method development and validation for particle size and ... · pdf filemethod development and...
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Ulf WillénDivisional Product ManagerAnalytical Imaging SystemsMalvern Instruments Ltd, Malvern, UK.
Method Development and Validation for Particle Size and Shape Measurements
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3.3.1 New Drug Substances(b) Particle size: For some new drug substances intended for usein solid or suspension drug products, particle size can have a significant effect on dissolution rates, bioavailability, and/or stability. In such instances, testing for particle size distribution should be carried out using an appropriate procedure, and acceptance criteria should be provided.Decision Tree #3 provides additional guidance on when particle size testing should be considered.
FDA guidance: when should particle size be measured?
International Conference on Harmonization;Guidance on Q6A Specifications:
Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances*
*Federal Register/Vol. 65, No.251, Friday December 29, 2000/ Notices p. 83041-83054
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FDA guidance: when should particle size be measured?
Critical to dissolution, solubility,
bioavailability?
Critical to drug product
processability?
Critical to product stability?
Critical to product content
uniformity?
Set acceptance criterion
No acceptance criterion necessary
Solid dosage form or liquid with
undissolved drug?
No drug substance particle size criterion required for solution
dosage forms
Yes
No
Yes to any?
No to all?
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Comparing techniques: assessing different technologies
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Comparing techniques: assessing different technologies
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Better Characterisation - Size and Shape
%
Size
%
Size
Size Only
Size
Circ
ular
ity
Size
Circ
ular
itySize andShape
Aggregates (Low circularity)Large Primary Particles
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Convexity - Dissolution behaviourLower convexity – higher surface areaIncreased surface area – faster dissolution
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Laser Diffraction & Optical Imaging
Laser Diffraction(USP <429> , EP 2.9.31, ISO13320-1)
Optical Microscopy(USP <776>, ISO 13322-1)
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What information should be included in the particle What information should be included in the particle size specification?size specification?
ICH Q6A GuidanceICH Q6A GuidanceAnalytical Procedure (system suitability, sampling, dispersion,, etc.)Method Validation (precision, ruggedness, dispersion stability, robustness, etc.)Acceptance Criteria (upper and lower limits)
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“The normal concepts of validation may differ for particle size methodologies as compared to other analytical methodologies such as HPLC.”
“… the system should be calibrated according to the manufacturers and/or the laboratory’s specification, as appropriate”.
“The methods validation usually involves evaluation of intermediate precision and robustness.”
“Assurance should be provided that the data generated are reproducible and control the product’s quality.”
FDA guidance: Analytical Procedures and Methods Validation*
*Section F: Methodologies relating to particle size analysis;
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Professor Harold Heywood (1905-1971)
“However, it must be realised that particle size analysis is not an objective in itself but is a means to an end, the end being the correlation of powder properties with some process of manufacture, usage or preparation”
H Heywood Proc. 1st Particle Size Anal. Conf. September 1966 p 355 - 359 (Heffer)
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Accuracy can be difficult to define for size analysisEasy for spherical particlesFor non-spherical particles all sizing techniques give different answers.
For laser diffraction:You do need to verify the system
• See ISO13320 / USP<429> / EP 2.9.31 for detailsMicroscopy is the most important referee method
FDA guidance: why should accuracy not be assessed?
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Method development and validation: PASG definition of sample preparation*
“The pre-treatment and the presentation of the sample to the measuring technique in a meaningful manner.”
Need to considerHow the primary sample is obtainedHow the material is dispersed
• Wet or dry dispersion?• Dispersed or agglomerated state?
*See Bell, R., Dennis, A., Henriksen, B., North, N., and Sherwood, J., (1999) “Position Paper on Particle Sizing: Sample Preparation, Method Validation and Data Presentation” Pharmaceutical Technology Europe, November
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Sample presentation: what do we need to consider?
“Novices in the size measurement field must
understand that most errors in size measurement arise
through poor sampling and dispersion and not through instrument inadequacies.”
T. Allen, Advances in Ceramics, Vol 21: Ceramic Powder Science, page 721, The
American Ceramic Society Inc. (1987)
Dr. Henk Merkus “Quality Assurance in Particle Size Measurement” from Improving Standards in Particle Size Distribution Measurement, February 17-
19, 1997, at the Engineering Research Centre for Particle Science andTechnology
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Sampling: particle segregation
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From: T. Allen Particle Size Measurement Chapman and Hall 4th Edition 1993 Page 39. Figures based on a 60:40 sand mixture.
