PROCESS SURROGATES & DUSTING TESTING - Matt Meiners, CIH Division Manager, Laboratory Services Maxxam Analytics - Lake Zurich, IL
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PROCESS SURROGATES &
DUSTING TESTING
Matt Meiners, CIH
Division Manager, Laboratory Services
Maxxam Analytics – Lake Zurich, IL
1
Surrogate Selection
There is no perfect surrogate material, but there are
standardized materials – the best choice will depend upon the
particular manufacturing process and the situational priority of a
variety of variables.
2
Surrogate Selection Variables
Meets Requirements for the Manufacturing Process
Flowability (bulk powder movement)
Compactability and adhesion (tableting)
Solubility (emulsion vs. solution)
3
Surrogate Selection Variables
Relative Hazard or Toxicity of Test (surrogate) Material
OEL or other health limit
Process safety concerns
4
Surrogate Selection Variables
Quality Concerns
API vs. non-API
Cleanability
Established cleaning procedures
5
Surrogate Selection Variables
Test Material Availability and Cost
How much test material is needed?
Cost of bulk material
“Off the shelf” vs. Custom manufacture (micronization)
6
Surrogate Selection Variables
“Containment Challenge” Similar to Target Material
“Dustiness” - defined as the propensity of a material to emit
dust during manufacturing: may be considered analogous
to vapor pressure on a molecular scale.
Determined by a complex interrelationship of factors. Can
not be predicted reliably by theory and must be measured
empirically.
A standardized measure of “dustiness” has not been
established.
A variety of individual particle
characteristics effect relative dustiness – though
particle size provides the best correlation.
7
Material Characteristics Relative to Dustiness
Particle Size and Size Distribution
Characteristic with the greatest impact on
powder dustiness
Generally, decrease in particle size
results in increase in dustiness
Powders blended to contain only a
portion of small particles were found to
be nearly as dusty as powders
comprised entirely of small particles
For most materials, as the proportion of
small particles in a blend diminishes, the
faction of small particles in the generated dust increases.
8
Common Process Surrogates
The most commonly used process surrogates in the
Pharmaceutical and Containment Industry
Lactose
Naproxen Sodium
Mannitol
Acetaminophen
Riboflavin
Sucrose
Arizona Road Dust
Insulin
9Surrogate Selection Criteria – Analytical Method
Surrogate Maxxam LOQ Method
Mass/Sample Selectivity
Lactose 2.5 ng ► Good
Naproxen Sodium 0.05 to 0.2 ng ► Very Good
Mannitol 1.0 ng ► Good
Acetaminophen 0.5 ng ► Exceptional
Riboflavin 5 ng ► Good
Sucrose 5 ng ► Good
Arizona Road Dust 10,000 ng ► Poor
Insulin NA ► Exceptional
10Surrogate Selection Criteria – Quality Concerns
Surrogate Type Cleanability
Lactose Excipient ► Highly Soluble
Naproxen Sodium API ► Highly Soluble
Mannitol Excipient ► Highly Soluble
Acetaminophen API ► Modestly Soluble
Riboflavin API ► Sparingly Soluble
Sucrose Excipient ► Highly Soluble
Arizona Road Dust Dirt ► Insoluble
Insulin API ► Poorly Soluble
11Surrogate Selection Criteria – Availability & Cost
Surrogate Relative Cost Multiple Specification
Lactose 1 ► Yes – wide variety
Naproxen Sodium 100-1000 ► Custom
Mannitol 5 ► Yes – variety
Acetaminophen 5-10 ► Custom
Riboflavin 15 ► Custom
Sucrose 5 ► Yes – variety
Arizona Road Dust 10-20 ► Yes – variety
Insulin Very high ► NA
12Surrogate Selection Criteria – Summing it up…
Selection of the best surrogate material for
your application depends upon…
• which criteria are your drivers
• particular surrogate characteristics that
may also drive the selection process…
13Lactose
Selection Drivers Potential Concerns
Least expensive in bulk, wide variety Common excipient – may be used in
of specifications (particle size the test formulation or facility may
distribution) available “off the shelf” have background levels.
Low hazard International shipments can be
complicated by bovine product
Minimal quality concerns, easily
import concerns
cleanable
May lose specification upon storage
Sensitive and specific method
of micronized material
available (2.5 ng/sample)
(agglomeration)
Specified surrogate in ISPE
Complicated analytical method
guidance document
limits options for analysis
Dustiness independent of humidity
and moisture content
14Naproxen Sodium
Selection Drivers Potential Concerns
Highest sensitivity (0.05 to 0.2 High relative material cost if
ng/sample) handling in bulk
Easily cleanable API introduction may cause
quality concerns
Uncomplicated analysis
increases availability of method Custom sieving or micronization
needed for specific size
Widely accepted surrogate, first
distribution
alternative in ISPE Guidance
Document
Good containment challenge
(high dustiness index)
15Mannitol and Sucrose
Selection Drivers Potential Concerns
Low cost in bulk, variety of Common excipients – may be
specifications (particle size used in the test formulation or
distribution) available facility may have background
levels.
Low hazard
Complicated analytical method
Minimal quality concerns, easily
limits options for analysis
cleanable
Sensitive and specific method
available (Mannitol is 1.0
ng/sample)
Good alternative if Lactose is
present in formulation or facility
16Acetaminophen (Paracetamol)
Selection Drivers Potential Concerns
Relatively low cost API in bulk API introduction may cause
quality concerns
Highly sensitive and specific
method available (0.5 ng/sample) More difficult to clean
Good surrogate for tableting or Custom sieving or micronization
tablet handling activities. needed for specific size
distribution
Was one of the first commonly
used surrogate materials (EU) Unusual elongation ratio for
crystals
High cost and limited options for
analysis (LC/MS/MS)
17Riboflavin (Sodium Acetate)
Selection Drivers Potential Concerns
Common use for CIP coverage API introduction may cause
testing may eliminate quality quality concerns
concerns
More difficult to clean
Surface contamination can be
Custom sieving or micronization
visualized by black light
needed for specific size
distribution
Low level environmental
background common
18The Next Step –
Ongoing Containment Verification
FAT and SAT testing is performed in order to predict with some
degree of certainty, that CPTs and worker exposures are not
exceeding limits.
FAT and SAT testing is performed on newly installed
equipment, in optimal working conditions.
Performance of containment equipment can degrade or fail
over time.
Ongoing evaluations of containment and employee exposures
during routine operations is the only means to be confident
that containment is maintained, and potent materials are
handled safely!
19THANK YOU.
PROCESS SURROGATES &
DUSTING TESTING
Matt Meiners, CIH
Division Manager, Laboratory Services
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