Module 7 Analytical instrument qualification.pdf

USP’s Perspective on Drug

USP s Perspective on Drug

Product Performance Test

Dissolution Test – Sources of Variability

• Variability in the formulation or due to variability in the manufacturing process may lead to:

manufacturing process may lead to: – Poor content uniformity

– Poor disintegration homogeneity

– Poor dissolution homogeneity i.e.; highly variable results • Within one run

• Between runs

– Examples for variable dissolution results: • Hard gelatine capsules

• Hard gelatine capsules • HPMC containg tablets • Buoyant dosage forms

Dissolution Test - Variability of Results

• High variability in results can make it difficult to identify trends or effects of formulation changes

effects of formulation changes

• High variability caused by the test make it impossible to describe differences in product quality

Di l ti lt b id d hi hl i bl if th l ti

• Dissolution results may be considered highly variable if the relative standard deviation (RSD) is greater than 20% at time points of 10 minutes or less and greater than 10% at later time points (test & product)

product)

• Most dissolution results exhibit less variability

Sources of Apparatus and Method Variability

• Sources of Variability:

• The Dissolution Apparatus (instrument qualification) – Vessels (instrument qualification)

• Perturbation studies provide proofPerturbation studies provide proof – Cover of waterbath

Sources of Apparatus and Method Variability

• The Method (method validation) Physical

– Physical

• deaeration • evaporation • Adsorbance

Ph sicochemical – Physicochemical • Precipitation

– Chemical

Dissolution Test – Causes Of Artifacts

• Artifacts associated with the test procedure

Coning tablets sticking to the vessel wall or basket screen – Coning, tablets sticking to the vessel wall or basket screen

– Any time the dosage contents do not disperse freely throughout the vessel in a uniform fashion, aberrant results can occur

• Reactions taking place at different rates during dissolution:Reactions taking place at different rates during dissolution: – excipient interactions or interferences

» film coatings (pellicule forming) » aged capsule shell (“cross-linking”) » aged capsule shell ( cross linking )

» secondary inclusions of drugs in excipients (“dead extraction”)

Dissolution Test – Decreasing Variability

• Usual remedies during method development include:

Ch i th t t d f it ti d ti

– Changing the apparatus type, speed of agitation, or deaeration – Consideration and/or examination of sinker type

– Changing the composition of the medium – Changing other parts of instrumentation

• Sinkers • ProbesProbes

• Vessels (size, material)

– Modifications to the apparatus may also be useful, with proper justification and validation

justification and validation

Sources of Variability

• For an integrated dissolution testing system in general, the sources of variability may come from:

th di l ti t ti t th t t th t t l ti

– the dissolution testing apparatus that generates the test solutions – including its environment

– The devices used for • SamplingSampling

• Processing – Filtration – Dilution – Transfer

– the details of the testing procedure

– the analytical instruments and method used to quantify the

di l d d b t i th t t l ti

dissolved drug substance in the test solution – the analyst

– Remember:the specimen under investigation and their intrinsic – Remember:the specimen under investigation and their intrinsic

Sources of Variability

• Test Assembly:

M h i d fl id d i

– Mechanics and fluid dynamics

– Instrumental and environmental vibrations – Vessel dimensions, asymmetry and surface

irregularities

– Vessel or shaft verticality

– Wobble, height, centering, rotation speedg g p – Paddle or basket dimensions

– Levelness

The Dissolution Apparatus

– The basic concepts of the dissolution apparatus were

established by empirical means rather than sound scientific and established by empirical means rather than sound scientific and engineering considerations

Th d i f t d di l ti t t h l d t

– The design of most modern dissolution testers has evolved to precisely control physical parameters, test conditions and

alignment to ensure that the release of drug from a dosage form will be determined consistently from one tester to another and will be determined consistently from one tester to another and from one laboratory to another

However apparatus found around the world are not all – However, apparatus found around the world are not all

Qualification of Dissolution Apparatus

• USP Chapter <711>

Formerly apparatus suitability test – Formerly apparatus suitability test

– Now performance verification test (PVT) • Use of reference i.e.; standard tablet

• tablet qualified by collaborative trial including labs of • tablet qualified by collaborative trial including labs of

– USP – FDA

HPB and abo t 30 others – HPB…. and about 30 others

• Spec‘s established for each new lot individually

• The how-to are part of the USP education course titled “Dissolution: Theory and Best PracticesDissolution: Theory and Best Practices”

– Mechanical Qualification is a prerequisite • may be more detailed in the future

