Method Development and Setting Clinically Relevant Dissolution Specifications, including Quality by Design Vivian A. Gray USP Expert Committee Dissolution Workshop March 7, 2013
QBD and Dissolution Method Development Looking at QBD Concepts Not different from doing a thorough job of developing a meaningful dissolution test
USP Chapter <1092> The Dissolution Procedure: Development and Validation Purpose Elaborate on validation USP <1225> little dissolution coverage Instructions on Method Development USP <1088> instructions too brief Introduction to new technology and equipment Encourage usage of automation by giving validation parameters
Dissolution Curve Moderate variability Gradual increase in profile yielding several points before 85% Good for Similarity Profile-F2 No longer is a simple fast test appropriate (except for BCS class 1)
Typical Dissolution Curve
Method Development Should be a team effort Formulators PK To provide information about Critical Quality attributes Provide dosage forms that reflect variables for the DOE Provide the IN VIVO side of the IVIVC Analytical Develops the method Regulatory BE and biowaivers
Know Your Critical Drug Properties pka Particle size, shape, distribution Stability in dissolution media Absorption site for drug Crystal structure (solvent changes), shape
Know Your Critical Dosage Form Properties Understand Release Mechanism(s) what are factors that influence this Presence of solubility enhancers Moisture-what happens on stability? Polymorph conversions, particle size changes
Excipients-More Emphasis on Quality/Understanding Magnesium stearate, sodium starch glycolate, starch (potato, corn), ethylcellulose Based on natural products-inherent variability Physical properties Particle size, shape, polymorph, Particle size relative to API particle size
Excipients Chemical properties-adherence to specifications Identity, purity, grade, stability Viscosity, molecular weight
Method Development Mechanical Properties Poorly understood Tensile strength Brittle fracture index Degree of viscoelasticity Granule density Melting point
Method Development Mechanical Properties Plastic Deformation Pressure Flow properties, grain size Friability Water reactivity/binding on surfaces
Critical Manufacturing Variables Compression force Addition order Coating methods Equipment capabilities, size Amount of water used, depth of fill Mixing/shearing Press, feeder, impeller speed
Controlled Release Critical Characteristics Coating characteristics-uniformity of thickness, layering, top coat Core, pore size Matrix excipients quality-polymers Porosity, roughness Swelling characteristics Dose dumping
Controlled Release Critical Characteristics Intermediate steps Spray drying, freeze drying, capsule powder Beads Encapsulation Polymers Variations, lot to lot
Biopharmaceutics Classification System Solubility is a primary aspect
Guidance for Industry Biopharmaceutics Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate- Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System FDA/CDER August 2000 http://www.fda.gov/cder/guidance/3618fnl.htm
Biopharmaceutics Classification System Class 1 Class 2 Class 3 Class 4 Highly Soluble Poorly Soluble Highly Soluble Poorly Soluble Highly Permeable Highly Permeable Poorly Permeable Poorly Permeable
Three aspects of BCS API solubility Absorption/permeability level Dissolution test rate in 3 media 0.1 N HCl Acetate buffer, 4.5 ph Phosphate buffer, 6.8 ph
Biopharmaceutics Classification System Solubility range Amount equivalent to highest dose strength dissolves in 250 ml of ph 1-6.8 media at 37º Use USP standard buffers/acid
BCS Dissolution rate in 0.1 N HCl, 4.5 ph Acetate buffer, and 6.8 ph Phosphate buffer 85% in 15 minutes or 30 minutes in all media Paddle 50 rpm, basket 100 rpm
Method Development Determine the BCS class Class 1- media selection is simple 0.1 N HCl, ph 4.5 acetate, or ph 6.8 phosphate 900mL, Basket/100, Paddle/50
Method Development For Class 1, pick one of the media for the regulatory test. Have profiles in the other for future comparisons Usually pick the one with slowest profile for F2 points FDA seems to be leaning toward 6.8 ph as media of choice
Choices of Media Acid Hydrochloric acid (0.1, 0.01, 0.001 N) Buffers (use USP preparation instructions) Acetate (ph 4.1--5.5; 0.05 M) Phosphate (ph 5.8--8.0; 0.05M) ph 6.8 is very common for ER
Choice of Media Surfactants plus acid or buffers can be a good combination Be consistent with grade and supplier Saline solutions offer viscosity
Surfactants Sodium lauryl sulfate (SLS same as SDS) Polysorbate (Tween) 20-80 Cetrimide (C-Tab) LDAO, Lauryldimethylamineoxide Brij, Triton X, Cremophor Solutol (polyethylene glycol hydroxystearate)
Surfactant Media Justification of surfactant level Sink Poorly soluble in ph range necessary before going on to surfactants Provide profile data in the chosen range
Fed and Fasted Media Some modifications have been published and presented Dressman Vertzoni Mullertz Klein Commercially available SIF powder Complex of taurocholate and lecithin
Fed and Fasted Media Gastric fed and fasted dissolution medium Simulated Gastric Fluid-Fasted Preparation in USP, ph 1.2, without enzyme Modified simulated gastric fluid-fasted Same as above with 0.1 % w/v Triton X 100 Milk (fed) Bovine milk, 3.5 % fat, Ensure
Fed and Fasted Media Intestinal fed and fasted medium Fasted intestinal fluid (FaSSIF) Fed intestinal fluid (FeSSIF)
FaSSIF (Fasted), One Liter ph 6.5 Osmolality--270+10 mosmol Sodium taurocholate--3 mm Lecithin--0.75 mm KH 2 PO 4 --(Monobasic)3.9 g KCl--7.7 g NaOH-- Qs ph 6.5
FeSSIF (Fed), One Liter ph 5.0 Osmolality--635+10 mosmol Sodium taurocholate--15 mm Lecithin--3.75 mm Acetic acid--8.65 g KCl--15.2 g NaOH-- Qs ph 5.0
