Transcript Controlled Extractables

History
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Initial discussions in February 2007
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Companies wanted to:
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Reduce duplicative safety evaluation
associated with leachables and extractables
Encourage accessibility and use of
extractables safety information early in the
development process, e.g., during materials
selection
ELSIE formally established in May 2007
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Impetus for Formation:
Identify “Best” Knowledge and Increase Knowledge Sharing
Safety Database
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Eliminates repetitive literature searches on the
same chemicals
Encourages shared peer knowledge
Reduces duplicative effort and minimizes
testing
Speeds new medicines to market
Reduces cost while improving the safety of all
medicines
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Impetus for Formation:
Improve Risk Assessment & Decision-making
Materials Database
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Allows for a QbD approach to packaging
selection
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Screening of materials for safety issues
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Simplifies the regulatory testing
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Reduces the risk of poor material choices
Enables rapid start to leachables testing on
individual drug products
Speeds new medicines to market while
reducing costs
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Core Objective
ELSIE’s core objective is to establish a
comprehensive database that will provide a
jointly-developed and credible source of
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Safety information on extractables and
leachables and
Extraction profiles and standardized study
protocols for a range of materials commonly
used in pharmaceutical, biological and
device applications and processes (e.g.,
container closure systems, devices,
manufacturing/processing)
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Membership
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Abbott
AstraZeneca
Baxter
Boehringer Ingelheim
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Eli Lilly
GSK
Pfizer
sanofi-aventis
All pharmaceutical, biotechnology, and medical
device companies are invited to join ELSIE.
Several additional companies are actively
considering membership.
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Benefits of ELSIE Deliverables
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Advance ICH Q8, Q9, Q10 principles and Quality by Design
concepts by enhancing the prospects for identifying potential
safety issues at the initial stages of the development process,
when container-closure materials are being screened and
selected
Reduce duplication of effort and minimize testing
Facilitate development of high quality and safe products for
patients
Confirm patient safety and product quality as priority goals of
the medical products industry
Strengthen supplier-manufacturer relationships
Serve as a forum for exchanging experience and perspectives
among experts
Decrease the risk of substantial, unanticipated delays and
associated costs
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Governing Structure
Board of Directors
(2 Reps from each member company)
Materials Information
Working Group
Safety Information
Working Group
ELSIE activities supported by Secretariat
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Role of Secretariat
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Drinker, Biddle and Reath LLP (law firm) serves
as Secretariat and Legal Counsel
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Pharmaceutical practice group comprised of lawyers
and science advisors
Secretariat provides legal advice, project
management, scientific guidance, and other
support to ELSIE
In particular, Secretariat ensures that ELSIE’s
activities are appropriate from an antitrust
perspective
Secretariat also facilitates consensus building
among members and assists with strategic
planning, external communications and other
regulatory/policy developments
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Safety Information Working Group
Goal
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Develop database of safety information
on extractables and leachables
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Safety Information Working Group:
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Developed safety information template
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Chemical Summary
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Safety Summary
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Key government assessments
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Details on types of studies
Flow and structure of the database follows the
Common Technical Document (CTD)
Developed detailed “user requirements” for safety
database, including search capability and other
tools
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Safety Information Working Group:
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Compiled list of leachables and extractables for
inclusion in safety database
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Approximately 210 compounds
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Facilitates priority-setting
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Continuously updated with new compounds of
interest
Created prototype database meeting user
requirements
Populating database
Protocols for data entry, updating and quality control
under development
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15 Priority Compounds for Initial Phase
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Antioxidants
 Irganox 1010
 Irgafos 168
 Butylated hydroxytoluene
 2-4-di-t-butyl phenol
Anti-Slip Agents
 Erucamide
 Oleamide
Plasticizers
 DEHP
Cross-Linking Agents Peroxides
 Di-tert-butylperoxide
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Lubricants
 Stearic acid
 Palmitic acid
 Silicone Oil
Monomer – Starting Material
 BPA
 2-ethyl-1hexanol
Surfactants
 Nonylphenol
Acid Scavengers
