Post on 29-Mar-2018
transcript
Kailas Thakker, PhDPresident Tergus Pharma, LLC.
Value of a Performance Test Efficacy of a drug product is measured by the
performance of the product during clinical trials which are:
Expensive
Time consuming
Unsuitable as routine tests
A performance test for a dosage form may serve as a surrogate test used to assure product quality.
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2
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Attributes of a Performance TestProvides a scientific rationale for
formulation selection
Ensures consistency in quality and manufacturing of a dosage form
Provides a uniform standard for comparing dosage forms across industry
Provides a measurable index to anticipate performance of the dosage form in the clinic
Dissolution and/or Drug
Release
Identify Critical Manufacturing
Variables
Formulation Development
Quality Control
Product Performance Assessment
Post Approval Changes
Gauge in-vivoPerformance
Why a Performance Test?
Regulatory Perspective on Performance Testing
Dosage Form Test
Parenteral Dosage forms Not Required
Immediate Solid Oral Dosage forms
Dissolution
Extended Release Oral Dosage forms
Dissolution/labeling
Transdermal Dosage forms Dissolution, In Vitro Release Testing(IVRT)
Inhalation Dosage forms None developed yet
Topical Dosage forms In Vitro Release Testing(IVRT)
Topical Dosage Forms Creams
Ointments
Gels
Emulsions
Topical Solutions
Topical Suspensions
Foams
Suppositories
Topical Aerosols
Transdermal Systems
Product Quality TestsUniversal Tests Specific Tests
Description Uniformity of Dosage Units
Identity Water Content
Assay Microbial Limits
Impurities Antimicrobial Preservative
Content
Antioxidant Content
Sterility
pH
Particle Size
USP Chapter <1724> To be official in fall 2013
Describes the apparatus to be used for performance test for topical and transdermal dosage forms
For topical dosage forms: Vertical diffusion cells –three models
immersion cells
USP apparatus 4
For transdermal dosage forms: USP apparatus 5 Paddle over disk
USP apparatus 7
Performance tests for topical dosage forms: USP
Chapter <1724> describes
Different apparatus and modifications of each that can be used to develop performance test (IVRT) for topical dosage forms
Guidance in developing IVRT with respect to the selection of key parameters
Recommendations on validation attributes and test parameters hat should be validated
In Vitro Release Test (IVRT) Traditionally, a variety of physical and
chemical tests such as
solubility
particle size
viscosity
form of API (crystalline or amorphous)
have been used to assure product performance for a semisolid dosage form
More recently, In Vitro Release Test (IVRT) has
provided a means of comprehensively and more directly assuring
performance of a dosage form.
In Vitro Release Test (IVRT): Apparatus
Vertical diffusion cells
Immersion cells
USP Apparatus 4
The principle is to determine the diffusion of active ingredient from the semisolid matrix
across a membrane
into an appropriate medium
representing the clinical use of semisolid dosage form as close as possible
Vertical Diffusion Cells General specifications are:
Cell body made of borosilicate glass. Other materials are acceptable as long as there is not interaction between the cell material and sample
Diameter of the orifice the donor chamber must be always smaller than or equal to the diameter of the receiving chamber
All cells should have same nominal value (± 10%) and the volume must be determined experimentally
Stirring rate should remain constant during the test
Thickness of the receiving chamber is generally 1.5 mm (±10% of the specified value)
Vertical Diffusion Cells In practice:
The cells are designed after well known Franz Diffusion Cells
Basic design includes two chambers(receiving and donor chambers) separated by a barrier
A jacketed receiving chamber with volume between 7 to 15 ml, stirred at constant speed
Donor chamber to hold the dosage form, can be occluded if required
Sampling arm to allow sampling just below the dosage form