Sampling: typical errors associated with different techniques
0.42Spinning Riffler
3.4Chute Riffler
7.0Table Sampling
17.1Scoop Sampling
22.7Cone & Quartering
Estimated max error (%)Method
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Sampling: using a spinning riffler
Sample stream from a vibrating
hopper
Sample pots on a revolving tray
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Measurement Number
0 2 4 6 8 10 12 14 16 18 20
Siz
e / M
icro
ns
0
50
100
150
200
250
300
350
Dv10Dv50Dv90
Sampling: riffled sample measurements
Dv10: 2.8%Dv50: 2.9%Dv90: 1.4%
RSDs
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Sampling: obtaining unbiased samples from slurry systems
Speed of sample rise matches sample
extraction velocity
Stirrer
Flow baffles
Isokinetic sampling probe
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Sample preparation: product form
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0.01 0.1 1 10 100 1000 10000Particle Size / Microns
10-5
10-4
10-3
10-2
10-1
100
101
102
103
104
105
106
107Fo
rce
of A
dhes
ion
/ Gra
vita
tiona
l For
ce
Adhesion
Sample presentation: force of adhesion / cohesion between particles
From: Aerosol Science, Ed. C N Davies, Academic Press, London and New York, 1966
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0 5 10 15 20Measurement Number
0
50
100
150
200
250
Part
icle
Siz
e / M
icro
ns
Ultrasound Applied
Dv10Dv50Dv90
Ultrasound OffInitial Dispersion (Pump and Stirrer)
Sample presentation: affect of sonication on the particle size reported by laser diffraction
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With reduced level of sonication – no broken particles
After inappropriate level of sonication – broken particles
Using image analysis as a referee method
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Wide size and shape distributions
Images show high degree of agglomeration
Pharmaceutical dispersed in cyclohexaneWith no surfactant a high level of agglomeration is observed
Using image analysis as a referee method
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Narrower and smoother size and shape distributions
Images confirm individual particles and little agglomeration
Same sample but with addition of lecithin
Using image analysis as a referee method
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Sample presentation: changes in size as a function of pressure
0 1 2 3 4Dispersion Pressure / bar
0
20
40
60
80
Size
/ M
icro
ns
Dv10Dv50Dv90
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Sample presentation: changes in size as a function of pressure –microscopy as a referee technique
High Pressure – Increased proportion of fines less large material
Low Pressure – More large material fewer fines
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Sample presentation: changes in size as a function of pressure –microscopy as a referee technique
56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
0 1 2 3 4
CE
Dia
met
er M
ean
(µm
)
injectionPressure
0.57
0.58
0.59
0.60
0.61
0.62
Aspect Ratio M
ean
Trend Graph
CE Diameter Mean (µm) Aspect Ratio Mean
Pressure titration against Particle Size and Aspect ratio
Increased pressure = reduced Size
Increased pressure = Increased Aspect Ratio
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Sample presentation: changes in size as a function of pressure –microscopy as a referee technique
Low pressure dispersion –example images of largest particles – long, low aspect ratio (needle like)
High pressure dispersion – example images of largest particles - short, high aspect ratio.
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12.76.52.7Morphologi G3
12.75.12.0Mastersizer 2000
Dv90 / Microns
Dv50 / Microns
Dv10 / Microns
Using image analysis as a referee method
5.302.661.44Morphologi G3
5.002.311.03Mastersizer 2000
Dv90 / Microns
Dv50 / Microns
Dv10 / Microns
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Sample presentation: using image analysis as a referee method
1 10 100 1000
Particle Size / Microns
0
2
4
6
8
Volu
me
(%)
Mastersizer 2000
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Sample presentation: using image analysis as a referee method
1 10 100 1000
Particle Size / Microns
0
10
20
30
40
50
Vol
ume
(%)
Morphologi G3 CE diameterMorphologi G3 lengthMorphologi G3 widthMastersizer 2000
USP<792>: ‘For irregularly shaped particles, characterisation of particle size must include information on particle shape.’
