The Dissolution Procedure: Development and Validation · The Dissolution Procedure: Development and...

The Dissolution Procedure: Development and Validation

Based on: <1092> as published in Pharmacopoeial Forum, Vol. 31 (5), 2005

Dr. Elisabeth KrugLilly Forschung GmbHGermany

Dr. Elisabeth Krug25. Jan. 2006 - SAQ

Company ConfidentialCopyright © 2000 Eli Lilly and Company

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Dissolution – Outline

General considerations for dissolution proceduresMediumIn vivo – In vitro correlationApparatusAgitationSinkersStudy DesignObservations SamplingFiltersAssayValidationAnalysisAcceptance Criteria



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Dissolution – General ConsiderationsØDissolution is a performance test, applicable to many

dosage formsØIt yields data to allow an accept/reject decisionØOne test amongst a series of othersØThe USP provides the following General Chapters:

Disintegration <701>Drug Release <724>Dissolution <711>

MediumApparatus/Agitation RateStudy DesignAssayAcceptance Criteria



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Dissolution – General ConsiderationsWhat is needed?Apparatus, medium, and test conditions

How should the acceptance criteria look like?Should be representative for multiple batches with the same nominal composition and manufacturing process

What are the requirements for a dissolution procedure?ØMust provide a method rugged and reproducible as well as transferableØMust be appropriately discriminating, i.e. capable of distinguishing significant changes in a composition or manufacturing process that might be expected to affect in vivo performance



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Dissolution – General Considerationsthe discriminating method…

Differences in vitro for batches without differences in vivo – What to do?

Ø Carefully evaluate whether the procedure is too sensitive or appropriately discriminating

Ø Assess the results from multiple batches that represent typical variability in composition and manufacturing parameters

Ø Intentionally vary manufacturing parameters (lubrication, blend time, compression force, drying parameters)



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Dissolution – General Considerations… more requirements for the dissolution procedure

Ø Reflection of relevant changes in the drug product over time caused by temperature, humidity, photosensitivity, and other stress

Ø No significant analytical solution stability problems should be associated with the test

Ø Not highly variable: RSD > 20% at 10 min or lessRSD > 10% at later time point

Ø Identify sources of variability: Ø Formulation (API, excipients, manufacturing process, poor

CU, process inconsistency, film coat, capsule shell aging, hardening or softening of dosage forms)

Ø Test procedure artifacts (coning, tablet sticking, air bubbles etc.)



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Dissolution – Medium – Criteria for Selection

Ø Physical and chemical data for:

Ødrug substanceØSolubility and solution state stability as a function of pH ØEvaluation of influence of buffer, pH value and

surfactants

Ødosage unitØRelease mechanism (immediate, delayed, modified)ØDisintegration rate as affected by hardness, friability,

presence of solubility enhancers, other excipients



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Dissolution – Medium – Sink Condition

The term sink condition is based on the theory that the drug concentration on both sides of the epithelial layer of the intestinal wall approach equilibrium in a short time and that the gastrointestinal tract acts as a natural sink; i.e., the drug is absorbed instantaneously the moment it dissolves.

dc/dt = K S (Csat – Csol)

Where: dc/dt = dissolution rate, K = dissolution constantS = surface area Csat = concentration of saturated solutionCsol = concentration at any given time

Under sink conditions (Csat>>>Csol) the concentration gradient effect is eliminated, thus a better representation of the performance of the dosage form is given (rather than a solubility issue of the drug substance)

Test Method should yield biopharmaceutically relevant results

FIP

Quantity of medium used should be not less than 3 times that required to form a saturated solution

USP

Solubility requirements (Sink Conditions)

Desirable but not mandatory FDA



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Dissolution – Medium – Acceptable with Justification

Ø Medium that does not provide sink conditions is acceptable, if it has a better discriminatory power

Ø Aqueous-organic solvent mixtures are discouraged, but acceptable with appropriate justification

Ø Purified water is “not ideal”Ø Disadvantage

Ø Source of water can determine qualityØ pH value not controlled and can vary from day to dayØ pH value of water can vary within the run

Ø AdvantageØ InexpensiveØ Readily availableØ Easy disposalØ Suitable for products with release rates independent

from pH value



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Dissolution – Medium – Selection for Oral Dosage Forms

Evaluate dissolution characteristics in the physiological pH rangeØ 1.2 – 6.8 for immediate release formulationsØ 1.2 – 7.5 for modified-release formulationsØ Measure pH value before and after the testØ Evaluate solubilizing effects of molarity of buffer or acid

