This document discusses various aspects of in vitro drug product performance testing and evaluation, including dissolution profile comparisons, meeting dissolution requirements, problems in dissolution testing, and in vitro-in vivo correlation (IVIVC). It describes model-independent and model-dependent approaches to comparing dissolution profiles using difference factor (f1) and similarity factor (f2). It also discusses the four levels of IVIVC (A, B, C, and multiple C) and their applications and limitations. Finally, it covers considerations for drug product stability and design.

1. INVITRO DRUG PRODUCT
PERFORMANCE
SILAMBARASAN I
M PHARM(PHARMACEUTICS)
MTPG & RIHS

2. CONTENT
• DISSOLUTION PROFILE COMPARISON
• MEETING DISSOLUTION REQUIREMENT
• PROBLEMS OFVARIABLE CONTROL IN DISSOLUTION TESTING
• INVITRO INVIVO CORRELATION
• DRUG PRODUCT STABILITY
• CONSIDDERATION INTHE DESIGN OF DRUG PRODUCT

3. DISSOLUTION PROFILE COMPARISONS
DEFINITION:
• It is graphical representation [in terms of concentration vs. time] of complete
release of A.P.I. from a dosage form in an appropriate selected dissolution medium.
• i.e. in short it is the measure of the release of A.P.I from a dosage form with respect to
time.

4. • To develop invitro-invivo correlation which can help to reduced costs, speed-up
product development and reduced the need of perform costly bioavailability
human volunteer studies.
• To stabilize final dissolution specification for the pharmacological dosage form.
• Establish the similarity of pharmaceutical dosage forms, for which composition,
manufacture site, scale of manufacture, manufacture process and/or equipment may have
changed within defined limits.
OBJECTIVE

5. IMPORTANCE OF DISSOLUTION PROFILE
• Dissolution profile of an A.P.I. reflects its release pattern under the selected condition
sets. i.e. either sustained release or immediate release of the formulated formulas.
• For optimizing the dosage formula by comparing the dissolution profiles of various
formulas of the same A.P.I
• Dissolution profile comparison between pre change and post change products for
SUPAC (scale up post approval change ) related changes or with different strengths,
helps to assure the similarity in the product performance and green signals to
bioequivalence.

6. METHOD TO COMPARE DISSOLUTION
PROFILE
• Model independent approach
• Model independent multi variate confidence region procedure
• Model dependent approach

7. MODEL INDEPENDENT APPROACH
1) DIFFERENCE FACTOR( f1)
The difference factor (f1) as defined by FDA calculates the % difference
between two curves at each time point and is a measurement of the relative error
between two curves.
where, n = number of time points
Rt = % dissolved at time t of reference product (pre change)
Tt = % dissolved at time t of test product (post change)

8. 2)SIMILARITY FACTOR (F2)
Similarity factor are defined by FDA is logarithmic reciprocal square root
transformation of sum of squared error and is a measurement of the similarity in the
percentage (%) dissolution between the two curves.
where, n = number of time points
Rt = % dissolved at time t of reference product (pre change)
Tt = % dissolved at time t of test product (post change)

9. GUIDANCE FOR INDUSTRY
A specific procedure to determine difference and similarity factors is as follows:
• Determine the dissolution profile of two products (12 units each) of the test
(postchange) and reference (prechange) products.
• Using the mean dissolution values from both curves at each time interval, calculate the
difference factor (f1 ) and similarity factor (f2) using the equations.
• For curves to be considered similar, f1 values should be close to 0, and f2 values should be
close to 100.
• Generally, f1 values up to 15 (0-15) and f2 values greater than 50 (50-100) ensure
equivalence of the two curves and thus, of the performance of the test (postchange) and
reference (prechange) products.
• This model independent method is most suitable for dissolution profile comparison when
three to four or more dissolution time points are available.

