Download the full presentation and recording: http://resources.rqteam.com/rq-iuvo-webinar-1 This joint webinar was presented by Regulatory and Quality Solutions (R&Q) and iuvo BioScience is focused on the requirements for chemical characterization in the healthcare industry. Specifically, it discussed the standards required for ISO 10993-18 chemical characterization for medical devices and compare the ISO requirements with the pharmaceutical industry requirements and best practices for extractables and leachables testing. The webinar explained the standards for both industries, discussed the testing methodologies required, and provided some case study experience from an E&L perspective. Participants learned: Basic terminology used in these studies, the difference between an extractable and a leachable, and how these terms are used in the medical device and pharmaceutical industries The chemical characterization requirements for both the medical device industry and pharmaceutical industry, and the implications for combination products Basic parameters for when these studies are required and how they are set up, including some things to look out for when designing a study Some real world case study experience from extractables and leachables testing

2. A B O U T R & Q
Regulatory and Quality Solutions (R&Q) provides industry-leading regulatory
and quality engineering services throughout the entire product lifecycle.

3. A B O U T I U V O B I O S C I E N C E
iuvo BioScience is a contract research organization serving the pharmaceutical
and medical device industries. With a focus on safety and biocompatibility, iuvo
provides assistance through the full product development life cycle, from
research to release, in the areas of GLP-compliant toxicology, microbiology and
analytical chemistry testing laboratories along with contract ethylene oxide
sterilization.

4. A B O U T T O D A Y ’ S S P E A K E R S
 Focused on the product
development lifecycle
 CAPA and complaint systems,
design control processes, and
International approval
(510k, PMA, CE)
 Auditing quality systems against
ISO and QSR regulations
Christine Santagate, RAC, Client Solutions Advisor

5. A B O U T T O D A Y ’ S S P E A K E R S
 Director of Analytical Chemistry
at iuvo BioScience with analytical
development experience at
Pharmacia, Pfizer, and
Bausch + Lomb
 15 years’ experience in design,
execution, interpretation, and
registration of E&L studies
 Member of the PQRI Working
Group on E&L in Parenteral and
Ophthalmic Drug Products
Chris Houston, PhD, Director of Analytical Chemistry

6. A G E N D A
 Device Definition
 Material Selection
 Test Selection Considerations
 Test Construct
 Design Changes
 Excluded Devices
 Combination Products

7. M E D I C A L D E V I C E D E F I N I T I O N
 "an instrument, apparatus, implement, machine, contrivance, implant, in vitro
reagent, or other similar or related article, including a component part, or
accessory which is:
 recognized in the official National Formulary, or the United States Pharmacopoeia,
or any supplement to them,
 intended for use in the diagnosis of disease or other conditions, or in the cure,
mitigation, treatment, or prevention of disease, in man or other animals, or
 intended to affect the structure or any function of the body of man or other
animals, and which does not achieve its primary intended purposes through
chemical action within or on the body of man or other animals and which is not
dependent upon being metabolized for the achievement of any of its primary
intended purposes."

8. B I O C O M P A T I B I L I T Y
Biocompatibility answers two fundamental questions:
 Is the material safe?
 Does it have the necessary physical and mechanical properties for its proposed
function
The extent to which a material needs to be characterized depends on :
 Type of Material
 End use of the device
 Function of the material within the device
 Availability of existing data on the material

9. M A T E R I A L S E L E C T I O N
 Biocompatibility is ultimately a function of a completed device, so it
encompasses all of its components, assembly processes and overall design and
must be considered at design onset.
 Use known biocompatible materials
 Individual components as well as overall packaging must be considered.
 Material testing is performed to determine toxicity of the material, leachable
substances and degradation products.
 When selecting materials, ask if the manufacturer has performed component
level biocompatibility.
 Thoughtful material selection can help ensure the overall biocompatibility of a
finished product.

10. E&L Overview - Pharma
• Nuts and bolts
o Pharma definitions – focus on packaging
o Plastic additives
o Beginning with the end in mind
 Guidelines, working group outputs, etc.
• Experimental considerations
o Special cases
o Case studies

11. Definitions in the Pharma Space
• Extractable: A chemical species that can be removed from an individual
packaging component by force (solvents). Extractables are potential drug
product impurities.
o Simulation studies generate extractables using realistic mimics of drug
products – analogous to leachables in the medical device space.
• Leachable: An extractable that migrates into drug product under nominal
conditions. Leachables are generally a practical subset of extractables –
they are the substances that affect quality, safety, and/or efficacy.
• Migrants: Extractables that cross a physical barrier to enter the drug
product (e.g., those from secondary packaging).
• Primary Packaging: Make direct contact with the
drug product.
• Secondary Packaging: Do not make direct
contact w/ product.
Extractables
Leachables

12. Plastic Additives – Why?
• Antimicrobials
• Antistats
• Colorants / opacifiers
• UV blockers
• Optical brighteners
• Light stabilizers
• Slip agents: e.g., glycerol monostearate
• Plasticizers: e.g., diethylhexyl phthalate (DEHP)
• Antioxidants
o Primary: e.g., hindered phenols as free radical scavengers, long term
stabilization (BHT, Irganox 1010, 1076, 3114)
o Secondary: e.g., trivalent phosphorus compounds, hydroperoxide
scavengers, sacrificial process stabilization (Irgafos 126, 168)
Additives allow the material to perform as required

13. Pharma E&L Concerns – Where It All Began
• Late 1980s and into the 1990s
o Replacement of chlorofluorocarbons (CFCs) in metered dose inhalers (MDIs)
with hydrofluorocarbons (HFCs)
o CFC and HFC propellants are strong organic extraction solvents
o In the MDI world, “all extractables are leachables”
• Orally inhaled and nasal drug product (OINDP) concerns based on agents
present in elastomeric gasket/valve components
o Polyaromatic hydrocarbons (PAHs) / polynuclear aromatics (PNAs)
 In carbon black used as a filler in sulfur-cured elastomers
o N-nitrosamines
 Derived from curing agents for vulcanized components
o 2-mercaptobenzothiozole (2-MBT)
 Elastomeric curing agent
o All substances recognized as genotoxic at low levels
• Concern: compounds efficiently leached by MDI formulations and dosed
directly to the diseased organs of a sensitive patient population
Norwood, Nagao, Stults. PDA J Pharm Sci and Tech 2013, 67 413-429

14. FDA Guidelines – Focus on OINDP
• Metered Dose Inhaler (MDI) and Dry Powder
Inhaler (DPI) Drug Products (DRAFT, 1998)
o Still in draft state
• Container Closure Systems for Packaging
Human Drugs and Biologics (May 1999)
o Introduces concept of risk based on dosage form and route of administration
(next slide)
o Focus on OINDP, few specifics for other routes of administration
• Nasal Spray and Inhalation Solution, Suspension, and Spray Drug Products
(July 2002)
• Inhalation Drug Products Packaged in Semipermeable Container Closure
Systems (DRAFT, July 2002)
o Concern over label components migrating into DP through LDPE
• None of these documents provide practical guidelines on how low to test
for leachables: this is a critical question for analytical chemists

15. chris.houston@iuvobioscience.com
Thank you!
csantagate@rqteam.com
RQTeam.com iuvobioscience.com