Typical MediaØ dilute HCl bufferØ buffersØ simulated gastric or intestinal fluids: FASSIF, FESSIF, FASGF etc.Ø waterØ surfactants (with or without acids of buffers): polysorbate 80, SLS, bile salts

For highly soluble, highly permeable compounds for selection of medium and apparatus, follow the FDA Guidance (FDA Guidance for Industry: Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on a Biopharmacutics Classification System, August 2000; www.fda.gov/cder/guidance)



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Very poorly soluble compounds may require the addition of surfactants…

Definition: Surfactant (surface active agent) is a molecule that, when added to a liquid at low concentration, changes the properties of that liquid at a surface or interface.

General structure: a hydrophilic and a hydrophobic portion.

Area of application:Ø improvement of wetting / spreadingØ compatibilizing formulation components Ø modification of viscosity…Ø not to be used to improve performance of a formulation in vitro

SLS/ SDS (anionic) Cetyl Trimethyl Ammonium Bromide CTAB (cationic)

Polysorbate 80, Brij (nonionic) Lauryldimethylamine-oxide (LDAO)



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The lowest concentration providing sink conditions is the one of choice!

Profiles need to be provided at several different surfactant concentrations.

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0.01% Polysorbate 800.1% Polysorbate 800.25% Polysorbate 800.5% Polysorbate 801% Polysorbate 802% Polysorbate 80



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Dissolution – Medium – Volume and Addition of Enzymes

VolumeApparatus 1 and Apparatus 2 500ml – 900ml - 1000ml

Volume can be raised between 2000ml – 4000ml with justification

EnzymesEnzymes are permitted in accordance with Dissolution <711> whendissolution failures occur as a result of cross-linking (1, 2) with gelatinCapsules or gelatin-coated products

(1) Deepti Gholap, Saranjit Singh: The influence of drugs on gelatin cross-linking; Pharmaceutical Technology, April, 2004

(2) Clyde M. Ofner III * et al.: Crosslinking studies in gelatin capsules treated with formaldehyde and in capsules exposed to elevated temperature and humidityJournal of Pharmaceutical Sciences, Volume 90, Issue 1 , Pages 79 - 88



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Dissolution – Medium – Deaeration

Air Bubbles can…… act as a barrier (if present on the dosage form or basket)… can cause particles to cling to the apparatus… can increase buoyancy leading to higher rates… decrease the surface area exposed to the medium

leading to lower rates

Determine significance of dissolved gases (create profiles in deaerated and non-deaerated media).

(No exact) method described in the pharmacopoeias (1)

Ø Heated vacuum filtrationØ Helium sparging

Deaeration method is part of the dissolution method.Media containing surfactants do not require deaeration (2).

(1) Degenhardt et al.; Dissolution Technologies February 2004(2) Fliszar et al.; Dissolution Technologies August 2005



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Dissolution – In Vitro - In Vivo Correlation<1088> In Vitro and In Vivo Evaluation of Dosage Forms

Biorelevant medium:

Ø Has some relevance to the in vivo performance of the dosage unitØ Choice based on mechanistic approach that considers

site of absorption and the knowledge about the rate limiting step(dissolution vs. permeability)

Ø Example: compound dissolves quickly in stomach and is highly permeable, gastric emptying time may be the rate limiting stepØ Dissolution test should show quick release in acidic conditions

Ø Influence of fed and fasted states can effect the absorption or solubilityØ Often different from routine mediumØ Media compositions found in literature, often contain natural surfactants

Ø For QC purposes, substitution of e.g. bile salts by synthetic surfactants is recommended



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Dissolution – Apparatus

Apparatus Description Used for…

Apparatus 1 Rotating Basket Immediate Release Tablets and Capsules

Apparatus 2 Rotating Paddle Immediate Release Tablets and Capsules

Apparatus 3 Reciprocating Cylinder

Controlled or Extended Release Dosage Forms ( e.g. bead type modified release; soft gelatin capsules, suppositories) or Poorly Soluble Drug Products

Apparatus 4 Flow Through Cell

Extended Release (e.g. bead type modified release; soft gelatin capsules, suppositories) or Poorly Soluble Drug Products

Apparatus 5 Paddle over Disk Transdermal Delivery Systems

Apparatus 6 Rotating Cylinder Transdermal Delivery Systems

Apparatus 7 Reciprocating Holder

Transdermal Delivery Systems and nondisitegrating oral modified-release dosage forms

Cell Method e.g. Franz Cell Apparatus Semi-Solid Dosage Forms (creams, ointments)

