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Pira International Conference
Extractables Testing for
Pumps and Valves
Francois Billard, M.S.
Laboratory Manager, Valois of America
October 2006
USP Requirements
Pump or Valve = Container
<87> Biological Reactivity Test, in Vitro
<88> Biological Reactivity Test, in Vivo
<381> Elastomeric Closures for Injections
<661> Containers – Plastics
Guidances
• Metered Dose Inhaler (MDI) and Dry Powder Inhaler (DPI)
Drug Products Chemistry, Manufacturing and Controls
Documentation (October 1998)
• Nasal Spray and Inhalation Solution, Suspension and Drug
Products - Chemistry, Manufacturing and Controls
Documentation (July 2002)
• IPAC-RS (International Pharmaceutical Aerosol Consortium
on Regulation and Science) offers GMP guidelines for
suppliers of OINDP components
• Future guidance may be based on “PQRI Safety Thresholds
and Best Practices for Extractables and Leachables in Orally
Inhaled and Nasal Drug Products” (2007?)
FDA Requirements
Specifications and analytical methods
should exist for the primary packaging
components for:
• Extractables
• Degradation products
• Unknown foreign substances
Why Control Extractables?
• Extractables can migrate into the drug product
during normal storage (Leachables) and affect
product quality and safety to the patient
• Guarantee the consistency of the device
components in terms of:
– composition (additives …)
– constant levels of extractables
• Guarantee that the process is under control
Extractables Definition
PQRI definition:
“Extractables are compounds that can be
extracted from Orally Inhaled Nasal Drug
Products (OINDP) device components or
surfaces of the OINDP container/closure
system in the presence of an appropriate
solvent(s) and/or condition(s)”
Pump Drawing
Ferrule
Sealing Gasket
Stem Gasket
Stem
Pre-Compression Spring
Piston
Spring Cap
Return Spring
Spring Support
Floating Gasket
Body
Diptube
Valve Drawing
UPPER
STEM
DOSAGE
CHAMBER
2nd STEM
GASKET
NECK
GASKET
BODY
1st STEM
GASKET
FERRULE
RING
LOWER
STEM
SPRING
Components
Valves or nasal pumps may contain over 12
components:
• Stem, turret, thread, piston, spring cap, spring
support, body, dip tube, ring (thermoplastics)
• Neck, stem and floating gaskets (elastomers)
• Ferrule, precompression spring, spring (metals)
Note: Other components are added to the device
and include: actuator, insert (pumps), spacer
(valves) and container (glass, metal or plastic)
Thermoplastic Materials
•
•
•
•
•
Polyethylene (PE)
Polypropylene (PP)
Polybutylene Terephthalate (PBT)
Polyacetal / Polyoxymethylene (POM)
Polyamide (Nylon)
Potential Extractables
from Plastics
• Chemical additives (antioxidants,
stabilizers, plasticizers)
• Degradation products from additives and
polymers
• By-products from polymerization
• Residual products from polymerization
(oligomers, monomers)
Gasket Materials
•
•
•
•
Butadiene Acrylonitrile Elastomer
Polychloroprene Elastomer
Butyl Elastomer
Ethylene Propylene Diene Monomer
(EPDM) Elastomer
• Thermoplastic Elastomers (TPE)
Main Ingredients in a Rubber
Formulation
TYPE
PRODUCTS
FUNCTIONS
Elastomer
(Raw Material)
Nitrile, EPDM, Butyl,
Polychloroprene
Seal
Fillers
Silica, Aluminum
silicate, Carbon black
Improve mechanical
properties
Processing aids
Fatty acid / Wax
Improve process
Antioxidant
Phenols / Phosphites
Improve the ageing of
the rubber
Plasticizer
Phtalate
Aromatics, paraffinics,
naphtenic oils
Reduce cost and
hardness, improve
process
Curing agent
Peroxide
Sulfur
Tridimensional
structure
Potential Extractables
from Elastomers
• By-products from polymerization (e.g. PNA’s,
Nitrosamines, fatty acids, semi-volatiles)
• Residual products from polymerization (e.g.
monomer)
• Chemical additives such as processing aids (e.g.
fatty acids), antioxidants (e.g. semi-volatiles)
• Degradation products from additives
• Secondary reaction products from curing (or
vulcanization) process (e.g. peroxide)
Metals
• Stainless steel
• Aluminum
Potential Extractables:
• Residual cleaning agents
• Organic surface residues (e.g. oils)
Other Potential Sources
of Extractables
• Processing aids used during assembly
process on machinery or component
• Mould release agents
• Lubricants
• Adhesive, glue, ink from labels or
secondary packaging
Material Selection
• Chemical/physical compatibility with drug
formulation
• Mechanical properties => device performance
• Sealing properties & moisture permeability
• Regulatory status & extractable profile
Selection of
Plastic Materials
All plastic materials must be in compliance
with existing regulations and pharmacopeia
(e.g. relevant 21 CFR chapters)
The materials selected from established
suppliers should be pharmaceutical or
medical grades whenever possible
Selection of
Elastomer Materials
Regulatory:
• Elastomer ingredients must comply with existing
regulations and pharmacopeia (e.g. relevant 21
CFR chapters).
