in vivo data. While the two-stage method allows for systematic model development, the one-stage method obviates the need for the administration of an intravenous, oral solution or immediate-release bolus dose.¹⁸

The most basic IVIVC models are expressed as a simple linear equation Y=mX+C between the in vivo drug absorption and in vitro drug dissolved (released). In this equation, m is the slope of the relationship, and C is the intercept. Ideally, m=1 and C=0, indicating a linear relationship. However, depending on the nature of the modified-release system, some data are better

fitted using nonlinear models, such as Sigmoid, Weibull, Higuchi, or Hixson-Crowell.¹⁹

Y=mX+C may be applied to most formulations with comparable in vitro and in vivo duration of release. However, for dosage forms with complicated mechanisms of release, which are of longer duration, in vitro release may not be in the same time scale as the in vivo release. Thus, in order to model such data, it is necessary to incorporate time-shifting and time-scaling parameters within the model. This is the kind of data that is routinely encountered in the development of sustained-release dosage forms.

In vivo release rate (X’vivo) can also be expressed as a function of in vitro release rate (X’rel,vitro) with parameters (a, b), which may be empirically selected and refined using appropriate mathematical processes such as X=f(a,b).¹⁸An iterative process may be used to compute the time-scaling and time-shifting parameters.

IVIVC Model Validation:

The objective of any mathematical predictive tool is to successfully predict the outcome (in vivo profile) with a given model and test condition (in vitro profile). Integral to the model development exercise is model validation, which can be accomplished using data from the formulations used to build the model (internal validation) or using data obtained from a different (new) formulation (external validation). While internal validation serves the purpose of providing basis for the acceptability of the model, external validation is superior and affords greater “confidence” in the model.

Biopharmaceutical Classification System:

The biopharmaceutical classification system was developed primarily in the context of immediate release (IR) solid oral dosage forms. It is the scientific framework for classifying drug substances based on their aqueous solubility and intestinal permeability ^24.It is a drug development tool that allows estimation of the contributions of three major factors, dissolution, solubility and intestinal permeability that affect oral drug absorption from immediate release solid oral dosage forms. The interest in this classification system is largely because of its application in early drug development and then in the management of product change through its life cycle.

a) Purpose of the BCS Guidance:

1) Expands the regulatory application of the BCS and recommends methods for classifying drugs.

2) Explains when a waiver for in vivo bioavailability and bioequivalence studies may be requested based on the approach of BCS.³⁰

Goals of the BCS Guidance:

1) To improve the efficiency of drug development and the review process by recommending a strategy for identifying expendable clinical bioequivalence tests.

²⁾To recommend a class of immediate-release (IR) solid oral dosage forms for which bioequivalence may be assessed based on in vitro dissolution tests^.

³⁾To recommend methods for classification according to dosage form dissolution, along with the solubility and permeability characteristics of the drug substance^{. 30}

(b)Classification: ²⁴

Class I: High Solubility – High Permeability

Class II: Low Solubility – High Permeability

Class III: High Solubility – Low Permeability

Class IV: Low Solubility – Low Permeability

(c) Relationship between BCS and immediate and Extended release dosage form and its IVIVC expectation:²³

The drug dissolution and gastrointestinal permeability are the fundamental parameter controlling rate and extent of drug absorption so the drugs are divided into four classes . The expectation regarding in vitro-in vivo correlation (IVIVC). Are summarized in the table 2, 3

Quantitative version of BCS (QBCS): ^22,24

Quantitative version of BCS termed as QBCS using the solubility/dose ratio as the key parameter for solubility classification since it is related to the characteristic of dissolution process. The QBCS utilizes a dose/solubility rate, permeability plane with scientifically –physiologically based cut-off values for compound classification.