Chewing Apparatus

Chewing Apparatus Gums



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Dissolution – ApparatusChanges to the Apparatus (allowed with justification!):

Ø Basket mesh size 40-mesh(e.g. 10, 20, 80 mesh)

Ø Non-compendial apparatus

Ø small volume with mini paddles and baskets for low dosage strengthproducts)

Ø rotating bottle or static tubes

Ø PeakTM vessels



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Dissolution – ApparatusNon-compendial apparatus

Ø modified flow through cells (1)

Ø (1) May 2005 Volume 12 Issue 2Special Edition on Flow Through Cell, USP Apparatus 4 Slide taken from presentation by V. Gray



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Dissolution – Agitation

Apparatus 1 (Basket)100 rpm

Apparatus 2 (Paddle)50 rpm – 75 rpm25 rpm – 50 rpm acceptable for suspensions75 rpm recommended when coning (mounting) is a problem100 rpm: extended release products

Other speeds are acceptable with justification!e.g. a better reflection of in vivo performance or improvement of

discriminatory power

100 rpm Basket ~ 50 rpm Paddle- < 25 rpm: inconsistency in hydrodynamics- > 150 rpm: turbulences



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Dissolution – Sinkers“… a detailed description of the sinker must be stated in the written procedure.”

Sinkers can significantly influence the dissolution profile!

Ph.Eur. 5.04:„A small, loose piece of non-reactive material, such as not more than a fewturns of wire helix, may be attached to dosage units that would otherwisefloat.“



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Dissolution – Study Design – Time Points

Immediate Release 30-60 min single time point specification is sufficient for Pharmacopoeialpurposes

But:“Industrial and regulatory concepts of product comparability and performancemay require additional time points, which may also be required for product registration and approval.”

No profile information needed, if more than 85% released within 15 min(highly soluble, highly permeable drug substance in rapidly dissolving product)

Most immediate release products reach 85% - 100% at 30 min – 45 min(dissolution time points at 15, 20, 30, 45, and 60 minor earlier: e.g. subpensions: 5 -10 minor later: slow releasing products)

Time points for pharmacopoeial purpose is chosen based on profile data.



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Extended Release at least three test time point

Ø Early time point: after 1 – 2h (“dose dumping test”)Ø Intermediate time point: to determine profileØ End time point: to show complete release of the drug

But:Additional time points may be required for drug approval purposes.

And:If more than one active drug substance is in the product, the release is to be determined for each of the active ingredients.



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Infinity points

Useful during development studiesAgitation speed increased at the end of the run for about 15 – 60 min

100% dissolution is not required to be shown, but infinity point can provide valuable information:

Ø Supplemental information to Content Uniformity Data

Ø Formulation characteristics during initial drug development

Ø Method bias

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Dissolution – ObservationsVery useful during method development and formulation

optimization!

Install proper lighting that allows good observations (CAVE: photodegradation)

Other potential observations:Ø Capsules may be surrounded by rubbery, swollen masses etc.Ø Floating particlesØ Disintegration rate/ complex disintegration of coated or enteric-coated products (e.g. partial

opening and splitting apart)

Observation Potential Reasons Uneven distribution of particles particles cling to sides of the vessel coning or mounting particles float at the surface film-coated tablets stick to vessels off-center mounds Air bubbles or sheen deaeration Dancing or spinning dosage units dosage unit hit by the paddle



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Dissolution – SamplingManual samplingØ at a site conforming with <711>Ø Plastic or glass syringesØ Stainless steel cannulaØ Filter Ø Filter holder

AutosamplingØ Needs to be cross-validated

with manual samplingØ Sampling site may differ from

<711> requests (e.g through the basket or paddle shaft), but acceptable with proper validation (i.e. demonstrated equivalence to manual sampling procedure)

Ø Concern: change in hydrodynamics

Standard bath with manual sampling

Fully automated computerized systemØ Requires

method comparability assessment



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Dissolution – Filters Ø Prevention of un-dissolved drug particles being analyzedØ Removal of insoluble excipients

Ø Filters can be in-line or at the end of the sampling probeØ Pore size: 0,45µm – 70µmØ Note:

Check particle size of drug substance (e.g. micronized material) Standard filter for automated systems are normally in a range of 10 – 20µm

Filter choice must be validatedØ Standard solution – filtered vs. unfiltered: determine recoveryØ Sample solution (prepared as a typical sample): determine recoveryØ No absorption or reaction with drug substanceØ No extractables