May not replace PVT as demonstrated by the “perturbation • May not replace PVT as demonstrated by the perturbation

Sources of Variability for Apparatus 1 and 2

• Mechanical variables easily controlled – Dimension of stirring elementsg

– Shaft verticality vertical

– Vessel eccentricity ±2mm

– Stirring element depthStirring element depth 25±2mm25±2mm

• Operational variables

– Stirring rateStirring rate ±4%±4%

– Temperature ±0.5°C

– Medium Volume ±1%

– pH valuepH value ±0.05±0.05

Sources of Variability for Apparatus 1 and 2

• Mechanical variables not precisely defined – Vessel verticalityy vertical

– Shaft wobble without significant wobble

– Vessel dimensions cylindrical with a hemispherical bottom 1L

vessels: diameter: 98mm - 106mm

height: 160mm 210mm height: 160mm - 210mm

– Vibrations not significant

• Variability due to the “sample preparation”

The Dissolution Apparatus

The Dissolution Apparatus

• The vessel, however, is loosely defined

• USP <711> vessel definition

– covered vessel made of glass or other inert, transparent material

– is cylindrical with a hemispherical bottomy p

– for a nominal capacity of 1 liter, the height is 160mm to 210mm and its inside diameter is 98mm to 106mm 210mm and its inside diameter is 98mm to 106mm

Dissolution Vessels

• The vessel is usually made by traditional glass-blowing techniques

– Each vessel is more or less unique since they are effectively ac esse s o e o ess u que s ce ey a e e ec e y hand-made

Dissolution Vessels

The hemisphere may be distorted due to the method of manufacture :

manufacture :

“flattened”

“seam”

Dissolution Vessels

Dissolution Vessels

Even with perfect manufacture, “within specification” differences are significant

98mm ID 106mm

ID

Dissolution Vessels

H i ht C li d 8 67 6 66 23 2% Height - Cylinder 8.67cm 6.66cm -23.2%

Volume

-Cylinder 654cm3 588cm3 -10.1%

Volume Volume

-Hemisphere 246cm3 312cm3 +26.8%

Volume Ratio 2.66 1.88

Surface Area – Surface Area –

Cylinder 267cm2 222cm2 -16.9%

Surface Area

-Hemisphere 151cm2 176cm2 +14.2%

Surface Area

Ratio 1.77 1.26

Total Surface

Area 418cm2 398cm2 -4.78%

Vessel Quality Parameter - CMM

• Vessel dimensions

Cylinder inner diameter – Cylinder inner diameter – Cylinder circularity

– Cylindricity

Perpendicularity – Perpendicularity – Spherical radius – Circularity of the

hemisphere hemisphere

– Concentricity between center of hemisphere to center of cylindery – Flange diameter – Flange thickness

Vessel Dimensions – Inner Diameter

0 2 4 6 8 10 12

Vessel Dimensions – Cylindricity

0 2 4 6 8 10 12

0 2 4 6 8 10 12

Vessel Dimensions – Radius of Hemisphere

0 2 4 6 8 10 12

Vessel Dimensions – Hemisphere Roundness

0 2 4 6 8 10 12

Source

H

Vessel Dimensions – Influence on Dissolution Results

75.0 75.0

Type B vessels Type A vessels

60.0 65.0 70.0 75.0 d is s o lved mean min max _60.0 65.0 70.0 75.0 d isso lved mean min max 40.0 45.0 50.0 55.0 pr e d in is one 40.0 45.0 50.0 55.0 p re d in is o n e 30.0 35.0

1 2 3 4 5 6

Vessel #

%

30.0 35.0

1 2 3 4 5 6

Vessel #

%

Vessel # Vessel #

Arithm. mean, min. and max values of six replicates.