A simple absorption model that considers transit flow, dissolution and permeation process was used to illustrate the primary importance of dose /solubility ratio and permeability of drug absorption. Simple mean time consideration for dissolution uptake , and transit were used to identify the relationship between the extent of absorption and the drug dissolution and permeability characteristics. The QBCS relies on the plane with cutoff points 2x10 ^-6-2 x 10 -5 cm/s for permeability and 0.5-1 (unit less) for the dose/solubility ratio axis. Permeability estimates, Papp were derived from caco 2 studies and a constant intestinal volume content of 250ml was used to express dose/solubility ratio as a dimensionless quantity (q). According to the quantitative biopharmaceutical classification system the cutoff points according to their paap, q values established are summarized in table4

Biowaivers: ^{28, 29}

Biowaivers means to get a waive of for doing bioavailability and bioequivalence studies

The following criteria are recommended for justifying the request for a waiver of in in vivo bio studies

1) the drug substance should be highly soluble and highly permeable

2) An immediate release (IR) drug product.

3) For waiver of an in vivo relative bioavailability study, dissolution should be greater than 85% in 30 minute in the three recommended dissolution media.

4) The drug should not be a narrow therapeutic index range,

5) Excipients used in the dosage should have been previously used in FDA approved IR solid dosage form .the quantity of excipient In IR product should be consistent with their intended function.

6) The drug must be stable in G.I. Tract and product is designed not to be Absorbed in oral cavity.^2,
3

APPLICATIONS OF THE BCS:

A) REGULATORY APPLICATIONS OF THE BCS: ²⁷

I) INDs/NDAs:

Evidence demonstrating in vivo BA or information to permit FDA to waive this evidence must be included in NDAs). A specific objective is to establish in vivo performance of the dosage form used in the clinical studies that provided primary evidence of efficacy and safety. The sponsor may wish to determine the relative BA of an IR solid oral dosage form by comparison with an oral solution, suspension, or intravenous injection The BA of the clinical trial dosage form should be optimized during the IND period.

Once the in vivo BA of a formulation is established during the IND period, waivers of subsequent in vivo BE studies, following major changes in components, composition, and/or method of manufacture (e.g., similar to SUPAC-IR Level 3 changes) may be possible using the BCS. BCS-based biowaivers are applicable to the to-be-marketed formulation when changes in components, composition, and/or method of manufacture occur to the clinical trial formulation, as long as the dosage forms have rapid and similar in vitro dissolution profiles (see sections II and III). This approach is useful only when the drug substance is highly soluble and highly permeable (BCS Class 1), and the formulations pre- and postchange are pharmaceutical equivalents BCS-based biowaivers are intended only for BE studies. They do not apply to food effect BA studies or other pharmacokinetic studies. ^{10-c, d}

II) ANDAs:

BCS-based biowaivers can be requested for rapidly dissolving IR test products containing highly soluble and highly permeable drug substances, provided that the reference listed drug product is also rapidly dissolving and the test product exhibits similar dissolution profiles to the reference listed drug product (see sections II and III). This approach is useful when the test and reference dosage forms are pharmaceutical equivalents. The choice of dissolution apparatus (USP Apparatus I or II) should be the same as that established for the reference listed drug product.^{9, 10c, d}

III) Post approval Changes:

BCS-based biowaivers can be requested for significant post approval changes (e.g., Level 3 changes in components and composition) to a rapidly dissolving IR product containing a highly soluble, highly permeable drug substance, provided that dissolution remains rapid for the post change product and both pre- and post change products exhibit similar dissolution profiles (see sections II and III). This approach is useful only when the drug products pre- and post change are pharmaceutical equivalents.

B) Applications of BCS in oral drug delivery technology: ²⁷

Once the solubility and permeability characteristics of the drug are known it becomes an easy task for the research scientist to decide upon which drug delivery technology to follow or develop.

The major challenge in development of drug delivery system for class I drugs is to achieve a target release profile associated with a particular pharmacokinetic and/or pharmacodynamic profile. Formulation approaches include both control of release rate and certain physicochemical properties of drugs like pH-solubility profile of drug.

The systems that are developed for class II drugs are based on micronisation, lyophilization, addition of surfactants, and formulation as emulsions and micro emulsions systems, use of complexing agents like cyclodextrins.

Class III drugs require the technologies that address to fundamental limitations of absolute or regional permeability. Peptides and proteins constitute the part of class III and the technologies handling such materials are on rise now days.

Class IV drugs present a major challenge for development of drug delivery system and the route of choice for administering such drugs is parenteral with the formulation containing solubility enhancers.

