The role of dissolution in the demonstration of bioequivalence

THE ROLE OF DISSOLUTION IN THE DEMONSTRATION OF BIOEQUIVALENCE Prof.Dr.Nevin ÇELEBİ Gazi University Faculty of Pharmacy Department of Pharmaceutical Technology PharmaCon 2007-Dubrovnik

OUTLINE
Definition (Dissolution and Dissolution rate)
Drug dissolution process
Dissolution test and dissolution apparatus
Comparison of dissolution profile
Dissolution in regulating pharmaceuticals

Dissolution
Dissolution is the process by which a solid substance dissolves. As a fundamental phenomenon, it is controlled by the affinity between the solid and the medium.

Dissolution rate
Dissolution rate may be defined as the amount of drug substance that goes in solution per unit time under standardized conditions of liquid/solid interface, temperature and solvent composition.

Drug absorption from a solid dosage form after oral administration depends on the release of the drug substance from the drug product, the dissolution or solubilization of the drug under physiological conditions, and the permeability across the gastrointestinal tract.

Effects of factors on dissolution rate of solid dosage forms
1.Physicochemical properties of the drug
Drug solubility
Crystallinity, salt form, polymorphism
Particle size
2.Formulation factors
Diluents
Disintegrants
Lubricants
Other additives
Coating components

3.Processing factors on dissolution rates
of tablets
Method of granulation
Compression force
4.Factors relating to the dissolution
apparatus

5.Effects of test parameters
Agitation
Stirring rate
Dissolution fluid
Influence of pH of dissolution
Effect of surface tension of the dissolution medium
Effect of the presence of unreactive and reactive additives in the dissolution medium
Volume of dissolution medium and sink conditions
Effect of temperature
Deaeration of dissolution medium

Dissolution test
The volume of the dissolution medium is generally 500, 900 or 1000mL.
Sink conditions are desirable

Dissolution test
In vitro dissolution test should be
simple
reliable
reproducible
able to discriminate between different degrees of product performance

Dissolution Test Equipment
Parameters: Temperature, speed,volume, sampling probe and position
Apparatus suitability test
Validation of automated system
Validation of analytical procedure
accuracy, precision (reproducibility and repeatability),specificity, linearity

Official dissolution apparatus
USP 28 classification
Rotating Basket
Paddle
Reciprocating Cylinder
Flow Through Cell
Paddle Over Disk
Rotating Cylinder
Reciprocating Holder

USP apparatus 1 - Basket
Useful for
capsules
beads
delayed release / enteric coated dosage forms
floating dosage forms
surfactants in media
Standard volume
900 ml
1, 2, 4 liter vessels
Klein S., Hands-on-Dissollution workshop,İstanbul,2005

USP apparatus 1 - Basket
Advantages
breadth of experience (more than 200 monographs)
full pH change during the test
can be easily automated which is important for routine investigations

USP apparatus 2 - Paddle
Useful for
tablets
capsules
beads
delayed release / enteric coated dosage forms
Standard volume
900 ml
Method of first choice !!!

USP apparatus 3 – Reciprocating cylinder
Useful for
tablets
beads
controlled release formulations
Standard volume
200-250 ml per station

USP apparatus 4 – Flow-Through Cell
Useful for
low solubility drugs
microparticulates
implants
suppositories
controlled release
formulations
Variations
open system
closed system

USP apparatus 5 – Paddle over disk
Useful for
transdermal patches
Standard volume
900 ml

Dissolution test has been extensively used as a quality control tool for drug products.
In vitro dissolution may be relevant to the prediction of in vivo performance.

The dissolution test is important
in terms of the revealing of in
vitro/in vivo correlation (IVIVC).

Dissolution/In vitro Release Testing-Important Tool
Assess batch to batch quality of the product
Determine product stability/shelf life
Guide in the development and/or process control of formulations
Ensure quality and performance after changes in the formulation,the manufacturing process, the site of manufacture and the scale-up of manufacturing process
Bioequivalency Test: Biowaivers

Role of Dissolution Testing in Regulating Pharmaceuticals
I n vitro dissolution testing is relied on to assure product performance.
An appropriate dissolution test procedure is a simple and economical method that can be utilized effectively to assure acceptable drug product quality.
Appropriate dissolution test can be used as a s urrogate marker for BA/BE.