Centrifugation should not be considered!(unless adsorption to all common filters occurs)



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Dissolution – Assay

SpectrophotometryØ PreferredØ FastØ SimplerØ Fewer solvents

HPLCØ Can cope with significant interference from excipients or among drugsØ Improved analytical sensitivityØ Can be automatedØ Can provide for stability-indicating assay

Dissolution (Sample Preparation)

“Assay”(Quantitation)



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Dissolution – Validation - Preamble

Ø Validation elements to be addressed may vary, depending on the phase of development or intended use of the data

Ø Full validation expected by the time of Phase III clinical studiesØ Validation should address variations in the profile time points

Ø Validation needs to occur for each active ingredient separatelyØ Acceptance criteria are guidelines, may differ for some productsØ Recommendation: acceptance criteria should be stated in a firm’s SOP.

FormulationDevelopment

Quality Control

Prediction of in vivoperformanceBy IVIV correlation(for BCS class II and may be IV)

ProcessDevelopment

ProductStability Scale Up and

Post-Approval Change

Use of Dissolution Methods



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Dissolution – Validation – Specificity/ Placebo Interference

Definition from ICH Q2A:“...Specificity is the ability to asses unequivocally the analyte in the presenceof components which may be expected to be present.“ (i.e. no interference)

Placebo = all excipients and coatings (consider: inks, sinker, and capsule shell)

Practical Approach:Ø Weigh samples of placebo, dissolve in dissolution medium at „sample“

concentrationØ Prepare a 100% standard solutionØ Perform experiment at 37°C

I = InterferenceC = Concentration of the standard (mg/ ml)AP = Absorbance of placebo

Ø Calculate I = 100 C( AP / As) (V / L) As = Absorbance of standardV = Volume of medium (ml)L = Label Claim (mg)

Acceptance criterion:Interference should not exceed 2%.



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Dissolution – Validation – Specificity/ Placebo Interference

For extended release:Ø Placebo version of the finished dosage form rather than a placebo blend

is recommendedØ Consider to evaluate interference at multiple sampling points in the

profile

Interference > 2%?Ø Choose another wavelengthØ Use baseline substraction using a longer wavelengthØ Use HPLC

Note: If other active ingredients or degradation products at significant levels are present, it is necessary to demonstrate that they do not influence the resultPractical Approach: Determine the interference using matrix in presence and absence of the other active ingredient or degradant.Acceptance Criterion: The interference should not exceed 2%.



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Dissolution – Validation – Linearity and Range

Definition from ICH Q2A/ Q2B:“...The linearity of an analytical procedure is its ability (within a given range)

to obtain test results which are directly proportional to the concentration (amount) of analyte in the sample...”

“...For the establishment of linearity, a minimum of 5 concentrations is recommended. Other approaches should be justified...”

Practical Approach:

Ø Prepare solutions of the drug in concentrations from below the lowest expected concentration to above the highest concentration duringrelease

Ø for standard preparation the addition of not more than 5% (v/v) organic solvent for enhancing drug solubility is permitted without additional validation

Ø Calculate least-square regression



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Dissolution – Validation – Linearity and Range

Acceptance criteria:r2 = 0.98Y-intercept must not be significantly different from zero.

nominal test concentration [%]

0 20 40 60 80 100 120 140

area [mA

U*s]

0

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600

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1000

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1400

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standard ; dosage strength 1standard ; dosage strength 2combined regression line

parameters of combined regression line:y[0] -7.5006a 11.1540r ² 0.9990r 0.9995

nominal test concentration [%]

0 20 40 60 80 100 120 140

area [mA

U*s]

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1400

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standard spiked ; dosage strength 1standard spiked ; dosage strength 2combined regression line

Linearity Standard Standard spiked into

formulation matrix Linear slope: 11.1905 11.1540 y intercept: -7.0650 -7.5006

Correlation coefficient 0.9999 0.9995

-15

-10

-5

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0 20 40 60 80 100 120 140



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Dissolution – Validation – Accuracy and Recovery

Definition from ICH Q2A:“The accuracy of an analytical procedure expresses the closeness of agreement between the value which is accepted either as a conventional true value or an accepted reference value and the value found.This is sometimes termed trueness.”

Accuracy vs. PrecisionAccuracy is telling the truth . . . Precision is telling the same story over and over again. (Yiding Wang, [email protected])



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Practical Approach:Ø ICH Q2B: “...Several methods for determining accuracy are available…”

Ø Add known quantities of the drug substance to a synthetic mixture of the drug product components (include coating materials, capsule shell)

Ø 3 concentration levels, each 3 replicates, at the Specified Range +/- 20%“e.g., if the specifications for a controlled released product cover a region from 20%, after 1 hour, up to 90%, after 24 hours, the validated range would be 0-110% of the label claim.”