C) BCS Classification aid for Drug Development Program: ²⁷

The “Waiver of In-vivo Bioavailability and Bioequivalence Studies for Immediate Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System" is an FDA guidance document, which allows pharmaceutical companies to forego clinical bioequivalence studies, if their drug product meets the specification detailed in the guidance (The principles of the BCS classification system can be applied to NDA and ANDA approvals as well as to scale-up and post approval changes in drug manufacturing. BCS classification can therefore save pharmaceutical companies a significant amount in development time and reduce costs.

The BCS classification system is based on the scientific rationale that, if the highest dose of a drug candidate is readily soluble in the fluid volume on average present in the stomach (250 ml) and the drug is more than >90% absorbed, then the in vitro drug product dissolution profiles should allow assessment of the equivalence of different drug formulations. Solubility and dissolution can be easily measured in vitro. Extent of absorption has historically been determined by conducting mass balance studies both preclinical and clinically. However, our work and that of our collaborators has demonstrated that the effective intestinal permeability (Peff) of therapeutic agents correlates well with total fraction absorbed in both humans, rats and to a lesser extent in vitro tissue culture systems1-5. Based on these studies a drug candidate can fall into one of four BCS categories, with category I, High Permeability and High Solubility, being the subject of the BCS guidance. The WHO has recently recommended biowaivers for Class III and some Class II drugs and AAPS-FDA scientific conferences have recommended biowaivers for Class III compounds as well.

Table no.4-Cutoff points according to QBCS:

Classes	P app	q
class I	papp>10 -5 cm/sec	q< 0.5
class II	papp>10 -5 cm/sec	q>1
Class iii	papp<2 x 10 -6 cm/sec	q<0.5
Class IV	papp <2 x 10 -6 cm/sec	q>1
Borderline Drugs	2x 10 -6 < papp< 10 -5 cm/ sec	.05<q<1

APPLICATIONS OF IVIVC:

The most important application of IVIVC is to use in vitro dissolution study as surrogate for human bioequivalence (BE) studies. This will reduce the number of human bioequivalence studies during initial approval process as well as certain scale up and post approval changes (SUPAC)¹. The FDA guidance explains applications of IVIVC as biowaivers for changes in manufacturing of a drug product and setting dissolution specifications.

1. Early Development of Drug Product and Optimization:

In early stages of drug product development drug products are characterized by some in vitro systems and some in vivo studies in animal models to address efficacy and toxicity issue ^31. At this stage if preliminary relationship between in vitro and in vivo properties can be made, it can add better vision in design and development of drug product. ³¹Latter when valid IVIVC developed formulation can be optimized based on in vitro dissolution studies only.

2. Biowaiver for Minor Formulation and Process Changes:

When relationship between critical manufacturing variables and in vitro dissolution rate have been clearly defined for CR formulation and IVIVC has been established, it may be possible to use in vitro dissolution data to justify minor formulation and process changes. These changes may include minor changes in colour, shape, size, preservative, flavor, coating procedure, amount and composition of materials, source of inactive and active (if adequately characterized) ingredient, equipment or site of manufacturing³.

3. Setting Dissolution Specifications:

In absence of IVIVC, the range of dissolution specification rarely exceeds ± 10 percent of dissolution of pivotal batch. However, in presence of IVIVC, wider specifications may be applicable based on the predicted concentration time profile of test batches being bioequivalent to reference batch¹.

The specification should be optimally established such that all batches with dissolution profile between fastest and slowest batch are bioequivalent and less optimally bioequivalent to reference batch¹. The above exercise in achieving the widest possible dissolution specification, allow majority of batches to pass. This is possible only when valid level A model is available. Modified release dosage forms typically require dissolution testing over multiple time points, and IVIVC plays important role in setting. These specifications ^{32, 33}

REFERENCES:

1. US FDA, CDER. Guidance for Industry: Extended Release Oral Dosage Forms: Development, Evaluation, and Application of In vitro/In vivo Correlations. 1997

2. U.S. Department of Health and Human Services. (September 1997). Guidance for industrial. Extended release oral dosage forms: Development, evaluation and application of In Vitro/In Vivo correlations. Food and Drug Administration, Center for Drug Evaluation and Research (CDER). Rockville, MD.