Policy Related Dissolution BA/BE Guidances
IR Dissolution Guidance
ER (IVIVC) Dissolution Guidance
BCS (Waiver) Guidance
General BA/BE Guidance
http://www.fda.gov/cder/guidance/index.htm

Setting Dissolution Specification (FDA)
In vitro dissolution specifications are established to ensure batch-to-batch consistency and to signal potential problems with in vivo bioavailability.
For NDAs, the dissolution specifications should based on acceptable clinical, pivotal bioavailability, and/or bioequivalence batches.
For ANDAs/AADAs, the dissolution specifications should be based on the performance of acceptable bioequivalence batches of the drug product.

Setting Dissolution Specification(FDA)
The NDA dissolution specifications should be based on experience gained during the drug development process and the in vitro performance of appropriate test batches.
In the case of generic drug product, the dissolution specifications are generally the same as the reference listed drug (RLD)
Once a dissolution specification is set, the drug product should comply with that specification throughout its shelf life

Guidance of BY/BE (EMEA2001)
Dissolution studies can serve several purposes:
I-Quality assurance
To get information on the test batches used in BY/BE studies and pivotal clinical studies to support specifications for quality control
To be used a tool in quality control to demonstrate consistency in manufacture
To get information on the reference product used in BY/BE studies and pivotal clinical studies

Guidance of BY/BE (EMEA2001)
II.Bioequivalence surrogate interface
To demonstrate similarity between different formulations of an active substance (variations and new, essentially similar products included) and the reference medicinal product.
To collect information on batch to batch consistency of the products (test and reference) to be used as basis for the selection of appropriate batches for in vivo study.
To demonstrate similarity between reference products from different Member States.

Dissolution-Based Biowavers
In vitro dissolution test can also be used to waive for lower strenghts of immediate release and extended release drug products under certain conditions (dose proportional formulation and similar release mechanism)

IR Products
Lower strenghts-Formulation Proportionality
Dissolution Profile f 2
BCS Class I:HS/HP/RD
Post-approval changes
Dissolution profile f 2

ER Products
Lower Strenghts-tablet dosage form
Compositionally proportional
Same release mechanism
Similar dissolution profile in pH 1.2,4.5 and 6.8 buffer media, f 2

Dissolution Specifications (FDA)
Three catogories of dissolution test specifications for immediate release drug products are described in the guidance.
Single point specifications
Two-point specifications
Dissolution profile comparison

Dissolution Specifications (FDA)
Single Point
For routine quality control test
Two Points F or characterizing the quality of the drug p roduct
As a routine quality control test for certain types of drug products (e.g., slow dissolving or poorly water soluble drug product like carbamazepine )

The comparison of dissolution profiles
The dissolution profiles similarity may be compared by;
Model independent
Model dependent
Linear regression of the percentage dissolved at specified time points
Statistical comparison of the parameters of the Weibull function
Calculating a similarity factor

The comparison of dissolution profiles
Model independent approach using a similarity factor
A simple model independent approach uses a difference factor (f 1 ) and a similarity factor (f 2 ) to compare dissolution profiles.

Difference factor (f 1 ) n is the number of time points R t is the dissolution value of the reference batch at time t, and T t is the dissolution value of the test batch at time t.

Similarity factor (f 2 ) n is the number of time points Rt is the mean percent drug dissolved of e.g a reference product, Tt is the mean percent drug dissolved of e.g a test product

Similarity factor (f 2 )
The evaluation of similarity is based on the conditions of
a minumum of three time points (zero excluded)
12 individual values for every time point for each formulation
not more than one mean value of <85 % dissolved for each formulation
That the standard deviation of the mean of any product should be less than 10 % from second to last time point.

Similarity factor (f 2 )
An f 2 value between 50 and 100 suggests that the two dissolution profiles are similar.

In cases where more than 85% of the drug are dissolved within 15 minutes, dissolution profiles may be accepted as similar without further mathematical evaluation.

Biopharmaceutics Classification System(BCS)
The BCS is a scientific framework for classifying a drug substance based on its aqueous solubility and intestinal permeability.
The FDA issued a guidance for industry on waivers in vivo for IR solid oral dosage forms based on the BCS in A u gust 2000.

According to BCS,drug substances are classified as follows:
Based on in vitro solubility and in vivo permeability dru g s can be divided into four groups:
BCS for Immediate Release (IR) products Case by case Low Low IV Permeability Low High III Dissolution High Low II Gastric Emptying High High I Absorption rate control Permeability Solubility Class

BCS (Cont’d)
The BCS guidance recommends that sponsors may request biowaivers for highly soluble and highly permeable drug substances (Class I) in IR solid dosage forms that exhibit rapid in vitro dissolution, provided the following conditions are met:
the drug must be stable in the gastrointestinal tract,

BCS (Cont’d)
excipients used in the IR solid oral dosage forms have no significant effect on the rate and extent of oral drug absorption,
the drug must not have a narrow therapeutic index,
the product is designed to not be absorbed in the oral cavity

BCS (Cont’d)
According to the tenets of the BCS, certain drug products can be considered for biowaivers, i.e. Approving the product based on in vitro dissolution test rather than bioequivalence studies in human subjects.