 Calcium stearate
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Materials Information Working Group
Goal
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Define the extractables knowledge
space for container closure systems
and devices that could:
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Provide a basis to reduce the risk of
selecting “unacceptable” materials; and
Expedite further product-specific
extraction and/or leachable studies
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Materials Information Working Group
Database and Pilot Program
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Materials information database would include
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Extractables profiles generated from raw materials and
materials processed/molded at extremes of
recommended time/temperature (see following figures)
Protocol(s) used to generate profiles
Materials information database would be linked to the safety
information database
Conducting Pilot Program with 11 CROs
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Determine feasibility of generating useful data
Develop controlled extraction study protocol to serve as
basis for a standard protocol that could be used on a
variety of materials to generate data for database
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Minimum residence time
Max. vendor recommended residence time
C
Temp
Max. vendor recommended
temperature
Molding window for
dimensional control
of component
Window B: component
extractables
B
Minimum temperature
Window A: material
extractables (knowledge space)
A
Time 
Extractables information on plastic at point A and point C plus knowledge of
potential degradation pathways is used to build the molding “knowledge
space”
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E&L Knowledge Space
Extractables
Knowledge Space for Material XYZ is
Determined and Stored by ELSIE in a
Database -- includes all extractables
determined from points A and C (previous slide)
E
C
A
B
D
FG
Knowledge Space
7 solvents
plus
4 analytical
techniques
K
H
I
J
L
M
NP
Controlled
Extractables
Forced
Extraction
Testing
Multiple solvents over a wide span of polarity followed by
analysis using multiple techniques to “cover” most drug
product types
….its all about Increasing our knowledge around CCS materials.
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E&L Design Space
Leachables
Within the Knowledge Space
of Material XYZ multiple Design Spaces exist
Each unique formulation will have a
unique Design leachables space
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C
A
B
D
FG
Knowledge Space
Drug Product A
Leachables
Product A
Design Space
C
A
D
K
J
Drug Product B
Leachables
K
H
I
J
L
M
NP
Controlled
Extractables
Forced
Extraction
Testing
E
Product B
Design Space
C
M
A
K
H J
….its all about Increasing our knowledge around CCS materials.
M
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Materials Information Working Group:
Protocol for Pilot Program
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Controlled Extraction Studies on Materials for ELSIE Database –
Qualitative and Semi-Quantitative Studies
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Identified and conducted molding studies on 2 materials for pilot
program: PVC and polyethylene
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Studies to be conducted on the 2 materials (molded and
unmolded forms)
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Covers studies for all common product types (e.g., parenterals,
inhalation products, ophthalmics), therefore includes wide variety
of solvents, and extraction and analytical techniques
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Follows principals set forth in PQRI L&E Recommendations for
OINDP
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General principals and findings from the Pilot Program will be
used to create a more focused protocol
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Protocol: Solvents
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Range of solvents to address a wide variety of
end uses (organic solvents of varying polarity,
water of varying pH)
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Water at pH 2.5
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Water at pH 9.5
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Water
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IPA:water (1:1)
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IPA
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Dichloromethane
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Iso-hexane
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Protocol: Extraction Methods
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Sonication
Reflux
Soxhlet
Sealed container
Microwave
ASE
Headspace
Results from pilot program will be used to select appropriate extraction methods for
final protocol
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Protocol: Analytical Methods
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Headspace GC/MS (volatiles)
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GC/FID/MS (semi-volatiles)
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LC/DAD/MS (non-volatiles)
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ICP/MS (metal ions)
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Materials Information Working Group:
Current Priority Activities
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Working with CROs to complete controlled
extraction studies (pilot program)
Engaging suppliers to determine interest and
develop relationships
Developing prototype Materials Database
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ELSIE Outreach to Regulators
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FDA CDER and CDRH have expressed interest in
the ELSIE effort
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CDER indicated interest in a future meeting once
further data and progress has been made
CDRH indicated interest in continuing dialogue with
ELSIE
Outreach with Health Canada and European
regulatory authorities planned for 2010
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13 September 2010: Meeting with MHRA
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