Repeatability/Reproducibility

Analyst Position Run # ₁₁ Run # ₂₂ Run # ₃₃ Run # ₄₄ Run # ₅₅ Run # ₆₆

A 5 70.4 64.3 65.1 62.7 72.4 71.5

A 6 74.4 71.6 68.4 66.7 56.1 69.3

B 6 70.6 74.4 74.9 71.4 71.5 67.0

C 6 69.9 69.2 65.3 70.8 68.2 70.2

D 5 67.5 71.1 62.9 70.5 69.1 63.1

D 6 64.3 71.3 65.0 55.7 56.0 61.2

Prednisone RS Tablets, Lot P, % prednisone dissolved,

Tester α, Paddle Apparatus, 500 ml deaerated Water, 50 rpm

Switching Vessels

Tester : Alpha

α-Vessels ε-Vessels

α-Vessels ε-Vessels

Analyst Mean* SD RSD, % Mean* SD RSD, %

A-α 61.2 8.5 13.8 - -

-B-α 57.2 9.0 15.8 41.4 1.7 4.2

C-α 53.7 9.4 17.5 44.7 2.9 6.6

D-α 55.5 9.5 17.1 - -

-Mean 56.9 9.1 16.1 43.0 2.3 5.4

Tester : Gamma

ε-Vessels α-Vessels

ε-Vessels α-Vessels

Analyst Mean* SD RSD, % Mean* SD RSD, %

A-γ 46.0 2.3 4.9 - -

-B-γ 46.5 2.0 4.3 49.7 7.6 15.3

C-γ 43.7 1.7 3.8 44.0 2.6 5.9

D-γ 47.7 2.6 5.4 - -

-E-γ - - - 42.9 2.6 6.2

F-γ 41.4 1.8 4.3 - -

Perturbation Studies on Apparatus 2

Table 1. Variables Included in Design of Experiment Study

Variable Units –1 Value +1 Value

Temperature °C 36.5 37.5

Shaft wobble mm total runout 0.0 0.5

Rotation speed rpm 48 0 52 0

Rotation speed rpm 48.0 52.0

Vessel centering mm total runout 0.0 2.0

Vessel tilt ° 0.0 1.0

Paddle height mm 23.0 25.0

Paddle height mm 23.0 25.0

Base plate levelness ° 0.0 1.0

Vessel types N/A Manufacturer’s Replacement

Level of deaeration N/A USP-deaerated Non-deaerated

To evaluate the effect of deaeration is considered to be part of method validation. The USP prednisone reference tablets were used for the pertubation studies:

Perturbation Studies on Apparatus 2

Table 2. Experimental Design and Results

Run Temp Shaft Rotation Vessel Vessel Paddle Base Plate Vessels Deaeration

Wobble Speed Centering Tilt Height Levelness Mean SD

A 37.0° - 50 - - + - - - 43.3 1.2

B 37.0° - 50 - - + - - - 44.1 1.7

C 37 0° 50 + 43 3 1

Percent Dissolved

C 37.0° - 50 - - + - - - 43.3 1

1 + - + - - - - - - 46.3 1.5

2 - + - - + - + + + 58 7.6

3 - + + + - + - + + 87.6 0.7

4 + + - - + - - - + 49.8 1.1

5 + - - - - - + + - 48.1 8.7

45 + + + + 44 5 2 9

45 + + - - + - - + - 44.5 2.9

Perturbation Studies on Apparatus 2

Table 3. Effects List for Mean Percent Dissolved Results

T e r m E ffe c t* % C o n tr ib u tio n

T e m p e ra tu re – 4 .5 1 .1

S h a ft w o b b le 0 .9 0 .7

R o ta tio n s p e e d 1 2 .1 9 .4

V e s s e l c e n te rin g – 0 .7 0 .4

V e s s e l tilt 1 .6 0 .0

P d d l h i h t 2 4 0 5

P a d d le h e ig h t – 2 .4 0.5

B a s e p la te le v e ln e s s – 2 .2 1 .2

V e s s e l ty p e 1 2 .8 1 0 .4

L e v e l o f d e a e ra tio n 3 1 .0 5 2 .3

A ll 2 -fa c to r in te ra c tio n s (n = 3 6 ) N /A 2 4 .2

T o ta l N /A 1 0 0 .0

FDA Guidance For Industry Jan. 2010

• The Guideline: Use of Mechanical Calibration of Dissolution Apparatus 1 and 2 – Current Good Manufacturing Practice refers to

2 Current Good Manufacturing Practice refers to – Internal CDER procedure

– ASTM Document E 2503-07: Standard Practice for Qualification of Basket and Paddle Apparatuspp

• Apparatus setup • Maintenance

• Mechanical calibration • Operation

Dissolution Toolkit

• Toolkit - Dissolution Procedure: Mechanical Calibration and Performance Verification Test

– http://www.usp.org/pdf/EN/dissolutionProcedureToolkit2010-03.pdf

– Assurance of the integrity of the dissolution procedure is

achieved through careful assembly qualification, analyst training, and use of validated analytical procedures

Th T lkit id

• The Toolkit provides

– Enhanced procedures and control limits for mechanical qualification

A guide to generate accurate Performance Verification Test – A guide to generate accurate Performance Verification Test

results

– A complete information basis to develop SOP for the GMP environment