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1 10 100 1000Particle Size / μm
0
2
4
6
8
10
12
Vol
ume
(%)
Initial Result (RI = 1.53)
Using image analysis as a referee method : verifying optical properties
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1 10 100 1000Particle Size / μm
0
2
4
6
8
10
12
Volu
me
(%)
Final Result (RI = 1.345)
Comparing imaging and diffraction: verifying optical properties
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ISO13320-1: Section 6.4Dv50 - 5 different readings: COV < 3%Dv10 and Dv90: COV < 5%“Below 10μm, these maximum values should be doubled.”
USP <429>Provides reproducibility rangesDv50 or any central value: <10%Dv10, Dv90 or any non-central value: <15%“Below 10μm, these maximum values should be doubled.”
EP 2.9.31 provides similar advice to USP<429>
Method development: available guidance for laser diffraction measurements
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Measurements of multiple samples (n≥6) by a single operatorRSD within USP <429> and ISO13320 limits for laser diffraction
variation in Dv10 due to dispersionvariation in Dv90 due to sampling
• Scoop sampling used in this case….
Sample Number Dv10 / μm Dv50 / μm Dv90 / μm
1 1.22 23.68 63.23 2 1.17 23.77 60.02 3 1.09 22.79 56.59 4 1.16 23.63 62.55 5 1.11 22.26 59.68 6 1.18 22.78 65.36 7 1.12 23.41 61.47
Mean 1.15 23.19 61.27 COV (%) 3.95 2.50 4.63
Method validation: precision for excipient measurements using laser diffraction
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Method validation: intermediate precision for excipient measurements using laser diffraction
Pooled RSD for both analysts is within the USP<429> and ISO13320 limits.
Sample Number Dv10 / μm Dv50 / μm Dv90 / μm
1 1.06 22.92 61.01 2 1.08 22.08 56.54 3 1.04 21.66 62.17 4 0.97 22.55 60.23 5 1.04 22.74 57.98 6 0.99 23.58 59.86 7 0.95 22.11 62.78
Mean 1.02 22.52 60.08 COV (%) 4.79 2.83 3.69
Parameter Pooled Value Mean Dv50 / μm 22.85 Standard Deviation 0.68 COV (%) 2.98
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Method validation: reproducibility
Should now go on to test reproducibilityDefined as the precision between laboratories*
Modern sizing systems can store and replay measurement procedures
method files can then be emailed to other sitesMain challenge is related to the control of the laboratory conditions and dispersant quality
*See Bell, R., Dennis, A., Henriksen, B., North, N., and Sherwood, J., (1999) “Position Paper on Particle Sizing: Sample Preparation, Method Validation and data Presentation” Pharmaceutical Technology Europe, November
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Microscopy - how many particles do I need to measure?
ISO 13322-1 Particle size analysis – Image analysis methods – Part1: Static image analysis methods - proposes a method to evaluate minimum number of particles to achieve certain confidence of mass mediandiameter (Dv50) being within a certain statistical error
Maths can be reduced to one input: standard deviationExample: Sample with GSD of 1.6 needs 61,000 particles to achieve mass median diameter within 5% error with 95% probability
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Using image analysis as a referee method
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Morphologi G3 – Automated Particle Image Analyser
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Mixture of API and Starch
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.1 1 10 100 1000 10000
%
CE Diameter (µm)
Volume transformation: CE Diameter (µm) smoothed over 50 points
Record 2: API Starch 1 classed
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Mixture of API and Starch
Starch - onlyHigh circularityLow elongation
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Mixture of API and Starch
API - onlyHigh elongationLow circularity
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Mixture of API and Starch
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
1.1
0.1 1 10 100 1000 10000
%
CE Diameter (µm)
Volume transformation: CE Diameter (µm) smoothed over 50 points
Record 2: API Starch 1 classed Record 9: API Starch 1 classed - API Record 10: API Starch 1 classed -Starch
CE Diam. (vol) for Mixture, API(39%) and Starch (61%)
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Need to consider the Precision, Intermediate Precision and Robustness of measurements during method development and validation
Requires an understanding of how the sampling and dispersion is achieved
Need to ensure that the sample preparation method is reasonable in terms of predicting the properties of the product being tested
Remember to look for specific guidance relating to the expected precision of the measurements
Conclusions
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Where can I find out more?
www.malvern.comProduct informationApplication NotesLive WebinarsOn-demand PresentationsUseful Links