RQA Ireland Regional Forum - Athlone, May 2016 Quality Considerations Pharma and Biopharma Performance Testing of Novel Dosage Forms Terry Way BPharm MAPS Dissolution Science Consultant Glasside Technologies Ltd. 2016 Glasside Technologies Ltd., UK All Rights Reserved 0
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.
An Overview of Dissolution Dissolution is not just about orally ingested products such as tablets and capsules. We also test : suspensions and powders coated beads and granules ointments, creams, gels transdermal patches micro-needle patches implants, stents medicated contact lenses wound care products bone cement powders for inhalation chewing gums, etc. 2
An Overview of Dissolution Dissolution is an important tool for characterizing the biopharmaceutical properties of a pharmaceutical product at different stages throughout its life cycle. Product Development API characterisation, Formulation evaluation, Stability testing Bioavailability In Vitro / In Vivo Correlation, Bioequivalence Quality Control Pass / Fail product release Scale-Up and Post-Approval Changes Raw materials, Formulation, Process, Manufacturing site
An Overview of Dissolution Dissolution assesses the performance of drug products To be effective, the test should be: Predictive Comparative Discriminatory Reproducible
An Overview of Dissolution The dissolution apparatus must maintain reproducible hydrodynamics: Physical uniformity and alignment Temperature control Agitation rate Volume control (esp. evaporation) Vibration control Precision The apparatus must also meet Analytical Instrument Qualification requirements: IQ, OQ & PQ
Challenges Low Dose Formulations Oral dosage units containing concentrations of analyte at microgram or nanogram levels. Ocular or other mucous membrane direct applications. Inhalations Small volumes Analytical challenges LCMS? 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 formulations Continuous release of low concentrations Days, weeks, months. Implants and depots Transdermals, micro-needles Drug-eluting stents Bone cement
Challenges Rapid release formulations Immediate release seconds, minutes. Sub-linguals Gel films Sampling challenge
Challenges Poor solubility Sink conditions Large volumes Multiple volumes Continuous flow Analytical challenge LCMS? Bi-phasic?
Variety of Dissolution and Drug Release Apparatus
Compendial Dissolution Apparatus USP <711> Apparatus 1 & 2 Nominal 1000ml Vessel 2l and 4l vessels also official Operational minimum 400 ml Tablets, capsules, suspensions, suppositories, chewable tablets, powders Transdermal systems (Apparatus 5&6)
Compendial Dissolution Apparatus Modified apparatus: Stationary Basket assembly Basket for USP Felodipine Extended Release Tablets
Compendial Dissolution Apparatus USP <711> Apparatus 3 Nominal 300ml Vessel Typically 175ml to 275ml volume 10cm dip Extended 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
Compendial Dissolution Apparatus 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
Compendial Dissolution Apparatus USP <724> Apparatus 7 Also 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 dip Used for: extended release tablets, capsules, beads, implants, transdermals, osmotic pumps, stents and other novel dosage forms 16
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 holders Drug-eluting stents Micro-particulates Medicated contact lenses Pace-maker electrodes Micro-needle patches
Compendial Dissolution Apparatus Semi-Solids The requirement for testing the release rate of drugs from semisolid 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 Cell Immersion Cell Insert for Apparatus 4
Compendial Dissolution Apparatus USP <1724> Vertical Diffusion Cell Three versions of this apparatus are described based on the classic Franz cell. Model A Model B Model C volume ~7ml ~5ml ~10ml
Compendial Dissolution Apparatus USP <1724> Immersion Cell Method Used in conventional dissolution testers with a special vessel and mini-paddle. Volume of medium: 50-200ml
Compendial Dissolution Apparatus 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&2 Mini-Paddle Apparatus Mini-Basket Apparatus 100 or 200ml vessels Operational minimum 30ml Tablets, Capsules, Powders
Non-Compendial Dissolution Apparatus
Non-Compendial Dissolution Apparatus Oral patch in 100ml 300ml vessel Apparatus 2 basket at 50rpm Direct UV measurement with fibre-optic probes 90% dissolved in 10 minutes
Non-Compendial Dissolution Apparatus Modifications for 5l Vessels for routine testing of lowsolubility formulations
Non-Compendial Dissolution Apparatus Vaginal rings are often tested in swirling flask apparatus in incubators typically in 250ml saline at 130rpm for 12 hours Manual sampling
Non-Compendial Dissolution Apparatus 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.
Non-Compendial Dissolution Apparatus 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 formulation Collected 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 Way terry.way@glasside.co.uk