3. Leeson, L. J. (1995). In vitro/ In vivo correlations. Drug Information Journal. 29,903-915.

4 Gillispie WR., Convolution Based Approaches for In vitro in vivo correlation modeling. In: Young Devane J, Butler J Eds. In vitro in vivo correlations. New York, NY: Plume Press: 1997; 423:53-65.

5 Skelley JP, AmidonGL, Barr WH. Report of the workshop on in vitro and in vivo testing and correlation for oral controlled/modified-release dosage forms. J.Pharm.Sci 1990; 79 (9): 849 – 854.

6 Chattaraj, S. C., and Das, S. K. (1990). Effect of formulation variables on the preparation and in vitro-in vivo evaluation of cimetidine release from ethyl cellulose micropellets. Drug Development and Industrial Pharmacy. 16(2), 283-292.

7 Hussein, Z., and Friedman, M. (1990). Release and absorption characteristics of novel theophylline sustained-release formulations: In vitro-in vivo correlation

8 Lin, S., Kao, Y., and Chang, H. (1990). Preliminary evaluation of the correlation between in vitro release and in vivo bioavailability of two aminophylline slowrelease tablets. Journal of Pharmaceutical Sciences. 79(4), 326-330.

9 Drewe, J., and Guitard, P. (1993). In vitro-in vivo correlation for modified-releaseformulations. Journal of Pharmaceutical Sciences. 82(2), 132-137.

10 Ammar, H. O., and Khalil, R. M. (1993). Discrepancy among dissolution rates ofcommercial tablets as a function of dissolution method. Part 3: In vitro/in vivocorrelation of paracetamol tablets. Pharmazie. 48(Feb), 136-139.

11 Brock, M. H., Dansereau, R. J., and Patel, V. S. (1994). Use of in vitro and in vivo data in thedesign, development, and quality control of sustained-release decongestant dosage form.Pharmacotherapy. 14, 430-437.

12 Hayashi, T, Ogura, T., and Takagishi, Y.(1995). New evaluation method for in vitro/in vivo correlation of enteric-coated multiple unit dosage forms. Pharmaceutical Research. 12 (9), 1333-1337.

13 Qui, Y., Cheskin, H., Briskin, J., and Engh, K. (1997). Sustained-release hydrophilic matrixtablets of zileuton: formulation and in vitro/in vivo studies. Journal of Controlled release. 45, 249-256.

14 Jung, H., Milan, R. C., Girard, M. E., Leon, F., and Montoya, M. A. (1997). Bioequivalence study of carbamazepine tablets: in vitro/in vivo correlation. International Journal of Pharmaceutics. 152, 37-44.

15 Abuzarur-aloul, R., Gjellan, K., Sjound, M., and Graffner, C. (1998). Critical dissolution testsof oral systems based on statistically designed experiments. III. In vitro/in vivo correlation formultiple-unit capsules of paracetamol based on PLS modeling. Drug Development and IndustrialPharmacy. 24, 371-383.

16 wagner JG., Nelson E. Kinetic analysis of blood levels and urinary excretion in the absorptive phase after single doses of drug. J. Pharm. Sci. 1968; 53(11):1392-1402.

17 Loo JC, Riegelman S. New methods for calculating the intrinsic absorption rate of drugs J. Pharm. Sci 1968; 57(6): 918-924.

18 Gillispie WR., Convolution Based Approaches for In vitro in vivo correlation modeling. In: Young Devane J, Butler J Eds. In vitro in vivo correlations. New York, NY: Plume Press: 1997; 423:53-65

19 Mendell-Harary J, Dowell J, Bigora S, et al. Nonlinear in vitro in vivo correlation. In: Young Devane J, Butler J Eds. In vitro in vivo correlations. New York, NY: Plume Press: 1997; 423:199-206.

20 Al-Behaisi S, Antal I, Morovjan G, Szunyog J, Drabant S, Marton S, Klebovich I. In vitro simulation of food effect on dissolution of Deramciclane film coated tablets and correlation with in vivo data in healthy volunteers, Eur. J. of Pharm. Sci. 2002; 15: 157–162.