Fed and Fasted Media Good for early read of effect of food Good for IVIVC Good for increased discrimination tests Not good for regulatory test as expensive and analytically challenging See preparation presented in May, 2004 issue of Dissolution Technologies
Target Media Lung Colon Mouth/saliva Skin Blood/plasma Tears/eye/Lacrimal See August 2011 issue of Dissolution Technologies for comprehensive preparation review
Dose Dumping with Alcohol Alcohol consumption by patient with Extended release dosage forms 40% alcohol dissolution medium used to mimic alcohol intake
FDA Data base of Dissolution Methods FDA has made public the database containing the dissolution conditions for products approved by the agency. The website was created on November 2, 2005 The website address is www.accessdata.fda.gov/scripts/cder/di ssolution/index.cfm
Media used for FDA approved IVIVC ph 1.2 buffer, Simulated Gastric TS (w/o pepsin) 0.01 N HCl with 0.05% SLS and 0.7% NaCl 0.04 M Sodium phosphate buffer ph 6.8 containing 2 % SLS Water (drug product has condition independent dissolution) 37
Media used for FDA approved IVIVC 0.05 M sodium citrate and 0.09 N NaOH, ph 4.8. At 5 hours, ph is adjusted to 6.6 with addition of 100 ml media: 0.05 M sodium phosphate and 0.46 N NaOH Ethanol/water IVIVC can be successful with simple USP listed methods 38
Apparatus Selection Apparatus 1 and 2 should be first choice Apparatus 3--Good research tool may be good for Delayed release and some new dosage forms and beaded products
Typical Apparatus/Speeds Paddles 50 rpm preferred-speed for BCS 75 rpm to eliminate coning, variability 25 rpm or more used for suspensions Used with tablets or capsules with sinkers 100 rpm used frequently with Extended release
Typical Apparatus/Speeds Basket 50-100 rpm preferred Over 100 rpm sometimes necessary Used for floating dosage forms Used for slowly disintegrating dosage forms
Paddle or basket? Justification not needed for using one over the other Start with Paddle unless a capsule (basket) Basket at 50 rpm will provide a slower dissolution
USP Apparatus 3- Reciprocating Cylinder Critical factors Dip rate Deaeration Screen mesh Temperature Levelness Vessels
Apparatus 4 Flow through cell Open system, adaptable to controlled degrees of closed system Infinite sink conditions Change ph during test 46
Apparatus 4 47
Tablet cell 12 mm Tablet cell 22.6 mm Cell for powders and granulates Cell for implants Cell for suppositories and soft gelatin capsules Temperature- Measuring Head 48
Understanding the Release Mechanism(s) Develop the best Dissolution method Free of artifacts Controlled variability Good profile shape Must be challenged to pick up changes in Critical Quality Attributes 49
Considerations for Extended Release Extended release specs biggest problem is need for wide specification windows to accommodate high variability in dissolution rates.
Role of Variability High variability Difficulty in determining truly significant differences Causes problems in setting and meeting specifications
F2 Rules on Variability RSD should be NMT 20% at < 15 minutes RSD NMT 10% for all other points Only mention of variability limits in FDA guidances What is too variable?
Role of Variability Must minimize and understand the source(s) Cause of variability should be identified Formulation Dissolution method Observations Validation
Spotting Causes of Variability through Observations Look at all vessels for uniformity of an observation- Important feedback to formulators and manufacturing groups
Spotting Causes of Variability through Observations Pellicles (ballooning), crosslinking Floating chunks at surface Spinning Coning BUBBLES anywhere (basket screen)
Spotting Causes of Variability through Observations Center/off-center position of dosage form Sticking to vessel with film coated tablets or capsules Change in observable particle size and shape Extended release - swelling, splitting
Critically Relevant Specifications FDA goal is to have a method that will discriminate between bioequivalent and bioinequivalent products Demonstrate the dissolution method distinguishes between critical drug substance, drug product and manufacturing variables ESPECIALLY MANUFACTURING VARIABLES 57
Critical steps for Specification Setting Understand Release Mechanism(s)- linked to clinical outcome Design of Experiments (DOE) Form list of critical attributes What variables will have an impact Dissolution run on varied formulations 58
Design of Experiments (DOE) Challenge the Method, find the weaknesses May be part of the IVIVC development process A Heavy duty Robustness Validation parameter 59
The Future from FDA QBD- Quality by Design Implications-IVIVC expected with Extended release and even poorly soluble (BCS Class 2) Immediate release
Clinically Relevant Specs Improve quality of dissolution test FDA goal presumably is to have a method that will discriminate between bioequivalent and bioinequivalent batches The Dissolution performance is considered the link to the pivotal biobatch
Dissolution Resources Websites Dissolution Technologies at www.dissolutiontech.com (Searchable) www.fda.gov/cder www.usppf.com (Pharmacopeial Forum now free online)
Dissolution Resources FDA, JAPAN, WHO and European Guidances USP General Chapters and Stimuli Articles and Revisions <1092> Dissolution validation and method development _UPDATE COMING SOON ICH Documents
Dissolution Resources Dissolution Technologies, Questions and Answers Edited by Marques and Brown Handbook of Dissolution Testing, Third Edition, Hanson and Gray Chinese translation Pharmaceutical Dissolution Testing, Edited by Dressman and Kramer
Dissolution Resources Dissolution Theory, Methodology and Testing, Edited by A. Palmieri Journal of the Controlled Release Society
Question and Answer Session vagray@rcn.com