3.0 & 4.0 Basic Understanding of E&L - Addressing The Reg & Quality - Jen
3.0 & 4.0 Basic Understanding of E&L - Addressing The Reg & Quality - Jen
3.0 & 4.0 Basic Understanding of E&L - Addressing The Reg & Quality - Jen
Jennifer L. Riter
Senior Director, Analytical Services and Integrated Solutions
11 & 13 Nov 2019
Container
Closure Particulate
Integrity
Fit for
Purpose
Extractables
& Leachables Performance
© 2019 West Pharmaceutical Services, Inc. All rights reserved
3
Basic Requirements and
Understanding
Compendia
▪ Regulatory expectation that materials for pharmaceutical
uses comply with local regulations and compendia
▪ Suitability for use is not assured via compendia
compliance
▪ Material composition must be considered
▪ Material/component can pass the compendia tests, but
based on composition may be suited for one application,
but not another.
Desmond Hunt-USP Training Course, 2011
• 30 samples per test with each sample integrity tested according to leak test
method of choice
• For systems like syringes with a plunger and a needle shield
separate/different types of leak tests may be required
• Chosen leak tests to be capable of verifying systems’ inherent integrity to
MALL for the intended product packaging/delivery system.
USP <1382> and <382> Changes
Source: Daniel Bantz, West Pharmaceutical Services. PDA Container Closure Performance and Integrity Conference, June 2018
Early Package Compatibility/Comparison
▪ Intended to gather information on how
different package candidates may react
with a particular product or matrix (Only
provides gross differences)
▪ Can be performed using
▪ Drug product placebo
▪ Drug product
▪ Other solution to mimic extracting
propensity of the drug product
Early Package Compatibility/Screening
▪ Samples can be stored at temperature in which
product does not degrade (e.g. 50ºC at 0, 4, and 8
weeks)
▪ Product/Package Combination 1
▪ Product/Package Combination 2
▪ Bulk in Teflon™ container used as a control
sample
Cytotoxicity (In vitro MEM Elution) <87> 10993-5 7.03 not required if N/A
USP 87 Grade 0
Systemic Toxicity (In vivo) <88> 10993-11 7.03 required if USP 87 0004200/5-2015
Grade 1 or higher
▪ Soaking
▪ Sonication
▪ Reflux/Soxhlet
▪ Microwave
▪ Sealed Vessel
Analytical Evaluation Threshold
▪ The AET is the threshold at/above which an extractable
and/or leachable should be reported.
▪ Derived directly from SCT
▪ SCT for OINDP = 0.15 µg/day
▪ SCT for PODP = 1.5 µg/day
▪ Considers Doses per day; Doses per container
▪ Incorporates Mass of component
AET = 6.67
USP <1664> Leachable Assessment
▪ Framework for the design and justification of drug product
leachables
▪ Intended for drug product developers, manufacturers,
and suppliers for understanding sources of leachables
▪ How to evaluate and manage leachables during the
drug development/manufacturing process
▪ Does not establish specific
▪ analytical methods
▪ specifications/acceptance criteria for any drug
product or packaging system!
USP <1664> Utilization of Leachable Assessments
▪ Facilitate the timely development of safe and
effective drug products
▪ Identify trends in drug product shelf life studies of
leachable accumulation
▪ Facilitate change-control processes for drug
packaging/delivery systems
▪ Facilitate investigations into the origin of identified
leachables whose presence causes OOS results
for marked drug
Leachable Studies
▪ Specific to Drug Product
▪ Target/sensitive method development
▪ Robust methods to discover unexpected
▪ Method optimization and validation
▪ Material Characterization
▪ Individual component assessment
▪ Controlled Extractables Study
▪ Risk Assessment
▪ Simulation Study
▪ Probable leachable study
▪ Data Assessment
▪ Determine targets for leachables
▪ Leachables Study
▪ Method Development and
Validation
E&L Approach
Risk Assessment:
Evaluate and organize extractable data based on
risk ranking
Leachables Evaluation:
Develop and validate Leachables Methods and
monitor over the shelf life of the drug product
Component Selection
▪ What information am I able to obtain from
my vendor as to material characteristics and
safety?
▪ Extractable information
▪ Regulatory certificates of additives of
concern
▪ Does this material have inherent properties
to be hazardous?
