RQA Ireland Regional Forum - Athlone, May 2016 Quality ... · An Overview of Dissolution The dissolution test has evolved to become a definitive tool used to characterize the performance

Performance Testing of Novel Dosage Forms

Terry Way BPharm MAPS

Dissolution Science ConsultantGlasside Technologies Ltd.

© 2016 – Glasside Technologies Ltd., UK All Rights Reserved

RQA Ireland Regional Forum - Athlone, May 2016Quality Considerations – Pharma and Biopharma

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An Overview of Dissolution

The dissolution test has evolved to become a definitive tool used to characterize the performance characteristics of many types of pharmaceutical dosage forms.

As dosage forms have become more varied over the last fifty years, dissolution apparatus has required continuous improvement and modification to provide suitable conditions for performance testing.

However, probably 99% of dissolution testing is performed on traditional tablets and capsules.


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Dissolution is not just about orally ingested products such as tablets and capsules.We also test :

suspensions and powderscoated beads and granulesointments, creams, gelstransdermal patches micro-needle patchesimplants, stentsmedicated contact lenseswound care productsbone cementpowders for inhalationchewing gums, etc….


Dissolution is an important tool for characterizing the biopharmaceutical properties of a pharmaceutical product at different stages throughout its life cycle.Product DevelopmentAPI characterisation, Formulation evaluation, Stability testing

BioavailabilityIn Vitro / In Vivo Correlation, Bioequivalence

Quality ControlPass / Fail product release

Scale-Up and Post-Approval ChangesRaw materials, Formulation, Process, Manufacturing site


Dissolution assesses the performance of drug products

To be effective, the test should be: PredictiveComparative DiscriminatoryReproducible


The dissolution apparatus must maintain reproducible hydrodynamics:Physical uniformity and alignmentTemperature controlAgitation rateVolume control (esp. evaporation)Vibration controlPrecision

The apparatus must also meet Analytical Instrument Qualification requirements: IQ, OQ & PQ

Challenges

Low Dose FormulationsOral dosage units containing concentrations of analyte at

microgram or nanogram levels.Ocular or other mucous membrane direct applications.Inhalations

Small volumesAnalytical challengesLCMS?

Quantitation Limit – the lowest amount of analyte in a sample that can be determined with acceptable precision and accuracy under the stated experimental conditions.

Challenges

Long-term extended release formulationsContinuous release of low concentrationsDays, weeks, months….Implants and depotsTransdermals, micro-needlesDrug-eluting stentsBone cement

Challenges

Rapid release formulationsImmediate releaseseconds, minutes….Sub-lingualsGel films

Sampling challenge

Challenges

Poor solubilitySink conditionsLarge volumesMultiple volumesContinuous flow

Analytical challengeLCMS?Bi-phasic?

Variety of Dissolution and Drug Release Apparatus

Compendial Dissolution Apparatus

USP <711> Apparatus 1 & 2Nominal 1000ml Vessel2l and 4l vessels also officialOperational minimum – 400 ml Tablets, capsules, suspensions,

suppositories, chewable tablets, powders

Transdermal systems (Apparatus 5&6)


Modified apparatus: Stationary Basket assembly

Basket for USP FelodipineExtended Release Tablets


USP <711> Apparatus 3Nominal 300ml VesselTypically 175ml to 275ml volume10cm dipExtended release tablets,

capsules, beads, chewable tablets with glass beads added.

Modifications have been made to accommodate 1000ml vessels

Apparatus 3 – novel dosage forms

Nasal sponges Oral patches


USP <711> Apparatus 4 Initially designed for poorly

soluble extended release compounds

Typical flow rates from 4ml per minute up to 16ml per minute

A closed system with a small media reservoir could reduce volume to less than 30ml

Extended release tablets, beads, suppositories and implants

Special cells for powders, implants and suppositories

Flow Cell

Piston Pump

Fresh Medium


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USP <724> Apparatus 7Also known as the “Alza apparatus”

USP Apparatus 7 has evolved to handle not only transdermal systems but other extended release products.

The apparatus is derived from the Bio-Dis (Apparatus 3) and typically uses volumes of 25 – 50ml Modifications have been made to

accommodate vessels from 5ml to 300ml

2cm dipUsed for: extended release tablets,

capsules, beads, implants, transdermals, osmotic pumps, stents and other novel dosage forms

Apparatus 7 - Variations

Apparatus for Small Volumes

Larger Volumes for Transdermals

Small Volume Drug Release Apparatus – 400-DS

Temperature probe and sampling port at bottom of the dissolution cells

• Small Volume: 5-10ml

• Low Evaporative Loss

• Use of organic solvent media

• Automated Sampling and Media Replacement

400-DS Reciprocating Holder Options

Variety of sample holdersDrug-eluting stentsMicro-particulatesMedicated contact lensesPace-maker electrodes

Micro-needle patches


Semi-SolidsThe requirement for testing the release rate of drugs from semi-

solid dosage forms has increased in recent years.Products tested include ointments, creams, pastes, gels and

lotions.USP has recently published General Chapter <1724> “Semisolid

Drug Products - Performance Tests”. This provides general information on testing semi-solids including descriptions of three apparatus:Vertical Diffusion CellImmersion CellInsert for Apparatus 4


USP <1724> Vertical Diffusion Cell Three versions of this apparatus are described based on the classic Franz cell.

Model A Model B Model Cvolume ~7ml ~5ml ~10ml


USP <1724> Immersion Cell Method Used in conventional dissolution testers with a special vessel and “mini-paddle”. Volume of medium: 50-200ml


USP <1724> Flow-Through Cell Method Used in Apparatus 4 equipment

Modifications and Non-Compendial Dissolution Apparatus

Non-Compendial Dissolution Apparatus

Based on USP Apparatus 1&2Mini-Paddle ApparatusMini-Basket Apparatus100 or 200ml vesselsOperational minimum 30mlTablets, Capsules, Powders



Oral patch in 100ml300ml vesselApparatus 2 basket at 50rpmDirect UV measurement with

fibre-optic probes90% dissolved in 10 minutes


Modifications for 5l Vesselsfor routine testing of low-

solubility formulations


Vaginal rings are often tested in swirling flask apparatus in incubators typically in 250ml saline at

130rpm for 12 hoursManual sampling


Medicated chewing gums have become popular especially for Nicotine. Ph. Eur. describes one apparatus in 2.9.40 - DissolutionTest for Medicated

Chewing Gums“The gum is artificially chewed by the horizontal pistons, and the vertical piston ensures that the gum stays in the right place between chews.”

Volume of medium ~20ml“60 chews per minute”

USP has an Advisory Panel looking into a suitable procedure.


Inhalations There are currently no requirements for dissolution testing of particulates from

MDI/DPI aerosol products. Various devices have been used for research purposes:

Powder cell in Apparatus 4 using whole formulationCollected fractions from Anderson Cascade Impactor: filters from each fraction placed between membranes

in a special cell for Apparatus 4

Using NGI apparatus, special collection cups are covered with a membrane and dissolution measured in Apparatus 2:

Thank You!

Terry [email protected]

Documents

RQA Ireland Regional Forum - Athlone, May 2016 Quality ... · An Overview of Dissolution The dissolution test has evolved to become a definitive tool used to characterize the performance