Regulation aspects of drug dissolution from a European perspective (Con’t)
The qulity assessors of the virtual agency of EU,EMEA, pay strong attention to how well the composition of the dosage forms and the different steps of manufacturing process are chosen and uderstood.

In addition , the ability of the dissolution test to detect deviations in those formulation factors that are defined to be critical in respect to drug absorption is emphasised (EMEA,1998,2005)

Reference product-EU origin
Another situation where a dissolution test might be a valuable tool is when the reference product used in a bioequivalence study is taken from another EU market than the one aimed for the applied generic product.

Reference product-EU origin
Still there are medicinal products with different compositions available from innovator company on the different member states markets of EU and it is therefore, up to the generic company to prove that the reference product chosen in the bioequivalence study is approprate.

Graffner C., Eur.Pharm.Sci.,29,288-298 (2006)

Summary
In vitro dissolution testing is a powerful and useful method for determining product quality and sometimes to evaluate the clinical performance of dosage forms.

Thank You….
e-mail: nevin@ tr.net

Dissolution
Dissolution can be considered as a specific type of certain heterogenous reaction in which a mass transfer results as a net effect between the escape and deposition of solute molecules at a solid surface.

Dissolution
These heterogeneous reactions can be classified into three main categories:
1. The reaction or interaction at the interface is much faster than the transport of reactants to and products from the interface. In this case, the rate is controlled by transport process. For dissolution, this would be the diffusion or convective transport of solute from the interfacial bondaries to the bulk of the solution.

Dissolution
2. The reaction at the interface proceeds at a significantly slower speed than the transport process, and hence, it becomes the rate controlling step. In case of dissolution, this would occur if the process of releasing and depositing the solute molecules at the interface is the rate determining step.

Dissolution
3. The rate constants of both processes are approximately equivalent, and in this case, the rate of dissolution would be a fraction of both the rate of the reaction at the interface as well as the rate of the transport process.

Dissolution test
The dissolution studies should be carry out under different conditions;
e.g., pH agitation, ionic strenght, surfactants, viscosity, osmotic pressure is important since the behaviour of the solid system in vivo may be critical for the drug dissolution independent of the physicochemical properties of the active substance.

Dissolution Guidance
Provides methods for dissolution recommendations on the development of dissolution test methodology, approaches for setting specifications and the regulatory applications
profile comparison and indications as to when dissolution is sufficient for biowaivers

ER Products
Lower Strenghts-beads in a capsule
In vivo BE on highest strenght
Strengths differ only in number/amount of active beads (same release mechanism), linear PK
Dissolution profile comparison, f 2

Profile Profile comparison for granting biowaivers
For accepting product “sameness” under scale-up and post-approval changes

Regulation aspects of drug dissolution from a European perspective
During the development of a dosage form, it is therefore, important for the pharmaceutical companies to have a tool, a dissolution test, which makes it possible to evaluate the combined effects of different formulation factors, such as physicochemical properties of the active substance, properties of different excipients and different steps in the manufacturing process, on the rate and extent of drug absorption
Graffner C.,Eur.J.Pharm.Sci.,29,288-293(2006)

An application dossier contains documentation on evidence of the effect, safety and pharmaceutical quality of a potential medicinal product and the role of regulatory authority is to ensure the appropriateness of the candidate product based on a scrutiny of scientific documentation submitted.
Graffner C.,Eur.J.Pharm.Sci.,29,288-293(2006)

If the dissolution rate is not critical an appropriate test is still requested,e.g. For oral dosage forms, for controlling that the dissolution properties are consistent both within a manufactured batch and between batches.

If the potential medicinal product is a modified-release dosage form, the discriminatory power of the dissolution test is expected, to be discussed based on an in vitro-in vivo correlation, i.e. a predictive mathematical model describing the relationship between in vitro dissolution properties and a relevant in vivo response (EMEA, 1999)

By establishing a meaningful correlation between in vitro release characteristics an in vivo bioavailability parameters, the in vitro dissolution test can serve as a surrogate marker for in vivo behaviour.

By applying the present mutual recognition approval systems of EU, such differences in the properties of product of a company product are, of course, not expected in the future.

Graffner C., Eur.Pharm.Sci.,29,288-298 (2006)

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The role of dissolution in the demonstration of bioequivalence

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