10. The following recommendations should also be considered:
• The dissolution measurements of the test and reference batches should be made under
exactly the same conditions.
• The dissolution time points for both the profiles should be the same (e.g., 15, 30, 45, 60
minutes).
• The reference batch used should be the most recently manufactured prechange
product.
• Only one measurement should be considered after 85% dissolution of both the products.
• To allow use of mean data, the percent coefficient of variation at the earlier time points (e.g.,
15 minutes) should not be more than 20%, and at other time points should not be more
than 10%.
• The mean dissolution values for R can be derived either from
(1) last prechange (reference) batch or
(2) last two or more consecutively manufactured prechange batches.

11. MEETING DISSOLUTION REQUIREMENT
For the selection of the dissolution acceptance criteria ,the following points should be
considered,
• The dissolution profile data from the pivotal clinical batches and primary stability batches used
for setting of the dissolution acceptance criteria of the product .
• Specification should be established based on average invitro dissolution data for each lot under study,
equivalent to USP stage 2 testing (n=12)
• For immediate release formulation ,the last time point should be the time point where atleast 80 %
of drug has been released.
• For extended release formulation ,a minimum of three time points is recommended to set the
specification .
• The dissolution acceptance criterion should be set in a way to ensure consistent performance from
lot to lot ,and these not allow the release of any lot with dissolution profiles outside those that were
studied clinically.

12. PROBLEMS OF VARIABLE CONTROL IN
DISSOLUTION TESTING
• Centering
• Turbulence
• Wobbling and tilting
• Clogging of gummy material
• Air bubbles formation
• Location of tablet on the vessel
• Hydrodynamic effect.

13. INVITRO IN VIVO CORRELATION
Food and Drug Administration (FDA) definition
• IVIVC is the predictive mathematical model that describes the relationship between an
invitro property (such as rate and extent of dissolution) of a dosage form and invivo
response (such as plasma drug concentration).
United State Pharmacopoeia (USP) definition
• The establishment of a rational relationship between a biological property
produced from a dosage form and a physiochemical property of the same
dosage form.

14. Applications of IVIVC
• To ensure batch to batch consistency in the physiological performance of a drug product
by use of such in vitro values
• To serve as a tool in the development of a new dosage form with desired in vivo
performance
• To assist in validating or setting dissolution specifications i.e. the dissolutions specifications
are based on the performance of product in vivo
• It minimizes the number of bioequivalence studies performed during the initial approval
process and during scaling up and post approval changes
• It assists in validating dissolution specifications
• Biowaiver for minor formulation and process changes

15. QUANTITATIVE INVITRO INVIVO
CORRELATION
A) Correlation based on the plasma level data:
Parameters used for correlating in vitro dissolution with plasma data

16. B. Correlations based on the urinary excretion data:
Parameters such as amount of drug excreted unchanged in the urine, cumulative
amount of drug excreted as a function of time.
C. Correlation based on the pharmacological response :
An acute pharmacological effect such as LD50 in animals in related to any of the
dissolution parameters.
Statistical moments theory:
It can be used to determine the relationship such as mean dissolution time vs.
mean residence time.

17. LEVELS OF IVIVC
• There are four levels of IVIVC that have been described in the FDA guidance,
which include levels A, B, C, and multiple C.
• The concept of correlation level is based upon the ability of the correlation to
reflect the complete plasma drug level-time profile which will result from
administration of the given dosage form.

18. • Point-to-Point relationship.
• Usually Correlations are linear, and no formal guidance on the non-linear IVIVC.
• The data treatment involves a two stage Deconvolution Method.
• Estimation of the in vivo absorption profile usingWagner-Nelson or Loo-Riegelman
method
• Comparison of fraction of drug absorbed (Fa) and fraction of drug dissolved (Fd) in-
vitro to obtain a linear correlation.
• PURPOSE – DEFINE DIRECT RELATIONSHIP
LEVEL A CORRELATION

19. • Formulations showing Level A correlation require no additional human studies to justify change
in manufacturing site, raw material supplier or minor formulation changes.
• Most informative and very useful from a regulatory perspective
Figure 2: Correlation between percent theophylline dissolved in vitro and percent
theophylline absorbed after administration of extended release product

20. Importance of level A correlation
• The in vivo dissolution serves as in vivo indicating quality control procedure
for predicting dosage form performance.
• Determining stable release characteristics of the product over time.
• A point to point correlation is developed.