Vertical Diffusion Cell (VDC)
Transdermal and Topical Release-Rate
Testing Rev. 7-11 ©2011 Hanson Research Corp. 14
Vertical Diffusion Cell
Crown Glass Model
Layout of IVRT Apparatus
Automated Apparatus
Application of IVRT Methods During Development Cycle
DEVELOPMENT PHASE
Selection of appropriate clinical candidate formulation and
characterization of the dosage form
CLINICAL PHASES
Monitoring and correlating the in- vivovs. in- vitro results—
further characterization of final formulation
POST –APPROVAL
Changes in manufacturing site,
composition, manufacturing process
Theory Fick’s first law of diffusion:
J= -D δc/δx where
J = rate of transfer per unit surface area(flux)
c = the concentration of the diffusing substance
x = distance the substance travels at right angles to the plane and
D = the diffusion coefficient in (length)2(time)-1
Theory Fick’s second law of diffusion:
δc/δt = D(δ2C/δx2 + δ2C/δy2 + δ2C/δz2 )
More simply,
δc/δt = D*δ2C/δx2
In case of release of active ingredient from a stationary matrix such as an ointment, (“moving boundary”case) the model can be simplified as follows:
Theory When the drug particles are uniformly distributed in the
matrix, and when their size is much smaller than the distance they have to travel, and when the sink conditions prevail in the receptor phase,
M ~ (2A-Cs) { Dvt/(1+{2(A-Cs)/Cs})}1/2
When A>>Cs,
M ~ (2ADvCst)1/2 and dM/dt ~ (ADvCs/2t)1/2
Theory For a case where the drug is dissolved in the matrix,
Higuchi derived the equation
M = h A{1 – 8/Π2 Σ *exp*-D(2m + 1)2 Π2]]/(2m+1)
Where h = the thickness of the ointment phase
For the first 30% of the release, the equation simplifies to:
M = 2A (D * t/Π)1/2
Calculation of Release RateThe cumulative amount (Q) of API released per surface area of membrane is:
n-1
Q = { CnV + Σ Ci S }/A i=1
Where:
Q = Cumulative amount of API released per surface area of membrane (mg/cm2)
Cn = Concentration of API (mg/mL) determined at nth sampling interval
V = Volume of individual Franz diffusion cell; determined by weighing out the receivingmedium required to fill the chamber and then dividing the weight by density toobtain the volume of the cell
n-1
ΣCi = Sum of concentrations of API (mg/mL) determined at sampling intervals 1 through n-1i=1
S = Volume of sampling aliquot, 0.2 mL
A = Surface area of sample well
The release rate is the slope of the line described by Q values verses the square root of time
Conditions under which the equation holds are:
Only the drug diffuses into the receptor phase while other components, excipients, do not diffuse or evaporate
The diffusion coefficient of the drug remains constant
The barrier membrane does not interact with the drug
Factors Affecting the Release of API from a Semisolid Dosage Form
1. Particle size of API
2. pH of API
3. Incorporation of API in semisolid matrix
4. Solubility of API in semisolid matrix
1. Viscosity
2. Spread ability
3. Overall pH
4. Moisture content of dosage form
1. Presence of emollients and penetration enhancers
2. Effect of excipients on release of API from matrix
3. Compatibility of excipients with API and with environmental agents such as moisture, gases, to affect the release of API
4. Manufacturing process
5. Manufacturing site
Considerations in Developing a Release Test Using Vertical Diffusion Cells
The Release Test Must be
Accurate in providing same release profile from day to day for the same lot of formulation
Discriminatory for different dosage strengths
Sensitive to differences in excipients
Rugged
Robust
Steps in Developing a Release Test
Assay Method –May need modifications
Selection of Membrane: Inert holding surface
Selection of Receiving Medium: Sink conditions must prevail, 30% rule
Introduction - Summary In principle, release tests are based on passive diffusion
of active ingredient from the product matrix into a receiving medium
There are many tests/apparatuses for different types of semisolid dosage forms
Among these, release testing using Vertical diffusion cells is widely used for many traditional and novel topical products