▪ Formulation characteristics
▪ Extractable information
▪ Regulatory certificates of additives of
concern
▪ Decision point: Select components
Pre-Planning and Component Selection
▪ Is the container closure system “Fit for Purpose” for
the pharmaceutical in question? What vendor data is
available?
▪ Formulation Characteristics/Material Data
Sheets, Theoretical Extractables Lists and other
vendor information
▪ Material Characterization – analytical studies
designed to cast a wide net
Risk Assessment:
Evaluate and organize extractable data based on
risk ranking
Leachables Evaluation:
Develop and validate Leachables Methods and
monitor over the shelf life of the drug product
Extractable Assessment and Evaluation
▪ What information is available to evaluate
patient risk? What is missing?
▪ Have all compounds (volatiles, semi-volatiles,
inorganic, non-volatiles) been evaluated?
▪ Has testing been completed in a solvent similar
to the drug product?
▪ What is the drug product contact (time and
temperature) and how can that increase or
decrease patient risk?
▪ What is missing based on what the vendor
provided?
▪ Decision point: What additional
evaluations, if any, are needed?
Extraction Study Considerations
▪ Consider all systems that come in
contact with the product during its life
cycle:
▪ Raw material containers
▪ Processing equipment
▪ Intermediate containers
▪ Packaging equipment
▪ Final container closure
▪ Delivery devices
Extraction Study Considerations
▪ Some vendors provide potential extractable
(PE) lists for their materials
▪ These theoretical lists, based on information
about the raw materials and manufacturing
process, can be helpful in the determination of
feasible targets or for identification of
unknowns detected during the extraction study
▪ They should not be used in place of
extractables data because potential of
migration is not used as a factor of what goes
on the list
Extraction Study Considerations
An initial, qualitative/semi-quantitative determination of
the types of chemical species that can be extracted
from a material under extreme conditions that are
designed to be more rigorous than anything the
material would experience under actual use.
▪ Focused on individual components of the system
▪ Use of multiple solvents of various polarities and
solvent properties
▪ Use of known and surrogate standards to obtain
semi-quantitative data
▪ Identification and estimation of target compounds
AET = 6.67
Identification Categories
▪ Confirmed:
▪ Mass spectrometric fragmentation behavior
▪ Confirmation of molecular weight or confirmation of
elemental composition
▪ Mass spectrum matches automated library or mass
spectrum and chromatographic retention index match
authentic specimen
▪ Confident:
▪ Sufficient data to preclude all but the most closely related
structures have been obtained
▪ Tentative:
▪ Data have been obtained that are consistent with a class
of molecule only
▪ Unknown: Insufficient data exist to categorize
Additional Considerations
for Extractables
55
Changes in Extractables Profile can
Result from Lifecycle Management
Cumulative Component
Experience Storage Potential
Sterilize Changes to
Coat
Wash Extractables
Film Profile
Bulk Device
Vial Syringe
Risk Assessment:
Evaluate and organize extractable data based on
risk ranking
Leachables Evaluation:
Develop and validate Leachables Methods and
monitor over the shelf life of the drug product
Risk Assessment
▪ What is the relative risk of the compounds found?
▪ Tools:
▪ E2L (West tool)
▪ Toxicological Assessments
▪ Consultation/Industry references
▪ Not all drug products carry the same amount of risk
▪ Indication
▪ Patient population
▪ Route of administration
▪ Decision point: Which analytes, at what levels, should move to
leachable development, validation and monitoring?
Assessment of the Extractable Data
Risk Assessment:
Evaluate and organize extractable data based on
risk ranking
Leachables Evaluation:
Develop and validate Leachables Methods and
monitor over the shelf life of the drug product
Complex Drug Product Matrix - Leachables
Leachable Studies
Specific to Drug Product
▪ Target/sensitive method development
▪ Robust methods to discover unexpected
▪ Method optimization and validation
Established by Full Shelf-Life Stability Studies
▪ Accelerated testing not always indicative
▪ A system found acceptable for one drug product is not
automatically assumed to be appropriate for another
FDA Guidance for Industry:
Container Closure Systems for Packaging Human Drugs and Biologics
Leachables Stability Data
Accelerated
3 Month
Real Time
Leachables Studies
Detection of a leachable
Risk Assessment:
What to focus on for
Leachables? Evaluate and organize all extractable data
based on risk ranking
Leachables Evaluation:
Method Dev, Develop and validate Leachables
Validation, Methods and monitor over the shelf life
Leachables Testing of the drug product
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