Mechanical:
• Swelling (potential for swelling if strong affinity
with propellant mixture)
• Mechanical properties + retention of mechanical
properties throughout product shelf life (valve shelf
life combined with filled inhaler shelf life)
Selection of
Elastomer Materials (Cont.)
Elastomer materials should be as “clean as possible”:
• Minimize use of carbon black (known carcinogenic) by
using inorganic fillers (e.g. silica)
• Eliminate plasticizers by using a continuous curing
process
• Preferably use “clean” pharmaceutical grades of gaskets
obtained through different treatments (e.g. ethanol
extraction)
• Extractables: elimination of toxics extracts (e.g. PNAs,
Nitrosamines)
Controlled Extraction
Studies
Controlled extraction studies are performed to characterize
the extractables profiles. They are done in 3 steps:
1) Obtain as much information as possible from suppliers
on the composition of the raw materials and on the
manufacturing process
2) Select extraction conditions using multiple solvents (with
varying polarities) and extraction techniques.
3) Use of appropriate analytical techniques (with
appropriate sensitivity).
Typical Method
• Grind sample
• Weigh sample
• Extract sample in a solvent using very
aggressive conditions to maximize extractables
levels
• Collect extract
• Concentrate extract
• Reconstitute extract into a fixed volume of
mobile phase
• Analyze extract
Solvents of various polarities
•
•
•
•
•
•
Methylene chloride
Water
Isopropanol
Hexane
Ethanol (MDI’s)
Etc…
Extraction Parameters
• Sample preparation: grinding, compression (film)
• Extraction techniques: accelerated solvent
extractor, microwave, reflux, soxhlet, sonication
• Extraction Volume, Time and Temperature
• Evaporation step
Analytical Techniques
UV-spectrophotometry (e.g. formaldehyde)
HPLC-UV (plastics and fatty acid quantification)
HPLC-ELS (non-chromophoric analytes)
HPLC-MS (identification and quantification)
GC-FID (semi-volatiles quantification)
GC-MS (identification and quantification)
GC-NPD (e.g. acrylonitrile)
GC-TEA (e.g. nitrosamines)
Atomic Spectroscopy (Absorption)
Controlled Extraction Studies
• Extraction techniques should be optimized
to maximize extract levels
• Analytical methods should be validated to
meet ICH and FDA Guidelines
Routine Extractables Testing
A systematic control of extractables should be performed
for the critical components (or the raw material provided
that a correlation can be established between the two).
The extraction and analytical methods should be based on
the controlled extraction studies:
•The extraction should be done using very aggressive
conditions (solvent, technique) to maximize extracts levels.
•The analytical method should be validated and the
sensitivity appropriate.
Example: Routine Extractables
Testing on Plastics
The analysis of extractables in plastics is done by reverse
phase HPLC-UV.
Example of additives investigated:
• Irganox 1010
• Irganox 1076
• Irganox 245
• Irganox 259
• BHT
• Irgafos 168
• Oleamide
Routine Extractables - Plastics
A calibration solution contains all the tested additives.
Extraction procedure:
• Samples are ground to a fine powder (can be done from
plastic beads or molded components)
• Extraction is done under reflux using suitable solvent
identified for each type of material (e.g. Methylene
Chloride, Chloroform, etc)
• The procedure is optimized so that the extractable levels
measured is representative of the RM composition.
Extractables Specifications
Specifications are established for each material
based on:
 Extractables profiles from multiple lots of raw
material
 Extractables profiles from molded components
(try to correlate levels in the components to the
corresponding lots of raw material)
 Limits are set for each extractable
 A specification (reporting limit) is also set for
unknowns at the LOQ of the method
Conclusion
Timeline and Cost for Extractables and
Leachables programs depends mainly on:
• Choice of packaging materials
• Extracting power of formulation
• Cooperation with device supplier
Making the right choice of materials and
starting the program early enough are key
factors in minimizing costs and duration
Questions ?