Case Study #1: Performance Test for a Topical Vaginal Gel – Method Development
API is
An anti-microbial agent
Needs to be formulated in a gel for vaginal use
Solubility profile shows pH dependence
Formulation is
Vaginal gel
Pharmacological data showed a dependence of moisture present in the environment to affect the release rate
Selection of Membrane: Filter Interference
Membrane % Recovery vs. unfiltered standard
Formulation1(0.02%)
Formulation 2(0.02%)
Formulation 3(0.05%)
Formulation 4(0.05%)
Cellulosic 83 82 90 87
Fluoropore 89 86 97 90
Nylon 92 85 99 89
Polycarbonate 96 90 104 95
Supor 89 85 96 89
Selection of Receiving Medium: Solubility of API in Receiving Medium
*Phosphate buffer pH 4.0
Solubility of API in 30:70 EtOH:phosphate buffer is too low for sink conditions especially for doses higher than 0.05%
Solubility of API in 40:60 EtOH:phosphate buffer is sufficient to allow for sink conditions 40:60 receiving medium was selected for next studies
Solvent Ratio(EtOH:Aqueous*)
Solubility(µg/mL)
Aqueous Sparingly Soluble
30:70 6.89
40:60 64.09
50:50 216.61
Preliminary Release Rate Test Conditions Preliminary IVRT conditions:
Heater/circulator set to 37 ± 0.05°C for vaginal application
Cells filled with receiving medium (ethanol:phosphate buffer pH 4.0, 40:60)
Membrane (polycarbonate) clamped onto bottom of each of 6 cells
~300mg vaginal gel applied to each cell
200µL aliquot removed at 0.5, 1, 2, 4, 6, and 24 hours and replaced with fresh medium
API concentration in receiving medium determined by reversed-phase HPLC
The conditions were further optimized during method development (noted in subsequent slides)
Preliminary Studies: Test Gel Variants
Form. No. API (%) Gel Type Gel Content Variations
A 0.01 Solution PG, polymers, pH 7
B 0.02 Suspension EtOH, polymers, pH 6
C 0.02 Suspension
Vitamin E, TPGS, PG, polymers, pH 6D 0.05 Suspension
E 0.02 Solution
F 0.01 Solution
G 0.02 SolutionCremophor, PG, polymers, pH 6
H 0.01 Solution
J 0.02 SolutionTween20, PG, polymers, pH 6
K 0.01 Solution
Variables to be Evaluated for Dependence on Release Rate:
Composition of Formulation
Dosage form Strength
Particle Size of API
Stress/viscosity
Air exposure
Sample weight
Consistency in release rate over time
Release Rate Dependence on Formulation Composition
API
(% w/w)Formulation
Release Rate
(mg/cm2/hr 0.5)
Standard
Deviation%RSD
0.012% vitamin E TPGS, 28% propylene glycol, modified
polymers, pH62.90 0.64 22
0.012% Tween 20,
28% propylene glycol, modified polymers, pH65.63 0.36 6.4
0.012% Cremophor,
28% propylene glycol, modified polymers, pH65.86 0.93 16
0.01 40% propylene glycol, modified polymers, pH7 6.14 1.2 19
0.0252% Cremophor,
28% propylene glycol, modified polymers, pH611.7 1.1 9.3
0.0252% vitamin E TPGS, 28% propylene glycol, modified
polymers, pH611.9 1.3 11
0.0252% Tween 20,
28% propylene glycol, modified polymers, pH613.9 2.0 15
0.025vitamin E TPGS,
5% propylene glycol, modified polymers, pH614.7 2.3 16
0.0254% ethanol,
modified polymers, pH615.4 2.0 13
Release Rate Dependence on Particle Size
Formula 2 Formula 1
Formulation Number
A-2 A-5 A-6 A-1 A-3 A-4
API Conc. 0.025% 0.05% 0.05% stressedb 0.10% 0.05% 0.05% 0.025% 0.05% .1% 0.05% .05%
% Dose 50 100 100 200 100 100 50 100 200 100 100
Milling Type Source
Milled at facility 1c
Milled at
facility 2d
Non-milled Milled at facility 1c
Milled at
facility 2d
Non-milled
Particle Size (d90)
<5 µm15.1 µm
144 µm <5 µm15.1 µm
144 µm
a The primary and secondary formulations are similar water-based gels that differ in solvent and preservative content. The primary formulations contained deionized water, methylparaben, propylparaben, HEC, polycarbophil, NaOH solution, propylene glycol, and vitamin E. Secondary formulations contained deionized water, sorbic acid, NaOH solution, dapivirine, HEC, Pluronic F127NF, and Klucel MF Pharm.
b Compound was stressed at 60 C for 4 weeksc Jet micronization at Facility 1d Jet micronization at Facility 2
Application of Release Rate Measurement During Stability Testing: 30 C 60% R.H.