Ø Special Case: Delayed-Release Dosage Forms in the Acid Stage: A limit of notmore than 10% needs to be validated (“if compound degrades in acid, the validationexperiment must address this fact.“)

Ø For poorly soluble drugs:Ø either add of up to 5% (v/v) of organic solvent when preparing standard solutionØ or – instead of using drug powder - add stock solution (equivalent to the targeted label

claim) to the vessel

Ø For very low doses:Ø Use stock solutions than attempting to weigh very small amounts



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% Theory % Recovery

97.50 Average 97.25 96.34 Lower 95% CL 95.22

16.38

97.92 Upper 95% CL 99.29 97.94 Average 97.86 98.08 Lower 95% CL 97.21

81.88


106.45


131.80

97.33 Upper 95% CL 99.75 Average (n=12) [%] 97.75

RSD [%] 0.70 95% CI of Average ± 0.44%

ØReference Standard solutions were preparedØ1000 minus x mLdissolution medium were given into a vessel, one placebo tablet was addedØThe solution was heated to 37°CØx mL of the reference standard solution wereaddedØSamples were pulled after 45 minutes, filtered and assayed

Acceptance criterion:

Recovery should be 95% - 105% of the amount addedBraceting or matrixing of multiple strengths may be useful



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Dissolution – Validation – Precision

Definition from ICH Q2A:

“...The Precision of an analytical procedure expresses the closeness of agreement between a series of measurements obtained from multiple sampling of the same homogenous sample under the prescribed conditions.

Precision may be considered at three levels...“:Repeatability: intra-assay precisionIntermediate Precision: within-laboratory precisionReproducibility: precision between laboratories

Precision should be investigated using homogenous, authentic samples (e.g. a well characterized drug product lot of tight Content Uniformity). However, if it is not possible to obtain a homogeneous sample it may be investigated using artificially prepared samples or sample solutions...



48

Dissolution – Validation – Repeatability

Practical Approach:

Replicate measurements (multiple injections or spectrophotometricmeasurements) of standard and/ or sample solutions

a) a minimum of 6 replicate determinations at 100% of the test concentration

b) a minimum of 9 determinations covering the specified range for the procedure

Recommended Data:

RSD (Coefficient of variation) and Confidence Interval should be reported



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Dissolution – Validation – Intermediate Precision

Practical Approach:Use of an experimental design is encouraged

Ø Profiles on the same sampleØ Two analystsØ Each analyst preparing standard solutions and mediumØ Different bathsØ Different spectrophotometers or HPLCs (with different columns)Ø Different daysØ Bracketing between high and low strengths may be accptable.

Acceptance criterion:Mean value between the dissolution results at any two conditions using thesame strength does not exceed an absolute…

…10% (at time points with < 85% dissolved)… 5% (at time points with = 85% dissolved)



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Dissolution – Validation – Robustness

Definition from ICH Q2A:“...The robustness of an analytical procedure is a measure of its capacity to remain unaffected by small, but deliberate variations in method parameters and provides an indication of its reliability during normal usage...“

A side note: Robustness versus Ruggedness:Robustness: "internal" conditions to the assay Ruggedness: "external" conditions

(e.g. when and where the assay gets done, ambient temperature and humidity, alternative sources of raw materials and lot-by-lot changes)

Practical Approach:Use of an experimental design is encouragedAcceptance criterion:Mean value between the dissolution results at any two conditions using thesame strength does not exceed an absolute…



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Dissolution – Validation – Robustness

Statistical Designs were used(including sample preparationand assay)