21 Dressman JB,Amidon GL,,Reppas C,Shah VP.Dissolution testing as a prognostic tool for oral drug absorption :immediate release dosage forms. Pharm Res 1999;15(1):11-22

22 Draft Guidance for Industry, Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate Release Solid Oral Dosage Forms containing certain Active Moieties/ Active Ingredients based on a Biopharmaceutic Classification System, February 1999, CDER/FDA.

23 Corrigan Ol. The biopharmaceutics drug classification and and drug administred in extended release (ER) formulation. In Young D,Devane J,Butler J eds. In vitro in vivo correlations .New York, NY: Plenum press ;1997;423;111-128

24 Amidon G.L., Lennernas H., Shah V.P., Crison J.R.A., A Theoretical Basis For a Biopharmaceutic Drug Classification: The Correlation of In Vitro Drug Product Dissolution and In Vivo Bioavailability. Pharm. Res. 12: 413-420 (1995)

25 Guidance for Industry, Immediate Release Solid Oral Dosage Forms: Scale Up and Post Approval Changes, November 1995, CDER/FDA.

26 Medicamento Generico from website .http:www.anvisa.go

27 Devane J., Oral drug delivery technology: addressing the solubility/ permeability paradigm, Pharm. Technol. 68-74, November 1998.

28 United States Food and Drug Administration. Guidance for Industry: Waiver of InVivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System. August 2000.

29 European Agency for the Evaluation of Medicinal Products. Note for guidance on the investigation of bioavailability and bioequivalence, (CPMP/EWP/QWP/1401/98), Committee for proprietary medicinal products, July 26 2001.

30 Guidance for Industry, Immediate Release Solid Oral Dosage Forms: Scale Up and Post Approval Changes, November 1995, CDER/FDA

31 Venkatesh S, Lipper RA. Role of development scientist in compound lead selection and optimization. J. Pharm. Sci. 2000; 89 (2): 145-154.

32 Modi NB, Lam A ,lindemulder E, WangB, Gupta SK. Application of in vitro- in vivo correlation (IVIVC) in setting formulation release specification . Biopharm drug dispos. 2000;21: 321-326

Received on 17.11.2008 Modified on 24.12.2008

Research J. Pharm. and Tech. 2(1): Jan.-Mar. 2009; Page 72-79

LEVEL OF CORRELATION	REGULATORY SIGNIFICANCE	USE
Level A	Most prefered	This allows biowaiver for changes in manufacturing site, raw material suppliers, and minor changes in formulation^1,3.
Level Band Level C	Least prefered	in formulation development, for example, for selecting the appropriate excipients and optimizing manufacturing processes, for quality control purposes, and for characterizing the release patterns of a newly formulated immediate release (IR) and modified release (MR) products relative to the reference ^(6-15) in formulation development, for example, for selecting the appropriate excipients and optimizing manufacturing processes, for quality control purposes, and for characterizing the release patterns of a newly formulated immediate release (IR) and modified release (MR) products relative
Level D	Not prefered	Least or not useful.

CLASS	SOLUBILITY	PERMIABILITY	IVIVC
IA	High and site independent	High and site independent	IVIVC level A expected
IB	High and site independent	Dependent on site and narrow absorption window	IVIVC level C expected
IIa	Low and site independent	High and site independent	IVIVC level A expected
IIb	Low and site independent	Dependent on site and narrow absorption window	Little or NO IVIVC
sVa(acidic)	variable	variable	Little or NO IVIVC
Vb(basic)	variable	variable	IVIVC level A expected

Class	Solubility	permeability	Absorption rate control	IVIVC Limitation for immediate release product	Possibility of predicting IVIVC from dissolution data
I	High	High	Gastric emptying	IVIVC expected if dissolution rate is slower than gastric emptying rate otherwise limited or no correlation	No
II	Low	High	dissolution	IVIVC expected if in vitro dissolution rate is similar to in vivo rate, unless does it very high	Yes
III	High	Low	Permeability	Absorption (permeability) is rate determining and limited or IVIVC with dissolution.	NO
IV	Low	Low	Case by case	Limited IVIVC expe	No