Case Study #1: Conclusions Dose proportionality was demonstrated for two lead formulations
selected from a range of API concentrations of 0.025% to 0.1% (w/w)
Release profiles depended on formulation composition and on stress-induced viscosity changes
The IVRT method could distinguish between stressed and unstressed gels that differed in magnitude of viscosity from 8.26 kPa to 10.8 kPa, and showed a trend between milled and non-milled API
Release Rate was consistent over several months for the two lead formulations
Release Rate showed little variability during stability storage at 30°C/60% RH and 40°C/75% RH.
Case Study #2: Using Performance Test to Support Development of a Formulation for an Age Defying Cream
API is a light sensitive molecule, well studied
Hydrophobic with low aqueous solubility
Purpose: Needed formulation support to select appropriate formulation for clinical studies
Action: Determined sensitivity of the release profile to several physico-chemical parameters
IVRT Method Cellulose Acetate Membrane 0.45 µ
Receiving Medium: 35:65 Ethanol: pH 3.5 Phosphate Buffer
Sampling over 0.5, 1, 2, 4, 6 and 24 hours
32 ͦC
Formulation not occluded
Validation of an IVRT MethodAttributes that are Desired to be validated:
Intra-run Precision between 6 cells
Inter day precision –at least over 3 days
Discriminatory power:
Dose proportionality
Sensitivity to changes in
Excipient type
Amount of Excipient
Size of Batch
Method of manufacture
Validation of IVRT Method
Ruggedness : analyst, instrumentation
Robustness
Media composition
Membrane supplier, type
Dosage form application : method, volume
Cell design
Mass Balance
Back Diffusion of Alcohol into the Dosage Form
IVRT Method Ruggedness
Discrimination: Sensitivity to Changes: Process
Average Flux For Compound 1 Formulations (μg/cm2/hours1/2)
Formulation Drug Dissolved in Flux
1-A 100% pre-dissolved in organic solvent 0.189
1-B60% pre-dissolved in organic solvent, 40% dissolved directly into oil phase
0.110
2-A 100% dissolved in oil phase 0.603
2-B 100% pre-dissolved in organic solvent 1.406
Discrimination: Sensitivity to Changes: Scale-up
Average Flux For Compound 1 Formulations (μg/cm2/hours1/2)
Formulation Lot #Avg Flux
μg/cm2/hours1/2
Avg. Total Amt. Released After 6 hours std. dev.
1 A (3 kg) 0.347 1.200 0.071
1 B (100 kg) 0.406 1.412 0.028
2 A (3 kg) 0.054 0.145 0.021
2 B (100 kg) --- 0.020 0.013
3 C (3 kg) 0.290 0.855 0.140
3 C (100 kg) 0.258 0.799 0.085
Discrimination: Sensitivity to Change: Physical Parameters — Effect of Viscosity Builder
FormulationExcipient(%w/w)
Flux (μg/cm2/hours1/2)
Avg. Total Amt. Released after 6 hours (μg)
1 10 0.406 1.412
2 10 0.347 1.200
3 5 1.391 4.766
4 0 2.134 7.287
5 10 0.258 0.799
6 10 0.290 0.855
7 0 1.473 4.458
8 10 -- 0.020
9 10 0.054 0.145
10 10 0.084 0.256
11 0 0.078 0.231
Conclusions: Case Study #2The IVRT method is
Accurate and Precise
Rugged
Sensitive to differences in Excipients,
Dosage strength,
Viscosity of formulation
Process changes
Other Applications of Vertical Diffusion Cells
Rapidly disintegrating oral tablets
Ocular dosage forms – solutions, suspensions-release across ocular membrane — modified Franz cell to mimic clinical application
Film forming dosage forms, devices — useful characterization of the dosage form.
Transdermal dosage forms
Case Study #3: Characterization of a Polymer Film
The polymer film is a device used for curing toe nail fungus.
Our objective was to characterize the film for its integrity to permeation of small and large molecules.
Vertical diffusion cells were used where the permeation profiles of two marker compounds from a cream applied on the polymer film were evaluated for the integrity of the polymer film.