Factor Low Level Mid Level High Level Rotational Speed of

baskets 95rpm 100rpm 105rpm

Surfactant concentration 0.20% 0.25% 0.30% Temperature 36°C 37°C 38°C

Concentration of Acid 0.9mM 1.0mM 1.1mM Analyst A n/a B

Instrument 1 n/a 2 Dose strength 1 n/a 2

Day Acid %ACN Salt Flow Temp Wlength Instrument Analyst Vtime Vspeed Column

1 4 29 23,35 g 1.1 37 274 Highlander A 35 300 A1 4 29 23,35 g 0.9 43 286 Kuno B 25 200 A1 6 31 25,35 g 1.1 43 286 Highlander B 35 300 A1 6 31 25,35 g 0.9 37 274 Kuno A 25 200 A2 6 29 25,35 g 0.9 37 274 Kuno B 35 300 A2 6 29 25,35 g 1.1 43 286 Highlander A 25 200 A2 4 31 23,35 g 1.1 37 274 Highlander B 25 200 A2 4 31 23,35 g 0.9 43 286 Kuno A 35 300 A3 4 29 25,35 g 1.1 37 286 Kuno A 35 200 A3 4 29 25,35 g 0.9 43 274 Highlander B 25 300 A3 6 31 23,35 g 0.9 37 286 Highlander A 25 300 A3 6 31 23,35 g 1.1 43 274 Kuno B 35 200 A4 5 30 24,35 g 1.0 40 280 Kuno A 30 250 A4 5 30 24,35 g 1.0 40 280 Kuno A 30 250 A4 5 30 24,35 g 1.0 40 280 Kuno B 30 250 B4 5 30 24,35 g 1.0 40 280 Kuno B 30 250 C4 5 30 24,35 g 1.0 40 280 Kuno A 30 250 C4 5 30 24,35 g 1.0 40 280 Kuno B 30 250 B5 6 29 23,35 g 0.9 37 286 Highlander B 35 200 A5 6 29 23,35 g 1.1 43 274 Kuno A 25 300 A5 4 31 25,35 g 1.1 37 286 Kuno B 25 300 A5 4 31 25,35 g 0.9 43 274 Highlander A 35 200 A



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Dissolution – Validation – Standard and Sample Solution Stability

The standard and sample solutions must be stored under conditions thatensure stability. The procedure text should indicate expiry for the solutions.

Practical Approach:Standard: analyze solutions of a specified period of time, using a

freshly prepared standard solution at each time interval forcomparions

Sample: analyze sample solutions over a specified period of time using the original sample solution response as comparison.

Acceptance criterion:Recovery between 98% and 102%

If solutions are not stable, evaluate different storage temperature(refrigeration), light protection or different container material (plastic orglass).



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Dissolution – Validation – Dissolution Medium Stability

Not requested per <1082>, but by our QC laboratory customers:

The Approach

Dissolution medium was prepared and stored under ambient laboratory conditions for 28 days. Comparison of ProfilesUsing the Similarity Factor (f2) The f2 factor obtained comparing the results after 14

days of storage under ambient laboratory conditions with the results at initial was 94. For the 28 days time point compared to initial a f2 of 89 was calculated, respectively. This indicates comparability of profiles.

min

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Freshly prepared mediumMedium stored for two weeksMedium stored for four weeks



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Dissolution – Spectrophotometric AnalysisInstrument: routine performance checks, cleaning and maintenance

Measurement:Wavelength: examination of the UV-spectrum of the drug in solutionSampling: automatically or manuallyCell path lengths: 0.02cm – 1cmStandards: typically at 100% or at Q-value,

for profiles: several concentrations may be usefulAnalysis: Blanks and standards are expected at beginning and end

of analysis bracketting the samples

Criteria: Mean absorbance of the blank may not exceed 1% of the standardTypical RSD for UV-analysis is not more than 2%

Absorptivity: - calculated by dividing the mean standard absorbance by theconcentration (mg/ml) divided by the flow-cell path length (cm). - may be valuable when troubleshooting of aberrant data.

“Fiber optics as sampling and determinative method with proper validation, is an option.“



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Dissolution – HPLCMeasurement:ØInvestigate compatibility of medium and mobile phase

(especially important for large injection volumes)ØSingle injections of each vessel time point with standards throughout runØStandard concentration typically at 100%ØInterference with placebo needs to be evaluatedØPotential of late eluters needs to be evaluated

(by performing extended runs)ØSystem suitability: retention window and inhection precision

Criteria:ØMean absorbance of the blank may not exceed 1% of the standardØTypical RSD for 5 or 6 standard injections is not more than 2%

Documentation:Validation documentation should include overlaid chromatograms of blank, placebo, standard and sample.



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Dissolution – Acceptance Criteria

Ph. Eur. 5.04:



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Dissolution – Acceptance CriteriaØ Q = 75% - 80%

Ø Q-values typically not greater than 80% (as allowance needs to be made for Assay and ContentUniformity)

Ø Acceptance criteria are established on the basis of an evaluation of the dissolution profile data

Ø Should be consistent with historical data

Ø Should be set that way that acceptable batches will haveresults that fall within the criteria.



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The Dissolution Procedure: Development and Validation

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