21. • A predictive model for relationship between summary parameters that characterize the
in-vitro and in-vivo time course.
• It compares
1) MDT vitro to MDTvivo,
2) MDT vitro to MRT,
3) In-vitro Dissolution Rate Constant (kd) to Absorption Rate Constant (ka).
• Comparison using Statistical moment analytical method.
• This type of correlation uses all of the in vitro and in vivo data.
• This is of limited interest and least useful for regulatory purposes because more than one
kind of plasma curve produces similar MRT.
LEVEL B CORRELATION

22. • LEVEL B CORRELATION:
Figure 2: Correlation of mean in vitro dissolution
time(MDT) and mean absorption time(MAT).

23. Limitations
• Level B correlation is not unique, because MRT remains same, though the
shape of in vivo curves are different.
• Therefore it fails to justify the formulation modifications.

24. LEVEL C CORRELATION
• Predictive mathematical model which relates one dissolution time point(e.g.t50%) to one
pharmacokinetic parameter that characterizes in-vivo time course.
(e.g., Cmax,Tmax,T1/2 or AUC).
• Level C correlations can be useful in the early stages of formulation development when pilot
formulations are being selected.
• Lowest correlation level
• Does not reflect a complete shape of plasma concentration time curve.

25. LEVEL C CORRELATION
Figure 3: correlation between mean dissolution time and AUC
of plasma drug time curve of four formulations.

26. MULTIPLE LEVEL C CORRELATION
• It relates one or more pharmacokinetic parameters to the percent
drug dissolved at several time points of dissolution profile and thus
may be more useful.
• A 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.

27. • Complexity of the drug absorption:
A number of biological factors influence the drug absorption.These
factors cannot be mimicked in in vitro.
• Weakness of the dissolution design:
Being in vitro model, it is natural to have certain limitations.The
physics of tableting as well as nature of mechanical and hydrodynamic forces
that operate during dissolution are not well understood.
LIMITATIONS OF IVIVC

28. DRUG PRODUCT STABILITY
• Drug Stability:The capacity or capability of a particular drug formulation in a
specific container to remain within a particular chemical, microbiological,
therapeutically, physical & toxicological specification in a specified period of time.
• The United States Pharmacopoeia define the drug stability as extent to which a
particular drug product retains intake within a specified limit throughout its storage
and use i.e. shelf life.
• Drug Instability:The incapacity or incapability of a particular formulation in a
specific container to remain within a particular chemical, microbiological,
therapeutically, physical & toxicological specification.

29. Shelf life:
Shelf life may be defined as the time required to degrade a pharmaceutical product to 10% which is
pharmaceutically acceptable. It is indicated as t90 and the unit is time/conc.
Factors effecting drug stability:
• PH
• Temperature
• Moisture
• Humidity
• Light
• Storage closure and containers
• Oxygen
• Particle size (suspension and emulsion)
• Additives
• Molecular binding
• Diffusion of drugs and excipients .

30. CONSIDERATION IN THE DESIGN OF
DRUG PRODUCT
• Biopharmaceutic consideration
• Pharmacodynamic consideration
• Drug substance consideration
• Pharmacokinetics of the drug
• Bioavailability of the drug
• Dose consideration
• Dosing frequency
• Patients consideration
• Route of drug administration

31. REFERENCES
1) BIOPHARMACEUTICS AND PHARMACOKINETICS :
D.M.BRAHMANKAR
SUNIL B.JAISWAL
2)APPLIED BIOPHARMACEUTICS AND PHARMCOKINETICS
LEON SHARGEL
ANDREW B.CYU

32. THANK YOU