Study Design
Polymer film prepared on nylon membrane
Polymer applied on the membrane using the brush provided using smooth strokes in one direction
For multiple applications (layers), film allowed to air dry and the next layer applied at right angles to the first one, using the same smooth strokes
Integrity of the film tested for permeation of hydrophobic (hydrocortisone) and hydrophilic (lucifer yellow) markers.
Case Study #4: Using IVRT for a Sublingual Tablet
Sub-lingual tablets release their active ingredient in the mouth; the active then moves across the mucosal membrane of mouth/tongue.
The disintegration of a sub-lingual tablet takes place instantaneously as it is placed in an aqueous environment.
The two-step process can be simulated using an IVRT VDC.
The flux of the active across a relevant membrane was determined after dosing the sublingual tablet to a VDC.
Donor chamber
Receiving chamber
Vertical Diffusion Cell (VDC)
Study Design Biologically relevant membrane is human mucosal
membrane
Next best option would be pig tongue or Goat Mucosa
Both are hard to obtain and use
Cultured cell lines - artificially grown cells - were used instead
Trade name: EpiOral®
Use of Vertical Diffusion Cells for
Implementation of SUPAC-SS Guidelines
US FDA
SUPAC-SS Guidance Issued in May 1997
IVRT can be substituted for a clinical trial in certain cases
Excipients:
Level 2 change: changes that are likely to have a significant impact on formulation quality and performance. Examples are:
changes in >5% but <10% of an approved excipient
changes in supplier or technical grade of a structure forming excipient
changes in particle size of API when it is suspension
Level 3 change: changes that are likely to have a significant impact on formulation quality and performance. Examples are:
changes in excipient beyond the ranges in level 2
changes in crystalline form of API—IVRT not required but highly encouraged
Manufacturing and ProcessesManufacturing:
Level 2 change
change in equipment to a different design or different operating principles—IVRT required
Process:
Level 2 change
process change such as rate of mixing
mixing times, rate of cooling
operating speeds
holding times outside approved application ranges (IVRT required)
Manufacturing and ProcessesBatch size:
Level 2 change
Changes in batch size beyond a factor of ten times the pivotal/clinical batch (IVRT required)
Manufacturing site
Level 3 change
Different campus (IVRT required)
Implementation of SUPAC-SS Requirements IVRT method should be established during development phase
Data is collected for one or more likely candidates for clinical formulation
IVRT method is validated for at least one final formulation
Upon post approval change(s), the new batch manufactured after change is compared with reference batch (manufactured before change)
First Level of Comparison 6-cell run each with reference and test batch carried
out simultaneously
For each run, it is suggested that the experiments be run as follows:
Slopes are calculated for each cell.
Ratios of slopes are calculated as shown in example and ranked.
Criteria: 8th and 29th ranked slope ratios should fall between 75% and 133.33%.
T R T
R T R
Example of SUPAC-SS Statistical Comparison Between Two Formulations
T/R Ratios 25.03 25.26 23.14 29.98 27.10 22.79
21.29 117.57 118.67 108.68 140.85 127.32 107.06
20.13 124.33 125.50 114.94 148.95 134.65 113.22
20.09 124.60 125.77 115.18 149.27 134.94 113.47
19.50 128.34 129.54 118.64 153.75 138.99 116.87
21.00 119.18 120.30 110.17 142.78 129.07 108.53
21.74 115.12 116.19 106.41 137.91 124.67 104.83
Rank order
20 22 11 38 30 9
25 28 15 40 34 13
26 29 17 41 35 14
31 33 21 42 37 19
23 24 12 39 32 10
16 18 8 36 27 7
Second Level of Testing Failure at first level triggers the second level
of comparison
4 additional runs of 6-cell each are carried out and slopes are computed.
A total of 18 slopes for each batch is obtained and same T/R ratios are computed and ranked.
Criteria: 115th and 225th ranked ratios should fall within 75 to 133.33%
Summary IVRT is a useful test during product development,
allowing appropriate selection of a clinical candidate and can serve as a cost effective means to monitor the consistency in manufacturing of semi-solid dosage forms during clinical trials.
Vertical diffusion cells can be used to develop performance tests for a variety of dosage forms including semi solids, film formers, occular, nasal etc.
THANK YOUQuestions???
Kailas Thakker
Kailas.Thakker@terguspharma.com
919-549-9700 ex 100
www.terguspharma.com